Multi-component synthesis of peptide-sugar conjugates

Article abstract of DOI:10.1039/c3ob27176e

Recent years have witnessed a growing interest in the development of new methods for linking sugars to peptides or proteins because natural glycopeptides or neoglycoconjugates with well defined chemical structures are very important tools to study diverse biological phenomena. Herein we report a novel, one-pot, three-component process for the synthesis of peptide-urea conjugates incorporating a hexafluorovaline or an aspartic acid alkyl ester residue under very mild conditions and high yields. The reaction has been exploited for the synthesis of a wide array of structurally diverse peptide-sugar conjugates through a regiospecific four-component, one-pot sequential domino process, by generating the reacting sugar-carbodiimides in situ from readily accessible starting materials. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27176e

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Multi-component synthesis of peptide–sugar
conjugates†
Cite this: DOI: 10.1039/c3ob27176e
Maria Cristina Bellucci,a Giancarlo Terraneob and Alessandro Volonterio*b
Recent years have witnessed a growing interest in the development of new methods for linking sugars to
peptides or proteins because natural glycopeptides or neoglycoconjugates with well defined chemical
structures are very important tools to study diverse biological phenomena. Herein we report a novel,
one-pot, three-component process for the synthesis of peptide–urea conjugates incorporating a hexa-
fluorovaline or an aspartic acid alkyl ester residue under very mild conditions and high yields. The reac-
tion has been exploited for the synthesis of a wide array of structurally diverse peptide–sugar conjugates
through a regiospecific four-component, one-pot sequential domino process, by generating the reacting
sugar-carbodiimides in situ from readily accessible starting materials.
Received 8th November 2012,
Accepted 21st January 2013
DOI: 10.1039/c3ob27176e
www.rsc.org/obc
complicated by low glycosylation efficiencies and extensive pro-
tection regimes to ensure regioselectivity. However, glycosyla-
Introduction
Glyco-conjugates is the general classification for carbohydrates tion could be intended in a broader sense: as a method that
covalently linked to other chemical species, termed aglycones. allows the introduction of carbohydrates to structures, such as
They play an important role in various biological events and peptides, rather than necessarily as a definition of the for-
are classified in accordance with the type of attached agly- mation of the glycosidic bond.6 Consequently, many research
cone.1 For example, if the aglycone is a peptide or a protein, efforts in contemporary carbohydrate chemistry aim to develop
the corresponding glycoconjugates are known as glycopeptides strategies that enable the linking of carbohydrates to a certain
or glycoproteins, respectively. Glycopeptides are important in core, not through natural glycosidic linkage. Moreover, these
biochemical processes ranging from cell growth regulation, linkages may be made more stable towards enzymatic degra-
immune response, binding of pathogens to intercellular com- dation, and be designed to afford regiochemically and stereo-
munication, intercellular targeting, cancer cell metastasis, and chemically defined compounds. Examples of these strategies
inflammation.2 The fundamental problem associated with have been reported in the preparation of synthetic mimics of
glycopeptides and glycoproteins arises from the difficulty in natural glycoconjugates, for instance neoglycopeptides.7 In
generating homogeneous sources since protein glycosylation is this sense, conjugation at primary positions of 6-amino-
not under direct genetic control.3 Several approaches have hexoses and 5-aminopentoses could be an easier way to
attempted to overcome this limitation through both biological accomplish such achievement providing peptide–sugar conju-
and chemical processes (or a combination of the two) and are gates with enzymatically stable artificial linkages, also consid-
now allowing the exploitation of synthetic glycoproteins in ering the fact that the –CH2NH2 moiety present in these sugars
some potentially useful therapeutic strategies.4 A large number might mimic some elements of the glycine structure.8 For
of elegant methods have been developed for the synthesis and instance, the 6-position of L-galactose has been conjugated to
assembly of native N- and O-linked as well as non-native different amino acids in the synthesis of sialyl Lewis
C- and S-linked glycopeptides,5 but these methods may be X mimetics9 as well as the primary 6′10- and 5′′-position11 of
neomycin in the modification of aminoglycoside antibiotics
targeting RNA. However, glycoconjugate synthesis involving
aDepartment of Food, Environmental and Nutritional Sciences, Università degli Studi
sugar and amino acids or peptides remains a formidable task
di Milano, via Celoria 2, 20133 Milano, Italy
since the developed synthetic protocols are quite demanding
and involve multiple reaction steps. The problem may be in
part or completely obviated through the use of multicompo-
nent reactions (MCRs). In fact, applications of MCRs in all
areas of applied chemistry are popular because they offer a
wealth of products, while requiring only a minimum effort
combining many elements of an ideal synthesis, such as
bDepartment of Chemistry, Materials and Chemical Engineering “Giulio Natta”,
Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy.
E-mail: alessandro.volonterio@polimi.it; Fax: +39 0223993080;
Tel: +39 0223993136
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of all new compounds. CCDC 892811 for (S)-6b and 775425 for
27b. For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob27176e
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operational simplicity, atom economy, bond-forming
efficiency, and the access to molecular complexity from simple
starting materials.12 As such, MCRs become the cornerstones
of both combinatorial chemistry and diversity-oriented syn-
thesis, thus playing a central role in the development of
modern synthetic methodology for pharmaceutical and drug
discovery research. In this context, the development of practi-
cal, simple and convenient new MC methods for linking
sugars to peptides or proteins is of paramount importance.13
Herein, we wish to report on the development of a novel
straightforward MC domino process for the synthesis of
peptide–urea and peptide–sugar conjugates incorporating a
hexafluorovaline (hfVal) or an aspartic acid alkyl ester residue
which occurs under very mild conditions and high yields. It is
noteworthy that highly fluorinated amino acids such as hfVal
and hexafluoroleucine (hfLeu) have been used to stabilize pro-
teins14 for potential application in various protein-based bio-
technologies, such as protein therapeutics, industrial scale
biotransformations and biosensors. Moreover, the incorpor-
ation of fluorinated amino acids into peptides or proteins can
significantly increase diffusion across membranes such as the
blood–brain barrier,15 improve the pharmacokinetic properties
of the peptide-based drug16 and allow monitoring of the
chemical environment of the fluorine-containing residues by
non-invasive 19F NMR.17 On the other hand, peptide–sugar
conjugates incorporating an aspartic acid orthogonally pro-
tected at the β-carboxylic moiety with respect to the glyco
moiety and to the terminal ester function of the peptidic chain
are very intriguing synthons because they could be further
functionalized after simple chemoselective hydrolysis.
Scheme 1 Proposed mechanism for the synthesis of urea–peptide conjugates 4.
conjugate 4 in high yields. The latter step is faster than the
O→N acyl migration pathway which would have led to the for-
mation of the corresponding hydantoin.18b Moreover, when
the carbodiimide reactant is generated in situ starting with
suitable sugar-azides and isocyanates, we could obtain the
regioselective formation of even more intriguing sugar–peptide
conjugates incorporating an hfVal residue through a four-com-
ponent sequential domino process.19
Results and discussion
Within the frame of a project aimed at developing new
domino processes for the synthesis of small heterocycles, we
have demonstrated that carbodiimides, when treated with suit-
able carboxylic acids, such as activated α,β-unsaturated and
α-bromo carboxylic acids, are useful reagents for the synthesis,
under very mild conditions, of diversely substituted hydan-
Since the process worked very well and under very mild con-
ditions (room temperature) and considering that the products
are very interesting scaffolds, we decided to apply this
methodology to the carboxylic acids 1b–g which were active in
the synthesis of hydantoins with the same domino process
performed in the absence of a nucleophile (Scheme 2).18b,e,k
Very interestingly, fumaric acid monoethyl and monobenzyl
esters 1b,c, respectively, reacted smoothly with DIC 2 and
H-Ala-OBn 3a under the same conditions, i.e. in the presence
of 1 equiv. of 2,4,6-trimethylpyridine (TMP) and CH3CN as a
solvent, giving rise to the formation of an equimolecular
mixture of the diastereoisomeric urea–peptide conjugates 7a
and 8a in very high yields (eqn (2) and (3), Scheme 2).20 Unfor-
tunately, the corresponding tert-butylester 1d produced in high
yield the amide 9 (eqn (4), Scheme 2). In this case, the intra-
molecular aza-Michael reaction is slow, likely due to the steric
hindrance of the tert-butyl substituent, rendering the nucleo-
philic attack to the activated carbonyl group of the O-acyl-
isourea like 5 as the only viable pathway. Acid 1e was found to
be too reactive undergoing first an intermolecular aza-Michael
addition of the aminoester to the highly activated CvC double
toins through
a
regiospecific domino condensation/
aza-Michael/O→N acyl migration one-pot process (see
Scheme 1).18 Very recently, we have also discovered that the
same process, when carried out with 4,4,4-trifluoro-3-trifluoro-
methyl (Tfm)-crotonic acid and in the presence of a nucleo-
phile, such as amines or aminoesters, leads to the formation
of intriguing urea–peptide conjugates through a three-com-
ponent domino process.19 The process has been proposed to
arise through the mechanism depicted in Scheme 1.
Acid 1a readily reacts with carbodiimide 2 leading to the
formation of the highly reactive O-acylisourea intermediate 5.
The intramolecular aza-Michael reaction in 5 is faster than the
intermolecular nucleophilic attack of the amine nucleophile 3,
which would have led to the formation of the classical amide
product. In fact, it is likely that once intermediate 6 is formed
it is attacked by nucleophile 3, producing the urea–peptide
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yields (entries 3 and 5, Table 1).21 Moreover, other symmetric
N,N′-dialkylcarbodiimides can be used in order to obtain urea-
derivatives with different appendages. In fact, we could achieve
derivatives 15b and 16b in high yields by reacting N,N′-di-
benzyl- and N,N′-di-cyclo-hexylcarbodiimides 2b,c with acids
1b,c, respectively, and in the presence of benzylamine 13a
(entries 6 and 7, Table 1).
Thus, in order to demonstrate the feasibility of this metho-
dology for the synthesis of more interesting urea–peptides con-
jugates incorporating an hfVal or an aspartic acid alkyl ester
residue, we explored the reactivity of less nucleophilic α-amino
esters and derivatives (Table 2). As already depicted in
Scheme 2, acids 1a–c reacted smoothly with DIC 2 and H-Ala-
OBn 3a giving rise to the formation of an equimolar ratio of
diastereoisomers 6a–8a, respectively.20 Also more sterically
hindered H-Val-O-tertBu 3b was active producing urea–pep-
tides 6b and 7b with DIC and acids 1a,b, respectively (entries 1
and 2, Table 2). Moreover, 3b also reacted efficiently with DCC
2c and fumaric acid monobenzyl ester 1c leading to the for-
mation of urea–peptide 8b with very good yields (entry 3,
Table 2). Gratifyingly, the process also worked smoothly with
N-disubstituted nucleophiles such as H-Pro-OBn 3c, and
N-alkylated α-amino acid esters 3d,e. However, while 3c
reacted with acids 1a,b leading to the formation of compounds
6c and 7c, respectively, in high yields (entries 4 and 5,
Table 2), particularly hindered N-benzyl-aminoester 3d pro-
duced peptides 6d,7d with the same acids 1a,b (entries 6 and
7, Table 2) and N-allyl-Ala-OBn 3e urea–peptide 6e with acid 1a
(entry 8, Table 2) in lower yields, probably due to the steric hin-
drance of the nucleophiles.22 The MC domino process proved
to be highly versatile since also less nucleophilic α-amino acid
amides H-Gly-NH2 3f and H-Phe-NHCH3 3g reacted thoroughly
with acids 1a,b producing urea–peptide conjugates 6d,e
(entries 9 and 11, Table 2) and 7d,e (entries 10 and 12,
Table 2), respectively, in high yields. Finally, we tried the reac-
tion with dipeptide 3h as a nucleophile in order to prove that
such a process could be used for the synthesis of longer urea–
peptide conjugates. Accordingly, also in this case the reaction
worked very well giving rise to the formation of urea–tripeptide
conjugates 6h and 7g when 3h was reacted with acids 1a,b,
respectively, in very high yields in both cases (entries 13 and
14, Table 2).23
Scheme 2 The process with acids 1a–g.
bond followed by coupling of a second equivalent of the
nucleophile, giving rise to the formation of a mixture of dia-
stereoisomers 10 in 45% yield (eqn (5), Scheme 2). In contrast,
the CvC double bond of acid 1f was too unreactive, and the
reaction produced only compound 11 arising from the reaction
of the O-acylisourea-like intermediates 5 with the nucleophilic
α-aminoester 3a (eqn (6), Scheme 2). The same kind of
product, namely derivative 12, was obtained when acid 1g was
reacted under the same conditions, even if the carbon bearing
the bromine leaving group is highly electrophilic, thus reactive
in the intramolecular nucleophilic substitution step, because
it is in the α position with respect to an aryl and a carboxylic
group (eqn (7), Scheme 2).
With these results in hand, we studied more in depth the
reactivity of acids 1a–c with different carbodiimides and
N-nucleophiles in order to demonstrate the versatility of the
process, and the possibility to obtain a wide array of struc-
turally diverse urea–amide and urea–peptide conjugates. First,
we focused our attention on the reactivity of these acids with
highly nucleophilic amines 13 and symmetric N,N′-dialkyl-
carbodiimides 2 (Table 1).
The process worked efficiently with either primary, second-
ary or aryl amines. Indeed, 4,4,4-trifluoro-3-Tfm-crotonic acid
1a and fumaric acid monoethyl ester 1b reacted smoothly with
benzyl amine 13a in the presence of DIC 2a producing urea–
amide derivatives 14a and 15a, respectively, in very high yields
(entries 1 and 4, Table 1). The same fluorinated acid 1a
reacted smoothly also with a secondary amine, such as mor-
pholine 13b, giving rise to the formation of compound 14b
(entry 2, Table 1). Also less nucleophilic aromatic amines,
such as p-toluidine 13c, worked nicely producing derivatives
14c and 16a, respectively with acids 1a,c, although in lower
To support the proposed mechanism and to enhance the
usefulness of this methodology for the synthesis of more com-
plicated scaffolds (such as glyco-peptide conjugates, see below)
by getting regioselectivity with asymmetric carbodiimides, we
thought of performing the reaction starting from “weakly
asymmetric” carbodiimides,18b i.e. carbodiimides bearing two
N-substituents very different in terms of steric hindrance, and
from “highly asymmetric” carbodiimides,18b i.e. carbodiimides
bearing N-alkyl and N′-aryl substituents, thus very different in
terms of electronic features. Moreover, since such carbodi-
imides are not commercially available and could be efficiently
prepared by the Staudinger reaction starting from the corre-
sponding easily accessible azides and iso(thio)cyanates, we
studied the possibility of performing the process in
a
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Table 1 MC domino process with amines and symmetric N,N’-dialkylcarbodiimides
Entry
1
Acid
Carbodiimide
N-nucleophile
Product
Yielda (%)
92
2
3
87
73b
4
5
91
70b
6
7
88
84
a Isolated yields. b A ca. 10% yield of the corresponding hydantoin derivatives was detected.
“one-pot” sequential fashion by generating in situ the carbodii- intramolecular aza-Michael step.25 Very interestingly, the same
mides that could be directly reacted with the acids and result, with almost the same yields, was achieved starting from
α-amino esters without isolation (Scheme 3). Firstly, we allyl azide 19a and commercially available tert-butyl isocyanate
demonstrated that the process is favorably regioselective when 20a and performing the process in a sequential “one-pot”
“weakly asymmetric” carbodiimides were used, by reacting car- fashion (eqn (2), Scheme 3).
bodiimide 17a24 with fluorinated acid 1a in the presence of
The latter could be considered a four-component “one-pot”
H-Ala-OBn 3a (eqn (1), Scheme 3). As expected from the mech- sequential domino process for the synthesis of urea–peptide
anism proposed (see Scheme 1), we obtained the regioselective conjugates incorporating an hfVal residue under very mild
formation of an equimolar mixture of diastereoisomers 18 conditions. Also fumaric acid monoethylester 1b reacted
arising from the nucleophilic attack of the less congested smoothly with “weakly asymmetric” carbodiimide 17b in situ
nitrogen bearing the primary alkyl substituent in the generated from azide 13b and isocyanate 20a, giving rise to the
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Table 2 MC domino process with α-amino esters and derivatives
Entry
1
Acid
Carbodiimide
N-nucleophile
Producta
Yieldb (%)
85
2
3
90c
77
4
5
81
84
6
7
8
60d
58d
53d
9
67
71
84
10
11
12
74
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Table 2 (Contd.)
Entry
13
Acid
Carbodiimide
N-nucleophile
Producta
Yieldb (%)
75
14
72
a Equimolar ratio of two diastereoisomers. b Overall yields. c Unseparable mixture of diastereoisomers. d A ca. 20% yield of the corresponding
hydantoin derivatives was recovered.
proposed mechanism.26 In fact, the attack of the more nucleo-
philic N-alkyl rather than the N′-aryl moiety in the aza-Michael
step would have led to the formation of intermediate II and
subsequent formation of regioisomer III after the intermole-
cular attack of the nucleophile (pathway A, Scheme 4). The
exclusive formation of the other regioisomers could be
explained through a second mechanism, pathway B, depicted
in Scheme 4. O-Acylisourea intermediate I could exist in two
tautomeric forms Ia and Ib,c, being the second favoured due
to the conjugation of the imine CvN bond with the aromatic
ring. This conjugation probably renders intermediate Ib,c less
nucleophilic27 and more prone to undergo nucleophilic attack
by the amine which likely arises through a concerted mechan-
ism leading to the formation of regioisomer IV.
Once we studied in detail the behaviour of this four-com-
ponent “one-pot” sequential domino process used for the syn-
thesis under very mild conditions of urea–peptide conjugates
incorporating an hfVal or an aspartic ester residue, we decided
to investigate the possibility to use such a process for the MC
Scheme 3 Four-component sequential domino process with “weakly asym-
synthesis of sugar–urea–peptide conjugates by incorporating
the glycosyl moiety into the carbodiimide framework.28 Since
the process is completely regioselective with asymmetric carbo-
diimides, we began our study by in situ preparing “weakly
asymmetric” carbodiimides 25 starting from easily accessible
primary glycosyl azides 24 and commercially available tert-
butyl isocyanate 20a (Table 3).
Accordingly, when azidogalactose derivative 24a was reacted
with isocyanate 20a in CH3CN in the presence of triphenyl-
phosphine, carbodiimide 25a and triphenylphosphine oxide
byproducts were cleanly formed at rt after 3 h.29 By adding to
the resulting solution TMP followed by the hydrochloride salt
of H-Ala-OBn 3a and a solution of acid 1a, we were able to
metric” and “strongly asymmetric” carbodiimides.
formation of diastereoisomeric urea–peptide conjugates 21 in
high yields and as the only regioisomers (eqn (3), Scheme 3).
Interestingly the process was completely regioselective also
when performed starting with “strongly asymmetric” carbodi-
imides. Indeed, reacting the in situ generated carbodiimides
17c,d with acids 1a,b in the presence of H-Ala-OBn 3a, we
could obtain the regioselective formation of conjugates 22 and
23, respectively, in good yields (eqn (4) and (5), Scheme 3).
However, to our surprise, the latter urea–peptide conjugates
possess the opposite regiochemistry to that expected from the
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diastereoisomers 28b in excellent yields (entry 9, Table 3). The
process was very versatile giving good results also when steri-
cally hindered nucleophiles were used. In fact, H-Val-O-tert-Bu
hydrochloride 3b reacted efficiently with acid 1a producing
conjugates 26f in good yields (entry 10, Table 3), while N-sub-
stituted α-amino esters, such as 3d,e, led to the formation of
hfVal conjugates 26g,h, respectively, with lower, even if reason-
able yields (entries 11 and 12, Table 3).31 As expected, we
obtained very good results on performing the reaction also
with dipeptide 3h and acid 1a affording the hfVal-tetrapeptide
conjugate 26i in very good yields (entry 13, Table 3).32
Gratifyingly, the process was completely regioselective also
starting from “strongly asymmetric” glyco-carbodiimides.
Accordingly, glyco-azide 24a reacted efficiently with phenyl iso-
cyanate 20b in the presence of Ph3P leading to the clean for-
mation of the corresponding carbodiimide after 3 h at rt in
CH3CN (Scheme 5). After the addition in situ of TMP, H-Ala-
OBn 3a followed by acid 1a, we obtained the formation of a
3.5 : 1 mixture of the only regioisomers 26j in high yields.
All the results described above demonstrate that through
this “one-pot” MC sequential procedure we can have access to
a large array of glyco-urea–peptide derivatives in which the
glyco-conjugation arises at the primary positions of the sugar
moiety. Any attempt to prepare conjugates at the anomeric
carbon failed because the corresponding carbodiimides were
not reactive at all, probably because of their low electrophili-
city. However, the preparation of compounds in which a glyco-
syl residue is linked to another sugar or non-sugar moiety,
such as amino acids and peptides, through the anomeric
carbon is very important since the resulting compounds have
application in medicinal chemistry as leads for new drug dis-
covery and for improvement of known drugs acting as inhibi-
tors of carbohydrate processing enzymes, and in glycobiology
for studying the role of carbohydrates in biological processes.2
Thus, we decided to synthesize azido sugars 24c,d in which
the anomeric carbons of the sugars are tethered to a simple
linker bearing a primary azido group (Scheme 6).
Thus, acetylation of glucose 29 and lactose 30 followed by
selective bromination of the anomeric carbons and hydrolysis
led us to prepare derivatives 31, 32, respectively, which were
submitted to O-glycosylation, via trichloroacetimidate, with
3-Br-propanol, and finally transformed to the targets azido
sugars 24c,d by nucleophilic displacement of the bromine
atom.
By the use of the 3-azido-propanol linker, we were able to
synthesize glycosyl-urea–peptide conjugates 34–36 tethered to
the anomeric carbon in a very efficient way (Table 4). Accord-
ingly, an equimolar mixture of diastereoisomers 34a and 35a
was obtained in high yields and as the only regioisomers when
peracetylated azido sugar derivative 24c was treated firstly with
isocyanate 10a, in order to obtain the carbodiimide intermedi-
ate 33a, followed by TMP, H-Ala-OBn hydrochloride 3a and
acids 1a,b, respectively (entries 1 and 2, Table 4). Also fumaric
acid monobenzyl ester 1c reacted smoothly with the same
carbodiimide in the presence of sterically hindered H-Val-OtBu
3b giving rise to the formation of glyco-urea–peptide
Scheme 4 Mechanism for the reaction with “strongly asymmetric”
carbodiimides.
obtain the desired sugar-conjugates 26a, in high yields and
with complete regiocontrol, in a 3.5 to 1 diastereoisomeric
ratio (dr) (entry 1, Table 3).30 Gratifyingly, the process worked
well also with fumaric acid monoethylester 1b giving rise to
the formation of diastereoisomers 27a as the only regioisomer,
in a 3.2 to 1 dr (entry 2, Table 3). Again, to prove the versatility
of the process, we performed the reaction with different
amino-esters, -amides, and -peptides as nucleophiles. Accord-
ingly, H-Ile-OBn and -OMe hydrochlorides 3i,k reacted in the
presence of the same carbodiimide with acids 1a,c, respecti-
vely, producing conjugates 26b and 28a in high yields and as
the only regioisomers (entries 3 and 4, Table 3). Starting with
in situ formed sugar-carbodiimide 25a, the process worked
smoothly also by using α-amino amide 3j and dipeptide 3l
with which we could obtain the one-pot MC synthesis of hfVal-
glyco-dipeptide 26c and -tripeptide 26d in very high yields
(entries 5 and 6, Table 3). Finally, we tried the reaction starting
with another glycosyl azide, namely 5-azido-5-deoxy-2,3-O-iso-
propylidene-β-ribofuranoside 24b. Here again, we were able to
obtain an almost equimolecular ratio (1.5 : 1 dr) of the conju-
gates 26e and 27b in high yields and with total regiocontrol,
after generating in situ the carbodiimide 25b with tert-butyl
isocyanate 20a and performing the reaction with the hydro-
chloride salt of H-Ala-OBn 3a and acids 1a,b, respectively
(entries 7 and 8, Table 3). Moreover, also fumaric acid mono-
benzyl ester 1c reacted smoothly with H-Ile-OMe hydrochloride
3k giving rise to the regiospecific formation of
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Table 3 MC domino process with in situ prepared glyco-carbodiimides 25
Entry
1
Sugar-CH2-N3
Carbodiimide
Acid
H-AA1-AA2-OR
Product
Yielda (%)
82b
2
3
4
5
76c
75b
78c
73b
6
7
68b
85d
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Table 3 (Contd.)
Entry
8
Sugar-CH2-N3
Carbodiimide
Acid
H-AA1-AA2-OR
Product
Yielda (%)
73e
9
69e
10
77d
11
12
54d,f
48d,f
13
71d
a Overall isolated yields. b 3.5 : 1 ratio of two diastereoisomers. c 3.2 : 1 ratio of two diastereoisomers. d 1.5 : 1 ratio of two diastereoisomers. e 1.3 : 1
ratio of two diastereoisomers. f The corresponding hydantoin derivatives were detected as byproduct.
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hydrogenolysis while maintaining the acetyl protecting groups
at the glycosyl moiety and the terminal tert-butyl ester function
and coupled with propargyl amine leading to the efficient for-
mation of clickable propargyl amide 38.
Scheme 5 Reaction with “strongly asymmetric” glyco-carbodiimide.
Conclusions
In conclusion, we have developed an efficient process for the
synthesis of libraries of urea–peptide and glyco-urea–peptide
conjugates incorporating a hexafluorovaline or an aspartic acid
alkyl ester residue through an MC sequential domino process
involving simple and readily accessible starting materials such
as (glyco)-azides, isocyanates, amines or α-amino acid deriva-
tives, including dipeptides, and suitable carboxylic acids. The
process is completely regioselective when both “strongly asym-
metric” and “weakly asymmetric” carbodiimides were used.
These multifunctional compounds could be used to increase
the diversity of sugar frameworks and may find application as
potential glycomimetics and/or peptidomimetics. For instance,
it is worth noting that β-ribofuranose is the central sugar of
many aminoglycoside antibiotics, such as neomycin and paro-
momycin, and that their 5′′ position (5 position of ribofura-
nose) has been often functionalized in order to obtain more
potent/selective antibiotics.33 The functionalization of such a
position by our MC methodology is currently in progress in
our laboratories. The operational simplicity, the very good
chemical yields and the mild conditions combined with favor-
able atom economy aspects and a small number of synthetic
steps render this strategy attractive and promising for the prep-
aration of a novel class of glyco-conjugates and particularly
suitable for solid phase/combinatorial chemistry. These
aspects are currently being investigated.
Scheme 6 Synthesis of glyco-azides 24c,d.
conjugates 36a in a very efficient way (entry 3, Table 4). The
process worked nicely also with dipeptide as nucleophiles,
such as H-Ala-Phe-OMe 3l which reacted with acids 1a,b and
in situ formed carbodiimide 33a, leading to the formation of
glycosyl-tripeptide conjugates 34b and 35b, respectively, in a
very practical way (entries 4 and 5, Table 4). Finally, lactosyl-
azide derivative 24d reacted smoothly with tert-butyl isocyanate
10a in the presence of Ph3P producing the clean formation of
the corresponding carbodiimide 33b along with Ph3PO (TLC
monitoring). After addition of TMP followed by acid 1a and
H-Ala-OBn 3a we were able to obtain the formation of glycosyl-
urea–dipeptide 34c incorporating hfVal in high yields (entry 6,
Table 4). The same lactosyl-carbodiimide 33b reacted smoothly
with acids 1a,b and dipeptide 3l leading to the efficient for-
mation of tripeptide conjugates 34d and 35b incorporating
hfVal and aspartic acid ethyl ester respectively (entries 7 and 8,
Table 4).
Experimental section
Some of the derivatives described above, namely the glyco-
conjugates derived from the reaction of fumaric acid mono-
esters 1b,c, and α-amino esters or peptides 3 could be further
selectively modified, for example in order to elongate the pep-
tidic chain or to functionalize the aspartic acid ester moiety. It
is worth noting that since the MC sequential domino process
works efficiently with fumaric acid monoethyl and mono-
benzyl esters, one can always have the possibility to hydrolyze
chemoselectively one of the ester functions, for instance, the
aspartic acid ester functionality, while maintaining the other
ester moiety on the peptidic chain and the protecting groups
on the glyco moiety, or vice versa, by choosing suitable starting
materials. For example, by hydrogenolysis of glyco-conjugate
28b with a catalytic amount of Pd/C in a H2 atmosphere, we
obtained the chemoselective hydrolysis of the aspartic acid
benzyl ester moiety producing the corresponding free carb-
oxylic acid which was coupled with propargyl amine to form
clickable glyco-urea–peptide conjugate 37 in very high overall
yields (Scheme 7). Similarly, glycosyl-conjugate 36a was selec-
tively hydrolyzed at the aspartic benzyl ester moiety by
General methods
Commercially available reagent-grade solvents were employed
without purification. TLC were run on silica gel 60 F254 Merck.
Flash chromatography (FC) was performed with silica gel 60
(60–200 m, Merck). 1H NMR spectra were recorded on 250, 400
or 500 MHz spectrometers. Chemical shifts are expressed in
ppm (δ), using tetramethylsilane (TMS) as an internal standard
1
for H and 13C nuclei (δH and δC = 0.00), while C6F6 was used
as an external standard (δF 162.90) for 19F. Glycosyl azides 24a,
b were prepared following reported procedures.34
General procedure for the three-component synthesis of
urea–peptide conjugates: synthesis of 6a
To a stirred solution of carbodiimide 2a (1 equiv., 60.6 mg) in
CH3CN (0.1 M) amino acid derivative 3a (1 equiv., 103.7 mg)
followed by TMP (1 equiv. or 2 equiv. when the hydrochloride
salts of the amino acid derivatives were used, 116.3 mg) and a
solution of acid 1a (1 equiv., 100.0 mg) in a minimum amount
of CH3CN were added at 0 °C. The resulting solution was
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Table 4 MC domino process for the synthesis of sugar–urea–peptides 33 tethered to the anomeric carbon
Entry
1
Azides
Carbodiimide
Acid
Nucleophile
Producta
Yieldb (%)
75
1a
3a
2
3
4
1b
1c
1a
3a
3b
3l
81
71
73
5
1b
3l
69
6
7
1a
1a
3a
3l
73
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Scheme 7 Chemoselective functionalization of the glycol–urea–peptides incor-
porating aspartic acid esters.
stirred until the reaction was complete (TLC monitoring)
leaving the temperature to slowly reach rt. A 1 N HCl aqueous
solution was added and the mixture extracted three times with
AcOEt. The combined organic layers were dried over anhydrous
Na2SO4, filtered, concentrated under vacuum and the crude
purified by flash chromatography (FC) obtaining 197.4 mg of
6a (80% yield).
(S)-6a: Rf = 0.41 (hexane : AcOEt 70 : 30); [α]2D0 = +80.5° (c =
0.48, CHCl3); 1H-NMR (250 MHz, CDCl3): δ = 9.05 (br d, J =
6.4 Hz, 1H), 7.33 (m, 5H), 5.17 (d, J = 12.0 Hz, 1H), 5.11 (d, J =
12.0 Hz, 1H), 4.80 (m, 1H), 4.54 (quintet, J = 7.2 Hz, 1H), 4.40
(d, J = 7.2 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 3.94 (octet, J = 6.4
Hz, 1H), 3.76 (septet, J = 7.2 Hz, 1H), 1.40 (d, J = 7.2 Hz, 3H),
1.28–1.16 (m, 12H); 19F-NMR (235.6 MHz, CDCl3): δ = −64.9
(quintet, J = 7.2 Hz, 3F), −63.9 (quintet, J = 7.2 Hz, 3F);
13C-NMR (62.9 MHz, CDCl3): δ = 172.3, 169.0, 158.4, 135.5,
128.5, 128.3, 128.0, 123.0 (q, J = 281.2 Hz), 122.3 (q, J = 282.0
Hz), 66.8, 50.9, 48.2, 46.7 (septet, J = 25.9 Hz), 43.0, 23.0, 21.3,
20.0, 17.5; ESI (m/z) 514 [M+, (5)], 222 (89), 91 (100); Anal. calcd
for C22H29F6N3O4: C 51.46, H 5.69, N 8.18; found: C 51.51, H
5.62, N 8.16.
(R)-6a: Rf = 0.35 (hexane : AcOEt 70 : 30); [α]2D0 = −33.1° (c =
1
0.64, CHCl3); H-NMR (250 MHz, CDCl3): δ = 8.83 (br s, 1H),
7.35 (m, 5H), 5.20 (d, J = 12.0 Hz, 1H), 5.14 (d, J = 12.0 Hz, 1H),
4.71 (m, 1H), 4.54 (m, 2H), 4.34 (br d, J = 9.6 Hz, 1H), 3.94
(octet, J = 6.4 Hz, 1H), 3.78 (septet, J = 7.2 Hz, 1H), 1.39 (d, J =
7.2 Hz, 3H), 1.28–1.16 (m, 12H); 19F-NMR (235.6 MHz, CDCl3):
δ = −64.6 (m, 3F), −64.1 (m, 3F); 13C-NMR (62.9 MHz, CDCl3):
δ = 171.9, 168.7, 158.3, 135.4, 128.5, 128.3, 67.0, 56.0, 50.3,
48.4, 46.8 (septet, J = 27.7 Hz), 42.9, 23.0, 21.2, 20.5, 18.0. The
CF3 signal was obscured due to its low intensity; ESI (m/z) 514
[M+, (9)], 222 (93), 91 (100); Anal. calcd for C22H29F6N3O4: C
51.46, H 5.69, N 8.18; found: C 51.40, H 5.60, N 8.19.
(S)-6b: Rf = 0.47 (hexane : AcOEt 80 : 20); [α]2D0 = +81.7° (c =
1
0.63, CHCl3); H-NMR (500 MHz, CDCl3): δ = 8.82 (br s, 1H),
4.82 (m, 1H), 4.46 (d, J = 7.5 Hz, 1H), 4.19 (br d, J = 11.3 Hz,
1H), 4.14 (dd, J = 7.5 and 4.7 Hz, 1H), 3.97 (octet, J = 6.6 Hz,
1H), 3.81 (septet, J = 6.6 Hz, 1H), 2.14 (m, 1H), 1.26–1.24 (m,
6H), 1.19 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H), 0.96 (d, J =
6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H); 19F-NMR (235.4 MHz,
CDCl3): δ = −64.7 (m, 3F), −63.8 (m, 3F); 13C-NMR (125.7 MHz,
CDCl3): δ = 170.5, 169.5, 158.4, 123.0 (q, J = 283.4 Hz), 122.7 (q,
J = 281.7 Hz), 81.2, 58.7, 56.6, 50.8, 47.0 (septet, J = 26.7 Hz),
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42.9, 30.2, 27.9, 23.1, 23.0, 21.3, 19.0, 17.9; ESI (m/z) 530.0 21.1, 14.3; ESI (m/z) 450.0 [M+ + Na, (100)], 528.0 [M+ + 1, (8)];
[M+ + Na, (100)]; Anal. calcd for C21H35F6N3O4: C 49.70, H 6.95, Anal. calcd for C23H31F6N3O4: C 52.37, H 5.92, N 7.97; found:
N 8.28; found: C 49.76, H 6.91, N 8.29.
C 52.31, H 5.99, N 7.89.
(R)-6b: Rf = 0.34 (hexane : AcOEt 80 : 20); [α]2D0 = −34.1° (c =
(R/S)-6e, mixture of diastereoisomers: Rf = 0.34 (hexane :
1
1
1.07, CHCl3); H-NMR (500 MHz, CDCl3): δ = 8.61 (br s, 1H), AcOEt 50 : 50); H-NMR (400 MHz, CDCl3): δ = 7.34 (m, 10H),
4.74 (br s, 1H), 4.52 (d, J = 7.0 Hz, 1H), 4.40 (br s, 1H), 4.33 6.03 (m, 2H), 5.31 (m, 4H), 5.14 (m, 4H), 4.84 (m, 1H), 4.70 (m,
(dd, J = 8.9 and 5.2 Hz, 1H), 4.01 (octet, J = 6.7 Hz, 1H), 3.77 1H), 4.53 (m 3H), 4.45 (d, J = 7.2 Hz, 1H), 4.36 (m, 1H), 4.17 (d,
(septet, J = 6.7 Hz, 1H), 2.14 (m, 1H), 1.29 (d, J = 6.7 Hz, 3H), J = 11.3 Hz, 1H), 3.95 (m, 6H), 3.76 (m, 2H), 1.41–1.38 (m, 6H),
1.21 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.7 1.27–1.16 (m, 24H); 13C-NMR (125.7 MHz, CDCl3): δ = 172.3,
Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H), 0.89 (d, J = 6.7 Hz, 3H); 171.9, 169.0, 168.7, 158.4, 158.3, 135.5, 135.4, 134.2, 128.5,
19F-NMR (235.4 MHz, CDCl3): δ = −64.5 (m, 3F), −64.1 (m, 3F); 128.3, 128.2, 128.1, 123.0 (q, J = 281.5 Hz), 122.7 (q, J = 282.3
13C-NMR (125.7 MHz, CDCl3): δ = 170.2, 168.8, 158.1, 123.1 (q, Hz), 119.0, 67.0, 66.8, 56.4, 50.8, 48.4, 48.2, 46.8 (septet, J =
J = 282.5 Hz), 81.7, 58.0, 47.0 (septet, J = 26.7 Hz), 31.3, 28.0, 26.3 Hz), 43.0, 42.9, 32.8, 23.0, 21.3, 21.2, 20.0, 18.0, 17.5; ESI
27.9, 23.2, 23.1, 21.3, 19.0, 17.6; ESI (m/z) 530.0 [M+ + Na, (m/z) 554.3 [M+ + H, (100)]; Anal. calcd for C25H33F6N3O4: C
(100)]; Anal. calcd for C21H35F6N3O4: C 49.70, H 6.95, N 8.28; 54.25, H 6.01, N 9.35; found: C 54.22, H 6.06, N 7.60.
found: C 49.77, H 6.94, N 8.20.
6f: Rf = 0.31 (DCM : MeOH 96 : 4); 1H-NMR (500 MHz,
(S)-6c: Rf = 0.41 (hexane : AcOEt 70 : 30); [α]2D0 = +17.8° (c = CDCl3): δ = 8.76 (br s, 1H), 6.38 (br s, 1H), 5.87 (br s, 1H), 4.72
1.41, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.34 (m, 5H), 5.92 (m, 1H), 4.58 (d, J = 7.0 Hz), 4.33 (d, J = 10.3 Hz, 1H), 3.91 (m,
(br s, 1H), 5.15 (s, 2H), 4.90 (br s, 1H), 4.52 (dd, J = 8.9 and 3.7 3H), 3.81 (m, 1H), 1.27 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 6.6 Hz,
Hz, 1H), 4.10 (m, 1H), 3.98 (m, 2H), 3.79 (m, 1H), 3.67 (m, 1H), 3H), 1.18 (d, J = 6.6 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H); 19F-NMR
2.18 (m, 1H), 2.05–1.98 (m, 3H), 1.35 (d, J = 7.0 Hz, 3H), 1.23 (470.6 MHz, CDCl3): δ = −64.4 (m, 3F), −64.1 (m, 3F); 13C-NMR
(d, J = 7.0 Hz, 3H), 1.19 (d, J = 7.0 Hz, 3H), 1.17 (d, J = 7.0 Hz, (125.7 MHz, CDCl3): δ = 171.3, 170.2, 158.2, 122.9 (q, J = 280.0
3H); 19F-NMR (235.6 MHz, CDCl3): δ = −64.5 (m, 3F), −63.4 Hz), 55.9, 50.5, 46.9 (q, J = 25.8 Hz), 43.4, 43.1, 23.0, 21.4, 20.4;
(quintet, J = 10.1 Hz, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = ESI (m/z) 447.0 [M+ + K, (4)], 431.0 [M+ + Na, (100)]; Anal. calcd
171.4, 167.0, 156.6, 135.6, 128.6, 128.3, 128.0, 123.2 (q, J = for C14H22F6N4O3: C 41.18, H 5.43, N 13.72; found: C 41.15, H
285.9 Hz), 123.0 (q, J = 281.7 Hz), 66.8, 59.6, 50.7, 48.0 (septet, 5.41, N 13.68.
J = 26.7 Hz), 47.5, 43.1, 29.1, 24.8, 23.1, 21.0; ESI (m/z) 562.2
[M+ + Na, (100)]; Anal. calcd for C24H31F6N3O4: C 53.43, H 5.79, 0.83, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 8.79 (d, J = 7.4
N 7.79; found: C 53.39, H 5.71, N 7.75. Hz, 1H), 7.16 (m, 5H), 6.31 (br s, 1H), 4.72 (m, 1H), 4.54 (m,
(S)-6g: Rf = 0.30 (hexane : AcOEt 50 : 50); [α]2D0 = −138.2° (c =
(R)-6c: Rf = 0.20 (hexane : AcOEt 70 : 30); [α]2D0 = −116.6° (c = 1H), 4.31 (d, J = 7.4 Hz, 1H), 3.98 (d, J = 10.6 Hz, 1H), 3.96
1.01, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.34 (m, 5H), 5.91 (octet, J = 7.2 Hz, 1H), 3.49 (septet, J = 7.2 Hz, 1H), 3.24 (dd, J =
(d, J = 10.3 Hz, 1H), 5.20 (d, J = 12.2 Hz, 1H), 5.11 (d, J = 12.2 14.7 and 4.8 Hz, 1H), 2.92 (dd, J = 14.7 and 9.9 Hz, 1H), 2.74
Hz, 1H), 4.57 (br s, 1H), 4.44 (dd, J = 8.9 and 4.2 Hz, 1H), 4.14 (d, J = 5.6 Hz, 3H), 1.24 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 7.2 Hz,
(m, 1H), 3.98 (octet, J = 6.6 Hz, 1H), 3.84 (septet, J = 6.6 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 0.68 (d, J = 7.2 Hz, 3H); 19F-NMR
1H), 3.73 (m, 1H), 3.67 (m, 1H), 2.15–1.93 (m, 4H), 1.38 (d, J = (235.4 MHz, CDCl3): δ = −64.6 (dq, J = 12.1 and 7.8 Hz, 3F),
6.6 Hz, 3H), 1.18 (m, 6H), 1.10 (d, J = 6.6 Hz, 1H); 19F-NMR −63.9 (dq, J = 12.1 and 8.1 Hz, 3F); 13C-NMR (100.6 MHz,
(235.4 MHz, CDCl3): δ = −65.0 (quintet, J = 8.4 Hz, 3F), −63.3 CDCl3): δ = 171.3, 170.6, 158.7, 129.6, 128.8, 127.0, 123.2 (q, J =
(d, J = 9.9 Hz, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = 171.0, 281.0 Hz), 56.5, 55.4, 51.1, 46.9 (septet, J = 26.7 Hz), 43.5, 37.6,
166.4, 156.5, 135.6, 128.5, 128.3, 128.2, 123.1 (q, J = 280.0 Hz), 26.4, 23.4, 23.3, 21.2, 20.2; ESI (m/z) 535.0 [M+ + Na, (100)];
66.9, 59.7, 51.5, 47.5 (septet, J = 25.8 Hz), 47.0, 45.9, 43.2, 29.1, Anal. calcd for C22H30F6N4O3: C 51.56, H 5.90, N 10.93; found:
24.7, 23.2, 23.1, 22.5, 20.4; ESI (m/z) 562.2 [M+ + Na, (100)]; C 51.55, H 5.98, N 10.87.
Anal. calcd for C24H31F6N3O4: C 53.43, H 5.79, N 7.79; found:
C 53.51, H 5.75, N 7.73.
(R)-6g: Rf = 0.17 (hexane : AcOEt 50 : 50); [α]2D0 = +29.3° (c =
1.05, CHCl3); H-NMR (400 MHz, CDCl3): δ = 8.79 (br s, 1H),
1
6d: Rf = 0.50 (hexane : AcOEt 70 : 30); 1H-NMR (400 MHz, 7.22 (m, 5H), 6.20 (br s, 1H), 4.51 (m, 1H), 4.38 (q, J = 7.7 Hz,
CDCl3), 1 : 1 mixture of two amidic isomers: δ = 7.28–7.20 (m, 1H), 4.25 (br d, J = 10.2 Hz, 1H), 3.97 (octet, J = 6.8 Hz, 1H),
5H), 6.34 (d, J = 10.4 Hz, 0.5H), 6.13 (d, J = 10.4 Hz, 0.5H), 5.01 3.73 (septet, J = 6.4 Hz, 1H), 3.12 (dd, J = 13.8 and 6.4 Hz, 1H),
(t, J = 15.2 Hz, 1H), 4.54 (m, 1H), 4.43 (br d, J = 6.4 Hz, 0.5H), 2.95 (dd, J = 13.8 and 8.3 Hz, 1H), 2.67 (d, J = 4.9 Hz, 3H),
4.12 (m, 5H), 3.91 (m, 2H), 3.77 (d, J = 16.4 Hz, 0.5H), 1.21–1.08 (m, 12H); 19F-NMR (235.4 MHz, CDCl3): δ = −64.6
1.40–1.15 (m, 15H); 19F-NMR (235.4 MHz, CDCl3), mixture of (m, 3F), −64.5 (m, 3F); 13C-NMR (100.6 MHz, CDCl3): δ = 171.5,
two amidic isomers: δ = −64.3 (quintet, J = 8.2 Hz, 3F), −64.2 170.2, 158.6, 137.3, 129.9, 129.0, 127.3, 123.2 (q, J = 283.5 Hz),
(quintet, J = 7.3 Hz, 3F), −63.1 (quintet, J = 8.9 Hz, 3F), −63.0 123.0 (q, J = 283.5 Hz), 56.3, 55.9, 50.8, 47.2 (septet, J = 26.7
(quintet, J = 10.6 Hz, 3F); 13C-NMR (100.6 MHz, CDCl3), Hz), 43.4, 37.4, 26.3, 23.8, 23.4, 21.4, 20.7; ESI (m/z) 535.0
mixture of two amidic isomers: δ = 168.8, 168.7, 156.6, 156.4, [M+ + Na, (100)]; Anal. calcd for C22H30F6N4O3: C 51.56, H 5.90,
135.8, 135.4, 129.4, 129.3, 129.2, 129.0, 128.5, 128.4, 128.3, N 10.93; found: C 51.50, H 5.87, N 10.97.
124.5 (q, J = 280.8 Hz), 61.7, 61.5, 51.2, 50.5, 50.2, 49.7, 48.4,
47.2, 46.0, 45.7, 43.6, 43.5, 23.5, 23.4, 23.3, 23.2, 23.1, 21.3, +65.4° (c = 1.05, CHCl3); H-NMR (400 MHz, CDCl3): δ = 8.91
(S)-6h: Rf = 0.41 (cyclo-hexane : acetone 70 : 30); [α]D20
=
1
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(br s, 1H), 7.25 (m, 5H), 6.98 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 18H), 0.90 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz); 13C-NMR
9.0 Hz, 2H), 6.43 (d, J = 7.7 Hz, 1H), 4.74 (q, J = 5.8 Hz, 1H), (125.7 MHz, CDCl3): δ = 171.7, 171.6, 171.5, 171.4, 170.6,
4.59 (m, 1H), 4.49 (d, J = 7.7 Hz, 1H), 4.45 (q, J = 7.7 Hz, 1H), 170.5, 157.3, 156.7, 81.9, 81.8, 60.8, 57.8, 57.7, 53.5, 53.4, 47.6,
4.19 (br d, J = 10.9 Hz, 1H), 3.88 (octet, J = 6.7 Hz, 1H), 3.72 47.2, 42.8, 42.6, 36.2, 35.8, 31.4, 31.0, 27.9, 23.3, 23.2, 23.1,
(septet, J = 6.7 Hz, 1H), 3.61 (s, 3H), 3.08 (dd, J = 14.1 and 22.9, 21.4, 21.3, 20.9, 18.9, 18.8, 17.6, 17.5, 14.0; ESI (m/z)
6.4 Hz, 1H), 3.00 (m, 3H), 2.26 (s, 3H), 1.16 (m, 9H), 1.02 (d, J = 444.2 [M+ + H, (100)]; Anal. calcd for C22H41N3O6: C 59.57, H
6.7 Hz, 3H); 19F-NMR (235.4 MHz, CDCl3): δ = −64.6 (m, 3F), 9.32, N 9.47; found: C 59.58, H 7.89.39, N 9.45.
−64.2 (m, 3F); 13C-NMR (100.6 MHz, CDCl3): δ = 171.5, 170.7,
(R/S)-7c, mixture of diastereoisomers: Rf = 0.29 (hexane :
1
170.1, 169.7, 158.7, 150.1, 136.9, 133.8, 130.6, 129.7, 128.9, AcOEt 50 : 50); H-NMR (500 MHz, CDCl3): δ = 7.35 (m, 10H),
127.3, 123.3 (q, J = 281.0 Hz), 122.9 (q, J = 281.0 Hz), 121.9, 5.60 (br d, J = 5.5 Hz, 1H), 5.34 (dd, J = 8.5 and 5.5 Hz, 1H),
56.4, 55.9, 53.7, 52.5, 50.7, 47.2 (septet, J = 26.7 Hz), 43.4, 37.8, 5.19 (d, J = 12.5 Hz, 2H), 5.13 (d, J = 12.5 Hz, 2H), 5.06 (dd, J =
37.7, 27.3, 23.4, 23.3, 21.6, 21.4, 20.6; ESI (m/z) 741.1 [M+ + Na, 8.5 and 5.5 Hz, 1H), 4.97 (br s, 1H), 4.53 (dd, J = 8.5 and
(100)]; Anal. calcd for C33H40F6N4O7: C 55.15, H 5.61, N 7.80; 5.5 Hz, 1H), 4.49 (dd, J = 8.5 and 3.5 Hz, 1H), 4.12 (m, 4H),
found: C 55.06, H 5.53, N 7.74.
3.96 (octet, J = 6.5 Hz, 1H), 3.91 (octet, J = 6.5 Hz, 1H), 3.77 (m,
2H), 3.64 (m, 4H), 3.09 (dd, J = 16.0 and 8.5 Hz, 1H), 2.90 (dd,
(R)-6h: Rf = 0.34 (cyclo-hexane : acetone 70 : 30); [α]D20
=
1
−56.6° (c = 1.28, CHCl3); H-NMR (400 MHz, CDCl3): δ = 9.03 J = 17.0 and 5.5 Hz, 1H), 2.80 (dd, J = 17.0 and 9.0 Hz, 1H),
(d, J = 7.7 Hz, 1H), 7.20 (m, 5H), 7.09 (d, J = 8.4 Hz, 2H), 7.01 2.54 (dd, J = 16.0 and 5.5 Hz, 1H), 2.22 (m, 2H), 2.13 (m, 2H),
(d, J = 8.4 Hz, 2H), 6.51 (d, J = 7.4 Hz, 1H), 4.77 (q, J = 6.4 Hz, 2.04–1.93 (m, 4H), 1.31–1.22 (m, 12H), 1.18–1.15 (m, 6H);
1H), 4.69 (m, 1H), 4.59 (m, 1H), 4.30 (d, J = 7.7 Hz, 1H), 4.04 13C-NMR (125.7 MHz, CDCl3): δ = 172.2, 171.7, 171.6, 171.5,
(d, J = 11.2 Hz, 1H), 3.97 (octet, J = 6.7 Hz, 1H), 3.63 (s, 3H), 169.9, 169.4, 157.3, 156.6, 135.7, 135.6, 128.5, 128.4, 128.3,
3.51 (septet, J = 6.7 Hz, 1H), 3.16 (dd, J = 14.1 and 5.1 Hz, 1H), 128.2, 128.1, 128.0, 66.8, 66.7, 61.1, 60.7, 59.5, 59.4, 54.2, 53.4,
3.08 (dd, J = 13.8 and 5.4 Hz, 1H), 2.99 (dd, J = 13.8 and 6.4 Hz, 46.9, 46.8, 46.5, 46.4, 42.6, 42.3, 35.1, 35.0, 29.1, 29.0, 25.2,
1H), 2.88 (dd, J = 14.1 and 9.6 Hz, 1H), 2.25 (s, 3H), 1.25 (d, J = 24.6, 23.5, 23.4, 23.3, 23.2, 23.0, 21.6, 21.5, 21.3, 20.9, 14.1; ESI
6.7 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H), (m/z) 476 [M+ + H, (9)], 498.1 [M+ + Na, (100)]; Anal. calcd for
0.72 (d, J = 6.7 Hz, 3H); 19F-NMR (235.4 MHz, CDCl3): δ = C25H37N3O6: C 63.14, H 7.84, N 8.84; found: C 63.20, H 7.88, N
−64.6 (m, 3F), −63.6 (m, 3F); 13C-NMR (100.6 MHz, CDCl3): δ = 8.84.
171.5, 170.4, 170.3, 169.6, 158.8, 150.2, 137.5, 133.7, 130.6,
(R/S)-7d, mixture of amidic isomers: Rf = 0.20 (hexane :
129.7, 129.6, 128.9, 128.8, 127.0, 123.3 (q, J = 282.2 Hz), 123.1 AcOEt 70 : 30); 1H-NMR (500 MHz, CDCl3): δ = 7.29 (m, 5H),
(q, J = 281.0 Hz), 122.0, 55.6, 55.3, 53.8, 53.7, 52.5, 51.1, 46.9 5.68 (dd, J = 8.4 and 5.1 Hz, 0.6H), 5.39 (t, J = 7.0 H, 0.4H), 5.03
(septet, J = 26.7 Hz), 43.4, 38.0, 37.7, 27.3, 23.4, 23.3, 23.2, (d, J = 15.5 Hz, 0.6H), 4.86 (d, J = 6.1 Hz, 0.4H), 4.70 (d, J =
21.4, 21.2, 20.3; ESI (m/z) 741.1 [M+ + Na, (100)]; Anal. calcd for 6.6 Hz, 0.6H), 4.64 (d, J = 15.0 Hz, 0.4H), 4.60 (d, J = 15.0 Hz,
C33H40F6N4O7: C 55.15, H 5.61, N 7.80; found: C 55.08, H 5.56, 0.4H), 4.39 (d, J = 16.0 Hz, 0.6H), 4.35 (d, J = 16.0 H, 0.6H),
N 7.84.
4.13 (m, 4H), 3.92 (m, 1H), 3.74 (m, 1H), 3.54 (d, J = 16.9 Hz,
(R/S)-7a, mixture of diastereoisomers: Rf = 0.22 (hexane : 0.6H), 3.10 (dd, J = 16.5 and 9.4 Hz, 0.6H), 3.02 (dd, J = 16.5
1
AcOEt 50 : 50); H-NMR (400 MHz, CDCl3): δ = 7.33 (m, 10H), and 7.0 Hz, 0.4H), 2.71 (dd, J = 16.5 and 7.0 Hz, 0.4H), 2.62
7.22 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 5.15 (m, 4H), (dd, J = 16.5 and 5.6 Hz, 0.6H), 1.42–1.11 (m, 18H); 13C-NMR
4.85 (m, 1H), 4.67 (m, 1H), 4.59 (septet, J = 7.2 Hz, 1H), 4.54 (125.7 MHz, CDCl3): δ = 171.5, 171.2, 171.1, 170.9, 169.1,
(m, 1H), 4.42 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 4.09 (m, 2H), 168.9, 156.4, 156.1, 136.1, 135.7, 128.8, 128.7, 128.6, 127.8,
3.94 (m, 2H), 3.26 (dd, J = 16.4 and 8.4 Hz, 2H), 2.63 (dd, J = 127.7, 127.6, 61.4, 61.0, 60.9, 60.7, 52.1, 52.0, 51.3, 50.0, 47.8,
16.4 and 5.6 Hz, 1H), 2.56 (dd, J = 16.4 and 5.2 Hz, 1H), 1.41 46.6, 45.8, 42.7, 42.6, 35.6, 35.4, 23.3, 23.2, 23.1, 21.7, 21.6,
(d, J = 7.2 Hz, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.25 (m, 12H), 1.15 21.5, 21.4, 14.1, 14.0; ESI (m/z) 486.1 [M+ + Na, (100)]; Anal.
(m, 12H); 13C-NMR (125.7 MHz, CDCl3): δ = 172.4, 171.6, calcd for C24H37N3O6: C 62.18, H 8.04, N 9.06; found: C 62.16,
171.4, 171.3, 157.4, 156.9, 135.3, 128.6, 128.4, 128.2, 128.1, H 8.00, N 9.01.
67.1, 60.9, 60.8, 53.7, 48.4, 47.7, 47.4, 42.8, 42.7, 35.9, 35.7,
7e: Rf = 0.21 (DCM : MeOH 95 : 5); 1H-NMR (400 MHz,
23.2, 23.1, 23.0, 22.9, 21.3, 21.1, 21.0, 18.1, 18.0, 14.1; ESI (m/z) CD3OD): δ = 6.23 (d, J = 8.0 Hz, 1H), 4.35 (dd, J = 8.0 and
450.3 [M+ + H, (1)], 472.3 [M+ + Na, (100)]; Anal. calcd for 4.0 Hz, 1H), 4.08 (m, 3H), 4.02 (d, J = 16.0 Hz, 1H), 3.88 (m, 1H),
C23H35N3O6: C 61.45, H 7.85, N 9.35; found: C 61.41, H 7.89, 3.55 (d, J = 16.0 Hz, 1H), 3.47 (dd, J = 16.0 and 8.0 Hz, 1H), 2.36
N 9.33.
(dd, J = 16.0 and 4.0 Hz, 1H), 1.34 (d, J = 8.0 Hz, 3H), 1.25 (t, J =
(R/S)-7b, mixture of diastereoisomers: Rf = 0.32 (hexane : 8.0 Hz, 3H), 1.16 (d, J = 8.0 Hz, 3H), 1.14 (d, J = 8.0 Hz, 3H);
AcOEt 50 : 50); 1H-NMR (400 MHz, CDCl3): δ = 7.00 (d, J = 13C-NMR (125.7 MHz, CD3OD): δ = 175.3, 174.7, 174.0, 159.1,
8.4 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 4.91 (d, J = 6.2 Hz, 1H), 62.0, 53.9, 44.1, 43.9, 38.2, 23.4, 23.3, 21.6, 21.3, 14.6; ESI (m/z)
4.74 (d, J = 6.8 Hz, 1H), 4.48 (m, 1H), 4.36–4.30 (m, 3H), 367.2 [M+ + Na, (45)]; Anal. calcd for C15H28N4O5: C 52.31, H
4.17–4.10 (m, 6H), 3.92 (octet, J = 6.6 Hz, 2H), 3.33 (dd, J = 16.6 8.19, N 16.27; found: C 52.28, H 8.22, N 16.22.
and 8.0 Hz, 1H), 3.29 (dd, J = 16.6 and 8.4 Hz, 1H), 2.58 (dd,
J = 16.6 and 4.9 Hz, 1H), 2.51 (dd, J = 16.6 and 4.7 Hz, 1H), AcOEt 40 : 60); H-NMR (400 MHz, CD3Cl): δ = 7.45 (br q, J =
1.43 (s, 9H), 1.42 (s, 9H), 1.30–1.21 (m, 12H), 1.17–1.11 (m, 4.4 Hz, 1H), 7.21 (m, 6H), 7.11 (m, 4H), 6.96 (d, J = 8.0 Hz, 1H),
(R/S)-7f, mixture of two diastereoisomers: Rf = 0.12 (hexane :
1
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6.73 (br q, J = 4.4 Hz, 1H), 6.11 (d, J = 8.4 Hz, 1H), 4.85 (br s, 16.0 and 4.0 Hz, 1H), 1.41 (d, J = 8.0 Hz, 3H), 1.26 (d, J = 8.0
1H), 4.66 (m, 1H), 4.55 (m, 2H), 4.35 (dd, J = 8.8 and 4.0 Hz, Hz, 3H), 1.17–1.13 (m, 9H); 13C-NMR (62.9 MHz, CDCl3): δ =
1H), 4.19 (m, 1H), 4.09 (m, 4H), 3.86 (m, 2H), 3.80 (m, 1H), 172.6, 171.7, 171.5, 157.1, 136.0, 128.8, 128.6, 128.4, 128.3,
3.67 (septet, J = 6.8 Hz, 1H), 3.48 (dd, J = 16.8 and 7.6 Hz, 1H), 67.3, 66.8, 54.0, 48.6, 47.9, 42.9, 36.1, 23.4, 23.3, 21.5, 21.4,
3.33 (dd, J = 14.0 and 6.0 Hz, 1H), 3.27 (dd, J = 16.8 and 18.4; ESI (m/z) 512.3 [M+ + H, (10)], 534.3 [M+ + Na, (100)];
9.2 Hz, 1H), 3.17 (dd, J = 14.0 and 5.6 Hz, 1H), 3.06 (dd, J = Anal. calcd for C28H37N3O6: C 65.73, H 7.29, N 8.21; found: C
14.0 and 8.0 Hz, 1H), 3.00 (dd, J = 14.4 and 6.0 Hz, 1H), 2.73 65.77, H 7.31, N 8.26.
(m, 1H), 2.70 (s, 3H), 2.69 (s, 3H), 2.45 (dd, J = 16.8 and 4.4 Hz,
(R/S)-8b, mixture of two diastereoisomers: Rf = 0.42
1H), 2.34 (m, 2H), 2.28 (dd, J = 16.8 and 4.0 Hz, 1H), 1.22 (t, J = (hexane : AcOEt 50 : 50); 1H-NMR (500 MHz, CD3Cl): δ = 7.31
7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.15–1.09 (m, 18H), 1.00 (m, 10H), 6.98 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 5.13
(d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); 13C-NMR (d, J = 12.0 Hz, 2H), 5.07 (d, J = 12.0 Hz, 2H), 4.86 (d, J = 7.0
(125.7 MHz, CD3Cl): δ = 171.9, 171.7, 171.6, 171.4, 171.0, Hz, 1H), 4.74 (d, J = 7.5 Hz, 1H), 4.44 (m, 1H), 4.35 (m, 2H),
169.4, 157.3, 156.9, 156.8, 149.6, 149.5, 136.8, 136.4, 134.4, 4.28 (dd, J = 8.5 and 4.5 Hz, 1H), 3.76 (m, 1H), 3.68 (m, 1H),
133.8, 130.2, 130.1, 129.3, 128.6, 128.5, 127.0, 126.8, 121.5, 3.57 (m, 2H), 3.41 (m, 2H), 2.60 (dd, J = 16.5 and 5.0 Hz, 1H),
121.4, 60.9, 60.8, 55.1, 53.5, 53.3, 53.1, 48.1, 47.4, 42.8, 42.7, 2.53 (dd, J = 16.5 and 4.5 Hz, 1H), 2.11 (m, 2H), 1.83–1.11 (m,
41.9, 37.0, 36.9, 36.8, 36.6, 35.8, 23.4, 23.3, 23.2, 23.1, 21.1, 16H), 1.42 (s, 9H), 1.41 (s, 9H), 0.86 (m, 12H); 13C-NMR
21.0, 20.9, 20.8, 14.1, 14.0; ESI (m/z) 449.3 [M+ + H, (11)], 471.3 (125.7 MHz, CD3Cl): δ = 171.7, 171.6, 171.5, 171.4, 170.6,
[M+ + Na, (100)], 487.3 [M+ + K, (21)]; Anal. calcd for 170.5, 157.0, 156.6, 135.8, 128.5, 128.2, 82.0, 81.9, 66.7, 57.9,
C23H36N4O5: C 61.59, H 8.09, N 12.49; found: C 61.56, H 8.04, 57.8, 56.6, 56.1, 54.3, 54.0, 49.7, 49.6, 36.4, 36.1, 33.8, 33.6,
N 12.44.
33.5, 33.4, 32.1, 31.6, 31.3, 28.1, 28.0, 26.2, 26.0, 25.7, 25.6,
(R/S)-7g, mixture of two diastereoisomers: Rf = 0.27 (DCM : 25.3, 25.2, 25.0, 19.0, 18.8, 17.7, 17.6; ESI (m/z) 586.1 [M+ + H,
MeOH 95 : 5); 1H-NMR (400 MHz, CD3Cl): δ = 7.38 (d, J = (100)]; Anal. calcd for C33H51N3O6: C 67.66, H 8.78, N 7.17;
6.4 Hz, 1H), 7.20 (m, 10H), 7.11 (m, 2H), 6.99 (m, 6H), 6.75 (d, found: C 67.61, H 8.77, N 7.15.
J = 6.0 Hz, 1H), 6.67 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 5.6 Hz, 1H),
14a: Rf = 0.34 (hexane : AcOEt 80 : 20); 1H-NMR (500 MHz,
4.70 (m, 2H), 4.63 (q, J = 11.6 Hz, 1H), 4.56 (q, J = 11.6 Hz, 1H), CDCl3): δ = 8.65 (br s, 1H), 7.25 (m, 5H), 4.71 (br s, 1H), 4.58
4.49 (d, J = 6.0 Hz, 1H), 4.35 (m, 4H), 4.17 (dd, J = 5.6 and (br d, J = 7.0 Hz, 1H), 4.49 (dd, J = 15.0 and 6.0 Hz, 1H), 4.40
4.0 Hz, 1H), 4.13 (m, 6H), 3.84 (m, 6H), 3.69 (septet, J = 6.0 Hz, (br s, 1H), 4.28 (dd, J = 15.0 and 6.0 Hz, 1H), 3.91 (octet, J = 6.5
1H), 3.66 (s, 3H), 3.63 (s, 3H), 3.31 (dd, J = 13.2 and 6.0 Hz, Hz, 1H), 3.77 (septet, J = 7.0 Hz, 1H), 1.26 (d, J = 6.5 Hz, 3H),
1H), 3.27 (dd, J = 13.2 and 6.8 Hz, 1H), 3.04 (m, 6H), 2.50 (t, J = 1.18 (d, J = 6.5 Hz, 3H), 1.15 (d, J = 6.5 Hz, 3H), 1.13 (d, J = 6.5
12.8 Hz, 1H), 2.49 (t, J = 12.8 Hz, 1H), 2.27 (s, 3H), 2.26 (s, 3H), Hz, 3H); 19F-NMR (235.4 MHz, CDCl3): δ = −64.6 (br s, 3F),
1.26–0.95 (m, 30H); 13C-NMR (125.7 MHz, CD3Cl): δ = 171.9, −64.1 (br s, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = 169.1, 158.4,
171.7, 171.6, 171.4, 171.0, 170.5, 169.4, 157.3, 156.9, 156.8, 137.9, 128.5, 127.6, 127.3, 123.0 (q, J = 281.8 Hz), 122.8 (q, J =
149.6, 149.5, 136.8, 136.4, 134.4, 133.8, 130.2, 130.1, 129.3, 282.1 Hz), 56.4, 50.4, 47.0 (septet, J = 26.8 Hz), 43.6, 43.0, 23.0,
128.6, 128.5, 127.0, 126.8, 121.5, 121.4, 115.6, 60.9, 60.8, 54.8, 21.1, 20.5; ESI (m/z) 480.0 [M+ + K, (4)], 464.1 [M+ + Na, (100)];
54.0, 53.7, 53.6, 53.3, 52.2, 52.1, 48.1, 47.4, 42.8, 42.7, 41.9, 37.0, Anal. calcd for C19H25F6N3O2: C 51.70, H 5.71, N 9.52; found:
36.9, 36.8, 36.6, 35.8, 23.4, 23.3, 23.2, 23.1, 21.1, 21.0, 20.9, 20.7, C 51.61, H 5.67, N 9.50.
14.1, 14.0; ESI (m/z) 655.3 [M+ + H, (3)], 677.4 [M+ + Na, (100)],
693.3 [M+ + K, (8)]; Anal. calcd for C34H46N4O9: C 62.37, H 7.08, CDCl3): δ = 5.96 (d, J = 10.0 Hz, 1H), 4.46 (br s, 1H), 4.13 (m,
N 8.56; found: C 62.33, H 7.04, N 8.55. 1H), 3.88 (octet, J = 6.4 Hz, 1H), 3.75 (septet, J = 6.8 Hz, 1H),
14b: Rf = 0.37 (hexane : AcOEt 60 : 40); 1H-NMR (400 MHz,
(S)-8a: Rf = 0.40 (hexane : AcOEt 50 : 50); [α]2D0 = +0.44° (c = 3.63–3.54 (br m, 7H), 3.40 (br s, 1H), 1.29 (d, J = 7.2 Hz, 3H),
0.9, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.35 (m 10H), 7.20 1.08 (d, J = 6.4 Hz, 6H), 1.05 (d, J = 6.4 Hz, 3H); 19F-NMR
(d, J = 8.0 Hz, 1H), 5.17 (m, 4H), 4.76 (d, J = 4.0 Hz, 1H), 4.57 (235.4 MHz, CDCl3): δ = −64.9 (quintet, J = 7.8 Hz, 3F), −63.4
(m, 2H), 4.06 (septet, J = 8.0 Hz, 1H), 3.94 (octet, J = 8.0 Hz, (quintet, J = 9.4 Hz, 3F); 13C-NMR (100.6 MHz, CDCl3): δ =
1H), 3.34 (dd, J = 16.0 and 8.0 Hz, 1H), 2.65 (dd, J = 16.0 and 166.5, 155.9, 123.1 (q, J = 282.2 Hz), 129.9 (q, J = 279.5 Hz),
4.0 Hz, 1H), 1.41 (d, J = 8.0 Hz, 3H), 1.25 (d, J = 8.0 Hz, 3H), 66.6, 66.4, 48.8, 47.9 (septet, J = 26.3 Hz), 45.9, 45.4, 43.2, 42.8,
1.18–1.13 (m, 9H); 13C-NMR (62.9 MHz, CDCl3): δ = 172.4, 23.1, 22.9, 20.5; ESI (m/z) 460.0 [M+ + K, (8)], 444.1 [M+ + Na,
171.4, 171.2, 157.4, 135.7, 128.6, 128.5, 128.4, 28.2, 128.1, 67.1, (100)]; Anal. calcd for C16H25F6N3O3: C 45.61, H 5.98, N 9.97;
66.6, 53.8, 48.4, 47.4, 42.8, 35.6, 23.3, 23.0, 21.3, 1.0, 18.0; ESI found: C 45.56, H 5.95, N 9.91.
(m/z) 512.3 [M+ + H, (5)], 534.3 [M+ + Na, (100)]; Anal. calcd for
C28H37N3O6: C 65.73, H 7.29, N 8.21; found: C 65.70, H 7.32, CDCl3): δ = 10.55 (br s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.11 (d, J =
N 8.23. 8.0 Hz, 2H), 4.79 (br s, 1H), 4.51 (m, 1H), 4.36 (br s, 1H), 3.98
14c: Rf = 0.22 (hexane : AcOEt 60 : 40); 1H-NMR (500 MHz,
(R)-8a: Rf = 0.34 (hexane : AcOEt 50 : 50); [α]2D0 = −5.0° (c = (m, 1H), 3.80 (m, 1H), 2.30 (s, 3H), 1.29 (d, J = 7.0 Hz, 3H), 1.26
0.6, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.35 (m, 10H), 7.23 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 7.0 Hz,
(d, J = 8.0 Hz, 1H), 5.17 (m, 4H), 4.58 (m, 3H), 4.46 (dd, J = 4.0 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 167.2, 159.1, 135.8,
and 1.2 Hz, 1H), 4.07 (septet, J = 8.0 Hz, 1H), 3.94 (octet, J = 134.2, 129.73, 129.71, 120.3, 47.2 (quintet, J = 20.1 Hz), 43.5,
8.0 Hz, 1H), 3.35 (dd, J = 16.0 and 8.0 Hz, 1H), 2.73 (dd, J = 23.3, 21.1; ESI (m/z) 464.1 [M+ + Na, (100)], 442.1 [M+ + H, (11)];
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Anal. calcd for C19H25F6N3O2: C 51.70, H 5.71, N 9.52; found: 157.1, 135.4, 134.9, 128.6, 128.4, 128.1, 123.0 (q, J = 281.7 Hz),
C 51.68, H 5.70, N 9.46.
118.1, 67.1, 60.3, 51.5, 48.3, 46.6 (septet, J = 26.7 Hz), 29.1,
15a: Rf = 0.22 (hexane : AcOEt 60 : 40); 1H-NMR (400 MHz, 17.9; ESI (m/z) 548.1 [M+ + Na, (100)]; Anal. calcd for
CDCl3): δ = 7.29 (m, 5H), 7.09 (br s, 1H), 4.76 (d, J = 6.8 Hz, C23H29F6N3O4: C 52.57, H 5.56, N 8.00; found: C 52.58, H 5.59,
1H), 4.55 (m, 1H), 4.44 (m, 2H), 4.15 (q, J = 7.2 Hz, 2H), 4.04 N 7.99.
(septet, J = 7.2 Hz, 1H), 3.93 (octet, J = 6.4 Hz, 1H), 3.28 (dd, J =
(R)-18: Rf = 0.42 (hexane : AcOEt 80 : 20); [α]2D0 = −37.2° (c =
1
16.4 and 8.0 Hz, 1H), 2.65 (dd, J = 16.4 and 6.0 Hz, 1H), 0.72, CHCl3); H-NMR (500 MHz, CDCl3): δ = 7.48 (br s, 1H),
1.27–1.11 (m, 15H); 13C-NMR (100.6 MHz, CDCl3): δ = 171.7, 7.34 (m, 5H), 5.73 (m, 1H), 5.26–514 (m, 5H), 4.80 (s, 1H), 4.52
171.4, 157.3, 138.0, 128.7, 128.6, 127.6, 127.4, 60.7, 53.9, 47.3, (septet, J = 7.5 Hz, 1H), 3.90 (m, 1H), 3.66 (dd, J = 17.4 and
43.6, 42.7, 35.7, 27.6, 23.2, 21.3, 21.2, 14.1; ESI (m/z) 400.3 6.1 Hz, 1H), 1.39 (d, J = 7.0 Hz, 3H), 1.31 (s, 9H); 19F-NMR
[M+ + Na, (100)], 378.3 [M+ + H, (9)]; Anal. calcd for C20H31N3O4: (470.6 MHz, CDCl3): δ = −65.3 (m, 3F), −64.5 (m, 3F); 13C-NMR
C 63.64, H 8.28, N 11.13; found: C 63.60, H 8.23, N 11.10.
(125.7 MHz, CDCl3): δ = 171.7, 167.0, 157.0, 135.4, 133.8,
15b: Rf = 0.22 (hexane : AcOEt 60 : 40); 1H-NMR (400 MHz, 128.6, 128.5, 128.4, 128.2, 127.0, 123 (q, J = 280.9 Hz), 122.8 (q,
CDCl3): δ = 7.26–7.06 (m, 15H), 6.96 (br s, 1H), 5.29 (br t, J = J = 284.2 Hz), 118.1, 67.1, 65.2, 51.7, 48.6, 46.7 (septet, J = 26.7
6.8 Hz, 1H), 5.23 (br t, J = 5.2 Hz, 1H), 4.58 (d, J = 17.2 Hz 1H), Hz), 29.0, 17.6; ESI (m/z) 548.1 [M+ + Na, (100)]; Anal. calcd for
4.37 (m, 5H), 4.10 (dq, J = 7.2 and 1.6 Hz, 2H), 3.09 (dd, J = C23H29F6N3O4: C 52.57, H 5.56, N 8.00; found: C 52.53, H 5.51,
16.8 and 8.4 Hz, 1H), 2.64 (dd, J = 16.8 and 6.4 Hz, 1H), 1.20 (t, N 7.97.
J = 7.2 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 170.9, 170.5,
(S)-21: Rf = 0.32 (hexane : AcOEt 80 : 20); [α]2D0 = +28.5° (c =
158.9, 138.9, 138.1, 137.3, 129.1, 128.6, 128.5, 127.8, 127.6, 1.6, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.35 (m, 10H), 5.33
127.3, 127.2, 127.1, 126.5, 60.9, 55.4, 48.9, 44.9, 43.5, 34.1, (dd, J = 8.4 and 6.0 Hz, 1H), 5.20 (d, J = 12.4 Hz, 1H), 5.13 (d,
14.1; ESI (m/z) 512.2 [M+ + K, (8)], 496.3 [M+ + Na, (100)], 474.3 J = 12.4 Hz, 1H), 4.52 (m, 2H), 3.46 (d, J = 17.6 Hz, 1H), 4.18 (d,
[M+ + H, (10)]; Anal. calcd for C28H31N3O4: C 71.01, H 6.60, J = 17.6 Hz, 1H), 4.13 (m, 2H), 3.02 (dd, J = 16.4 and 8.8 Hz,
N 8.87; found: C 71.06, H 6.57, N 8.94.
1H), 2.53 (dd, J = 16.4 and 5.6 Hz, 1H), 1.39 (d, J = 7.2 Hz, 3H),
16a: Rf = 0.13 (hexane : AcOEt 60 : 40); 1H-NMR (400 MHz, 1.22 (m, 12H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.4, 170.8,
CDCl3): δ = 9.24 (br s, 1H), 7.34 (m, 7H), 7.11 (d, J = 8.4 Hz, 158.7, 137.5, 135.5, 129.0, 128.5, 128.1, 127.7, 127.5, 126.4,
2H), 5.17 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 4.77 (br 66.9, 60.7, 54.1, 51.1, 48.9, 48.3, 48.1, 33.8, 29.5, 29.0, 17.8,
s, 1H), 4.52 (d, J = 7.2 Hz, 1H), 4.99 (octet, J = 6.4 Hz, 1H), 3.89 14.0; ESI (m/z) 534.3 [M+ + Na, (100)]; Anal. calcd for
(septet, J = 6.8 Hz, 1H), 3.25 (dd, J = 16.0 and 7.2 Hz, 1H), 2.93 C28H37N3O6: C 65.73, H 7.29, N 8.21; found: C 65.70, H 7.32, N
(dd, J = 16.0 and 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 3H), 1.21 (d, 8.22.
J = 9.6 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 9.6 Hz, 3H);
(R)-21: Rf = 0.29 (hexane : AcOEt 80 : 20); [α]2D0 = −38.1° (c =
13C-NMR (100.6 MHz, CDCl3): δ = 170.9, 169.9, 158.1, 135.7, 0.4, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.36 (m, 10H), 7.00
135.4, 133.7, 129.4, 128.5, 128.3, 119.9, 66.7, 55.7, 47.8, 42.9, (d, J = 7.6 Hz, 1H), 5.19 (d, J = 12.4 Hz, 1H), 5.13 (d, J =
35.1, 23.2, 21.8, 21.1, 20.8; ESI (m/z) 478.2 [M+ + K, (12)], 462.1 12.4 Hz, 1H), 4.65 (br s, 1H), 4.53 (m, 2H), 4.32 (d, J = 17.2 Hz,
[M+ + Na, (100)], 440.2 [M+ + H, (9)]; Anal. calcd for 1H), 4.25 (d, J = 17.2 Hz, 1H), 4.11 (m, 2H), 1.34 (d, J = 7.2 Hz,
C25H33N3O4: C 68.31, H 7.57, N 9.56; found: C 68.28, H 7.58, N 3H), 1.22 (m, 12H); 13C-NMR (125.7 MHz, CDCl3): δ = 172.0,
9.50.
170.9, 170.4, 157.9, 137.7, 135.5, 129.1, 128.6, 128.1, 127.8,
16b: Rf = 0.23 (hexane : AcOEt 50 : 50); 1H-NMR (400 MHz, 127.7, 126.7, 126.4, 67.0, 60.8, 55.4, 51.1, 49.5, 48.3, 34.2, 29.1,
CDCl3): δ = 7.35–7.26 (m, 10H), 7.04 (t, J = 5.2 Hz, 1H), 5.17 (d, 18.1, 14.1; ESI (m/z) 534.3 [M+ + Na, (100)]; Anal. calcd for
J = 12.4 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 4.76 (d, J = 7.2 Hz, C28H37N3O6: C 65.73, H 7.29, N 8.21; found: C 65.71, H 7.25,
1H), 4.54 (m, 1H), 4.49 (dd, J = 15.2 and 6.4 Hz, 1H), 4.36 (dd, N 8.17.
J = 15.2 and 5.6 Hz, 1H), 3.61 (m, 2H), 3.39 (dd, J = 16.4 and
(S)-22: Rf = 0.68 (hexane : AcOEt 70 : 30); [α]2D0 = +11.6° (c =
8.0 Hz, 1H), 2.71 (dd, J = 16.4 and 5.6 Hz, 1H), 1.86–1.07 (m, 0.3, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 8.80 (d, J = 7.6 Hz,
20H); 13C-NMR (100.6 MHz, CDCl3): δ = 171.8, 171.3, 157.1, 1H), 7.35 (m, 10H), 5.24 (d, J = 12.4 Hz, 1H), 5.17 (d, J = 12.4
138.0, 135.7, 128.6, 128.5, 128.2, 127.6, 127.4, 66.7, 56.4, 54.5, Hz, 1H), 5.00 (m, 1H), 4.62 (septet, J = 7.6 Hz, 1H), 4.32 (d, J =
49.6, 43.7, 33.6, 33.5, 31.9, 31.8, 26.1, 26.0, 25.6, 25.2, 24.9, 11.6 Hz, 1H), 4.24 (d, J = 8.0 Hz, 1H), 3.58 (m, 1H), 1.83 (m,
24.8; ESI (m/z) 558.2 [M+ + K, (6)], 542.1 [M+ + Na, (100)], 520.3 2H), 1.56 (m, 2H), 1.45 (d, J = 7.2 Hz, 3H), 1.29 (m, 3H), 0.97
[M+ + H, (4)]; Anal. calcd for C31H41N3O4: C 71.65, H 7.95, (m, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.5, 167.6, 157.6,
N 8.09; found: C 71.63, H 7.99, N 8.02.
141.9, 135.7, 130.5, 128.9, 128.6, 128.3, 128.0, 123.3 (q, J =
(S)-18: Rf = 0.53 (hexane : AcOEt 80 : 20); [α]2D0 = +15.9° (c = 282.6 Hz), 66.9, 66.6, 64.3, 49.8, 48.4, 47.7 (septet, J = 26.0 Hz),
0.34, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.34 (m, 5H), 7.10 33.1, 33.0, 25.5, 25.4, 24.7, 24.5, 17.5; ESI (m/z) 588.2 [M+ + H,
(br s, 1H), 5.79 (m, 1H), 5.54 (br s, 1H), 5.22–5.14 (m, 4H), 4.88 (100)]; Anal. calcd for C28H31F6N3O4: C 57.24, H 5.32, N 7.15;
(s, 1H), 4.55 (septet, J = 9.6 Hz, 1H), 4.12 (q, J = 7.1 Hz, 1H), found: C 57.21, H 5.30, N 7.18.
3.82 (dd, J = 17.4 and 5.2 Hz, 1H), 3.63 (dd, J = 17.4 and 6.6 Hz,
(R)-22: Rf = 0.61 (hexane : AcOEt 70 : 30); [α]2D0 = −8.8° (c =
1
1H), 1.40 (d, J = 7.1 Hz, 3H), 1.31 (s, 9H); 19F-NMR (470.6 MHz, 0.7, CHCl3); H-NMR (400 MHz, CDCl3): δ = 8.43 (d, J = 7.2 Hz,
CDCl3): δ = −65.5 (quintet, J = 9.6 Hz, 3F), −64.2 (quintet, J = 1H), 7.34 (m, 10H), 5.22 (d, J = 7.2 Hz, 1H), 5.17 (d, J = 7.2 Hz,
9.6 Hz, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = 171.9, 167.0, 1H), 4.81 (m, 1H), 4.59 (septet, J = 7.2 Hz, 1H), 4.54 (d, J =
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11.2 Hz, 1H), 4.25 (d, J = 8.0 Hz, 1H), 3.61 (m, 1H), 1.82 (m, 2H), 1H), 4.21 (dd, J = 8.0 and 2.3 Hz, 1H), 4.12 (q, J = 7.0 Hz, 1H),
1.57 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H), 1.31 (m, 3H), 0.99 (m, 3H); 3.97–3.73 (br m, 2H), 3.15 (br m, 1H), 1.45 (s, 6H), 1.33–1.30
ESI (m/z) 610.1 [M+ + Na, (100)]; Anal. calcd for C28H31F6N3O4: C (m, 15H), 1.25 (s, 3H); 19F-NMR (235.4 MHz, CDCl3): δ = −65.1
57.24, H 5.32, N 7.15; found: C 57.25, H 5.30, N 7.19.
(m, 3F), −64.2 (m, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = 171.3,
(S)-23: Rf = 0.36 (Tol : AcOEt 70 : 30); [α]2D0 = +31.0° (c = 1.4, 171.1, 167.9, 135.5, 128.6, 128.3, 128.2, 123.7 (q, J = 281.6 Hz),
CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.64 (d, J = 7.0 Hz, 1H), 123.0 (q, J = 282.5 Hz), 109.4, 96.2, 70.6, 70.5, 66.9, 60.3, 51.2,
7.36–7.15 (m, 9H), 6.82 (m, 4H), 5.64 (dd, J = 8.4 and 6.6 Hz, 51.1, 49.0, 46.4 (septet, J = 29.1 Hz), 28.7, 25.9, 25.8, 25.0, 24.2,
1H), 5.26 (d, J = 12.7 Hz, 1H), 5.17 (d, J = 12.7 Hz, 1H), 4.63 20.9, 14.2; ESI (m/z) 750.1 [M+ + Na, (100)]; Anal. calcd for
(septet, J = 7.0 Hz, 1H), 4.59 (m, 1H), 4.36 (dd, J = 15.0 and 5.6 C32H43F6N3O9: C 52.82, H 5.96, N 5.77; found: C 52.88, H 5.89,
Hz, 1H), 4.31 (dd, J = 15.0 and 5.6 Hz, 1H), 4.15 (m, 2H), 3.79 (s, N 5.82.
3H), 3.77 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H);
(S)-26a: Rf = 0.15 (hexane : AcOEt 80 : 20); [α]2D0 = −25.2° (c =
13C-NMR (100.6 MHz, CDCl3): δ = 172.8, 170.9, 170.6, 159.7, 0.50, CHCl3); H-NMR (500 MHz, CDCl3): δ = 8.10 (br s, 1H),
158.4, 131.2, 128.6, 128.3, 127.9, 115.3, 114.7, 114.1, 113.9, 66.8, 7.33 (m, 5H), 6.05 (br s, 1H), 5.51 (d, J = 4.5 Hz, 1H), 5.16 (d,
60.6, 55.4, 54.2, 48.1, 44.2, 33.8, 17.7, 14.1; ESI (m/z) 592.3 J = 12.5 Hz, 1H), 5.13 (d, J = 12.5 Hz, 1H), 4.79 (br s, 2H), 4.64
[M+ + H, (2)], 614.3 [M+ + Na, (100)]; Anal. calcd for C32H37N3O8: (dd, J = 7.0 and 2.0 Hz, 1H), 4.57 (septet, J = 7.0 Hz, 1H), 4.32
1
C 64.96, H 6.30, N 7.10; found: C 64.92, H 6.26, N 7.15.
(dd, J = 5.0 and 2.0 Hz, 1H), 4.18 (dd, J = 7.5 and 2.0 Hz, 1H),
(R)-23: Rf = 0.24 (Tol : AcOEt 70 : 30); [α]2D0 = −41.1° (c = 0.8, 3.96 (m, 1H), 3.47 (br m, 1H), 3.33 (dd, J = 16.5 and 6.0 Hz,
CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 7.0 Hz, 1H), 1H), 1.47 (s, 6H), 1.38–1.31 (m, 9H); 19F-NMR (235.4 MHz,
7.37 (m, 5H), 7.10 (d, J = 8.5 Hz, 4H), 6.87 (d, J = 8.9 Hz, 2H), CDCl3): δ = −64.9 (m, 3F), −64.3 (m, 3F); 13C-NMR (100.6 MHz,
6.80 (d, J = 8.9 Hz, 2H), 5.47 (t, J = 7.5 Hz, 1H), 5.23 (d, J = 12.2 CDCl3): δ = 172.0, 167.2, 158.7, 135.6, 128.5, 128.2, 128.0, 123.2
Hz, 1H), 5.17 (d, J = 12.2 Hz, 1H), 4.60 (septet, J = 7.0 Hz, 1H), (q, J = 280.7 Hz), 122.9 (q, J = 281.5 Hz), 109.5, 109.2, 96.3,
4.57 (t, J = 6.1 Hz, 1H), 4.34 (dd, J = 15.5 and 5.6 Hz, 1H), 4.27 70.8, 70.2, 66.8, 65.5, 51.2, 48.5, 47.2 (septet, J = 26.7 Hz), 28.9,
(dd, J = 15.0 and 5.6 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.79 (s, 26.0, 25.6, 24.8, 24.3, 17.5; ESI (m/z) 750.1 [M+ + Na, (100)];
3H), 3.76 (s, 3H), 2.71 (dd, J = 16.4 and 7.6 Hz, 1H), 2.48 (dd, J Anal. calcd for C32H43F6N3O9: C 52.82, H 5.96, N 5.77; found:
= 16.4 and 7.6 Hz, 1H), 1.44 (d, J = 7.6 Hz, 3H), 1.21 (t, J = 7.1 C 52.89, H 5.87, N 5.73.
Hz, 3H); 13C-NMR (125.7 MHz, CDCl3): δ = 172.2, 170.8, 170.7,
(R)-26b: Rf = 0.33 (hexane : AcOEt 80 : 20); [α]2D0 = −28.9° (c =
1
159.7, 158.8, 157.9, 135.6, 131.4, 130.9, 128.6, 128.4, 128.3, 0.63, CHCl3); H-NMR (400 MHz, CDCl3): δ = 8.09 (br s, 1H),
128.1, 67.0, 60.9, 55.7, 55.3, 48.4, 44.2, 34.3, 18.1, 14.1; ESI 7.35 (m, 5H), 5.75 (br s, 1H), 5.49 (d, J = 4.0 Hz, 1H), 5.16 (d, J
(m/z) 592.3 [M+ + H, (2)], 614.3 [M+ + Na, (100)]; Anal. calcd for = 12.7 Hz, 1H), 5.13 (d, J = 12.7 Hz, 1H), 4.56 (m, 3H), 4.29 (m,
C32H37N3O8: C 64.96, H 6.30, N 7.10; found: C 64.94, H 6.32, N 1H), 4.18 (m, 1H), 4.08 (m, 1H), 3.89 (br m, 1H), 3.20 (br m,
7.13.
1H), 1.68 (m, 3H), 1.60 (s, 3H), 1.46 (s, 3H), 1.33 (s, 3H), 1.30
(s, 9H), 1.28 (s, 3H), 0.92 (d, J = 4.8 Hz, 3H), 0.89 (d, J = 4.8 Hz,
3H); 19F-NMR (470.6 MHz, CDCl3): δ = −64.8 (quintet, J = 8.9
Hz, 3F), −64.5 (quintet, J = 8.9 Hz, 3F); 13C-NMR (62.9 MHz,
General procedure for the four-component sequential
synthesis of peptide–sugar conjugates: synthesis of 26a
To a stirred solution of glycosyl azide 24a (1 equiv., 136.8 mg) CDCl3): δ = 171.4, 168.3, 157.9, 135.6, 128.5, 128.2, 128.1, 123.0
in CH3CN (0.1 M) neat isocyanate 20 (1 equiv., 47.5 mg) fol- (q, J = 279.6 Hz), 122.9 (q, J = 281.0 Hz), 109.4, 109.3, 96.2,
lowed by a solution of Ph3P (1 equiv., 125.7 mg) in a minimum 71.4, 71.1, 70.5, 70.4, 66.7, 51.4, 51.2, 46.5 (septet, J = 27.0 Hz),
amount of CH3CN were added at rt. After the formation of the 42.0, 39.9, 28.7, 25.9, 25.8, 24.9, 24.7, 24.1, 22.8, 21.3; ESI (m/z)
corresponding carbodiimide was complete (TLC monitoring, 792.2 [M+ + Na, (100)]; Anal. calcd for C35H49F6N3O9: C 54.61,
ca. 3 h), the solution was cooled to 0 °C and amino acid deriva- H 6.42, N 5.46; found: C 54.64, H 6.40, N 5.48.
tive 3a (1 equiv., 103.7 mg) followed by TMP (1 equiv. or 2
(S)-26b: this diastereoisomer was not isolated in analytically
equiv. when the hydrochloride salts of the amino acid deriva- pure form.
tives were used, 116.3 mg) and a solution of acid 1a (1 equiv.,
(R)-26c: Rf = 0.22 (hexane : AcOEt 40 : 60); [α]2D0 = −11.7° (c =
100.0 mg) in a minimum amount of CH3CN were added. The 0.96, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.32 (d, J =
resulting solution was stirred until the reaction was complete 7.5 Hz, 1H), 7.06 (br s, 1H), 5.56 (d, J = 4.5 Hz, 1H), 4.74–4.64
(TLC monitoring) leaving the temperature to slowly reach rt. A (m, 3H), 4.56 (septet, J = 7.5 Hz, 1H), 4.38 (dd, J = 5.0 and
1 N HCl aqueous solution was added and the mixture extracted 2.5 Hz, 1H), 4.15 (m, 2H), 4.15 (br m, 1H), 3.55 (d, J = 16.5 Hz,
three times with AcOEt. The combined organic layers were 1H), 3.36 (dd, J = 16.5 and 10.0 Hz, 1H), 2.73 (d, J = 4.5 Hz,
dried over anhydrous Na2SO4, filtered, concentrated under 3H), 1.49–1.46 (m, 9H), 1.34 (s, 3H), 1.32 (s, 3H), 1.31 (s, 9H);
vacuum and the crude purified by flash chromatography, 19F-NMR (470.6 MHz, CDCl3): δ = −66.0 (m, 3F), −63.6
obtaining 286.1 mg of 26a (82% yield).
(quintet, J = 7.5 Hz, 3F); 13C-NMR (125.7 MHz, CDCl3): δ =
(R)-26a: Rf = 0.22 (hexane : AcOEt 80 : 20); [α]2D0 = −8.3° (c = 172.7, 167.4, 156.3, 96.2, 71.1, 70.6, 70.5, 67.0, 51.9, 49.7, 29.2,
0.9, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.96 (br s, 1H), 26.4, 25.9, 25.8, 24.7, 24.1, 16.5. The CF3 and C-CF3 signals
7.35 (m, 5H), 5.87 (br s, 1H), 5.49 (d, J = 4.7 Hz, 1H), 5.19 (d, were obscured due to their low intensity; ESI (m/z) 673.1
J = 12.7 Hz, 1H), 5.12 (d, J = 12.7 Hz, 1H), 4.55 (br d, J = 6.6 Hz, [M+ + Na, (100)]; Anal. calcd for C26H40F6N4O8: C 48.00, H 6.20,
1H), 4.44 (septet, J = 7.0 Hz, 1H), 4.27 (dd, J = 4.7 and 2.3 Hz, N 8.61; found: C 48.02, H 6.11, N 8.67.
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(S)-26c: Rf = 0.18 (hexane : AcOEt 40 : 60); [α]2D0 = −38.9° (c = 45.4, 29.2, 26.5, 24.8, 17.6; ESI (m/z) 694.2 [M+ + Na, (100)];
1
0.95, CHCl3); H-NMR (500 MHz, CDCl3): δ = 7.49 (br s, 1H), Anal. calcd for C29H39F6N3O8: C 51.86, H 5.85, N 6.26; found:
6.54 (br s, 1H), 5.55 (m, 2H), 4.77 (br m, 1H), 4.65 (dd, J = 8.0 C 51.80, H 5.83, N 6.19.
and 2.5 Hz, 1H), 4.37 (dd, J = 5.0 and 2.5 Hz, 1H), 4.34 (octet,
(S)-26e: Rf = 0.18 (hexane : AcOEt 80 : 20); [α]2D0 = −46.9° (c =
1
J = 6.5 Hz, 1H), 4.17 (dd, J = 8.5 and 2.0 Hz, 1H), 4.13 (m, 1H), 0.6, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.33 (m, 5H), 5.46
3.99 (m, 1H), 3.72 (m, 1H), 3.21 (dd, J = 16.0 and 3.0 Hz, 1H), (s, 1H), 5.16 (s, 2H), 5.00 (s, 1H), 4.59–4.56 (m, 5H), 4.34 (dd,
2.75 (d, J = 5.0 Hz, 3H), 1.51 (s, 3H), 1.46 (s, 3H), 1.40 (d, J = J = 8.4 and 4.8 Hz, 1H), 3.46 (dd, J = 15.6 and 7.2 Hz, 1H), 3.38
7.0 Hz, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.29 (s, 9H); 19F-NMR (s, 3H), 3.18 (dd, J = 16.0 and 4.8 Hz, 1H), 1.47 (s, 3H), 1.38 (d,
(470.6 MHz, CDCl3): δ = −65.2 (m, 3F), −64.0 (m, 3F); 13C-NMR J = 6.8 Hz, 3H), 1.32 (s, 9H), 1.30 (s, 3H); 19F-NMR (235.4 MHz,
(62.9 MHz, CDCl3): δ = 172.2, 167.7, 158.3, 123.3 (q, J = 281.1 CDCl3): δ = −65.0 (quintet, J = 8.7 Hz, 3F), −64.1 (q, J = 8.0 Hz,
Hz), 123.1 (q, J = 282.0 Hz), 109.7, 109.5, 96.3, 71.0, 70.7, 70.1, 3F); 13C-NMR (100.6 MHz, CDCl3): δ = 172.4, 167.7, 157.4,
65.9, 60.4, 51.1, 50.6, 49.7, 47.1 (septet, J = 26.6 Hz), 29.0, 26.3, 135.9, 128.9, 128.7, 123.7 (q, J = 280.8 Hz), 123.3 (q, J = 284.9),
26.0, 25.4, 24.6, 24.2, 21.0, 16.4; ESI (m/z) 673.1 [M+ + Na, 135.8, 110.7, 85.5, 84.8, 82.3, 67.3, 56.0, 51.9, 49.0, 47.1 (septet,
(100)]; Anal. calcd for C26H40F6N4O8: C 48.00, H 6.20, N 8.61; J = 26.7 Hz), 29.4, 26.8, 25.3, 18.0; ESI (m/z) 694.2 [M+ + Na,
found: C 48.01, H 6.21, N 8.66.
(100)]; Anal. calcd for C29H39F6N3O8: C 51.86, H 5.85, N 6.26;
(R)-26d: Rf = 0.33 (hexane : AcOEt 60 : 40); [α]2D0 = −14.5° (c = found: C 51.85, H 5.88, N 6.25.
1
1.15, CHCl3); H-NMR (500 MHz, CDCl3): δ = 8.05 (br s, 1H),
(R)-26f: Rf = 0.32 (hexane : AcOEt 80 : 20); [α]2D0 = +25.2° (c =
1
7.27 (m, 3H), 7.16 (m, 2H), 6.75 (br s, 1H), 5.65 (br s, 1H), 5.52 0.40, CHCl3); H-NMR (400 MHz, CDCl3): δ = 8.41 (br s, 1H),
(d, J = 5.0 Hz, 1H), 4.75 (q, J = 6.5 Hz, 1H), 4.60 (dd, J = 8.5 and 5.47 (br s, 1H), 4.96 (s, 1H), 4.55–4.46 (m, 5H), 4.33 (dd, J = 8.8
2.5 Hz, 1H), 4.51 (br m, 1H), 3.32 (m, 2H), 4.16 (d, J = 8.5 Hz, and 4.4 Hz, 1H), 4.32 (br m, 1H), 3.36 (s, 3H), 3.27 (m, 1H),
1H), 4.02 (m, 1H), 3.65 (s, 3H), 3.60 (m, 1H), 3.32 (m, 1H), 3.10 2.86 (m, 1H), 2.14 (m, 1H), 1.37 (s, 12H), 1.23 (s, 3H), 1.21 (s,
(d, J = 6.5 Hz, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.37 (d, J = 6.5 Hz, 9H), 0.85 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H); 19F-NMR
3H), 1.33 (s, 3H), 1.30 (s, 12H); 19F-NMR (470.6 MHz, CDCl3): (235.4 MHz, CDCl3): δ = −66.0 (m, 3F), −63.9 (m, 3F); 13C-NMR
δ = −65.1 (m, 3F), −64.2 (m, 3F); 13C-NMR (100.6 MHz, CDCl3): (100.6 MHz, CDCl3): δ = 169.4, 168.5, 155.3, 123.1 (q, J = 283.5
δ = 171.5, 171.1, 168.2, 157.2, 135.9, 129.3, 128.5, 127.0, 123.1 Hz), 112.8, 111.3, 110.4, 87.8, 84.3, 84.2, 82.0, 58.4, 58.2, 55.9,
(q, J = 280.7 Hz), 123.0 (q, J = 282.1 Hz), 109.6, 109.3, 96.1, 51.1, 46.0 (septet, J = 26.7 Hz), 31.0, 29.0, 28.9, 28.3, 28.0, 26.3,
71.5, 70.5, 70.4, 53.5, 52.0, 51.3, 50.1, 46.5 (septet, J = 26.2 Hz), 25.0, 18.8, 17.5; ESI (m/z) 688.2 [M+ + Na, (100)]; Anal. calcd for
37.8, 28.8, 25.9, 25.8, 24.8, 24.2, 17.0; ESI (m/z) 821.1 [M+ + Na, C28H45F6N3O8: C 50.52, H 6.81, N 6.31; found: C 50.59, H 6.83,
(100)]; Anal. calcd for C35H48F6N4O10: C 52.63, H 6.06, N 7.01; N 6.31.
found: C 52.58, H 6.11, N 7.10.
(S)-26f: Rf = 0.26 (hexane : AcOEt 80 : 20); [α]2D0 = −19.7° (c =
1
(S)-26d: Rf = 0.28 (hexane : AcOEt 60 : 40); [α]2D0 = −48.8° (c = 0.64, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.04 (br s, 1H),
1.37, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.27 (m, 4H), 7.13 5.73 (br s, 1H), 4.93 (s, 1H), 4.52 (m, 2H), 4.38 (br m, 1H), 4.32
(m, 2H), 6.73 (br d, J = 6.0 Hz, 1H), 5.74 (br m, 1H), 5.55 (d, J = (m, 1H), 4.24 (dd, J = 8.4 and 4.4 Hz, 1H), 3.31 (s, 3H), 3.26 (m,
5.5 Hz, 1H), 4.74 (q, J = 7.0 Hz, 1H), 4.67 (br m, 1H), 4.64 (dd, 1H), 3.19 (dd, J = 16.0 and 3.6 Hz, 1H), 2.09 (m, 1H), 1.42 (s,
J = 7.5 and 2.5 Hz, 1H), 4.35 (dd, J = 4.5 and 2.0 Hz, 1H), 4.32 3H), 1.36 (s, 9H), 1.25 (s, 9H), 1.20 (s, 3H), 0.84 (d, J = 6.8 Hz,
(m, 1H), 4.18 (dd, J = 8.0 and 1.5 Hz, 1H), 3.96 (m, 1H), 3.66 (s, 3H), 0.82 (d, J = 6.8 Hz, 3H); 19F-NMR (235.4 MHz, CDCl3): δ =
3H), 3.53 (br m, 1H), 3.31 (dd, J = 16.5 and 4.5 Hz, 1H), 3.09 −65.0 (m, 3F), −63.8 (quintet, J = 9.4 Hz, 3F); 13C-NMR
(m, 2H), 1.46 (s, 3H), 1.43 (s, 3H), 1.36 (s, 3H), 1.34–1.29 (m, (100.6 MHz, CDCl3): δ = 170.0, 167.4, 157.3, 113.2, 110.4, 84.4,
15H); 19F-NMR (235.4 MHz, CDCl3): δ = −65.2 (quintet, J = 81.6, 58.2, 55.6, 51.4, 46.9 (septet, J = 27.8 Hz), 30.6, 29.0, 28.9,
5.4 Hz, 3F), −63.6 (m, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = 27.9, 26.3, 24.9, 18.5, 17.5. The CF3 signal was obscured due to
171.7, 171.4, 167.9, 157.9, 136.0, 129.2, 128.5, 128.4, 127.0, its low intensity; ESI (m/z) 688.2 [M+ + Na, (100)]; Anal. calcd
109.7, 109.4, 96.4, 70.8, 70.2, 60.3, 53.7, 53.6, 52.1, 51.3, 51.1, for C28H45F6N3O8: C 50.52, H 6.81, N 6.31; found: C 50.48, H
49.8, 47.0 (septet, J = 26.8 Hz), 37.8, 28.9, 28.8, 26.0, 25.5, 24.7, 6.89, N 6.29.
24.3. The CF3 signal was obscured due to its low intensity; ESI
(m/z) 821.1 [M+ + Na, (100)]; Anal. calcd for C35H48F6N4O10: C 0.67, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.26 (m, 5H), 6.03
52.63, H 6.06, N 7.01; found: C 52.68, H 6.13, N 7.03. (d, J = 10.0 Hz, 1H), 5.71 (m, 1H), 5.26 (m, 2H), 5.09 (d, J = 12.4
(R)-26h: Rf = 0.48 (toluene : AcOEt 85 : 15); [α]2D0 = −13.7° (c =
(R)-26e: Rf = 0.27 (hexane : AcOEt 80 : 20); [α]2D0 = +46.9° (c = Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H), 5.02 (m, 1H), 4.87 (m, 1H),
0.75, CHCl3); 1H-NMR (400 MHz, DMSO-d6): δ = 8.76 (br s, 4.50 (m, 2H), 4.45 (d, J = 6.0 Hz, 1H), 4.19 (m, 2H), 4.04 (t, J =
1H), 7.35 (m, 5H), 6.16 (br s, 1H), 5.11 (s, 2H), 4.99 (s, 1H), 7.6 Hz, 1H), 3.89 (dd, J = 16.8 and 5.6 Hz, 1H), 3.32 (m, 1H),
4.61 (m, 3H), 4.40 (septet, J = 7.6 Hz, 1H), 4.24 (br s, 1H), 3.83 3.29 (s, 3H), 3.04 (dd, J = 16.8 and 8.0 Hz, 1H), 1.39 (d, J = 7.2
(br d, J = 15.6 Hz, 1H), 3.29 (s, 3H), 3.03 (dd, J = 14.0 and 8.0 Hz, 3H), 1.34 (s, 3H), 1.28 (s, 3H), 1.20 (s, 3H); 19F-NMR
Hz, 1H), 1.33 (s, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H), 1.22 (235.4 MHz, CDCl3): δ = −64.9 (quintet, J = 8.5, 3F), −63.8
(s, 3H); 19F-NMR (235.4 MHz, CDCl3): δ = −64.1 (m, 3F), −63.3 (quintet, J = 10.3 Hz, 3F); 13C-NMR (100.6 MHz, CDCl3): δ =
(quintet, J = 9.9 Hz, 3F); 13C-NMR (62.9 MHz, DMSO-d6): δ = 171.1, 168.3, 155.4, 135.6, 133.2, 128.3, 128.2, 118.5, 112.4,
172.0, 167.4, 155.7, 128.9, 128.5, 128.1, 123.7 (q, J = 280.7 Hz), 110.0, 85.3, 84.9, 81.5, 66.8, 55.1, 54.7, 51.7, 47.6, 46.7, 29.0,
111.8, 110.8, 87.1, 84.1, 82.7, 66.5, 55.7, 51.0, 48.3, 46.2, 45.8, 26.2, 24.8, 13.7. The CF3 and C-CF3 signals were obscured due
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to their low intensity; ESI (m/z) 734.2 [M+ + Na, (100)]; Anal. CDCl3): δ = 172.0, 166.8, 157.7, 140.3, 135.5, 130.3, 128.9,
calcd for C32H43F6N3O8: C 54.00, H 6.09, N 5.90; found: C 128.6, 128.4, 128.2, 109.4, 108.6, 92.2, 71.6, 70.8, 70.6, 67.1,
53.94, H 6.15, N 6.05.
66.4, 48.6, 47.8 (septet, J = 27.0 Hz), 41.2, 26.0, 25.8, 24.9, 24.2,
(S)-26h, mixture of two amidic isomers: Rf = 0.42 (toluene : 18.1. The CF3 signal was obscured due to low intensity; ESI
AcOEt 85 : 15); [α]D20 = −29.7° (c = 0.40, CHCl3); 1H-NMR (m/z) 748 [M+ + H, (31)], 770.1 [M+ + Na, (100)]; Anal. calcd for
(400 MHz, CDCl3): δ = 7.25 (m, 5H), 6.07 (d, J = 10.8 Hz, 1H), C34H39F6N3O9: C 54.62, H 5.26, N 5.62; found: C 54.65, H 5.21,
5.92 (s, 1H), 5.68 (m, 1H), 5.35 (m, 2H), 5.14 (d, J = 12.4 Hz, N 5.64.
1H), 4.98 (d, J = 12.4 Hz, 1H), 4.88 (m, 1H), 4.63 (q, J = 7.2 Hz,
(R)-27a: Rf = 0.28 (Et2O : hexane 60 : 40); [α]2D0 = −16.1° (c =
1H), 4.45 (m, 2H), 4.19 (m, 1H), 4.06 (m, 1H), 3.81 (m, 1H), 1.1, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.67 (br s, 1H),
3.68 (m, 1H), 3.24 (s, 3H), 3.22 (m, 2H), 1.39 (d, J = 7.2 Hz, 3H), 7.34 (m, 5H), 5.47 (d, J = 5.0 Hz, 1H), 5.18 (d, J = 12.5 Hz, 1H),
1.33 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H); 19F-NMR (235.6 MHz, 5.12 (d, J = 12.5 Hz, 1H), 4.72 (br s, 1H), 4.57 (dd, J = 8.0 and
CDCl3): δ = −64.2 (m, 3F), −63.6 (m, 3F); ESI (m/z) 688.2 2.5 Hz, 1H), 4.53 (quintet, J = 7.0 Hz, 1H), 4.27 (dd, J = 5.0 and
[M+ + Na, (100)].
2.5 Hz, 1H), 4.23 (dd, J = 8.0 and 2.0 Hz, 1H), 4.14 (q, J =
(R)-26i: Rf = 0.38 (hexane : AcOEt 50 : 50); [α]2D0 = −23.4° (c = 14.5 Hz, 2H), 4.08 (br d, J = 7.5 Hz, 1H), 3.84 (m, 1H), 3.18 (dd,
1
0.47, CHCl3); H-NMR (500 MHz, CDCl3): δ = 7.29 (br s, 1H), J = 16.5 and 7.0 Hz, 1H), 3.07 (dd, J = 15.5 and 8.5 Hz, 1H),
7.17 (m, 5H), 6.91 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 2.72 (dd, J = 16.0 and 7.0 Hz, 1H), 1.47 (s, 3H), 1.45 (s, 3H),
6.07 (br d, J = 7.0 Hz, 1H), 5.41 (br s, 1H), 4.92 (s, 1H), 4.61 (q, 1.44 (d, J = 7.0 Hz, 3H), 1.33 (s, 3H), 1.31 (s, 12H), 1.25 (t, J =
J = 7.5 Hz, 1H), 4.50 (d, J = 6.5 Hz, 1H), 4.45 (d, J = 6.5 Hz, 1H), 14.5 Hz, 3H); 13C-NMR (125.7 MHz, CDCl3): δ = 174.6, 172.1,
4.37 (m, 2H), 4.22 (dd, J = 8.5 and 4.0 Hz, 1H), 3.51 (s, 3H), 171.4, 170.9, 135.8, 128.5, 128.4, 128.2, 128.1, 109.4, 109.2,
3.32 (s, 3H), 3.03–2.89 (m, 5H), 2.18 (s, 3H), 1.38 (s, 3H), 1.24 96.2, 71.4, 70.8, 70.7, 66.8, 60.8, 51.1, 48.5, 34.1, 28.9, 26.1,
(s, 9H), 1.22 (s, 3H); 19F-NMR (470.6 MHz, CDCl3): δ = −64.9 25.1, 24.2, 14.1; ESI (m/z) 664.4 [M+ + H, (3)], 686.4 [M+ + Na,
(m, 3F), −63.9 (m, 3F); 13C-NMR (125.7 MHz, CDCl3): δ = 171.0, (100)]; Anal. calcd for C33H49N3O11: C 59.71, H 7.44, N 6.33;
169.7, 169.3, 167.4, 157.0, 149.7, 130.2, 129.3, 129.0, 128.6, found: C 59.68, H 7.41, N 6.37.
126.9, 125.3, 121.6, 113.2, 110.5, 84.3, 81.9, 55.7, 53.3, 52.1,
(S)-27a: Rf = 0.15 (Et2O : hexane 80 : 20); [α]2D0 = −98.4° (c =
51.5, 37.4, 37.1, 29.1, 26.4, 24.8, 21.1. The CF3 and C-CF3 1.0, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.41 (br s, 1H),
signals were obscured due to their low intensity; ESI (m/z) 7.34 (m, 5H), 6.00 (br s, 1H), 5.52 (d, J = 5.2 Hz, 1H), 5.18 (d,
899.1 [M+ + Na, (100)]; Anal. calcd for C40H50F6N4O11: C 54.79, J = 12.7 Hz, 1H), 5.13 (d, J = 12.7 Hz, 1H), 4.90 (br s, 1H), 4.60
H 5.75, N 6.39; found: C 54.71, H 5.69, N 6.35.
(dd, J = 7.5 and 2.4 Hz, 1H), 4.52 (t, J = 7.1 Hz, 1H), 4.31 (dd,
(S)-26i: Rf
=
0.35 (hexane : AcOEt 50 : 50); 1H-NMR J = 5.2 and 2.3 Hz, 1H), 4.19 (dd, J = 6.4 and 1.9 Hz, 1H), 4.13
(250 MHz, CDCl3): δ = 7.98 (br s, 1H), 7.22 (m, 5H), 6.99 (m, (m, 2H), 3.91 (br d, J = 8.0 Hz, 1H), 3.41 (dd, J = 16.0 and 8.4
4H), 6.67 (br m, 1H), 5.52 (br s, 1H), 4.81 (s, 1H), 4.58 (q, J = Hz, 1H), 3.33 (dd, J = 16.0 and 2.8 Hz, 1H), 3.12 (m, 1H), 2.62
7.5 Hz, 1H), 4.48–4.29 (m, 5H), 3.65 (s, 3H), 3.41 (s, 3H), (dd, J = 16.4 and 6.1 Hz, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.37 (d,
3.17–3.00 (m, 5H), 2.28 (s, 3H), 1.47 (s, 3H), 1.33 (s, 3H), 1.31 J = 7.5 Hz, 3H), 1.33 (s, 3H), 1.31 (s, 9H), 1.30 (s, 3H), 1.22 (t,
(s, 3H); 19F-NMR (235.4 MHz, CDCl3): δ = −65.7 (m, 3F), −64.1 J = 7.1 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 172.2, 170.7,
(m, 3F); ESI (m/z) 899.1 [M+ + Na, (100)].
135.7, 128.5, 128.4, 128.2, 128.1, 128.0, 109.4, 109.1, 96.2, 71.5,
(R)-26j: Rf = 0.37 (hexane : AcOEt 70 : 30); [α]2D0 = +18.9° (c = 70.7, 70.4, 66.8, 60.7, 50.7, 48.4, 34.8, 29.1, 28.9, 26.0, 24.8,
0.3, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 8.76 (d, J = 7.5 Hz, 24.2, 17.8, 14.1; ESI (m/z) 664.4 [M+ + H, (1)], 686.4 [M+ + Na,
1H), 7.35 (m, 10H), 5.44 (d, J = 4.7 Hz, 1H), 5.24 (d, 12.7 Hz, (100)]; Anal. calcd for C33H49N3O11: C 59.71, H 7.44, N 6.33;
1H), 5.17 (d, J = 12.7 Hz, 1H), 4.98 (m, 1H), 4.89 (m, 1H), 4.63 found: C 59.67, H 7.40, N 6.35.
(septet, J = 7.5 Hz, 1H), 4.56 (dd, J = 8.0 and 1.9 Hz, 1H), 4.33
(R)-27b: Rf = 0.23 (Et2O : hexane 70 : 30); [α]2D0 = +18.8° (c =
(d, J = 8.0 Hz, 1H), 4.27 (m, 1H), 4.19 (dd, J = 7.5 and 1.4 Hz, 1.1, CHCl3); 1H-NMR (500 MHz, CDCl3): δ = 7.88 (br s, 1H),
1H), 3.90 (m, 1H), 1.51 (s, 3H), 1.45 (d, J = 7.1 Hz, 3H), 1.35 (s, 7.33 (m, 5H), 5.15 (m, 3H), 5.00 (s, 1H), 4.66 (m, 1H), 4.55 (m,
3H), 1.33 (s, 3H), 1.29 (s, 3H); 13C-NMR (125.7 MHz, CDCl3): δ 3H), 4.42 (m, 1H), 4.15–4.09 (m, 2H), 3.94 (br d, J = 14.0 Hz,
= 172.8, 167.8, 158.5, 142.0, 135.9, 130.8, 129.2, 128.9, 128.6, 1H), 3.15 (s, 3H), 3.37 (d, J = 2.0 Hz, 1H), 3.16 (dd, J = 16.8 and
128.3, 128.2, 109.4, 108.9, 96.5, 71.6, 71.1, 70.8, 67.3, 66.6, 7.6 Hz, 1H), 2.99 (dd, J = 14.8 and 9.2 Hz, 1H), 2.68 (dd, J =
64.6, 48.6, 41.4, 26.7, 26.1, 25.2, 24.4, 17.7. The CF3 and C-CF3 16.8 and 6.8 Hz, 1H), 1.44 (s, 3H), 1.30 (m, 12H), 1.28 (s, 3H),
signals were obscured due to their low intensity; ESI (m/z) 748 1.24 (t, J = 6.8 Hz, 1H); 13C-NMR (125.7 MHz, CDCl3): δ =
[M+ + H, (18)], 770.1 [M+ + Na, (100)]; Anal. calcd for 171.6, 171.4, 135.9, 128.7, 128.5, 111.1, 110.7, 87.5, 85.1, 82.2,
C34H39F6N3O9: C 54.62, H 5.26, N 5.62; found: C 54.66, H 5.28, 67.3, 67.2, 61.2, 56.4, 51.6, 48.8, 48.7, 34.1, 29.1, 25.3, 18.0,
N 5.59.
(S)-26j: Rf
14.5; ESI (m/z) 646.4 [M+ + K, (24)], 630.3 [M+ + Na, (100)];
=
0.26 (hexane : AcOEt 70 : 30); 1H-NMR Anal. calcd for C30H45N3O10: C 59.29, H 7.46, N 6.91; found: C
(250 MHz, CDCl3): δ = 8.12 (br d, J = 6.6 Hz, 1H), 7.35 (m, 59.24, H 7.41, N 6.90.
10H), 5.38 (d, J = 4.8 Hz, 1H), 5.22 (d, J = 12.5 Hz, 1H), 5.17 (d,
(S)-27b: Rf = 0.12 (Et2O : hexane 70 : 30); [α]2D0 = −55.1° (c =
1
J = 12.5 Hz, 1H), 4.88 (m, 2H), 4.56 (m, 3H), 4.25 (m, 1H), 4.12 2.3, CHCl3); H-NMR (500 MHz, CDCl3): δ = 7.34 (m, 5H), 5.51
(d, J = 8.0 Hz, 1H), 3.80 (m, 1H), 3.55 (m, 1H), 3.24 (m, 1H), (s, 1H), 5.17 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 4.98
1.46 (s, 3H), 1.30 (s, 6H), 1.28 (s, 3H); 13C-NMR (125.7 MHz, (s, 1H), 4.71 (m, 1H), 4.55 (m, 4H), 4.30 (m, 1H), 4.11 (m, 2H),
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3.37 (s, 3H), 3.32 (m, 2H), 3.19 (dd, J = 16.8 and 7.2 Hz, 1H), (d, J = 8.0 Hz, 1H), 5.54 (s, 1H), 5.14 (s, 2H), 4.99 (s, 1H), 4.77
2.74 (dd, J = 16.4 and 7.2 Hz, 1H), 1.47 (s, 3H), 1.35 (d, J = (m, 1H), 4.54 (m, 2H), 4.50 (dd, J = 6.0 and 2.0 Hz, 1H), 4.29
7.2 Hz, 3H), 1.31 (s, 3H), 1.30 (s, 9H), 1.22 (t, J = 7.2 Hz, 1H); (br d, J = 9.2 Hz, 1H), 3.70 (s, 3H), 3.40 (s, 3H), 3.32–3.25 (m,
13C-NMR (100.6 MHz, CDCl3): δ = 172.6, 171.4, 170.9, 128.9, 3H), 2.87 (dd, J = 16.8 and 7.2 Hz, 1H), 1.62 (m, 3H), 1.49 (s,
128.6, 128.5, 128.4, 110.7, 110.4, 87.0, 85.9, 84.7, 82.5, 82.3, 3H), 1.32 (s, 12H), 0.90 (d, J = 5.6 Hz, 6H); 13C-NMR
82.2, 67.2, 61.1, 56.4, 55.6, 51.4, 43.3, 34.7, 29.9, 29.5, 26.9, (100.6 MHz, CDCl3): δ = 172.8, 171.3, 170.6, 157.7, 135.1,
25.5, 25.3, 18.3, 14.4; ESI (m/z) 646.3 [M+ + K, (32)], 630.3 [M+ + 128.5, 128.1, 113.4, 110.3, 86.4, 84.3, 81.9, 66.5, 55.8, 52.1,
Na, (100)], 608 [M+ + H, (3)]; Anal. calcd for C30H45N3O10: C 51.0, 50.9, 41.1, 34.3, 29.2, 26.6, 25.1, 24.6, 22.9, 21.6; ESI (m/z)
59.29, H 7.46, N 6.91; found: C 59.25, H 7.44, N 6.89.
658.3 [M+ + Na, (100)], 636.3 [M+ + H, (5)]; Anal. calcd for
(R)-28a: Rf = 0.45 (hexane : AcOEt 60 : 40); [α]D20 = −14.5° (c = C32H49N3O10: C 60.46, H 7.77, N 6.61; found: C 60.44, H 7.72,
0.6, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.49 (br s, 1H), N 6.63.
7.34 (m, 5H), 5.46 (d, J = 6.0 Hz, 1H), 5.38 (br s, 1H), 5.14 (d,
(R)-34a: this diastereoisomer was not isolated in analytically
J = 15.0 Hz, 1H), 5.11 (d, J = 15.0 Hz, 1H), 4.70 (m, 2H), 4.56 pure form.
(dd, J = 8.0 and 2.0 Hz, 1H), 4.51 (m, 1H), 4.38 (m, 1H), 4.27
(S)-34a: Rf = 0.21 (Et2O : hexane 70 : 30); [α]2D0 = −49.2° (c =
(dd, J = 5.2 and 2.4 Hz, 1H), 4.20 (d, J = 7.6 Hz, 1H), 4.07 (m, 0.50, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.26 (m, 5H), 5.14
1H), 3.85 (br d, J = 14.4 Hz, 1H), 3.69 (s, 3H), 3.25 (dd, J = 16.4 (t, J = 6.4 Hz, 1H), 5.09 (d, J = 12.8 Hz, 1H), 5.06 (d, J = 12.8 Hz,
and 7.2 Hz, 1H), 3.06 (dd, J = 15.6 and 8.4 Hz, 1H), 2.78 (dd, J = 1H), 4.97 (m, 2H), 4.86 (dd, J = 9.2 and 7.8 Hz, 1H), 4.40 (m,
16.8 and 7.2 Hz, 1H), 1.67 (m, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 3H), 4.19 (dd, J = 7.8 and 4.0 Hz, 1H), 4.06 (m, 2H), 3.85 (m,
1.33 (s, 3H), 1.32 (s, 9H), 1.31 (s, 3H), 0.94 (m, 6H); 13C-NMR 1H), 3.62 (m, 1H), 3.34 (m, 1H), 3.09 (m, 1H), 1.99 (s, 3H), 1.95
(125.7 MHz, CDCl3): δ = 175.1, 172.8, 171.2, 156.7, 135.7, 128.5, (s, 6H), 1.93 (s, 3H), 1.73 (m, 2H), 1.29 (m, 12H); 13C-NMR
128.2, 128.1, 127.5, 126.9, 109.4, 109.1, 96.2, 71.3, 70.7, 70.6, (100.6 MHz, CDCl3): δ = 171.8, 170.6, 170.2, 169.5, 167.8,
67.8, 66.6, 52.0, 51.4, 51.2, 51.1, 50.5, 42.2, 40.1, 34.1, 28.9, 26.0, 135.5, 128.6, 128.4, 128.1, 101.2, 72.5, 71.9, 71.2, 68.2, 67.0,
25.1, 24.8, 24.7, 24.2, 22.8, 22.7, 22.1, 21.5; ESI (m/z) 714.4 [M+ + 61.8, 51.6, 48.4, 29.0, 20.6, 20.5, 17.5; ESI (m/z) 896.1 [M+ + Na,
Na, (100)], 692.4 [M+ + H, (65)]; Anal. calcd for C35H53N3O11: C (100)]; Anal. calcd for C37H49F6N3O14: C 50.86, H 5.65, N 4.81;
60.76, H 7.72, N 6.07; found: C 60.77, H 7.70, N 6.00.
found: C 50.84, H 5.60, N 4.80.
(S)-28a: Rf = 0.38 (hexane : AcOEt 70 : 30); [α]2D0 = −9.5° (c =
(R)-34b: Rf = 0.39 (AcOEt : hexane 50 : 50); [α]2D0 = +7.3° (c =
0.5, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.47 (br s, 1H), 0.9, CHCl3); 1H-NMR (400 MHz, CD3OD): δ = 7.28–7.20 (m,
7.33 (m, 5H), 5.44 (d, J = 4.8 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 5H), 5.23 (t, J = 9.6 Hz, 1H), 4.97 (t, J = 10.0 Hz, 1H), 4.87 (s,
5.10 (d, J = 12.4 Hz, 1H), 4.73 (br s, 1H), 4.56 (dd, J = 8.0 and 2H), 4.62 (t, J = 6.4 Hz, 2H), 4.38 (m, 1H), 4.35 (q, J = 7.2 Hz,
2.0 Hz, 1H), 4.50 (m, 1H), 4.26 (dd, J = 4.8 and 2.0 Hz, 1H), 1H), 4.25 (dd, J = 12.4 and 4.4 Hz, 1H), 4.08 (m, 1H), 3.84 (m,
4.19 (d, J = 8.8 Hz, 1H), 3.84 (br d, J = 15.6 Hz, 1H), 3.68 (s, 1H), 3.66 (s, 3H), 3.60 (m, 1H), 3.52 (m, 1H), 3.24 (m, 1H), 3.12
3H), 3.24 (dd, J = 16.8 and 7.6 Hz, 1H), 3.05 (dd, J = 15.2 and (dd, J = 14.0 and 5.6 Hz, 1H), 2.99 (dd, J = 14.0 and 8.0 Hz,
8.4 Hz, 1H), 2.77 (dd, J = 16.8 and 7.2 Hz, 1H), 1.66 (m, 3H), 1H), 2.02 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.33 (s,
1.47 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H), 1.31 (s, 9H), 1.28 (s, 3H), 9H), 1.30 (d, J = 6.8 Hz, 3H); 13C-NMR (125.7 MHz, CDCl3): δ =
0.93 (d, J = 6.0 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H); 13C-NMR 171.45, 170.9, 170.5, 170.1, 169.4, 169.3, 168.1, 135.7, 129.2,
(100.6 MHz, CDCl3): δ = 172.8, 171.1, 171.0, 135.6, 128.5, 128.6, 128.5, 127.2, 101.1, 72.6, 72.1, 71.3, 68.3, 67.0, 61.8,
128.2, 128.1, 128.0, 109.4, 109.1, 96.2, 71.3, 70.7, 70.6, 67.7, 53.3, 52.2, 51.6, 49.2, 46.8 (septet, J = 27.8 Hz), 37.9, 29.0, 20.6,
66.6, 51.9, 51.2, 51.0, 40.1, 34.0, 28.9, 26.0, 25.9, 25.1, 24.8, 18.0; ESI (m/z) 967.1 [M+ + Na, (100)]; Anal. calcd for
24.2, 22.8, 21.5; ESI (m/z) 714.4 [M+ + Na, (100)], 692.4 [M+ + H, C40H54F6N4O15: C 50.85, H 5.76, N 5.93; found: C 50.80, H
(3)]; Anal. calcd for C35H53N3O11: C 60.76, H 7.72, N 6.07; 5.77, N 5.98.
found: C 60.75, H 7.73, N 6.05.
(S)-34b: Rf = 0.43 (Et2O : hexane 70 : 30); [α]2D0 = −31.3° (c =
(R)-28b: Rf = 0.22 (Et2O : hexane 70 : 30); [α]2D0 = +9.4° (c = 0.4, CHCl3); 1H-NMR (400 MHz, CD3OD): δ = 7.26–7.19 (m,
0.8, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.75 (br s, 1H), 5H), 5.27 (m, 2H), 4.99 (t, J = 10.0 Hz, 1H), 4.86 (s, 2H), 4.65
7.35 (m, 5H), 5.16 (s, 1H), 5.10 (s, 3H), 4.96 (s, 1H), 4.69 (s, (m, 2H), 4.36–4.26 (m, 3H), 4.10 (m, 1H), 3.86 (m, 1H), 3.65 (s,
2H), 4.53 (m, 3H), 4.40 (dd, J = 9.2 and 2.8 Hz, 1H), 3.90 (d, J = 3H), 3.49 (m, 1H), 3.25 (m, 1H), 3.11 (dd, J = 14.0 and 6.0 Hz,
15.2 Hz, 1H), 3.69 (s, 3H), 3.38 (s, 3H), 3.21 (dd, J = 16.8 and 1H), 3.00 (dd, J = 14.0 and 8.0 Hz, 1H), 2.04 (s, 3H), 2.01 (s,
7.2 Hz, 1H), 2.97 (dd, J = 15.2 and 9.6 Hz, 1H), 2.76 (dd, J = 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.62 (m, 2H), 1.36 (s, 9H), 1.29
16.8 and 6.8 Hz, 1H), 1.66 (m, 3H), 1.45 (s, 3H), 1.31 (s, 9H), (d, J = 6.8 Hz, 3H); 13C-NMR (100.6 MHz, CD3OD): δ = 174.0,
0.93 (m, 6H); 13C-NMR (125.7 MHz, CDCl3): δ = 172.5, 171.2, 173.2, 172.3, 171.4, 171.2, 168.9, 157.9, 157.8, 137.9, 130.4,
170.9, 156.3, 135.7, 128.5, 128.3, 128.2, 128.1, 128.0, 127.6, 129.6, 126.2, 101.9, 74.1, 72.9, 69.8, 63.0, 55.2, 52.7, 50.6, 38.4,
126.9, 112.7, 110.8, 87.3, 84.6, 81.7, 66.7, 55.9, 52.1, 51.2, 41.1, 30.7, 29.6, 29.5, 20.6, 18.7; ESI (m/z) 967.4 [M+ + Na, (100)];
33.8, 29.2, 29.1, 26.5, 25.0, 24.8, 22.8, 21.8; ESI (m/z) 658.3 [M+ Anal. calcd for C40H54F6N4O15: C 50.85, H 5.76, N 5.93; found:
+ Na, (100)], 636.3 [M+ + H, (5)]; Anal. calcd for C32H49N3O10: C C 50.83, H 5.72, N 5.94.
60.46, H 7.77, N 6.61; found: C 60.41, H 7.73, N 6.64.
(R)-34c: Rf = 0.51 (AcOEt : hexane 50 : 50); [α]2D0 = +8.42° (c =
(S)-28b: Rf = 0.15 (Et2O : hexane 70 : 30); [α]2D0 = −59.9° (c = 1.2, CHCl3); 1H-NMR (400 MHz, CD3OD): δ = 7.25 (m, 5H), 5.31
1
0.3, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.34 (m, 5H), 7.24 (d, J = 4.0 Hz, 1H), 5.27 (t, J = 9.6 Hz, 2H), 5.15 (t, J = 9.2 Hz,
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1H), 5.07 (s, 2H), 4.96 (t, J = 10.0 Hz, 1H), 4.77 (dd, J = 10.8 and CDCl3): δ = 171.7, 171.1, 170.7, 170.6, 170.5, 170.3, 170.1,
4.0 Hz, 1H), 4.68 (m, 1H), 4.42 (m, 4H), 4.14 (m, 3H), 3.99 (dd, 169.8, 169.6, 135.9, 129.5, 128.8, 127.4, 95.8, 75.5, 72.9, 72.7,
J = 12.4 and 2.0 Hz, 1H), 3.87 (m, 3H), 3.58 (m, 1H), 3.46 (m, 72.3, 70.2, 69.5, 68.8, 68.3, 67.2, 62.9, 61.7, 55.5, 52.4, 51.8,
1H), 3.01 (m, 2H), 2.04 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.93 49.5, 38.1, 29.9, 29.3, 28.0, 21.1, 20.9, 20.8, 20.7, 18.2. The CF3
(s, 3H), 1.91 (m, 9H), 1.65 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 1.25 and C-CF3 signals were obscured due to their low intensity; ESI
(s, 9H); 13C-NMR (125.7 MHz, CDCl3): δ = 171.7, 170.4, 170.0, (m/z) 1255.3 [M+ + Na, (100)]; Anal. calcd for C52H70F6N4O23: C
169.9, 169.4, 169.3, 167.4, 135.4, 128.5, 128.4, 128.0, 122.9 (q, 50.65, H 5.72, N 4.54; found: C 50.67, H 5.77, N 4.50.
J = 299.7 Hz), 75.3, 72.2, 72.1, 72.0, 68.8, 68.7, 68.6, 68.5, 68.4,
(R/S)-35a, mixture of two diastereoisomers: Rf = 0.34
1
68.3, 62.7, 61.5, 51.4, 48.2, 46.6 (septet, J = 27.2 Hz), 30.3, 29.1, (AcOEt : hexane 50 : 50); H-NMR (400 MHz, CD3OD): δ = 7.22
28.3, 28.2, 27.6, 20.6, 20.4, 18.0; ESI (m/z) 1184.4 [M+ + Na, (m, 12H), 5.09–4.93 (m, 14H), 4.71 (m, 1H), 4.39 (m, 5H), 4.13
(100)]; Anal. calcd for C49H65F6N3O22: C 50.65, H 5.64, N 3.62; (m, 2H), 4.00 (m, 8H), 3.73 (m, 2H), 3.60 (m, 2H), 3.40 (m, 2H),
found: C 50.68, H 5.61, N 3.69.
3.11–2.86 (m, 6H), 2.65 (dd, J = 12.4 and 8.6 Hz, 1H), 2.46 (dd,
(S)-34c: Rf = 0.48 (AcOEt : hexane 50 : 50); [α]2D0 = −21.5° (c = J = 12.6 and 8.4 Hz, 1H), 1.95 (s, 3H), 1.94 (s, 3H), 1.93 (s, 3H),
0.2, CHCl3); 1H-NMR (400 MHz, CD3OD): δ = 7.25 (m, 5H), 5.32 1.90 (s, 6H), 1.87 (s, 6H), 1.65 (m, 4H), 1.26–1.23 (m, 24H),
(d, J = 4.6 Hz, 1H), 5.28 (t, J = 12.4 Hz, 1H), 5.18 (t, J = 8.6 Hz, 1.12 (t, J = 7.5 Hz, 3H), 1.11 (t, J = 3H); 13C-NMR (100.6 MHz,
1H), 5.08 (d, J = 12.8 Hz, 1H), 5.05 (d, J = 12.8 Hz, 1H), 4.97 (t, CD3OD): δ = 172.2, 172.1, 171.0, 170.9, 170.8, 170.3, 170.0,
J = 12.4 Hz, 1H), 4.78 (dd, J = 12.4 and 4.0 Hz, 1H), 4.69 (dd, J = 169.3, 169.2, 158.0, 157.4, 135.6, 135.5, 128.5, 128.2, 128.0,
8.6 and 2.0 Hz, 1H), 4.41 (m, 3H), 4.14 (m, 2H), 3.89 (m, 2H), 127.9, 100.9, 72.7, 72.6, 72.0, 71.9, 71.3, 71.2, 68.3, 67.1, 66.8,
3.80 (m, 1H), 3.59 (m, 1H), 3.37 (m, 1H), 3.10 (m, 2H), 2.04 (s, 66.7, 61.8, 60.6, 54.8, 51.1, 51.0, 48.2, 48.0, 42.8, 42.0, 34.3,
3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H), 1.92 (s, 34.2, 20.5, 20.4, 17.9, 17.8, 14.0; ESI (m/z) 832.4 [M+ + Na,
3H), 1.91 (s, 3H), 1.65 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H), 1.26 (s, (100)]; Anal. calcd for C38H55N3O16: C 56.36, H 6.85, N 5.19;
9H); 13C-NMR (100.6 MHz, CD3OD): δ = 172.0, 170.7, 170.6, found: C 56.32, H 6.80, N 5.11.
170.5, 170.2, 170.1, 169.8, 169.6, 168.0, 135.7, 128.8, 128.6,
(R)-35b: Rf = 0.21 (AcOEt : hexane 80 : 20); [α]2D0 = +24.2° (c =
1
128.3, 112.0, 107.0, 75.4, 73.1, 72.7, 72.4, 70.3, 69.6, 68.9, 68.4, 1.0, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.19 (m, 3H), 7.14
67.2, 63.0, 61.8, 51.8, 48.6, 30.6, 29.4, 29.3, 21.1, 20.9, 20.8, (d, J = 7.2 Hz, 1H), 7.06 (m, 2H), 6.58 (d, J = 7.6 Hz, 1H), 5.11
20.7, 20.6, 20.5, 17.8; ESI (m/z) 1184.4 [M+ + Na, (100)]; Anal. (t, J = 9.6 Hz, 1H), 4.96 (d, J = 10.0 Hz, 1H), 4.94 (d, J = 10.0 Hz,
calcd for C49H65F6N3O22: C 50.65, H 5.64, N 3.62; found: C 1H), 4.85 (dd, J = 9.6 and 8.4 Hz, 1H), 4.72–4.66 (m, 2H), 4.41
50.70, H 5.63, N 3.59.
(d, J = 8.0 Hz, 1H), 4.24 (quintet, J = 7.2 Hz, 1H), 4.17 (dd, J =
(R)-34d: Rf = 0.36 (AcOEt : hexane 80 : 20); [α]2D0 = +43.0° (c = 12.4 and 4.8 Hz, 1H), 4.07–4.02 (m, 2H), 3.77 (m, 1H), 3.62 (m,
0.6, CHCl3); 1H-NMR (400 MHz, CD3OD): δ = 7.19 (m, 3H), 7.02 1H), 3.59 (s, 3H), 3.45 (m, 1H), 3.11–3.00 (m, 5H), 2.61 (dd, J =
(m, 2H), 6.28 (d, J = 8.0 Hz, 1H), 5.32 (d, J = 4.0 Hz, 1H), 5.27 16.4 and 7.2 Hz, 1H), 1.98 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H),
(t, J = 10.4 Hz, 1H), 5.16 (t, J = 8.8 Hz, 1H), 4.97 (t, J = 9.6 Hz, 1.91 (s, 3H), 1.71 (m, 2H), 1.26 (s, 9H), 1.22 (d, J = 7.2 Hz, 3H),
1H), 4.86 (m, 1H), 4.77 (dd, J = 10.4 and 4.0 Hz, 1H), 4.71 (m, 1.16 (t, J = 7.2 Hz, 3H); 13C-NMR (125.7 MHz, CDCl3): δ =
2H), 4.43 (d, J = 8.0 Hz, 1H), 4.39 (dd, J = 12.0 and 2.4 Hz, 1H), 171.6, 171.2, 171.1, 170.4, 170.0, 169.3, 169.3, 162.5, 157.6,
4.28 (quintet, J = 7.2 Hz, 1H), 4.14 (m, 2H), 3.99 (dd, J = 12.4 136.0, 129.2, 128.5, 126.9, 101.0, 72.0, 71.2, 68.4, 67.1, 61.8,
and 2.4 Hz, 1H), 3.87 (m, 2H), 3.62 (m, 2H), 3.60 (s, 3H), 3.48 60.7, 56.8, 53.4, 52.1, 51.2, 49.2, 43.3, 37.8, 36.4, 34.5, 31.4,
(m, 1H), 3.14 (m, 1H), 3.05 (m, 2H), 2.04 (s, 3H), 2.01 (s, 3H), 29.4, 29.1, 20.6, 20.5, 20.4, 17.7; ESI (m/z) 881.4 [M+ + H, (2)],
1.96 (s, 3H), 1.94 (s, 3H), 1.92 (s, 3H), 1.91 (s, 6H), 1.26 (s, 9H), 903.4 [M+ + Na, (100)]; Anal. calcd for C41H60N4O17: C 55.90, H
1.23 (d, J = 6.8 Hz, 3H); 13C-NMR (125.7 MHz, CDCl3): δ = 6.87, N 6.36; found: C 55.86, H 6.89, N 6.32.
171.7, 171.1, 170.7, 170.6, 170.5, 170.3, 170.1, 169.8, 169.6,
(S)-35b: Rf = 0.16 (AcOEt : hexane 80 : 20); [α]2D0 = −54.6° (c =
1
135.9, 129.5, 128.8, 127.4, 95.8, 75.5, 72.9, 72.7, 72.3, 70.2, 0.7, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.18 (m, 3H), 7.14
69.5, 68.8, 68.3, 67.2, 62.9, 61.7, 55.5, 52.4, 51.8, 49.5, 38.1, (d, J = 6.8 Hz, 1H), 7.06 (m, 2H), 7.02 (d, J = 7.2 Hz, 1H), 6.73
29.9, 29.3, 28.0, 21.1, 20.9, 20.8, 20.7, 18.2. The CF3 and C-CF3 (d, J = 7.6 Hz, 1H), 5.12 (t, J = 9.6 Hz, 1H), 4.96 (m, 2H), 4.86 (t,
signals were obscured due to their low intensity; ESI (m/z) J = 8.4 Hz, 1H), 4.79 (m, 1H), 4.69 (q, J = 6.8 Hz, 1H), 4.41 (d, J
1255.3 [M+ + Na, (100)]; Anal. calcd for C52H70F6N4O23: C = 8.0 Hz, 1H), 4.26 (quintet, J = 7.2 Hz, 1H), 4.16 (dd, J = 12.4
50.65, H 5.72, N 4.54; found: C 50.62, H 5.70, N 4.51.
and 4.8 Hz, 1H), 4.04 (m, 3H), 3.75 (m, 1H), 3.60 (m, 1H), 3.59
(S)-34d: Rf = 0.32 (AcOEt : hexane 80 : 20); [α]2D0 = +0.7° (c = (s, 3H), 3.08 (m, 3H), 2.96 (m, 2H), 2.56 (dd, J = 16.4 and 6.4
0.6, CHCl3); 1H-NMR (400 MHz, CD3OD): δ = 7.20 (m, 3H), 7.00 Hz, 1H), 1.98 (s, 3H), 1.97 (s, 3H), 1.93 (s, 3H), 1.91 (s, 3H),
(m, 2H), 6.26 (d, J = 7.2 Hz, 1H), 5.30 (d, J = 4.8 Hz, 1H), 5.28 1.72–1.65 (m, 2H), 1.27 (s, 9H), 1.26 (d, J = 7.2 Hz, 3H), 1.17 (t,
(t, J = 9.6 Hz, 1H), 5.18 (t, J = 8.8 Hz, 1H), 4.97 (t, J = 10.0 Hz, J = 6.8 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): δ = 171.9, 171.8,
1H), 4.88 (m, 1H), 4.78 (dd, J = 10.4 and 4.0 Hz, 1H), 4.70 (m, 171.5, 170.7, 170.3, 169.6, 162.8, 157.6, 136.5, 129.5, 128.7,
2H), 4.41 (m, 2H), 4.21 (quintet, J = 6.8 Hz, 1H), 4.16 (m, 2H), 127.1, 101.2, 72.9, 72.3, 71.6, 68.7, 67.3, 62.1, 61.1, 53.7, 52.3,
4.02 (m, 1H), 3.87 (m, 3H), 3.60 (s, 3H), 3.59 (m, 1H), 3.33 (m, 51.5, 49.2, 37.9, 36.6, 34.4, 31.6, 29.4, 29.3, 20.8, 20.7, 20.6,
1H), 3.02 (m, 4H), 2.04 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H), 1.95 17.4, 14.3; ESI (m/z) 881.4 [M+ + H, (1)], 903.4 [M+ + Na, (100)];
(s, 3H), 1.94 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.46 (m, 2H), Anal. calcd for C41H60N4O17: C 55.90, H 6.87, N 6.36; found: C
1.27 (s, 9H), 1.21 (d, J = 7.2 Hz, 3H); 13C-NMR (125.7 MHz, 55.85, H 6.90, N 6.34.
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(R)-35c: Rf = 0.36 (AcOEt : hexane 80 : 20); [α]2D0 = +57.9° (c = 1H), 5.95 (m, 1H), 5.50 (s, 1H), 5.02 (s, 1H), 4.60–4.53 (m, 3H),
1
1.3, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.17 (m, 3H), 7.04 4.45 (m, 1H), 4.35 (m, 1H), 3.70 (s, 3H), 3.42 (s, 3H), 3.39 (m,
(m, 2H), 6.61 (d, J = 7.6 Hz, 1H), 5.29 (d, J = 4.0 Hz, 1H), 5.25 2H), 3.21–3.12 (m, 3H), 2.73 (dd, J = 14.4 and 6.8 Hz, 1H), 1.67
(t, J = 10.4 Hz, 1H), 5.14 (t, J = 9.2 Hz, 1H), 4.95 (t, J = 10.0 Hz, (m, 3H), 1.50 (s, 3H), 1.33 (s, 9H), 1.32 (s, 3H), 0.91 (m, 6H);
1H), 4.89 (s, 1H), 4.75 (dd, J = 10.8 and 4.0 Hz, 1H), 4.69 (m, 13C-NMR (100.6 MHz, CDCl3): δ = 172.8, 171.1, 170.8, 157.5,
2H), 4.40 (m, 2H), 4.22 (quintet, J = 7.2 Hz, 1H), 4.11 (m, 2H), 113.4, 110.4, 85.8, 84.3, 81.8, 57.7, 55.8, 52.0, 50.9, 50.8, 41.3,
4.05–3.94 (m, 3H), 3.87 (m, 1H), 3.85 (t, J = 9.2 Hz, 1H), 3.71 41.2, 37.5, 29.2, 26.6, 25.1, 24.6, 22.9, 22.8, 21.5, 11.3; ESI (m/z)
(m, 1H), 3.57 (s, 3H), 3.44 (m, 1H), 3.07–2.95 (m, 5H), 2.57 (dd, 587 [M+ + 4], 609.4 [M+ + 4 + Na, (100)]; Anal. calcd for
J = 16.4 and 6.8 Hz, 1H), 2.02 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H), C28H46N4O9: C 57.72, H 7.96, N 9.62; found: C 57.70, H 7.98,
1.92 (s, 3H), 1.90 (s, 3H), 1.89 (s, 6H), 1.23–1.20 (m, 12H), 1.14 N 9.65.
(t, J = 7.2 Hz, 3H); 13C-NMR (125.7 MHz, CDCl3): δ = 171.9,
(R/S)-38, mixture of diastereoisomers: Rf = 0.34 (AcOEt :
1
171.8, 171.5, 170.6, 170.5, 170.4, 170.3, 170.1, 169.8, 169.5, hexane 80 : 20); H-NMR (400 MHz, CDCl3): δ = 7.46 (br d, J =
162.7, 157.7, 136.2, 129.4, 128.7, 127.2, 100.7, 95.8, 75.5, 72.9, 7.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.27 (br s, 1H), 6.18 (br s,
72.6, 72.2, 70.2, 69.5, 68.7, 68.2, 67.4, 62.9, 61.7, 60.9, 53.6, 1H), 5.22 (m, 4H), 5.07 (t, J = 10.0 Hz, 1H), 5.06 (t, J = 9.6 Hz,
52.3, 51.4, 49.4, 37.9, 36.6, 34.8, 31.6, 29.5, 29.4, 29.3, 21.0, 1H), 4.96 (q, J = 9.2 Hz, 2H), 4.66 (m, 1H), 4.53 (m, 1H), 4.51
20.9, 20.8, 20.7, 20.6, 20.5, 18.0, 14.3; ESI (m/z) 1255.3 [M+
+
(d, J = 2.8 Hz, 1H), 4.50 (d, J = 2.8 Hz, 1H), 4.34–4.25 (m, 4H),
Na, (100)]; Anal. calcd for C53H76N4O25: C 54.45, H 6.55, 4.14 (m, 1H), 4.10 (m, 1H), 3.88 (m, 2H), 3.71 (m, 2H), 3.53 (m,
N 4.79; found: C 54.44, H 6.51, N 4.75.
2H), 3.29–3.10 (m, 8H), 3.00 (dd, J = 14.8 and 6.8 Hz, 1H), 2.93
(S)-35c: Rf = 0.31 (AcOEt : hexane 80 : 20); [α]2D0 = −19.2° (c = (dd, J = 14.8 and 6.0 Hz, 1H), 2.77 (m, 2H), 2.16 (m, 2H), 2.09
1
0.3, CHCl3); H-NMR (400 MHz, CDCl3): δ = 7.20 (m, 3H), 7.05 (s, 3H), 2.08 (s, 6H), 2.06 (s, 3H), 2.03 (s, 6H), 2.01 (s, 3H), 2.00
(m, 2H), 6.92 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.31 (s, 3H), 1.82 (m, 4H), 1.49 (m, 4H), 1.45 (s, 9H), 1.44 (s, 9H),
(d, J = 4.0 Hz, 1H), 5.27 (t, J = 10.0 Hz, 1H), 4.96 (t, J = 9.6 Hz, 1.36 (s, 18H), 0.94–0.88 (m, 18H); 13C-NMR (100.6 MHz,
1H), 4.90 (s, 1H), 4.79–4.67 (m, 4H), 4.43 (d, J = 8.0 Hz, 1H), CDCl3): δ = 171.7, 171.2, 170.6, 170.5, 170.4, 170.1, 169.7,
4.40 (dd, J = 12.0 and 2.4 Hz, 1H), 4.26 (quintet, J = 7.2 Hz, 169.4, 158.1, 157.7, 101.1, 100.9, 81.6, 81.5, 72.7, 72.6, 72.0,
1H), 4.15 (m, 2H), 4.06–3.97 (m, 4H), 3.87 (m, 2H), 3.72 (m, 71.4, 71.3, 68.3, 67.3, 67.0, 61.9, 61.8, 58.9, 57.7, 51.1, 51.0; ESI
1H), 3.59 (m, 4H), 3.45 (m, 1H), 3.09–3.04 (m, 3H), 2.97 (m, (m/z) 839.4 [M+ + 4 + Na, (100)]; Anal. calcd for C38H60N4O15:
2H), 2.55 (dd, J = 16.4 and 6.8 Hz, 1H), 2.04 (s, 3H), 2.00 (s, C 56.15, H 7.44, N 6.89; found: C 56.11, H 7.49, N 6.86.
3H), 1.95 (s, 3H), 1.94 (s, 3H), 1.93 (s, 3H), 1.92 (s, 3H), 1.91 (s,
3H), 1.90 (s, 3H), 1.67 (m, 2H), 1.25 (s, 9H), 1.18–1.14 (m, 6H);
13C-NMR (100.6 MHz, CDCl3): δ = 171.6, 171.5, 171.2, 171.1,
170.4, 170.3, 170.2, 169.9, 169.8, 169.6, 169.3, 157.3, 136.2,
129.2, 128.4, 126.9, 100.5, 95.6, 75.2, 72.8, 72.5, 72.1, 70.0,
Notes and references
69.3, 68.6, 68.1, 67.1, 62.7, 61.5, 60.8, 60.3, 55.3, 53.4, 52.0,
51.1, 48.9, 42.4, 37.7, 34.2, 29.2, 20.9, 20.8, 20.7, 20.5, 20.4,
17.1, 14.1, 14.0; ESI (m/z) 1255.2 [M+ + Na, (100)]; Anal. calcd
for C53H76N4O25: C 54.45, H 6.55, N 4.79; found: C 54.41,
H 6.53, N 4.76.
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(R/S)-36a: mixture of two diastereoisomers: Rf = 0.42
(AcOEt : hexane 50 : 50); H-NMR (400 MHz, CD3OD): δ = 7.31
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1
(m, 10H), 7.22 (br d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H),
5.18–4.92 (m, 14H), 4.47 (d, J = 8.0 Hz, 1H), 4.46 (d, J = 8.0 Hz,
1H), 4.27–4.22 (m, 4H), 4.10 (m, 3H), 3.81 (m, 2H), 3.66 (m,
2H), 3.47 (m, 2H), 3.21–3.08 (m, 6H), 2.83 (dd, J = 16.4 and 8.0
Hz, 1H), 2.70 (dd, J = 16.4 and 7.2 Hz, 1H), 2.11 (m, 4H), 2.05
(s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 2.00 (s, 6H), 1.98
(s, 6H), 1.73 (4H), 1.43 (s, 9H), 1.41 (s, 9H), 1.34 (s, 9H), 1.33
(s, 9H), 0.91–0.85 (m, 12H); 13C-NMR (100.6 MHz, CD3OD): δ =
171.2, 171.0, 170.9, 170.8, 170.4, 170.3, 170.2, 170.1, 170.0,
169.3, 169.2, 158.0, 157.4, 135.7, 128.5, 128.2, 128.1, 101.0,
100.9, 81.5, 81.2, 72.8, 72.7, 71.9, 71.2, 68.3, 67.2, 67.1, 66.5,
66.4, 61.8, 57.7, 51.2, 51.1, 34.4, 34.3, 30.9, 30.7, 29.2, 28.0,
20.6, 20.5, 20.4, 19.0, 18.9, 17.5; ESI (m/z) 865.2 [M+, (100)];
Anal. calcd for C42H63N3O16: C 58.25, H 7.33, N 4.85; found:
C 58.22, H 7.36, N 4.80.
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(R)-37: Rf = 0.29 (AcOEt : hexane 80 : 20); [α]2D0 = −56.6° (c =
0.4, CHCl3); 1H-NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 8.0 Hz,
6 B. G. Davis, J. Chem. Soc., Perkin Trans. 1, 1999, 3215.
Org. Biomol. Chem.
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some
reviews
on
MC
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selective because the stereogenic α-amino acid ester steps
in the process once the new stereogenic center is already
formed (see the proposed mechanism). However, from the
perspective of combinatorial application, the formation of
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14 For a review see: N. C. Yoder and K. Kumar, Chem. Soc.
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used as a nucleophile.
Rev., 2002, 31, 335. See also(a) K.-H. Lee, H.-Y. Lee, 22 In these cases, a ca. 20% yield of the corresponding hydan-
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produced hydantoin arising from the nucleophilic attack of
the less congested N-allyl moiety (see ref. 18h) and (2) by
treating 18 in acidic media, we obtained the formation of
hydantoin 43 probably through acid catalyzed nucleophilic
displacement of the alanine moiety by the tert-butyl-NH
group.
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1
(e) P. K. Mikhailiuk, S. Afonin, A. N. Chernega, 26 At the H NMR, the urea NH signals of compounds 22 and
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23 clearly appeared as a doublet and a triplet, respectively,
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confirming the regiochemistry assigned to both com-
pounds (see ESI†).
organic solvent followed by short-path flash chromato-
graphy purification of the crude.
27 This observation is also supported by the fact that 30 It is worth noting that since the diastereoselectivity of the
the process performed with “strongly asymmetric”
carbodiimides and in the absence of the nucleophile, in
some cases, led to the formation of the hydantoins
along with the corresponding N-acylurea derivatives
process depends on the nucleophilic attack of the chiral
primary glycosyl-amino moiety, we obtained the same
diastereoisomeric ratio when using the same acid along
with the same carbodiimide.
(see ref. 18b). In these latter cases the O→N acyl migration 31 Also in this case, the diastereoisomeric glycosyl-hydantoin
mechanism became competitive to the intramolecular aza- conjugates were recovered as byproducts (see ref. 18j).
Michael just because the O-acylurea intermediates are less 32 The stereochemistry of the major diastereoisomers was
nucleophilic.
assessed by X-ray diffraction of sugar–peptides (R)-27b and
on the basis of their spectroscopic and analytical features
(see ESI†).
28 Some works dealing with the use of glyco-carbodiimides:
(a) J. M. Garcia Fernandez, C. Ortiz Mellet, V. M. Diaz
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29 It is worth noting that this kind of carbodiimide could be
easily isolated in high yields by simple evaporation of the
J. P. Kamerling and J. F. G. Vliegenthart, Eur. J. Org. Chem.,
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Org. Biomol. Chem.
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