Stereoselective Pd-catalyzed synthesis of quaternary α-d-C-mannosyl- (S)-amino acids

Article abstract of DOI:10.1021/jo2002962

In this paper, we report the stereoselective synthesis of α-d-C-mannosyl-(S)-amino acids exploiting, as a key step, an allylic alkylation of glycal-derived π-allyl Pd(II) intermediates, prepared by oxidative addition of Pd(0) species to 2,3-unsaturated py

Full text of DOI:10.1021/jo2002962

ARTICLE
pubs.acs.org/joc
Stereoselective Pd-Catalyzed Synthesis of Quaternary
r-D-C-Mannosyl-(S)-amino Acids
Marcello Di Giacomo,* Massimo Serra,* Marco Brusasca, and Lino Colombo
Dipartimento di Chimica Farmaceutica, Universitꢀa degli Studi di Pavia, viale Taramelli 12, 27100 Pavia, Italy.
S Supporting Information
b
ABSTRACT: In this paper, we report the stereoselective
synthesis of R-D-C-mannosyl-(S)-amino acids exploiting, as a
key step, an allylic alkylation of glycal-derived π-allyl Pd(II)
intermediates, prepared by oxidative addition of Pd(0) species
to 2,3-unsaturated pyranosides (pseudoglycals). The reaction
of 4,6-di-O-acetyl R-pseudoglucal carbonate 10a with racemic
alanine-, valine-, and phenylalanine-derived azlactones gave the
corresponding (4S)-4-R-D-C-mannosyl-2-phenyloxazol-5(4H)-ones as the major diastereoisomers in high yields. The final R-D-C-
mannosyl-(S)-amino acids were obtained in a few steps comprising highly diastereoselective dihydroxylation of the glucal derivative
double bond followed by the one-pot hydrolysis of the benzamido and acetate protecting groups. Main features of this method are
the conciseness of the synthetic sequence, the high diastereoselection of the allylic alkylation step, the use of racemic R-amino acids
as starting material, and the good overall yields.
’ INTRODUCTION
It has been reported, for example, that C-linked carbohydrates
exert conformational restrictions on a peptide backbone, and this
effect was ascribed to unfavorable steric interactions and limita-
tions of the conformational space of the glycosyl side chain.15
Well-defined conformational constraints could also be imparted
to a peptide chain by the insertion of quaternary R-amino acids.16
While significant research has been undertaken in the design
of restricted peptides, the field of conformationally constrained
glycopeptides remains relatively unexplored, and most of the
restrictions studied are centered in the saccharide moiety.17
We reasoned that a combined effect could be derived by
attaching a sugar moiety to the R-carbon of monosubstituted R-
amino acids. It thus appeared interesting to combine the hydro-
lytic stability of carbohydrate analogues such as C-glycosides with
conformational properties of constrained C-glycosylated qua-
ternary amino acids, in order to carry out the synthesis of a new
class of potential mimetics of glycopeptides.
In the course of our research project aimed at the design of
novel selectin antagonists, we became interested primarly in the
synthesis of quaternary C-R-mannosyl amino acids as building
blocks for the development of a new class of conformationally
restricted mimetics of tetrasaccharide Sialyl Lewis X. Indeed,
R-D-mannosides have been successfully used as L-fucose equiva-
lents in the design of SLeX mimetics.18
Naturally occurring glycoproteins, glycopeptides, and pepti-
doglycans represent an extensive and important class of com-
pounds which are widely distributed among living organisms play-
ing a significant role in a multitude of key biological processes.1
Protein glycosylation not only affects their physical properties
as folding and conformation2 but also influences their biological
functions.3 Recent studies demonstrated that the carbohydrate
moieties of the membrane-associated N- and O-glycoproteins are
directly involved in recognition phenomena including, for ex-
ample, viral and bacterial infection,4 cancer metastasis,5 inflam-
matory and immunity response,6 and many other receptor-
mediated signaling processes.
As a consequence, glycoproteins and glycopeptides7 involved
in such processes are of great pharmaceutical interest. However,
these natural products are of low metabolic and chemical
stability, thus limiting their use as potential drug candidates.8
In order to circumvent this drawback, the synthesis of
C-glycoside derivatives9 has been an attractive goal in recent
years because of their increased stability to chemical and enzy-
matic cleavage10 and favorable conformational properties11 that
allow the use of such compounds as mimics of more common,
naturally occurring N- and O-glycoconjugates. Moreover, the
sugar component can also modulate the biological properties of a
protein, improving its water solubility as well as its bioavailability
by accelerating its transport across membranes.12
Within this general class of compounds, C-glycosyl R-amino
acids13 have emerged as an important class of building blocks for
the construction of C-glycosylated peptides.14 The interest in this
class of glycopeptide mimetics stems not only from enhanced
resistance to enzymatic hydrolysis but also from potential super-
ior properties for specific therapeutic or biological applications.
Moreover, recent studies demonstrated that C-D-glucopyrano-
sides with an amino function on the carbon directly linked to the
anomeric sugar center are potent inhibitors for glycosidases.19
Several recent syntheses of C-glycosyl amino acids have been
recently reported in the literature, and most of them are isosteres
Received: February 8, 2011
Published: May 19, 2011
r
2011 American Chemical Society
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of natural N- or O-linked glycoamino acid.13 To the best of our
knowledge, there are only two examples of C-glycosylated
R-amino acids possessing a quaternary stereocenter on the CR
of the amino acid moiety.20 The principal reason lies in the
difficulty in creating simultaneously the CꢀC bond between
the anomeric carbon of the sugar moiety and the R-carbon of the
amino acid with a high level of diastereoselectivity.
The high stereochemical control accompanying transition-
metal-mediated transformations has prompted several groups to
employ such methods for C-glycosylations. It is in this context
that we describe herein a novel catalytic asymmetric synthesis of
carbon-linked glycosyl-R-amino acids through the asymmetric
allylic alkylation (AAA) reaction promoted by chiral palladium
catalysts.21
Trost method with respect to the variation of the 4-alkyl
substituent of the azlactone could allow the preparation of
different C-glycosylated R-amino acids. However, in the Trost
papers major attention was paid to the reaction of acyclic
asymmetric allyl derivatives, and only two cyclic allyl acetates
were studied. Moreover, the poor reactivity of glycal donors for
η3-Pd complex mediated reactions could be a challenge to this
approach.24 The use of more activated pyranone derivatives or
Zn(II) activation of the glycal donors to accelerate ionization
were shown to give a partial solution to this limitation.25 As
anticipated by these precedents, preliminary experiments with
glycal acetonides 4ꢀ6 (Scheme 2, A) confirmed their reluctance
to form π-allyl Pd intermediates. The O-acetyl and O-t-Boc
derivatives 4 and 6 were recovered unchanged; only the O-
trifluoroacetyl derivative 5 gave the desired adducts 2a,b as a
mixture of diastereoisomers in trace amounts, and only using the
sodium enolate of the azlactone 7. In this case, the major product
was the deacylated glucal acetonide, likely arising from the attack
of the nucleophilic enolate at the trifluoroacetate carbonyl. The
same disappointing results were obtained starting from the
corresponding epimeric acetonide-protected D-arabino-hex-1-
enitol derivatives.
An alternative way of forming glycal-derived π-allyl Pd inter-
mediates would be the oxidative addition of Pd(0) species to 2,3-
unsaturated glycosyl carbonates (pseudoglycals). Although this
reaction has received scant attention, the rare examples reported
in the literature demonstrated its usefulness for the synthesis of
C-glycosides because of its very high regio- and stereoselectivity
and mild experimental conditions.26 These considerations
prompted us to study the Pd-catalyzed allylic alkylation reaction
of pseudoglucal 10a with azlactones 7ꢀ9 (Scheme 2, B). For any
synthetic method to be useful, the substrates must be readily
accessible: compound 10a can be prepared by as few as two steps
from commercial tri-O-acetyl-D-glucal in 76% yield and 4-alkyl-5-
oxazolones in one step from N-benzoyl-R-amino acids.28
In a preceding paper,20c we reported on the preparation of
R-D-C-mannosyl-(R)-alanine 3 through an approach relying on
the Steglich variant of the Claisen rearrangement of the esters 1
(Scheme 1). Although this method is practical and high yielding,
it is not without limitations: (1) the starting acetonide protected
D-ribo-hex-1-enitol must be prepared in four steps from commer-
cially available 3,4,6-tri-O-acetyl-D-glucal; (2) the diastereoselec-
tion of the ClaisenꢀSteglich rearrangement is rather low,
providing the two epimeric R-C-glycosylated azlactones 2a and
2b in a 2.6:1 ratio; and (3) the method is limited to alanine
derivatives as attempts to extend its scope to other amino acids
such as phenylalanine and valine resulted in unacceptably low
yields.
Inspired by reports by Trost22 in which quaternary R-amino
acids were prepared enantioselectively by Pd-catalyzed reaction
of allylic acetates with 4-alkyl-2-phenyloxazol-5(4H)-ones,23 we
tried to expand this methodology to glycal derivatives. If this were
successful, the last two limitations of our previous method could
be obviated. The use of chiral phosphine ligands matching the
stereoinduction exerted by the sugar moiety could improve the
stereoselection of the process. Moreover, the wide scope of the
Scheme 1
’ RESULTS AND DISCUSSION
Exploratory experiments with simple and cheap monopho-
sphines such as triphenyl- and tri-O-tolylphosphine, in the presence
of Pd(OAc)2 as palladium source, showed that pseudoglucal 10a
was indeed a suitable substrate for the formation of the corre-
sponding π-allyl Pd complex as the C-glycosylated azlactone 11
was formed, albeit in low yields (29ꢀ45%) and as a mixture of
Scheme 2
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Table 1. Reaction of Pseudoglycal 10a with Alanine-Derived Azlactone 7
entrya
solventb
base
Pd2(dba)3 (mol %)
phosphine
phosphine (mol %)
time (h)
isolated yieldc (%)
drd (11a/11b)
1e
2e
3
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
DCM
MeCN
THF
TEA
TEA
TEA
TEA
TEA
NaH
TEA
TEA
DIEA
TEA
TEA
TEA
TEA
1.5
20
1.5
1.5
5
TPP
TPP
TPP
TPP
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
dppe
4.5
60
9
24
1
29
45
67
70
64
35
82
85
74
71
69
74
79
69:31
76:24
72:28
74:26
87:13
83:17
93:7
1
4
12
15
15
20
6
0.5
1
5
6
5
3
7
5
0.5
0.5
1
8
1.5
1.5
1.5
5
93:7
9
6
89:11
93:7
10
11
12
13f
6
1
15
6
1
68:32
87:13
87:13
1.5
1.5
0.5
0.5
6
a Reaction conditions: Reactions were performed on a 0.075ꢀ0.15 mmol scale (0.1 M) at rt using 1.0 equiv of R-pseudoglucal, 2.0 equiv of azlactone 7,
Pd2(dba)3-chloroform adduct as catalyst precursor, and 1.3 equiv of base. b All solvents were freshly distilled from the appropriate drying agent. c Isolated
1
yield of the major diastereoisomer. d dr = diastereoisomeric ratio, determined by 400 MHz H NMR analysis of the crude mixture: average from
diagnostic signals of H-20, H-30, and H-40. e Reaction performed with Pd(OAc)2 as catalyst precursor. f Reaction performed with [(η3-allyl)PdCl]2 as
catalyst precursor.
diastereoisomers 11a and 11b (for configurational assignments
see below) with poor selectivity (69ꢀ76%), despite the use of a
large amount of catalyst (20 mol %) (Table 1, entries 1 and 2). In
all cases, the major product was the dimeric adduct deriving from
the attack of the azlactone enolate to the carbonyl carbon of a
second azlactone molecule. Switching the palladium source to
Pd2(dba)3 the allylic alkylation could be carried out with
improved yields (70%) and a comparable diastereoselection
value of 74% (Table 1, entry 4).
These results led us to consider the use of dppe (1,2-bis-
(diphenylphosphino)ethane) as Pd ligand. Indeed, a paper by
Hayashi30 reports an example of allylic alkylation were the use of
tetrakis (triphenylphosphine)palladium(0), “which has been
used conventionally for many of the palladium-catalyzed allyla-
tion reactions” gave only 4% of the products, while a much higher
yield of 96% was obtained only switching to dppe as a ligand.
As shown by the results summarized in Table 1 (entries
5ꢀ13), yields could be considerably improved by using a Pd/
dppe catalyst, prepared in a separate flask by mixing Pd2(dba)3
with 1,2-bis(diphenylphosphino)ethane prior to addition to a
premixed mixture of all other reagents.
Several reaction variables were then investigated including Pd
source, solvent, base, and Pd to diphosphine ratio; all of the
reactions were complete within 1 h at room temperature.
Comparison between the two most commonly used Pd
precatalysts, Pd2(dba)3 and [(η3-allyl)PdCl]2 (entry 8 vs entry
13), revealed that both the diastereoselection and the yield were
slightly higher with the former. Taking into account this result,
but also the lower cost and the better properties as to long-term
storage of Pd2(dba)3, we used this precatalyst for the following
optimization experiments.
the base, triethylamine was superior to diisopropylethylamine
and stronger inorganic bases such as NaH (entries 5 vs 6 and 8 vs
9). Finally, the most critical variable for achieving diastereoselec-
tion values higher than 90% was the Pd/diphosphine ratio. In the
enantioselective allylic alkylation reactions of azlactones reported
by Trost an 1/1.5 ratio was always adopted.31 Using this same
ratio yields were uniformly close to 70%, but diastereoselection
was still low (entries 5 and 11). Unexpectedly, when the Pd/dppe
ratio was raised to 1:4, yields were improved to 82%, and the
diastereoselection reached an acceptable value of 93% (entry 7).
With these optimized conditions available, we then looked to see
if the Pd loading could be lowered below 5%, and we found that
as little as 1.5 mol % of Pd2(dba)3 could be used with no
diminution in yields and diastereoselectivity (entry 8).
In order to expand the scope of this method to other amino
acid derivatives, valine- and phenylalanine-derived azlactones 8
and 9 (Scheme 2, B) were reacted with the same pseudoglycal
10a under the optimized conditions found for the alanine
derivative 7.
Table 2 summarizes the alkylation reactions for this range of
derivatives. Notably, the size of the 4-alkyl substituent did not
effect the diastereoselection that was uniformly higher than 90%
for all compounds. Compounds 11aꢀ13a could be isolated
diastereomerically pure after chromatographic separation of the
corresponding minor diastereomers 11bꢀ13b in good yields
(73ꢀ85%).
29
An explanation of how the achiral phosphine ligands could
affect the stereoinduction at the nucleophile could only be
speculative since, in allylic alkylation, the attacking nucleophile
is remote from the phosphine ligands. Excluding a direct inter-
action between the phosphine and the azlactone, we can suppose
that variation of the phosphine structure reflects into a con-
formational change of the cyclic π-allyl-Pd complex. The sense of
stereoinduction at the nucleophile could be explained taking into
consideration the diastereoisomeric transition states of nucleo-
philic attack of azlactone enolates on the π-allyl-Pd complex as
hypothesized by Trost.22 The approach of the nucleophile could
be directed by interaction between the negatively charged oxygen
and the positively charged C30 of the π-allyl-Pd intermediate,
The solvent effect was not extensively studied. The results in
Table 1 indicate that in terms of diastereoselection either
dichloromethane or tetrahydrofuran was a suitable solvent
(entries 8 and 10 vs entry 12), the only remarkable difference
being the increase of the reaction rate effected by the use of THF.
This probably reflects also an improvement of yields as an increased
reaction rate could minimize the formation of side products
deriving from self-condensation of the azlactone. With regard to
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Table 2. Alkylation of Alanine-, Valine-, and Phenylalanine-
Derived Azlactones under Optimized Conditions
enhance the low diastereoselection exerted by the substrate
alone. Keeping in mind that forcing the chiral environment to
embrace the substrate by opening the bite angle is necessary for
high chiral recognition,33,21 we explored the use of both en-
antiomers of 2,3-bis-(diphenylphosphine)butane (dppb), and
2,4-bis-(diphenylphosphine)pentane (bdpp).
Results reported in Table 3 (entries 1, 7, and 12) clearly
indicate that the use of the more flexible dppp (bite angle 91°)
caused a remarkable loss in stereoselectivity if compared to dppe
(bite angle 86°).
We can only speculate on the origin of this effect and put
forward the hypothesis that a more flexible ligand imparts to the
Pd complex a geometry more similar to that obtained in the case
of monophosphine ligands. On the basis of this result, which
seemed to give the indication that a more rigid five-membered
ring in the π-allyl-Pd complex coordinated with dppe would
enhance the diastereoselection, we tested whether replacement
of dppe by either enantiomers of a chiral ethylene diphosphine
could reinforce the inherent stereodirecting effect of the sugar
portion of the π-allyl complex (matching effect). Unfortunately,
reaction of the most reactive azlactone 7 in the presence of both
(R,R)- and (S,S)-dppb under the same previously optimized
conditions afforded only trace amounts of the desired glycosyl
oxazolone 11a (entries 2 and 3).
entrya
azlactone
time (h) isolated yieldb (%)
drc
1
2
3
7 (CH3)
8 (iPr)
0.5
1
85
79
73
93:7 (11a/11b)
93:7 (12a/12b)
90:10 (13a/13b)
9 (CH2Ph)
2.5
a Reaction conditions: reactions were performed at rt on a 0.075ꢀ0.15
mmol scale (0.1 M) in anhydrous THF using 1.0 equiv of R-pseudoglu-
cal, 2.0 equiv of azlactone, 1.3 equiv of TEA, 1.5 mol % of Pd2-
(dba)3ꢀchloroform adduct as catalyst precursor, and 6 mol % of dppe
c
as ligand. b Isolated yields of the major diastereoisomer. dr = diaste-
1
reoisomeric ratio, determined by 400 MHz H NMR analysis of the
crude mixture: average from diagnostic signals of H-20, H-30, and H-40.
leading to chairlike (A) or boatlike (B) transition states arising
from the two different spatial orientations of the azlactone (Figure 1).
The observed Si-face selectivity of the π-allyl-Pd intermediate
clearly indicates that the reaction proceeds through the more favored
chairlike transition state A. Indeed, transition state B involving
the attack of the π-allyl unit on the Re-face of the enolate
becomes destabilized because of a steric interaction between
the alkyl substituent of the azlactone and the pseudoaxial H50.
Encouraged by these initial results, we further proceeded to
optimize the reaction conditions in order to improve (if possible)
both diastereomeric ratio and reaction yield. For this purpose, we
decided to explore the use of several bidentate phosphine ligands
(Figure 2) in the presence of Pd2(dba)3 as palladium source.
Since it has been reported that diphosphine ligands have a
marked influence on the reactivity and selectivity of transition-
metal catalysts, in our first attempts we considered the use of
bis(diphenylphosphino)propane (dppp), a diphosphine ligand
which is characterized by a wider bite angle than dppe. Indeed, as
it is commonly accepted, a wide bite angle can both increase the
effective steric bulk of the bidentate ligand and electronically
favor or disfavor certain geometries of transition metal complexes.32
Moreover, a double stereodifferentiation with chiral ligands was
considered in order to determine if catalyst control could
We were then curious to see whether the “chiral shift”, applied
to the case of the worse performing dppp, would produce the
same or even worse results.
Contrary to our expectations, reaction of azlactone 7 in the
presence of (R,R)- and (S,S)-bdpp gave yields (56ꢀ65%)
comparable to the achiral version (entries 4ꢀ6), and notably, a
matching effect exerted by the (R,R) enantiomer was apparent, as
evidenced by enhanced diastereoisomeric ratio (90:10) (entry 4
vs 1). Similar results were obtained by doubling the catalyst
amount apart from an expected slight increase in yield (entry 6).
Contradictory results were obtained in the case of the least
reactive isopropyl oxazolone 8 where experiments with doubled
catalyst loading were needed in order to obtain more than a trace
amount of the final product 12a (entries 10 and 11). A slight
matching effect by the (R,R) enantiomer was observed also in this
case (entry 10) when considering the diastereoselection en-
hancement, but this was not accompanied by an increase in yield
and reaction rate as it is common for matched pairs. Unexpect-
edly, the matching effect of the (R,R)-bdpp was not observed in
the case of benzyl oxazolone 9 (entry 15). Even if a loss in
diastereoselectivity was obtained with both bdpp enantiomers,
this detrimental effect was more pronounced with (R,R)-bdpp.
These discouraging results convinced us to deeply investigate
the reaction stereoselectivity testing other chiral diphosphine
ligands. For this purpose, we selected three of the most repre-
sentative bidentate phosphines usually employed in Pd-catalyzed
Figure 1. Possible approaches of the azlactone to the π-allyl-Pd complex.
Figure 2. Employed bidentate phosphine ligands.
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Table 3. Effect of the Ligand on the Diastereoselectivity of the Allylic Alkylation of 7ꢀ9
entrya
azlactone
Pd2(dba)3 (mol %)
phosphine
phosphine (mol %)
time (h)
isolated yieldb (%)
drc
1
2
7 (CH3)
1.5
1.5
1.5
1.5
1.5
3
dppp
6
6
0.5
24
24
2
62
81:19 (11a/11b)
(R,R)-dppb
(S,S)-dppb
(R,R)-bdpp
(S,S)-bdpp
(R,R)-bdpp
dppp
trace
trace
56
nd
3
6
nd
4
6
90:10
5
6
3
60
68:32
6
12
6
0.3
1
65
90:10
7
8 (iPr)
1.5
1.5
1.5
3
55
80:20 (12a/12b)
8
(R,R)-bdpp
(S,S)-bdpp
(R,R)-bdpp
(S,S)-bdpp
dppp
6
24
24
18
8
trace
trace
35
nd
9
6
nd
10
11
12
13
14
15
16
12
12
6
85:15
3
57
66:33
9 (CH2Ph)
1.5
1.5
1.5
3
2.5
48
24
20
5
55
77:23 (13a/13b)
nd
(R,R)-bdpp
(S,S)-bdpp
(R,R)-bdpp
(S,S)-bdpp
6
18
6
46
55:45
12
12
60
69:31
3
77
75:25
a Reaction conditions: reactions were performed at rt on a 0.075ꢀ0.15 mmol scale (0.09 M) of anhydrous THF using 1.0 equiv of R-pseudoglucal, 2.0 equiv of
azlactone, 1.3 equiv of TEA, and Pd2(dba)3ꢀchloroform adduct as catalyst precursor. b Isolated yield of the major diastereomer. c dr = diastereomeric ratio,
determined by 400 MHz 1H NMR analysis of the crude mixture: average from diagnostic signals of H-20, H-30, and H-40. e nd = not determined.
Table 4. Alkylation Reactions with BINAP, PHOX, and DACH-phenyl Trost Ligand
entrya
azlactone
Pd catalyst (mol %)
phosphine
phosphine (mmol %)
time (h)
isolated yieldc (%)
drd
1
2
7 (CH3)
2
(R)-BINAP
(S)-BINAP
(R)-PHOX
(S)-PHOX
8
8
6
6
6
6
6
6
8
8
8
6
6
6
6
6
6
8
8
8
6
6
6
6
6
6
6.5
6.5
1.5
24
0.3
1
47
80:20 (11a/11b)
80:20
2
50
3
1.5
1.5
1.5
1.5
1.5
1.5
2
59
93:7
4
55
91:9
5
(R,R)-DACH
(R,R)-DACH
(R,R)-DACH
(S,S)-DACH
(R)-BINAP
(R)-BINAP
(S)-BINAP
(R)-PHOX
(S)-PHOX
78
94:6
6
78e
79e,f
ndg
40
94:6
7
1
94:6
8
24
48
48
48
72
72
0.7
2
nd
9
8 (iPr)
75:25 (12a/12b)
75:25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
26
27
2 b
26
2
55
75:25
1.5
1.5
1.5
1.5
1.5
1.5
2
50
89:11
51
87:13
(R,R)-DACH
(R,R)-DACH
(R,R)-DACH
(S,S)-DACH
(R)-BINAP
(S)-BINAP
(S)-BINAP
(R)-PHOX
(S)-PHOX
81
98:2 (12a/12b)
98: 2
83e
88e,f
50
2
98:2
24
18
6.5
0.7
24
6
90:10
9 (CH2Ph)
33
70:30 (13a/13b)
71:29
2
54
2 b
1.5
1.5
1.5
1.5
1.5
1.5
30
50:50
50
80:20
49
62:38
(R,R)-DACH
(R,R)-DACH
(R,R)-DACH
(S,S)-DACH
1
77
96:4
1
76e
90e,f
67
96:4
2
96:4
1.5
85:15
a Reaction conditions: reactions were performed at rt on a 0.075ꢀ0.15 mmol scale (0.1 M) of anhydrous THF, 1.0 equiv of R-pseudoglucal, 2.0 equiv
of azlactone, 0.2ꢀ1.3 equiv of TEA, 1.5 mol % of Pd2(dba)3ꢀchloroform adduct as catalyst precursor. b Reaction performed with [(η3-allyl)PdCl]2.
c Isolated yield of the major diastereomer. d dr = diastereomeric ratio, determined by 400 MHz 1H NMR analysis of the crude mixture: average from
diagnostic signals of H-20, H-30, and H-40. e Reaction performed with 0.2 equiv of TEA. f Reaction performed with 4 Å molecular sieves. g nd = not
determined.
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ARTICLE
enantioselective allylations34,21b such as BINAP,35 PHOX,36 and
DACH-phenyl Trost ligand.37,33
Experiments, performed utilizing the C-2-symmetric biden-
tate BINAP, showed a marked decrease of yields (47ꢀ55%) and
stereoselectivity (70ꢀ80%) (Table 4, entries 1, 2, 9, 11, 18, and
19). Moreover, no matching effect was exerted by either en-
antiomeric ligand, and only a marginal increase in yields was
effected by the use of the S-enantiomer. Changing the palladium
source from Pd2(dba)3 to [(η3-allyl)PdCl]2 had a deleterious
effect on both yields and stereoselectivity (entries 10 and 20). The
major diastereoisomer has the same configuration as that ob-
tained with achiral diphosphines showing the predominant
stereodirecting effect of the sugar moiety. This behavior was
substantially identical for all azlactones. Switching to the bidentate
N,P-phosphine-oxazoline PHOX ligand led to results compar-
able with those obtained employing BINAP (entries 3, 4, 12, 13,
21, and 22). Much better results were finally obtained by using
the more flexible and larger bite angle (110°) bidentate DACH-
phenyl phosphines (Trost ligand) considered as one of the most
efficient Pd catalysts for enantioselective allylic alkylation
reactions.33
Figure 3. Cartoon model for the transition state of the allylic alkylation
reaction with (R,R)-DACH.
Table 5. Solvent Optimization Studies
entrya azlactone solventb time (h) isolated yieldc (%) drd (11a/11b)
1
2
7 (CH3)
THF
0.3
1
78
94:6
95:5
DCM
72
3
dioxane
PhCH3
MeCN
MeCN
MeCN
MeCN
0.6
0.3
0.3
0.7
1
57
85:15
86:14
99:1
Results reported in Table 4 show that (R,R)-DACH gave a
slightly better diastereoselection in the case of the methyl azlactone
7 (88 vs 86 de, entries 5ꢀ7), and a remarkable matching effect
was observed in the case of the more sterically hindered isopropyl
(>96% de) and benzyl derivatives (92% de). Notably, when a
catalytic amount of base (20%) was used in combination with the
presence of 4 Å molecular sieves the reaction proceeds without
loss in diastereoselectivity, and in addition, yields were substan-
tially increased to 88ꢀ90% (entries 16 and 26).
4
71
5
82
82e,f
6
99:1
7
8 (iPr)
79
>99:1
>99:1
99:1
8
1
84e,f
81
84e
9
9 (CH2Ph) MeCN
0.5
0.7
10
MeCN
99:1
a Reaction conditions: reactions were performed at rt on a 0.075ꢀ0.15
mmol scale (0.1 M), 1.0 equiv of R-pseudoglucal, 2.0 equiv of azlactone,
1.3 equiv of TEA, 1.5 mol % of Pd2(dba)3ꢀchloroform adduct as
catalyst precursor, and 6 mol % of (R,R)-DACH phenyl Trost ligand.
b All solvents were freshly distilled from the appropriate drying agent.
c Isolated yield of the major diastereomer. d dr = diastereomeric ratio,
determined by 400 MHz 1H NMR analysis of the crude mixture: average
The underlying causes for the improvement of stereoselectiv-
ity observed with (R,R)-DACH are difficult to be rationalized. An
explanation based (solely) on the enlargement of the bite angle
relies on tenuous ground as it is not quite consistent with the
results obtained in the case of achiral phosphines.
e
from diagnostic signals of H-20, H-30, and H-40. Reaction performed
The “cartoon model” proposed by Trost and based on steric
deactivation of the nucleophile by the pendant phenyl groups of
the ligand22 has been recently questioned by Lloyd-Jones and
collaborators.38 They demonstrated that η3-cyclohexenyl com-
plexes, at 2ꢀ4.2 mM concentrations, exist as monomeric exo-
isomers, and the approach of a malonate anion is guided “by an
H-bonding interaction between the enolate oxygen of the malonate
and the amide NH on the concave surface of Pd-coordinated
(R,R)-DACH”. This interaction is particularly important in our
case where a weakly coordinating escort ion of the enolate was
used. Transposed to our substrate, this selectivity model is
outlined in cartoon form in Figure 3.
Finally control experiments were performed as we have
wondered whether the use of solvents other than THF and
DCM, which were shown to be optimal when using achiral dppe,
would further improve stereoselectivity. It was indeed fortunate
that these control experiments were carried out. Conducting the
reaction in toluene or dioxane had a detrimental effect on the
levels of stereoselectivity while showing little impact on the
reactivity (Table 5). The best results were obtained performing
the allylic alkylation in MeCN which allowed the diastereoiso-
meric ratios to be improved to values g99:1.
with 0.2 equiv of TEA. f Reaction performed with 4 Å molecular sieves.
afforded directly lactones 14ꢀ16 as single diastereoisomers in
satisfactory yields (Scheme 3).
Combined analysis of coupling constants and NOE correla-
tions between relevant hydrogen atoms clearly demonstrated the
S configuration of the quaternary lactone stereocenter, the R
stereochemistry of the anomeric carbon, and the β-attack of the
OsO4 reagent from the upper face of the sugar moiety (Figure 4).
Particularly diagnostic for the R anomeric configuration was the
NOE between H-10 and H-60a or H-60b. The S configuration
of the quaternary stereocenter was evidenced by NOE correla-
tion between the H-10 and the methyl, methylene, or methine
hydrogens of the R-N-benzoyl lactone substituents, while the
benzamido proton was correlated to H-20. Worthy of note is the
1
preference of the pyranose ring to adopt a C4 conformation,
placing the most sterically demanding substituent at C-10 in an
equatorial position, as evidenced by the large coupling constants
(9.8ꢀ10.0 Hz) between H-10 and H-20.
Configurational assignment of the minor diastereoisomer 11b
was made in an analogous fashion by conversion into the lactone
14b. The R-mannosyl configuration of the anomeric center was
evidenced by an NOE between H-10 and H-60a or H-60b and the
10 Hz coupling constant relating H-10 and H-20. The opposite R
configuration of the quaternary stereocenter was deduced by the
presence of NOE between the methyl substituent and H-20.
Configurational assignments were postponed to the prepara-
tion of a more advanced lactone intermediates 14ꢀ16 in which
the presence of a more rigid fused bicyclic system could allow to
determine stereochemical correlations by NOE experiments. In
the event, treatment of 11aꢀ13a with catalytic OsO4 and NMO
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ARTICLE
Scheme 3a
a Reagents and conditions: (i) OsO4, NMO, Me2COꢀH2O, rt, 24 h; (ii) 6 N, HCl, 80 °C, 4 h; (iii) MeONa, MeOH, rt, few minutes; (iv) (1) LiOH,
THFꢀMeOH, rt, 3 h, (2) 6 N, HCl, 80 °C, 4 h.
’ EXPERIMENTAL SECTION
Synthesis of 10-O-tert-Butoxycarbonyl-40,60-di-O-acetyl-
20,30-dideoxy-r/β-D-erythro-20-hexenopyranosides 10a and
10b. Triacetyl glucal (10 g, 18.4 mmol) was dissolved in boiling water
(180 mL, 0.1 M), and hydroquinone was added (646 mg, 2.94 mmol).
The reaction was stirred for 1 h in the dark. After reaction completion was
monitored by TLC analysis (hexane/AcOEt 70:30), most of the water
was removed under reduced pressure. The crude was dissolved in DCM
(90 mL, 0.2 M) and added with di-tert-butyl dicarbonate (4.4 g, 20.2 mmol),
Et3N (2.8 mL, 20.2 mmol), and DMAP (112 mg, 0.92 mmol). After reac-
tion completion (0.5 h), the solvent was removed under reduced pressure.
The crude mixture was purified by flash chromatography (hexane/ethyl
acetate/chloroform 75:17:5) to obtain the pure diastereisomers 10a
(R-anomer) (76%) and 10b (β-anomer) (15%). Compound 10a was
Figure 4. Relevant coupling constants and NOEs exhibited by com-
pounds 14a, 14b, 15, and 16.
obtained as a colorless oil: Rf = 0.42 (hexane/AcOEt 75:25); [R]22
=
Final hydrolysis of lactone 14a with 6 NHClat 80 °C afforded in
93% yield the final R-D-C-mannosyl-(S)-alanine 20 completely
identical (1H and 13C NMR, IR, ESI-MS, and RD) with a sample
previously prepared by us through the sequence reported in ref 20b.
Final acid hydrolysis proceeded uneventfully only in the case
of the alanine derivative 14a, while mannosyl lactones 15 and 16
were resistant even to harsh reaction conditions and gave only
trace amounts of the desired amino acids 21 and 22. After
extensive experimentation, this lack of reactivity could be cir-
cumvented by a somewhat awkward, but high yielding, three-step
sequence. Treatment of 15 and 16 with a methanol solution of
sodium methoxide simultaneously removed the acetate groups
and converted the lactone function into the corresponding
methyl esters 18 and 19. Saponification of 18 and 19 with LiOH
followed by hydrolysis of the residual benzamido group with 6 N
HCl afforded the final amino acids 21 and 22 in 90% and 85%
yield, respectively. The same three sequence procedure could
also be performed with high yields in the case of the alanine
derivative 14a via methyl ester intermediate 17.
In summary, we have utilized a catalytic asymmetric allylic
alkylation for the synthesis of quaternary R-D-C-mannosyl-(S)-
amino acids. The synthesis proceeds in good overall yield starting
from commercial tri-O-acetyl-D-glucal and racemic N-benzoyl-R-
amino acids. The main features of this method are the concise-
ness of the synthetic sequence and the complete stereocontrol of
the key allylic alkylation step leading to the generation of two
new stereocenters. Experiments to explore the versatility of this
methodology for the synthesis of analogues C-glucosyl and
C-galactosyl amino acids are currently underway. In addition, the
potential of these compounds as glycomimetics will be evaluated.
D
þ42.7 (c = 0.99, CHCl3); IR (neat, cmꢀ1) 1738, 1369, 1222, 1149, 1029,
938, 844, 729; 1H NMR (CDCl3, 400 MHz) δ 1.51 (s, 9H, t-Bu), 2.07 (s,
3H, AcO), 2.09 (s, 3H, AcO), 4.10ꢀ4.17 (m, 1H, H-50), 4.19 (dd, J6 aꢀ6 b
=
=
0
0
0
0
0
0
0
0
0
12.3Hz, J6 aꢀ5 = 2.6Hz, 1H, H-6 a), 4.23 (dd, J6 bꢀ6 a = 12.3 Hz, J6 bꢀ5
0
0
0
0
0
0
0
4.9 Hz, 1H, H-6 b), 5.39 (ddd, J4 ꢀ5 =9.7Hz,J4 ꢀ3 =3.5Hz, J4 ꢀ2 =1.8Hz,
1H, H-40), 5.89 (ddd, J2 ꢀ3 = 10.2Hz, J2 ꢀ1 = 2.9 Hz, J2 ꢀ4 = 1.9 Hz, 1H,
0
0
0
0
0
0
0
0
H-20), 6.04 (br d, J3 ꢀ2 = 10.2 Hz, 1H, H-3 ), 6.15ꢀ6.19 (m, 1H, H-1 );
13C NMR (CDCl3,100 MHz) δ 21.2, 21.3, 28.1, 62.9 (t), 64.9, 69.1, 83.4
(s), 90.7, 125.8, 131.3, 152.4 (s), 170.4 (s), 171.1 (s); MS (ESI) m/z
352.9 [M þ Na]þ, 682.6 [2M þ Na]þ. Anal. Calcd for C15H22O8: C,
54.54;H, 6.71. Found: C, 54.68; H, 6.72. Compound 10bwas obtained as
0
0
a white solid: mp 45ꢀ46 °C; Rf = 0.36 (hexane/AcOEt 75:25); [R]22
=
D
þ89.0 (c = 0.97, CHCl3); IR (neat, cmꢀ1) 1736, 1369, 1226, 1158, 1023,
936, 844, 730; 1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 9H, t-Bu), 2.08 (s,
6H, AcO), 4.17ꢀ4.29 (m, 3H, H-60a þ H-60b þ H-50), 5.10ꢀ5.15 (m,
1H, H-40), 6.00 (ddd, J2 ꢀ3 = 10.2Hz, J2 ꢀ1 = 2.4 Hz, J2 ꢀ4 = 0.8 Hz, 1H,
0
0
0
0
0
0
H-20), 6.13 (ddd, J3 ꢀ2 = 10.2 Hz, J3 ꢀ4 = 4.6 Hz, J3 ꢀ1 = 1.3 Hz, 1H,
H-30), 6.18ꢀ6.21 (m, 1H, H-10); 13C NMR (CDCl3, 100 MHz) δ 21.2,
21.3, 28.1, 63.3, 63.4 (t), 73.3, 83.5 (s), 89.7, 126.5, 128.4, 152.4 (s),
170.7 (s), 170.9 (s); MS (ESI) m/z 352.9 [M þ Na]þ, 682.6 [2M þ
Na]þ. Anal. Calcd for C15H22O8: C, 54.54; H, 6.71. Found: C, 54.62;
H, 6.74.
0
0
0
0
0
0
General Procedure A: Synthesis of Compounds 11aꢀ13a.
To a solution of azlactones 7ꢀ9 (0.79 mmol) in 2.5 mL of dry THF,
under nitrogen, were added sequentially triethylamine (0.51 mmol), a
solution of the R-pseudoglucal 10a (0.39 mmol) in 1 mL of dry THF, and
the palladium complex prepared by mixing Pd2(dba)3CHCl3 (1.5 mol %)
and 1,2-bis(diphenylphosphino)ethane (6 mol %) under nitrogen
atmosphere in 1 mL of dry THF. The reaction mixture was stirred at
room temperature (2ꢀ4 h). After reaction completion was monitored
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ARTICLE
by TLC analysis, phosphate buffer was added to quench the reaction.
THF was removed under reduced pressure, and the aqueous phase was
extracted with DCM for 11a and 12a and AcOEt for 13a. The organic
phases were collected, dried with anhydrous Na2SO4, and evaporated in
vacuo. The crude mixture was purified by flash chromatography
(hexane/ethyl acetate 75:25) to obtain the pure major diastereisomers
11a (85%), 12a (79.0%), and 13a (73.0%) and the corresponding minor
diastereomers 11b (5%), 12b (5%), and 13b (7%).
(4R) Epimer 12b. Compound 12b was obtained as a colorless oil,
following general procedure A: Rf = 0.22 (hexane/AcOEt 75:25);
[R]22D = ꢀ68.1 (c = 1.0, CHCl3); IR (neat, cmꢀ1) 1813, 1738, 1650,
1580, 1494, 1451, 1369, 1321, 1290, 1225, 1158, 1138, 1097, 1078, 1045,
1021, 972, 881, 815, 780, 753, 722, 693, 670; H NMR (CDCl3, 400
MHz) δ 1.00 (d, J = 6.8 Hz, 3H, CH3 iPr), 1.10 (d, J = 6.9 Hz, 3H,
CH3iPr), 1.87 (s, 3H, AcO), 2.04 (s, 3H, AcO), 2.44 (septuplet, 1H,
1
CHiPr), 4.02 (dd, J6 aꢀ6 b = 11.8 Hz, J6 aꢀ5 = 3.2 Hz, 1H, H-60a), 4.09
0
0
0
0
(4S)-4-Methyl-4-(40,60-di-O-acetyl-20-30-dideoxy-R-D-ery-
thro-20-hexenopyranosyl)-2-phenyl-5(4H)-oxazolone (11a).
Compound 11a was obtained as a colorless oil, following general
0
0
0
0
0
0
0
(dd, J6 bꢀ6 a = 11.8 Hz, J6 bꢀ5 = 6.9 Hz, 1H, H-6 b), 4.17 (ddd, J5 ꢀ4
=
=
=
5 ꢀ6 b = 6.9 Hz, J5 ꢀ6 a = 3.2 Hz, 1H, H-50), 4.79 (ddd, J1 ꢀ2 = J1 ꢀ3
0
0
0
0
0
0
0
0
J
J1 ꢀ4 = 2.3 Hz, 1H, H-10), 5.06 (dddd, J4 ꢀ5 = 6.9 Hz, J4 ꢀ1 = J4 ꢀ2
0
0
0
0
0
0
0
0
procedure A: Rf = 0.25 (hexane/AcOEt 75:25); [R]22 = ꢀ24.4 (c =
0
0
0
0
0
0
0
0
0
J4 ꢀ3 = 2.3 Hz, 1H, H-4 ), 6.01 (ddd, J2 ꢀ3 = 10.5 Hz, J2 ꢀ1 = J2 ꢀ4 = 2.3
D
1.0, CHCl3); IR (neat, cmꢀ1) 1816, 1737, 1654, 1580, 1544, 1494, 1451,
1369, 1321, 1291, 1226, 1153, 1106, 1085, 1070, 1031, 1003, 940, 885,
872, 850, 809, 780, 750, 721, 696, 667; 1H NMR (CDCl3, 400 MHz) δ
0
0
0
0
0
0
Hz, 1H, H-20), 6.06 (ddd, J3 ꢀ2 = 10.5 Hz, J3 ꢀ1 = J3 ꢀ4 = 2.3 Hz, 1H,
H-30), 7.49ꢀ7.57 (m, 2H, ArH), 7.59ꢀ7.66 (m, 1H, ArH), 8.01ꢀ8.09
(m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 15.9, 17.0, 20.4, 20.9, 31.8,
62.7 (t), 64.3, 71.2, 72.1, 80.1 (s), 125.5 (s), 125.7, 128.0, 128.1, 128.7, 132.8,
161.6 (s), 170.2 (s), 170.6 (s), 177.6 (s); MS (ESI) m/z 416.1 [M þ H]þ,
438.1 [M þ Na]þ, 852.8 [2M þ Na]þ. Anal. Calcd for C22H25NO7: C,
63.60; H, 6.07; N, 3.37. Found: C, 63.47; H, 6.08; N, 3.41.
1.65 (s, 3H, CH3), 2.02 (s, 3H, AcO), 2.07 (s, 3H, AcO), 4.18 (dd,
0
0
0
0
0
0
0
J
6 aꢀ6 b = 12.0 Hz, J6 aꢀ5 = 3.4 Hz, 1H, H-6 a), 4.23 (dd, J6 bꢀ6 a = 12.0 Hz,
0
0
0
0
0
0
0
J6 bꢀ5 = 6.1 Hz, 1H, H-6 b), 4.38 (ddd, J5 ꢀ4 = 7.0 Hz, J5 ꢀ6 b = 6.2 Hz,
J5 ꢀ6 a = 3.4 Hz, 1H, H-50), 4.48 (ddd, J1 ꢀ2 = J1 ꢀ3 = J1 ꢀ4 = 2.4 Hz, 1H,
0
0
0
0
0
0
0
0
H-10), 5.14 (dddd, J4 ꢀ5 = 7.0 Hz, J4 ꢀ3 = J4 ꢀ1 = 2.4 Hz, J4 ꢀ2 = 1.7 Hz,
(4S)-4-Benzyl-4-(40,60-di-O-acetyl-20-30-dideoxy-R-D-ery-
thro-20-hexenopyranosyl)-2-phenyl-5(4H)-oxazolone (13a).
Compound 13a was obtained as a white solid, following general pro-
0
0
0
0
0
0
0
0
1H, H-40), 5.78 (ddd, J2 ꢀ3 = 10.5 Hz, J2 ꢀ1 = 2.5 Hz, J2 ꢀ4 = 1.7 Hz,
0
0
0
0
0
0
1H, H-20), 5.95 (td, J3 ꢀ2 = 10.5 Hz, J3 ꢀ1 = J3 ꢀ4 = 2.4 Hz, 1H, H-3 ),
7.46ꢀ7.54 (m, 2H, ArH), 7.56ꢀ7.63 (m, 1H, ArH), 7.98ꢀ8.05 (m, 2H,
ArH); 13C NMR (CDCl3,100 MHz) δ 21.0, 21.1, 21.4, 63.3 (t), 64.8,
71.5, 72.9 (s), 75.8, 126.1 (s), 126.2, 128.5, 128.6, 129.2, 133.3, 160.7 (s),
170.7 (s), 171.2 (s), 178.9 (s); MS (ESI) m/z 388.0 [M þ H]þ, 410.1
[M þ Na]þ, 796.6 [2M þ Na]þ. Anal. Calcd. for C20H21NO7: C, 62.01;
H, 5.46; N, 3.62. Found: C, 62.19; H, 5.47; N, 3.61
0
0
0
0
0
0
0
cedure A: Rf = 0.29 (hexane/AcOEt 75:25); mp 37ꢀ38 °C; [R]22
=
D
ꢀ172.6 (c = 1.0, CHCl3); IR (neat, cmꢀ1) 1812, 1736, 1653, 1600, 1580,
1494, 1451, 1430, 1369, 1321, 1291, 1225, 1195, 1141, 1098, 1046, 1025,
1
976, 892, 873, 835, 798, 779, 750, 698, 667; H NMR (CDCl3, 400
MHz) δ 2.08 (s, 6H, AcO), 3.28 (d, J = 13.5 Hz, 1H, CH2Ph), 3.55 (d, J =
13.5 Hz, 1H, CH2Ph), 4.25ꢀ4.29 (m, 2H, H-60a, H-60b), 4.58 (ddd,
J5 ꢀ4 = 7.8, J5 ꢀ6 b = 5.3 Hz, J5 ꢀ6 a = 4.2 Hz, 1H, H-50), 4.64 (ddd,
0
0
0
0
0
0
(4R) Epimer 11b. Compound 11b was obtained as an oil, following
general procedure A: Rf = 0.21 (hexane/AcOEt 75:25); [R]22D = ꢀ8.9
(c =1.0, CHCl3); IR (neat, cmꢀ1) 1823, 1733, 1651, 1580, 1494, 1451,
1370, 1322, 1291, 1224, 1093, 1044, 1005, 883, 812, 781, 718, 699; 1H
NMR (CDCl3, 400 MHz) δ 1.56 (s, 3H, CH3), 1.82 (s, 3H, AcO), 2.02
0
0
0
0
0
0
0
0
J1 ꢀ2 = J1 ꢀ3 = J1 ꢀ4 = 2.3 Hz, 1H, H-1 ), 5.16ꢀ5.22 (m, 1H, H-4 ), 5.75
(ddd, J3 ꢀ2 = 10.4 Hz, J3 ꢀ1 = 2.4 Hz, J3 ꢀ4 = 1.6 Hz, 1H, H-30), 5.93
0
0
0
0
0
0
0
0
0
0
0
0
0
(td, J2 ꢀ3 = 10.4 Hz, J2 ꢀ1 = J2 ꢀ4 = 2.3 Hz, 1H, H-2 ), 7.08ꢀ7.19 (m,
5H, ArH), 7.38ꢀ7.46 (m, 2H, ArH), 7.49ꢀ7.57 (m, 1H, ArH), 7.81ꢀ
7.88 (m, 2H, ArH); 13C NMR (CDCl3,100 MHz) δ: 21.2, 21.4, 40.8 (t),
63.6 (t), 65.1, 71.6, 75.7, 78.1 (s), 125.8 (s), 126.2, 127.7, 128.3, 128.6,
129.0, 129.1, 130.6, 133.1, 134.3 (s), 160.6 (s), 170.7 (s), 171.2 (s),
177.8 (s); MS (ESI) m/z 464.0 [M þ H]þ, 486.1 [M þ Na]þ, 948.7
[2M þ Na]þ. Anal. Calcd. for C26H25NO7: C, 67.38; H, 5.44; N, 3.02.
Found: C, 67.51; H, 5.33; N, 3.13
(s, 3H, AcO), 3.96ꢀ4.08 (m, 3H, H-50,H-60a, H-60b), 4.59 (ddd, J1 ꢀ2
=
0
0
0
0
0
0
0
0
J1 ꢀ3 = J1 ꢀ4 = 2.2 Hz, 1H, H-1 ), 5.00ꢀ5.06 (m, 1H, H-4 ), 6.06 (ddd,
J2 ꢀ3 = 10.5 Hz, J2 ꢀ1 = J2 ꢀ4 = 2.2 Hz, 1H, H-20), 6.13 (ddd, J3 ꢀ2
=
0
0
0
0
0
0
0
0
10.5 Hz, J3 ꢀ1 = J3 ꢀ4 = 2.2 Hz, 1H, H-30), 7.47ꢀ7.54 (m, 2H, ArH),
7.57ꢀ7.64 (m, 1H, ArH), 8.00ꢀ8.05 (m, 2H, ArH); 13C NMR
(CDCl3,100 MHz) δ 19.8, 20.3, 20.8, 62.7 (t), 64.2, 71.4, 73.4 (s),
74.7, 125.3, 125.6 (s), 128.0, 128.1, 128.7, 132.9, 161.5 (s), 170.2 (s),
170.6 (s), 178.9 (s); MS (ESI) m/z 388.2 [M þ H]þ, 410.2 [M þ Na]þ,
796.9 [2M þ Na]þ. Anal. Calcd. for C20H21NO7: C, 62.01; H, 5.46; N,
3.62. Found: C, 62.13; H, 5.45; N, 3.71.
0
0
0
0
(4R) Epimer 13b. Compound 13b was obtained as a white solid
following general procedure A: Rf = 0.24 (hexane/AcOEt 7:3); mp
48ꢀ50 °C; [R]22D = ꢀ196.0 (c = 1.0, CHCl3); IR (neat, cmꢀ1) 1817,
1735, 1650, 1579, 1494, 1451, 1369, 1321, 1291, 1225, 1091, 1045, 994,
1
(4S)-4-Isopropyl-4-(40,60-di-O-acetyl-20-30-dideoxy-R-D-ery-
thro-20-hexenopyranosyl)-2-phenyl-5(4H)-oxazolone (12a).
Compound 12a was obtained as a white solid, following general pro-
670; H NMR (CDCl3, 400 MHz) δ 1.84 (s, 3H, AcO), 2.04 (s, 3H,
AcO), 3.24 (d, J = 13.2 Hz, 1H, CH2Ph), 3.30 (d, J = 13.2 Hz, 1H,
CH2Ph), 4.03 (dd, J6 aꢀ6 b = 11.9 Hz, J6 aꢀ5 = 3.2 Hz, 1H, H-60a) 4.08
0
0
0
0
cedure A: Rf = 0.35 (hexane/AcOEt 75:25); mp 100ꢀ101 °C; [R]22
=
0
0
0
0
0
0
0
(dd, J6 bꢀ6 a = 11.9 Hz, J6 bꢀ5 = 6.9 Hz, 1H, H-6 b), 4.17 (ddd, J5 ꢀ4
=
=
D
ꢀ70.7 (c = 1.0, CHCl3); IR (neat, cmꢀ1) 1813, 1739, 1654, 1602, 1581,
1513, 1494, 1472, 1451, 1423, 1369, 1320, 1291, 1225, 1196, 1176, 1157,
1092, 1042, 1020, 975, 951, 928, 880, 834, 810, 779, 723, 697, 671; 1HNMR
(CDCl3, 400 MHz) δ 0.99 (d, J = 6.9 Hz, 3H, CH3iPr), 1.11 (d, J = 6.8 Hz,
3H, CH3iPr,), 2.00 (s, 3H, AcO), 2.07 (s, 3H, AcO), 2.51 (septuplet, J =
J5 ꢀ6 b = 6.9, J5 ꢀ6 a = 3.2 Hz, 1H, H-50), 4.74 (ddd, J1 ꢀ2 = J1 ꢀ3 = J1 ꢀ4
0
0
0
0
0
0
0
0
0
0
2.2 Hz, 1H, H-10), 5.08 (dddd, J4 ꢀ5 = 6.9 Hz, J4 ꢀ2 = J4 ꢀ1 = 2.2 Hz,
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
J4 ꢀ3 = 1.5 Hz, 1H, H-4 ), 6.10 (ddd, J2 ꢀ3 =10.5Hz,J2 ꢀ1 =J2 ꢀ4 =2.2Hz,
1H, H-20), 6.16 (ddd, J3 ꢀ2 = 10.5 Hz, J3 ꢀ1 = 2.1 Hz, J3 ꢀ4 = 1.5 Hz,
1H, H-30), 7.12ꢀ7.19 (m, 5H, ArH), 7.40ꢀ7.48 (m, 2H, ArH), 7.52ꢀ
7.58 (m, 1H, ArH), 7.84ꢀ7.89 (m, 2H, ArH); 13C NMR (CDCl3,100
MHz) δ 20.4, 20.8, 39.3 (t), 62.8 (t), 64.3, 71.3, 74.3, 78.8 (s), 125.4 (s),
125.5, 127.3, 127.9, 128.2, 128.3, 128.6, 130.1, 132.8, 133.2 (s), 161.6
(s), 170.2 (s), 170.6 (s), 177.4 (s); MS (ESI) m/z 464.0 [M þ H]þ,
486.1 [M þ Na]þ, 948.7 [2M þ Na]þ. Anal. Calcd. for C26H25NO7: C,
67.38; H, 5.44; N, 3.02. Found: C, 67.24; H, 5.37; N, 3.19
0
0
0
0
0
0
0
0
0
0
6.9 Hz, 1H, CHiPr), 4.17 (dd, J6 aꢀ6 b = 11.9 Hz, J6 aꢀ5 = 3.5 Hz, 1H,
H-60a), 4.22 (dd, J6 bꢀ6 a = 11.9 Hz, J6 bꢀ5 = 6.0 Hz, 1H, H-60b), 4.37
0
0
0
0
(ddd, J5 ꢀ4 = 7.1 Hz, J5 ꢀ6 b = 6.0 Hz, J5 ꢀ6 a = 3.5 Hz, 1H, H-500), 4.73
0
0
0
0
0
0 0
0
0
0
0
0
0
(ddd, J1 ꢀ2 = J1 ꢀ3 = J1 ꢀ4 = 2.4 Hz, 1H, H-1 ), 5.13 (m, 1H, H-4 ), 5.76
(ddd, J3 -2 = 10.5 Hz, J3 ꢀ1 = 2.4 Hz, J3 ꢀ4 = 1.6 Hz, 1H, H-30), 5.94
0
0
0
0
0
0
0
0
0
0
0
0
0
(ddd, J2 ꢀ3 = 10.5 Hz, J2 ꢀ1 = J2 ꢀ4 = 2.4 Hz, 1H, H-2 ), 7.46ꢀ7.54 (m,
2H, ArH), 7.55ꢀ7.62 (m, 1H, ArH), 7.98ꢀ8.07 (m, 2H, ArH); 13C
NMR (CDCl3, 100 MHz) δ 16.9, 17.4, 21.1, 21.5, 32.7, 63.4 (t), 64.9,
71.5, 73.4, 79.8 (s), 126.1 (s), 126.5, 128.4, 128.5, 129.2, 133.2, 160.9 (s),
170.8 (s), 171.2 (s), 177.9 (s); MS (ESI) m/z 416.1 [M þ H]þ, 438.1
[M þ Na]þ, 852.7 [2M þ Na]þ. Anal. Calcd for C22H25NO7: C, 63.60;
H, 6.07; N, 3.37. Found: C, 63.72; H, 6.06; N, 3.52
General Procedure B: Synthesis of Compounds 14a, 14b,
15, and 16. Glycosylated azlactones 11aꢀ13a and 11b (0.73 mmol)
were dissolved, under nitrogen atmosphere, in acetone (7 mL) and
water (50 μL) and added with NMO (1.09 mmol) and a 2.5% w/v
solution of OsO4 in t-BuOH (0.07 mmol). The reaction mixture was
stirred overnight at room temperature. After reaction completion by
5254
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The Journal of Organic Chemistry
ARTICLE
TLC analysis, the solvent was evaporated in vacuo, and the crude
mixture was purified by flash chromatography to obtain 14a (94%), 14b
(70%), 15 (85%), and 16 (78%).
(AcOEt/hexane 60:40); mp 155ꢀ157 °C; [R]22D = ꢀ101 (c = 1.0, Py);
IR (neat, cmꢀ1) 3320, 1794, 1739, 1720, 1653, 1595, 1579, 1531, 1494,
1458, 1364, 1225, 1144, 1106, 1030, 980, 935, 881, 799, 715, 698; 1H
NMR (DMSO-d6, 400 MHz) δ 1.96 (s, 3H, AcO), 2.14 (s, 3H, AcO),
2-(40,60-Di-O-acetyl-R-D-mannopyranosyl)-2-benzamido-
(2S)-propionic Acid 10,20-Lactone (14a). Compound 14a was
obtained as a white solid, following general procedure B: Rf = 0.35
3.26 (d, J = 13.6 Hz, 1H, CH2Ph), 3.38 (d, J = 13.6 Hz, 1H, CH2Ph), 4.02
0
0
0
0
0
0
0
(dd, J6 aꢀ6 b = 12.2 Hz, J6 aꢀ5 = 3.8 Hz, 1H, H-6 a), 4.05 (d, J1 ꢀ2 = 10.0
Hz, 1H, H-10), 4.13ꢀ4.20 (m, 2H, H-30,H-50), 4.31ꢀ4.40 (m, 2H, H-20,
H-60b), 4.75 (app d, J = 3.6 Hz, 1H, H-40), 5.93 (s, 1H, OH, exchanges
with D2O), 7.15ꢀ7.21 (m, 2H, ArH), 7.24ꢀ7.31 (m, 3H, ArH), 7.48ꢀ
7.55 (m, 2H, ArH), 7.56ꢀ7.63 (m, 1H, ArH), 7.87ꢀ7.94 (m, 2H, ArH),
8.64 (s, 1H, NH); 13C NMR (DMSO-d6, 100 MHz) δ 21.5, 21.6, 40.5
(t), 61.6 (s), 61.8 (t), 64.5, 67.8, 71.9, 75.6, 76.8, 128.1, 128.6, 129.2, 129.3,
131.5, 132.7, 134.0 (s), 135.8 (s), 167.2 (s), 170.0 (s), 171.0 (s), 172.5 (s);
MS (ESI) m/z 498.1 [M þ H]þ, 520.1 [M þ Na]þ, 1017.0 [2M þ Na]þ.
Anal. Calcd for C26H27NO9: C, 62.77; H, 5.47; N, 2.82. Found: C, 62.83;
H, 5.46; N, 2.82.
(AcOEt/hexane 60:40); mp 90ꢀ95 °C; [R]22 = ꢀ78.6 (c = 1.5,
D
CHCl3); IR (neat, cmꢀ1) 3316, 1791, 1738, 1644, 1601, 1580, 1536,
1491, 1447, 1369, 1220, 1181, 1105.8, 1088, 1027, 970, 940, 905, 883,
851, 802, 703, 661; 1H NMR (CDCl3, 400 MHz) δ 1.65 (s, 3H, CH3),
2.04 (s, 3H, AcO), 2.11 (s, 3H, AcO), 2.93ꢀ3.14 (br s, 1H, OH,
0
0
0
0
exchanges with D2O), 4.02 (dd, J6 aꢀ6 b = 12.3 Hz, J6 aꢀ5 = 4.5 Hz, 1H,
H-60a), 4.20 (dd, J5 ꢀ6 b = 9.7 Hz, J5 ꢀ6 a = 4.5 Hz,01H, H-50), 4.28 (d,
0
0
0
0
0
0
0
0
0
J1 ꢀ2 = 10.0 Hz, 1H, H-1 ), 4.43ꢀ4.50 (m, 1H, H-3 ), 4.58 (dd, J2 ꢀ1
=
10.0 Hz, J2 ꢀ3 = 2.4 Hz, 1H, H-20), 4.97 (d, J4 ꢀ3 = 3.3 Hz, 1H, H-40),
0
0
0
5.03 (dd, J6 bꢀ6 a = 12.3 Hz, J6 bꢀ5 = 9.7 Hz, 1H, H-60b), 6.20 (s, 1H,
NH), 7.40ꢀ7.49 (m, 2H, ArH), 7.50ꢀ7.57 (m, 1H, ArH), 7.74ꢀ7.83
(m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 21.3, 21.4, 23.0, 57.4
(s), 60.9 (t), 65.9, 71.3, 72.2, 75.8, 77.7, 127.7, 129.1, 132.6, 133.5 (s),
167.3 (s), 170.2 (s), 171.2 (s), 173.0 (s); MS (ESI) m/z 422.0 [M þ H]þ
444.1 [M þ Na]þ, 864.9. [2M þ Na]þ. Anal. Calcd. for C20H23NO9: C,
57.00; H, 5.50; N, 3.32. Found: C, 57.23; H, 5.47; N, 3.42
0
0
0
0
General Procedure C: Synthesis of Compounds 17ꢀ19. A
solution of NaOMe, prepared from Na (2.44 mmol) in dry MeOH
(6.9 mL), was added, under nitrogen atmosphere, to a solution of com-
pounds 14ꢀ16 (0.61 mmol) in dry MeOH (9.4 mL). After a few minutes,
TLC (AcOEt/MeOH 9:1) showed no residual starting material. HCl (1 N,
3 mL) was added to the reaction mixture. MeOH was removed under
reducedpressure, and the residue was extracted with AcOEt. The organic
layers were collected, dried with anhydrous Na2SO4, and concentrated
in vacuo. The crude mixture was purified by flash chromatography (ethyl
acetate/MeOH 90:10) yielding 17 (92%), 18 (88%), and 19 (73%).
2-(r-D-C-Mannopyranosyl)-(S)-N-benzoylalanine Methyl
Ester (17). Compound 17 was obtained as a white solid, following
general procedure C: Rf = 0.30 (AcOEt/MeOH 90:10); mp 79ꢀ83 °C;
[R]22D = þ68.6 (c = 1.0, CH3OH); IR (neat, cmꢀ1) 3332, 2947, 1728,
1640, 1602, 1578, 1531, 1487, 1447, 1267, 1043, 690; 1H NMR (D2O,
400 MHz) δ 1.54 (s, 3H, CH3), 3.23 (s, 0.55 H, NH, partially ex0changes
2-(40,60-Di-O-acetyl-R-D-mannopyranosyl)-2-benzamido-
(2R)-propionic Acid 10,20-Lactone (14b). Compound 14b was
obtained as a white solid, following general procedure B: Rf = 0.23
(AcOEt/hexane 60:40); mp 248 °C; [R]22D = þ28.7 (c = 0.81, DMSO);
IR (neat, cmꢀ1) 3341, 1783, 1722, 1707, 1661, 1517, 1283, 1269, 1244,
1116, 1072, 1044, 910, 807, 733; 1H NMR (DMSO-d6, 400 MHz) δ 1.45
0
0
(s, 3H, CH3), 1.88 (s, 3H, AcO), 2.09 (s, 3H, AcO), 4.02 (dd, J6 aꢀ6 b
=
=
0
0
0
0
0
0
0
11.8 Hz, J6 aꢀ5 = 4.7 Hz, 1H, H-6 a), 4.10 (dd, J5 ꢀ6 b = 9.1 Hz, J5 ꢀ6 a
4.7 Hz, 1H, H-50), 4.26 (br t, J3 ꢀ2 = J3 ꢀ40 = 2.8 Hz, 1H, H-3 ), 4.28 (dd,
0
0
0
0
0
0
0
0
0
0
0
J2 ꢀ1 = 10.0 Hz, J2 ꢀ3 = 02.4 Hz, 1H, H-2 ), 4.64 (dd, J6 bꢀ6 a = 11.8 Hz,
0
0
0
0
0
with D2O), 3.60 (dd, J6 aꢀ6 b = 12.1 Hz, J6 aꢀ5 = 3.6 Hz, 1H, H-6 a), 3.67
0
0
0
0
J6 bꢀ5 = 9.1 Hz, 1H, H-6 b), 4.81 (d, J4 ꢀ3 = 2.9 Hz, 1H, H-4 ), 5.21 (d,
0
J1 ꢀ2 = 10.0 Hz, 1H, H-10), 6.27 (bs, 1H, OH, exchanges with D2O),
7.48 (app t, J = 7.4 Hz, 2H, ArH), 7.56 (app t, J = 7.3 Hz, 1H, ArH), 7.86
(app d, J = 7.3 Hz, 2H, ArH), 8.67 (s, 1H, NH, partially exchanges with
D2O); 13C NMR (DMSO-d6, 100 MHz) δ: 15.0, 21.3, 21.7, 59.8 (s),
61.2 (t), 65.6, 67.6, 72.2, 75.5, 76.9, 128.5, 129.0, 132.4, 134.5 (s), 166.9
(s), 170.2 (s), 170.6 (s), 174.1 (s); MS (ESI) m/z 422.0 [M þ H]þ
444.1 [M þ Na]þ, 864.9 [2M þ Na]þ. Anal. Calcd for C20H23NO9: C,
57.00; H, 5.50; N, 3.32. Found: C, 57.11; H, 5.43; N, 3.42
0
0
0
0
(s, 3H, COOCH3), 3.71 (dd, J4 ꢀ3 = 5.1 Hz, J4 ꢀ5 = 3.5 Hz, 1H, H-4 ),
0
0
3.73ꢀ3.78 (m, 1H, H-50), 3.81(dd, J3 ꢀ2 = 3.3 Hz, J3 ꢀ4 = 05.1 Hz, 1H,
0
0
0
0
H-30), 3.89 (dd, J6 bꢀ6 a = 12.1 Hz, J6 bꢀ5 = 8.4 Hz, 1H, H-6 b), 4.12 (d,
0
0
0
0
0
0
0
0
0
0
0
J1 ꢀ2 = 8.3 Hz, 1H, H-1 ), 4.16 (dd, J2 ꢀ1 = 8.3 Hz, J2 ꢀ3 = 3.3 Hz, 1H,
H-20), 7.38ꢀ7.45 (m, 2H, ArH), 7.49ꢀ7.55 (m, 1H, ArH), 7.60ꢀ7.65
(m, 2H, ArH); 13C NMR (D2O, 100 MHz) δ 17.3, 53.5, 59.4 (t), 62.3
(s), 66.2, 68.7, 71.1, 73.3, 79.4, 127.3, 129.3, 132.7 (s), 133.0, 169.3 (s),
174.8 (s); MS (ESI) m/z 370.1 [M þ H]þ, 392.2 [M þ Na]þ, 760.9
[2M þ Na]þ. Anal. Calcd for C17H23NO8: C, 55.28; H, 6.28; N, 3.79.
Found: C, 55.17; H, 6.31; N, 3.90.
2-(40,60-Di-O-acetyl-R-D-mannopyranosyl)-2-benzamido-
(2S)-3-methylbutanoic Acid 10,20-Lactone (15). Compound 15
was obtained as a white solid, following general procedure B: Rf = 0.56
(AcOEt/hexane 60:40); mp 47ꢀ50 °C; [R]22D = ꢀ50.6 (c = 1.0, CDCl3);
IR (neat, cmꢀ1) 3365, 1790, 1736, 1655, 1601, 1580, 1516, 1487, 1449,
1370, 1225, 1163, 1126, 1094, 1068, 1025, 977, 935, 906, 864, 800, 711,
694; 1H NMR (CDCl3, 400 MHz) δ 1.10 (d, J = 6.8 Hz, 3H, CH3iPr),
1.19 (d, J = 6.8 Hz, 3H, CH3iPr), 2.04 (s, 3H, AcO), 2.09 (s, 3H, AcO),
2.48 (septuplet, J = 6.8 Hz, 1H, CHiPr), 2.70ꢀ2.85 (br s, 1H, OH,
2-(r-D-C-Mannopyranosyl)-(S)-N-benzoylvaline Methyl Ester
(18). Compound 18 was prepared following general procedure C as a
white amorphous solid: Rf = 0.41 (AcOEt/MeOH 90:10); mp 72ꢀ76 °C;
[R]22D = ꢀ11.3 (c = 1.0, CHCl3); IR (neat, cmꢀ1) 3333, 2933, 1726,
1645, 1602, 1578, 1525, 1488, 1435, 1235, 1040, 797, 690; 1H NMR (D2O,
400 MHz) δ 0.90 (d, J = 6.8 Hz, 3H, CH3iPr), 1.01 (d, J = 6.8 Hz, 3H,
0
CH3iPr), 2.63 (septuplet, J = 6.8 Hz, 1H, CHiPr), 3.47 (dd, J3 ꢀ4 = 8.60Hz,
0
0
0
00
0
0
0
0
0
0
J3 ꢀ2 = 3.4 Hz, 1H, H-3 ), 3.53ꢀ3.71 (m, 4H, H-4 , H-5 , H-6 a, H-6 b),
exchanges with D2O), 4.22 (dd, J6 aꢀ6 b = 13.8 Hz, J6 aꢀ5 = 4.9 Hz, 1H,
H-60a), 4.23 (dd, J5 ꢀ6 b = 11.3 Hz, J5 ꢀ6 a = 4.9 Hz, 1H, H-50), 4.43 (d,
0
0
0
0
0
0
0
0
3.68 (s, 3H, COOCH3), 4.41 (dd, J2 ꢀ3 = 3.4 Hz, J2 ꢀ1 = 2.4 Hz, 1H,
H-20), 4.58 (d, J1 ꢀ2 = 2.4 Hz, 1H, H-1 ), 7.37ꢀ7.45 (m, 2H, ArH), 7.48ꢀ
7.55 (m, 1H, ArH), 7.60ꢀ7.65 (m, 2H, ArH); 13CNMR(CDCl3,100MHz)
δ: 18.3, 18.6, 32.2, 53.0, 61.8 (t), 67.9, 68.4, 69.7 (s), 72.1, 74.7, 79.1, 127.6,
129.1, 132.3, 134.9 (s), 168.6 (s), 171.9 (s); MS (ESI) m/z398.2 [M þ H]þ,
420.3 [M þ Na]þ, 817.0 [2M þ Na]þ. Anal. Calcd for C19H27NO8: C,
57.42; H, 6.85; N, 3.52. Found: C, 57.21; H, 6.82; N, 3.52.
0
0
0
0
0
0
0
0
0
J1 ꢀ2 = 9.8 Hz, 1H, H-1 ), 4.46ꢀ4.50 (m, 1H, H-3 ), 4.55 (dd, J2 ꢀ1
=
=
0
0
0
0
0
0
0
9.8 Hz, J2 -3 = 2.4 Hz, 1H, H-2 ), 4.85 (ddd, J6 bꢀ6 a = 13.9 Hz, J6 bꢀ5
0
0
0
0
0
0
J6 bꢀ3 =11.3Hz, 1H,H-6 b), 4.98 (d, J4 ꢀ3 = 3.2 Hz, 1H, H-4 ), 6.37 (s, 1H,
NH), 7.44ꢀ7.52 (m, 2H, ArH), 7.53ꢀ7.59 (m, 1H, ArH), 7.78ꢀ7.84
(m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ: 17.0, 18.2, 21.2, 21.3,
33.4, 60.9 (t), 63.0 (s), 66.1, 67.9, 71.1, 75.1, 77.1, 127.6, 129.2, 132.6, 133.8
(s),167.4(s),170.0(s),171.1(s),171.5(s);MS(ESI) m/z450.1 [M þ H]þ
472.2 [M þ Na]þ, 921.0 [2M þ Na]þ. Anal. Calcd for C22H27NO9: C,
58.79; H, 6.06; N, 3.12. Found: C, 58.53; H, 6.15; N, 3.23
2-(r-D-C-Mannopyranosyl)-(S)-N-benzoylphenylalanine
Methyl Ester (19). Compound 19 was prepared following general
procedure C as a white amorphous solid: Rf = 0.36 (AcOEt/MeOH
2-(40,60-Di-O-acetyl-R-D-mannopyranosyl)-2-benzamido-
(2S)-3-phenylpropanoic Acid 10,20-Lactone (16). Compound 16
was obtained as a white solid, following general procedure B: Rf = 0.44
90:10); mp 163ꢀ165 °C; [R]22 = ꢀ13.2 (c = 1.0, CHCl3); IR
D
(neat, cmꢀ1) 3320, 3171, 1732, 1639, 1602, 1578, 1517, 1487, 1451,
1437, 1221, 1032, 907, 700; 1H NMR (D2O, 400 MHz) δ 3.27 (d, J =
5255
dx.doi.org/10.1021/jo2002962 |J. Org. Chem. 2011, 76, 5247–5257

The Journal of Organic Chemistry
ARTICLE
0
0
0
0
0
13.5 Hz, 1H, CH2Ph), 3.53 (dd, J3 ꢀ4 = 7.7 Hz, J3 ꢀ2 = 3.4, 1H, H-3 ),
3.59ꢀ3.64 (m, 1H, H-40), 3.60 (d, J = 13.5 Hz, 1H, CH2Ph), 3.66 (s, 3H,
COOCH3), 3.68ꢀ3.73 (m, 2H, H-60a þ H-60b), 3.74ꢀ3.80 (m, 1H,
filtered, and the aqueous phase was first carefully washed with DCM to
eliminate all traces of benzoic acid and then evaporated in vacuo. The
crude was dried over P2O5 to obtain R-D-C-mannosyl-(S)-aminoacids
20 (91%), 21 (90%), and 22 (85%) as hydrochloride salt.
H-50), 4.24 (dd, J1 ꢀ2 = 4.3 Hz, 1H, H-10), 4.31 (br t, J = 3.7 Hz, 1H,
H-20), 7.11ꢀ7.24 (m, 5H, ArH), 7.36ꢀ7.44 (app t, J = 7.7 Hz, 2H, ArH),
7.48ꢀ7.55 (app t, J = 7.7 Hz, 1H, ArH), 7.59 (app d, J = 8.0 Hz, 2H,
ArH); 13C NMR (CDCl3, 100 MHz) δ 37.7 (t), 53.5, 61.9 (t), 67.5 (s),
67.6, 68.1, 72.1, 77.2, 78.4, 127.4, 127.5, 128.6, 129.2, 130.7, 132.2, 135.0
(s), 135.8 (s), 168.4 (s), 172.8 (s); MS (ESI) m/z 446.2 [M þ H]þ,
468.4 [M þ Na]þ, 913.2 [2M þ Na]þ. Anal. Calcd for C23H27NO8: C,
62.01; H, 6.11; N, 3.14, Found: C, 62.19; H, 6.27; N, 3.18
0
0
2-(r-D-C-Mannopyranosyl)-(S)-alanine Hydrochloride (20).
Compound 20 was prepared following general procedure D as a white
hygroscopic solid. Experimental data are in accordance with ref 20b.
Preparation by acid hydrolysis of 14: A suspension of lactone 14 (0.10
mmol) in 6 N HCl (0.7 mL) in a screw-cap vial was heated at 80 °C for
6 h. The suspended solid dissolved after ca. 30 min. The pale yellow
solution was cooled to room temperature and the precipitated benzoic
acid extracted with methylene chloride. The aqueous phase was evapo-
rated and desiccated under vacuum over P2O5 to a constant weight to
afford 20 (93%) as hydrochloride salts.
2-(r-D-C-Mannopyranosyl)-(S)-valine Hydrochloride (21).
Compound 21 was prepared following general procedure D as a white
hygroscopic solid: mp dec >230 °C; [R]22D = þ15.18 (c = 0.5, D2O); IR
(neat, cmꢀ1) 3379, 2488, 1727, 1637, 1411, 1203, 1050, 1014; 1H NMR
(D2O, 400 MHz) δ 0.93 (d, J = 6.9 Hz, 3H, CH3iPr), 0.96 (d, J = 6.9 Hz,
General Procedure for the Synthesis of Lithium Salts of
Compounds 17ꢀ19 (L17ꢀL19). A solution of methyl esters
17ꢀ19 (0.17 mmol) in H2O (1.7 mL, 0.1 M) was added with LiOH
3
H2O (0.70 mmol). After 3 h, the reaction was complete. The solvent
was removed under reduced pressure to obtain quantitatively the
corresponding lithium salts L17ꢀL19.
2-r-D-Mannopyranosyl-2-benzamido-(2S)-propionic acid
lithium salt (L17): white solid; mp 108 °C; [R]22D = 36.64 (c = 0.5,
D2O); IR (neat, cmꢀ1) 3565, 1514, 1473, 1419, 968, 861, 690; 1H NMR
(D2O, 400 MHz) δ 1.47 (s, 3H, CH3), 1.78 (s, 0.4H, NH, partially
0
0
3H, CH3iPr), 2.44 (septuplet, J = 6.9 Hz, 1H, CHiPr), 3.58 (dd, J6 aꢀ6 b
0
0
0
0
0
0
0
= 12.4 Hz, J6 aꢀ5 = 3.0 Hz, 1H, H-6 a), 3.66 (dd, J4 ꢀ3 = 6.1 Hz, J4 ꢀ5
=
4.0 Hz, 1H, H-40), 3.71ꢀ3.78 (m, 1H, H-50), 3.81 (dd, J3 ꢀ4 = 6.1 Hz,
0
0
0
0
0
0
exchanges with D2O), 3.56 (dd, J6 aꢀ6 b = 12.1 Hz, J6 aꢀ5 = 3.0 Hz, 1H,
0
H-60a), 3.59 (dd, J4 ꢀ3 = 6.4 Hz, J4 ꢀ5 = 5.3 Hz, 1H, H-4 ), 3.66ꢀ3.73
0
0
0
0
0
0
0
0
0
0
0
J3 ꢀ2 = 3.7 Hz, 1H, H-3 ), 3.91 (dd, J6 bꢀ6 a = 12.4 Hz, J6 bꢀ5 = 8.6 Hz,
0
0
0
0
1H, H-60b), 4.13 (d, J1 ꢀ2 = 7.8 Hz, 1H, H-1 ), 4.24 (dd, J2 ꢀ1 = 7.8 Hz,
0
(m, 1H, H-50), 3.74 (dd, J3 ꢀ4 = 6.4 Hz, J3 ꢀ2 =03.8 Hz, 1H, H-3 ) 3.79
0
0
0
0
0
J2 ꢀ3 = 3.6 Hz, 1H, H-20); 13C NMR (D2O, 100 MHz) δ 16.3, 17.1,
30.8, 59.6 (t), 65.4, 68.6, 69.7 (s), 70.8, 71.9, 80.4, 171.5 (s); HRMS
(ESI) calcd for C11H22O7N 280.13908, found 280.13919.
0
0
0
0
0
0
0
0
(dd, J6 bꢀ6 a = 12.1 Hz, J6 bꢀ5 = 7.7 Hz, 1H, H-6 b), 4.10 (d, J1 ꢀ2 = 6.7
Hz, 1H, H-10), 4.19 (dd, J2 ꢀ1 = 6.7 Hz, J2 ꢀ3 = 3.8 Hz, 1H, H-2 ) 7.36ꢀ
7.42 (m, 2H, ArH), 7.44ꢀ7.50 (m, 1H, ArH), 7.60ꢀ7. 67 (m, 2H, ArH);
13C NMR (D2O, 100 MHz) δ 18.6, 60.7 (t), 63.7 (s), 67.4, 69.2, 71.9,
75.7, 79.0, 127.2, 129.1, 132.3, 134.1 (s), 168.7 (s), 179.1 (s), MS (ESI)
(negative ion mode) m/z 354.2 [M ꢀ Li]ꢀ. Anal. Calcd for C16H20Li-
NO8: C, 53.19; H, 5.58; N, 3.88. Found: C, 53.29; H, 5.43; N, 3.81.
2-r-D-Mannopyranosyl-2-benzamido-(2S)-3-methylbuta-
0
0
0
0
0
Correct elemental analysis could not be obtained because of the
hygroscopic character of the compound.
2-(r-D-C-Mannopyranosyl)-(S)-phenylalanine Hydrochloride
(22). Compound 22 was prepared following general procedure D as a
white hygroscopic solid: mp >205 °C dec; [R]22 = þ42.78 (c = 0.5,
D
D2O); IR (neat, cmꢀ1) 3368, 2489, 1635, 1416, 1052, 1010; 1H NMR
noic Acid Lithium Salt (L18): white solid; mp 105 °C; [R]22
=
D
ꢀ99.5 (c = 0.52, CH3OH); IR (neat, cmꢀ1) 3331, 1600, 1576, 1514,
(D2O, 400 MHz) δ 3.18 (d, J = 14.5 Hz, 1H, CH2Ph), 3.47 (d, J = 14.5
1
0
0
0
0
Hz, 1H, CH2Ph), 3.60 (dd, J6 aꢀ6 b = 12.4 Hz, J6 aꢀ5 = 3.2 Hz, 1H,
1483, 1384; H NMR (D2O, 400 MHz) δ 0.87 (d, J = 6.8 Hz, 3H,
H-60a), 3.71 (dd, J4 ꢀ3 = 5.4 Hz, J4 ꢀ5 = 3.7 Hz, 1H, H-4 ), 3.79ꢀ3.86
0
0
0
0
0
CH3iPr), 0.91 (d, J = 6.8 Hz, 3H, CH3iPr), 2.66 (septuplet, J = 6.8 Hz,
(m, 1H, H-50), 3.88 (dd, J3 ꢀ4 = 5.4 Hz, J3 ꢀ2 = 3.6 Hz,0 1H, H-30),
0
0
0
0
0
0
1H, CHiPr), 3.49ꢀ3.59 (m, 3H), 3.61ꢀ3.70 (m, 2H), 4.33 (dd, J2 ꢀ1
=
3.92ꢀ4.01 (m, 1H, H-60b), 4.10 (d, J1 ꢀ2 = 8.3 Hz, 1H, H-1 ), 4.26 (dd,
0
0
0
0 0
0
0
0
0
J2 ꢀ3 = 4.0 Hz, 1H, H-2 ), 4.76 (d, J1 ꢀ2 = 4.0 Hz, 1H, H-1 ), 7.36ꢀ7.43
(m, 2H, ArH), 7.44ꢀ7.51 (m, 1H, ArH), 7.63ꢀ7. 69 (m, 2H, ArH); 13C
NMR (D2O, 100 MHz) δ 17.9, 18.0, 30.6, 61.8 (t), 69.1, 69.2, 70.8 (s),
72.0, 77.1, 78.9, 127.1, 129.1, 132.3, 135.1 (s), 169.6 (s), 175.7 (s); MS
(ESI) (negative ion mode) m/z 382.2 [M ꢀ Li]ꢀ. Anal. Calcd for C18H24-
LiNO8: C, 55.53; H, 6.21; N, 3.60. Found: C, 55.34; H, 6.23; N, 3.6.
2-r-D-Mannopyranosyl-2-benzamido-(2S)-3-phenylpropa-
0
0
0
0
J2 ꢀ1 = 8.3 Hz, J2 ꢀ3 = 3.6 Hz, 1H, H-2 ), 7.17ꢀ7.24 (m, 2H), 7.27ꢀ7.
34 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 39.0 (t), 59.4 (t), 65.5, 66.8
(s), 68.7, 71.0, 73.3, 80.1, 128.7, 129.6, 130.7, 133.0 (s), 171.7 (s);
HRMS (ESI) calcd for C15H22O7N 328.13908, found 328.13910.
Correct elemental analysis could not be obtained because of the hygro-
scopic character of the compound.
noic Acid Lithium Salt (L19): white solid; mp 136 °C; [R]22
=
D
ꢀ125.5 (c = 1.0, D2O); IR (neat, cmꢀ1) 3340, 1510, 1481, 1418, 1030,
’ ASSOCIATED CONTENT
1
862, 690; H NMR (D2O, 400 MHz) δ 3.33 (d, J = 13.3 Hz, 1H,
CH2Ph), 3.48ꢀ3.64 (m, 4H, H-40, H-50, H-60a, H-60b), 3.53 (d, J = 13.3
1
S
Supporting Information. General procedures, H and
b
Hz, 1H, CH2Ph), 3.83 (dd, J3 ꢀ4 = 8.0 Hz, J3 ꢀ2 = 4.0 Hz, 1H, H-30),
13C spectra for all reported new compounds, and COSY and
NOESY spectra for compounds 10a, 10b, 14a, 14b, 15, and 16.
This material is available free of charge via the Internet at http://
pubs.acs.org
0
0
0
0
4.52 (app t, J2 ꢀ1 = J2 ꢀ3 = 4.0 Hz, 1H, H-20), 4.58 (d, J1 ꢀ2 = 4.1 Hz,
1H, H-10), 7.05ꢀ7.16 (m, 5H, ArH), 7.31ꢀ7.38 (m, 2H, ArH), 7.42ꢀ7.
53 (m, 3H, ArH); 13C NMR (D2O, 100 MHz) δ 37.7 (t), 61.2 (t), 68.3,
68.4 (s), 68.6, 71.7, 78.4, 78.5, 126.9, 127.1, 128.6, 129.1, 130.3, 132.3,
134.8 (s), 137.1 (s), 169.5 (s), 176.3 (s); MS (ESI) (negative ion mode)
m/z 430.2 [M ꢀ Li]ꢀ. Anal. Calcd for C22H24LiNO8: C, 60.41; H, 5.53;
N, 3.20. Found: C, 60.62; H, 5.44; N, 3.11.
0
0
0
0
0
0
’ AUTHOR INFORMATION
Corresponding Authors
*E-mail: (M.D.G.) marcello.digiacomo@unipv.it; (M.S.) massimo.
serra@unipv.it.
General Procedure D: Synthesis of Compounds 20ꢀ22. A
solution of methyl esters 17ꢀ19 (0.17 mmol) in H2O (1.7 mL, 0.1 M)
was added with LiOH •H2O (0.70 mmol). After 3 h, the reaction was
3
complete. The solvent was removed under reduced pressure to obtain
quantitatively the corresponding lithium salts . The crude was treated
with 6 N HCl (4 mL), and the resulting suspension was heated at 80 °C.
After 7ꢀ8 h at 80 °C, the reaction mixture was cooled to rt, and benzoic
acid crystals were allowed to precipitate. The reaction mixture was
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