Base induced chiral substituted furans and imidazoles from carbohydrate-derived 2-haloenones

Article abstract of DOI:10.1021/acs.joc.5b02500

Chiral substituted furans and imidazoles are key intermediates to access biologically important molecules. We describe herein a catalyst/ligand free cascade Michael-type addition/intramolecular cyclization/carbohydrate-ring opening of 2-haloenones with 1,

Full text of DOI:10.1021/acs.joc.5b02500

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Article
Base Induced Chiral Substituted Furans and
Imidazoles from Carbohydrate-Derived 2-Haloenones
Kanchan Mal, and Indrajit Das
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 8, 2016
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Base Induced Chiral Substituted Furans and Imidazoles from
CarbohydrateꢀDerived 2ꢀHaloenones
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Kanchan Mal and Indrajit Das*
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Organic and Medicinal Chemistry Division, CSIRꢀIndian Institute of Chemical Biology, 4,
Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India.
Abstract: Chiral substituted furans and imidazoles are key intermediates to access
biologically important molecules. We describe herein a catalyst/ligand free cascade Michaelꢀ
type addition/intramolecular cyclization/carbohydrateꢀring opening of 2ꢀhaloenones with 1,3ꢀ
dicarbonyl compounds or amidines utilizing K2CO3/DMSO at ambient temperature, that
provides a straightforward approach to a variety of optically active (poly)hydroxy furans and
imidazoles containing multiple stereocentres with good yield and excellent regioselectivity.
The furan intermediates provide efficient access to synthetically valuable substituted αꢀ
benzyloxyvinyl ketones. The NMR spectrum of the substituted 2ꢀmethylfurans shows an
unusual longꢀrange (5JHꢀH) 1Hꢀ1H COSY crossꢀpeak between C2ꢀCH3 and C4ꢀH signals.
INTRODUCTION
Substituted furans, constituting the core structural unit in numerous biologically active
natural products, pharmaceuticals and significant synthetic intermediates, are highly soughtꢀ
after in heterocyclic chemistry.1aꢀf In particular, trisubstituted furans bearing an ester or ketoꢀ
group at Cꢀ3 are extremely useful intermediates and promising building blocks in synthetic
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processes (Figure 1).1gꢀh Chiral substituted furanyl αꢀketones too form prominent structural
motifs present in valueꢀadded compounds.2a More significantly, the ketones after reduction to
furanyl αꢀcarbinols can be easily transformed under Achmatowicz reaction conditions to
versatile synthetic intermediates,2b which can be further transformed to modified higherꢀ
carbon sugars and aza sugars.2a Like Substituted furans, substituted imidazoles/optically
active (poly)hydroxyꢀsubstituted imidazoles are also commonly found in many biologically
relevant natural products (Figure 1), with applications in targetꢀoriented synthesis, Nꢀ
heterocyclic carbene precursors, and ionic liquids.3
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Figure 1. Pharmacologically active and naturally occurring compounds containing chiral substituted imidazoles
and furanꢀ3ꢀcarboxylic acid esters.
The chiral furanyl αꢀketones/αꢀcarbinols are prepared either by using asymmetric Friedelꢀ
Crafts reaction or chiral pool precursors, or by enzymatic as well as kinetic resolutions of
racemic mixtures.4 There are also sporadic reports on efficient synthetic strategies for
optically active (poly)hydroxyꢀsubstituted imidazoles,5 In spite of these, the development of
efficient and regioselective routes to these essential scaffolds utilizing operationally simple
processes under mild reaction conditions is still in great demand.
Carbohydrates have been recognized as one of the most potential sources of chirality in
target oriented synthesis of complex molecules.6 In particular, 2ꢀiodoenones/enones 1 derived
from carbohydrates are important synthetic intermediates for diverse reactions such as Dielsꢀ
Alder reaction, Michaelꢀtype addition and Heckꢀtype reaction/1,4ꢀaddition for Cꢀ
glycosylation [A, Scheme 1, (a)].7 Recently, we have described the synthesis of substituted
chiral 3ꢀformylfurans from these 2ꢀiodoenones 1 [B, Scheme 1, (b)].8 This finding prompted
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us to investigate whether the combination of such haloenones 1 with bidentate nucleophiles
such as amidines or with active methylene compounds could constitute an unprecendented
cascade annulation process to afford the optically active substituted imidazoles 2 and furans
3. Herein, we report the successful execution of this hypothesis by utilizing amidines and
active methylene compounds through Michaelꢀtype addition followed by substitution and
rearrangement.
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Scheme 1. Previous Work from 1 and Our Hypothesis for Accessing Chiral Substituted Imidazoles and
Furans
(a) General reported reactions with carbohydrate-derived substituted 2-iodoenones/enones (ref 7)
O
O
R1
R
1. Organocuprates or Grignard reagents
(Michael-type additions)
OR
n(PGO)
n(PGO)
X
2. Boronic acids, Metal
(Heck-type reaction or 1,4-addition for
C-glycosylation)
O
O
A
1
R = PO(OEt)2, Me, H
R1 = Ar, Alk, others
[X = I, H, PO(OEt)2, Me]
PG = protecting groups
(b) Our previous work (ref 8)
OHC
OH
O
Sonogashira Coupling
AuCl3
1
OR
n(PGO)
OR
R
Ar/Alk/TMS
Heck Coupling
X = I
NBS
O
PGO
O
Ar/Alk
B
Chiral 3-formylfurans
(c) This work
R
H
N
R
.
(amidines)
NH2 HCl
O
OH
R1
HN
n(PGO)
N
Base, Solvent, r.t.
(X = I, Br)
X
PGO
2
O
O
O
O
Chiral substituted imidazoles
1
R1
R2
COR2
(1,3-dicarbonyl
compounds)
R
OH
O
R1
Base, Solvent, r.t.
O
3
PGO
Chiral substituted furans
RESULTS AND DISCUSSION
To optimize the reaction conditions for chiral imidazole derivatives, we initiated screening
studies by utilizing 1a as the substrate and benzamidine hydrochloride as the 1,3ꢀ
dinucleophilic species in the presence of different bases and solvents. Pleasantly, use of
K2CO3 (3 equiv) as a base in DMSO led to the formation of a product which from
preliminary spectroscopic analysis appeared to be 2a’ (Table 1). Due to the unusual signal
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Table 1. Optimization of Reaction Conditionsa
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H
H
N
N
Ph
OH
Ph
Base, Solvent,
r.t., time
OAc
O
Ph
BnO
BnO
N
.
BnO
N
NH2 HCl
BnO
followed by
Acetylation
I
HN
BnO
BnO
O
1.0 equiv)
O
O
2a'
2a
1a (1.0 equiv)
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Entry
Base
Equiv
Solvent
time
Yield (%)
1
K2CO3
KOtBu
Na2CO3
Cs2CO3
Ag2CO3
Li2CO3
KOH
3
3
3
3
3
3
3
3
3
2
1
3
3
3
3
-
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
75 min
15 min
1.5 h
84
38
76
80
53
62
61
40
62
78
69
77
47
60
62
n.d.
2
3
4
45 min
3.0 h
14 h
2.5 h
45 min
1 h
5
6
7
8
DBU
9
Et3N
10
11
12
13
14
15
16b
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
-
1.5 h
6 h
16 h
22 h
16 h
22 h
24 h
THF
1,4-Dioxane
CH3CN
DMSO
aAll reactions were carried out with 1a (0.03 g, 0.067 mmol, 1.0 equiv), benzamidine hydrochloride (0.01 g, 0.067
mmol, 1.0 equiv), base (equiv/mmol), and solvent (1.0 mL/equiv) in open air at rt. The product obtained was
acetylated with Ac2O, py, DMAP at 0 oC for 1 h. Yields are of isolated products in two-step. bNot detected; starting
materials isolated.
broadening in 13C NMR and difficulty in purification by column chromatography, this was
acetylated with Ac2O to isolate 2a, which could be easily spectrally analysed, in 84% overall
yield (Table 1, entry 1). As demonstrtated in Table 1, different bases such as KOtBu,
Na2CO3, Cs2CO3, Ag2CO3, Li2CO3, KOH, DBU, or Et3N could all initiate this
transformation, but the product 2a was formed either in lower yields or it was necessary to
conduct the reaction for a longer period (entries 2ꢀ9, Table 1). Furthermore, employing
K2CO3 in lower ratios (2.0 equiv)/(1.0 equiv) only reduced the yields (entries 10ꢀ11, Table 1),
while the reaction did not proceed at all in absence of a base (entry 16). The use of other
solvents (DMF, THF, 1,4ꢀdioxane, and CH3CN; entries 12−15, Table 1) also failed to deliver
the required products in good yields. More importantly, despite the use of basic reaction
conditions (K2CO3), no racemization was observed in the stereogenic centre next to the
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carbonyl group. Thus, we concluded that the combination of K2CO3 (3.0 equiv) and DMSO
at room temperature (entry 1, Table 1) constitutes the optimum reaction conditions.
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Figure 2. Substituted 2ꢀhaloenones 1aꢀg derived from glycals used in this study.
We next examined the substrate scope and generality of the approach using various 2ꢀ
haloenones 1 (Figure 2)7c,8ꢀ9 and aromatic/aliphatic amidines (Table 2). It is noteworthy that
the electronic nature and location of the substituents on the aromatic/aliphatic ring of
amidines or substitution/protection at carbohydrate components 1 did not influence the
outcome of the reactions significantly (Table 2). In general, 2ꢀiodoenones 1aꢀe reacted with
aromatic amidines containing an electronꢀneutral, electronꢀdonating, or electronꢀdeficient
substituents on the aromatic ring or with aliphatic amidines such as tertꢀbutylcarboxamidine
hydrochloride or cyclopropylcarboxamidine hydrochloride to give chiral 2ꢀsubstitutedꢀ
imidazoles with (poly)hydroxylated side chains in moderate to excellent yields (2aꢀv, Table
2). 2ꢀbromoenone (1g) also underwent similar conversion (to 2a, 2f, and 2n, Table 2) under
standard conditions, but the yields were 58ꢀ60%. The drop in yield with bromoenone
compared to iodoenones may be due to the poor leaving character of bromide. To
demonstrate the versatility of our developed approach, the same sequence of reactions was
carried out with 1a or 1b, and the product obtained was iodinated (rather than acetylation) to
produce optically active 5ꢀiodoimidazoles 2w and 2x (Table 2).
We next turned our attention to explore the substrate scope and generality of the reaction
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Table 2. Substrate Scope for Chiral Substituted Imidazolesa
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R1
R2
O
H
R
N
K2CO3, DMSO, rt
I/H
R
NH2.HCl
HO/AcO
R3
followed by acetylation
or iodination
X
N
HN
1.0 equiv)
O
R2
1 (0.05 g, 1.0 equiv)
(R = aliphatic,
aromatic)
yield up to 88%
24 examples
O
(X = I, Br)
2a-x
H
H
N
H
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H
N
N
N
C6H5
C6H5
BnO
OAc
C6H5
OAc
C6H5
OAc
OAc
N
Me
N
N
N
BnO
BnO
BnO
O
BnO
O
BnO
O
O
2a; 75 min, 84%
2a; 75 min, 58%b
2c; 45 min, 85%
2b; 75 min, 74%
2d; 60 min, 69%
H
N
H
N
H
N
C6H5
C6H4-p-OMe
OAc
OAc
C6H4-p-OMe
OAc
Me
BnO
N
N
N
BnO
BnO
BnO
BnO
O
O
O
2e; 120 min, 87%
2f; 60 min, 77%
2f; 60 min, 60%b
2g; 60 min, 79%
H
N
H
N
H
N
C6H4-p-OMe
OAc
C6H4-p-Cl
OAc
C6H4-p-OMe
OAc
Me
BnO
Me
BnO
N
N
N
BnO
BnO
O
O
O
2h; 90 min, 76%
2i; 90 min, 86%
2j; 90 min, 72%
H
N
H
N
H
N
C6H4-p-Cl
C6H4-p-Cl
C6H4-p-Cl
OAc
OAc
OAc
Me
BnO
Me
BnO
N
N
N
BnO
BnO
O
O
O
2l; 45 min, 68%
2k; 90 min, 51%
2m; 120 min, 79%
H
N
H
N
H
H
N
N
OAc
OAc
OAc
OAc
N
BnO
Me
N
N
BnO
N
BnO
O
BnO
BnO
BnO
O
O
O
2n; 60 min, 74%
2n; 60 min, 52%b
2o; 60 min, 76%
2p; 45 min, 53%
2q; 120 min, 75%
H
N
H
N
H
N
H
N
OAc
OAc
OAc
OAc
Me
BnO
N
Me
N
N
BnO
BnO
N
BnO
BnO
O
O
O
BnO
2u; 90 min, 43%
O
2s; 120 min, 64%
2r; 120 min, 88%
2t; 120 min, 49%
H
N
OH
OH
I
I
BnO
OAc
BnO
BnO
Me
BnO
NH
NH
N
BnO
N
N
Ph
Ph
O
O
O
2w; 75 min, 62%
2x; 75 min, 63%
2v; 120 min, 63%
aIsolated yields of 2 in two-step utilizing 2-iodoenones as substrates. bIsolated yields of 2a, 2f,
and 2n from 2-bromoenone 1g.
using various 2ꢀhaloenones 1 and 1,3ꢀdicarbonyl compounds under similar reaction
conditions. As shown in Table 3, the reaction is tolerant of variation in substituents in the
substituted haloenones and active methylenes, which were smoothly converted into the
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Table 3. Substrate scope for chiral substituted furansa
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O
R2
R1
O
O
R2
R1
R3
R4
K2CO3
OH
R4
R3
OH
R3COCH2COR4
(1.0 equiv)
R2
DMSO, rt
X
O
R1
26 examples
Yield up to 85%
O
(X = I, Br)
O
O
1 (0.05 g, 1.0 equiv)
O
3; major
4; minor/trace
O
O
O
CH3
CH3
H3C
H3C
H3C
OH
OH
O
O
OH
O
10
11
12
13
14
15
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BnO
BnO
BnO
CH3
CH3
O
O
O
O
O
O
3a; 15 min, 78%, single
3c; 20 min, 67%, (90:10)
3b; 15 min, 73%, (95:5)
O
O
O
CH3
CH3
CH3
H3C
H3C
H3C
OH
OH
O
O
OH
O
BnO
BnO
BnO
OMe
CH3
O
O
O
O
O
Cl
O
3f; 10 min, 80%, (95:5)
3e; 40 min, 40%, single
3d; 60 min, 40%, single
O
O
O
CH3
H3C
CH3
H3C
H3C
OH
O
OH
OH
O
O
BnO
BnO
BnO
CH3
O
O
OCH3
O
O
O
O
3i; 10 min, 64%, (95:5)
3g; 20 min, 64%, single
3h; 30 min, 48%, single
O
O
O
CH3
CH3
BnO
BnO
BnO
BnO
BnO
BnO
OH
O
OH
OH
O
O
CH3
CH3
CH3
O
O
O
O
O
O
3j; 10 min, 74%, (93:7)
3k; 10 min, 75%, single
3l; 15 min, 71%, (93:7)
O
O
O
CH3
CH3
BnO
BnO
BnO
BnO
OH
BnO
BnO
O
OH
O
OH
O
CH3
O
O
O
O
O
CH3
O
3o; 10 min, 61%, (95:5)
3m; 10 min, 85%, (94:6)
3n; 10 min, 56%, single
O
O
O
CH3
CH3
CH3
BnO
BnO
BnO
BnO
OH
BnO
BnO
O
OH
O
OH
O
OCH3
O
O
O
O
O
O
Cl
3p; 15 min, 60%, single
3r; 60 min, 50%, single
3q; 20 min, 61%, single
CH3
O
O
O
O
BnO
BnO
OH
BnO
OH
TBDPSO
HO
OH
BnO
O
CH3
O
O
O
O
O
3t; 90 min, 41%, (86:14)b
3u; 120 min, 16%, (88:12)
3s; 20 min, 44%, single
O
O
O
CH3
CH3
CH3
BnO
BnO
BnO
BnO
OH
O
BnO
BnO
OH
O
OH
O
O
O
O
O
CH3
O
O
Cl
3v; 10 min, 60%, (86:14) b
3v; 20 min, 45%, (86:14)b,c
3w; 15 min, 56%, (90:10)
3x; 60 min, 43%, (88:12)b
O
O
CH3
HO
BnO
OH
O
O
BnO
BnO
OCH3
3y; 60 min, 40%, single
CH3
O
O
O
O
3z; 10 min, 76%, single
aIsolated yields of 3 utilizing 2-iodoenones as substrates. The ratio of furan 3 and its regioisomer 4 was
measured based on 1H NMR analysis of the crude reaction mixture. The minor or trace products 4 proved
inseparable by chromatography. bInseparable mixtures. cIsolated yield of 3v from 2-bromoenone 1g.
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corresponding optically active substituted furanylꢀαꢀketones in moderate to good yields and
with an excellent level of regioselectivity (3aꢀz, Table 3). The drop in yield with a TBDPS
group instead of benzyl group might be due to the hydrolysis of the primary silyl protection
under strongly basic conditions (3s, Table 3). The reaction did not work well with βꢀ
diketones (3tꢀu, Table 3) compared to the other active methylene compounds, although the
exact reason is not very clear at this moment.
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The structures of selected optically active substituted imidazoles (2a, 2g, 2i, 2q) and furans
(3a, 3c, 3f, 3k, 3r, 3y) were established by extensive 1D and 2D NMR analyses, while those
of other products 2 and 3 were assigned by comparison of the 1D NMR chemical shift values
for the characteristic resonances (Figure 3 and the Supporting Information for details). In
addition, the singleꢀcrystal Xꢀray analysis of the αꢀbenzyloxyvinyl ketone 5a was carried out
to confirm the proposed structure (see Scheme 4, vide infra). It must be mentioned here that
though we indicate the formation of only one imidazole tautomer (Table 2), a perusal of the
literature reveals that extremely fast proton transfers, depending upon solvent polarity and
temperature, occur in solution between two tautomers of imidazole derivatives and these are
indistinguishable by NMR technique.5c,10 Therefore, the chiral imidazoles 2 might also exist
in equilibrium between two tautomers and which are too fast in the NMR timescale.
HMBC
COSY;
CH3
O
H
O
O
O
H
H
H
BnO
CH3
OH
OH
H
H
H
H
O
N
BnO
BnO
O
CH3
H3C
H
BnO
H
N
BnO
O
H
O
H
O
O
H
O
H
2a
3k
3a
Figure 3. Key COSY and HMBC correlations observed with 2a, 3a, 3k (stereochemistry omitted for clarity).
1
Interestingly, during the analyses of the Hꢀ1H COSY NMR experiments (2D) for
substituted furans, we are surprised to observe the longꢀrange (5JHꢀH) crossꢀpeak between C2ꢀ
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CH3 and C4ꢀH signal for all the tested substituted 2ꢀmethyl furans (3a, 3f, 3k, 5a), which is
quite unexpected and extremely rare in the literature (see the Supporting Information).11 The
zigꢀzag pathway (Wꢀtype coupling) between the concerned protons may account for this
unusual correlation.
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In order to gain insights into the mechanistic pathway, several control experiments were
carried out (Scheme 2). When the reaction of 1a and benzamidine hydrochloride was
conducted with TEMPO (1.0 equiv) under optimized conditions, exclusive formation of 2a in
71% yield occurred, ruling out the possibility of any radical reaction pathway (Scheme 2). To
determine whether atmospheric oxygen (open air) has any effect in this cascade, the reaction
was conducted under Ar atmosphere. This afforded 2a in 84% yield, thus suggesting no role
for atmospheric oxygen in the proposed mechanism. Moreover, when 1a was subjected to the
standard conditions with benzylamine, morpholine, or phenyl hydrazine hydrochloride, only
degradation of the starting materials took place, may be due to the lack of 1,3ꢀdinucleophilic
species. This experiment also supports the formation of intermediate IV as a carbohydrateꢀ
imidazoliumꢀbased intermediate as described in Scheme 3. Furthermore, to confirm whether
Scheme 2. Control Experiments
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the substrates with a conjugated α,βꢀunsaturated αꢀiodocarbonyl are necessary, we performed
two parallel experiments with 4a and 4b12 under optimized reaction conditions (Scheme 2).
However, no expected product was ever observed even upon heating the reaction mixture for
several hours, thus suggesting that the formation of optically active imidazoles 2 may proceed
through 1,4ꢀaddition (Michaelꢀtype addition) followed by intramolecular nucleophilic ring
closure.
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Based on the experimental results given in Table 2 and Table 3, the control experiments
described in Scheme 2, and literature reports for Michaelꢀtype additions to carbohydrateꢀ
derived enones,7bꢀd,f a plausible mechanism for this novel cascade reaction is outlined in
Scheme 3. We presume that initial baseꢀinduced Michaelꢀtype addition reaction of amidines
or 1,3ꢀdicarbonyl compounds to the haloenone 1 could lead to haloenolate I, which
undergoes immediate proton transfer to generate intermediate II through enolꢀketo
tautomerism. Intermediate II could form another enolate III and subsequent intramolecular
Scheme 3. Proposed Reaction Mechanism
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nucleophilic attack by nitrogen (for imidazoles) or oxygen (for furans) to eliminate the
halogen produces the corresponding intermediate IV. This would then collapse by baseꢀ
catalyzed sugarꢀring opening via alkoxide elimination, leading to the formation of 3 via
protonation of intermediate V. For imidazole derivatives, V could undergo a prototropic
tautomerism to produce 2a’. Unfortunately, attempts to isolate any of the proposed
intermediates were unsuccessful. On the other hand, the formation of the minor/trace product
4 could be explained by baseꢀmediated formation of an activated 1,2ꢀcyclopropanated sugar
VI, which undergoes intramolecular rearrangement to produce intermediate VII, as described
in the literature.13 This intermediate could then follow the pathway as described earlier for 3
in the proposed reaction mechanism (Scheme 3).
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The efficacy of these developed procedures was demonstrated by accessing 2a, 3a, and 3k
on a large scale without any significant diminution in the yield (Table 4). Furthermore, to
highlight the potentiality of these intermediates, the conversion of substituted furans 3z and
3b to synthetically valuable αꢀbenzyloxyvinyl ketones 5aꢀb was achieved in two steps
(Scheme 4). The structure of 5a was unambiguously established by singleꢀcrystal Xꢀray
diffraction analysis (Scheme 4).14
Table 4. Scaleꢀup Batches for Chiral Derivatives
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Scheme 4. Synthetic Transformations to FuranꢀDerived αꢀBenzyloxyvinyl Ketones
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CONCLUSION
In conclusion, we have developed a general and catalyst/ligand free cascade for the
construction of chiral substituted imidazoles and furans under basic conditions at ambient
temperature, utilizing readily available and inexpensive carbohydrates and amidines/1,3ꢀ
dicarbonyls as starting materials. This cascade annulations process provides a straightforward
access to these valuable scaffolds with good yields and excellent regioselectivity. The furan
intermediates provide efficient access to synthetically valuable substituted αꢀbenzyloxyvinyl
ketones. The substituted 2ꢀmethylfurans show an intense longꢀrange (5JHꢀH) crossꢀpeak
between C2ꢀCH3 and C4ꢀH in 1Hꢀ1H COSY NMR experiments, which is rare in the literature.
Further applications of these carbohydrateꢀderived 2ꢀhaloenones as potentially important
synthetic precursors are being explored in our laboratory.
EXPERIMENTAL SECTION
General Information
Melting points were determined in openꢀend capillary tubes and are uncorrected. TLC was
performed on silica gel plates (Merck silica gel 60, f254), and the spots were visualized with
UV light (254 and 365 nm) or by charring the plate dipped in 5% H2SO4ꢀMeOH or vanillin
charring solution. H and 13C NMR spectra were recorded in CDCl3 or DMSOꢀd6 solvent
1
using TMS as the internal standard. HRMS (m/z) were measured using EI (magnetic sector,
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positive ion) and ESI (QꢀTOF, positive ion) techniques. Infrared (IR) spectra were recorded
on Fourier transform infrared spectroscopy, only intense peaks were reported.
Experimental Section:
9
General Procedure for the synthesis of 1aꢀg. To a wellꢀstirred solution of corresponding
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carbohydrateꢀderived enones (0.1 g, 1 equiv) in CCl4/pyridine (1:1, 4 mL) at 0 C, iodine or
bromine (2.1 equiv) dissolved in CCl4/pyridine (1:1, 4 mL) was added dropwise into it.
Resulting reaction mixture was stirred for 2 h at ambient temperature (for iodination) or 0 oC
for 1 h (for bromination). After completion of the reaction (TLC), the reaction mixture was
extracted with DCM (20 mL), and washed successively with H2O (10 mL), 1 N HCl (2 x 10
mL), and 20% aqueous Na2S2O3 (10 mL) solution. The combined organic layer was dried
over anhyd Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to
get a residue. The crude residue was purified by silica gel column chromatography [230ꢀ400;
eluent: ethyl acetate/nꢀhexane] to obtain 1aꢀg. The analytical data of compounds 1a, 1b, 1c,
1d, 1e was exactly matched with those of the reported values.7c,8b,9
General Procedure for the Synthesis of 2. 2ꢀIodoenones/2ꢀbromoenones 1 (0.05 g, 1.0
equiv), corresponding amidine salt (1.0 equiv), K2CO3 (3.0 equiv), and DMSO (1.0 mL) were
added successively to a round bottom flask under open air at room temperature, and the
mixture was stirred at the same temperature employing time as mentioned. After completion
of the reaction (TLC), saturated ammonium chloride solution was added, and the product was
extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and
filtered, and the filtrate was concentrated under reduced pressure to get a residue. The crude
residue was passed through a short pad of silica gel column [230ꢀ400; eluent: ethyl acetate/ nꢀ
hexane] to obtain a residue. The residue was acetylated with Ac2O (2.0 equiv), DMAP
o
(catalytic), py (0.5 mL) at 0 C for 1 h. After completion of the reaction (TLC), saturated
sodium bicarbonate solution was added at the same temperature, and the product was
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extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and
filtered, and the filtrate was concentrated under reduced pressure to get a residue. The crude
residue was purified over silica gel column chromatography [230ꢀ400; eluent: ethyl acetate/
nꢀhexane] to obtain 2.
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General procedure for the synthesis of 2wꢀx. 1a or 1b (0.05 g, 1.0 equiv), corresponding
amidine salt (1.0 equiv), K2CO3 (3.0 equiv), and DMSO (1.0 mL) was added successively in
a round bottom flask under open air at room temperature, and the mixtures were stirred at the
same temperature employing time as mentioned. After completion of the reaction (TLC),
saturated ammonium chloride solution was added, and the product was extracted with EtOAc.
The combined organic layers were dried over anhydrous Na2SO4 and filtered, and the filtrate
was concentrated under reduced pressure to get a residue. The crude residue was passed
through a short pad of silica gel column [230ꢀ400; eluent: ethyl acetate/ nꢀhexane] to obtain a
residue. The residue was treated with I2 (2.0 equiv), K2CO3 (2.0 equiv), DMSO (1.0 mL) at
room temperature for 1 h. After completion of the reaction (TLC), saturated sodium
thiosulfate solution was added into it. The product was extracted with EtOAc, and the organic
layer was washed with brine solution. The combined organic layers were dried over
anhydrous Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to
get a residue. The crude residue was purified over silica gel column chromatography [230ꢀ
400; eluent: ethyl acetate/nꢀhexane] to obtain 2wꢀx.
General Procedure for the synthesis of 3. 2ꢀIodoenones/2ꢀbromoenones 1 (0.05 g, 1.0
equiv), K2CO3 (3.0 equiv), DMSO (1.0 mL), and the corresponding 1,3ꢀdicarbonyls 2 (1.0
equiv) were added successively to a round bottom flask at ambient temperature under argon
atmosphere, and the mixture was stirred at the same temperature employing time as
mentioned. After completion of the reaction (TLC), saturated ammonium chloride solution
was added, and the product was extracted with EtOAc. The combined organic layer was dried
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over anhydrous Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure
to get a residue. The crude residue was purified over silica gel column chromatography [230ꢀ
400; eluent: ethyl acetate/nꢀhexane] to obtain 3.
9
General procedure for the synthesis of 5aꢀb. To a wellꢀstirred solution of 3z or 3b (0.05 g,
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1 equiv) in dry pyridine (1.5 mL) at 0 C, benzoyl chloride (1.1 equiv/mmol) dissolved in
pyridine (0.5 mL) and was added dropwise into it. The resulting reaction mixture was stirred
at the same temperature for 30 min. After completion of the reaction (TLC), saturated sodium
bicarbonate solution was added, and the product was extracted with EtOAc. The combined
organic layer was dried over anhydrous Na2SO4 and filtered, and the filtrate was concentrated
under reduced pressure to get a residue. The crude residue was passed through a short pad of
silica gel column [230ꢀ400; eluent: ethyl acetate/nꢀhexane] to obtain a residue. The residue
was treated with Et3N (1.0 mL, neat) at room temperature for 16ꢀ36 h. After completion of
the reaction (TLC), saturated ammonium chloride solution was added, and the product was
extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and
filtered, and the filtrate was concentrated under reduced pressure to get a residue. The crude
residue was purified over silica gel column chromatography [230ꢀ400; eluent: ethyl acetate/nꢀ
hexane] to obtain 5aꢀb.
(2R,3R)ꢀ2ꢀ(((tertꢀbutyldiphenylsilyl)oxy)methyl)ꢀ3ꢀhydroxyꢀ5ꢀiodoꢀ2,3ꢀdihydroꢀ4Hꢀ
pyranꢀ4ꢀone 1f. Prepared according to the general procedure discussed above: Rf = 0.30;
20
eluent, EtOAc/nꢀhexane (10%); isolated yield = 0.105 g, 76%; [α]D = +88 (c = 0.11 in
MeOH); colorless gum. 1H NMR (600 MHz, CDCl3): δ = 7.79 (s, 1 H), 7.69 ꢀ 7.72 (m, 4 H),
7.44 ꢀ 7.47 (m, 2 H), 7.40 ꢀ 7.42 (m, 4 H), 4.66 (dd, J = 1.8, 13.2 Hz, 1 H), 4.30 (dt, J = 2.4,
13.2 Hz, 1 H), 4.10 (dd, J = 1.8, 12.0 Hz, 1 H), 4.07 (dd, J = 3.0, 12.0 Hz, 1 H), 3.45 (d, J =
1.8 Hz, 1 H), 1.08 ppm (s, 9 H); 13C NMR (150 MHz, CDCl3): δ = 190.3, 167.0, 135.6 (4
CH), 132.9, 132.8, 129.8, 127.8 (3 CH), 127.7 (2 CH), 83.8, 70.1, 67.6, 61.9 (CH2), 26.7 (3
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CH3), 19.4 ppm; IR (KBr): ṽmax = 2930, 2857, 1686, 1569, 1427, 1142, 1093, 1035, 968, 787,
742, 703, 610, 506 cmꢀ1; HRMS (ESI): m/z calcd for C22H25IO4SiNa [M + Na]+: 531.0465;
found: 531.0456.
9
(2R,3S)ꢀ3ꢀ(benzyloxy)ꢀ2ꢀ((benzyloxy)methyl)ꢀ5ꢀbromoꢀ2,3ꢀdihydroꢀ4Hꢀpyranꢀ4ꢀone 1g.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
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hexane (10%); isolated yield = 0.045 g, 72%; [α]D = +4 (c = 0.14 in MeOH); white solid;
mp 127 ꢀ 130 °C. 1H NMR (600 MHz, CDCl3): δ = 7.71 (s, 1 H), 7.34 ꢀ 7.37 (m, 3 H), 7.31 ꢀ
7.33 (m, 3 H), 7.28 ꢀ 7.30 (m, 4 H), 4.72 (d, J = 12.0 Hz, 1 H), 4.56 ꢀ 4.58 (m, 2 H), 4.50 (d, J
=12.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 3.94 (d, J = 2.4 Hz, 1 H), 3.90 (dd, J = 7.2, 10.8
Hz, 1 H), 3.76 ppm (dd, J = 6.0, 10.2 Hz, 1 H); 13C NMR (150 MHz, CDCl3): δ = 182.6,
161.5, 137.2, 136.5, 128.5 (2 CH), 128.5 (2 CH), 128.4 (2 CH), 128.2, 128.0, 127.8 (2 CH),
100.7, 81.4, 74.2, 73.7 (CH2), 72.3 (CH2), 67.1 (CH2) ppm; IR (KBr): ṽmax = 3039, 2876,
1684, 1574, 1364, 1272, 1089, 1032, 743, 697, 570 cmꢀ1; HRMS (ESI): m/z calcd for
C20H19BrO4Na [M + Na]+: 425.0365; found: 425.0369.
(2R,3S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀoxoꢀ4ꢀ(2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)butanꢀ2ꢀyl acetate 2a.
Prepared according to the general procedure discussed above: eluent, Rf = 0.30; EtOAc/nꢀ
20
hexane (35%); isolated yield = 0.045 g, 84%; [α]D = −2 (c = 0.065 in MeOH); colorless
gum. 1H NMR (600 MHz, CDCl3): δ = 11.08 (br. s., 1 H), 8.13 (s, 1 H), 8.01 ꢀ 8.02 (m, 2 H),
7.40 ꢀ 7.46 (m, 3 H), 7.22 ꢀ 7.33 (m, 10 H), 5.45 ꢀ 5.47 (m, 1 H), 4.74 (d, J = 12.0 Hz, 1 H),
4.59 (d, J = 4.2 Hz, 1 H), 4.49 (d, J = 11.4 Hz, 1 H), 4.46 (d, J = 6.0 Hz, 2 H), 3.73 (dd, J =
6.6, 9.6 Hz, 1 H), 3.62 (dd, J = 5.4, 10.2 Hz, 1 H), 1.92 ppm (s, 3 H); 13C NMR (75 MHz,
CDCl3): δ = 189.2, 170.1, 151.2, 140.0, 137.4, 136.5, 131.2, 130.3, 129.0 (2 CH), 128.5 (2
CH), 128.4, 128.3 (4 CH), 128.2 (2 CH), 127.7, 127.6 (2 CH), 126.4, 81.6, 73.4 (CH2), 73.2
(CH2), 72.2, 67.4 (CH2), 20.7 ppm; IR (KBr): ṽmax = 2925, 2867, 1745, 1662, 1525, 1457,
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1374, 1232, 1101, 1050, 745, 699 cmꢀ1; HRMS (ESI): m/z calcd for C29H28N2O5Na [M +
Na]+: 507.1896; found: 507.1896.
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(2R,3R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀoxoꢀ4ꢀ(2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)butanꢀ2ꢀyl acetate 2b.
Prepared according to the general procedure discussed above: Rf = 0.40; eluent, EtOAc/nꢀ
hexane (35%); isolated yield = 0.039 g, 74%; [α]D20 = +3 (c = 0.12 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 10.49 (br. s., 1 H), 8.11 (s, 1 H), 7.89 ꢀ 7.92 (m, 2 H), 7.47 ꢀ
7.49 (m, 3 H), 7.34 (m, 4 H), 7.25 ꢀ 7.28 (m, 6 H), 5.45 (q, J = 4.8 Hz, 1 H), 4.76 (d, J = 11.7
Hz, 1 H), 4.65 (d, J = 4.5 Hz, 1 H), 4.56 (d, J = 11.4 Hz, 1 H), 4.49 (m, 2 H), 3.80 (d, J = 4.5
Hz, 2 H), 2.01 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): δ = 187.7, 170.4, 150.6, 139.3,
137.6, 136.6, 131.0, 130.3, 129.0 (2 CH), 128.5 (2 CH), 128.5, 128.3 (2 CH), 128.2, 128.2 (2
CH), 127.6, 127.6 (2 CH), 126.2 (2 CH), 81.0, 73.3, 73.2 (CH2), 73.1 (CH2), 67.4 (CH2), 20.9
ppm; IR (KBr): ṽmax = 2924, 1742, 1659, 1458, 1373, 1234, 1097, 698 cmꢀ1; HRMS (ESI):
m/z calcd for C29H28N2O5Na [M + Na]+: 507.1896; found: 507.1884.
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(R)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀoxoꢀ3ꢀ(2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)propyl acetate 2c. Prepared
according to the general procedure discussed above: Rf = 0.40; eluent, EtOAc/nꢀhexane
20
1
(40%); isolated yield = 0.047 g, 85%; [α]D = +3 (c = 0.17 in MeOH); colorless gum. H
NMR (600 MHz, CDCl3): δ = 11.11 (br. s., 1 H), 8.15 (s, 1 H), 7.99 ꢀ 8.01 (m, 2 H), 7.44 ꢀ
7.45 (m, 3 H), 7.32 ꢀ 7.35 (m, 5 H), 4.75 (d, J = 11.4 Hz, 1 H), 4.62 (d, J = 11.4 Hz, 1 H),
4.53 ꢀ 4.57 (m, 2 H), 4.41 ꢀ 4.45 (m, 1 H), 2.01 ppm (s, 3 H); 13C NMR (150 MHz, CDCl3): δ
= 189.3, 171.7, 152.1, 140.9, 137.5, 131.8, 131.5, 130.1 (2 CH), 129.7 (2 CH), 129.4, 129.3,
129.2 (2 CH), 127.3 (2 CH), 82.1, 73.8 (CH2), 65.3 (CH2), 21.8 ppm; IR (KBr): ṽmax = 2924,
1743, 1663, 1525, 1457, 1379, 1231, 1118, 1044, 699 cmꢀ1; HRMS (ESI): m/z calcd for
C21H20N2O4Na [M + Na]+: 387.1321; found: 387.1317.
(2S,3S)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀoxoꢀ4ꢀ(2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)butanꢀ2ꢀyl
acetate
2d.
Prepared according to the general procedure discussed above: Rf = 0.40; eluent, EtOAc/nꢀ
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hexane (30%); isolated yield = 0.038 g, 69%; [α]D = −24 (c = 0.10 in MeOH); colorless
gum. 1H NMR (300 MHz, CDCl3): δ = 10.65 (br. s., 1 H), 8.13 (s, 1 H), 7.92 ꢀ 7.95 (m, 2 H),
7.46 ꢀ 7.51 (m, 3 H), 7.35 (m, 5 H), 5.27 ꢀ 5.35 (m, 1 H), 4.78 (d, J = 12.0 Hz, 1 H), 4.55 (d, J
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= 11.7 Hz, 1 H), 4.47 (d, J = 3.6 Hz, 1 H), 1.99 (s, 3 H), 1.33 ppm (d, J = 6.6 Hz, 3 H); C
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NMR (75 MHz, CDCl3): δ = 188.4, 170.5, 151.1, 139.8, 136.8, 131.1, 130.4, 129.1 (2 CH),
128.6 (3 CH), 128.2, 128.1 (2 CH), 126.4 (2 CH), 83.8, 72.9 (CH2), 71.4, 21.1, 15.3 ppm; IR
(KBr): ṽmax = 2927, 1738, 1659, 1458, 1374, 1238, 1074, 700 cmꢀ1; HRMS (ESI): m/z calcd
for C22H22N2O4Na [M + Na]+: 401.1478; found: 401.1491.
(2S,3R)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀoxoꢀ4ꢀ(2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)butanꢀ2ꢀyl
acetate
2e.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
20
hexane (35%); isolated yield = 0.048 g, 87%; [α]D = +18 (c = 0.10 in MeOH); colorless
gum. 1H NMR (300 MHz, CDCl3): δ = 10.74 (br. s., 1 H), 8.14 (s, 1 H), 7.96 ꢀ 7.97 (m, 2 H),
7.46 ꢀ 7.48 (m, 3 H), 7.33 (m, 5 H), 5.34 (quin, J = 6.0 Hz, 1 H), 4.77 (d, J = 11.7 Hz, 1 H),
4.50 (d, J = 11.7 Hz, 1 H), 4.22 (d, J = 4.8 Hz, 1 H), 1.94 (s, 3 H), 1.32 ppm (d, J = 6.3 Hz, 3
H); 13C NMR (75 MHz, CDCl3): δ = 189.4, 170.3, 151.1, 140.0, 136.5, 131.2, 130.4, 129.0 (2
CH), 128.5 (3 CH), 128.2 (3 CH), 126.4 (2 CH), 85.1, 73.2 (CH2), 70.4, 21.0, 16.5 ppm; IR
(KBr): ṽmax = 2928, 1740, 1660, 1525, 1457, 1375, 1238, 1069, 751, 700 cmꢀ1; HRMS (ESI):
m/z calcd for C22H22N2O4Na [M + Na]+: 401.1478; found: 401.1496.
(2R,3S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl
acetate 2f. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
20
EtOAc/nꢀhexane (40%); isolated yield = 0.044 g, 77%; [α]D = −5 (c = 0.10 in MeOH);
colorless gum. 1H NMR (300 MHz, CDCl3): δ = 10.33 (br. s., 1 H), 8.06 (s, 1 H), 7.86 (d, J =
9.0 Hz, 2 H), 7.22 ꢀ 7.30 (m, 10 H), 6.98 (d, J = 8.7 Hz, 2 H), 5.41 ꢀ 5.47 (m, 1 H), 4.73 (d, J
= 11.4 Hz, 1 H), 4.53 (d, J = 3.9 Hz, 1 H), 4.46 ꢀ 4.50 (m, 3 H), 3.85 (s, 3 H), 3.71 (dd, J =
6.3, 9.6 Hz, 1 H), 3.61 (dd, J = 5.7, 9.9 Hz, 1 H), 1.94 ppm (s, 3 H); 13C NMR (75 MHz,
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CDCl3): δ = 188.8, 170.1, 161.4, 151.6, 140.3, 137.5, 136.6, 131.1, 128.5 (2 CH), 128.4 (2
CH), 128.2 (2 CH), 128.2 (2 CH), 128.2, 127.7, 127.6 (2 CH), 121.1, 114.5 (2 CH), 81.4,
73.3 (CH2), 73.3 (CH2), 72.3, 67.5 (CH2), 55.3, 20.8 ppm; IR (KBr): ṽmax = 2926, 1744, 1656,
1614, 1496, 1374, 1254, 1093, 1030, 839, 742, 699 cmꢀ1; HRMS (ESI): m/z calcd for
C30H30N2O6Na [M + Na]+: 537.2002; found: 537.2015.
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(2R,3R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl
acetate 2g. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
20
EtOAc/nꢀhexane (40%); isolated yield = 0.045 g, 79%; [α]D = +6 (c = 0.11 in MeOH);
colorless gum. 1H NMR (600 MHz, CDCl3): δ = 10.85 (br. s., 1 H), 8.10 (s, 1 H), 7.94 (d, J =
9.0 Hz, 2 H), 7.29 ꢀ 7.34 (m, 5 H), 7.24 ꢀ 7.25 (m, 2 H), 7.20 ꢀ 7.22 (m, 3 H), 6.96 (d, J = 9.0
Hz, 2 H), 5.42 (q, J = 4.8 Hz, 1 H), 4.74 (d, J = 12.0 Hz, 1 H), 4.68 (d, J = 4.8 Hz, 1 H), 4.51
(d, J = 11.4 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 3.83 (s, 3 H),
3.80 (dd, J = 5.4, 10.2 Hz, 1 H), 3.76 (dd, J = 4.2, 10.8 Hz, 1 H), 1.97 ppm (s, 3 H); 13C NMR
(150 MHz, CDCl3): δ = 187.4, 170.4, 161.3, 151.0, 139.5, 137.6, 136.7, 130.8, 128.5 (2 CH),
128.3 (2 CH), 128.2, 128.1 (2 CH), 127.9 (2 CH), 127.6, 127.6 (2 CH), 121.2, 114.4 (2 CH),
80.9, 73.4, 73.2 (CH2), 73.0 (CH2), 67.5 (CH2), 55.4, 20.9 ppm; IR (KBr): ṽmax = 2927, 1742,
1654, 1614, 1496, 1476, 1374, 1254, 1092, 1029, 838, 741, 699 cmꢀ1; HRMS (ESI): m/z calcd
for C30H30N2O6Na [M + Na]+: 537.2002; found: 537.2010.
(2S,3S)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl
acetate 2h. Prepared according to the general procedure discussed above: Rf = 0.40; eluent,
20
EtOAc/nꢀhexane (40%); isolated yield = 0.045 g, 76%; [α]D = −7 (c = 0.10 in MeOH);
colorless gum. 1H NMR (300 MHz, CDCl3): δ = 10.55 (br. s., 1 H), 8.13 (s, 1 H), 7.91 (d, J =
8.7 Hz, 2 H), 7.36 (m, 5 H), 7.00 (d, J = 9.0 Hz, 2 H), 5.28 ꢀ 5.36 (m, 1 H), 4.80 (d, J = 11.7
Hz, 1 H), 4.55 (d, J = 11.7 Hz, 1 H), 4.48 (d, J = 3.6 Hz, 1 H), 3.88 (s, 3 H), 2.01 (s, 3 H),
1.35 ppm (d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ = 188.1, 170.4, 161.4, 151.5,
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140.2, 136.9, 130.9, 128.5 (2 CH), 128.2 (2 CH), 128.1 (3 CH), 121.2, 114.4 (2 CH), 83.6,
72.8 (CH2), 71.4, 55.3, 21.1, 15.3 ppm; IR (KBr): ṽmax = 2933, 1740, 1656, 1615, 1497, 1375,
1252, 1181, 1070, 1028, 840, 744, 699 cmꢀ1; HRMS (ESI): m/z calcd for C23H24N2O5Na [M +
Na]+: 431.1583; found: 431.1567.
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(2S,3R)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀmethoxyphenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl
acetate 2i. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
20
EtOAc/nꢀhexane (40%); isolated yield = 0.051 g, 86%; [α]D = +1 (c = 0.11 in MeOH);
colorless gum. 1H NMR (600 MHz, CDCl3): δ = 11.28 (br. s., 1 H), 8.14 (s, 1 H), 8.03 (d, J =
8.4 Hz, 2 H), 7.29 ꢀ 7.34 (m, 5 H), 6.96 (d, J = 9.0 Hz, 2 H), 5.34 ꢀ 5.38 (m, 1 H), 4.77 (d, J =
12.0 Hz, 1 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.28 (d, J = 4.8 Hz, 1 H), 3.84 (s, 3 H), 1.94 (s, 3
H), 1.31 ppm (d, J = 6.6 Hz, 3 H); 13C NMR (150 MHz, CDCl3): δ = 189.0, 170.3, 161.4,
151.4, 140.2, 136.6, 131.0, 128.5 (2 CH), 128.2, 128.1 (2 CH), 128.1 (2 CH), 121.1, 114.4 (2
CH), 84.8, 73.1 (CH2), 70.4, 55.3, 21.0, 16.5 ppm; IR (KBr): ṽmax = 2932, 1738, 1654, 1614,
1497, 1477, 1374, 1252, 1181, 1078, 1030, 838, 744, 699 cmꢀ1; HRMS (ESI): m/z calcd for
C23H24N2O5Na [M + Na]+: 431.1583; found: 431.1573.
(2R,3S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl
acetate 2j. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
20
EtOAc/nꢀhexane (35%); isolated yield = 0.041 g, 72%; [α]D = −4 (c = 0.13 in MeOH);
colorless gum. 1H NMR (300 MHz, CDCl3): δ = 10.84 (br. s., 1 H), 8.10 (s, 1 H), 7.91 (d, J =
8.1 Hz, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.28 ꢀ 7.32 (m, 10 H), 5.42 ꢀ 5.47 (m, 1 H), 4.73 (d, J
= 11.7 Hz, 1 H), 4.57 (d, J = 3.9 Hz, 1 H), 4.49 ꢀ 4.53 (m, 3 H), 3.73 (dd, J = 7.2, 9.6 Hz, 1
H), 3.63 (dd, J = 5.7, 9.9 Hz, 1 H), 1.95 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): δ = 189.5,
170.1, 150.3, 140.1, 137.4, 136.5, 136.4, 131.4, 129.3 (2 CH), 128.6 (2 CH), 128.4 (4 CH),
128.3 (2 CH), 127.8 (2 CH), 127.7 (2 CH), 127.0, 81.5, 73.5 (CH2), 73.3 (CH2), 72.3, 67.3
(CH2), 20.8 ppm; IR (KBr): ṽmax = 2925, 2866, 1745, 1662, 1480, 1425, 1373, 1231, 1095,
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1050, 738, 698 cmꢀ1; HRMS (ESI): m/z calcd for C29H27ClN2O5Na [M + Na]+: 541.1506;
found: 541.1506.
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(2R,3R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl
acetate 2k. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
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EtOAc/nꢀhexane (%); isolated yield = 0.029 g, 51%; [α]D = +3 (c = 0.13 in MeOH);
colorless gum. 1H NMR (300 MHz, CDCl3): δ = 10.73 (br. s., 1 H), 8.11 (s, 1 H), 7.87 (d, J =
8.4 Hz, 2 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.23 ꢀ 7.34 (m, 10 H), 5.40 ꢀ 5.45 (m, 1 H), 4.76 (d, J
= 11.4 Hz, 1 H), 4.66 (d, J = 4.2 Hz, 1 H), 4.55 (d, J = 11.7 Hz, 1 H), 4.48 (s, 2 H), 3.80 (d, J
= 5.4 Hz, 2 H), 2.01 ppm (s, 3 H); 13C NMR (75 MHz, CDCl3): δ = 188.0, 170.4, 149.9,
139.6, 137.5, 136.5, 136.4, 131.2, 129.3 (2 CH), 128.6 (2 CH), 128.3 (4 CH), 128.2 (2 CH),
127.7 (2 CH), 127.6 (2 CH), 127.0, 80.9, 73.4, 73.3 (CH2), 73.2 (CH2), 67.4 (CH2), 20.9 ppm;
IR (KBr): ṽmax = 2925, 1742, 1659, 1462, 1372, 1234, 1094, 837, 738, 699 cmꢀ1; HRMS
(ESI): m/z calcd for C29H27ClN2O5Na [M + Na]+: 541.1506; found: 541.1504.
(2S,3S)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate
2l. Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (30%); isolated yield = 0.040 g, 68%; [α]D20 = −8 (c = 0.11 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 11.00 (br. s., 1 H), 8.14 (s, 1 H), 7.94 (d, J = 8.4 Hz, 2 H),
7.43 (d, J = 8.4 Hz, 2 H), 7.34 (m, 5 H), 5.26 ꢀ 5.34 (m, 1 H), 4.77 (d, J = 11.7 Hz, 1 H), 4.54
(d, J = 11.7 Hz, 1 H), 4.50 (d, J = 4.2 Hz, 1 H), 1.99 (s, 3 H), 1.33 ppm (d, J = 6.6 Hz, 3 H);
13C NMR (75 MHz, CDCl3): δ = 188.1, 170.1, 149.9, 139.6, 136.3, 136.1, 130.9, 128.9 (2
CH), 128.2 (2 CH), 127.9, 127.8 (2 CH), 127.4 (2 CH), 126.7, 83.2, 72.6 (CH2), 71.0, 20.7,
14.8 ppm; IR (KBr): ṽmax = 2927, 1738, 1658, 1478, 1464, 1373, 1238, 1089, 836, 737, 698
cmꢀ1; HRMS (ESI): m/z calcd for C22H21ClN2O4Na [M + Na]+: 435.1088; found: 435.1080.
(2S,3R)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀ(4ꢀchlorophenyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate
2m. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
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EtOAc/nꢀhexane (35%); isolated yield = 0.047 g, 79%; [α]D = +1 (c = 0.10 in MeOH);
colorless gum. 1H NMR (300 MHz, CDCl3): δ = 10.71 (br. s., 1 H), 8.11 (s, 1 H), 7.89 (d, J =
8.7 Hz, 2 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.32 ꢀ 7.33 (m, 5 H), 5.29 ꢀ 5.37 (m, 1 H), 4.75 (d, J =
11.7 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1 H), 4.20 (d, J = 5.1 Hz, 1 H), 1.94 (s, 3 H), 1.32 ppm
(d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ = 189.6, 170.4, 150.4, 140.1, 136.6,
136.4, 131.4, 129.3 (2 CH), 128.6 (2 CH), 128.4, 128.2 (2 CH), 127.9 (2 CH), 127.0, 84.8,
73.3 (CH2), 70.4, 21.0, 16.6 ppm; IR (KBr): ṽmax = 2927, 1741, 1660, 1481, 1425, 1374,
1237, 1090, 1070, 838, 738, 697 cmꢀ1; HRMS (ESI): m/z calcd for C22H21ClN2O4Na
[M+Na]+: 435.1088; found: 435.1090.
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(2R,3S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀ(tertꢀbutyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate
2n. Prepared according to the general procedure discussed above: Rf = 0.40; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.038 g, 74%; [α]D20 = −4 (c = 0.13 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 9.74 (br. s., 1 H), 7.92 (s, 1 H), 7.23 ꢀ 7.32 (m, 10 H), 5.37 ꢀ
5.43 (m, 1 H), 4.70 (d, J = 11.7 Hz, 1 H), 4.43 ꢀ 4.49 (m, 4 H), 3.68 (dd, J = 6.3, 9.9 Hz, 1 H),
3.59 (dd, J = 5.7, 9.6 Hz, 1 H), 1.94 (s, 3 H), 1.37 ppm (s, 9 H); 13C NMR (75 MHz, CDCl3):
δ = 188.6, 170.1, 161.1, 138.3, 137.6, 136.6, 129.7, 128.5 (2 CH), 128.3 (2 CH), 128.1 (CH),
128.1 (2 CH), 127.7, 127.6 (2 CH), 81.5, 73.3 (CH2), 73.2 (CH2), 72.0, 67.4 (CH2), 33.1, 29.0
(3 CH3), 20.8 ppm; IR (KBr): ṽmax = 2966, 2927, 2870, 1745, 1660, 1532, 1371, 1231, 1106,
1051, 742, 699 cmꢀ1; HRMS (ESI): m/z calcd for C27H32N2O5Na [M + Na]+: 487.2209; found:
487.2203.
(2R,3R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀ(tertꢀbutyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate
2o. Prepared according to the general procedure discussed above: Rf = 0.40; eluent, EtOAc/nꢀ
hexane (35%); isolated yield = 0.039 g, 76%; [α]D20 = +1 (c = 0.15 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 9.79 (br. s., 1 H), 7.95 (s, 1 H), 7.28 ꢀ 7.32 (m, 10 H), 5.42
(br. s., 1 H), 4.72 (d, J = 11.1 Hz, 1 H), 4.60 (br. s., 1 H), 4.49 ꢀ 4.53 (m, 3 H), 3.77 (br. s., 2
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H), 1.99 (s, 3 H), 1.38 ppm (s, 9 H); 13C NMR (75 MHz, CDCl3): δ = 187.5, 170.2, 161.1,
138.0, 137.8, 136.7, 129.7, 128.5 (2 CH), 128.3 (2 CH), 128.1, 128.1 (2 CH), 127.6, 127.5 (2
CH), 80.9, 73.2 (1 CH & 1 CH2), 73.0 (CH2), 67.6 (CH2), 33.1, 29.1 (3 CH3), 20.9 ppm; IR
(KBr): ṽmax = 2965, 2928, 2870, 1743, 1662, 1532, 1457, 1370, 1234, 1110, 741, 699 cmꢀ1;
HRMS (ESI): m/z calcd for C27H32N2O5Na [M + Na]+: 487.2209; found: 487.2213.
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(R)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀ(2ꢀ(tertꢀbutyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ3ꢀoxopropyl acetate 2p. Prepared
according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀhexane
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1
(40%); isolated yield = 0.028 g, 53%; [α]D = +1 (c = 0.12 in MeOH); colorless gum. H
NMR (600 MHz, CDCl3): δ = 9.93 (br. s., 1 H), 7.96 (s, 1 H), 7.31 ꢀ 7.36 (m, 5 H), 4.72 (d, J
= 12.0 Hz, 1 H), 4.57 (d, J = 11.4 Hz, 1 H), 4.46 ꢀ 4.49 (m, 2 H), 4.35 ꢀ 4.39 (m, 1 H), 2.01 (s,
3 H), 1.39 ppm (s, 9 H); 13C NMR (150 MHz, CDCl3): δ = 189.0, 171.6, 162.4, 139.5, 137.6,
130.4, 129.6 (2 CH), 129.3, 129.1 (2 CH), 82.0, 73.7 (CH2), 65.3 (CH2), 34.2, 30.1 (3 CH3),
21.8 ppm; IR (KBr): ṽmax = 2965, 2928, 1744, 1661, 1533, 1458, 1372, 1228, 1111, 1045,
742, 699 cmꢀ1; HRMS (ESI): m/z calcd for C19H24N2O4Na [M + Na]+: 367.1634; found:
367.1637.
(2S,3S)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀ(tertꢀbutyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate 2q.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.039 g, 75%; [α]D20 = −7 (c = 0.11 in MeOH); colorless gum.
1H NMR (600 MHz, CDCl3): δ = 10.09 (br. s., 1 H), 7.98 (s, 1 H), 7.29 ꢀ 7.36 (m, 5 H), 5.24 ꢀ
5.28 (m, 1 H), 4.75 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.42 (d, J = 4.2 Hz, 1 H),
1.97 (s, 3 H), 1.40 (s, 9 H), 1.31 ppm (d, J = 6.6 Hz, 3 H); 13C NMR (150 MHz, CDCl3): δ =
188.0, 170.3, 161.2, 138.4, 136.8, 129.7, 128.5 (2 CH), 128.1, 128.0 (2 CH), 83.7, 72.8
(CH2), 71.3, 33.1, 29.1 (3 CH3), 21.1, 15.1 ppm; IR (KBr): ṽmax = 2969, 1739, 1661, 1532,
1371, 1240, 1072, 748 cmꢀ1; HRMS (ESI): m/z calcd for C20H26N2O4Na [M + Na]+:
381.1791; found: 381.1778.
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(2S,3R)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀ(tertꢀbutyl)ꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate 2r.
Prepared according to the general procedure discussed above: Rf = 0.40; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.046 g, 88%; [α]D20 = +1 (c = 0.11 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 9.84 (br. s., 1 H), 7.96 (s, 1 H), 7.29 ꢀ 7.38 (m, 5 H), 5.29
(quin, J = 6.0 Hz, 1 H), 4.73 (d, J = 11.7 Hz, 1 H), 4.46 (d, J = 11.7 Hz, 1 H), 4.15 (d, J = 4.8
Hz, 1 H), 1.94 (s, 3 H), 1.39 (s, 9 H), 1.28 ppm (d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz,
CDCl3): δ = 189.0, 170.2, 161.3, 138.5, 136.6, 129.8, 128.5 (2 CH), 128.1, 128.0 (2 CH),
85.3, 73.1 (CH2), 70.3, 33.2, 29.1 (3 CH3), 21.0, 16.5 ppm; IR (KBr): ṽmax = 2968, 2931,
1741, 1658, 1532, 1372, 1238, 1070, 742, 698 cmꢀ1; HRMS (ESI): m/z calcd for
C20H26N2O4Na [M+Na]+: 381.1791; found: 381.1800.
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(2R,3S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀcyclopropylꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate
2s. Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.032 g, 64%; [α]D20 = −6 (c = 0.10 in MeOH); colorless gum.
1H NMR (600 MHz, CDCl3): δ = 10.49 (br. s., 1 H), 7.90 (s, 1 H), 7.29 ꢀ 7.32 (m, 4 H), 7.26 ꢀ
7.28 (m, 4 H), 7.22 (d, J = 7.2 Hz, 2 H), 5.39 ꢀ 5.41 (m, 1 H), 4.71 (d, J = 12.0 Hz, 1 H), 4.49
(d, J = 3.6 Hz, 1 H), 4.42 ꢀ 4.47 (m, 3 H), 3.68 (dd, J = 6.6, 10.2 Hz, 1 H), 3.58 (dd, J = 6.0,
9.6 Hz, 1 H), 1.97 ꢀ 2.00 (m, 1 H), 1.94 (s, 3 H), 1.08 (m, 2 H), 1.03 ꢀ 1.06 ppm (m, 2 H); 13C
NMR (150 MHz, CDCl3): δ = 189.1, 171.2, 157.2, 140.1, 138.6, 137.6, 131.0, 129.5 (2 CH),
129.4 (2 CH), 129.2, 129.2 (2 CH), 128.7, 128.6 (2 CH), 82.4, 74.2 (CH2), 74.2 (CH2), 73.1,
68.6 (CH2), 21.8, 10.3, 10.0 ppm (2 CH2); IR (KBr): ṽmax = 2925, 2868, 1744, 1657, 1526,
1372, 1232, 1105, 1054, 742, 699 cmꢀ1; HRMS (ESI): m/z calcd for C26H28N2O5Na [M +
Na]+: 471.1896; found: 471.1902.
(2R,3R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀ(2ꢀcyclopropylꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate
2t. Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.024 g, 49%; [α]D20 = +1 (c = 0.1 in MeOH); colorless gum.
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1H NMR (300 MHz, CDCl3): δ = 10.01 (br. s., 1 H), 7.89 (s, 1 H), 7.28 ꢀ 7.32 (m, 10 H), 5.40
(m, 1 H), 4.72 (d, J = 11.1 Hz, 1 H), 4.57 (m, 1 H), 4.48 (m, 3 H), 3.77 (m, 2 H), 1.99 (s, 3
H), 1.93 ꢀ 1.95 (m, 1 H), 1.08 ppm (m, 4 H); 13C NMR (75 MHz, CDCl3): δ = 187.0, 170.2,
156.0, 138.8, 137.7, 136.8, 129.9, 128.5 (2 CH), 128.3 (2 CH), 128.1, 128.0 (2 CH), 127.6,
127.5 (2 CH), 80.7, 73.2, 73.2 (CH2) 73.0 (CH2), 67.6 (CH2), 20.9, 9.3, 8.9 ppm (2 CH2); IR
(KBr): ṽmax = 2924, 1742, 1657, 1522, 1371, 1234, 1107, 740, 699 cmꢀ1; HRMS (ESI): m/z
calcd for C26H28N2O5Na [M + Na]+: 471.1896; found: 471.1887.
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(2S,3S)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀcyclopropylꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate 2u.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (43%); isolated yield = 0.021 g, 43%; [α]D20 = −8 (c = 0.11 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 10.73 (br. s., 1 H), 7.94 (s, 1 H), 7.29 ꢀ 7.36 (m, 5 H), 5.22 ꢀ
5.29 (m, 1 H), 4.74 (d, J = 12.0 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.40 (br. s., 1 H), 1.98 ꢀ
2.06 (m, 1 H), 1.96 (s, 3 H), 1.29 (d, J = 6.6 Hz, 3 H), 1.04 ꢀ 1.10 ppm (m, 4 H); 13C NMR
(150 MHz, CDCl3): δ = 188.6, 171.3, 157.2, 140.1, 137.9, 130.9, 129.5 (2 CH), 129.1, 128.9
(2 CH), 84.7, 73.8 (CH2), 72.4, 22.1, 16.2, 10.3, 9.9 (2 CH2) ppm; IR (KBr): ṽmax = 2926,
1738, 1656, 1523, 1239, 1070 cmꢀ1; HRMS (ESI): m/z calcd for C19H22N2O4Na [M + Na]+:
365.1478; found: 365.1470.
(2S,3R)ꢀ3ꢀ(benzyloxy)ꢀ4ꢀ(2ꢀcyclopropylꢀ1Hꢀimidazolꢀ4ꢀyl)ꢀ4ꢀoxobutanꢀ2ꢀyl acetate 2v.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.031 g, 63%; [α]D20 = +4 (c = 0.11 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 10.05 (br. s., 1 H), 7.91 (s, 1 H), 7.30 ꢀ 7.32 (m, 5 H), 5.27
(quin, J = 6.0 Hz, 1 H), 4.73 (d, J = 11.7 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.13 (d, J = 4.8
Hz, 1 H), 1.96 ꢀ 2.01 (m, 1 H), 1.94 (s, 3 H), 1.26 (d, J = 6.6 Hz, 3 H), 1.07 ꢀ 1.10 ppm (m, 4
H); 13C NMR (75 MHz, CDCl3): δ = 188.5, 170.3, 156.5, 139.4, 136.7, 130.0, 128.5 (2 CH),
128.1, 128.0 (2 CH), 84.9, 73.0 (CH2), 70.4, 21.0, 16.5, 9.3, 9.0 (2 CH2) ppm; IR (KBr): ṽmax
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= 2927, 1740, 1656, 1526, 1374, 1238, 1069, 747, 699 cmꢀ1; HRMS (ESI): m/z calcd for
C19H22N2O4Na [M + Na]+: 365.1478; found: 365.1460.
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(2S,3R)ꢀ2,4ꢀbis(benzyloxy)ꢀ3ꢀhydroxyꢀ1ꢀ(5ꢀiodoꢀ2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)butanꢀ1ꢀone
2w. Prepared according to the general procedure discussed above: Rf = 0.30; eluent,
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EtOAc/nꢀhexane (35%); isolated yield = 0.039 g, 62%; [α]D = −9 (c = 0.12 in MeOH);
colorless gum. 1H NMR (600 MHz, CDCl3): δ = 11.15 (br. s., 1 H), 7.64 ꢀ 7.65 (m, 2 H), 7.40
ꢀ 7.43 (m, 1 H), 7.35 ꢀ 7.38 (m, 2 H), 7.27 ꢀ 7.34 (m, 8 H), 7.23 ꢀ 7.24 (m, 2 H), 4.59 (d, J =
10.8 Hz, 1 H), 4.56 (d, J = 12.0 Hz, 1 H), 4.51 ꢀ 4.55 (m, 2 H), 4.50 (d, J = 3.0 Hz, 1 H), 4.25
ꢀ 4.26 (m, 1 H), 3.72 (dd, J = 6.6, 9.6 Hz, 1 H), 3.65 (dd, J = 5.4, 10.2 Hz, 1 H), 2.95 ppm (d,
J = 4.2 Hz, 1 H); 13C NMR (150 MHz, CDCl3): δ = 188.3, 150.7, 137.4, 136.1, 130.5, 130.4,
128.9 (2 CH), 128.7 (2 CH), 128.6, 128.5 (4 CH), 127.9, 127.8 (2 CH), 127.7, 125.9 (2 CH),
94.4, 84.1, 73.6 (2 CH2), 71.3, 70.6 (CH2) ppm; IR (KBr): ṽmax = 2924, 2858, 1661, 1591,
1458, 1385, 1236, 1074, 741, 698 cmꢀ1; HRMS (ESI): m/z calcd for C27H25IN2O4Na [M +
Na]+: 591.0757; found: 591.0777.
(2R,3R)ꢀ2,4ꢀbis(benzyloxy)ꢀ3ꢀhydroxyꢀ1ꢀ(5ꢀiodoꢀ2ꢀphenylꢀ1Hꢀimidazolꢀ4ꢀyl)butanꢀ1ꢀone
2x. Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (35%); isolated yield = 0.040 g, 63%; [α]D20 = −1 (c = 0.12 in MeOH); colorless gum.
1H NMR (600 MHz, CDCl3): δ = 11.16 (br. s., 1 H), 7.64 (d, J = 7.2 Hz, 2 H), 7.40 (t, J = 7.2
Hz, 1 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.30 ꢀ 7.31 (m, 3 H), 7.23 ꢀ 7.29 (m, 7 H), 4.63 (d, J =
10.8 Hz, 2 H), 4.59 (d, J = 11.4 Hz, 1 H), 4.49 (s, 2 H), 4.34 (m, 1 H), 3.69 (dd, J = 4.2, 10.2
Hz, 1 H), 3.60 (dd, J = 6.6, 9.6 Hz, 1 H), 3.01 ppm (br. s., 1 H); 13C NMR (150 MHz,
CDCl3): δ = 187.8, 150.6, 137.3, 136.3, 131.0, 130.4, 128.9 (2 CH), 128.8 (2 CH), 128.5,
128.4 (2 CH), 128.4 (2 CH), 127.9, 127.8 (2 CH), 127.6, 125.9 (2 CH), 94.6, 84.4, 73.6
(CH2), 73.4 (CH2), 71.7, 70.0 (CH2) ppm; IR (KBr): ṽmax = 2924, 2860, 1661, 1496, 1459,
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1233, 1093, 745, 698 cmꢀ1; HRMS (ESI): m/z calcd for C27H25IN2O4Na [M + Na]+: 591.0757;
found: 591.0770.
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Ethyl 5ꢀ((2R,3S)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀhydroxybutanoyl)ꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate 3a.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
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hexane (22%); isolated yield = 0.039 g, 78%; [α]D = +8 (c = 0.10 in MeOH); colorless
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gum. H NMR (600 MHz, CDCl3): δ = 7.67 (s, 1 H), 7.30 ꢀ 7.36 (m, 5 H), 4.72 (d, J = 11.4
Hz, 1 H), 4.47 (d, J = 11.4 Hz, 1 H), 4.32 (q, J = 7.8, 14.4 Hz, 2 H), 4.14 (d, J = 6.0 Hz, 1 H),
4.07 ꢀ 4.12 (m, 1 H), 2.69 (s, 3 H), 2.62 (d, J = 4.8 Hz, 1 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.19
ppm (d, J = 6.0 Hz, 3 H); 13C NMR (150 MHz, CDCl3): δ = 188.6, 165.2, 163.7, 149.7,
137.6, 129.6 (2 CH), 129.4 (2 CH), 129.4, 122.5, 117.3, 88.2, 74.1 (CH2), 69.9, 61.8 (CH2),
19.7, 15.3, 15.3 ppm; IR (KBr): ṽmax = 2927, 1719, 1668, 1592, 1528, 1432, 1241, 1097 cmꢀ1;
HRMS (ESI): m/z calcd for C19H22O6Na [M + Na]+: 369.1314; found: 369.1321.
Benzyl 5ꢀ((2R,3S)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀhydroxybutanoyl)ꢀ2ꢀmethylfuranꢀ3ꢀcarboxylate 3b.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
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hexane (20%); isolated yield = 0.043 g, 73%; [α]D = +4 (c = 0.25 in MeOH); colorless
gum. 1H NMR (300 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.42 (m, 5 H), 7.32 (m, 5 H), 5.32 (s, 2
H), 4.72 (d, J = 11.4 Hz, 1 H), 4.48 (d, J = 11.4 Hz, 1 H), 4.07 ꢀ 4.16 (m, 2 H), 2.71 (s, 3 H),
2.60 (d, J = 4.2 Hz, 1 H), 1.20 ppm (d, J = 6.0 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ =
187.6, 164.4, 162.5, 148.8, 136.5, 135.5, 128.6 (2 CH), 128.5 (2 CH), 128.4, 128.3 (2 CH),
128.3 (2 CH), 128.1, 121.2, 115.9, 87.1, 73.1 (CH2), 68.8, 66.5 (CH2), 18.7, 14.3 ppm; IR
(KBr): ṽmax = 2926, 1721, 1670, 1592, 1529, 1454, 1235, 1094, 748, 700 cmꢀ1; HRMS (ESI):
m/z calcd for C24H24O6Na [M + Na]+: 431.1471; found: 431.1462.
Ethyl 5ꢀ((2R,3S)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀhydroxybutanoyl)ꢀ2ꢀphenylfuranꢀ3ꢀcarboxylate 3c.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (20%); isolated yield = 0.040 g, 67%; [α]D20 = +1 (c = 0.2 in MeOH); colorless gum.
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1H NMR (600 MHz, CDCl3): δ = 8.07 ꢀ 8.09 (m, 2 H), 7.82 (s, 1 H), 7.46 ꢀ 7.50 (m, 3 H),
7.31 ꢀ 7.37 (m, 5 H), 4.76 (d, J = 11.4 Hz, 1 H), 4.53 (d, J = 11.4 Hz, 1 H), 4.35 (dd, J = 0.6,
7.2 Hz, 1 H), 4.33 (dd, J = 1.2, 7.2 Hz, 1 H), 4.25 (d, J = 6.6 Hz, 1 H), 4.17 (quin, J = 6.6 Hz,
1 H), 2.68 (br. s., 1 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.24 ppm (d, J = 6.6 Hz, 3 H); 13C NMR
(150 MHz, CDCl3): δ = 187.8, 162.4, 160.8, 148.7, 136.6, 130.9, 129.1 (2 CH), 128.6 (2 CH),
128.4 (2 CH), 128.4, 128.3 (2 CH), 128.2, 122.9, 116.0, 87.2, 73.2 (CH2), 68.8, 61.1 (CH2),
18.8, 14.2 ppm; IR (KBr): ṽmax = 2979, 2929, 1722, 1668, 1574, 1525, 1484, 1218, 1101, 763,
696 cmꢀ1; HRMS (ESI): m/z calcd for C24H24O6Na [M + Na]+: 431.1471; found: 431.1489.
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Ethyl
5ꢀ((2R,3S)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀhydroxybutanoyl)ꢀ2ꢀ(4ꢀchlorophenyl)furanꢀ3ꢀ
carboxylate 3d. Prepared according to the general procedure discussed above: Rf = 0.40;
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eluent, EtOAc/nꢀhexane (25%); isolated yield = 0.026 g, 40%; [α]D = −4 (c = 0.33 in
MeOH); colorless gum. 1H NMR (600 MHz, CDCl3): δ = 8.08 (d, J = 8.4 Hz, 2 H), 7.82 (s, 1
H), 7.46 (d, J = 8.4 Hz, 2 H), 7.33 ꢀ 7.36 (m, 5 H), 4.76 (d, J = 11.4 Hz, 1 H), 4.54 (d, J =
11.4 Hz, 1 H), 4.35 (q, J = 7.2, 14.4 Hz, 2 H), 4.22 (d, J = 6.0 Hz, 1 H), 4.15 ꢀ 4.17 (m, 1 H),
2.64 (br. s., 1 H), 1.37 (t, J = 6.6 Hz, 3 H), 1.24 ppm (d, J = 6.6 Hz, 3 H); 13C NMR (150
MHz, CDCl3): δ = 187.8, 162.2, 159.5, 148.7, 137.1, 136.5, 130.4 (2 CH), 128.7 (2 CH),
128.6 (2 CH), 128.4 (2 CH), 128.4, 126.6, 122.9, 116.2, 87.3, 73.2 (CH2), 68.8, 61.3 (CH2),
18.7, 14.2 ppm; IR (KBr): ṽmax = 2923, 2853, 1722, 1668, 1585, 1479, 1219, 1095, 838, 698
cmꢀ1; HRMS (ESI): m/z calcd for C24H23ClO6Na [M + Na]+: 465.1081; found: 465.1098.
Methyl 5ꢀ((2R,3S)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀhydroxybutanoyl)ꢀ2ꢀmethoxyfuranꢀ3ꢀcarboxylate 3e.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (40%); isolated yield = 0.020 g, 40%; [α]D20 = +1 (c = 0.12 in MeOH); colorless gum.
1H NMR (600 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.31 ꢀ 7.37 (m, 5 H), 4.72 (d, J = 11.4 Hz, 1
H), 4.47 (d, J = 11.4 Hz, 1 H), 4.27 (s, 3 H), 4.04 ꢀ 4.08 (m, 2 H), 3.83 (s, 3 H), 2.67 (br. s., 1
H), 1.18 ppm (d, J = 5.4 Hz, 3 H); 13C NMR (150 MHz, CDCl3): δ = 185.5, 164.2, 162.1,
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141.1, 136.5, 128.6 (2 CH), 128.4 (2 CH), 128.3, 125.1, 94.4, 87.1, 73.0 (CH2), 69.0, 58.6,
51.7, 18.6 ppm; IR (KBr): ṽmax = 2928, 1718, 1657, 1597, 1544, 1409, 1243, 1100, 776 cmꢀ1;
HRMS (ESI): m/z calcd for C18H20O7Na [M + Na]+: 371.1107; found: 371.1126.
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Prepared according to the general procedure discussed above: Rf = 0.32; eluent, EtOAc/nꢀ
hexane (20%); isolated yield = 0.040 g, 80%; [α]D20 = −1 (c = 0.12 in MeOH); colorless gum.
1H NMR (600 MHz, CDCl3): δ = 7.66 (s, 1 H), 7.30 ꢀ 7.36 (m, 5 H), 4.73 (d, J = 11.4 Hz, 1
H), 4.47 (d, J = 11.4 Hz, 1 H), 4.34 (d, J = 4.8 Hz, 1 H), 4.31 (q, J = 7.2, 14.4 Hz, 2 H), 4.18 ꢀ
4.21 (m, 1 H), 2.68 (s, 3 H), 2.31 (d, J = 6.0 Hz, 1 H), 1.36 (t, J = 7.2 Hz, 3 H), 1.25 ppm (d,
J = 6.6 Hz, 3 H); 13C NMR (150 MHz, CDCl3): δ = 187.5, 163.9, 162.7, 148.9, 136.8, 128.5
(2 CH), 128.1 (3 CH), 121.2, 116.2, 85.8, 72.9 (CH2), 68.8, 60.7 (CH2), 18.9, 14.3, 14.2 ppm;
IR (KBr): ṽmax = 2980, 2931, 1719, 1675, 1593, 1528, 1434, 1242, 1098, 746, 700 cmꢀ1;
HRMS (ESI): m/z calcd for C19H22O6Na [M + Na]+: 369.1314; found: 369.1319.
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Ethyl 5ꢀ((2S,3S)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀhydroxybutanoyl)ꢀ2ꢀphenylfuranꢀ3ꢀcarboxylate 3g.
Prepared according to the general procedure discussed above: Rf = 0.30; eluent, EtOAc/nꢀ
hexane (20%); isolated yield = 0.038 g, 64%; [α]D20 = −1 (c = 0.10 in MeOH); colorless gum.
1H NMR (300 MHz, CDCl3): δ = 8.06 ꢀ 8.09 (m, 2 H), 7.80 (s, 1 H), 7.45 ꢀ 7.49 (m, 3 H),
7.31 ꢀ 7.36 (m, 5 H), 4.78 (d, J = 11.4 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.45 (d, J = 5.1
Hz, 1 H), 4.33 (q, J = 7.2, 14.4 Hz, 2 H), 4.22 ꢀ 4.30 (m, 1 H), 2.20 (d, J = 6.9 Hz, 1 H), 1.35
(t, J = 7.2 Hz, 3 H), 1.28 ppm (d, J = 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ = 187.8,
162.4, 160.7, 148.9, 136.9, 130.8, 129.1 (2 CH), 128.5 (2 CH), 128.3 (3 CH), 128.2 (2 CH,
C0), 122.7, 115.9, 85.9, 72.9 (CH2), 68.8, 61.1 (CH2), 19.0, 14.2 ppm; IR (KBr): ṽmax = 2980,
2929, 1722, 1675, 1572, 1525, 1485, 1450, 1218, 1102, 762, 695 cmꢀ1; HRMS (ESI): m/z
calcd for C24H24O6Na [M + Na]+: 431.1471; found: 431.1484.
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