doubly Customizable Unit for the Generation of Structural Diversity: From Pure Enantiomeric Amines to Peptide Derivatives

Article abstract of DOI:10.1021/acs.joc.0c02751

Readily available, low-cost 4R-hydroxy-l-proline (Hyp) is introduced as a doubly customizable unit for the generation of libraries of structurally diverse compounds. Hyp can be cleaved at two points, followed by the introduction of new functionalities. In the first cycle, the removal and replacement of the carboxylic group are carried out, followed (second cycle) by the scission of the 4,5-position and manipulation of the resulting chains. In this way, three new chains are generated and can be transformed independently to afford a diversity of products with tailored substituents, such as β-amino aldehydes, diamines, β-amino acid derivatives, including N-alkylated ones, or modified peptides. Many of these products are high-profit compounds but, in spite of their commercial value, are still scarce. Moreover, the process takes place with stereochemical control, and either pure R or S isomers can be obtained with small variations of the synthetic route.

Full text of DOI:10.1021/acs.joc.0c02751

pubs.acs.org/joc
Article
“Doubly Customizable” Unit for the Generation of Structural
Diversity: From Pure Enantiomeric Amines to Peptide Derivatives
́
Dacil Hernandez,* Carmen Carro, and Alicia Boto*
Cite This: J. Org. Chem. 2021, 86, 2796−2809
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Readily available, low-cost 4R-hydroxy-L-proline (Hyp) is
introduced as a “doubly customizable” unit for the generation of libraries of
structurally diverse compounds. Hyp can be cleaved at two points, followed
by the introduction of new functionalities. In the first cycle, the removal and
replacement of the carboxylic group are carried out, followed (second cycle)
by the scission of the 4,5-position and manipulation of the resulting chains.
In this way, three new chains are generated and can be transformed
independently to afford a diversity of products with tailored substituents,
such as β-amino aldehydes, diamines, β-amino acid derivatives, including N-
alkylated ones, or modified peptides. Many of these products are high-profit
compounds but, in spite of their commercial value, are still scarce. Moreover, the process takes place with stereochemical control,
and either pure R or S isomers can be obtained with small variations of the synthetic route.
Scheme 1. Introduction of the Doubly Customizable Hyp
Unit
INTRODUCTION
■
“Customizable” amino acid units such as Hyp, Ser/Thr, or Glu
have proven to be valuable for the conversion of readily
available amino acids into a variety of nonproteinogenic
residues or amino acid analogues.1,2 In addition, these units
allow the site-selective modification of peptides and the fast
generation of peptide libraries.3
Customizable units undergo the cleavage of a certain
functional group or C−C bond, followed by the introduction
of novel groups such as acetoxy, amino, thioalkyl, phosphoryl,
alkyl, or aryl, depending on the reaction conditions (Scheme
1).1,2 We had previously introduced 4-hydroxyproline (Hyp)
as a customizable unit, where the C4−C5 bond was cleaved
using a domino radical scission−oxidation process (conversion
1 → 2, Scheme 1), generating an N-acetoxymethyl 4-
oxohomoalanine derivative with new N- and α-chains, which
could be functionalized independently.1,4 Resulting products 3
presented two new tailored chains and high S purity.
In the present paper, we report a Hyp-derived doubly
customizable unit, where two different C−C bonds are cleaved
sequentially, generating three new chains that can be
manipulated separately (conversion 4 → 6, Scheme 1).
Moreover, both the nature and the stereochemistry of the
resulting product can be tailored, by choosing the appropriate
set of reaction conditions, affording an important structural
diversity. Amines, diamines, amino acids, and amino acid
analogues with either R or S configuration can be obtained
from a single, low-cost L-Hyp unit. The application of this
doubly customizable unit to generate branched peptides will
also be highlighted.
Received: November 17, 2020
Published: January 12, 2021
https://dx.doi.org/10.1021/acs.joc.0c02751
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 2796−2809
2796

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
treated in situ with a Lewis acid to generate an iminium ion
(8a or 9a), which was trapped by C-nucleophiles.6,7 In the case
of small nucleophile allyltrimethylsilane (allylTMS), both
substrates were transformed into 2,4-cis products 10 and 11.
The prevalence of the cis product over the less hindered trans
isomer8 is due to a stereoelectronic effect described by
Woerpel for 4-substituted five-membered cyclic iminium
ions.8a,b Thus, when the substituent at C-4 is an oxygenated
function, the iminium intermediate 8a or 9a adopts an envelop
conformation, where axial H-groups hinder the introduction of
nucleophiles from the face opposite to the OP group.
RESULTS AND DISCUSSION
One-pot decarboxylation of the Hyp unit and introduction of a
new chain at C-2 were studied first (Scheme 2). Natural 4R-
■
Scheme 2. Influence of the Protecting Group P in the
Stereochemical Outcome
With bulkier nucleophiles, such as 1-phenyl-2-
(trimethylsilyloxy)ethene, the ratio of 2,4-cis and trans isomers
depended on the size of the protecting group P. Thus, for P =
Bn, cis isomer 12 was obtained as the sole product, but for the
much larger P = TBDPS, a separable cis/trans mixture 13:14
was obtained, in good global yield.
The previous major products (2,4-cis) had a 2S config-
uration for compounds 10 and 11 and a 2R configuration for
products 12 and 13. To obtain the other 2-isomers, a second
approach was followed, where the inversion of the config-
uration at C-4 was carried out readily (conversion 15 → 16,
Scheme 3) by an intramolecular Mitsunobo reaction, followed
Scheme 3. Prevalence of the Other 2-Isomers
by cleavage of the strained ring to afford ester 17.9 The
preparation of benzyl ether 18 and silyl enol ether 19 was
carried out as before,5,10 and then the one-pot radical scission−
oxidation−alkylation was studied. To our satisfaction, the
stereochemistry of the new substrate did not favor side
reactions, and the scission proceeded readily. The nucleophile
allylTMS was added, giving similar results as before. New
products 20/21 are again 2,4-cis (no 2,4-trans compounds
were observed), but the 2R isomers were obtained instead.
With the possibility to obtain either 2R or 2S isomers, the
introduction of different nucleophiles was studied using the
less bulky tert-butyldimethylsilyl (TBS) ether 22 as the
substrate (Scheme 4).10 The sequential radical scission−
oxidation−alkylation was carried out with allylTMS, PhC-
(OTMS)CH2, and the silyl ketene Me2CC(OTMS)OMe
to afford products 23−26. Interestingly, the two first
nucleophiles afforded only the 2,4-cis product, but the ketene
hydroxyproline presents a stereogenic center at C-4, which
could be used after decarboxylation for the stereocontrolled
introduction of new chains on C-2. Two strategies were
studied: in the first one, the role of the protecting group P in
inducing R or S stereochemistry was explored. Readily available
and removable groups were chosen, such as benzyl and silyl
ethers. Thus, commercial hydroxyproline derivative 7 was
transformed into benzyl ether 8 and bulky silyl ether 9 in good
yields.5 These substrates underwent radical decarboxylation−
oxidation by treatment with (diacetoxyiodo)benzene (DIB)
and iodine under irradiation with visible light, generating a 2-
acetoxypyrrolidine (not shown).6 This intermediate was
2797
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 4. Preparation of the Substrates for the Second
Cycle of Transformations
Scheme 6. Second Cycle of Transformations to Give Acyclic
β-Amino Aldehydes
provided separable mixtures of the cis and trans isomers. This
is due to the steric hindrance generated during the approach of
this crowded, tetrasubstituted ketene to the iminium
intermediate. It should be pointed out that β-amino acids,
such as compounds 25 and 26, are valuable reagents for the
preparation of bioactive peptides with superior resistance to
protease degradation11 and also for the development of
foldamers with tunable properties in material science.12 This
method readily affords β-units with the unusual D-stereo-
chemistry (e.g. 25), while the L-isomers could be obtained
from substrate 17.
The deprotection of the different hydroxy derivatives was
carried out under different conditions, as shown in Scheme 5,
providing the substrates for the second scission in good to
excellent yields.
Then, substrates 27, 29, 30, 32, and 33 underwent the
scission reaction to give N-acetoxymethyl derivatives 34−38 in
good yields (Scheme 6).4 These aldehydes (and related ones)
can be readily oxidized using mild conditions13 to afford
different β-amino acids, which are valuable commercial
products.
The transformation of products 10, 12, 20, 21, and 23−26
into acyclic derivatives, by scission of the C4−C5 bond (second
cycle of transformations), was studied next (Schemes 5 and 6).
The aldehyde can also undergo reductive amination4c to give
different chiral diamines, as illustrated with transformations 36
→ 39 and 38 → 41 (Scheme 7). In the case of ketone 39, the
reaction proceeded selectively and the ketone was unaffected
due to the higher reactivity of the aldehyde. As shown in the
scheme, the reductive amination proceeds without affecting the
N,O-acetal. Then, the acetal can be transformed independently
(conversions 39 → 40 and 41 → 42), adding diversity to the
product libraries. It should be pointed out that the addition of
allylTMS to substrate 39 proceeds chemoselectively, and only
the N,O-acetal is transformed, while the ketone remains intact.
The ready introduction of an olefinic chain to the amine in
product 40 is noteworthy since it can be used for ligation to
other molecules.14 Finally, the reduction of the N,O-acetal in
37 to a methyl group provided N-methyl β-amino ester 41.
Although N-alkyl β-amino acids are valuable components of
foldamers, they are commercially scarce; this route could
provide easy access to these compounds.
Scheme 5. Removal of the Protecting Group to Provide
Scission Substrates 27−33
The reductive amination can be useful to generate many
different δ-amino-substituted β-amino esters, with either L- or
D-residues, as shown by conversions 37 → 43 and 38 → 44
(Scheme 8), where a morpholino group found in the
antimicrobial Cobicistat was introduced.15 In addition, the
reductive amination can provide branched peptides16a with β-
amino acid units16b (conversions 37 → 45 and 38 → 46),
2798
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 7. Selective Functionalization of the Carbonylic
Chain and the N,O-Acetal, Expanding Library Diversity
Scheme 8. Preparation of β,δ-Diamino Esters 43/44 and
Branched Dipeptides 45/46
pathogens and phytopathogens.21 These results will be
communicated in due course.
which could be components of functional materials or peptide
drugs.
CONCLUSIONS
Finally, the β-amino aldehydes can also be functionalized
with other reactions, as shown in Scheme 9 for the synthesis of
peptides with a rigid dehydroamino acid unit.17 The Horner−
Wadsworth−Emmons (HWE) reaction of aldehydes 34−36
with peptide-derived phosphonates 47 and 481c afforded
peptides 49−51 in 83−86% yield. The products were obtained
as the Z isomers, as shown in the nuclear Overhauser
enhancement spectroscopy (NOESY) experiments (Support-
ing information). Interestingly, with ketone substrate 36, the
reaction took place chemoselectively, and only the aldehyde
reacted with the phosphonate. In all of the cases, no
epimerizations were observed under the mild reaction
conditions, and the desired products were obtained with
high enantiomeric (or diastereomeric) purity.
Since the amino group from 34 to 36 could be used to
attach another peptide chain, this methodology could allow the
creation of new branched peptides, where turns or other
secondary structure elements could be induced.18 The
introduction of amino acids containing aryl ketones in these
peptides could be particularly interesting since they not only
are components of bioactive compounds such as daptomycin
(Cubicin),19 but some, such as 6-(2-dimethylaminonaphthoyl)
alanine (DANA)/aladan,20a,b or AcF,20c serve as fluorophores
in medical probes and molecular imaging.20
■
A novel, Hyp-derived “doubly customizable unit” for the ready
generation of libraries of amines and amino acid-derived
compounds, including modified peptides, is presented herein.
This unit can be cleaved at two points, followed by the
introduction of new functionalities. Starting from readily
available, low-cost 4R-hydroxy-L-proline, three new chains are
generated and can be manipulated independently to afford a
diversity of products with tailored substituents.
Moreover, the process takes place with stereochemical
control, and either pure R or S isomers can be obtained with
small variations of the synthetic route. In two transformation
cycles, the customizable Hyp unit is converted into β-amino
aldehydes, diamines, β-amino acid derivatives, including N-
alkylated ones, or modified peptides. Many of these products
are high-profit compounds but, in spite of their commercial
value, are still scarce.
The first step is a one-pot radical decarboxylation−
oxidation−alkylation reaction, where the carboxyl group at
C-2 is removed and replaced by an alkyl chain. The
stereochemistry of the new product is controlled by the
adjacent stereogenic center at C-4. In a second transformation
cycle, the reactive hydroxy group at C-4 is deprotected and
activated for a second scission, which cleaves the C4−C5 bond.
The resulting product has a new acyclic α-chain and an N,O-
acetal that can be processed separately, increasing the library
diversity.
This versatile methodology, which allows the creation of
three new chains with stereochemical control will be used to
create libraries of potential antimicrobial compounds against
2799
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 9. Preparation of Modified Peptides
mass analyzer. Merck silica gel 60 PF254 and 60 (0.063−0.2 mm) were
used for preparative thin-layer chromatography (TLC) and column
chromatography, respectively. The reagent for TLC analysis was
KMnO4 in NaOH/K2CO3 aqueous (aq) solution, and the TLC was
heated until development of color.
The synthesis of branched and modified peptides, including
some with rigid dehydroamino acid units, is illustrated as well.
The process takes place under mild conditions and good
overall yields. The versatility of this doubly customizable unit
allows the synthesis of many different structures and will be
further explored in the future.
Preparation of Scission Substrates for Transformation
Cycle 1. The characterization data of the following compounds was
already reported: Compound 7;4c compounds 9,5b 10, and 12;8d
compound 17;22 product 22;10 and compounds 23 and 24.8c
(2S,4R)-4-(Benzyloxy)-N-(methoxycarbonyl)-L-proline (8). 4R-
Benzyloxy-N-(methoxycarbonyl) proline methyl ester 5223 (204 mg,
0.70 mmol) was dissolved in 1 M KOH in 9:1 methanol (MeOH)/
H2O (5 mL), and the reaction mixture was stirred at 0 °C for 3 h.
Then, 5% aq HCl was added until pH 2 and the mixture was extracted
by ethyl acetate (EtOAc). The organic layer was dried over sodium
sulfate, filtered, and the solvent was removed under vacuum, affording
EXPERIMENTAL SECTION
■
General Methods. Commercially available reagents and solvents
were of analytical grade or were purified by standard procedures prior
to use. All reactions involving air- or moisture-sensitive materials were
carried out under a nitrogen atmosphere. Melting points were
determined by a hot-stage apparatus and were uncorrected. Optical
rotations were measured at the sodium line and ambient temperature
(26 °C) in CHCl3 solutions. NMR spectra were determined at 500 or
400 MHz for 1H and 125.7 or 100.6 MHz for 13C, at 26 or 70 °C, as
stated for each case. Sometimes, due to slower rotamer
interconversion at 26 °C, two (or more) sets of signals were visible
at room temperature, while only one set of signals (rotamer average)
was seen at 70 °C due to faster rotamer interconversion. For some
20
compound 8 as a viscous oil (194 mg, 99%): [α]D −57 (c 0.15,
1
CHCl3). IR (CHCl3) νmax: 1699, 1455, 1394, 1199 cm−1. H NMR
((CD3)2CO, 500 MHz, 70 °C) rotamer equilibrium. Two sets of
signals at 26 °C, one set at 70 °C: δ 7.30−7.25 (m, 4H), 7.25−7.20
(m, 1H), 4.52−4.48 (m, 2H), 4.43 (t, J = 7.4 Hz, 1H), 4.24−4.19 (m,
1H), 3.67 (s, 3H), 3.68−3.62 (m, 1H), 3.58 (dd, J = 11.5, 5.0 Hz,
1H), 2.44−2.35 (m, 1H), 2.19 (ddd, J = 13.3, 6.4, 5.5 Hz, 1H).
13C{1H} NMR ((CD3)2CO, 125.7 MHz, 26 °C): δ 173.9/173.6 (C),
155.9/155.4 (C), 138.6 (C), 128.7 (2 × CH), 128.0 (2 × CH), 127.9
(CH), 77.3/76.4 (CH), 71.2 (CH), 58.3/57.9 (CH3), 52.5 (CH3),
52.4/52.1 (CH2), 37.0/35.8 (CH2). High-resolution mass spectrom-
etry (HRMS) (ESI) m/z: [M + Na]+ calcd for C14H17NO5Na
1
compounds, the H NMR spectra show some signals as broad bands
(br b) due to equilibria between rotamers.
1H NMR spectra are reported as follows (s = singlet, d = doublet, t
= triplet, dd = doublet of doublets, ddd = doublet of doublet of
doublets, q = quartet, m = multiplet, br = broad, br b = broad band, br
s = broad singlet; coupling constant(s) in Hertz). Mass spectra were
recorded using electrospray ionization techniques (ESI) or electronic
impact (EI); the latter was determined at 70 eV using an ion trap
2800
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
302.1004; found 302.1004. Anal. calcd for C14H17NO5: C, 60.21; H,
6.14; N, 5.02. Found: C, 60.38; H, 6.27; N, 5.26.
viscous oil (170 mg, 90%): [α]D20 −24 (c 0.24, CHCl3). IR (CHCl3)
1
νmax: 1755, 1737, 1701, 1455, 1393, 1094 cm−1. H NMR (CD3OD,
Methyl (1S,4S)-3-Oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-car-
boxylate (16). A solution of (2S,4R)-N-methoxycarbonyl-4-hydroxy-
L-proline 15 (800 mg, 4.23 mmol) and triphenylphosphine (1.27 g,
4.84 mmol) in dry tetrahydrofuran (THF) (80 mL) was cooled to 0
°C and treated with diethylazodicarboxylate (0.76 mL, 4.84 mmol).
The mixture was stirred at room temperature for 20 h; then, the
solvent was removed under vacuum and the residue was purified by
column chromatography on silica gel (CH2Cl2/acetone, 97:3),
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δ 7.34−7.22 (m, 5H), 4.50 (d, J = 12.0 Hz, 1H),
4.46 (d, J = 11.5 Hz, 1H), 4.40−4.32 (m, 1H), 4.20−4.16 (m, 1H),
3.68 (s, 3H), 3.67−3.63 (m, 1H), 3.52 (dd, J = 11.5, 2.5 Hz, 1H),
2.45−2.33 (m, 2H). 13C{1H} NMR (CD3OD, 125.7 MHz, 70 °C): δ
175.2 (C), 161.0 (C), 139.5 (C), 129.3 (2 × CH), 128.6 (2 × CH),
128.0 (CH), 72.0 (CH), 65.3 (CH2), 59.1 (CH), 53.2 (CH2), 53.1
(CH3), 36.6 (CH2). MS m/z (rel intensity) 279 (M+, 1), 91 (PhCH2,
100). HRMS (EI) m/z: [M]+ calcd for C14H17NO5 279.1107; found
279.1111; [PhCH2]+ calcd for C7H7 91.0548; found 91.0545. Anal.
calcd for C14H17NO5: C, 60.21; H, 6.14; N, 5.02. Found: C, 60.48; H,
6.38; N, 4.86.
20
yielding compound 16 as a viscous oil (512 mg, 71%): [α]D +53
(c 0.31, CHCl3). IR (CHCl3) νmax: 1801, 1709, 1450, 1392, 1329,
1
1121 cm−1. H NMR (CDCl3, 500 MHz, 26 °C): δ 5.10−5.09 (m,
1H), 4.65−4.55 (m, 1H), 3.74 (s, 3H), 3.58 (d, J = 10.5 Hz, 1H),
3.48 (d, J = 10.5 Hz, 1H), 2.25−2.21 (m, 1H), 2.02 (d, J = 11 Hz,
1H). 13C{1H} NMR (CDCl3, 125.7 MHz, 26 °C): δ 170.7 (C), 155.0
(C), 78.3 (CH), 57.4 (CH), 53.1 (CH3), 50.0 (CH2), 39.1 (CH2).
MS m/z (rel intensity) 171 (M+, 3), 127 (M+ − CO2, 16). HRMS
(EI) m/z: [M]+ calcd for C7H9NO4 171.0532; found 171.0536; [M −
CO2]+ calcd for C6H9NO2 127.0633; found 127.0638. Anal. calcd for
C7H9NO4: C, 49.12; H, 5.30; N, 8.18. Found: C, 49.17; H, 5.52; N,
8.01.
Methyl (2S, 4S)-4-(tert-Butyldiphenylsilyloxy)-N-
(methoxycarbonyl)proline (19a). Compound 17 (1.0 g, 4.92
mmol) was dissolved in dry DMF (15 mL) and treated with
imidazole (1.26 g, 18.51 mmol) and tert-butyldiphenylsilyl chloride
(3.40 g, 12.38 mmol) at 0 °C. The reaction mixture was stirred at
room temperature for 16 h, poured into water, and extracted with
EtOAc. The organic layer was dried over sodium sulfate and
concentrated under vacuum. The residue was purified by column
chromatography (hexanes/EtOAc 80:20), yielding compound 19a as
Methyl (2S,4S)-4-(Hydroxy)-N-(methoxycarbonyl)proline (17).
Compound 16 (220 mg, 1.29 mmol) was dissolved in MeOH (10
mL) and treated at 0 °C with sodium methoxide (348 mg, 6.45
mmol). The reaction mixture was stirred for 6 h and then was poured
into water and extracted with EtOAc. The organic layer was dried
over sodium sulfate and concentrated under vacuum, and the residue
was purified by column chromatography on silica gel (hexane/EtOAc,
20
a viscous oil (1.45 mg, 67%): [α]D −29 (c 0.43, MeOH). IR
(CHCl3) νmax: 1754, 1696, 1455, 1394, 1092 cm−1. 1H NMR (CDCl3,
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δH 7.68−7.61 (m, 4H), 7.47−7.36 (m, 6H), 4.39−
4.35 (m, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.60−3.40 (m, 2H), 2.28−
2.12 (m, 2H), 1.04 (s, 9H). 13C{1H} NMR (CDCl3, 100.6 MHz, 26
°C): δ 172.3/172.1 (C), 155.5/155.1 (C), 135.68 (2 × CH), 135.65
(2 × CH), 133.33/133.25 (C), 133.13/133.11 (C), 129.90/129.88
(CH), 129.86/129.84 (CH), 127.78/127.76 (2 × CH), 127.74/
127.72 (2 × CH), 71.6/70.7 (CH), 57.9/57.7 (CH), 55.0/54.5
(CH2), 55.59/52.55 (CH3), 52.2 (CH3), 39.4/38.4 (CH2), 26.7 (3 ×
CH3), 18.9 (C). MS m/z (rel intensity) 441 (M+, <1), 384 (M+ −
tBu, 100). HRMS (EI) m/z: [M]+ calcd for C24H31NO5Si 441.1972;
20
30:70), yielding compound 17 as a viscous oil (215 mg, 83%): [α]D
−22 (c 0.65, CHCl3). IR (CHCl3) νmax: 3606, 3476, 1728, 1702,
1456, 1391, 1084 cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer
equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ 4.42−
4.36 (m, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.65−3.55 (m, 2H), 2.87
(br s, 1H, OH), 2.32 (ddd, J = 14.0, 9.5, 4.5 Hz, 1H), 2.11 (d, J = 13.9
Hz, 1H). 13C{1H} NMR (CDCl3, 125.7 MHz, 70 °C): δ 174.7 (C),
155.2 (C), 70.5 (CH), 58.1 (CH), 55.9 (CH2), 52.6 (CH3), 52.5
(CH3), 38.2 (CH2). MS m/z (rel intensity) 203 (M+, 1), 144 (M+ −
CO2Me, 100). HRMS (EI) m/z: [M]+ calcd for C8H13NO5 203.0794;
found 203.0799; [M − CO2Me]+ calcd for C6H10NO3 144.0661;
found 144.0667. Anal. calcd for C8H13NO5: C, 47.29; H, 6.45; N,
6.89. Found: C, 47.10; H, 6.68; N, 6.87.
found 441.1988; [M − tBu]+ calcd for C20H22NO5Si 384.1267; found
384.1267. Anal. calcd for C24H31NO5Si: C, 65.28; H, 7.08; N, 3.17.
Found: C, 65.46; H, 7.35; N, 3.00.
(2S,4S)-4-(tert-Butyldiphenylsilyloxy)-N-(methoxycarbonyl)-
proline (19). The methyl ester 19a (860 mg, 1.95 mmol) was
dissolved in 1 M KOH in 9:1 MeOH/H2O (8 mL), and the reaction
mixture was stirred at 0 °C for 16 h. Then, 5% aq HCl was added until
pH 2 and the mixture was extracted with EtOAc. The organic layer
was dried over sodium sulfate and concentrated under vacuum,
affording compound 19 as a viscous oil (781 mg, 94%): [α]D20 −33 (c
0.44, CHCl3). IR (CHCl3) νmax: 1754, 1701, 1457, 1393, 1093 cm−1.
1H NMR (CD3OD, 500 MHz, 70 °C) rotamer equilibrium. Two sets
of signals at 26 °C, one set at 70 °C: δ 7.74−7.60 (m, 4H), 7.48−7.32
(m, 6H), 4.43−4.32 (m, 2H), 3.67 (s, 3H), 3.48−3.39 (m, 2H),
2.30−2.20 (m, 2H), 1.04 (s, 6H), 1.03 (s, 3H). 13C{1H} NMR
(CD3OD, 100.6 MHz, 26 °C): δ 175.2/175.0 (C), 157.4/157.3 (C),
137.3 (C), 136.9/136.8 (2 × CH), 136.6 (C), 136.0 (CH), 131.1
(CH), 131.0/130.4 (2 × CH), 128.9/128.5 (4 × CH), 73.3/72.4
(CH), 59.3/59.0 (CH), 56.4/56.0 (CH2), 53.2 (CH3), 40.3/39.4
(CH2), 27.2 (2 × CH3), 27.1 (CH3), 19.8 (C). MS m/z (rel
intensity) 426 (M+ − H, <1), 199 ([Ph2SiOH]+, 100). HRMS (EI)
m/z: [M − H]+ calcd for C23H28NO5Si 426.1737; found 426.1755;
[Ph2SiOH]+ calcd for C12H11OSi 199.0579; found 199.0579. Anal.
calcd for C23H29NO5Si: C, 64.61; H, 6.84; N, 3.28. Found: C, 64.82;
H, 6.87; N, 3.11.
General Procedure for the Decarboxylation−Oxidation−
Alkylation Process. To a solution of the hydroxyproline substrate
(0.2 mmol) in dry dichloromethane (DCM, 4 mL) were added iodine
(25 mg, 0.1 mmol) and DIB (129 mg, 0.4 mmol). The resulting
mixture was stirred for 3 h at 26 °C, under irradiation with visible
light (80 W tungsten-filament lamp). Then, the reaction mixture was
cooled to 0 °C and treated with BF3·OEt2 (50 μL, 57 mg, 0.4 mmol)
and the nucleophile (0.6 mmol). The mixture was stirred for 1 h and
then poured into a 1:1 mixture of 10% aqueous Na2S2O3 and
Methyl (2S,4S)-4-(Benzyloxy)-N-(methoxycarbonyl)proline (18a).
A solution of the hydroxyproline derivative 17 (300 mg, 1.48 mmol)
in dry dimethylformamide (DMF) (5 mL) was treated with benzyl
bromide (0.26 mL, 2.2 mmol) and silver oxide (342 mg, 1.48 mmol).
The reaction mixture was stirred at room temperature, in the absence
of light, for 16 h. Then, it was filtered and washed with 5% aq HCl
and water, dried over anhydrous Na2SO4, and concentrated under
vacuum. The residue was purified by column chromatography
(hexanes/EtOAc 80:20), yielding compound 18a as a viscous oil
(296 mg, 68%): [α]D20 −33 (c 0.62, MeOH). IR (CHCl3) νmax: 1746,
1
1699, 1455, 1228, 1096 cm−1. H NMR (CDCl3, 500 MHz, 70 °C)
rotamer equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ
7.33−7.23 (m, 5H), 4.45 (s, 2H), 4.43−4.37 (m, 1H), 4.14−4.08 (m,
1H), 3.68 (s, 3H), 3.64 (s, 3H), 3.70−3.50 (m, 2H), 2.40−2.32 (m,
1H), 2.32−2.25 (m, 1H). 13C{1H} NMR (CDCl3, 125.7 MHz, 70
°C): δ 172.2 (C), 155.3 (C), 137.9 (C), 128.4 (2 × CH), 127.7
(CH), 127.5 (2 × CH), 76.1 (CH), 71.0 (CH2), 57.9 (CH), 52.5
(CH3), 52.1 (CH3), 52.0 (CH2), 36.4/35.3 (CH2). MS m/z (rel
intensity) 293 (M+, <1), 91 (PhCH2, 100). HRMS (EI) m/z: [M]+
calcd for C15H19NO5 293.1263; found 293.1261; [PhCH2]+ calcd for
C7H7 91.0548; found 91.0550. Anal. calcd for C15H19NO5: C, 61.42;
H, 6.53; N, 4.78. Found: C, 61.22; H, 6.69; N, 4.44.
(2S,4S)-4-(Benzyloxy)-N-(methoxycarbonyl)proline (18). Methyl
ester 18a (200 mg, 0.68 mmol) was dissolved in 1 M KOH in 9:1
MeOH/H2O (5 mL), and the solution was stirred at 0 °C for 3 h.
Then, 5% aq HCl was added until pH 2, and the mixture was
extracted with EtOAc. The organic layer was dried over sodium
sulfate and concentrated under vacuum, affording compound 18 as a
2801
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
saturated aqueous NaHCO3 (10 mL), followed by extraction with
CH2Cl2. The organic layer was dried over sodium sulfate, filtered, and
concentrated under vacuum. The residue was purified by chromatog-
raphy on silica gel (hexanes/ethyl acetate) to give the 2-alkyl
pyrrolidines.
(C), 155.3 (C), 138.1 (C), 137.5 (C), 132.8 (CH), 128.5 (3 × CH),
128.4 (2 × CH), 128.1 (2 × CH), 127.5 (2 × CH), 77.6 (CH), 71.1
(CH2), 54.1 (CH), 52.4 (CH2), 52.1 (CH3), 43.5 (CH2), 36.1
(CH2). MS m/z (rel intensity) 353 (M+, 1), 91 ([PhCH2]+, 100).
+
HRMS (EI) m/z: [M] calcd for C21H23NO4 353.1627; found
353.1624; [PhCH2]+ calcd for C7H7 91.0548; found 91.0546. Anal.
calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.66; H,
6.44; N, 4.02.
(2S,4R)-2-Allyl-4-benzyloxy-1-methoxycarbonyl Pyrrolidine (10).
Obtained from acid 8 (56 mg, 0.2 mmol) according to the general
scission−oxidation−alkylation sequence using allyltrimethylsilane (95
μL, 69 mg, 0.6 mmol) as the nucleophile. After work-up and solvent
evaporation, the residue was purified by radial chromatography
(hexanes/EtOAc, 80:20), yielding product 10 (40 mg, 73%, Rf =
(2R,4R)-4-(tert-Butyldiphenylsilyloxy)-1-methoxycarbonyl-2-(2-
oxo-2-phenylethyl)pyrrolidine (13) and its (2S,4R)-Isomer (14).
Obtained from acid 9 (85.4 mg, 0.2 mmol) according to the general
scission−oxidation−alkylation sequence using 1-phenyl-1-trimethylsi-
loxyethylene (125 μL, 115 mg, 0.6 mmol) as the nucleophile. After
work-up and solvent evaporation, the residue was purified by radial
chromatography (toluene/EtOAc, 99:1), yielding product 13 (62 mg,
62%, Rf = 0.17) and the minor isomer 14 (25 mg, 25%, Rf = 0.10).
(2R,4R)-4-(tert-Butyldiphenylsilyloxy)-1-methoxycarbonyl-2-(2-
0.11) as a viscous oil: [α]D20 +21 (c 0.85, CHCl3). IR (CHCl3) νmax
:
1686, 1455, 1391, 1121, 1095 cm−1.1H NMR (CDCl3, 500 MHz, 70
°C) rotamer equilibrium. Two sets of signals at 26 °C, one set at 70
°C: δ 7.32−7.22 (m, 5H), 5.81−5.73 (m, 1H), 5.07 (br d, J = 8.0 Hz,
1H), 5.05 (br d, J = 17.5 Hz, 1H), 4.51 (d, J = 11.5 Hz, 1H), 4.48 (d,
J = 11.5 Hz, 1H), 4.09−4.06 (m, 1H), 3.94−3.87 (m, 1H), 3.73−3.68
(m, 1H), 3.68 (s, 3H), 3.43 (dd, J = 12.0, 3.5 Hz, 1H), 2.70−2.62 (m,
1H), 2.38 (ddd, J = 13.5, 9.0, 8.0 Hz, 1H), 2.06 (ddd, J = 13.5, 8.0, 6.0
Hz, 1H), 2.00 (ddd, J = 13.5, 4.0, 3.5 Hz, 1H). 13C{1H} NMR
(CDCl3, 125.7 MHz, 70 °C): δ 155.5 (C), 138.3 (C), 135.2 (CH),
128.4 (2 × CH), 127.6 (CH), 127.5 (2 × CH), 117.0 (CH2), 77.2
(CH), 71.3 (CH2), 56.6 (CH), 52.2 (CH2), 52.0 (CH3), 38.9 (CH2),
35.2 (CH2). MS m/z (rel intensity) 274 (M+ − H, <1), 234 (M+ −
CH2CHCH2, 90), 91 ([PhCH2]+, 100). HRMS (EI) m/z: [M − H]+
calcd for C16H20NO3 274.1443; found 274.1445; [M −
CH2CHCH2]+ calcd for C13H16NO3 234.1130; found 234.1122;
[PhCH2]+ calcd for C7H7 91.0548; found 91.0547. Anal. calcd for
C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.69; H, 7.82; N,
5.31.
20
oxo-2-phenylethyl)pyrrolidine (13). [α]D +17 (c 1.0, CHCl3). IR
(CHCl3) νmax: 1684, 1455, 1391, 1104, 1025 cm−1. 1H NMR (CDCl3,
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δ 7.99 (d, J = 7.5 Hz, 2H), 7.64−7.60 (m, 4H), 7.53
(t, J = 7.3 Hz, 1H), 7.45−7.31 (m, 8H), 4.48−4.40 (m, 2H), 3.80 (br
b, 1H), 3.67 (s, 3H), 3.60−3.40 (m, 3H), 2.16 (ddd, J = 13.5, 8.3, 5.0
Hz, 1H), 1.96 (br d, J = 14.0 Hz, 1H), 1.06 (s, 9H). 13C{1H} NMR
(CDCl3, 125.7 MHz, 70 °C): δ 198.9 (C), 155.4 (C), 137.5 (C),
135.7 (4 × CH), 133.7 (C), 133.6 (C), 132.9 (CH), 129.90 (CH),
129.87 (CH), 128.6 (2 × CH), 128.2 (2 × CH), 127.83 (2 × CH),
127.79 (2 × CH), 72.3 (CH), 55.2 (CH2), 54.2 (CH), 52.1 (CH3),
43.5 (CH2), 39.5 (CH2), 27.0 (3 × CH3), 19.1 (C). MS m/z (rel
intensity) 444 (M+ − CMe3, 47), 199 (Ph2SiOH, 100), 105 (PhCO,
64). HRMS (EI) m/z: [M − CMe3]+ calcd for C26H26NO4Si
444.1631; found 444.1621; [Ph2SiOH]+ calcd for C12H11OSi
199.0579; found 199.0586; [PhCO]+ calcd for C7H5O 105.0340;
found 105.0338. Anal. calcd for C30H35NO4Si: C, 71.82; H, 7.03; N,
2.79. Found: C, 71.58; H, 7.20; N, 2.35.
(2S,4R)-2-Allyl-4-(tert-butyldiphenylsilyloxy)-1-methoxycarbonyl
Pyrrolidine (11). Obtained from the acid 9 (85.4 mg, 0.2 mmol)
according to the general scission−oxidation−alkylation sequence
using allyltrimethylsilane (95 μL, 69 mg, 0.6 mmol) as the
nucleophile. After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 98:2), yielding
(2S,4R)-4-(tert-Butyldiphenylsilyloxy)-1-methoxycarbonyl-2-(2-
20
20
oxo-2-phenylethyl)pyrrolidine (14). [α]D −17 (c 0.45, CHCl3). IR
product 11 (65 mg, 77%, Rf = 0.10) as a viscous oil: [α]D +17 (c
(CHCl3) νmax: 1686, 1453, 1392, 1113, 1025 cm−1. 1H NMR (CDCl3,
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δ 7.84 (d, J = 7.6 Hz, 2H), 7.55−7.52 (m, 4H), 7.43
(dd, J = 7.2, 7.0 Hz, 1H), 7.35−7.23 (m, 8H), 4.45−4.41 (m, 1H),
4.31 (dddd, J = 4.5, 4.5, 4.0, 4.0 Hz, 1H), 3.58 (s, 3H), 3.62−3.52 (m,
1H), 3.43 (br d, J = 10.5 Hz, 1H), 3.23 (dd, J = 11.3, 4.7 Hz, 1H),
2.74 (dd, J = 9.3, 15.3 Hz, 1H), 2.20−2.16 (m, 1H), 1.70 (ddd, J =
13.5, 7.0, 6.0 Hz, 1H), 0.96 (s, 9H). 13C{1H} NMR (CDCl3, 125.7
MHz, 70 °C): δ 198.4 (C), 155.9 (C), 137.5 (C), 135.7 (4 × CH),
134.0 (C), 133.9 (C), 132.9 (CH), 129.8 (2 × CH), 128.5 (2 × CH),
128.2 (2 × CH), 127.8 (4 × CH), 71.3 (CH), 54.8 (CH2), 53.8
(CH), 52.1 (CH3), 43.5 (CH2), 40.8 (CH2), 27.0 (3 × CH3), 19.1
(C). MS m/z (rel intensity) 444 (M+ − CMe3, 65), 105 (PhCO,
100). HRMS (EI) m/z: [M − CMe3]+ calcd for C26H26NO4Si
444.1631; found 444.1631; [PhCO]+ calcd for C7H5O 105.0340;
found 105.0338. Anal. calcd for C30H35NO4Si: C, 71.82; H, 7.03; N,
2.79. Found: C, 71.74; H, 7.20; N, 3.20.
0.90, CHCl3). IR (CHCl3) νmax: 1687, 1455, 1391, 1235, 1112 cm−1.
1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two sets of
signals at 26 °C, one set at 70 °C: δ 7.69−7.63 (m, 4H), 7.47−7.36
(m, 6H), 5.83−5.76 (m, 1H), 5.11 (d, J = 17.0 Hz, 1H), 5.07 (d, J =
10.0 Hz, 1H), 4.38−4.34 (m, 1H), 3.88−3.83 (m, 1H), 3.68 (s, 3H),
3.59−3.53 (m, 1H), 3.33 (dd, J = 11.5, 4.0 Hz, 1H), 2.72 (br b, 1H),
2.54 (ddd, J = 13.8, 8.8, 8.0 Hz, 1H), 1.98 (ddd, J = 13.8, 8.2, 6.0 Hz,
1H), 1.88 (dt, J = 13.0, 4.0 Hz, 1H), 1.10 (s, 9H). 13C{1H} NMR
(CDCl3, 125.7 MHz, 70 °C): δ 155.5 (C), 135.79 (2 × CH), 135.75
(2 × CH), 135.2 (CH), 133.91 (C), 133.86 (C), 129.85 (CH),
129.83 (CH), 127.78 (2 × CH), 127.76 (2 × CH), 117.0 (CH2), 71.9
(CH), 56.8 (CH), 54.8 (CH2), 52.0 (CH3), 38.9 (CH2), 38.5 (CH2),
27.0 (3 × CH3), 19.1 (C). MS m/z (rel intensity) 424 (M+ + H, 6),
366 (M+ − CMe3, 100). HRMS (EI) m/z: [M + H]+ calcd for
C25H34NO3Si 424.2308; found 424.2314; [M − CMe3]+ calcd for
C21H24NO3Si 366.1525; found 366.1527. Anal. calcd for
C25H33NO3Si: C, 70.88; H, 7.85; N, 3.31. Found: C, 70.97; H,
7.85; N, 3.30.
(2R,4S)-2-Allyl-4-benzyloxy-1-(methoxycarbonyl)pyrrolidine
(20). Obtained from acid 18 (56 mg, 0.2 mmol) according to the
general scission−oxidation−alkylation sequence using allyltrimethyl-
silane (95 μL, 69 mg, 0.6 mmol) as the nucleophile. After work-up
and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 80:20), yielding product 20 (35
mg, 63%, Rf = 0.18) as a viscous oil: [α]D20 −19 (c 0.63, CHCl3). IR
(CHCl3) νmax: 1686, 1455, 1392, 1122, 1094 cm−1. 1H NMR (CDCl3,
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δ 7.32−7.22 (m, 5H), 5.81−5.75 (m, 1H), 5.07−
5.02 (m, 2H), 4.51 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H),
4.10−4.06 (m, 1H), 3.93−3.88 (m, 1H), 3.73−3.68 (m, 1H), 3.68 (s,
3H), 3.43 (dd, J = 11.8, 3.3 Hz, 1H), 2.70−2.60 (m, 1H), 2.38 (ddd, J
= 13.6, 9.2, 7.9 Hz, 1H), 2.06 (ddd, J = 13.6, 8.2, 6.0 Hz, 1H), 2.00
(dt, J = 13.6, 3.8 Hz). 13C{1H} NMR (CDCl3, 100.6 MHz, 26 °C): δ
155.5 (C), 138.3 (C), 135.2 (CH), 128.4 (2 × CH), 127.6 (CH),
(2R,4R)-4-Benzyloxy-1-methoxycarbonyl-2-(2-oxo-2-
phenylethyl)pyrrolidine (12). Obtained from acid 8 (56 mg, 0.2
mmol) according to the general scission−oxidation−alkylation
sequence using 1-phenyl-1-trimethylsiloxyethylene (125 μL, 115 mg,
0.6 mmol) as the nucleophile. After work-up and solvent evaporation,
the residue was purified by radial chromatography (hexanes/EtOAc,
80:20), yielding product 12 (59.3 mg, 84%, Rf = 0.11) as a viscous oil:
20
[α]D +14 (c 0.23, CHCl3). IR (CHCl3) νmax: 3090, 3066, 1684,
1455, 1391, 1199 cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer
equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ 7.93 (br
d, J = 8.0 Hz, 2H), 7.50 (dd, J = 7.5, 7.3 Hz, 1H), 7.46−7.30 (m, 2H),
7.28−7.22 (m, 5H), 4.48 (s, 2H), 4.47−4.43 (m, 1H), 4.14−4.10 (m,
1H), 3.71−3.64 (m, 1H), 3.67 (s, 3H), 3.62−3.59 (m, 2H), 3.42−
3.31 (m, 1H), 2.19 (ddd, J = 13.8, 8.2, 5.3 Hz, 1H), 2.10 (br d, J =
14.5 Hz, 1H). 13C{1H} NMR (CDCl3, 125.7 MHz, 70 °C): δ 199.0
2802
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
127.5 (2 × CH), 117.0 (CH2), 77.2 (CH), 71.3 (CH2), 56.6 (CH),
52.2 (CH2), 52.0 (CH3), 38.9 (CH2), 35.2 (CH2). MS m/z (rel
intensity) 275 (M+, <1), 274 (M+ − H, 1), 91 ([PhCH2]+, 100).
HRMS (EI) m/z: [M]+ calcd for C16H21NO3 275.1521; found
275.1512; [M − H]+ calcd for C16H20NO3 274.1443; found
274.1446; [PhCH2]+ calcd for C7H7 91.0548; found 91.0549. Anal.
calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.51; H,
8.06; N, 5.00.
CH3), 18.0 (C), −4.9 (CH3), −5.0 (CH3). MS m/z (rel intensity)
320 (M+ − CMe3, 67), 105 (PhCO, 100). HRMS (EI) m/z: [M −
CMe3]+ calcd for C16H22NO4Si 320.1318; found 320.1310; [PhCO]+
calcd for C7H5O 105.0340; found 105.0338. Anal. calcd for
C20H31NO4Si: C, 63.62; H, 8.28; N, 3.71. Found: C, 63.64; H,
8.39; N, 3.87.
(2R,4R)-2-(1,1-Dimethyl-2-methoxy-2-oxoethyl)-4-(tert-butyldi-
methylsilyloxy)-1-(methoxycarbonyl)pyrrolidine (25) and Its
(2S,4R)-Isomer (26). Obtained from acid 22 (61 mg, 0.2 mmol)
using 1-methoxy-2-methyl-1-(trimethylsilyloxy)propene (125 μL, 108
mg, 0.6 mmol) according to the general decarboxylation−oxidation−
alkylation sequence. After work-up and solvent evaporation, the
residue was purified by radial chromatography (hexanes/EtOAc,
80:20), yielding products 25 (27 mg, 38%, Rf = 0.12) and 26 (25 mg,
35%, Rf = 0.15) as viscous oils.
(2R,4S)-2-Allyl-4-(tert-butyldiphenylsilyloxy)-1-methoxycarbonyl
Pyrrolidine (21). Obtained from acid 19 (85.4 mg, 0.2 mmol)
according to the general scission−oxidation−alkylation sequence
using allyltrimethylsilane (95 μL, 69 mg, 0.6 mmol) as the
nucleophile. After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 98:2), yielding
20
product 21 (60 mg, 71%, Rf = 0.10) as a viscous oil: [α]D −20 (c
20
0.47, CHCl3). IR (CHCl3) νmax: 1685, 1455, 1391, 1236, 1112 cm−1.
1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two sets of
signals at 26 °C, one set at 70 °C: δH 7.65−7.61 (m, 4H), 7.42−7.34
(m, 6H), 5.81−5.74 (m, 1H), 5.08 (d, J = 17.0 Hz, 1H), 5.05 (d, J =
10.0 Hz, 1H), 4.35−4.31 (m, 1H), 3.86−3.80 (m, 1H), 3.65 (s, 3H),
3.59−3.45 (m, 1H), 3.31 (dd, J = 11.3, 3.2 Hz, 1H), 2.77−2.63 (m,
1H), 2.51 (1H, ddd, J = 13.5, 9.0, 8.0 Hz, 1H), 1.94 (ddd, J = 14.0,
8.0, 6.0 Hz, 1H), 1.85 (ddd, J = 13.0, 4.0, 3.5 Hz, 1H), 1.07 (s, 9H).
13C{1H} NMR (CDCl3, 125.7 MHz, 70 °C): δ 155.5 (C), 135.7 (4 ×
Product 25. [α]D +11 (c 0.41, CHCl3). IR (CHCl3) νmax: 1726,
1697, 1450, 1388, 1134 cm−1. 1H NMR (CD3OD, 500 MHz, 70 °C)
rotamer equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ
4.30 (dd, J = 8.7, 7.1 Hz, 1H), 4.29−4.23 (m, 1H), 3.96 (dd, J = 11.3,
7.3 Hz, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 2.89 (dd, J = 11.2, 8.0 Hz,
1H), 2.37−2.31 (m, 1H), 1.66−1.60 (m, 1H), 1.16 (s, 3H), 1.14 (s,
3H), 0.89 (s, 9H), 0.073 (s, 3H), 0.067 (s, 3H). 13C{1H} NMR
(CD3OD, 125.7 MHz, 70 °C): δ 178.9 (C), 158.2 (C), 70.8 (CH),
63.4 (CH), 55.8 (CH2), 53.1 (CH3), 52.4 (CH3), 48.3 (C), 37.8
(CH2), 26.2 (3 × CH3), 22.7 (CH3), 21.5 (CH3), 18.8 (C), −4.7
(CH3), −4.8 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd for
C17H33NO5SiNa 382.2026; found 382.2028. Anal. calcd for
C17H33NO5Si: C, 56.79; H, 9.25; N, 3.90. Found: C, 56.85; H,
8.93; N, 3.52.
CH), 135.2 (CH), 133.8 (2 × C), 129.8 (2 × CH), 127.7 (4 × CH),
117.1 (CH2), 71.9 (CH), 56.8 (CH), 54.8 (CH2), 52.0 (CH3), 38.8
(CH2), 38.4 (CH2), 27.0 (3 × CH3), 19.1 (C). MS m/z (rel
intensity) 422 (M+ − H, 6). HRMS (EI) m/z: [M − H]+ calcd for
C25H32NO3Si 422.2151; found 422.2158. Anal. calcd for
C25H33NO3Si: C, 70.88; H, 7.85; N, 3.31. Found: C, 70.76; H,
7.72; N, 3.70.
20
Product 26. [α]D −13 (c 0.59, CHCl3). IR (CHCl3) νmax: 1725,
1
1698, 1448, 1385, 837 cm−1. H NMR (500 MHz, CD3OD, 70 °C)
rotamer equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ
4.42−4.31 (m, 2H), 3.72 (br dd, J = 12.0, 4.0 Hz, 1H), 3.66 (s, 3H),
3.63 (s, 3H), 3.15 (dd, J = 12.0, 3.5 Hz, 1H), 1.96−1.86 (m, 2H),
1.12 (s, 3H), 1.10 (s, 3H), 0.85 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).
13C NMR (CD3OD, 125.7 MHz, 70 °C): δ 178.8 (C), 159.7 (C),
72.2 (CH), 63.7 (CH), 58.1 (CH2), 53.0 (CH3), 52.4 (CH3), 48.5
(C), 38.4 (CH2), 26.1 (3 × CH3), 22.3 (CH3), 21.7 (CH3), 18.7 (C),
−4.7 (CH3), −4.8 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd for
C17H33NO5SiNa 382.2026; found 382.2026. Anal. calcd for
C17H33NO5Si: C, 56.79; H, 9.25; N, 3.90. Found: C, 56.90; H,
8.87; N, 3.59.
General Procedures for the Synthesis of 2-alkyl-4-
(hydroxy)pyrrolidines. Method A (PG = Bn). Pd/C (10%, 30
mg) was added to a solution of the pyrrolidine derivative (0.3 mmol)
in dry MeOH (4 mL). The mixture was purged with successive cycles
of vaccuum/hydrogen to remove air and replace it by hydrogen (1
atm, H2 balloon) and stirred at room temperature for 16. Then, it was
filtered over celite, and the filtrate was concentrated under vacuum to
afford 4-(hydroxy)pyrrolidines.
(2S,4R)-2-Allyl-4-(tert-butyldimethylsilyloxy)-1-methoxycarbonyl
Pyrrolidine (23). Obtained from acid 22 (61 mg, 0.2 mmol) according
to the general scission−oxidation−alkylation sequence using allyl-
trimethylsilane (95 μL, 69 mg, 0.6 mmol) as the nucleophile. After
work-up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 95:5), yielding product 23 (46 mg,
20
77%, Rf = 0.10) as a viscous oil: [α]D +21 (c 0.40, CHCl3). IR
(CHCl3) νmax: 1685, 1455, 1391, 1257, 1085 cm−1. 1H NMR (CDCl3,
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δH 5.82−5.73 (m, 1H), 5.07 (dq, J = 17.0, 1.5 Hz,
1H), 5.05 (dq, J = 10.0, 1.0 Hz, 1H), 4.35−4.31 (m, 1H), 3.91−3.87
(m, 1H), 3.70 (s, 3H), 3.70−3.65 (m, 1H), 3.23 (dd, J = 11.3, 3.8 Hz,
1H), 2.67 (br s, 1H), 2.42 (ddd, J = 14.0, 9.0, 8.5 Hz, 1H), 2.06 (ddd,
J = 13.8, 8.5, 6.0 Hz, 1H), 1.79 (dt, J = 13.2, 4.0 Hz, 1H), 0.91 (s,
9H), 0.076 (s, 3H), 0.074 (s, 3H). 13C{1H} NMR (CDCl3, 125.7
MHz, 70 °C): δ 155.5 (C), 135.3 (CH), 116.9 (CH2), 70.9 (CH),
56.8 (CH), 55.1 (CH2), 52.0 (CH3), 38.7 (2 × CH2), 25.8 (3 ×
CH3), 18.0 (C), −4.86 (CH3), −4.89 (CH3). MS m/z (rel intensity)
258 (M+ − CH2CHCH2, 100). HRMS (EI) m/z: [M − CH2CH
CH2]+ calcd for C12H24NO3Si 258.1525; found 258.1513. Anal. calcd
for C15H29NO3Si: C, 60.16; H, 9.76; N, 4.68. Found: C, 60.33; H,
9.74; N, 4.62.
Method B (PG = tBuMe2Si or tBuPh2Si). The silylated product (0.3
mmol) was dissolved in dry THF (3 mL) and the mixture was cooled
to 0 °C and treated with tetra-n-butylammonium fluoride (TBAF)
(124.5 mg, 0.45 mmol). The solution was stirred at room temperature
for 3 h and then poured into water and extracted with EtOAc. The
organic layer was dried over sodium sulfate and concentrated under
vacuum, and the residue was purified by chromatography on silica gel
(hexanes/ethyl acetate) to give 4-(hydroxy)pyrrolidines.
(2R,4S)-4-(Hydroxy)-2-(propyl)-N-(methoxycarbonyl)pyrrolidine
(27). Obtained from product 20 (82.5 mg, 0.3 mmol) according to
procedure A. After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 90:10), yielding
compound 27 as a viscous oil (50.5 mg, 90%, Rf = 0.13): [α]D20 −42
(c 0.27, CHCl3). IR (CHCl3) νmax: 3613, 1684, 1455, 1392, 1119
cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two
sets of signals at 26 °C, one set at 70 °C: δH 4.42−4.38 (m, 1H),
3.88−3.83 (m, 1H), 3.75 (dd, J = 11.8, 6.0 Hz, 1H), 3.69 (s, 3H),
3.27 (ddd, J = 12.0, 4.0, 1.0 Hz, 1H), 2.20 (ddd, J = 13.5, 8.5, 6.3 Hz,
1H), 1.97−1.88 (m, 1H), 1.74 (ddd, J = 13.5, 4.3, 3.8 Hz, 1H), 1.67
(br s, 1H), 1.60−1.53 (m, 1H), 1.41−1.27 (m, 2H), 0.95 (t, J = 7.4
(2R,4R)-4-(tert-Butyldimethylsilyloxy)-1-methoxycarbonyl-2-(2-
oxo-2-phenylethyl)pyrrolidine (24). Obtained from acid 22 (61 mg,
0.2 mmol) according to the general scission−oxidation−alkylation
sequence using 1-phenyl-1-trimethylsiloxyethylene (125 μL, 115 mg,
0.6 mmol) as the nucleophile. After work-up and solvent evaporation,
the residue was purified by radial chromatography (hexanes/EtOAc,
90:10), yielding product 24 (50 mg, 66%, Rf = 0.11) as a viscous oil:
20
[α]D +19 (c 0.65, CHCl3). IR (CHCl3) νmax: 1683, 1455, 1391,
1257, 1103 cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer
equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ 7.97 (d,
J = 7.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.43 (dd, J = 8.0, 7.5 Hz,
2H), 4.47−4.37 (m, 2H), 3.68 (s, 3H), 3.67−3.63 (m, 2H), 3.42−
3.35 (m, 2H), 2.24 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 1.88 (br d, J =
13.5 Hz, 1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H). 13C{1H} NMR
(CDCl3, 125.7 MHz, 70 °C): δ 199.0 (C), 155.4 (C), 137.6 (C),
132.8 (CH), 128.5 (2 × CH), 128.1 (2 × CH), 71.3 (CH), 55.4
(CH2), 54.2 (CH), 52.1 (CH3), 43.8 (CH2), 40.0 (CH2), 25.8 (3 ×
2803
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Hz, 3H). 13C{1H} NMR (CDCl3, 125.7 MHz, 70 °C): δ 155.7 (C),
70.6 (CH), 57.2 (CH), 54.7 (CH2), 52.1 (CH3), 39.1 (CH2), 37.4
(CH2), 19.5 (CH2), 13.9 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd
for C9H17NO3Na 210.1106; found 210.1106. Anal. calcd for
C9H17NO3: C, 57.73; H, 9.15; N, 7.48. Found: C, 57.63; H, 9.36;
N, 7.58.
sets of signals at 26 °C, one set at 70 °C: δ 5.82−5.74 (m, 1H), 5.12−
5.05 (m, 2H), 4.41−4.37 (m, 1H), 3.95−3.90 (m, 1H), 3.72 (dd, J =
11.7, 5.7 Hz, 1H), 3.69 (s, 3H), 3.30 (dd, J = 11.8, 3.6 Hz, 1H), 2.70−
2.63 (m, 1H), 2.43 (ddd, J = 13.8, 8.7, 8.0 Hz, 1H), 2.16 (ddd, J =
13.8, 8.3, 6.0 Hz, 1H), 1.87 (br b, 1H), 1.83 (dt, J = 13.6, 3.8 Hz,
1H). 13C{1H} NMR (CDCl3, 125.7 MHz, 70 °C): δ 155.6 (C), 135.1
(CH), 117.3 (CH2), 70.5 (CH), 56.8 (CH), 55.1 (CH2), 52.1 (CH3),
39.0 (CH2), 38.5 (CH2). MS m/z (rel intensity) 185 (M+, <1), 144
([M − allyl]+, 100). HRMS (EI) m/z: [M]+ calcd for C9H15NO3
185.1052; found 185.1059; [M − allyl]+ calcd for C6H10NO3
144.0661; found 144.0654. Anal. calcd for C9H15NO3: C, 58.36; H,
8.16; N, 7.56. Found: C, 58.28; H, 8.34; N, 7.52.
(2R,4S)-2-Allyl-4-hydroxy-1-methoxycarbonylpyrrolidine (28).
Obtained from compound 21 (127 mg, 0.3 mmol) according to the
general method B. After work-up and solvent evaporation, the residue
was purified by radial chromatography (hexanes/EtOAc, 30:70),
20
yielding product 28 (52 mg, 94%, Rf = 0.25) as a viscous oil: [α]D
−47 (c 0.67, CHCl3). IR (CHCl3) νmax: 3611, 1686, 1455, 1391,
1121, 1075 cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer
equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ 5.84−
5.74 (m, 1H), 5.12−5.05 (m, 2H), 4.43−4.36 (m, 1H), 3.96−3.90
(m, 1H), 3.72 (dd, J = 11.7, 6.5 Hz, 1H), 3.70 (s, 3H), 3.31 (ddd, J =
11.5, 3.5, 1.1 Hz, 1H), 2.71−2.64 (m, 1H), 2.44 (br ddd, J = 14.0, 9.0,
8.0 Hz, 1H), 2.16 (ddd, J = 14.0, 8.0, 5.5 Hz, 1H), 1.83 (ddd, J = 13.5,
4.0, 3.5 Hz, 1H), 1.71 (br s, 1H). 13C{1H} NMR (CDCl3, 125.7
MHz, 70 °C): δ 155.6 (C), 135.1 (CH), 117.4 (CH2), 70.5 (CH),
56.8 (CH), 55.1 (CH2), 52.1 (CH3), 39.0 (CH2), 38.4 (CH2). HRMS
(ESI) m/z: [M + Na]+ calcd for C9H15NO3Na 208.0950; found
208.0948. Anal. calcd for C9H15NO3: C, 58.36; H, 8.16; N, 7.56.
Found: C, 58.44; H, 8.12; N, 7.86.
N-Methoxycarbonyl-(2S,4R)-[4-(hydroxy)-2-(1,1-dimethyl-2-me-
thoxy-2-oxoethyl)]pyrrolidine (32). Obtained from the silyl ether 25
(108 mg, 0.3 mmol) according to method B. After work-up and
solvent evaporation, the residue was purified by radial chromatog-
raphy (hexanes/EtOAc, 50:50), yielding alcohol 32 (65.5 mg, 89%, Rf
20
= 0.27) as a viscous oil: [α]D +29 (c 0.63, CHCl3). IR (CHCl3)
1
νmax: 3445, 1726, 1697, 1450, 1388 cm−1. H NMR (CDCl3, 500
MHz, 26 °C): δ 4.26 (dd, J = 8.5, 7.5 Hz, 1H), 4.21 (dddd, J = 7.9,
7.9, 7.9, 7.8 Hz, 1H), 4.07−3.97 (m, 1H), 3.65 (s, 3H), 3.60 (s, 3H),
2.91 (dd, J = 11.3, 8.2 Hz, 1H), 2.76 (br s, 1H), 2.34 (dt, J = 13.5, 8.2
Hz, 1H), 1.63 (ddd, J = 13.2, 7.6, 6.6 Hz, 1H), 1.15 (s, 3H), 1.13 (s,
3H). 13C{1H} NMR (CDCl3, 125.7 MHz, 26 °C): δ 177.4 (C), 156.4
(C), 68.7 (CH), 62.1 (CH), 54.0 (CH2), 52.5 (CH3), 51.9 (CH3),
46.9 (C), 36.0 (CH2), 22.2 (CH3), 21.0 (CH3). HRMS (ESI) m/z:
[M + Na]+ calcd for C11H19NO5Na 268.1161; found 268.1165. Anal.
calcd for C11H19NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.68; H,
8.21; N, 5.82.
(2S,4R)-4-(Hydroxy)-2-(propyl)-N-(methoxycarbonyl)pyrrolidine
(29). Obtained from compound 10 (82.5 mg, 0.3 mmol) according to
the general method A. After work-up and solvent evaporation, the
residue was purified by radial chromatography (hexanes/EtOAc,
20
30:70), yielding 29 as a viscous oil (45 mg, 80%, Rf = 0.24): [α]D
+39 (c 0.16, CHCl3). IR (CHCl3) νmax: 3610, 3448, 1683, 1455, 1392
cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two
sets of signals at 26 °C, one set at 70 °C: δ 4.43−4.37 (m, 1H), 3.89−
3.84 (m, 1H), 3.76 (dd, J = 12.0, 6.0 Hz, 1H), 3.69 (s, 3H), 3.27 (dd,
J = 12.0, 4.0 Hz, 1H), 2.20 (ddd, J = 14.0, 8.0, 6.0 Hz, 1H), 1.96−1.89
(m, 1H), 1.74 (dt, J = 13.5, 4.0 Hz, 1H), 1.63 (br b, 1H), 1.61−1.54
(m, 1H), 1.41−1.27 (m, 2H), 0.95 (dd, J = 7.5, 7.0 Hz, 3H). 13C{1H}
NMR (CDCl3, 125.7 MHz, 70 °C): δ 155.7 (C), 70.7 (CH), 57.3
(CH), 54.7 (CH2), 52.0 (CH3), 39.2 (CH2), 37.4 (CH2), 19.5
(CH2), 13.9 (CH3). MS m/z (rel intensity) 187 (M+, <1), 144 ([M −
propyl]+, 100). HRMS (EI) m/z: [M]+ calcd for C9H17NO3
187.1208; found 187.1212; [M − propyl]+ calcd for C6H10NO3
144.0661; found 144.0654. Anal. calcd for C9H17NO3: C, 57.73; H,
9.15; N, 7.48. Found: C, 57.70; H, 9.21; N, 7.30.
( 2 R , 4 R ) - 4 - ( Hy dr o x y ) - 2 - ( 2 - o x o - 2 - p h e n y l e t h y l) - N -
(methoxycarbonyl)pyrrolidine (30). Obtained from silyl ether 24
(113 mg, 0.3 mmol) according to the general method B. After work-
up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 30:70), yielding alcohol 30 (69.5
mg, 88%, Rf = 0.23) as a viscous oil. This product was also obtained
(67 mg, 85%) from compound 12 (106 mg, 0.3 mmol) according to
method A: [α]D20 +12 (c 0.58, CHCl3). IR (CHCl3) νmax: 3431, 1684,
1455, 1391 cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer
equilibrium. Two sets of signals at 26 °C, one set at 70 °C: δ 7.99 (d,
J = 7.5 Hz, 2H), 7.54 (dd, J = 7.0, 6.5 Hz, 1H), 7.44 (dd, J = 8.0, 7.5
Hz, 2H), 4.49−4.41 (m, 2H), 3.68 (s, 3H), 3.68−3.65 (m, 2H), 3.48
(d, J = 12.0 Hz, 1H), 3.42 (dd, J = 16.0, 10.0 Hz, 1H), 2.30 (ddd, J =
14.0, 8.5, 5.3 Hz, 1H), 2.08 (br s, 1H), 1.93 (br d, J = 13.5 Hz, 1H).
13C{1H} NMR (CDCl3, 125.7 MHz, 70 °C): δ 199.3 (C), 155.5 (C),
N-Methoxycarbonyl-(2R,4R)-[4-(hydroxy)-2-(1,1-dimethyl-2-me-
thoxy-2-oxoethyl)]pyrrolidine (33). Obtained from silyl ether 26
(108 mg, 0.3 mmol) according to method B. After work-up and
solvent evaporation, the residue was purified by radial chromatog-
raphy (hexanes/EtOAc, 50:50), yielding alcohol 33 (68 mg, 93%, Rf =
0.24) as a viscous oil: [α]D20 −26 (c 1.10, CHCl3). IR (CHCl3) νmax
:
3439, 1726, 1697, 1449, 1387 cm−1. 1H NMR (CDCl3, 500 MHz, 26
°C): δ 4.47 (dd, J = 8.0, 7.5 Hz, 1H), 4.32−4.30 (m, 1H), 3.85−3.72
(m, 1H), 3.65 (s, 3H), 3.63 (s, 3H), 3.19 (dd, J = 12.3, 3.2 Hz, 1H),
3.02 (br s, 1H), 2.02 (dd, J = 14.0, 8.0 Hz, 1H), 1.86 (ddd, J = 13.5,
7.5, 5.5 Hz, 1H), 1.11 (s, 3H), 1.08 (s, 3H). 13C{1H} NMR (CDCl3,
125.7 MHz, 26 °C): δ 177.1 (C), 157.5 (C), 70.0 (CH), 61.9 (CH),
56.6 (CH2), 52.6 (CH3), 51.9 (CH3), 46.7 (C), 36.6 (CH2), 21.7
(CH3), 21.1 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd for
C11H19NO5Na 268.1161; found 268.1162. Anal. calcd for
C11H19NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.64; H, 7.95;
N, 5.69.
General Procedure for the Scission of the Pyrrolidine C4−C5
Bond. To a solution of the 2-alkyl-2-hydroxypyrrolidine (0.2 mmol)
in dry dichloromethane (4 mL) were added iodine (25 mg, 0.1 mmol)
and DIB (129 mg, 0.4 mmol). The resulting mixture was stirred for 3
h at 26 °C, under irradiation with visible light (80 W tungsten-
filament lamp). Then, the reaction mixture was poured into 10%
aqueous Na2S2O3 (10 mL) and extracted with CH2Cl2. The organic
layer was dried over sodium sulfate, filtered, and concentrated under
vacuum. The residue was purified by chromatography on silica gel
(hexanes/ethyl acetate) to give the scission products.
N-(Acetoxymethyl)-N-(methoxycarbonyl)-(3R)-aminohexanal
(34). Obtained from hydroxypyrrolidine 27 (37.5 mg, 0.2 mmol)
according to the general pyrrolidine scission procedure. After work-up
and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 80:20), yielding aldehyde 34 (31
mg, 63%, Rf = 0.30) as a viscous oil: [α]D20 −16 (c 0.10, CHCl3). IR
137.5 (C), 133.0 (CH), 128.6 (2 × CH), 128.2 (2 × CH), 70.7
(CH), 55.3 (CH2), 54.3 (CH), 52.2 (CH3), 43.8 (CH2), 39.6 (CH2).
HRMS (ESI) m/z: [M + Na]+ calcd for C14H17NO4Na 286.1055;
found 286.1051. Anal. calcd for C14H17NO4: C, 63.87; H, 6.51; N,
5.32. Found: C, 63.78; H, 6.68; N, 5.32.
1
(CHCl3) νmax: 1733, 1695, 1454, 1238, 1103, 1046 cm−1. H NMR
(CDCl3, 500 MHz, 26 °C): δ 9.69 (s, 1H), 5.37 (br d, J = 10.0 Hz,
1H), 5.26 (br d, J = 10.5 Hz, 1H), 4.48−4.42 (m, 1H), 3.73 (br s,
3H), 2.83−2.67 (m, 1H), 2.58 (dd, J = 17.0, 5.5 Hz, 1H), 2.04 (s,
3H), 1.75−1.55 (br b, 1H), 1.55−1.43 (m, 1H), 1.36−1.25 (m, 2H),
0.91 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz, 26 °C):
δ 200.3/199.8 (CH), 170.6 (C), 155.9 (C), 70.2 (CH2), 53.2 (CH),
52.4/51.6 (CH3), 48.2/47.7 (CH2), 35.6/35.1 (CH2), 21.0 (CH3),
(2S,4R)-2-Allyl-4-hydroxy-1-(methoxycarbonyl)pyrrolidine (31).
Obtained from silyl ether 23 (90 mg, 0.3 mmol) according to the
general method B. After work-up and solvent evaporation, the residue
was purified by radial chromatography (hexanes/EtOAc, 30:70),
20
yielding product 31 (49 mg, 89%, Rf = 0.25) as a viscous oil: [α]D
+43 (c 0.73, CHCl3). IR (CHCl3) νmax: 3611, 3441, 1685, 1455, 1392
cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two
2804
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
19.4 (CH2), 13.7 (CH3). HRMS (ESI) m/z: [M + Na + MeOH]+
calcd for C12H23NO6Na 300.1423; found 300.1421. Anal. calcd for
C11H19NO5: C, 53.87; H, 7.81; N, 5.71. Found: C, 53.79; H, 7.93; N,
6.03.
24.4 (CH3), 22.1 (CH3), 20.8 (CH3). HRMS (ESI) m/z: [M + Na +
MeOH]+ calcd for C14H25NO8Na 358.1478; found 358.1466. Anal.
calcd for C13H21NO7: C, 51.48; H, 6.98; N, 4.62. Found: C, 51.26; H,
7.05; N, 4.47.
N-(Acetoxymethyl)-N-(methoxycarbonyl)-(3S)-aminohexanal
(35). Obtained from the 2-propyl-4-hydroxypyrrolidine 29 (37 mg,
0.2 mmol) according to the general pyrrolidine scission procedure.
After work-up and solvent evaporation, the residue was purified by
radial chromatography (hexanes/EtOAc, 80:20), yielding aldehyde 35
(31 mg, 64%, Rf = 0.30) as a viscous oil: [α]D20 +20 (c 0.66, CHCl3).
IR (CHCl3) νmax: 3027, 1699, 1450, 1273, 1020 cm−1. 1H NMR
(CDCl3, 400 MHz, 26 °C): δ 9.69 (1H, s), 5.37 (br d, J = 10.8 Hz,
1H), 5.26 (br d, J = 11.2 Hz, 1H), 4.49−4.42 (m, 1H), 3.73 (br s,
3H), 2.81−2.62 (m, 1H), 2.59 (dd, J = 16.8, 7.0 Hz, 1H), 2.04 (s,
3H), 1.72−1.55 (m, 1H), 1.55−1.40 (m, 1H), 1.25−1.38 (m, 2H),
0.90 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (CD3OD, 125.7 MHz, 26
°C): δ 200.8 (CH), 172.1 (C), 158.1 (C), 70.9 (CH2), 55.2 (CH),
53.6 (CH3), 41.6 (CH2), 36.7 (CH2), 20.9 (CH3), 20.4 (CH2), 14.1
(CH3). HRMS (ESI) m/z: [M + Na]+ calcd for C11H19NO5Na
268.1161; found 268.1167. Anal. calcd for C11H19NO5: C, 53.87; H,
7.81; N, 5.71. Found: C, 53.75; H, 7.76; N, 6.00.
General Reductive Amination Procedure. A solution of the
aldehyde (0.15 mmol) in dry dichloroethane (3 mL) was treated with
the corresponding amine (0.17 mmol) and Et3N (28 μL, 0.2 mmol).
The resulting mixture was stirred for 30 min and then NaBH(OAc)3
(95 mg, 0.45 mmol) was added. The stirring continued until the
disappearance of the starting material (4−16 h). Then, the mixture
was poured into saturated aqueous NaHCO3, and extracted with
CH2Cl2. The organic layer was dried over sodium sulfate, filtered, and
concentrated under vacuum. The residue was purified by chromatog-
raphy on silica gel (hexanes/ethyl acetate) to give the reductive
amination products.
(3R)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-5-(diben-
zylamino)-1-(phenyl)-1-pentanone (39). Obtained from aldehyde 36
(48 mg, 0.15 mmol) according to the general reductive amination
procedure using dibenzylamine (33 μL, 34 mg, 0.17 mmol). After
work-up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 90:10), yielding diamine 39 (51
20
(3R)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-5-(oxo)-5-
(phenyl)pentanal (36). Obtained from compound 30 (53 mg, 0.2
mmol) according to the general pyrrolidine scission procedure. After
work-up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 80:20), yielding aldehyde 36 (47
mg, 68%) as a viscous oil: [α]D +6 (c 0.85, CHCl3). IR (CHCl3)
1
νmax: 3091, 3067, 1707, 1449, 1237 cm−1. H NMR (CD3OD, 500
MHz, 26 °C) rotamer equilibrium. Two sets of signals at 26 °C: δ
7.87 (d, J = 7.0 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz,
2H), 7.32 (d, J = 7.5 Hz, 4H), 7.22 (dd, J = 8.0, 7.0 Hz, 4H), 7.12
(dd, J = 7.6, 7.4 Hz, 2H), 5.35/5.28 (d, J = 10.1 Hz/d, J = 8.0 Hz,
1H), 5.12 (d, J = 11.0 Hz, 1H), 4.65−4.54 (m, 1H), 3.63 (s, 3H),
3.63−3.55 (m, 2H), 3.42−3.37 (m, 2H), 3.40−3.20 (br b, 2H), 2.46−
2.40 (m, 2H), 2.05−1.75 (m, 2H), 1.65/1.57 (s/s, 3H). 13C{1H}
NMR (CD3OD, 125.7 MHz, 26 °C): δ 200.0 (C), 172.0 (C), 158.3/
157.4 (C), 140.7 (2 × C), 138.2 (C), 134.4 (CH), 130.2 (2 × CH),
129.7 (4 × CH), 129.3 (4 × CH), 129.2 (2 × CH), 128.1 (2 × CH),
73.1/72.1 (CH2), 59.3 (2 × CH2), 53.7/53.5 (CH), 52.7 (CH3), 50.6
(CH2), 41.9/41.6 (CH2), 31.6/30.9 (CH2), 20.6 (CH3). HRMS
(ESI) m/z: [M + H − CO2Me]+ calcd for C28H31N2O3 443.2335;
found 443.2327. Anal. calcd for C30H34N2O5: C, 71.69; H, 6.82; N,
5.57. Found: C, 71.78; H, 7.08; N, 5.92.
20
mg, 73%, Rf = 0.24) as a viscous oil: [α]D +14 (c 0.33, CHCl3). IR
(CHCl3) νmax: 1705, 1686, 1449, 1274, 1145 cm−1. 1H NMR (CDCl3,
500 MHz, 70 °C) rotamer equilibrium. Two sets of signals at 26 °C,
one set at 70 °C: δ 9.77 (t, J = 2.0 Hz, 1H), 7.93 (d, J = 7.0 Hz, 2H),
7.56 (dd, J = 7.9, 7.5 Hz, 1H), 7.46 (dd, J = 8.0, 7.5 Hz, 2H), 5.43 (d,
J = 13.0 Hz, 1H), 5.41 (d, J = 12.0 Hz, 1H), 4.85−4.76 (m, 1H), 3.73
(s, 3H), 3.63−3.52 (m, 1H), 3.33 (dd, J = 17.5, 6.0 Hz, 1H), 3.09−
3.01 (m, 1H), 2.90 (dd, J = 17.2, 5.5 Hz, 1H), 1.97 (s, 3H). 13C{1H}
NMR (CDCl3, 125.7 MHz, 70 °C): δ 199.3 (C), 197.2 (C), 170.3
(C), 155.7 (C), 137.0 (C), 133.4 (CH), 128.7 (2 × CH), 128.1 (2 ×
CH), 73.3 (CH2), 53.0 (CH3), 50.9 (CH), 47.5 (CH2), 42.0 (CH2),
20.7 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd for C16H19NO6Na
344.1110; found 344.1109. Anal. calcd for C16H19NO6: C, 59.81; H,
5.96; N, 4.36. Found: C, 59.87; H, 6.27; N, 4.75.
Methyl (3S)-Buten-1-yl(5-(dibenzylamino)-1-oxo-1-phenylpen-
tan-3-yl)carbamate (40). A solution of substrate 39 (45 mg, 0.09
mmol) in dry acetonitrile (2 mL) was treated at 0 °C with
allyltrimethylsilane (40 μL, 29 mg, 0.25 mmol) and trimethylsilyl
triflate (30 μL, 37 mg, 0.17 mmol). The resulting mixture was stirred
for 1.5 h, then poured into satured aqueous NaHCO3, and extracted
with EtOAc. The organic layer was dried over sodium sulfate and
concentrated under vacuum, and the residue was purified by
chromatography on silica gel (hexanes/ethyl 80:20) to give
Methyl (3R)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-
2,2-dimethyl-5-oxopentanoate (37). Obtained from compound 32
(49 mg, 0.2 mmol) according to the general pyrrolidine scission
procedure. After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 80:20), yielding
20
aldehyde 37 (38 mg, 63%, Rf = 0.10) as a viscous oil: [α]D +15 (c
0.54, CHCl3). IR (CHCl3) νmax: 1725, 1572, 1444, 1345, 1015 cm−1.
1H NMR (CDCl3, 500 MHz, 26 °C): δ 9.67 (s, 1H), 5.48−5.32 (br b,
20
compound 40 (31 mg, 71%, Rf = 0.29) as a viscous oil: [α]D +2
1H), 5.26 (br d, J = 11.5 Hz, 1H), 5.00−4.60 (br b, 1H), 3.75 (br s,
3H), 3.69 (s, 3H), 3.05−2.85 (m, 1H), 2.71 (br d, J = 13.6 Hz, 1H),
2.00 (s, 3H), 1.24 (s, 3H), 1.22 (s, 3H). 13C{1H} NMR (CDCl3,
125.7 MHz, 26 °C): δ 199.6 (CH), 176.0 (C), 170.3 (C), 156.7 (C),
70.2 (CH2), 57.6 (CH), 53.5 (CH3), 52.2 (CH3), 46.7 (C), 42.6
(CH2), 24.4 (CH3), 22.2 (CH3), 20.8 (CH3). HRMS (ESI) m/z: [M
+ Na + MeOH]+ calcd for C14H25NO8Na 358.1478; found 358.1468.
Anal. calcd for C13H21NO7: C, 51.48; H, 6.98; N, 4.62. Found: C,
51.59; H, 6.88; N, 4.35.
(c 0.21, CHCl3). IR (CHCl3) νmax: 1691, 1573, 1449, 1366, 1003
1
cm−1. H NMR (CD3OD, 500 MHz, 70 °C): δ 7.87 (d, J = 8.0 Hz,
2H), 7.58 (t, J = 7.5 Hz, 1H), 7.46 (dd, J = 8.0, 7.5 Hz, 2H), 7.31 (d, J
= 7.6 Hz, 4H), 7.24 (t, J = 7.6 Hz, 4H), 7.16 (dd, J = 7.5, 7.0 Hz, 2H),
5.69−5.61 (m, 1H), 4.94−4.91 (m, 2H), 4.15−4.00 (br b, 3H), 3.61
(d, J = 13.5 Hz, 2H), 3.55 (s, 3H), 3.50 (d, J = 13.5 Hz, 2H), 3.11−
2.98 (m, 2H), 2.47 (t, J = 6.8 Hz, 2H), 2.09 (q, J = 7.4 Hz, 2H),
1.95−1.80 (br s, 2H). 13C{1H} NMR (CD3OD, 125.7 MHz, 26 °C):
δ 200.5 (C), 158.3 (C), 140.4/140.3 (2 × C), 138.3/138.2 (C), 136.6
(CH), 134.4 (CH), 130.4 (2 × CH), 130.3 (2 × CH), 129.8 (2 ×
CH), 129.3 (4 × CH), 129.2 (2 × CH), 128.2 (2 × CH), 116.8
(CH2), 59.4 (2 × CH2), 54.5 (CH), 53.1 (CH2), 52.9 (CH3), 51.0
(CH2), 47.5/46.1 (CH2), 35.0/34.3 (CH2), 31.9/30.9 (CH2). HRMS
(ESI) m/z: [M + Na]+ calcd for C31H36N2O3Na 507.2624; found
507.2626. Anal. calcd for C31H36N2O3: C, 76.83; H, 7.49; N, 5.78.
Found: C, 77.05; H, 7.69; N, 5.71.
Methyl (3R)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-
2,2-(dimethyl)-5-dibenzylaminopentanoate (41). Obtained from
aldehyde 38 (37 mg, 0.15 mmol) according to the general procedure
for the reductive amination (16 h) using dibenzylamine as a reagent
(33 μL, 34 mg, 0.17 mmol). After work-up and solvent evaporation,
the residue was purified by radial chromatography (hexanes/EtOAc,
Methyl (3S)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-
2,2-dimethyl-5-oxopentanoate (38). Obtained from compound 33
(49 mg, 0.2 mmol) according to the general pyrrolidine scission
procedure. After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 70:30), yielding
20
aldehyde 38 (37 mg, 61%, Rf = 0.10) as a viscous oil: [α]D1 −17 (c
0.56, CHCl3). IR (CHCl3) νmax: 3022, 1726, 1445 cm−1. H NMR
(CDCl3, 400 MHz, 26 °C): δ 9.67 (br s, 1H), 5.48−5.32 (br b, 1H),
5.25 (br d, J = 11.4 Hz, 1H), 5.00−4.60 (m, 1H), 3.76 (br s, 3H),
3.70 (s, 3H), 3.05−2.85 (m, 1H), 2.71 (br d, J = 13.6 Hz, 1H), 2.02
(s, 3H), 1.23 (s, 3H), 1.22 (s, 3H). 13C{1H} NMR (CDCl3, 125.7
MHz, 26 °C): δ 199.7 (CH), 176.0 (C), 170.4 (C), 156.7 (C), 70.5
(CH2), 57.8 (CH), 53.5 (CH3), 52.2 (CH3), 46.6 (C), 42.6 (CH2),
2805
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
40:60), yielding diamine 41 (49 mg, 67%) as a viscous oil: [α]D20 −27
(c 1.01, CHCl3). IR (CHCl3) νmax: 1716, 1446, 1251, 1131 cm−1. 1H
NMR (CD3OD, 500 MHz, 26 °C): δ 7.36−7.34 (m, 4H), 7.29 (t, J =
7.5 Hz, 4H), 7.21 (dd, J = 7.5, 6.5 Hz, 2H), 5.20−5.10 (br b, 2H),
4.67−4.51 (m, 1H), 3.68 (s, 3H), 3.64 (br d, J = 13.5 Hz, 2H), 3.54
(s, 3H), 3.33 (br d, J = 12.0 Hz, 2H), 2.55−2.45 (m, 1H), 2.34−2.23
(m, 1H), 1.82 (s, 3H), 1.78−1.65 (m, 2H), 1.13 (s, 3H), 1.11 (s, 3H).
13C{1H} NMR (CD3OD, 125.7 MHz, 26 °C): δ 178.2 (C), 171.8
C15H27N2O5 315.1920; found 315.1914. Anal. calcd for C17H30N2O7:
C, 54.53; H, 8.08; N, 7.48. Found: C, 54.63; H, 8.04; N, 7.18.
Methyl (2S,4R)-1-[(R)-3-[(Acetoxymethyl)(methoxycarbonyl)-
amino]-5-methoxy-4,4-dimethyl-5-oxopentyl]-4-hydroxypyrroli-
dine-2-carboxylate (45). Obtained from aldehyde 37 (45.5 mg, 0.15
mmol) according to the reductive amination procedure (16 h) using
4-trans-hydroxyproline methyl ester hydrochloride as reagent (31 mg,
0.17 mmol). After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 30:70), yielding
(C), 158.9 (C), 140.7 (2 × C), 130.0 (4 × CH), 129.3 (4 × CH),
128.0 (2 × CH), 70.4 (CH2), 60.1 (CH), 59.6 (2 × CH2), 53.9
(CH3), 52.5 (CH3), 51.5 (CH2), 48.6 (C), 26.8 (CH2), 24.4 (CH3),
21.7 (CH3), 20.8 (CH3). HRMS (ESI) m/z: [M + H]+ calcd for
C27H37N2O6 485.2652; found 485.2644. Anal. calcd for C27H36N2O6:
C, 66.92; H, 7.49; N, 5.78. Found: C, 67.00; H, 7.22; N, 6.03.
Methyl (R)-5-(Dibenzylamino)-3-[(methoxycarbonyl)(methyl)-
amino]-2,2-dimethylpentanoate (42). A solution of substrate 41
(58 mg, 0.12 mmol) in dry acetonitrile (3 mL) was treated at 0 °C
with triethylsilane (96 μL, 70 mg, 0.6 mmol) and trimethylsilyl triflate
(43 μL, 53 mg, 0.24 mmol). The resulting mixture was stirred for 3 h,
then poured into satured aqueous NaHCO3, and extracted with
EtOAc. The organic layer was dried over sodium sulfate and
concentrated under vacuum, and the residue was purified by
chromatography on silica gel (hexanes/EtOAc 80:20) to give
20
diamine 45 (33 mg, 51%, Rf = 0.18) as a viscous oil: [α]D +40 (c
0.21, CHCl3). IR (CHCl3) νmax: 3356, 1722, 1568, 1260, 1159 cm−1.
1H NMR (CD3OD, 400 MHz, 26 °C): δ 5.37−5.25 (m, 2H), 4.70−
4.38 (br b, 1H), 4.40−4.30 (m, 1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.67
(s, 3H), 3.47 (t, J = 7.6 Hz, 1H), 3.35−3.30 (m, 1H), 2.78−2.68 (m,
1H), 2.46−2.36 (m, 2H), 2.04 (s, 3H), 2.15−1.90 (m, 2H), 1.80−
1.69 (m, 1H), 1.21 (s, 3H), 1.18 (s, 3H). 13C{1H} NMR (CD3OD,
125.7 MHz, 26 °C) δ 178.1 (C), 175.4 (C), 171.9 (C), 159.9 (C),
70.6 (CH2), 70.5 (CH), 65.9 (CH), 62.3 (CH2), 60.6 (CH), 53.9
(CH3), 53.6/53.2 (CH2), 52.5 (CH3), 52.4 (CH3), 39.9 (C), 38.9/
38.8 (CH2), 28.2 (CH2), 24.5/24.4 (CH3), 22.3/21.9 (CH3), 20.9
(CH3). HRMS (ESI) m/z: [M + Na]+ calcd for C19H32N2O9Na
455.2006; found 455.2002. Anal. calcd for C19H32N2O9: C, 52.77; H,
7.46; N, 6.48. Found: C, 52.81; H, 7.60; N, 6.47.
20
Methyl (2S,4R)-1-[(S)-3-[(Acetoxymethyl)(methoxycarbonyl)-
amino]-5-methoxy-4,4-dimethyl-5-oxopentyl]-4-hydroxypyrroli-
dine-2-carboxylate (46). Obtained from aldehyde 38 (45.5 mg, 0.15
mmol) according to the reductive amination procedure (16 h) using
4-trans-hydroxyproline methyl ester hydrochloride as a reagent (31
mg, 0.17 mmol). After work-up and solvent evaporation, the residue
was purified by radial chromatography (hexanes/EtOAc, 30:70),
compound 42 (37 mg, 73%, Rf = 0.20) as a viscous oil: [α]D −7
(c 0.10, CHCl3). IR (CHCl3) νmax: 1730, 1697, 1455, 1232, 1046
1
cm−1. H NMR (CDCl3, 500 MHz, 70 °C): δ 7.38 (d, J = 7.5 Hz,
4H), 7.34 (t, J = 7.5 Hz, 4H), 7.26 (t, J = 7.0 Hz, 2H), 4.38−4.24 (m,
1H), 3.69 (s, 3H), 3.65 (s, 3H), 3.62 (br s, 4H), 2.64/2.55 (s/s, 3H),
2.51−2.33 (m, 2H), 1.84−1.67 (m, 2H), 1.20 (br s, 3H), 1.18 (s,
3H). 13C{1H} NMR (CDCl3, 125.7 MHz, 26 °C): δ 176.9 (C), 157.9
(C), 139.7 (C), 139.6 (C), 128.9 (4 × CH), 128.2 (4 × CH), 126.9
(2 × CH), 60.0 (CH), 59.0 (CH2), 58.9 (CH2), 52.5 (CH3), 51.6
(CH3), 51.4 (CH2), 47.4 (C), 30.0 (CH3), 25.2 (CH2), 24.1 (CH3),
22.2 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd for C25H34N2O4Na
449.2416; found 449.2415. Anal. calcd for C25H34N2O4: C, 70.40; H,
8.03; N, 6.57. Found: C, 70.31; H, 7.82; N, 6.47.
Methyl (3S)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-
2,2-(dimethyl)-5-morpholinyl-pentanoate (43). Obtained from
aldehyde 37 (45 mg, 0.15 mmol) according to the reductive
amination procedure using morpholine (15 μL, 15 mg, 0.17 mmol).
After usual work-up and solvent removal, the residue was purified by
radial chromatography (hexanes/EtOAc, 40:60), yielding diamine 43
(41 mg, 73%, Rf = 0.15) as a viscous oil: [α]D20 +18 (c 0.78, CHCl3).
IR (CHCl3) νmax: 1720, 1570, 1450, 1274, 1138 cm−1. 1H NMR
(CD3OD, 400 MHz, 70 °C): δ 5.41 (d, J = 10.8 Hz, 1H), 5.29 (d, J =
10.8 Hz, 1H), 4.60−4.36 (br b, 1H), 3.80−3.67 (m, 4H), 3.67 (s,
6H), 2.46−2.33 (m, 6H), 2.02 (s, 3H), 1.80−1.74 (m, 2H), 1.22 (s,
3H), 1.20 (s, 3H). 13C{1H} NMR (CD3OD, 125.7 MHz, 70 °C): δ
179.7 (C), 177.7 (C), 157.7 (C), 69.2 (CH2), 61.9 (CH2), 61.7
(CH2), 60.1 (CH), 58.9 (CH2), 58.7 (CH2), 58.4 (CH2), 54.7
(CH3), 52.8 (CH3), 48.2 (C), 24.2 (CH2), 22.6 (2 × CH3), 20.3
(CH3). HRMS (ESI) m/z: [M − CO2Me]+ calcd for C15H27N2O5
315.1920; found 315.1915. Anal. calcd for C17H30N2O7: C, 54.53; H,
8.08; N, 7.48. Found: C, 54.26; H, 8.44; N, 7.41.
20
yielding diamine 46 (42 mg, 65%, Rf = 0.18) as a viscous oil: [α]D
−47 (c 0.17, CHCl3). IR (CHCl3) νmax: 3347, 1722, 1573, 1260, 1157
cm−1. 1H NMR (CD3OD, 400 MHz, 26 °C): δ 5.38 (d, J = 11.0 Hz,
1H), 5.29 (d, J = 10.5 Hz, 1H), 4.50 (br b, 1H), 4.37−4.31 (m, 1H),
3.73 (s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.48−3.30 (m, 2H), 2.75−
2.64 (m, 1H), 2.47−2.37 (m, 1H), 2.33−2.24 (m, 1H), 2.15−2.05
(m, 1H), 2.03 (s, 3H), 2.04−1.94 (m, 1H), 1.90−1.65 (m, 2H), 1.22
(s, 3H), 1.18 (s, 3H). 13C{1H} NMR (CD3OD, 125.7 MHz, 26 °C):
δ 178.1 (C), 175.4 (C), 172.0 (C), 159.3 (C), 70.6 (CH2), 70.5
(CH), 65.9 (CH), 62.3 (CH2), 60.6 (CH), 53.9 (CH3), 53.6 (CH2),
52.6 (CH3), 52.4 (CH3), 39.94 (CH2), 39.90 (C), 28.2 (CH2), 24.5
(CH3), 21.9 (CH3), 20.9 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd
for C19H32N2O9Na 455.2006; found 455.1991. Anal. calcd for
C19H32N2O9: C, 52.77; H, 7.46; N, 6.48. Found: C, 52.51; H, 7.52;
N, 6.20.
General Procedure for the Horner−Wadsworth−Emmons
Reaction for the Synthesis of Peptides with Dehydroamino
Acid Units. To a solution of the α-phosphonate (0.05 mmol) in dry
CH2Cl2 (2 mL) was added a solution of tetramethylguanidine (16 μL,
14.5 mg, 0.125 mmol) in dry CH2Cl2 (0.5 mL). The reaction mixture
was stirred for 10 min, and then, the aldehyde (0.1 mmol) in dry
CH2Cl2 (0.5 mL) was added. After stirring for 16 h, the solution was
poured into saturated aqueous NaHCO3 and extracted with CH2Cl2.
The organic layer was dried over sodium sulfate, filtered, and
evaporated under vacuum. The residue was purified by chromatog-
raphy on silica gel (hexanes/EtOAc) affording the peptides with
dehydroamino acid units 49−51.
(Z,R)-N-[5-((Acetoxymethyl)(methoxycarbonyl)amino)-2-(N-ben-
zoyl-O-benzyl-L-seryl)amino-2-octenoyl]-L-leucine Methyl Ester
(49). Obtained using aldehyde 34 (24.5 mg, 0.1 mmol) and
phosphonate 47 (31 mg, 0.05 mmol)1a according to the general
procedure for the Horner−Wadsworth−Emmons reaction. After
work-up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 50:50), yielding peptide 49 (30
mg, 85%, Rf = 0.10) as a viscous oil: [α]D20 −23 (c 0.52, CHCl3). IR
(CHCl3) νmax: 3413, 3337, 1734, 1705, 1655, 1508, 1481, 1241, 1015
cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two
sets of signals at 26 °C, one set at 70 °C: δ 7.88 (br s, 1H), 7.81 (d, J
= 7.0 Hz, 2H), 7.52 (dd, J = 7.5, 7.0 Hz, 1H), 7.43 (dd, J = 8.0, 7.5
Hz, 2H), 7.38−7.28 (m, 5H), 7.07 (d, J = 6.0 Hz, 1H), 6.76 (d, J =
7.5 Hz, 1H), 6.52 (t, J = 7.5 Hz, 1H), 5.27 (s, 2H), 4.82 (ddd, J = 6.0,
Methyl (3R)-[N-(Acetoxymethyl)-N-(methoxycarbonyl)amino]-
2,2-(dimethyl)-5-morpholinyl-pentanoate (44). Obtained from
aldehyde 38 (45 mg, 0.15 mmol) according to the general procedure
for the reductive amination, using morpholine (15 μL, 15 mg, 0.17
mmol). After work-up and solvent evaporation, the residue was
purified by radial chromatography (hexanes/EtOAc, 40:60), yielding
20
diamine 44 (38 mg, 68%, Rf = 0.15) as a viscous oil: [α]D1 −16 (c
1.06, CHCl3). IR (CHCl3) νmax: 1720, 1573, 1450 cm−1. H NMR
(CD3OD, 400 MHz, 26 °C): δ 5.41 (d, J = 11.2 Hz, 1H), 5.29 (d, J =
10.4 Hz, 1H), 4.63−4.35 (br b, 1H), 3.73 (m, 3H), 3.80−3.50 (m,
4H), 3.66 (s, 3H), 2.55−2.30 (m, 6H), 2.02 (s, 3H), 1.98−1.68 (m,
2H), 1.22 (s, 3H), 1.19 (s, 3H). 13C{1H} NMR (CD3OD, 125.7
MHz, 70 °C): δ 179.7 (C), 177.7 (C), 157.7 (C), 69.2 (CH2), 61.9
(CH2), 61.7 (CH2), 60.1 (CH), 58.9 (CH2), 58.5 (CH2), 58.4
(CH2), 54.7 (CH3), 52.8 (CH3), 48.2 (C), 24.2 (CH2), 22.6 (2 ×
CH3), 20.3 (CH3). HRMS (ESI) m/z: [M − CO2Me]+ calcd for
2806
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
6.0, 5.0 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H),
4.66−4.61 (m, 1H), 4.10 (dd, J = 9.7, 4.7 Hz, 1H), 3.98−3.92 (m,
1H), 3.84 (dd, J = 9.5, 6.5 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 2.50−
2.40 (m, 1H), 2.30 (ddd, J = 15.5, 6.6, 6.5 Hz, 1H), 2.00 (s, 3H),
1.63−1.69 (m, 2H), 1.62−1.54 (m, 2H), 1.50−1.39 (m, 1H), 1.35−
1.20 (m, 2H), 0.92 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H), 0.87
(dd, J = 7.5, 7.0 Hz, 3H). 13C{1H} NMR (CDCl3, 125.7 MHz, 70
°C): δ 173.2 (C), 170.6 (C), 169.1 (C), 167.7 (C), 163.6 (C), 156.8
(C), 139.3 (C), 137.5 (C), 133.6 (C), 132.0 (CH), 131.4 (CH),
128.7 (2 × CH), 128.6 (2 × CH), 128.2 (CH), 127.9 (2 × CH),
127.3 (2 × CH), 73.8 (CH2), 70.2 (CH2), 69.4 (CH2), 57.2 (CH),
54.2 (CH), 53.0 (CH3), 52.0 (CH3), 51.4 (CH), 41.6 (CH2), 35.6
(CH2), 32.5 (CH2), 24.9 (CH), 22.7 (CH3), 22.0 (CH3), 20.9
(CH3), 19.6 (CH2), 13.7 (CH3). HRMS (ESI) m/z: [M + Na]+ calcd
for C37H50N4O10Na 733.3425; found 733.3433. Anal. calcd for
C37H50N4O10: C, 62.52; H, 7.09; N, 7.88. Found: C, 62.67; H, 7.11;
N, 8.01.
(Z,S)-N-[5-((Acetoxymethyl)(methoxycarbonyl)amino)-2-(N-ben-
zoyl-O-benzyl-L-seryl)amino-2-octenoyl]-L-leucine Methyl Ester
(50). Obtained from aldehyde 35 (24.5 mg, 0.1 mmol) and
phosphonate 47 (31 mg, 0.05 mmol)1a according to the general
procedure for the Horner−Wadsworth−Emmons reaction. After
work-up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 50:50), yielding peptide 50 (31
mg, 87%, Rf = 0.10) as a viscous oil: [α]D20 −28 (c 0.68, CHCl3). IR
(CHCl3) νmax: 3410, 3336, 1735, 1705, 1653, 1515, 1481, 1241, 1015
cm−1. 1H NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two
sets of signals at 26 °C, one set at 70 °C: δ 7.90 (br s, 1H), 7.80 (d, J
= 7.5 Hz, 2H), 7.51 (dd, J = 7.5, 7.0 Hz, 1H), 7.42 (dd, J = 8.0, 7.5
Hz, 2H), 7.40−7.27 (m, 5H), 7.05 (d, J = 6.0 Hz, 1H), 6.78 (d, J =
8.0 Hz, 1H), 6.52 (t, J = 7.3 Hz, 1H), 5.26 (d, J = 11.0 Hz, 1H), 5.24
(d, J = 11.5 Hz, 1H), 4.79 (dt, J = 6.0, 5.5 Hz, 1H), 4.69 (d, J = 12.5
Hz, 1H), 4.65−4.61 (m, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.07 (dd, J =
9.5, 5.0 Hz, 1H), 4.00−3.93 (m, 1H), 3.85 (dd, J = 9.7, 6.2 Hz, 1H),
3.70 (s, 3H), 3.69 (s, 3H), 2.51−2.41 (m, 1H), 2.30 (dt, J = 15.5, 6.5
Hz, 1H), 1.99 (s, 3H), 1.72−1.62 (m, 2H), 1.61−1.50 (m, 2H),
1.50−1.38 (m, 1H), 1.35−1.20 (m, 2H), 0.90 (d, J = 6.0 Hz, 3H),
0.87 (dd, J = 8.0, 7.0 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H). 13C{1H}
NMR (CDCl3, 125.7 MHz, 70 °C) δ 173.3 (C), 170.6 (C), 169.0
(C), 167.8 (C), 163.6 (C), 156.7 (C), 139.3 (C), 137.4 (C), 133.4
(C), 132.1 (CH), 131.7 (CH), 128.7 (2 × CH), 128.6 (2 × CH),
128.1 (CH), 127.9 (2 × CH), 127.3 (2 × CH), 73.7 (CH2), 70.2
(CH2), 69.2 (CH2), 57.1 (CH), 54.3 (CH), 53.0 (CH3), 52.1 (CH3),
51.2 (CH), 41.5 (CH2), 35.5 (CH2), 32.3 (CH2), 24.8 (CH), 22.7
(CH3), 21.9 (CH3), 20.9 (CH3), 19.6 (CH2), 13.7 (CH3). HRMS
(ESI) m/z: [M + Na]+ calcd for C37H50N4O10Na 733.3425; found
733.3428. Anal. calcd for C37H50N4O10: C, 62.52; H, 7.09; N, 7.88.
Found: C, 62.83; H, 7.20; N, 7.65.
(CH), 128.64 (2 × CH), 128.59 (CH), 128.5 (4 × CH), 128.0 (2 ×
CH), 127.9 (CH), 127.8 (2 × CH), 127.2 (2 × CH), 73.6 (CH2),
73.1 (CH2), 69.3 (CH2), 58.8 (CH), 55.0 (CH), 53.1 (CH3), 52.4
(CH3), 41.8 (CH2), 31.8 (CH2), 20.8 (CH3). HRMS (ESI) m/z: [M
+ Na]+ calcd for C36H39N3O10Na 696.2533; found 696.2532. Anal.
calcd for C36H39N3O10: C, 64.18; H, 5.84; N, 6.24. Found: C, 64.36;
H, 5.78; N, 6.57.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02751.
■
sı
Procedures for the preparation of new substrates 8, 16,
18, 19, 22, and 27−33 and products 10−14, 20, 21,
1
23−26, and 34−51; their reproduction of H and 13C
NMR spectra; and NOESY and heteronuclear single
quantum coherence (HSQC) experiments of com-
pounds 49−51 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
Dacil Hernandez − Instituto de Productos Naturales y
Agrobiología del CSIC, 38206 La Laguna, Tenerife, Spain;
Email: dacil@ipna.csic.es
Alicia Boto − Instituto de Productos Naturales y Agrobiología
del CSIC, 38206 La Laguna, Tenerife, Spain; orcid.org/
0000-0002-7120-679X; Phone: +34-922-260112.;
Email: alicia@ipna.csic.es
Author
Carmen Carro − Instituto de Productos Naturales y
Agrobiología del CSIC, 38206 La Laguna, Tenerife, Spain;
BIOSIGMA, 38003 Santa Cruz de Tenerife, Tenerife, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02751
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partly financed by project APOGEO
(Cooperation Program INTERREG-MAC 2014−2020, with
European Funds for Regional Development-FEDER) and by
project SAF-2013-48399-R, Plan Estatal I+D-RETOS (MINE-
CO-MCIU)-European Social Funds (ESF). D.H. also acknowl-
edges her current contract (TRANSALUDAGRO) financed by
Cabildo de Tenerife, Program TF INNOVA 2016-21 (with
MEDI & FDCAN Funds). C.C. was granted a contract from
the Doctorados Industriales Programme (DI-14-06736) by
MINECO/Min. Science and Innovation, cofinanced by
BIOSIGMA SL. C.C. carried out her work as a Ph.D. student
of the program “Química e Ingeniería Química” of the
University of La Laguna (ULL).
(Z,R)-5-[(Acetoxymethyl)(methoxycarbonyl)amino]-2-(N-benzo-
yl-O-benzyl-L-seryl)amino-7-oxo-7-phenyl-hept-2-enoate Methyl
Ester (51). Obtained using aldehyde 36 (32 mg, 0.1 mmol) and
phosphonate 48 (25 mg, 0.05 mmol)1a according to the general
procedure for the Horner−Wadsworth−Emmons reaction. After
work-up and solvent evaporation, the residue was purified by radial
chromatography (hexanes/EtOAc, 50:50), yielding peptide 51 (28
20
mg, 83%, Rf = 0.08) as a viscous oil: [α]D +13 (c 0.73, CHCl3). IR
1
(CHCl3) νmax: 3412, 3314, 1715, 1660, 1481, 1258, 1017 cm−1. H
NMR (CDCl3, 500 MHz, 70 °C) rotamer equilibrium. Two sets of
signals at 26 °C, one set at 70 °C: δ 8.11 (s, 1H), 7.88 (d, J = 7.0 Hz,
2H), 7.84 (d, J = 7.0 Hz, 2H), 7.54 (dd, J = 7.5, 7.0 Hz, 1H), 7.50
(dd, J = 7.5, 7.0 Hz, 1H), 7.42 (dd, J = 8.0, 7.5 Hz, 4H), 7.35−7.24
(m, 5H), 7.14 (d, J = 6.5 Hz, 1H), 6.67 (t, J = 7.4 Hz, 1H), 5.44 (d, J
= 11.0 Hz, 1H), 5.31 (d, J = 11.0 Hz, 1H), 4.93 (dt, J = 6.7, 4.3 Hz,
1H), 4.69 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.56−4.40
(m, 1H), 4.10 (dd, J = 9.5, 4.0 Hz, 1H), 3.79 (dd, J = 9.5, 7.0 Hz,
1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.63−3.48 (m, 1H), 3.10 (dd, J =
17.5, 6.0 Hz, 1H), 2.86−2.67 (m, 1H), 2.53 (ddd, J = 15.5, 7.5, 6.1
Hz, 1H), 1.92 (s, 3H). 13C{1H} NMR (CDCl3, 125.7 MHz, 26 °C):
δc 197.5 (C), 170.6 (C), 168.9 (C), 167.4 (C), 164.2 (C), 155.5 (C),
137.6 (C), 136.5 (C), 133.7 (C), 133.6 (C), 133.4 (CH), 131.9
ABBREVIATIONS
DIB, (diacetoxyiodo)benzene; DCM, dichloromethane; Hyp,
hydroxyproline; MeOH, methanol; EtOAc, ethyl acetate
■
REFERENCES
■
(1) (a) For previous articles summarizing customizable units, see:
Saavedra, C. J.; Hernandez, D.; Boto, A. Metal-Free, Site-Selective
Peptide Modification by Conversion of “Customizable” Units into β-
Substituted Dehydroamino Acids. Chem. − Eur. J. 2018, 24, 599−607.
́
2807
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
́
́
(b) Romero-Estudillo, I.; Saavedra, C. J.; Boto, A.; Alvarez, E. Site-
selective modification of peptides: From “customizable units” to novel
α-aryl and α-alkyl glycine derivatives, and components of branched
peptides. Biopolymers 2015, 104, 650−662. (c) Saavedra, C. J.; Boto,
(6) (a) Boto, A.; Gallardo, J. A.; Hernandez, D.; Hernandez, R.
Synthesis of Unnatural Amino Acids from Serine Derivatives by β-
Fragmentation of Primary Alkoxyl Radicals. J. Org. Chem. 2007, 72,
7260−7269. (b) Carro, C.; Romero, I.; Boto, A. Microwave versus
Conventional Light Activation of O-Radical Scission Processes. Eur. J.
Org. Chem. 2017, 373−380 and references cited therein.
́
A.; Hernandez, R. Synthesis of α,γ-Peptide Hybrids by Selective
Conversion of Glutamic Acid Units. Org. Lett. 2012, 14, 3542−3545
and references cited therein.
(2) (a) For other articles on customizable units, see: Bloom, S.; Liu,
́
́
(7) Hernandez, D.; Boto, A.; Guzman, D.; Alvarez, E. Metal-free,
direct conversion of α-amino acids into α-keto γ-amino esters for the
synthesis of α,γ-peptides. Org. Biomol. Chem. 2017, 15, 7736−7742
and references cited therein.
̈
C.; Kolmel, D. K.; Qiao, J. X.; Zhang, Y.; Poss, M. A.; Ewing, W. R.;
MacMillan, D. W. C. Decarboxylative Alkylation: An Approach to
Site-Selective Bioconjugation of Native Proteins via Oxidation
Potentials. Nat. Chem. 2018, 10, 205−211. (b) Osberger, T. J.;
Rogness, D. C.; Kohrt, J. T.; Stepan, A. F.; White, M. C. Oxidative
diversification of amino acids and peptides by small-molecule iron
catalysis. Nature 2016, 537, 214−219. (c) Kazmaier, U.; Bayer, A.;
Deska, J. Palladium-Catalyzed Allylic Alkylations as Versatile Tool for
Amino Acid and Peptide Modifications. Synthesis 2013, 45, 1462−
(8) (a) Smith, D.; Woerpel, K. A. Electrostatic interactions in cations
and their importance in biology and chemistry. Org. Biomol. Chem.
2006, 4, 1195−1201. (b) Bonger, K. M.; Wennekes, T.; Filippov, D.
V.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S. The Effect of
Lewis Acids on the Stereochemistry in the Ugi Three-Component
Reaction with D-lyxo-Pyrroline. Eur. J. Org. Chem. 2008, 3678−3688.
(c) The 2,4-cis compound 23 (closely related to the allyl analogs 10
and 11) and the ketone 24 have been previously reported: Renaud,
P.; Seebach, D. Enantiomerenreine Pyrrolidin-Derivate aus trans-4-
Hydroxy-L-prolin durch elektrochemische oxidative Decarboxylierung
und Titantetrachlorid-vermittelte Umsetzung mit Nukleophilen. Helv.
Chim. Acta 1986, 69, 1704−1710. (d) Compound 12 is known: Boto,
A.; Hernandez, D.; Hernandez, R. Enantiopure alkaloid analogues and
iminosugars from proline derivatives: stereocontrol in sequential
processes. Tetrahedron Lett. 2009, 50, 3974−3977. (e) Compound
12 has similar coupling constants in the 1H NMR spectrum and
optical activity ([α]D +14) as compound 13 ([α]D +17), while
compound 14 has different optical activity ([α]D −17). (f) The
coupling constants and optical activities of compounds 13 and 14 also
́
1468. (d) Mazo, N.; García-Gonzalez, I.; Navo, C. D.; Corzana, F.;
́
́
Jimenez-Oses, G.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. Synthesis
of Mixed α/β2,2-Peptides by Site-Selective Ring-Opening of Cyclic
Quaternary Sulfamidates. Org. Lett. 2015, 17, 5804−5807. (e) Dyer,
F. B.; Park, C. M.; Joseph, R.; Garner, P. Aziridine-Mediated Ligation
and Site-Specific Modification of Unprotected Peptides. J. Am. Chem.
́
́
́
Soc. 2011, 133, 20033−20035. (f) Galonic, D. P.; Ide, N. D.; van der
Donk, W. A.; Gin, D. Y. Aziridine-2-carboxylic Acid-Containing
Peptides: Application to Solution- and Solid-Phase Convergent Site-
Selective Peptide Modification. J. Am. Chem. Soc. 2005, 127, 7359−
7369. (g) Chapman, C. J.; Hargrave, J. D.; Bish, G.; Frost, C. G.
Peptide modification through site-selective residue interconversion:
application of the rhodium-catalysed 1,4-addition of aryl siloxanes and
boronates. Tetrahedron 2008, 64, 9528−9539. (h) Ebran, J. P.; Jensen,
C. M.; Johannesen, S. A.; Karaffa, J.; Lindsay, K. B.; Taaning, R.;
Skrydstrup, T. Creating carbon−carbon bonds with samarium
diiodide for the synthesis of modified amino acids and peptides.
Org. Biomol. Chem. 2006, 4, 3553−3564 and references cited therein..
(3) (a) deGruyter, J. N.; Malins, L. R.; Baran, P. S. Residue-Specific
Peptide Modification: A Chemist’s Guide. Biochemistry 2017, 56,
3863−3873. (b) See also: Shadish, J. A.; DeForest, C. A. Site-
Selective Protein Modification: From Functionalized Proteins to
Functional Biomaterials. Matter 2020, 2, 50−77. (c) Hoyt, E. A.; Cal,
P. M. S. D.; Oliveira, B. L.; Bernardes, G. J. L. Contemporary
approaches to site-selective protein modification. Nat. Rev. Chem.
2019, 3, 147−171. (d) Isenegger, P. G.; Davis, B. G. Concepts of
Catalysis in Site-Selective Protein Modifications. J. Am. Chem. Soc.
2019, 141, 8005−8013. (e) Xuan, W.; Collins, D.; Koh, M.; Shao, S.;
Yao, A.; Xiao, H.; Garner, P.; Schultz, P. G. Site-Specific
Incorporation of a Thioester Containing Amino Acid into Proteins.
ACS Chem. Biol. 2018, 13, 578−581. (f) Krall, N.; da Cruz, F. P.;
Boutureira, O.; Bernardes, G. J. L. Site-selective protein-modification
chemistry for basic biology and drug development. Nat. Chem. 2016,
8, 103−113. (g) Boutureira, O.; Bernardes, G. J. L. Advances in
Chemical Protein Modification. Chem. Rev. 2015, 115, 2174−2195
and references cited therein..
20
20
20
match related 2,4-cis- and 2,4-trans 2-alkyl-4-acyloxypyrrolidines
́
́
commented in: Boto, A.; Hernandez, R.; Suarez, E. Tandem Radical
Decarboxylation-Oxidation of Amino Acids: A Mild and Efficient
Method for the Generation of N-Acyliminium Ions and Their
Nucleophilic Trapping. J. Org. Chem. 2000, 65, 4930−4937.
(9) (a) Arenas, I.; Ferrali, A.; Rodríguez-Escrich, C.; Bravo, F.;
Pericas, M. A. cis-4-Alkoxydialkyl- and cis-4-Alkoxydiarylprolinol
Organocatalysts: High Throughput Experimentation (HTE)-Based
and Design of Experiments (DoE)-Guided Development of a Highly
Enantioselective aza-Michael Addition of Cyclic Imides to α,β-
Unsaturated Aldehydes. Adv. Synth. Catal. 2017, 359, 2414−2424.
(b) He, C.; Ren, X.; Feng, Y.; Chai, Y.; Zhang, S.; Chen, W.
Diphenylprolinol silyl ether-derived thioureas as highly efficient
catalysts for the asymmetric Michael addition of aldehydes to
nitroalkenes. Tetrahedron Lett. 2015, 56, 4036−4038. (c) Bowers-
Nemia, M. M.; Joullie, M. M. A Short Improved Synthesis of N-
Substituted 5-Aza-2-oxa-3-oxo-bicyclo[2.2.1]heptanes. Heterocycles
1983, 20, 817−828.
̀
(10) Acids 18 and 19 were not described, but acid 22 was reported
in ref 5a and also: Thaning, M.; Wistrand, L. G. Intermolecular
Stereoselective Alkenylation of Chiral N-Acylpyrrolidinium Ions. Acta
Chem. Scand. 1992, 46, 194−199.
(11) (a) Aguilar, M. I.; Purcell, A. W.; Devi, R.; Lew, R.; Rossjohn,
J.; Smith, A. I.; Perlmutter, P. β-Amino acid-containing hybrid
peptidesnew opportunities in peptidomimetics. Org. Biomol. Chem.
2007, 5, 2884−2890. (b) Godballe, T.; Nilsson, L. L.; Petersen, P. D.;
Jenssen, H. Antimicrobial β-peptides and α-peptoids. Chem. Biol. Drug
Des. 2011, 77, 107−116. (c) Horne, W. S. Peptide and peptoid
foldamers in medicinal chemistry. Expert Opin. Drug Discovery 2011,
6, 1247−1262. (d) Cabrele, C.; Martinek, T. A.; Reiser, O.; Berlicki,
L. Peptides Containing β-Amino Acid Patterns: Challenges and
Successes in Medicinal Chemistry. J. Med. Chem. 2014, 57, 9718−
9739. (e) For a recent work on sitagliptin synthesis with more
references, see: Ravn, A. K.; Vilstrup, M. B. T.; Noerby, P.; Nielsen,
D. U.; Daasbjerg, K.; Skrydstrup, T. Carbon Isotope Labeling Strategy
for β-Amino Acid Derivatives via Carbonylation of Azanickellacycles.
J. Am. Chem. Soc. 2019, 141, 11821−11826.
(4) (a) Saavedra, C. J.; Cuevas, F.; Romero-Estudillo, I.; Boto, A.
Synthesis of Diketopiperazine Scaffolds with Tailored N- and α-
Chains by Selective Modification of Customizable Units. Adv. Synth.
Catal. 2020, 362, 3158−3169. (b) Saavedra, C. J.; Carro, C.;
́
Hernandez, D.; Boto, A. Conversion of “Customizable Units” into N-
Alkyl Amino Acids and Generation of N-Alkyl Peptides. J. Org. Chem.
2019, 84, 8392−8410. (c) Romero-Estudillo, I.; Boto, A. Domino
Process Achieves Site-Selective Peptide Modification with High
Optical Purity. Applications to Chain Diversification and Peptide
Ligation. J. Org. Chem. 2015, 80, 9379−9391.
(5) (a) Compounds 7 and 9 were previousy described: Barrett, A.
G.; Pilipauskas, D. Electrochemical oxidation of proline derivatives:
total syntheses of Bulgecinine and Bulgecin C. J. Org. Chem. 1991, 56,
2787−2800. (b) Boto, A.; Hernandez, D.; Hernandez, R. One-Pot
Synthesis of Azanucleosides from Proline Derivatives-Stereoselectivity
in Sequential Processes. Eur. J. Org. Chem. 2010, 3847−3857.
(12) (a) For reviews, see: Cheng, R. P.; Gellman, S. H.; DeGrado,
W. F. β-Peptides: From Structure to Function. Chem. Rev. 2001, 101,
3219−3232. (b) Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado,
2808
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
W. F. Foldamers as versatile frameworks for the design and evolution
of function. Nat. Chem. Biol. 2007, 3, 252−262. (c) Seebach, D.;
Gardiner, J. β-Peptidic Peptidomimetics. Acc. Chem. Res. 2008, 41,
1366−1375. (d) Horne, W. S.; Gellman, S. H. Foldamers with
heterogeneous backbones. Acc. Chem. Res. 2008, 41, 1399−1408.
(e) Yashima, E.; Maeda, K.; Iida, H.; Furusho, Y.; Nagai, K. Helical
Polymers: Synthesis, Structures, and Functions. Chem. Rev. 2009, 109,
Aspartic Acid. Heterocycles 2004, 63, 2735−2746. (f) Ndungu, J. M.;
Cain, J. P.; Davis, P.; Ma, S.-W.; Vanderah, T. W.; Lai, J.; Porreca, F.;
Hruby, V. J. Synthesis of constrained analogues of cholecystokinin/
opioid chimeric peptides. Tetrahedron Lett. 2006, 47, 2233−2236.
(g) Aillard, B.; Kilburn, J. D.; Blaydes, J. P.; Tizzard, G. J.; Findlow, S.;
Werner, J. M.; Bloodworth, S. Synthesis and evaluation of a
(3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane scaffold as a mimic of
Xaa-trans-Pro in poly-L-proline type II helix conformation. Org.
Biomol. Chem. 2015, 13, 4562−4569.
6102−6211. (f) Kiss, L.; Fu
̈
lop, F. Synthesis of Carbocyclic and
̈
Heterocyclic β-Aminocarboxylic Acids. Chem. Rev. 2014, 114, 1116−
(19) Jung, D.; Rozek, A.; Okon, M.; Hancock, R. E. Structural
transitions as determinants of the action of the calcium-dependent
antibiotic daptomycin. Chem. Biol. 2004, 11, 949−957.
́
́
́
́
1169. (g) See also: Nekka, I.; Bogdan, D.; Gati, T.; Beni, S.; Juhasz,
́
́
T.; Palko, M.; Paragi, G.; Toth, G. K.; Fulop, F.; Mandity, I. M. Flow-
̈
̈
́
chemistry enabled efficient synthesis of β-peptides: backbone
topology vs. helix formation. Chem. Commun. 2019, 55, 3061−3064
and references cited therein.
(13) For the oxidation with aqueous NaClO2 and K2HPO4 see:
Booker, J. E. M.; Boto, A.; Churchill, G. H.; Green, C. P.; Ling, M.;
Meek, G.; Prabhakaran, J.; Sinclair, D.; Blake, A. J.; Pattenden, G.
Approaches to the quaternary stereocentre and to the heterocyclic
core in diazonamide A using the Heck reaction and related coupling
reactions. Org. Biomol. Chem. 2006, 4, 4193−4205.
(14) (a) Messina, M. S.; Maynard, H. D. Modification of proteins
using olefin metathesis. Mater. Chem. Front. 2020, 4, 1040−1051.
(b) Lin, Y. A.; Chalker, J. M.; Davis, B. G. Olefin metathesis for site-
selective protein modification. ChemBioChem 2009, 10, 959−969.
(15) De Clercq, E. The Acyclic Nucleoside Phosphonates (ANPs):
(20) (a) Nitz, M.; Mezo, A. R.; Ali, M. H.; Imperiali, B.
Enantioselective synthesis and application of the highly fluorescent
and environment-sensitive amino acid 6-(2-dimethylaminonaphthoyl)
alanine (DANA). Chem. Commun. 2002, 1912−1913. (b) Abbyad, P.;
Shi, X.; Childs, W.; McAnaney, T. B.; Cohen, B. E.; Boxer, S. G.
Measurement of Solvation Responses at Multiple Sites in a Globular
Protein. J. Phys. Chem. B 2007, 111, 8269−8276. (c) Kim, J.; Seo, M.-
H.; Lee, S.; Cho, K.; Yang, A.; Woo, K.; Kim, H.-S.; Park, H.-S. Simple
and Efficient Strategy for Site-Specific Dual Labeling of Proteins for
Single-Molecule Fluorescence Resonance Energy Transfer Analysis.
Anal. Chem. 2013, 85, 1468−1474. (d) Katritzky, A. R.; Narindoshvili,
T. Fluorescent amino acids: advances in protein-extrinsic fluoro-
phores. Org. Biomol. Chem. 2009, 7, 627−634. (e) Krueger, A. T.;
Imperiali, B. Fluorescent amino acids: modular building blocks for the
assembly of new tools for chemical biology. ChemBioChem 2013, 14,
788−799. (f) Cheng, Z.; Kuru, E.; Sachdeva, A.; Vendrell, M.
Fluorescent amino acids as versatile building blocks for chemical
biology. Nat. Rev. Chem. 2020, 4, 275−290.
́
Holy’s Legacy. Med. Res. Rev. 2013, 33, 1278−1303.
(16) (a) For a review, see: Brunetti, J.; Falciani, C.; Bracci, L.; Pini,
A. Branched peptides as bioactive molecules for drug design. Pept. Sci.
2018, 110, No. e24089. (b) See also: Saavedra, C. J.; Boto, A.;
́
Hernandez, R.; Miranda, J. I.; Aizpurua, J. M. Conformation and
́
́
(21) (a) Boto, A.; Perez de la Lastra, J. M.; Gonzalez, C. C. The
Road from Host-Defense Peptides to a New Generation of
Antimicrobial Drugs. Molecules 2018, 23, 311−337. (b) Kastin, A.
J., Ed. Handbook of Biologically Active Peptides; Academic Press: San
Diego, 2006; Chapters 10−12 and 45−46.
Chiral Effects in α,β,α-Tripeptides. J. Org. Chem. 2012, 77, 5907−
5913 and references cited therein.
(17) (a) For a seminal contribution to HWE in the formation of
didehydroamino acids, see: Schmidt, U.; Griesser, H.; Leitenberger,
V.; Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Diaster-
eoselective Formation of (Z)-Didehydroamino Acid Esters. Synthesis
1992, 487−490. (b) See also: Ghosh, A. K.; Liu, W. Total Synthesis
of (+)-Sinefungin. J. Org. Chem. 1996, 61, 6175−6182. (c) Fuchs, T.;
Schmidt, R. R. Synthesis of Nojirimycinyl C-(l)-Serine. Synthesis
2000, 259−264. (d) Artale, E.; Banfi, G.; Belvisi, L.; Colombo, L.;
Colombo, M.; Manzoni, L.; Scolastico, C. Synthesis of substituted
conformationally constrained 6,5- and 7,5-fused bicyclic lactams as
dipeptide mimics. Tetrahedron 2003, 59, 6241−6250. (e) Miyazaki,
M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.; Kanemitsu, T.;
Nagata, K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. Catalytic
Asymmetric Allylation of 3,4-Dihydroisoquinolines and Its Applica-
tion to the Synthesis of Isoquinoline Alkaloids. J. Org. Chem. 2011, 76,
534−542. (f) See also: Mathur, P.; Ramakumar, S.; Chauhan, V. S.
Peptide design using α,β-dehydro amino acids: From β-turns to
helical hairpins. Biopolymers 2004, 76, 150−161. (g) Singh, T. P.;
Kaur, P. Conformation and design of peptides with α,β-dehydro
amino acid residues. Prog. Biophys. Mol. Biol. 1996, 66, 141−165 and
references cited therein.
(22) Compound 17: (a) Sigmund, A. E.; Hong, W.; Shapiro, R.;
DiCosimo, R. Chemoenzymatic Synthesis of cis-4-hydroxy-D-proline.
Adv. Synth. Catal. 2001, 343, 587−590. (b) Shono, T.; Matsumura,
Y.; Tsubata, K.; Sugihara, Y.; Yamane, S.; Kanazawa, T.; Aoki, T.
Electroorganic chemistry. 60. Electroorganic synthesis of enamides
and enecarbamates and their utilization in organic synthesis. J. Am.
Chem. Soc. 1982, 104, 6697−6703.
(23) Compound 52, precursor of compound 8: Uria, U.; Vicario, J.
L.; Badía, D.; Carrillo, L.; Reyes, E.; Pesquera, A. On Water’
Iminium/Enamine Catalysis: Organocatalytic Enantioselective Cyclo-
propanation of α,β-Unsaturated Aldehydes. Synthesis 2010, 701−713.
(18) (a) Mulzer, J.; Schulzchen, F.; Bats, J.-W. Rigid Dipeptide
̈
Mimetics. Stereocontrolled Synthesis of All Eight Stereoisomers of 2-
Oxo-3-(N-Cbz-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic Acid
Ester. Tetrahedron 2000, 56, 4289−4298. (b) Angiolini, M.; Araneo,
S.; Belvisi, L.; Cesarotti, E.; Checchia, A.; Crippa, L.; Manzoni, L.;
Scolastico, C. Synthesis of Azabicycloalkane Amino Acid Scaffolds as
Reverse-Turn Inducer Dipeptide Mimics. Eur. J. Org. Chem. 2000,
2571−2581. (c) Wang, W.; Yang, J.; Ying, J.; Xiong, C.; Zhang, J.;
Cai, C.; Hruby, V. J. Stereoselective Synthesis of Dipeptide β-Turn
Mimetics: 7-Benzyl and 8-Phenyl Substituted Azabicyclo[4.3.0]-
nonane Amino Acid Esters. J. Org. Chem. 2002, 67, 6353−6360.
(d) Zhang, J.; Xiong, C.; Ying, J.; Wang, W.; Hruby, V. J.
Stereoselective Synthesis of Novel Dipeptide β-Turn Mimetics
Targeting Melanocortin Peptide Receptors. Org. Lett. 2003, 5,
3115−3118. (e) Yonezawa, Y.; Konn, A.; Shin, C-g. Useful Synthesis
of 2,3,6-Tri- and 2,3,5,6-Tetrasubstituted Pyridine Derivatives from
2809
https://dx.doi.org/10.1021/acs.joc.0c02751
J. Org. Chem. 2021, 86, 2796−2809