Radical-Mediated Acyl Thiol-Ene Reaction for Rapid Synthesis of Biomolecular Thioester Derivatives

Article abstract of DOI:10.1002/ejoc.202100615

The thiol-ene ‘click’ reaction has emerged as a versatile process for carbon–sulfur bond formation with widespread applications in chemical biology, medicinal chemistry and materials science. Thioesters are key intermediates in a wide range of synthetic and biological processes and efficient methods for their synthesis are of considerable interest. Herein, we report the first examples of acyl-thiol-ene (ATE) for the synthesis of biomolecular thioesters, including peptide, lipid and carbohydrate derivatives. A key finding is the profound effect of the amino acid side chain on the outcome of the ATE reaction. Furthermore, radical generated thioesters underwent efficient S-to-N acyl transfer and desulfurisation to furnish ‘sulfur-free’ ligation products in an overall amidation process with diverse applications for chemical ligation and bioconjugation.

Full text of DOI:10.1002/ejoc.202100615

Full Papers
doi.org/10.1002/ejoc.202100615
Radical-Mediated Acyl Thiol-Ene Reaction for Rapid
Synthesis of Biomolecular Thioester Derivatives
+
[a]
+ [a]
[a]
[a]
Joshua T. McLean , Pierre Milbeo , Dylan M. Lynch, Lauren McSweeney, and
Eoin M. Scanlan*
[
a]
The thiol-ene ‘click’ reaction has emerged as a versatile process
for carbon–sulfur bond formation with widespread applications
in chemical biology, medicinal chemistry and materials science.
Thioesters are key intermediates in a wide range of synthetic
and biological processes and efficient methods for their syn-
thesis are of considerable interest. Herein, we report the first
examples of acyl-thiol-ene (ATE) for the synthesis of biomolec-
ular thioesters, including peptide, lipid and carbohydrate
derivatives. A key finding is the profound effect of the amino
acid side chain on the outcome of the ATE reaction.
Furthermore, radical generated thioesters underwent efficient
S-to-N acyl transfer and desulfurisation to furnish ‘sulfur-free’
ligation products in an overall amidation process with diverse
applications for chemical ligation and bioconjugation.
1
. Introduction
pertinent thiolactone substrates and has been exploited in both
intermolecular and intramolecular processes for the synthesis of
[11,12]
The thiol-ene reaction, hydrothiolation of an olefinic substrate
via a radical chain mechanism, is an archetypal ‘click’ reaction
by virtue of its high atom economy, excellent yields, complete
thioester derivatives (Figure 1b).
However, to the best of
our knowledge, no examples of ATE reactions involving
biomolecular derived thioacids including lipids, carbohydrates
or amino acids (AAs), have been reported to date. Herein, we
report an important advance in thiol-ene reactivity, exploring
radical-mediated formation of biomolecular thioester deriva-
tives via ATE chemistry. Furthermore, spontaneous, intramolec-
ular S-to-N acyl transfer and desulfurisation of radical generated
thioester intermediates is demonstrated, to furnish desulfurized
products in an overall amidation process that offers significant
potential for chemical ligation, bioconjugation and protein
modification (Figure 1d).
5
À 1 À 1 [1]
selectivity, fast kinetics (in the order of 10 M s ) and
[2]
compatibility with aqueous conditions. As a result of its
remarkable synthetic utility the reaction is well established
throughout the fields of natural product synthesis,
bioconjugation and polymerization chemistry. However,
these precedents have exclusively described thiol-ene reactions
yielding sulfur containing linkages which are problematic for
certain applications. Thioether-substituted conotoxin deriva-
tives have been shown to easily oxidize to the sulfoxide,
[3]
[2]
[4]
resulting in structural distortion and loss of biological activity.
To date, the ubiquity of sulfur in the products of thiol-ene
reactions remains something of an ‘Achilles’ heel’ for the
methodology. Although still susceptible to oxidation, thioesters
are more labile than thioethers and function as key intermedi-
[5–7]
ates in a wide range of fundamental biological processes
as
well as in the organic synthesis of valuable heterocyclic
[8,9]
molecules and natural products.
Syntheses of thioesters
typically rely on classical methods such as the condensation of
activated acyl compounds with thiols, often necessitating
strong base, long reaction times or the use of transition metal
[10]
catalysts. Our group has recently introduced the acyl-thiol-
ene (ATE) reaction as an efficient method to furnish thioesters
using thioacids under radical-mediated conditions. To date, the
methodology has permitted facile access to biologically
+
+
[
a] J. T. McLean, Dr. P. Milbeo, D. M. Lynch, Dr. L. McSweeney,
Prof. E. M. Scanlan
School of Chemistry
Trinity College Dublin, The University of Dublin
College Green, Dublin 2, Ireland
E-mail: scanlae@tcd.ie
Figure 1. (a) The Thiol-ene “click” reaction towards thioether products; (b)
Thio- esterification of thiols; (c) Thiolactone synthesis via intra and
intermolecular acyl-thiol-ene (ATE) reaction; (d) ATE towards peptidyl/
carbohydrate thioesters and amide bond formation (this work).
+
[
] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100615
Eur. J. Org. Chem. 2021, 4148–4160
4148
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
2. Results and Discussion
2
.1. Synthesis of Thioacid Surrogates
To investigate the ATE reaction for the synthesis of biomolecu-
lar thioesters we focused initially on the family of proteinogenic
AAs. AA substrates offered a broad range of functionalities to
probe the tolerance of the methodology and the applicability
of radical mediated ATE between a thioacid and an alkene in
mediating thioester bond formation. This required the synthesis
of suitable thioacid and olefinic components for the ATE
reaction. Numerous direct thiolation strategies are described in
the literature for the preparation of bimolecularly relevant
[13]
thioacids.
The majority rely on in situ generation of the
thioacid moiety from a suitable activated carboxylic acid
precursor prior to immediate reaction. This was not deemed
suitable in our case, as this process would preclude effective
evaluation of the ATE reaction due to possibility of incomplete
thioacid formation and competing side reactions. Coupling of
the carboxylic acid derivatives with trityl (Trt) thiol under
[14]
Steglich conditions as reported by Crich, was found to offer
an efficient route to a bench stable thioacid surrogates. The Trt
functionality is readily cleaved upon treatment with trifluoro-
acetic acid (TFA) to quantitatively yield the corresponding
thioacid upon concentration of the reaction mixture in vacuo,
prior to ATE with a suitable olefinic substrate. A range of
biomolecule Trt thioesters were synthesized under these
conditions from readily available starting materials (Scheme 1).
Moderate to excellent yields were obtained for formation of
Trt thioesters. The variation in yields observed for substrates 1–
Scheme 1. Thioester formation under Steglich conditions described by
Crich for use in ATE reactions.
1
9 was primarily dependent on the steric profile of the
carboxylic acid employed. The lower yields of Trt thioesters 14–
6 could be accounted for due to the considerable steric bulk
[
14]
1
of the carboxylic acid components of the corresponding
coupling reactions.
Table 1. Optimisation of Acyl thiol-ene (ATE) reaction of Gly thioacid and
alkenes 20–23.
2
.2. Synthesis of Olefinic ATE Substrates and ATE
Optimization
Olefinic substrates were required that would prove synthetically
accessible, capable of reliably furnishing thioester products and
permitting access to biologically relevant amidic products
through subsequent S-to-N acyl transfer processes. This
approach necessitated the synthesis of a suitable alkene
containing peptide substrates through the incorporation of
olefinic unnatural amino acids (UAAs) or unsaturated side-chain
auxiliaries (Table 1). Our initial approach sought to demonstrate
the efficiency of the intermolecular ATE reaction using unsatu-
rated O-auxiliaries attached to the side-chain of serine or
threonine residues by straightforward acylation of a Fmoc
protected amino methyl ester yielding substrates such as 20
[a]
Entry
Alkene
Eq. Thioacid
Solvent
Conc. (M)
Yield [%]
i
ii.
20
20
20
20
20
20
21
21
21
22
23
1
1
1.5
3
2
2
3
1.5
3
3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
EtOAc
EtOAc
EtOAc
EtOAc
0.05
0.10
0.075
0.075
0.075
0.10
0.10
0.10
0.10
0.10
0.10
34
52
66
99
76
93
67
59
93
91
91
iii.
iv.
v.
vi.
vii.
viii.
ix.
x.
xi.
3
(see ESI). Subsequently, the scope of the ATE reaction was
[
a] Isolated yields after silica gel flash chromatography.
explored at substrates more structurally analogous to naturals
AAs using unsaturated amino acids β,γ-didehydrovaline, vinyl-
glycine and allylglycine to yield dipeptides 21–23, respectively.
Unsaturated targets 21 and 22 were synthesized using
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4149
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
[
15,16]
strategies inspired by literature precedent
(see ESI) and
ATE methodology was found to be compatible with the Fmoc,
Boc and Bu protecting groups commonly used in synthetic
t
were obtained in high overall yields from commercially
available precursors in four and six synthetic steps respectively.
peptide chemistry. In general, amino acids containing a
heteroatom in the side chain were highly efficient in the ATE
coupling reaction, with the single exception of the Boc
protected lysine derivative 39. Of particular interest was the
finding that proline could function as an efficient thioacyl
radical derivative in the ligation reaction to yield 40. Forming a
thioester at the C-terminus of proline has proven extremely
challenging using traditional chemical methods. Formation of
the thioester on the side chain of glutamic acid to yield
thioester 42 proved successful, albeit in moderate yield. Adipic
acid was used as a substrate to furnish 43 to demonstrate that
ATE is suitable for thioester formation simultaneously at more
than one site. A rhamnosyl thioacid derivative furnished the
glycopeptide thioester derivative 44 in excellent yield, offering
interesting prospects for the development of carbohydrate acyl
transfer reagents and processes. A key finding from the scope
study was that the nature of the amino thioacid sidechain
appears to have a profound effect on the efficiency of the ATE
reaction. Indeed, the relative rate of the competing dethiocar-
boxylation process is likely contingent on the stability of the C-
centered radical formed upon elimination of carbonyl sulfide
(OCS, Scheme 2). Amino thioacids possessing alkylic sidechains
were found to be lower yielding in ATE reactions with alkenes
21–23 (Scheme 4), as dethiocarboxylation lead to the formation
of comparatively stable secondary carbon radicals. Five equiv-
alents of thioacid were required in order to achieve full
conversion to the thioester in cases of increased side-chain
steric hindrance and decreased alkene availability (46, 47, 49,
50, 52, 53). However, in stark contrast, amino thioacids
containing a heteroatom in the side chain were highly efficient
in ATE coupling reactions, with the exception of the Boc
protected lysine thioacid used to furnish 39. This finding
suggests that the heteroatoms in methionine, serine and
threonine may assist the radical addition reaction, likely by
lowering the rate of competing dethiocaboxylation through
diminution of the radical stabilization energy of the C-centered
radical species formed, as observed in previous studies with
2
3 was synthesized through straightforward amide coupling
from commercially available starting materials.
Initial optimization of the ATE reaction was carried out using
N-fluorenylmethyloxycarbonyl (Fmoc) serine methyl ester 20 as
the alkene component and Fmoc-glycine thioacid 1. Photolysis
of 1 in the presence of radical initiator 2,2-dimethoxy-2-phenyl-
acetophenone
(DPAP)
and
photosensitizer
4-meth-
oxyacetophenone (MAP) in dimethylformamide (DMF) at room
temperature for 2 hours furnished the thioester product 24 in
quantitative yield following optimization of the reaction
conditions (Table 1). It was determined that using an excess of
the thioacid (2 or 3 equiv.), was required in order to force the
reaction to quantitative conversion, due to a competing
[17]
unimolecular dethiocarboxylation reaction (Scheme 2).
Under these conditions the reaction of Boc-β,γ-didehydro-
valine containing dipeptide 21 with Fmoc-glycine thioacid 1 did
not reach full conversion to the corresponding thioester,
presumably due to the use of the more sterically hindered
alkene (Table 1, entry vii). Interestingly, the use of ethyl acetate
(EtOAc) as solvent in place of DMF furnished the corresponding
thioester in 93% yield (Table 1, entry ix). Equally, EtOAc offered
improved yields in the reactions of analogous vinylglycine and
allylglycine containing dipeptides 22 and 23, providing the
desired thioester products in high yield in both cases (Table 1,
entry x and xi).
2
.3. Exploration of ATE Scope
With optimized ATE conditions in hand, the scope of the
reaction was investigated for a range of thioacids derived from
Trt thioesters 1–18 in reaction with alkene 20 (Scheme 3). In the
case of the serine O-auxiliary alkene 20, both alkyl and aromatic
thioacid substrates underwent thioester formation in excellent
yields (28–31). Alkyl thioester derivative 29 is of particular
interest as it closely resembles the lipid thioester derivatives
formed as reactive acyl-transfer intermediates in bacterial cell-
[19,20
similar radical species.
. The effect of the alkene components
[18]
wall biosynthesis.
of these reactions (20–23) on thioester yield could also be
evaluated through inspection of these results. Thioesters were
obtainable in high isolated yields with all four alkenes 20–23.
However, the greater steric demands of alkenes 21–23 could be
observed in that complete conversion of these starting
materials to their phenylalanine and valine derived thioester
counterparts (46, 47, 49, 50, 52, 53, respectively) required 5
equivalents of thioacid starting material to reach full reaction
conversion. By comparison, the less sterically hindered 4-
pentenoyl auxiliary 20 necessitated the use of only 3 equiv-
alents of thioacid to fully consume the alkene starting material
to yield thioesters 34 and 35. To demonstrate more accurately
the rate of ATE, the reaction was monitored by NMR
spectroscopy using an internal standard (details available in
ESI). NMR experiments revealed that complete conversion of
alkene to ligated thioester product was achieved within the first
A diverse range of amino acid thioacids derived from Trt
thioesters 6–16 were screened to demonstrate the broad
applicability of this methodology (Scheme 3). Importantly, the
Scheme 2. Competing hydrothiolation (blue arrows) and dethiocarboxylation
(green arrows) reaction mechanisms.
1
5 minutes of UV irradiation. The scope study demonstrates
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4150 © 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
Scheme 3. Scope of the acyl thiol-ene (ATE) reaction utilizing alkene 20 and thioacids derived from the Trt deprotection of Trt thioesters 1–18. (Isolated yields
after silica gel column chromatography). Acyl thiol-ene was carried out in dried and degassed dimethylformamide.
that the ATE reaction provides a robust, facile and rapid means
to access a range of thioester substrates that is compatible with
a diverse range of alkyl, aromatic, amino acid and carbohydrate
derived thioacids and unsaturated ATE substrates.
To access ‘thiol-free’, amidation products an intramolecular
S-to-N acyl transfer step analogous to that in Native Chemical
Ligation (NCL) explored. Four intramolecular S-to-N acyl transfer
cyclic transitions state (TS) sizes were investigated using
thioesters obtained via the ATE reaction of five different
unsaturated peptidyl substrates 25, 26, 54, 55 and 56.
favored 6-membered cyclic TSs (25 and 26) permitted isolation
of the corresponding thiol-containing tripeptides (57 and 58)
expeditiously and in high yields, however those employing
larger TS sizes (54, 55, 56) did not provide the acyl transfer
products spontaneously, permitting isolation of free amines 59,
[
21]
60 and 61. These results, coupled to literature precedent,
suggest that S-to-N acyl transfers proceeding over large (>6)
cyclic TSs are highly substrate dependent and rely on significant
substrate preactivation.
(
Scheme 5a). The synthesis of unsaturated peptides 55 and 56
Thiol-free compounds could also be obtained from S-to-N
acyl transfer products 57 and 58 to yield native peptide
substrates. Compounds 57 readily underwent desulfurisation
through the metal-free procedure established by Danishefsky
was carried out through the esterification of serine and
threonine containing starting materials prior to ATE with Gly
thioacid 1 (See ESI). The N-terminal Boc protecting group of
each peptidyl thioester was removed using TFA (20% in DCM)
to furnish the corresponding trifluoroacetate ammonium salt
quantitatively. The S-to-N acyl transfer reaction was promoted
through dissolution of TFA-salts in a saturated solution of
[22]
and coworkers to provide the desired ‘thiol free’ product 62
(Scheme 5b). Desulfurisation methodologies are commonly
employed in the field of protein ligation and organic synthesis
and tolerate a wide range of functionalities having proven
capable of dethiolating the β- or γ- positions of fifteen different
NaHCO in acetonitrile (ACN). Thioesters investigated whereby
the S-to-N acyl transfer occurred over thermodynamically
3
[23]
amino acids to date . Methylation of thiol 58 using trimeth-
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4151
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
Scheme 4. Scope of the acyl thiol-ene (ATE) reaction utilizing alkenes 21–23
and thioacids derived from the Trt deprotection of Trt thioesters 1, 7–9.
Isolated yields after silica gel column chromatography). Acyl thiol-ene was
(
carried out in dried and degassed EtOAc. [a] 5 eq. of thioacid used to reach
full reaction conversion.
ylsilyldiazomethane was also carried out to demonstrate the
possibility of further synthetic elaboration if desired, furnishing
a methionine residue in tripeptide 63 (Scheme 5b).
2
.4. ATE and Sugar Templated S-to-N Acyl Transfer
Sugar templated S-to-N acyl transfer has been observed to offer
such preactivation, as demonstrated in the Sugar Assisted
Ligation (SAL) developed by Wong and co-workers. Having
succeeded in applying ATE reactivity to unsaturated peptide
substrates we examined the reactivity of unsaturated amino
GlcNAc derivative 69, capable of S-to-N acyl transfer (Scheme 6).
Scheme 5. (a) Isolated Products of deprotection and freebasing of Boc
protected thioesters 25, 26, 54, 55, 56. (b) Synthetic elaboration of thiolated
peptides 57 and 58 through desulfurisation and methylation, respectively, to
yield thiol-free tripeptides 62 and 63 (Isolated yields after silica gel flash
chromatography).
[24]
6
9 was accessed via installation of an azide moiety at the
anomeric position of unprotected GlcNAc to yield 65
Scheme 6). Subsequent protecting group manipulation and
products 70–74 after column chromatography in good yields
over 3 steps. (Scheme 6). This one pot cascade further
demonstrates the applicability of ATE for the synthesis of thiol
free amide products, and illustrates the potential for ATE in
carbohydrate ligation methodologies.
(
esterification with 4-pentenoic chloride yielded unsaturated
azido derivative 68. Reduction of the azide group of 68 yielded
the desired ATE substrate 69.
The one-pot cascade reaction involving (i) ATE, (ii) S-to-N-
acyl transfer through a 13-membered ring TS and (iii) ester
hydrolysis was successfully demonstrated with protected thio-
acids which all furnished the desired thiol-free N-linked GlcNAc
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4152
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
‘
sulfur-free’ products containing a robust amide linkage. This
approach represents a new frontier in thiol-ene chemistry with
considerable potential for bioconjugation, drug discovery,
peptide synthesis and materials chemistry.
Experimental Section
General Experimental Details
All commercial chemicals used were supplied by Sigma Aldrich
(
Merck), Fluorochem, VWR Carbosynth and Tokyo Chemical Industry
and used without further purification unless otherwise stated.
Deuterated solvents for NMR were purchased from Sigma Aldrich
(
Merck) or VWR. Solvents for synthesis purposes were used at GPR
grade. Anhydrous DCM, THF, ACN and Et O were obtained from a
2
PureSolv MD-4EN Solvent Purification System. All UV reactions were
carried out in a Luzchem photoreactor, LZC-EDU (110 V/ 60 Hz)
containing 10 UVA lamps centred at 365 nm. Silica gel 60 (Merck,
230–400 mesh) was used for silica gel flash chromatography and all
compounds were subject to purification using silica gel, unless
otherwise stated. Analytical thin layer chromatography (TLC) was
carried out with silica gel 60 (fluorescence indicator F254; Merck)
and visualized by UV irradiation or molybdenum staining
[
ammonium molybdate (5.0 g) and concentrated H SO (5.3 mL) in
00 mL H O]. NMR spectra were recorded using Bruker DPX 400
2
1 13
2 4
1
(400.13 MHz for H NMR and 100.61 MHz for C NMR), Bruker AV
1
13
6
00 (600.13 MHz for H NMR and 150.90 MHz for C NMR), Bruker
1
1
3
AV 400 (400.13 MHz for H NMR and 100.61 MHz for C NMR) or
1
13
Agilent MR400 (400.13 MHz for H NMR and 100.61 MHz for
C
NMR) instruments. Chemical shifts, δ, are in ppm. and referenced to
the internal solvent signals. NMR data was processed using Bruker
TopSpin software. The assignment of the signals was confirmed by
2
D spectra (COSY, HMBC, HSQC). Melting points are uncorrected
and were measured with a Stuart SP-10 melting point apparatus.
MALDI time of flight (TOF) spectra were acquired using a Waters
MALDI Q-Tof Premier in positive or negative mode with DCTB
(
trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]
Scheme 6. Synthesis of unsaturated carbohydrate 69 capable of one pot ATE
addition, S-to-N acyl transfer and auxiliary cleavage to yield anomeric amides
malononitrile) as the MALDI matrix. ESI mass spectra were acquired
in positive and negative modes as required, using a Micromass TOF
mass spectrometer, interfaced to a Waters 2690 HPLC or a Bruker
micrOTOFÀ Q III spectrometer interfaced to a Dionex UltiMate 3000
LC. APCI experiments were carried out on a Bruker micrOTOFÀ Q III
spectrometer interfaced to a Dionex UltiMate 3000 LC or direct
insertion probe in positive or negative modes. Infrared spectra (IR)
spectra were recorded on a Perkin-Elmer Spectrum 100 FT-IR
spectrometer.
7
0–74 upon reaction with thioacids derived from Trt thioesters 1–3, 19 and
thioacetic acid.
3. Conclusion
This work serves as an efficient proof-of-concept, demonstrating
the efficiency of the ATE reaction towards the formation of
biomolecular thioester derivatives. The methodology demon-
strates high tolerance to a range of diversely functionalized
biomolecular substrates and common protecting groups,
including those derived from the family of natural AA’s. The
nature of the amino thioacid sidechain has a profound effect on
the outcome of the ATE reaction, with AA‘s containing a
heteroatom in the side chain demonstrating highest efficiency
in ATE coupling reactions, through supression of the competing
CSO elimination pathway. The methodology requires only
catalytic quantities of organic photoactivators for ATE and offers
an efficient approach to access biomolecular thioester com-
pounds. Unlike the canonical thiol-ene reaction which furnishes
thioethers exclusively, products of ATE reactions can undergo
chemoselective acyl transfer reactions enabling preparation of
General Experimental Procedures
Preparation of S-trityl thioesters: To a stirred solution of carboxylic
acid in anhydrous DCM under Ar was added DMAP (0.1 eq.),
triphenylmethanethiol (1.0 eq.) and EDCI·HCl (1.2 eq.). The solution
was stirred for 18 h at rt under Ar. The solvent was removed in
vacuo and the resulting residue purified by silica gel flash
chromatography. Characterisation data for S-trityl thioesters 1–19
may be found in the supporting information.
Removal of S-trityl protecting groups: To a stirred solution of S-
trityl thioester in DCM under Ar was added triethylsilane (20.0 eq.).
TFA (20% v/v) was added and the reaction mixture stirred for 5 min
at rt, concentrated in vacuo and the resulting crude thioacid used
directly without further purification.
Intermolecular acyl thiol-ene: To a stirred solution of alkene
acceptor in DMF or EtOAc was added DPAP (0.2 eq.), MAP (0.2 eq.)
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4153
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
and thioacid dissolved in a minimum volume of the same solvent.
67.3 (Fmoc CHCH ), 57.3 (αCH), 56.4 (αCH), 52.4 (OCH ), 52.4 (OCH ),
2 3 3
The reaction mixture was subjected to UV irradiation for 2 h,
solvent removed in vacuo and the resulting mixture purified by
silica gel flash chromatography.
50.8 (Gly CH ), 50.7 (Gly CH ), 47.1 (Fmoc CHCH ), 47.1 (Fmoc
2
2
2
CHCH ), 41.2 (Gly CH ) 41.2 (Gly CH ), 37.1 (βCH), 36.7 (βCH), 32.3
2
2
2
(γCH ), 31.3 (γCH ), 28.3 (C(CH )), 28.3 (C(CH )), 16.3 (CH ), 14.4 (CH )
2
2
3
3
3
3
ppm. *Isolated as a mixture of diastereoisomers. HRMS (m/z APCI
Removal of N-Boc protecting groups and freebasing of trifluor-
oacetate salt: To a stirred solution of Boc protected amine in DCM
under Ar was added TES (10.0 eq.). TFA (20% v/v) was added and
the reaction mixture stirred for 2 h at rt. Solvent was removed in
vacuo to give the corresponding TFA salt. The resulting salt was
redissolved in ACN (0.1 M) and a sufficient quantity of NaHCO3
added to saturate the solution. The reaction mixture was stirred for
+
+
): calculated for C H N O S [M+H] , calcd. 600.2374, found
3
0
38
À 1
3
8
600.2375. νmax (film)/cm : 3321 (NH), 2978 (CÀ H), 1682 (C=O).
Methyl S-((((9H-fluoren-9-yl)methoxy)carbonyl)glycyl)-N-(tert-bu-
toxycarbonyl)-L-homocysteinylglycinate (26): R (50% EtOAc/Hex):
f
1
0.30. H NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.4 Hz, 2H, Ar-CH), 7.64
3
(d, J=7.4 Hz, 2H, Ar-CH), 7.43 (t, J=7.4 Hz, 2H, Ar-CH), 7.34 (t, J=
7.4 Hz, 2H, Ar-CH), 6.87 (bs, 1H, NH), 5.50 (t, J=5.5 Hz, 1H, NH), 5.27
2
h at rt and following filtration solvent was removed in vacuo and
the resulting mixture purified by silica gel flash chromatography.
(d, J=7.9 Hz, 1H, NH), 4.47 (d, J=7.0 Hz, 2H, Fmoc CHCH ), 4.27 (m,
2
2
5
1
2
1
1
1
H, Fmoc CHCH , αCH), 4.15 (d, J=6.0 Hz, 2H, Gly αCH ), 4.06 (d, J=
2
2
Thioacid addition, S-to-N-acyl shift and base hydrolysis of
unsaturated carbohydrate 70: To a mixture of alkene 70, DPAP
.5 Hz, 2H, Gly αCH ), 3.75 (s, 3H, OCH ), 3.11 (dt, J=14.0, 7.1 Hz,
2
3
H, SCH CH ), 2.95 (dt, J=14.0, 7.1 Hz, 1H, SCH CH ), 2.16 (dt, J=
2
2
2
2
(0.1 eq.) and MAP (0.1 eq.) in anhydrous DMF was added the crude
1.1, 7.1. Hz, 1H, SCH CH ), 1.94 (dt, J=21.1, 7.1 Hz, 1H, SCH CH ),
2
2
2
2
thioacid (1.1 or 1.5 eq.) and the reaction mixture irradiated in an UV
oven at rt without agitation for 1 h followed by stirring at rt for
13
.47 (s, 9H, C(CH )) ppm. C NMR (150 MHz, CDCl ) δ 198.1 (SC=O),
3
3
71.6 (C=O), 170.0 (C=O), 156.3 (C=O), 155.7 (C=O), 143.7 (Ar-qC),
41.3 (Ar-qC), 127.8 (Ar-CH), 127.1 (Ar-CH), 125.1 (Ar-CH), 120.0 (Ar-
1
6 h outside of the UV oven. The solvent was removed in vacuo
and the mixture was re-dissolved in MeOH:H O (10 mL, 8:2) and to
2
CH), 80.5 (C(CH )), 67.4 (Fmoc CHCH ), 53.2 (αCH), 52.4 (OCH ), 50.7
3
2
3
this was added TEA (25.0 eq.) and the solution was stirred at rt for
(
(
Gly αCH ), 47.1 (Fmoc CHCH ), 41.2 (Gly αCH ), 32.6 (SCH CH ), 28.3
2 2 2 2 2
4
h. The mixture was neutralised by the addition of DOWEX H+
C(CH )), 24.9 (SCH CH ) ppm. HRMS (m/z APCI+): Calculated for
3
2
2
resin and then filtered. The solvent was removed in vacuo and the
reaction mixture was subjected to chromatographic purification.
+
C H N O S ([M+H]) , Calcd. 586.2145, Found. 586.2225. ν
2
9
36
3
8
À 1
max
(film)/cm : 3318 (NÀ H), 2949 (CÀ H), 1708 (C=O), 1675 (C=O).
Methyl (S)-(5-(((((9H-fluoren-9-yl)methoxy)carbonyl)glycyl)thio)-2-
Characterisation Data for Thioesters 24–54 Synthesized via
Acyl Thiol-ene Reaction:
((tert-butoxycarbonyl)amino)pentanoyl)glycinate (27): Rf (50%
1
EtOAc/Hex): 0.12, H NMR (600 MHz, CDCl ) δ 7.77 (d, J=7.5 Hz, 2H,
3
Ar-CH), 7.61 (d, J=7.4 Hz, 2H, Ar-CH), 7.40 (t, J=7.5 Hz, 2H, Ar-CH),
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
7
5
2
1
.32 (t, J=7.4 Hz, 2H, Ar-CH), 6.64 (bs, 1H, NH), 5.51 (bs, 1H, NH),
oxopropyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)glycyl)thio)
pentanoate (24): R (40% EtOAc:Hex): 0.38. H NMR (400 MHz,
CDCl ) δ 7.79 (d, J=7.2 Hz, 4H, Ar-CH), 7.62 (d, J=7.2 Hz, 4H, Ar-
CH), 7.42 (t, J=7.2 Hz, 4H, Ar-CH), 7.33 (t, J=7.2 Hz, 4H, Ar-CH), 5.81
.07 (bs, 1H, NH), 4.45 (d, J=7.0 Hz, 2H, Fmoc CHCH ), 4.31–4.23 (m,
1
2
f
H, Fmoc CHCH , αCH), 4.22–4.09 (m, 3H, Gly αCH ), 3.95 (dd, J=
2
2
3
8.1, 4.4 Hz, 1H, Gly αCH ), 3.72 (s, 3H, OCH ), 3.16–3.08 (m, 1H,
2
3
SCH CH CH ), 2.94–2.88 (m, 1H, SCH CH CH ), 1.89–1.81 (m, 1H,
2
2
2
2
2
2
(d, J=8.2 Hz, 1H, NH), 5.58 (t, J=6.3 Hz, 1H, NH), 4.70-4.67 (m, 1H,
SCH CH CH ), 1.80–1.72 (m, 1H, SCH CH CH ), 1.68–1.60 (m, 2H,
2
2
2
2
2
2
Ser αCH), 4.53-4.41 (m, 6H, Fmoc CHCH , Fmoc CHCH , Ser βCH ),
4
6
13
2
2
2
SCH CH CH ), 1.44 (s, 9H, C(CH ) ) ppm. C NMR (150 MHz, CDCl ) δ
2
2
2
3 3
3
.28-4.23 (dd, J=7.1 Hz, 2H, Fmoc CHCH , Fmoc CHCH ), 4.11 (d, J=
2 2
1
1
98.4 (SC=O), 172.3 (C=O), 170.4 (C=O), 156.7 (C=O), 156.4 (C=O),
43.9 (Ar-qC), 141.5 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-
.0 Hz, 2H, αGly CH ), 3.80 (s, 3H, OCH ), 2.92 (t, J=6.8 Hz, 2H,
2
3
CH CH CH CH S), 2.37 (2H, t, J=6.8 Hz, CH CH CH CH S), 1.75-1.61
2
2
2
2
2
2
2
2
CH), 120.2 (Ar-CH), 80.4 (C(CH )), 67.4 (Fmoc CHCH ), 53.4 (αCH),
13
3
2
(
(
(
4H, m, CH CH CH CH S) ppm. C NMR (100 MHz, CDCl ) δ 197.8
SC=O), 172.7 (C=O), 170.0 (C=O), 156.3 (C=O), 155.8 (C=O), 143.8
Ar-qC), 143.7 (Ar-qC), 141.3 (Ar-qC), 127.8 (Ar-CH), 127.1 (Ar-CH),
2
2
2
2
3
5
3
2.6 (OCH ), 50.8 (Gly αCH ), 47.3 (Fmoc CHCH ), 41.3 (Gly αCH ),
3 2 2 2
1.6 (CH ), 31.1 (CH ), 28.5 (C(CH ) ), 27.8 (CH ), 25.7 (CH ) ppm.
2
2
3 3
2
2
+
HRMS (m/z ESI+): Calculated for C H N O S [M+H] , Calcd
3
0
38
3
8
1
5
3
25.1 (Ar-CH), 120.0 (Ar-CH), 67.3 (Fmoc CHCH ), 63.9 (Ser βCH ),
À 1
2
2
6
1
00.2301, found 600.2305. νmax (film)/cm : 3329 (NÀ H), 2927 (CÀ H),
741 (C=O), 1683.92 (C=O).
3.4 (Ser αCH), 52.9 (OCH ), 50.7 (Gly αCH ), 47.1 (Fmoc CHCH ),
3
2
2
3.3 (COCH CH CH CH S), 28.8 (COCH CH CH CH S), 28.0 (CH S) 23.8
2
2
2
2
2
2
2
2
2
(
[
(
COCH CH CH CH S) ppm. HRMS (m/z) calculated for C H N NaO S
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
2
2
2
2
41 40
2
9
+
À 1
M+Na] , calcd. 759.2333, found 759.2347. ν
NH), 1712 (C=O).
(film)/cm : 3345
oxopropyl5-((3-(p–tolyl)propanoyl)thio)pentanoate (28): R (20%
max
f
1
EtOAc:Hex): 0.45, H NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.4 Hz, 4H,
3
Ar-CH), 7.63 (d, J=7.4 Hz, 4H, Ar-CH), 7.42 (t, J=7.4 Hz, 4H, Ar-CH),
Methyl (S)-(4-(((((9H-fluoren-9-yl)methoxy)carbonyl)glycyl)thio)-2-
(tert-butoxycarbonyl)amino)-3-methylbutanoyl)glycinate (25): R
7.35 (4H, t, J=7.4 Hz, 4H, Ar-CH), 7.14–7.06 (m, 4H, Ar-CH), 5.66 (d,
(
f
J=7.8 Hz, 1H, NH), 4.69–4.65 (m, 1H, Ser αCH), 4.54–4.39 (m, 4H,
Fmoc CHCH , Ser βCH ), 4.25 (t, J=6.9 Hz, 1H, Fmoc CHCH ), 3.80 (s,
1
(
4
50% EtOAc:Hex): 0.35 H NMR (400 MHz, CDCl ) δ 7.78 (d, J=7.5 Hz,
H, Ar-CH), 7.64 (d, J=7.5 Hz, 4H, Ar-CH), 7.42 (t, J=7.5 Hz, 4H, Ar-
3
2
2
2
3
H, OCH ), 2.97-2.83 (m, 6H, CH , CH , CH ), 2.39-2.33 (m, 5H, CH ,
3 2 2 2 2
13
CH), 7.34 (t, J=7.5 Hz, 4H, Ar-CH), 6.94 (bs, 1H, NH), 6.74 (bs, 1H,
NH), 5.62 (bs, 1H, NH), 5.57 (bs, 1H, NH), 5.49 (d, J=8.4 Hz, 1H, NH),
CH , CH ), 1.73–1.58 (m, 4H, CH , CH ) ppm. C NMR (100 MHz,
2
3
2
2
CDCl ) δ 198.7 (SC=O), 172.8 (C=O), 170.0 (C=O), 155.9 (C=O), 143.8
3
5
.29 (d, J=8.4 Hz, 1H, NH), 4.49–4.44 (m, 4H, Fmoc CHCH ), 4.40 (m,
2
(
1
Ar-qC), 141.4 (Ar-qC), 137.0 (Ar-qC), 135.9 (Ar-qC), 129.3 (Ar-CH),
28.3 (Ar-CH), 127.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-
CH), 67.4 (Fmoc CHCH ), 64.0 (Ser βCH ), 53.5 (Ser αCH), 53.0
1H, αCH), 4.27 (t, J=7.0 Hz, 2H, Fmoc CHCH ), 4.19–4.00 (m, 9H, Gly
2
αCH , Gly αCH , αCH), 3.75 (s, 3H, OCH ), 3.72 (s, 3H, OCH ), 3.26
2
2
3
3
2
2
(
(
dd, J=14.0, 6.6 Hz, 1H, γCH ), 2.97 (d, J=6.6 Hz, 2H, γCH ), 2.79
2
2
(
(
OCH ), 47.2 (Fmoc CHCH ), 45.8 (CH ), 33.4 (CH ), 31.1 (CH ), 29.0
3 2 2 2 2
dd, J=14.0, 6.6 Hz, 1H, γCH ), 2.25 (d, J=6.2 Hz, 1H, βCH), 1.46 (s,
2
CH ), 28.4 (CH ), 23.9 (CH ), 21.1 (CH ) ppm. HRMS (m/z) calculated
2
2
2
3
1
8H, C(CH ) ), 1.04 (d, J=6.9 Hz, 3H, CH ), 1.00 (d, J=6.9 Hz, 3H,
+
3
1
3
3
3
for C H NNaO S [M+Na] , calcd. 626.2187, found 626.2183. ν
34 37
À 1
7
max
CH ) ppm. C NMR (150 MHz, CDCl ) δ 198.9 (SC=O), 197.7 (SC=O),
3
3
(film)/cm : 3357 (NH), 1733 (C=O).
1
1
1
71.4 (C=O), 170.8 (C=O), 170.1 (C=O), 170.0 (C=O), 156.4 (C=O),
56.3 (C=O), 155.9 (C=O), 155.7 (C=O), 143.8 (Ar-qC), 143.7 (Ar-qC),
41.3 (Ar-qC), 141.3 (Ar-qC), 127.8 (Ar-CH), 127.1 (Ar-CH), 127.1 (Ar-
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
oxopropyl 5-(heptanoylthio)pentanoate (29): R (20% EtOAc:Hex):
f
1
CH), 125.1 (Ar-CH), 120.0 (Ar-CH), 80.3 (C(CH )), 67.4 (Fmoc CHCH ),
0.35, H NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.5 Hz, 4H, Ar-CH), 7.63
3
2
3
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4154
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
(
7
d, J=7.5 Hz, 4H, Ar-CH), 7.43 (t, J=7.5 Hz, 4H, Ar-CH), 7.35 (t, J=
.5 Hz, 4H, Ar-CH), 5.66 (d, J=7.9 Hz, 2H, NH), 4.68–4.64 (m, 1H, Ser
αCH), 4.53-4.39 (m, 4H, Fmoc CHCH , Ser βCH ), 4.27 (t, J=6.8 Hz,
(OCH3), 47.3 (Fmoc CHCH2), 47.2 (Fmoc CHCH2), 33.4
(COCH CH CH CH S), 28.9 (COCH CH CH CH S), 28.4 (CH S), 23.9
2
2
2
2
2
2
2
2
2
(COCH CH CH CH S), 19.1 (Ala CH ) ppm.. HRMS (m/z) calculated for
2
2
2
2
2
2
3
+
1
2
1
(
(
1
5
H, Fmoc CHCH ), 3.82 (s, 3H, OCH ), 2.88 (t, J=7.1 Hz, 2H, CH S),
C H N NaO S [M+Na] , calcd. 773.2521, found 773.2503. ν
2
3
2
4
2
4
2
2
9
m
a
x
À 1
.55 (t, J=7.3 Hz, 2H, CH ), 1.75–1.58 (m, 6H, CH CH2, CH ), 1.36-
(film)/cm : 3330 (NH), 1729 (C=O).
2
2,
2
1
3
.27 (m, 6H, CH CH CH ), 0.90 (t, J=6.8 Hz, 3H, CH ) ppm. C NMR
2,
2,
2
3
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
100 MHz, CDCl ) δ 199.8 (SC=O), 172.9 (C=O), 170.0 (C=O), 155.9
3
oxopropyl
5-((N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-
C=O), 143.8 (Ar-qC), 141.4 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH),
1
butyl)-L-seryl)thio)pentanoate (33): R (30% EtOAc:Hex): 0.36,
H
f
25.2 (Ar-CH), 120.1 (Ar-CH), 67.4 (Fmoc CHCH ), 64.0 (Ser βCH ),
2
2
NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.4 Hz, 4H, Ar-CH), 7.65 (m, 4H,
3
3.5 (Ser αCH), 53.0 (OCH ), 47.2 (Fmoc CHCH ), 44.3 (CH ), 33.4
3
2
2
Ar-CH), 7.42 (t, J=7.4 Hz, 4H, Ar-CH), 7.34 (t, J=7.4 Hz, 4H, Ar-CH),
(
(
CH ), 31.5 (CH ), 29.1 (CH ), 28.7 (CH ), 28.3 (CH S), 25.7 (CH ), 23.9
2 2 2 2 2 2
5
.76 (d, J=8.8 Hz, 1H, NH), 5.67 (d, J=8.1 Hz, 1H, NH), 4.67–4.64 (m,
1H, Ser αCH), 4.52–4.36 (m, 7H, Fmoc CHCH2, Fmoc CHCH , Ser
), 3.92
CH ), 22.5 (CH ), 14.1 (CH ) ppm. HRMS (m/z) calculated for
2
2
3
+
2
C H NNaO S [M+Na] , calcd. 592.2344, found 592.2339. ν
3
1
39
7
max
À 1
βCH
2
, Ser αCH), 4.32–4.24 (m, 2H, Fmoc CHCH
2
, Fmoc CHCH
2
(film)/cm : 3357 (NH), 1726, 1688 (C=O).
(
dd, J=2.5 Hz, J=9.1 Hz, 1H, Ser βCH ), 3.80 (s, 3H, OCH ), 3.56 (dd,
2
3
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
J=2.5 Hz, J=9.1 Hz, 1H, Ser βCH ), 2.91 (t, J=6.8 Hz, 2H, CH S), 2.37
2
2
oxopropyl 5-((2-cyclohexylacetyl)thio)pentanoate (30): Rf (40%
EtOc:Hex): 0.35, H NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.5 Hz, 4H,
(t, J=6.8 Hz, 2H, COCH CH CH CH S), 1.73-1.62 (m, 4H,
2 2 2 2
13
1
COCH CH CH CH S), 1.18 (s, 9H, C(CH ) ) ppm. C NMR (100 MHz,
2 2 2 2 3 3
3
Ar-CH), 7.62 (d, J=7.5 Hz, 4H, Ar-CH), 7.43 (t, J=7.5 Hz, 4H, Ar-CH),
CDCl ) δ 200.3 (SC=O), 172.9 (C=O), 170.0 (C=O), 156.2 (C=O), 155.9
(C=O), 144.1 (Ar-qC), 143.8 (Ar-qC), 141.4 (Ar-qC), 127.9 (Ar-CH),
3
7.35 (t, J=7.5 Hz, 4H, Ar-CH), 5.65 (d, J=7.78 Hz, 1H, NH), 4.68-4.64
(
m, 1H, Ser αCH), 4.53–4.38 (m, 4H, Fmoc CHCH , Ser βCH ), 4.27 (t,
127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH), 73.7 (C(CH ) ), 67.4
2
2
3 3
J=6.9 Hz, 1H, Fmoc CHCH ), 3.80 (s, 3H, OCH ), 2.88 (t, J=6.4 Hz,
(Fmoc CHCH ), 64.0 (Ser βCH ), 62.0 (Ser βCH ), 61.2 (Ser αCH), 53.5
2
3
2
2
2
2
1
1
H, CH S), 2.43 (d, J=6.4 Hz, 2H, CH ), 2.37 (t, J=6.4 Hz, 2H, CH ),
(Ser αCH), 53.1 (OCH ), 47.3 (Fmoc CHCH ), 47.2 (Fmoc CHCH ), 33.1
(COCH CH CH CH S), 28.8 (COCH CH CH CH S), 28.5 (CH S), 27.4
2 2 2 2 2 2 2 2 2
2
2
2
3
2
2
.91-1.80 (m, 1H, CH), 1.74-1.58 (m, 9H, CH , CH , CH , CH , CH ),
2
2
2
2
2
1
3
.32-1.14 (m, 3H, CH , CH ), 1.02-0.92 (m, 2H, CH ) ppm. C NMR
(C(CH ) ), 23.9 (COCH CH CH CH S) ppm. HRMS (m/z) calculated for
3 3 2 2 2 2
+
2
2
2
(
(
100 MHz, CDCl ) δ 199.1 (SC=O), 172.9 (C=O), 170.1 (C=O), 155.9
C=O), 143.8 (Ar-qC), 141.5 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH),
C H N NaO S [M+Na] , calcd. 845.3082, found 845.3078. ν
46 50 2 10 max
3
À 1
(film)/cm : 3338 (NH), 1719 (C=O).
1
5
3
2
25.2 (Ar-CH), 120.2 (Ar-CH), 67.4 (Fmoc CHCH ), 64.0 (Ser βCH ),
2
2
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
3.6 (Ser αCH), 53.0 (OCH ), 51.9 (CH ) 47.3 (Fmoc CHCH ), 35.8 (CH),
3
2
2
oxopropyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalan-
yl)thio)pentanoate (34):
(400 MHz, CDCl ) δ 7.79 (d, J=7.8 Hz, 4H, Ar-CH), 7.66-7.54 (m, 4H,
Ar-CH), 7.44 (t, J=7.8 Hz, 4H, Ar-CH), 7.38–7.29 (m, 7H, Ar-CH, Phe
Ar-CH) 7.25-7.14 (m, 2H, Phe Ar-CH), 5.76 (d, J=7.8 Hz, 1H, NH), 5.35
(d, J=8.9 Hz, 1H, NH), 4.78-4.68 (m, 2H, Ser αCH, Phe αCH), 4.55-
4.40 (m, 6H, Fmoc CHCH , Fmoc CHCH , Ser βCH ), 4.29-4.20 (m, 2H,
3.4 (CH ), 33.0, (CH ), 29.2 (CH ), 28.4 (CH S), 26.2 (CH ), 26.1 (CH ),
2
2
2
2
2
2
1
+
R
f
(30% EtOAc:Hex): 0.33,
H NMR
4.0 (CH ), ppm. HRMS (m/z) calculated for C H NNaO S [M+Na] ,
2
32 39
À 1
7
3
calcd. 604.2362, found 604.2339. νmax (film)/cm : 3335 (NH), 1768
C=O).
(
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
oxopropyl 5-((2-phenylacetyl)thio)pentanoate (31): Rf (30%
2
2
2
1
EtOAc:Hex): 0.40, H NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.7 Hz, 4H,
Fmoc CHCH , Fmoc CHCH ), 3.81 (s, 3H, OCH ), 3.22 (dd, J=J=14.0,
3
2
2
3
Ar-CH), 7.63 (d, J=7.7 Hz, 4H, Ar-CH), 7.42 (t, J=7.7 Hz, 4H, Ar-CH),
5.2 Hz, 1H, Phe βCH ), 3.12–3.04 (m, 1H, βCH ) 2.92 (t, J=6.8 Hz, 2H,
2 2
7
.35 (t, J=7.7 Hz, 4H, Ar-CH), 5.68 (d, J=8.0 Hz, 1H, NH), 4.68-4.64
m, 1H, Ser αCH), 4.53-4.38 (m, 4H, Fmoc CHCH , Ser βCH ), 4.26 (t,
CH S), 2.38 (t, J=6.8 Hz, 2H, COCH CH CH CH S), 1.75–1.61 (m, 4H,
2 2 2 2 2
13
(
COCH CH CH CH S) ppm. C NMR (100 MHz, CDCl ) δ 200.4 (SC=O),
2 2 2 2 3
2
2
J=6.9 Hz, 1H, Fmoc CHCH ), 3.83 (s, 2H, CH Ph), 3.79 (s, 3H, OCH ),
172.7 (C=O), 170.0 (C=O), 155.8 (C=O), 155.7 (C=O), 143.8 (Ar-qC),
143.7 (Ar-qC), 141.3 (Ar-qC), 135.6 (Phe Ar-qC), 129.4 (Phe Ar-CH),
128.8 (Phe Ar-CH), 127.8 (Ar-CH), 127.2 (Phe Ar-CH), 127.1 (Ar-CH),
125.2 (Ar-CH), 120.1 (Ar-CH), 67.3 (Fmoc CHCH ), 67.2 (Fmoc CHCH ),
2
2
3
2
.87 (t, J=7.0 Hz, 2H, CH S), 2.35 (t, J=7.0 Hz, 2H,
2
13
COCH CH CH CH S), 1.73-1.56 (m, 4H, COCH CH CH CH S) ppm.
C
2
2
2
2
2
2
2
2
NMR (100 MHz, CDCl ) δ 197.6 (SC=O), 172.9 (C=O), 170.1 (C=O),
3
2
2
1
55.9 (C=O), 143.8 (Ar-qC), 141.4 (Ar-qC), 133.7 (Ar-qC), 129.7 (Ar-
CH), 128.8 (Ar-CH), 127.9 (Ar-CH), 127.5 (Ar-CH), 127.2 (Ar-CH), 125.2
Ar-CH), 120.1 (Ar-CH), 67.4 (Fmoc CHCH ), 64.0 (Ser βCH ), 53.5 (Ser
64.0 (Ser βCH ), 61.6 (Phe αCH), 53.5 (Ser αCH), 53.0 (OCH ), 47.1
2
3
(Fmoc CHCH ), 38.4 (Phe βCH ), 33.3 (COCH CH CH CH S), 28.7
2
2
2
2
2
2
(
(COCH CH CH CH S), 28.5 (CH S) 23.8 (COCH CH CH CH S), ppm.
2 2 2 2 2 2 2 2 2
+
2
2
αCH), 53.0 (OCH3), 50.6 (CH Ph), 47.2 (Fmoc CHCH2), 33.4
HRMS (m/z) calculated for C H N O S [M+Na] , calcd. 849.2822,
2
48 46
2
9
À 1
(
(
[
(
COCH CH CH CH S), 28.9, (COCH CH CH CH S), 28.8 (CH S), 23.9
COCH CH CH CH S) ppm. HRMS (m/z) calculated for C H NNaO S
M+Na] , calcd. 598.1857, found 598.1869. ν
NH), 1690 (C=O).
found 849.2816. νmax (film)/cm : 3332 (NH), 1728 (C=O).
2
2
2
2
2
2
2
2
2
2
2
2
2
32 33
À 1
7
+
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
oxopropyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl)thio)
(film)/cm : 2950
max
1
pentanoate (35): R (30% EtOAc:Hex): 0.29 H NMR (400 MHz, CDCl )
f
3
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
δ 7.79 (d, J=7.4 Hz, 4H, Ar-CH), 7.63 (d, J=7.4 Hz, 4H, Ar-CH), 7.42
(t, J=7.4 Hz, 4H, Ar-CH), 7.34 (t, J=7.4 Hz, 4H, Ar-CH), 5.76 (d, J=
8.0 Hz, 1H, NH), 5.41 (d, J=9.3 Hz, 1H, NH), 4.68-4.64 (m, 1H, Ser
αCH), 4.52-4.36 (m, 7H, Fmoc CHCH , Fmoc CHCH , Ser βCH , Val
oxopropyl5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanyl)thio)
pentanoate (32): R (40% EtOAc:Hex): 0.32, H NMR (400 MHz,
CDCl ) δ 7.79 (d, J=7.4 Hz, 4H, Ar-CH), 7.62 (d, J=7.4 Hz, 4H, Ar-
1
f
3
2
2
2
CH), 7.42 (t, J=7.4 Hz, 4H, Ar-CH), 7.33 (t, J=7.4 Hz, 4H, Ar-CH), 5.69
αCH), 4.25 (t, J=7.1 Hz, 2H, Fmoc CHCH , Fmoc CHCH ), 3.80 (s, 3H,
2
2
(d, J=8.4 Hz, 1H, NH), 5.31 (1H, d, J=8.0 Hz, 1H, NH), 4.68-4.64 (m,
OCH3), 2.91 (t, J=6.9 Hz, 2H, CH S), 2.36-2.32 (m, 2H,
2
1
H, Ser αCH), 4.52-4.37 (m, 7H, Fmoc CHCH , Fmoc CHCH , Ser
COCH CH CH CH S, Val CH), 1.74-1.59 (m, 4H, COCH CH CH CH S),
2
2
2
2
2
2
2
2
2
2
βCH , Ala αCH), 4.28–4.24 (m, 2H, Fmoc CHCH , Fmoc CHCH ), 3.80
1.02 (d, J=6.6 Hz, 3H, Val CH ), 0.90 (d, J=6.6 Hz, 3H, Val CH ) ppm.
3 3
3
2
2
2
1
(s, 3H, OCH ), 2.91 (t, J=6.5 Hz, 2H, CH S), 2.38 (t, J=6.5 Hz, 2H,
C NMR (100 MHz, CDCl ) δ 200.5 (SC=O), 172.7 (C=O), 170.0 (C=O),
3
3
2
COCH CH CH CH S), 1.74-1.61 (m, 4H, COCH CH CH CH S), 1.43 (d,
156.3 (C=O), 155.8 (C=O), 143.9 (Ar-qC), 143.7 (Ar-qC), 141.4 (Ar-qC),
141.3 (Ar-qC), 127.8 (Ar-CH), 127.1 (Ar-CH), 125.1 (Ar-CH), 120.1 (Ar-
CH), 67.3 (Fmoc CHCH ), 67.1 (Fmoc CHCH ), 65.9 (Val αCH), 63.9
2
2
2
2
2
2
2
2
13
J=6.5 Hz, 3H, Ala CH ) ppm. C NMR (100 MHz, CDCl ) δ 201.3
3
3
(SC=O), 172.8 (C=O), 170.1 (C=O), 155.9 (C=O), 155.7 (C=O), 144.0
2
2
(
1
Ar-qC), 143.9 (Ar-qC), 143.8 (Ar-qC), 141.5 (Ar-qC), 127.9 (Ar-CH),
(Ser βCH ), 53.5 (Ser αCH), 53.0 (OCH ), 47.3 (Fmoc CHCH ), 47.1
(Fmoc CHCH ), 33.3 (COCH CH CH CH S), 31.1 (Val βCH), 28.8
2 2 2 2 2
2
3
2
27.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH), 67.4 (Fmoc CHCH ), 67.2
2
(
Fmoc CHCH ), 64.0 (Ser βCH ), 56.9 (Ala αCH), 53.6 (Ser αCH), 53.1
(COCH CH CH CH S), 28.3 (CH S), 23.8 (COCH CH CH CH S), 19.5
2
2
2 2 2 2 2 2 2 2 2
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4155
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
(
Val CH3), 16.9 (Val CH ) ppm. HRMS (m/z) calculated for
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
2 6
3
+
C H N NaO S [M+Na] , calcd. 801.2805, found 801.2816. ν
oxopropyl 5-((N -(((9H-fluoren-9-yl)methoxy)carbonyl)-N -(tert-bu-
4
4
46
2
9
max
À 1
(film)/cm :3338 (NH), 1716 (C=O).
toxycarbonyl)-L-lysyl)thio)pentanoate (39): R (40% EtOAc:Hex):
f
1
0
7
.32, H NMR (400 MHz, CDCl ) δ 7.80-7.75 (d, J=7.7 Hz, 4H, Ar-CH),
3
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
.65-7.61 (m, 4H, Ar-CH), 7.55 (bs, 1H, NH), 7.42 (t, J=7.7 Hz, 4H, Ar-
oxopropyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-leucyl)thio)
CH), 7.33 (t, J=7.7 Hz, 4H, Ar-CH), 5.72 (d, J=6.9 Hz, 1H, NH), 5.52
d, J=6.6 Hz, 1H, NH), 4.68–4.64 (m, 1H, Ser αCH), 4.54-4.36 (m, 7H,
Fmoc CHCH Fmoc CHCH , Ser βCH , Lys αCH), 4.25 (t, J=6.9 Hz,
1
pentanoate (36): R (30% EtOAc:Hex): 0.36, H NMR (400 MHz,
CDCl ) δ 7.79 (d, J=7.8 Hz, 4H, Ar-CH), 7.62 (d, J=7.8 Hz, 4H, Ar-
CH), 7.42 (t, J=7.8 Hz, 4H, Ar-CH), 7.33 (t, J=7.8 Hz, 4H, Ar-CH), 5.69
f
(
3
2
2
2
2
H, Fmoc CHCH , Fmoc CHCH ), 3.80 (s, 3H, OCH ), 3.14-3.10 (m, 2H,
2
2
3
(
d, J=7.5 Hz, 1H, NH), 5.17 (d, J=7.5 Hz, 1H, NH), 4.68-4.64 (m, 1H,
Lys ɛCH ), 2.89 (t, J=6.2 Hz, 2H, CH S), 2.33 (t, J=6.2 Hz, 2H,
2
2
Ser αCH), 4.52-4.38 (m, 7H, Fmoc CHCH , Fmoc CHCH , Ser βCH ,
2
2
2
COCH CH CH CH S), 1.94-1.86 (m, 1H, Lys βCH ), 1.73-1.58 (5H, m,
2
2
2
2
2
Leu αCH), 4.25 (t, J=6.9 Hz, 2H, Fmoc CHCH , Fmoc CHCH ), 3.80 (s,
3
COCH CH CH CH S), 1.72–1.60 (m, 7H, COCH CH CH CH S, Leu
βCH , Leu γCH), 0.96 (d, J=2.5 Hz, 6H, Leu CH , Leu CH ) ppm.
NMR (100 MHz, CDCl ) δ 201.6 (SC=O), 172.8 (C=O), 170.1 (C=O),
1
2
2
Lys βCH , COCH CH CH CH S), 1.54-1.29 (m, 13H, C(CH ) , Lys δCH ,
2
2
2
2
2
3 3
2
H, OCH ), 2.89 (t, J=6.4 Hz, 2H, CH S), 2.37 (t, J=6.4 Hz, 2H,
13
3
2
Lys γCH ,) ppm. C NMR (100 MHz, CDCl ) δ 201.1 (SC=O), 172.7
2
3
2
2
2
2
2
2
2
2
(
(
7
C=O), 170.0 (C=O), 156.0 (C=O), 155.8 (C=O), 143.7 (Ar-qC), 141.3
Ar-qC), 127.8 (Ar-CH), 127.1 (Ar-CH), 125.2 (Ar-CH), 120.0 (Ar-CH),
1
3
C
2
3
3
3
9.4 (C(CH ) ), 67.3 (Fmoc CHCH ), 67.1 (Fmoc CHCH ), 63.9 (Ser
3 3 2 2
55.9 (C=O), 155.9 (C=O), 144.0 (Ar-qC), 143.8 (Ar-qC), 141.5 (Ar-qC),
41.4 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-
βCH ), 61.0 (Lys αCH), 53.4 (Ser αCH), 52.9 (OCH ), 47.2 (Fmoc
2
3
1
CHCH2), 47.1 (Fmoc CHCH2), 40.0 (Lys ɛCH ), 33.3
2
CH), 67.4 (Fmoc CHCH ), 67.1 (Fmoc CHCH ), 64.0 (Ser βCH ), 59.7
2
2
2
(
(
(
COCH CH CH CH S), 32.2 (Lys βCH2), 29.7 (Lys δCH ), 28.7
2
2
2
2
2
(
(
(
(
Leu αCH), 53.5 (Ser αCH), 53.1 (OCH ), 47.4 (Fmoc CHCH ), 47.2
3
2
COCH CH CH CH S), 23.8 (COCH CH CH CH S), 28.4 (C(CH ) ), 28.3
2
2
2
2
2
2
2
2
3 3
Fmoc CHCH ), 41.8 (Leu βCH ), 33.4 (COCH CH CH CH S), 28.8
2
2
2
2
2
2
CH S), 22.4 (Lys γCH ) ppm. HRMS (m/z) calculated for
2
2
COCH CH CH CH S), 28.4 (CH S), 24.9 (Leu γCH), 23.9
+
2
2
2
2
2
C H N NaO S [M+Na] , calcd. 930.3609, found 930.3606. ν
5
0
57
3
11
max
COCH CH CH CH S), 23.2 (Leu CH ), 21.6 (Leu CH ) ppm. HRMS (m/
À 1
2
2
2
2
3
3
(film)/cm : 3351 (NH), 1712 (C=O).
+
z) calculated for C H N O S [M+Na] , calcd. 815.2973, found
4
5
48
2
9
À 1
8
15.2972. νmax (film)/cm : 3331 (NH), 1724 (C=O).
(9H-Fluoren-9-yl)methyl
(S)-2-((S)-1-(9H-fluoren-9-yl)-5-(meth-
oxycarbonyl)-3,8-dioxo-2,7-dioxa-13-thia-4-azatetradecan-14-oyl)
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
1
pyrrolidine-1-carboxylate (40): R (40% EtOAc:Hex): 0.36. H NMR
f
oxopropyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-threonyl)
(
400 MHz, CDCl ) δ 7.81–7.78 (m, 4H, Ar-CH), 7.65-7.61 (m, 4H, Ar-
1
3
thio)pentanoate (37): R (30% EtOAc:Hex): 0.28, M.p. 60–62°C, H
f
CH), 7.46-7.41 (m, 4H, Ar-CH), 7.38-7.33 (m, 4H, Ar-CH), 5.67 (dd, J=
.0 Hz, J=39.1 Hz, 1H, NH), 4.67-4.62 (m, 1H, Ser αCH), 4.57–4.24
m, 9H, 2×Fmoc CHCH , Fmoc CHCH , Fmoc CHCH , Fmoc CHCH
2
NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.4 Hz, 4H,Ar-CH), 7.65-7.57 (m,
8
4
H, Ar-CH), 7.40 (t, J=7.4 Hz, 4H, Ar-CH), 7.31 (4H, t, J=7.4 Hz, Ar-
(
2
2
2
CH), 5.69 (d, J=7.7 Hz, 0.5H, 0.5xNH), 5.48 (d, J=7.6 Hz, 0.5H, 0.5×
NH), 4.67-4.55 (m, 2H, Ser αCH, NH), 4.53-4.36 (m, 8H, Fmoc CHCH2,
Fmoc CHCH Thr αCH, Thr βCH, Ser βCH ), 4.28-4.17 (m, 2H, Fmoc
Ser βCH , Pro αCH), 3.79 (s, 3H, OCH ), 3.71-3.50 (m, 2H, Pro CH ),
2
3
2
2
1
.92-2.80 (m, 2H, CH S), 2.39-2.28 (m, 2H, COCH CH CH CH S), 2.26-
2 2 2 2 2
2
2
.90 (m, 4H, 2×Pro CH ), 1.72-1.53 (m, 4H, COCH CH CH CH S)
2
2
2
2
2
CHCH , Fmoc CHCH ), 3.78 (s, 3H, OCH ), 2.87 (t, 2H, J=7.1 Hz,
CH S), 2.38-2.27 (2H, m, COCH CH CH CH S), 1.72-1.60 (m, 4H,
COCH CH CH CH S), 1.43 (s, 12H, C(CH ) , Thr CH ) ppm. C NMR
13
2
2
3
ppm.* C NMR (100 MHz, CDCl ) δ 202.2 (SC=O), 201.6 (SC=O),
3
2
2
2
2
2
1
1
72.9 (C=O), 172.8 (C=O), 170.0 (C=O), 155.9 (C=O), 155.2 (C=O),
54.7 (C=O), 144.2 (Ar-qC), 143.9 (Ar-qC), 141.4 (Ar-qC), 127.9 (Ar-
1
3
2
2
2
2
3 3
3
(100 MHz, CDCl3) δ 200.9 (SC=O), 172.7 (C=O), 170.0 (C=O), 156.2
(C=O), 155.8 (C=O), 143.8 (Ar-qC), 143.7 (Ar-qC), 141.3 (Ar-qC), 141.3
(Ar-qC), 127.8 (Ar-CH), 127.1 (Ar-CH), 125.1 (Ar-CH), 120.0 (Ar-CH),
CH), 127.8 (Ar-CH), 127.2 (Ar-CH), 127.1 (Ar-CH), 125.3 (Ar-CH), 125.2
(
(
(
(
(
(
Ar-CH), 120.1 (Ar-CH), 67.8 (Fmoc CHCH ), 67.4 (Fmoc CHCH ), 66.6
2
2
Pro αCH), 66.2 (Pro αCH), 64.0 (Ser βCH ), 53.5 (Ser αCH), 53.0
2
7
6
4
2
9.3 (C(CH ) ), 67.3 (Thr βCH), 67.1 ( Fmoc CHCH , Fmoc CHCH ),
3
3
2
2
OCH ), 47.4 (Fmoc CHCH ), 47.2 (Fmoc CHCH ), 46.9 (Pro CH ), 33.4
3
2
2
2
3.9 (Ser βCH ),60.9 (Thr αCH), 53.4 (Ser αCH), 53.1 (OCH ), 47.2,
2
3
COCH CH CH CH S), 31.9 (Pro CH2), 30.8 (Pro CH2), 28.9
2
2
2
2
7.2 ( Fmoc CHCH , Fmoc CHCH ), 33.3 (COCH CH CH CH S), 29.7,
2
2
2
2
2
2
COCH CH CH CH S), 28.2 (CH S), 23.9 (COCH CH CH CH S), 23.2
2
2
2
2
2
2
2
2
2
8.7 (COCH CH CH CH S), 28.4 (C(CH ) ), 28.3 (CH S), 23.8 (Thr CH )
2
2
2
2
3 3
2
3
Pro CH ) ppm.* *multiple signals correspond to an inseparable
+
2
ppm. HRMS (m/z) calculated for C H N O S [M+H] , calcd.
4
3
45
2
10
mixture of cis/trans prolyl isomers. HRMS (m/z) calculated for
À 1
7
81.2779, found 781.2789. νmax (film)/cm : 3385 (NH), 1705 (C=O).
+
C H N NaO S [M+Na] , calcd. 799.2659, found 799.2642. ν
4
4
44
2
9
max
À 1
(film)/cm : 3332 (NH), 1704 (C=O).
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
oxopropyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-methionyl)
(
S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
1
thio)pentanoate (38): R (30% EtOAc:Hex): 0.31, M.p. 33–35°C. H
f
oxopropyl (6S,9S)-9-isopropyl-2,2,6-trimethyl-4,7,10-trioxo-3-oxa-
1
NMR (400 MHz, CDCl ) δ 7.78 (d, J=7.4 Hz, 4H, Ar-CH), 7.62 (d, J=
3
1-thia-5,8-diazahexadecan-16-oate (41): Rf (80% EtOAc:Hex):
7
4
4
.4 Hz, 4H, Ar-CH), 7.42 (t, J=7.4 Hz, 4H, Ar-CH), 7.33 (t, J=7.4 Hz,
H, Ar-CH), 5.69 (d, J=8.3 Hz, 1H, NH), 5.51 (d, J=9.0 Hz, 1H, NH),
1
0
.42. H NMR (400 MHz, CDCl ) δ 7.78 (d, J=7.4 Hz, 4H, Ar-CH), 7.63
3
(
d, J=7.4 Hz, 4H, Ar-CH), 7.41 (t, J=7.4 Hz, 4H, Ar-CH), 7.32 (t, J=
.4 Hz, 4H, Ar-CH), 6.89 (bs, 1H, NH), 5.68 (d, J=6.7 Hz, 1H, NH), 4.98
bs, 1H, NH), 4.67–4.59 (m, 2H, Ser αCH, Val αCH), 4.55-4.38 (m, 4H,
Fmoc CHCH , Ser βCH ), 4.28-4.20 (m, 2H, Fmoc CHCH , Ala αCH),
.68-4.64 (m, 1H, Ser αCH), 4.60-4.40 (m, 7H, Fmoc CHCH , Fmoc
2
7
(
CHCH , Ser βCH , Met αCH), 4.25 (t, J=6.9 Hz, 2H, Fmoc CHCH
2
2
2,
Fmoc CHCH ), 3.80 (s, 3H, OCH ), 2.90 (m, 2H, CH S), 2.58-2.50 (m,
2
3
2
2
2
2
5
H, Met CH , Met βCH ), 2.36 (2H, t, J=6.6 Hz, COCH CH CH CH S),
3 2 2 2 2 2
3
.80 (s, 3H, OCH ), 2.89 (t, J=6.9 Hz, 2H, CH S), 2.37-2.30 (m, 3H,
3
2
2
.14-2.09 (2H, m, Met γCH ), 1.72-1.58 (4H, m, COCH CH CH CH S)
2
2
2
2
2
COCH CH CH CH S, Val βCH), 1.72-1.58 (m, 4H, COCH CH CH CH S),
13
2
2
2
2
2
2
2
2
ppm. C NMR (100 MHz, CDCl ) δ 200.4 (SC=O), 172.8 (C=O), 170.1
3
1
.47 (d, 9H, C(CH ) ), 1.39 (app. t, J=6.5 Hz, 3H, Ala CH ), 0.99-0.88
3 3 3
13
(
(
C=O), 155.9 (C=O), 144.0 (Ar-qC), 143.8 (Ar-qC), 141.5 (Ar-qC), 141.4
Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH),
(
(
(
m, 6H, Val CH , Val CH ) ppm. C NMR (100 MHz, CDCl ) δ 200.2
SC=O), 172.9 (C=O), 172.8 (C=O), 170.1 (C=O), 156.0 (C=O), 155.9
C=O), 143.8 (Ar-qC), 141.5 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH),
3
3
3
6
7.4 (Fmoc CHCH ), 67.2 (Fmoc CHCH ), 64.0 (Ser CH ), 60.4 (Met
2
2
2
αCH), 53.5 (Ser αCH), 53.1 (OCH ), 47.3 (Fmoc CHCH ), 47.2 (Fmoc
3
2
1
25.2 (Ar-CH), 120.2 (Ar-CH), 80.5 (C(CH ) ), 67.4 (Fmoc CHCH ), 64.0
3
3
2
CHCH ), 38.5 (Met CH ), 33.4 (COCH CH CH CH S), 32.1 (Met βCH ),
2
3
2
2
2
2
2
(Ser βCH ), 63.9 (Ala αCH), 53.5 (Ser αCH), 53.1 (OCH ), 50.1 (Thr
2
3
3
0.1 (Met γCH2), 28.7 (COCH CH CH CH S), 28.3 (CH S) 23.8
2 2 2 2 2
αCH), 47.2 (Fmoc CHCH ), 33.4 (COCH CH CH CH S), 31.2 (Thr βCH),
2
2
2
2
2
(
[
(
COCH CH CH CH S) ppm. HRMS (m/z) calculated for C H KN O S
2 2 2 2 2 9 2
+
44 46
À 1
2
9.8 (COCH CH CH CH S), 28.5 (C(CH3)3), 28.4 (CH S), 23.9
2
2
2
2
2
M+K] , calcd. 849.2282, found 849.2534. ν
NH), 1726 (C=O).
(film)/cm : 3325
max
(COCH CH CH CH S) 20.1 (Thr CH ), 19.5 (Thr CH ), 19.4 (Ala CH )
2 2 2 2 3 3 3
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4156
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
+
ppm. HRMS (m/z) calculated for C H N NaO S [M+Na] , calcd.
7
Methyl
((S)-4-((N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-
37
49
3
10
À 1
50.3045, found 750.3031. νmax (film)/cm : 3325 (NH), 1683 (C=O).
butyl)-L-seryl)thio)-2-((tert-butoxycarbonyl)amino)-3-meth-
ylbutanoyl)glycinate (45): Rf (50% EtOAc:Hex): 0.35. H NMR
1
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
oxopropyl 5-(((S)-4-acetamido-5-((2-methoxy-2-oxoethyl)amino)-
-oxopentanoyl)thio)pentanoate (42): R (100% EtOAc): 0.26. H
f
NMR (400 MHz, CDCl ) δ 7.78 (d, J=7.4 Hz, 4H, Ar-CH), 7.632 (d, J=
.4 Hz, 4H, Ar-CH), 7.41 (t, J=7.4 Hz, 4H, Ar-CH), 7.32 (t, J=7.4 Hz,
H, Ar-CH), 6.90 (d, J=5.7 Hz, 1H, NH), 5.86 (d, J=8.2 Hz, 0.5H, NH),
.83 (d, J=8.2 Hz, 0.5H, NH), 4.68-4.64 (m, 1H, Ser αCH), 4.58-4.37
m, 5H, Fmoc CHCH , Ser βCH , Glu αCH), 4.25 (t, J=6.8 Hz, 1H,
Fmoc CHCH ), 4.01 (d, J=5.7 Hz, 2H, Gly αCH ), 3.80-3.72 (m, 6H,
(
(
600 MHz, CDCl ) δ δ 7.79 (bs, 1H, NH) 7.69-7.62 (m, 8H, Ar-CH), 7.40
t, J=7.4 Hz, 4H, Ar-CH), 7.34-7.28 (m, 4H, Ar-CH), 7.05 (bs, 2H, NH),
3
1
5
6
.18 (app. t, 2H, NH), 5.74 (d, J=8.9 Hz, 2H, NH), 5.27-5.18 (m, 2H,
NH), 5.26 (d, J=8.5 Hz, 1H, NH), 4.89 (bs, 1H, Ser αCH), 4.73–4.65
m, 2H, Val αCH, Val αCH), 4.42-4.38 (m, 2H, Fmoc CHCH ), 4.16–
3
7
4
5
(
2
3
3
.91 (m, 5H, Ser αCH, Fmoc CHCH , Fmoc CHCH , Fmoc CHCH ),
.85–3.72 (m, 4H, Gly αCH , Gly αCH ), 3.68-3.66 (m, 6H, OCH ,
2 2 2
2
2
3
(
2 2
OCH ), 3.14 (d, J=11.0 Hz, 1H, Val γCH ), 3.06–2.93 (m, 4H, Ser βCH ,
3
2
2
2
2
Val γCH , Ser βCH ), 2.86-2.80 (m, 1H Ser βCH ), 2.78-2.71 (m, 2H, Val
2
2
2
Gly OCH , Ser OCH ), 2.87 (t, J=6.8 Hz, 2H, CH S), 2.75-2.65 (m, 2H,
Glu γCH ), 2.36 (t, J=6.8 Hz, 2H, COCH CH CH CH S), 2.17-2.00 (m,
3
3
2
γCH ), 2.22-2.12 (m, 2H, Val αCH, Val αCH), 1.46-1.44 (m, 18H,
2
2
2
2
2
2
C(CH ) , C(CH ) ), 1.37-1.24 (m, 18H, OC(CH ) , OC(CH ) ), 1.02-0.95
3
3
3 3
3 3
3 3
5
H, Glu βCH , COCH ), 1.70-1.53 (m, 4H, COCH CH CH CH S) ppm.
13
2
3
2
2
2
2
(
(
(
(
m, 6H, Val CH , Val CH ) ppm. C NMR (150 MHz, CDCl ) δ 200.2
1
3
3
3
3
C NMR (100 MHz, CDCl ) δ 199.4 (SC=O), 172.9 (C=O), 171.8 (C=O),
71.2 (C=O), 170.4 (C=O), 170.1 (C=O) 168.3 (C=O), 156.0 (C=O),
43.8 (Ar-qC), 141.4 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-
CH), 120.1 (Ar-CH), 67.4 (Fmoc CHCH ), 64.0 (Ser βCH ), 53.5 (Ser
αCH), 53.0 (Ser OCH ), 52.5 (Gly OCH ), 47.2 (Fmoc CHCH ), 41.2 (Gly
αCH2), 39.9 (Glu γCH2), 33.3 (COCH CH CH CH S), 28.9
COCH CH CH CH S), 28.5 (CH S), 27.9 (Glu βCH2), 23.8
COCH CH CH CH S), 23.0 (COCH ) ppm. HRMS (m/z) calculated for
3
SC=O), 199.9 (SC=O), 171.7 (C=O), 171.1 (C=O), 170.1 (C=O), 170.0
C=O), 156.9 (C=O), 156.7 (C=O), 156.1 (C=O), 155.8 (C=O), 146.1
Ar-qC), 146.1 (Ar-qC), 145.8 (Ar-qC), 145.6 (Ar-qC), 139.9 (Ar-qC),
1
1
2
2
1
39.9 (Ar-qC), 139.7 (Ar-qC), 139.7 (Ar-qC), 129.8 (Ar-CH), 129.7 (Ar-
3
3
2
CH), 128.2 (Ar-CH), 128.1 (Ar-CH), 125.3 (Ar-CH), 124.5, (Ar-CH) 120.3
2
2
2
2
(
8
Ar-CH), 120.3 (Ar-CH), 82.5 (C(CH ) ), 82.3 (C(CH ) ), 81.1 (C(CH ) ),
1.0 (C(CH ) ), 80.5 (C(CH ) ), 80.4 (C(CH ) ), 70.2 (Fmoc CHCH ), 70.1
3 3 3 3 3 3
(
(
2 2 2 2 2
3 3 3 3 3 3 2
2
2
2
2
3
(
(
Fmoc CHCH ), 58.0 (Ser αCH), 57.6 (Ser αCH), 57.1 (Val αCH), 55.7
Val αCH), 52.4 (OCH ), 52.4 (OCH ), 41.3 (Fmoc CHCH ), 41.2 (Fmoc
+
2
C H N NaO S [M+Na] , calcd. 722.2365, found 722.2354. ν
3
4
41
3
11
max
À 1
3
3
2
(
film)/cm : 3306 (NH), 1739, 1660 (C=O).
CHCH ), 41.1 (Gly αCH ), 41.1 (Gly αCH ), 37.6 (Ser βCH ), 37.5 (Ser
2
2
2
2
βCH ), 37.4 (Val βCH ), 36.3 (Val βCH ), 32.6 (Val γCH ), 31.7 (Val
(
S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-
2
2
2
2
γCH ), 28.4 (C(CH ) ), 28.3 (C(CH ) ), 15.8 (Val CH ), 14.8 (Val CH )
oxopropyl 5-(((S)-1-(9H-fluoren-9-yl)-5-(methoxycarbonyl)-3,8,13-
trioxo-2,7-dioxa-12-thia-4-azaoctadecan-18-oyl)thio)pentanoate
2
3 3
3 3
3
3
ppm. *Isolated as a mixture of diastereoisomers and rotamers at rt.
+
1
HRMS (m/z ESI+): Calculated for C H N O S [M+H] , Calcd
(
43): R (40% EtOAc:Hex): 0.35. H NMR (400 MHz, CDCl ) δ 7.79 (d,
37 44
3
8
f
3
À 1
6
1
90.2850, found 690.2844. νmax (film)/cm : 3331 (NÀ H), 2976 (CÀ H),
708 (C=O), 1682 (C=O)
J=7.5 Hz, 4H, Ar-CH), 7.63 (d, J=7.5 Hz, 4H, Ar-CH), 7.43 (t, J=
7
.5 Hz, 4H, Ar-CH), 7.34 (t, J=7.5 Hz, 4H, Ar-CH), 5.66 (d, J=8.3 Hz,
H, NH), 4.68-4.64 (m, 2H, Ser αCH), 4.53-4.39 (m, 8H, Fmoc CHCH2,
2
Methyl
((S)-4-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenyla-
Fmoc CHCH , Ser βCH , Ser βCH ), 4.27 (t, J=6.8 Hz, 2H, Fmoc
2
2
2
lanyl)thio)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)
CHCH , Fmoc CHCH ), 3.81 (s, 6H, OCH ), 2.88 (t, J=6.8 Hz, 4H,
CH S), 2.55 (t, J=5.7 Hz, 4H, CH , CH ), 2.37 (t, J=6.8 Hz, 4H, CH ,
CH ), 1.73–1.57 (m, 12H, CH , CH , CH , CH , CH , CH ) ppm. C NMR
1
2
2
3
glycinate (46): R (50% EtOAc/Hex): 0.35. H NMR (600 MHz, CDCl )
f
3
2
2
2
2
δ δ 7.82–7.73 (m, 4H, Ar-CH), 7.61–7.48 (m, 4H, Ar-CH), 7.41 (t, J=
.2 Hz, 4H, Ar-CH), 7.36–7.25 (m, 10H, Ar-CH), 7.19 (t, J=7.2 Hz, 4H,
Ar-CH), 6.92-6.72 (m, 2H, NH), 5.45-5.25 (m, 4H, NH), 4.80–4.63 (m,
1
3
2
2
2
2
2
2
2
7
(
100 MHz, CDCl ) δ 199.0 (SC=O), 172.9 (C=O), 170.1 (C=O), 155.9
3
(C=O), 143.8 (Ar-qC), 141.5 (Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH),
2
4
3
H, Phe αCH), 4.51–4.33 (m, 5H, Fmoc CHCH and Val αCH), 4.25-
2
1
25.2 (Ar-CH), 120.2 (Ar-CH), 67.4 (Fmoc CHCH ), 64.0 (Ser βCH ),
2
2
.17 (m, 2H, Fmoc CHCH ), 4.15-3.95 (m, 5H, Gly αCH , Val αCH),
2
2
5
3.6 (Ser αCH), 53.1 (OCH ), 47.3 (Fmoc CHCH ), 43.7 (CH ), 33.4
3
2
2
.78-3.68 (m, 6H, OCH ), 3.27–3.15 (m, 3H, Phe βCH , Val γCH ), 3.06
3
2
2
(CH ), 29.1 (CH ), 28.4 (CH S), 24.9 (CH , CH ), 23.9 (CH ) ppm. HRMS
2 2 2 2 2 2
+
(m/z) calculated for C H N NaO S [M+Na] , calcd. 1047.3378,
(dt, J=21.7, 10.7 Hz, 2H, Phe βCH ), 2.98–2.89 (m, 2H, Val γCH ),
2
2
54
60
2
14 2
2
1
.79 (dd, J=13.4, 7.6 Hz, 1H, Val γCH ), 2.29–2.12 (m, 2H, Val βCH),
À 1
2
found 1047.3378. νmax (film)/cm : 2949 (NH), 1737, 1682 (C=O).
.46 (s, 18H, C(CH ) ), 0.99 (dd, J=19.9, 6.7 Hz, 6H, Val γCH ) ppm.
3
3
3
1
3
C NMR (150 MHz, CDCl ) δ 200.7 (SC=O), 200.6 (SC=O), 171.6
(
2R,3R,4R,5S,6S)-2-(((S)-1-(9H-Fluoren-9-yl)-5-(methoxycarbonyl)-
,8,14-trioxo-2,7-dioxa-13-thia-4-azapentadecan-15-yl)oxy)-6-m
3
(
(
(
C=O), 171.0 (C=O), 170.1 (C=O), 170.0 (C=O), 156.1 (C=O), 156.3
C=O), 156.0 (C=O), 155.7 (C=O), 143.9 (Ar-qC), 143.8 (Ar-qC), 143.7
Ar-qC), 141.4 (Ar-qC), 135.6 (Ar-qC), 129.5 (Ar-CH), 129.4 (Ar-CH),
3
ethyltetrahydro-2H-pyran-3,4,5-triyl triacetate (44): Rf (40%
1
EtOAc:Hex): 0.33. H NMR (400 MHz, CDCl ) δ 7.79 (d, J=7.7 Hz, 4H,
Ar-CH), 7.64-7.60 (m, 4H, Ar-CH), 7.42 (t, J=7.7 Hz, 4H,Ar-CH), 7.34
3
1
28.9 (Ar-CH), 128.9 (Ar-CH), 127.8 (Ar-CH), 127.4 (Ar-CH), 127.2 (Ar-
CH), 125.2 (Ar-CH), 120.1 (Ar-CH), 80.4 (C(CH )), 80.3 (C(CH )), 67.4
(
2
(
t, J=7.7 Hz, 4H, Ar-CH), 5.70 (d, J=8.7 Hz, 1H, NH), 5.42-5.36 (m,
H, H-3, H-2), 5.11 (t, J=9.7 Hz, 1H, H-4), 4.84 (s, 1H, H-1), 4.68-4.64
m, 1H, Ser αCH), 4.53-4.39 (m, 4H, Fmoc CHCH , Ser βCH ), 4.28-
3
3
(
5
Fmoc CHCH ), 67.3 (Fmoc CHCH ), 62.0 (Phe αCH), 61.8 (Phe αCH),
7.8 (Val αCH), 56.4 (Val αCH), 52.6 (OCH ), 52.5 (OCH ), 52.4 (OCH ),
3 3 3
2
2
2
2
4
7.2 (Fmoc CHCH ), 47.2 (Fmoc CHCH ), 41.5 (Gly αCH ) 41.3 (Gly
4
.25 (m, 3H, Fmoc CHCH , OCH CO), 3.97-3.90 (m, 1H, H-5), 3.81 (s,
2
2
2
2
2
αCH ), 38.4 (Phe βCH ), 38.3 (Phe βCH ), 37.3 (Val βCH), 36.6 (βCH),
3
H, OCH ), 2.92 (t, J=7.2 Hz, 2H, CH S), 2.38 (t, J=7.2 Hz, 2H,
2
2
2
3
2
3
2.6 (γCH ), 31.9 (γCH ), 28.4 (C(CH )), 28.4 (C(CH )), 16.0 (CH ), 14.4
COCH CH CH CH S), 2.17 (s, 3H, COCH ), 2.08 (s, 3H, COCH ), 2.02 (s,
2 2 3 3 3
2
2
2
2
3
3
(
(
CH ) ppm. *Isolated as a mixture of diastereoisomers at rt. HRMS
3
+
3
6
1
1
7
6
H, COCH ), 1.75-1.61 (m, 4H, COCH CH CH CH S), 1.23 (d, J=
3
2
2
2
2
13
m/z ESI+): Calculated for C H N O S [M+H] , Calcd 690.2850,
.1 Hz, 3H, H-6) ppm. C NMR (100 MHz, CDCl ) δ 198.3 (SC=O),
37 44
3
8
3
À 1
found 690.2844. νmax (film)/cm : 3323 (NÀ H), 2963 (CÀ H), 1731
72.8 (C=O), 170.1 (C=O), 155.9 (C=O), 143.8 (Ar-qC), 141.4 (Ar-qC),
27.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH), 97.9 (C-1),
1.7 (OCH CO), 70.9 (C-4), 69.5 (C-2), 68.9 (C-3), 67.4 (Fmoc CHCH ),
(C=O), 1690 (C=O).
2
2
Methyl ((S)-4-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl)thio)-
7.1 (C-5), 64.1 (Ser βCH ), 53.5 (Ser αCH), 53.1 (OCH ), 47.2 (Fmoc
2
3
2
-((tert-butoxycarbonyl)amino)-3-methylbutanoyl)glycinate (47):
CHCH ), 33.4 (COCH CH CH CH S), 28.9 (COCH CH CH CH S), 27.5
1
2
2
2
2
2
2
2
2
2
R (50% EtOAc/Hex): 0.37. H NMR (600 MHz, CDCl ) δ 7.76 (d, J=
f
3
(
(
[
(
CH S), 23.9 (COCH CH CH CH S) 21.0 (COCH ), 20.9 (COCH ), 20.8
COCH ), 17.5 (C-6) ppm. HRMS (m/z) calculated for C H NNaO S
M+Na] , calcd. 810.2397, found 810.2402. ν
NH), 1741 (C=O).
2 2 2 2 2 3 3
7
.5 Hz, 4H, Ar-CH), 7.72–7.59 (m, 4H, Ar-CH), 7.45-7.37 (m, 4H, Ar-
CH), 7.36–7.28 (m, 4H, Ar-CH), 6.85-6.63 (m, 2H, NH), 5.37-5.15 (m,
H, NH), 4.55–4.30 (m, 6H, Fmoc CHCH , Fmoc Val αCH and Boc Val
3
38 45
15
+
À 1
(film)/cm : 3365
max
4
2
αCH), 4.32-4.19 (m, 3H, Fmoc CHCH , Fmoc Val αCH), 4.14-3.93 (m,
2
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4157
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
5
1
2
H, Gly αCH , Boc Val αCH), 3.74-3.65 (m, 6H, OCH ), 3.20 (dd, J=
J=7.4 Hz, 2H, Ar-CH), 6.89 (bs, 1H, NH), 5.52 (t, J=5.5 Hz, 1H, NH),
5.28 (d, J=7.9 Hz, 1H, NH), 4.49 (d, J=7.0 Hz, 2H, Fmoc CHCH2),
2
3
3.8, 5.4 Hz, 1H, Boc Val γCH ), 2.91 (d, J=6.7 Hz, 2H, Boc Val γCH ),
2
2
.77 (dd, J=13.8, 7.6 Hz, 1H, Boc Val γCH ), 2.40–2.08 (m, 1H, Boc
4.29 (m, 3H, Fmoc CHCH , Val αCH, αCH), 4.17 4.08 (d, J=5.5 Hz,
2
2
Val βCH, Fmoc Val βCH), 1.43 (s, 18H, C(CH ) ), 1.03-0.95 (m, 12H,
2H, Gly αCH ), 3.77 (s, 3H, OCH ), 3.13 (dt, J=14.0, 7.1 Hz, 1H,
3
3
2
3
Boc Val γCH , Fmoc Val γCH ), 0.90 (dd, J=13.3, 6.8 Hz, 6H, Fmoc
SCH CH ), 2.97 (dt, J=14.0, 7.1 Hz, 1H, SCH CH ), 2.31–2.29 (m, 1H,
Val βCH) 2.18 (dt, J=21.1, 7.1. Hz, 1H, SCH CH ), 1.96 (dt, J=21.1,
2 2
3
3
2
2
2
2
13
Val γCH ) ppm. C NMR (150 MHz, CDCl ) δ 201.0 (SC=O), 200.8
3
3
(
(
(
1
(
SC=O), 171.5 (C=O), 171.0 (C=O), 170.0 (C=O), 169.9 (C=O), 156.6
C=O), 156.3 (C=O), 156.0 (C=O), 155.7 (C=O), 144.1 (Ar-qC), 143.8
Ar-qC), 143.7 (Ar-qC), 141.5 (Ar-qC), 127.9 (Ar-CH), 127.3 (Ar-CH),
7.1 Hz, 1H, SCH CH ), 1.49 (s, 9H, C(CH ) ), 1.01-0.88 (m, 6H, Val CH ,
2 2 3 3 3
13
Val CH ) ppm. C NMR (150 MHz, CDCl ) δ 197.9 (SC=O), 171.4
3
3
(C=O), 169.8 (C=O), 156.1 (C=O), 155.6 (C=O), 143.5 (Ar-qC), 141.2
(Ar-qC), 127.6 (Ar-CH), 126.9 (Ar-CH), 124.9 (Ar-CH), 119.8.0 (Ar-CH),
80.3 (C(CH )), 67.2 (Fmoc CHCH ), 58.8 (Val αCH), 53.0 (αCH), 52.2
25.2 (Ar-CH), 120.1 (Ar-CH), 80.3 (C(CH )), 67.4 (Fmoc CHCH ), 67.3
3
2
Fmoc CHCH ), 66.4 (Fmoc Val αCH), 66.1 (Fmoc Val αCH), 57.9 (Val
2
3
2
αCH), 56.4 (Val αCH), 52.5 (OCH ), 52.3 (OCH ), 47.4 (Fmoc CHCH ),
(OCH )„ 46.9 (Fmoc CHCH ), 41.0 (Gly αCH ), 32.4 (SCH CH ), 30.9
3
3
2
3 2 2 2 2
4
1.3 (Gly αCH ), 37.3 (Boc Val βCH), 36.6 (Boc Val βCH), 32.5 (Boc Val
(Val βCH), 28.1 (C(CH )), 24.7 (SCH CH ), 19.3 (Val CH ) 16.8 (Val CH )
3 2 2 3 3
+
2
γCH ), 31.8 (Boc Val γCH ), 31.2 (Fmoc Val βCH), 31.0 (Fmoc Val
ppm. HRMS (m/z ESI+): Calculated for C H N O SNa [M+Na] ,
2
2
32 41
3
8
À 1
βCH), 28.4 (C(CH )), 19.6 (CH ), 17.4 (CH ), 17.1 (CH ), 16.0 (CH ), 15.6
Calcd. 650.2507, Found. 650.2506. νmax (film)/cm : 3318 (NÀ H),
3
3
3
3
3
(
CH ), 14.5 (CH ), 14.3 (CH ) ppm. *Isolated as a mixture of
2911 (CÀ H), 1752 (C=O), 1676 (C=O).
3 3 3
diastereoisomers at rt. HRMS (m/z ESI+): Calculated for C H N O S
3
3
44
À 1
3
8
+
Methyl
((S)-5-((N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-
[
(
M+H] , Calcd 642.2844, found 642.2847. ν
(film)/cm : 3323
max
butyl)-L-seryl)thio)-2-((tert-butoxycarbonyl)amino)pentanoyl)
NÀ H), 2927 (CÀ H), 1670 (C=O)
1
glycinate (51): R (50% EtOAc/Hex): 0.17. H NMR (600 MHz, CDCl )
f
3
Methyl S-(N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(tert-butyl)-L-
δ 7.77 (d, J=7.6 Hz, 2H, Ar-CH), 7.65 (d, J=7.7 Hz, 1H, Ar-CH), 7.63
(d, J=7.5 Hz, 1H, Ar-CH), 7.40 (t, J=7.6 Hz, 2H, Ar-CH), 7.32 (t, J=
7.4 Hz, 2H, Ar-CH), 6.74 (bs, 1H, NH), 5.74 (d, J=8.8 Hz, 1H, NH), 5.15
seryl)-N-(tert-butoxycarbonyl)-L-homocysteinyl glycinate (48): R
f
1
(
50% EtOAc/Hex): 0.35. H NMR (400 MHz, CDCl ) δ 7.76 (d, J=
3
7
7
5
3
.5 Hz, 2H, Ar-CH), 7.64 (dd, J=10.8, 7.6 Hz, 2H,Ar-CH), 7.39 (t, J=
.4 Hz, 2H, Ar-CH), 7.31 (t, J=7.4 Hz, 2H, Ar-CH), 6.81 (bs, 1H, NH),
.75 (d, J=8.7 Hz, 1H, NH), 5.20 (d, J=7.6 Hz, 1H, NH), 4.57–4.43 (m,
(d, J=7.5, 1H, NH), 4.54-4.46 (m, 2H, Ser αCH, Fmoc CHCH ), 4.38-
2
4.34 (m, 1H, Fmoc CHCH ), 4.28 (t, J=7.3 Hz, 1H, Fmoc CHCH ), 4.22
2
2
(bs, 1H, αCH), 4.00-3.98 (m, 2H, Gly αCH ), 3.89 (dd, J=2.3, 9.1 Hz,
2
H, Ser αCH, Fmoc CHCH ), 4.36 (t, J=7.1 Hz, 1H, αCH), 4.30-4.11
1H, Ser βCH ), 3.70 (s, 3H, OCH ), 3.56 (dd, J=3.4, 9.1 Hz, 1H, Ser
2
2
3
(m, 3H, Fmoc CHCH , Gly αCH ), 4.01 (d, J=5.3 Hz, 2H, Gly αCH ),
βCH2), 3.02-2.96 (m, 1H, SCH CH CH ), 2.93-2.86 (m, 1H,
2
2
2
2 2 2
3
.87 (dd, J=9.1, 3.1 Hz, 1H, Ser βCH ), 3.70 (s, 3H, OCH ), 3.55 (dd,
SCH CH CH ), 1.92–1.84 (m, 1H, SCH CH CH ), 1.76-1.60 (m, 3H,
2 2 2 2 2 2
2
3
J=9.1, 3.1 Hz, 1H, Ser βCH ), 3.05–2.99 (m, 1H, SCH CH ), 2.91–2.85
SCH CH CH , SCH CH CH ), 1.43 (s, 9H, Boc C(CH ) ), 1.14 (s, 9H, Ser
2 2 2 2 2 2 3 3
13
2
2
2
(m, 1H, SCH CH ), 2.13-2.05 (m, 1H, SCH CH ), 1.88 (dt, J=14.3,
C(CH ) ) ppm. C NMR (150 MHz, CDCl ) δ 200.5 (SC=O), 172.3
3 3 3
2
2
2
2
7
.7 Hz, 1H, SCH CH ), 1.43 (s, 9H, C(CH )), 1.15 (s, 9H, OC(CH )) ppm.*
(C=O), 170.1 (C=O), 156.2 (C=O), 155.8 (C=O), 144.0 (Ar-qC), 141.4
(Ar-qC), 127.9 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH),
80.2 (Boc C(CH ) ), 73.8 (Ser C(CH ) ), 67.4 (Fmoc CHCH ), 61.9 (Ser-
2
2
3
3
1
3C NMR (150 MHz, CDCl ) δ 200.7 (SC=O), 171.8 (C=O), 170.0
3
(
C=O), 156.3 (C=O), 155.8 (C=O) 143.8 (Ar-qC), 141.5 (Ar-qC), 127.9
3
3
3 3
2
(
8
6
(
(
Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH), 80.7 (C(CH ) ),
βCH ), 61.2 (Ser-αCH), 53.7 (αCH), 52.4 (OCH ), 47.3 (Fmoc CHCH ),
41.3 (Gly αCH ), 31.6 (CH ), 28.4 (Boc C(CH )), 28.3 (CH ), 27.4 (Ser
2 2 3 2
3
3
2
3
2
0.5 (C(CH ) ), 73.9 (Ser αCH), 70.4 (Ser αCH), 67.5 (Fmoc CHCH ),
3
3
2
1.9 (Ser βCH ), 61.4 (αCH), 52.5 (OCH ), 47.3 (Fmoc CHCH ), 41.3
C(CH ) ), 25.6 (CH ) ppm. HRMS (m/z ESI+): Calculated for
3 3 2
+
2
3
2
Gly αCH ), 34.3 (SCH CH ), 32.0 (SCH CH ), 28.4 (C(CH ) ), 27.4
C H N O S [M+H] , Calcd. 686.3106, found 686.3104. ν (film)/
2
2
2
2
2
3 3
35 48
3
9
max
À 1
C(CH ) ), 25.5 (SCH CH ) ppm.* *Multiple signals due to mixture of
cm : 3330 (NÀ H), 2974 (CÀ H), 1676 (C=O), 1243 (CÀ O).
3
3
2
2
rotamers at rt. HRMS (m/z APCI+): Calculated for C H N O S [M+
34
46
3
9
+
À 1
Methyl
((S)-5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenyla-
H] , Calcd. 672.2949, Found. 672.2949. ν (film)/cm : 3323 (NÀ H),
max
lanyl)thio)-2-((tert-butoxycarbonyl)amino)pentanoyl)glycinate
2
949 (CÀ H), 1728 (C=O), 1676 (C=O)
1
(
52): R (50% EtOAc/Hex): 0.25, H NMR (400 MHz, CDCl ) δ 7.75 (d,
f 3
Methyl S-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalanyl)-
J=7.6 Hz, 2H, Ar-CH), 7.55 (d, J=7.4 Hz, 1H, Ar-CH), 7.52 (d, J=
7.3 Hz, 1H, Ar-CH), 7.40 (t, J=7.4 Hz, 2H, Ar-CH), 7.32-7.24 (m, 5H,
Ar-CH), 7.15 (d, J=7.5 Hz, 2H, Ar-CH), 6.66 (bs, 1H, NH), 5.37 (d, J=
8.2 Hz, 1H, NH), 5.08 (bs, 1H, NH), 4.71 (dd, J=7.5, 14.0 Hz, 1H, Phe
N-(tert-butoxycarbonyl)-L-homocysteinylglycinate (49): R (50%
f
1
EtOAc/Hex): 0.4. H NMR (400 MHz, CDCl ) δ 7.75 (d, J=7.5 Hz, 2H,
3
Ar-CH), 7.53 (dd, J=14.1, 7.5 Hz, 2H, Ar-CH), 7.39 (t, J=7.5 Hz, 2H,
Ar-CH), 7.33–7.23 (m, 5H, Ar-CH), 7.16 (d, J=7.0 Hz, 2H, Ar-CH), 6.90
αCH), 4.43-4.35 (m, 2H, Fmoc CHCH ), 4.26 (bs, 1H, αCH), 4.19 (t, J=
2
(
bs, 1H, NH), 5.40-5.28 (m, 1H, NH), 4.68 (dd, J=13.5, 8.0 Hz, 1H, Phe
7.5 Hz, 1H, Fmoc CHCH ), 4.06 (dd, J=5.6, 18.5 Hz, 1H, Gly αCH ),
2
2
αCH), 4.38 (d, J=7.0 Hz, 2H, Fmoc CHCH ), 4.20 (m, 2H, αCH, Fmoc
3.97 (dd, J=5.0, 18.3 Hz, 1H, Gly αCH ), 3.69 (s, 3H, OCH ), 3.17 (dd,
2
2
3
CHCH ), 4.02 (d, J=5.2 Hz, 2H, Gly αCH ), 3.71 (s, 3H, OCH ), 3.19
J=5.6, 14.3 Hz, 1H, Phe- βCH ), 3.09-2.99 (m, 2H, Phe- βCH ,
2 2
2
2
3
(
dd, J=14.1, 5.2 Hz, 1H, Phe βCH ), 3.08–2.98 (m, 2H, Phe βCH ,
SCH CH CH ), 2.90-2.85 (m, 1H, SCH CH CH ), 1.89-1.80 (m, 1H,
2
2
2 2 2 2 2 2
SCH CH ), 2.96–2.87 (m, 1H, SCH CH ), 2.16–2.05 (m, 1H, SCH CH ),
SCH CH CH ), 1.77-1.68 (m, 1H, SCH CH CH ), 1.67-1.57 (m, 2H,
2 2 2 2 2 2
13
2
2
2
2
2
2
1
3
1
.94–1.83 (m, 1H, SCH CH ), 1.45 (s, 9H, C(CH ) ) ppm. C NMR
SCH CH CH ), 1.45 (s, 9H, C(CH ) ) ppm. C NMR (150 MHz, CDCl ) δ
2 2 2 3 3 3
2
2
3 3
(
(
(
150 MHz, CDCl ) δ 200.7 (SC=O), 171.8 (C=O), 170.1 (C=O), 155.9
C=O) 154.8 (C=O), 143.7 (Ar-qC), 141.4 (Ar-qC), 135.6 (Ar-qC), 129.4
Ar-CH), 128.9 (Ar-CH), 127.8 (Ar-CH), 127.4 (Ar-CH), 127.2 (Ar-CH),
200.9 (SC=O), 172.2 (C=O), 170.3 (C=O), 155.8 (C=O, C=O), 143.9
(Ar-qC), 141.4 (Ar-qC), 135.7 (Ar-qC), 129.5 (Ar-CH), 128.9 (Ar-CH),
127.9 (Ar-CH), 127.4 (Ar-CH), 127.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-
CH), 80.3 (C(CH )), 67.3 (Fmoc CHCH ), 61.6 (Phe-αCH), 53.5 (αCH),
3
1
25.2 (Ar-CH), 120.1 (Ar-CH), 80.6 (C(CH ) ), 67.3 (Fmoc CHCH ), 61.8
3
3
2
3
2
(
Phe αCH), 53.4 (αCH), 52.5 (OCH ), 47.2 (Fmoc CHCH ), 41.3 (Gly
52.5 (OCH ), 47.3 (Fmoc CHCH ), 41.3 (Gly αCH ), 38.4 (Phe-βCH ),
3
2
3 2 2 2
αCH2), 38.3 (Phe βCH2), 32.6 (SCH CH ), 28.4 (C(CH3)3), 25.3
31.6 (CH ), 28.5 (C(CH ) ), 28.2 (CH ), 25.6 (CH ) ppm. HRMS (m/z ESI
2 3 3 2 2
+
2
2
(SCH CH ) ppm. HRMS (m/z ESI+): Calculated for C H N O SNa [M
+): Calculated for C H N O S [M+H] , Calcd 690.2844, found
2
2
36 41
3
8
37 44
3
8
+
À 1
À 1
+
Na] , Calcd. 698.2507, Found. 698.2507. ν
(film)/cm : 2922
690.2840. νmax (film)/cm : 3325 (NÀ H), 2967 (CÀ H), 1732 (C=O),
1681 (C=O).
max
(CÀ H), 1766 (C=O), 1636 (C=O)
Methyl
S-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl)-N-(tert-
Methyl ((S)-5-(((((9H-fluoren-9-yl)methoxy)carbonyl)-L-valyl)thio)-
butoxycarbonyl)-L-homocysteinylglycinate (50): R (50% EtOAc/
Hex): 0.4. H NMR (400 MHz, CDCl ) δ 7.81 (d, J=7.4 Hz, 2H, Ar-CH),
2-((tert-butoxycarbonyl)amino)pentanoyl)glycinate (53): R (50%
f
f
1
1
EtOAc/Hex): 0.27. H NMR (600 MHz, CDCl ) δ 7.75 (d, J=7.6 Hz, 2H,
3
3
7.66 (d, J=7.4 Hz, 2H, Ar-CH), 7.45 (t, J=7.4 Hz, 2H, Ar-CH), 7.36 (t,
Ar-CH), 7.60 (t, J=8.0 Hz, 2H, Ar-CH), 7.39 (t, J=7.6 Hz, 2H, Ar-CH),
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4158
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
7
5
9
.30 (t, J=7.6 Hz, 2H, Ar-CH), 6.84 (bs, 1H, NH), 5.51 (bs, 1H, NH),
N-((2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymeth-
yl)tetrahydro-2H-pyran-2-yl)isobutyramide (73): δH (600 MHz,
DMSO): 4.77 (t, J=9.4 Hz, 1H, H-1), 3.66 (dd, J=11.8, 1.9 Hz, 1H, H-
6), 3.54 (td, J=9.8, 8.7 Hz, 1H, H-2), 3.42 (dd, J=11.8, 5.3 Hz, 1H, H-
6’), 3.33–3.27 (m, 1H, H-3), 3.12–3.01 (m, 2H, H-4, H-5), 2.33 (m, 1H,
CH), 1.77 (s, 3H, CH ), 0.95 (dd, J=6.9, 3.2 Hz, 6H, 2×CH ) ppm. δ
.21 (bs, 1H, NH), 4.47-4.40 (m, 2H, Fmoc CHCH ), 4.33 (dd, J=5.0,
2
.3 Hz, 1H, Val αCH), 4.29 (bs, 1H, αCH), 4.23 (t, J=6.8 Hz, 1H, Fmoc
CHCH ), 4.22 (bs, 1H, αCH ), 4.04 (dd, J=4.9, 18.1 Hz, 1H, Gly αCH ),
2
2
2
3
.96 (dd, J=4.7, 18.3 Hz, 1H, Gly αCH ), 3.69 (s, 3H, OCH ), 3.02 (bs,
2
3
1H, SCH CH CH ), 2.91–2.83 (m, 1H, SCH CH CH ), 2.31-2.21 (m, 1H,
2
2
2
2
2
2
3
3
C
Val βCH), 1.89-1.81 (m, 1H, SCH CH CH ), 1.76–1.67 (m, 1H,
(151 MHz, DMSO): 174.4 (C=O), 171.9 (C=O), 79.1 (C-1), 78.8 (C-5),
74.4 (C-3), 70.6 (C-4), 60.9 (C-6), 54.6 (C-2), 33.8 (CH), 22.8 (CH3),
19.7, 18.5 (CHCH ) ppm. HRMS: C H N O requires 289.1400. ESI:
Found 289.1396 [MÀ H] νmax (film)/cm : 3301 (NH), 2982 (OH),
1666 (C=O).
2
2
2
SCH CH CH ), 1.67-1.58 (m, 2H, SCH CH CH ), 1.43 (s, 9H, C(CH ) ),
2
2
2
2
2
2
3 3
0
.98 (d, J=6.6 Hz, 3H, Val CH ), 0.88 (d, J=6.7 Hz, 3H, Val CH ) ppm.
3
3
3
12 21
2
6
1
3
À
À 1
C NMR (150 MHz, CDCl ) δ 201.0 (SC=O), 172.3 (C=O), 170.2 (C=O),
3
156.4 (C=O), 155.8 (C=O), 144.0 (Ar-qC), 141.4 (Ar-qC), 127.8 (Ar-CH),
1
27.2 (Ar-CH), 125.2 (Ar-CH), 120.1 (Ar-CH), 80.2 (C(CH )), 67.2 (Fmoc
3
N,N’-((2R,3R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)
CHCH ), 66.0 (Val-αCH), 53.4 (αCH), 52.4 (OCH ), 47.3 (Fmoc CHCH ),
4
2
2
3
2
tetrahydro-2H-pyran-2,3-diyl)diacetamide (74): R : 0.24 (CH Cl :
f
2
2
1.2 (Gly αCH ), 31.7 (CH ), 31.1 (Val-βCH, 28.4 (C(CH ) ), 28.1 (CH ),
2
2
3
3
2
MeOH 90:10). δ (600 MHz, DMSO): 4.79 (t, J=9.4 Hz, 1H, H-1), 3.64
H
5.6 (CH ), 19.5 (ValCH , Val CH ) ppm. HRMS (m/z ESI+): Calculated
2
3
3
+
(dd, J=11.9, 1.8 Hz, 1H, H-6), 3.51 (m, 1H, H-2), 3.41 (dd, J=11.8,
5.0 Hz, 1H, H-6’), 3.32–3.27 (m, 1H, H-3), 3.09–3.03 (m, 2H, H-4. H-5),
for C H N O S [M+H] , Calcd. 642.2844, found 642.2855. ν
33
44
À 1
3
8
max
(film)/cm : 3313 (NÀ H), 2964 (CÀ H), 1736 (C=O), 1685 (C=O).
1
.79 (s, 3H, CH ), 1.78 (s, 3H, CH ) ppm. δ (151 MHz, DMSO): 169.8
3 3 C
(
(
C=O), 169.6 (C=O), 78.8 (C-1), 78.7 (C-5), 74.6 (C-3), 70.5 (C-4), 60.9
C-6), 54.5 (C-2), 22.9 (CH ), 22.8 (CH ) ppm. HRMS: C H N O
3
3
10 17
2
6
Characterisation Data for anomeric amides 70–74synthesized
via one pot acyl thiol-ene, S-to-N Acyl Transfer and auxiliary
cleavage:
À
À 1
requires 261.1087. ESI: Found 261.1091 [M - H] νmax (film)/cm :
269 (NH), 2924 (OH), 1646 (C=O), 1314 (CH).
3
(
9H-fluoren-9-yl)methyl (2-(((2R,3R,4R,5S,6R)-3-acetamido-4,5-di-
hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)-2-
oxoethyl)carbamate (70): Rf: 0.34 (CH Cl :MEOH 90:10). δH Acknowledgements
2
2
(600 MHz, MeOD): 7.82 (d, J=7.5 Hz, 2H, Ar-CH), 7.71 (dd, J=11.2,
7
.5 Hz, 2H, Ar-CH), 7.41 (t, J=7.5 Hz, 2H, Ar-CH), 7.34 (t, J=7.5 Hz,
H, Ar-CH), 4.97 (d, J=9.7 Hz, 1H, H-1), 4.45–4.36 (m, 2H, Fmoc-
This work was supported by Science Foundation Ireland (SFI)
under Grant No. 15/CDA/3310 (E.M.S.) and Grant No. 19/FFP/6667
2
CH ), 4.28 (t, J=7.0 Hz, 1H, Fmoc-CH), 3.89–3.66 (m, 4H, H-2, H-6, H-
2
(E.M.S.).
6
’, α-CH ), 3.53–3.46 (m, 1H, H-3), 3.43–3.34 (m, 2H, H-4, H-5), 2.01
2
(
(
(
(
3
4
3
d, J=10.3 Hz, 3H, NHC=OCH ) ppm. δC (151 MHz, MeOD): 174.7
3
C=O), 173.1 (C=O), 159.1 (Gly-NHC=O), 145.4 (qC), 145.2 (qC), 142.6
qC), 142.6 (qC), 128.8 (Ar-CH), 128.8 (Ar-CH), 128.2 (Ar-CH), 126.3
Ar-CH), 126.2 (Ar-CH), 120.9 (Ar-CH), 80.8 (C-1), 79.7 (C-5), 76.0 (C-
Conflict of Interest
), 71.9 (C-4), 68.3 (Fmoc-CH ), 62.6 (C-6), 55.9 (C-2), 47.9 (Fmoc-CH),
2
The authors declare no conflict of interest.
5.0 (α-CH ), 22.8 (NHC=OCH ) ppm. HRMS: C H NNaO requires
2
3
14 17
5
+
À 1
02.1004. ESI: Found 302.1009 [M+Na] . ν
(film)/cm : 3600
max
(
OH), 1867 (C=O), 1300 (CH).
Keywords: Amides · Click Chemistry · Hydrothiolation · Radical
Reactions · Thiol-ene
N-((2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymeth-
yl)tetrahydro-2H-pyran-2-yl)-3-(p–tolyl)propanamide (71): R : 0.32
f
(
1
CH Cl :MeOH 90:10). δ (600 MHz, DMSO): 8.07 (dd, J=9.2, 1.9 Hz,
H, NH), 7.79 (d, J=8.9 Hz, 1H, NH), 7.06 (s, 4H, Ar-CH), 4.81 (m, 1H,
2 2 H
H-1), 3.65 (dd, J=11.8, 1.9 Hz, 1H, H-6), 3.53 (m, 1H, H-2), 3.42 (dd,
J=11.8, 5.3 Hz, 1H, H-6), 3.30 (m, H-3), 3.12–2.99 (m, 2H, H-4, H-5),
[
[
1] B. H. Northrop, R. N. Coffey, J. Am. Chem. Soc. 2012, 134, 13804–13817.
2] C. E. Hoyle, C. N. Bowman, Angew. Chem. Int. Ed. 2010, 49, 1540–1573;
Angew. Chem. 2010, 122, 1584–1617.
2
.71 (m, 2H, CH ), 2.33 (m, 2H, CH ), 2.24 (s, 3H, CH ), 1.75 (s, 3H,
2
2
3
CH ) ppm. δ (151 MHz, DMSO): 171.7 (C=O), 169.8 (C=O), 138.1
3
C
[3] F. Dénès, M. Pichowicz, G. Povie, P. Renaud, Chem. Rev. 2014, 114,
(qC), 134.7 (qC), 128.8 (Ar-CH), 128.0 (Ar-CH), 78.9 (C-1), 78.7 (C-5),
2587–2693.
7
2
4.5 (C-3), 70.5 (C-4), 60.9 (C-6), 54.6 (C-2), 37.1 (CH ), 30.3 (CH ),
[4] Z. Dekan, I. Vetter, N. L. Daly, D. J. Craik, R. J. Lewis, P. F. Alewood, J. Am.
2
2
2.8 (CH ), 20.6 (CH ) ppm. HRMS: C H NNa O requires 389.1689.
Chem. Soc. 2011, 133, 15866–15869.
5] A. Plechanovova, E. G. Jaffray, S. A. McMahon, K. A. Johnson, I.
3
3
18 26
2
6
+
À 1
[
ESI: Found 389.1708 [M+Na] νmax (film)/cm : 3301 (NH), 2981
Navratilova, J. H. Naismith, R. T. May, Nat. Struct. Mol. Biol. 2011, 18,
(OH), 2981 (CH), 1655 (C=O).
1
052–1059.
[6] C. J. Noren, J. M. Wang, F. B. Perler, Angew. Chem. Int. Ed. 2000, 39, 450–
66; Angew. Chem. 2000, 112, 458–476.
N-((2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymeth-
yl)tetrahydro-2H-pyran-2-yl)butyramide (72): R : 0.3 (CH Cl :MeOH
9
4
f
2
2
[
7] A. P. A. Hendrickx, J. M. Budzik, S. Y. Oh, O. Schneewind, Nat. Rev.
1:9). δ (400 MHz, CH OD): 4.97 (d, J=9.7 Hz, 1H, H-1), 3.90–3.82
H
3
Microbiol. 2011, 9, 166–176.
8] T. Fukuyama, S. C. Lin, L. Li, J. Am. Chem. Soc. 1990, 112, 7050–7051.
9] T. Mukaiyama, M. Araki, H. Takei, J. Am. Chem. Soc. 1973, 95, 4763–4765.
(
m, 1H, H-6), 3.77 (t, J=10.0 Hz, 1H, H-2), 3.73–3.65 (m, 1H, H-6’),
.52–3.41 (m, 1H, H-3), 3.36-3.33 (m, 2H, H-4, H-5) 2.27–2.13 (m, 2H,
C=OCH ), 1.67–1.53 (m, 2H, CH ), 1.32 (m, 6H, 3×CH ), 1.00–0.89 (m,
[
[
3
2
2
2
[10] M. Kazemi, L. Shiri, J. Sulfur Chem. 2015, 36, 613–623.
[11] R. McCourt, F. Dénès, G. Sánchez, E. M. Scanlan, Org. Lett. 2018, 20,
2948–2951.
12] R. McCourt, E. M. Scanlan, Org. Lett. 2019, 21, 3460–3464.
13] N. Narendra, M. Vishwanatha, B. Thimmalapura, B. Hosamani, G. Prabhu,
L. Roopesh Kumarb, V. V. Sureshbabu, Org. Biomol. Chem. 2018, 16,
3
H, CH ) ppm. δ (101 MHz, CH OD): 176.8 (C=O), 174.3 (C=O), 80.4
3 C 3
(C-1), 79.8 (C-5), 76.3 (C-3), 71.8 (C-4), 62.7 (C-6), 56.1 (C-2),
[
[
3
7.3(C=OCH ), 32.7 (CH ), 29.9 (CH ), 26.7 (CH ), 23.6 (CH ), 22.8
2
2
2
2
2
(
CH CH , NHAc CH ), 14.4 (CH CH ) ppm. HRMS: C H N NaO
2 3 3 2 3 15 28 2 6
+
À 1
requires 355.1845. ESI: Found 355.1841 [M+Na] .νmax (film)/cm :
309 (NH), 2949 (OH), 1654 (C=O).
3524–3552
3
[
[
14] D. Crich, I. Sharma, Angew. Chem. Int. Ed. 2009, 48, 2355–2358; Angew.
Chem. 2009, 121, 2391–2394.
15] A. Afzaliardakani, H. Rapoport, J. Org. Chem. 1980, 45, 4817–4820.
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4159
© 2021 Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100615
[
[
[
16] Y. Yonezawa, K. Shimizu, K. S. Yoon, C. G. Shin, Synthesis 2000, 5, 634–
[22] Q. Wan, S. J. Danishefsky, Angew. Chem. Int. Ed. 2007, 46, 9248–9252;
6
36.
Angew. Chem. 2007, 119, 9408–9412.
17] T. Shimidzu, R. Miyajima, N. Naruse, K. Yamaoka, K. Aihara, A. Shigenaga,
[23] H. M. Burke, L. McSweeney, E. M. Scanlan, Nat. Commun. 2017, 8, 15655.
[24] a) A. Brik, Y. Y. Yang, S. Ficht, C. H. Wong, J. Am. Chem. Soc. 2006, 128,
5626–5627 b) Y. Y. Yang, S. Ficht, A. Brik, C. H. Wong, J. Am. Chem. Soc.
2007, 129, 7690–7701.
A. Otaka, Chem. Pharm. Bull. 2016, 64, 375–378.
18] M. Wiktor, D. Weichert, N. Howe, C. Y. Huang, V. Olieric, C. Boland, J.
Bailey, L. Vogeley, P. J. Stansfeld, N. Buddelmeiser, M. Wang, M. Caffrey,
Nat. Commun. 2017, 8, 15952.
[
19] M. L. Coote, C. Y. Lin, H. Zipse, in The Stability of Carbon-Centered
Radicals, ed. M. D. E. Forbes, John Wiley and Sons, inc., Hoboken, New
Jersey, 2009, Ch. 5, 83–104.
[
[
20] M. L. Coote, Macromolecules 2004, 37, 5023–5031.
21] a) S. S. Panda, C. D. Hall, A. A. Oliferenko, A. R. Katritzky, Acc. Chem. Res.
Manuscript received: May 20, 2021
Revised manuscript received: July 14, 2021
Accepted manuscript online: July 26, 2021
2014, 47, 1076–1087. b) J. C. M. Monbaliu, G. Dive, C. V. Stevens, A. R.
Katritzky, J. Chem. Theory Comput. 2013, 9, 927–934.
Eur. J. Org. Chem. 2021, 4148–4160
www.eurjoc.org
4160
© 2021 Wiley-VCH GmbH