Glycosylated vinyl ethers by the Julia-Lythgoe-Kocienski olefination: application to the synthesis of 2′,5′-dideoxydisaccharides and carbohydrated β-lactams

Article abstract of DOI:10.1016/j.tetasy.2009.05.039

α-Carbohydrated pyridinyl sulfones, prepared from commercially available d-(-)-ribose, d-(+)-galactose, and d-(+)-glucose through a five-step sequence, have been employed in the Julia-Lythgoe-Kocienski olefination with aldehydes. This one-pot protocol, us

Full text of DOI:10.1016/j.tetasy.2009.05.039

Tetrahedron: Asymmetry 20 (2009) 1646–1660
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Glycosylated vinyl ethers by the Julia–Lythgoe–Kocienski olefination:
application to the synthesis of 20,50-dideoxydisaccharides and carbohydrated
b-lactams
*
Iván Pérez Sánchez, Edward Turos
Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, University of South Florida CHE 205, 4202 East Fowler Avenue, Tampa, FL 33620, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Carbohydrated pyridinyl sulfones, prepared from commercially available
D
D
-(ꢀ)-ribose,
D-(+)-galactose,
Received 27 April 2009
Accepted 20 May 2009
Available online 28 July 2009
and -(+)-glucose through a five-step sequence, have been employed in the Julia–Lythgoe–Kocienski olef-
ination with aldehydes. This one-pot protocol, using solid KOH at room temperature, affords the corre-
sponding glycosidic enol ethers in moderate to excellent yields and (E)-stereoselectivities. These
glycosylated adducts undergo hetero-Diels–Alder reactions with 2-formyl-1-malondialdehyde to afford
20,50-dideoxygenated disaccharides in good yields and complete regio- and endo-selectivity. Alternatively,
the [2+2]-cycloaddition reaction of the glycosidic enol ethers with chlorosulfonyl isocyanate provided
glycosylated b-lactams regioselectively and with only trans-stereoselectivity. The b-lactams could be con-
verted to N-methylthio derivatives which show decent antibacterial activity toward methicillin-resistant
strains of Staphylococcus aureus.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
ogy to yet another historically important area of synthesis,
carbohydrates, through the development of glycosylated Julia re-
The construction of functionalized carbon–carbon double bonds
has remained among the most investigated and important syn-
thetic transformations, spawning the development of various
new methodologies which enable the efficient construction of
highly substituted olefins with control of double bond geometry.1
One of the most employed examples among these is the classical
Julia coupling, also known as the Julia–Lythgoe olefination.2 Dis-
closed more than 30 years ago, the Julia coupling employs a reduc-
tive elimination of b-acyloxy phenyl sulfones, which can be
prepared by the addition of phenylsulfonyl-stabilized carbanions
to carbonyl compounds, with conversion of the resulting alcohol
to the acyl ester. Since its discovery, significant advances have been
made to further improve the efficiency of the reaction, as well as to
apply its use as a key step in natural products synthesis.3 A recent
variant of this reaction, the Julia–Lythgoe–Kocienski olefination,
offers a convenient one-pot coupling procedure that has emerged
as a powerful synthetic tool. Its novelty stems from the replace-
ment of the commonly used phenylsulfonyl stabilizing moiety for
a heteroarylsulfonyl group, which permits the spontaneous elimina-
tion of the sulfonic acid and concomitant formation of the desired
olefin in a single operation.4
agents.5 As we began this study, we succeeded in finding only
one prior publication of an
a
-alkoxysulfone being employed in a
Julia olefination.6
Herein we report the preparation of the requisite
a
-carbohy-
drated pyridinylsulfones and some representative examples of
their reactions with aldehydes to prepare carbohydrated enol
ethers. We then explore the application of these adducts to the
synthesis of disaccharides and carbohydrated b-lactams by cyclo-
addition with 2-formyl-1-malondialdehyde and chlorosulfonyl iso-
cyanate, respectively.
2. Results and discussion
2.1. Preparation of a-glycosyloxymethyl pyridin-2-ylsulfones 5
For this study, we focused on several pyridin-2-ylsulfones 5.
These were readily prepared by reaction of 2-mercaptopyridine
with the corresponding O-chloromethyl glycoside 3 using NaH as
base and NaI as an anion transfer agent in THF at room tempera-
ture, to give sulfides 4 (Scheme 1). Subsequently, oxidation with
m-CPBA in the presence of a buffer solution of Na2HPO4 or with
hydrogen peroxide (30% H2O2) and a catalytic amount of sodium
tungstate (Na2WO4ꢁ2H2O) 10 mol % in methanol gave sulfones 5.
The requisite chloromethyl glycosides 3a–d for these syntheses
were prepared from the corresponding acetonide-protected
monosaccharides 1a–d using sodium hydride as a base and
In our studies relating to the development of methods for glyco-
sylation, we aimed to apply this popular and powerful methodol-
* Corresponding author. Tel.: +1 813 974 7312; fax: +1 813 974 1733.
E-mail address: eturos@cas.esf.edu (E. Turos).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.039

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1647
O
O
O
O
O
1. NaH, THF
O
O
O
Cl2 (g), CCl4
20 ºC, 1 min
O
20 ºC
O
O
O
2. CH3SCH2Cl
3. NaI
O
O
O
O
O
HO
1a
MeS
Cl
2a 71-89%
3a >95%
O
O
O
O
m-CPBA, Na2HPO4
1. NaH, THF, rt
N
SH
O
O
CH2Cl2, 0 to 20 ºC
O
O
2. 3a, NaI, THF
or
0 to 20 ºC
O
O
N
N
O
O
30% H2O2, Na2WO4
MeOH, 0 to 20 ºC
S
S
O
O
4a 64-66% (from 2a)
5a 76%
Yield %
77
1
2
Yield %
77
3
Yield %
>95
4
Yield %
5
O
1b
O
O
HO
73
3b
4b
5b
O
O
1c
1d
72
86
86
78
86
O
2c
3c
>95
>95
4c
5c
OMe
HO
O
O
See
compou
nds 6
and 7 in
Scheme
2
3d
4d
5d
BnO
BnO
O
O
O
HO
Scheme 1. Synthesis of glycosylated pyridin-2-ylsulfones 5a–d.
methylthiomethylene chloride followed by the addition of NaI to
give the O-alkylated product 2, which was then converted by chlo-
rination to chloromethyl derivatives 3. Overall isolated yields for
this two-step transformation ranged from 60% to 85%. In the case
of preparing compound 3d, the extra-annular acetonide moiety
of 2a was first replaced with benzyl groups to give sulfide 7 prior
to sulfone formation (Scheme 2).
BuLi and ꢀ25 °C for KHMDS) in THF, DME, or toluene as solvents.
The best results were observed using solid KOH pellets in anhy-
drous THF in the presence of tetrabutylammonium bromide
(TBAB). Using these conditions, we examined the olefination
reactions of sulfones 5a–d with a representative variety of non-
enolizable aldehydes to further evaluate the scope and limitations
(Table 1).
In terms of scope, this single-pot coupling reaction proceeded
successfully and with good to excellent efficiency with benzalde-
hyde to afford ethenyl ethers 8a,c,g,o in 63–78% yields (entries 1,
3, 7, and 15). The same was the case for aryl aldehydes bearing
electron-donating substituents to give ethenyl ethers 8d,e,h,i,l,m
in 70–91% yields (entries 4, 5, 8, 9, 12, and 13), and with 2-fural-
dehyde, which afforded 8n in 92% yield (entry 14). However, the
2.2. Julia–Lythgoe–Kocienski synthesis of ethenyl ethers 8
We initiated our studies of the olefination reactions using these
glycosylated sulfone reagents by examining different bases such as
KHMDS, LiHMDS, BuLi, and KOH, either at room temperature
(KOH) or at low temperatures (ꢀ78 °C for KHMDS, LiHMDS, and
HO
BnO
1. NaH (3 eq)
HO
BnO
O
O
Cl2 (g), CCl4
20 ºC, 1 min
NaHSO4.SiO2 (cat)
THF, 20 ºC
O
O
2a
3d
2. BnBr (5 eq)
20 ºC, 12 h
CH2Cl2:i-PrOH, 4:1
O
O
O
O
rt, 48 h
MeS
MeS
6
7
75-93%
74-86%
Scheme 2. Synthesis of O-chloromethyl glycoside 3d.

1648
I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
Table 1
Glycosylated enol ethers 8a–r produced via the Julia–Kocienski olefination
1. RCHO, TBAB (0.2 eq)
THF, 20 ºC, 10 min
N
R
OCarbohydrate
S
OCarbohydrate
2. KOH (15 eq), 20 ºC, 24 h
O
O
8
5
Entry
1
Sulfone 5
RCHO
Enol ether 8
Yielda (%)
63
E/Zb
O
O
PhCHO
8a
75/25
O
O
5a
N
O
2
O
4-FC6H4CHO
8b
54
75/25
S
O
O
96/4c
89/11
89/11
93/7
N
3
4
5
6
PhCHO
8c
8d
8e
8f
71
91
78
40
O
O
4-MeOC6H4CHO
2-MeOC6H4CHO
4-FC6H4CHO
O
O
S
O
5b
O
O
O
7
8
9
10
11
PhCHO
8g
8h
8i
8j
8k
72
88
83
48
45
94/6c
78/22
71/29
92/8
4-MeOC6H4CHO
2-MeOC6H4CHO
4-ClC6H4CHO
2-ClC6H4CHO
78/22
CHO
N
O
12
8l
70
81/19
OMe
S
O
5c
O
O
OMe
O
O
13
14
4-Me2NC6H4CHO
8m
8n
81
92
86/14
67/33d
CHO
O
BnO
BnO
15
16
PhCHO
8o
8p
8q
78
31
58
71/29
>1/99
69/31
O
5d
O
t-BuCHO
4-FC6H4CHO
O
N
O
S
O
17
O
a
Isolated yield after flash chromatography.
b
c
Determined by 1H NMR of the crude reaction mixture. Most enol ether mixtures can be enriched in one or the other diastereoisomer after column chromatography.
The major diastereomer (E) was isolated by column chromatography.
d
Diastereomers were separated by column chromatography.
yield of the coupling reaction dropped drastically (31–58%) when
electron-deficient haloaryl aldehydes (entries 2, 6, 10, 11, and 17)
or the bulky trimethylacetaldehyde (entry 16) was used as sub-
strate. The (E)-stereoselectivity was high with neutral or elec-
tron-poor aromatic aldehydes, and decreased slightly when
electron-rich aromatic aldehydes or heteroaryl aldehydes were
employed. It is noteworthy that the olefination reaction with piv-
aldehyde afforded the corresponding enol ether 8p with an oppo-
site (reversed) sense of stereoselectivity (geometry) [only the (Z)-
isomer], which was evident from its 1H NMR spectrum. This indi-
cates that E-stereoselection may be partially governed by the ste-
ric demands of the aldehyde. With respect to sulfone 5, we
observed no discernible differences in the yield of the reaction
when galactose 5b, ribose 5c, or glucoses 5a,d sulfone derivatives
were used with benzaldehyde in the presence of KOH and TBAB:
galactosyl and ribosyl sulfones, 5b and 5c, afforded ethenyl ethers
8c and 8g in 71% and 72% yield, respectively, and with excellent
diastereoselectivities (E/Z 96:4 and 94:6) (Table 1, entries 3 and
7). The analogous use of the two glucosyl sulfones 5a and 5d
led to enol ethers 8a and 8o (63% and 78%, respectively) but with
a markedly lower E-selectivity (E/Z 75:25 and 71:29) (Table 1, en-
tries 1 and 15). This indicates that the steric demands of the car-
bohydrate reagent may affect E-stereoselection, with sulfones
derived from secondary carbohydrate alcohols 5a and 5d
providing lower E-selectivity than those of primary alcohols 5b
and 5c.

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1649
In terms of the limitations of the reaction, so far, we have not
had success in applying the modified Julia–Lythgoe–Kocienski olef-
ination conditions to the sulfones 5a–d while attempting to use
readily enolizable alkyl aldehydes 9–12, 3-methyl-2-butenal 13,
paraformaldehyde 14, ethyl glyoxalate 15, 3-pyridinecarboxalde-
hyde 16, 4-nitrobenzaldehyde 17, methyl 4-formylbenzoate 18,
or 2-(methoxymethyloxy-methyl)benzaldehyde 19 (Fig. 1). In each
of these experiments, the corresponding 2-pyridinyl ether deriva-
tive 21, 22, or 23 was isolated in 30–55% yield. Curiously, these
unanticipated products do not retain the initial methylenesulfone
unit, which is apparently expelled through a pathway that we have
not yet deduced. In analogous reactions, sulfone 5c and 2-cyano-
benzaldehyde 20 afforded approximately 5% of the corresponding
enol desired ether 8 based on NMR evaluation of the crude product
mixture, which shows signals of clear doublets (J = 12.9 Hz) at d
5.80 and 7.03 for each of the vinyl protons that correspond to
the E-isomer of compound 8. However, this product was not fur-
ther purified.
The yield and stereoselectivity of these olefinations seem to be
sensitive to the nature of the base and solvent used. For instance,
reaction of ribosyl pyridinylsulfone 5c with benzaldehyde, which
provided the enol ether 8g in 72% and 94:6 ratio of E/Z isomers
with solid KOH as a base, gave only a 54% yield and 2.3:1 mixture
of E/Z diastereomers when solid NaOH was used instead. This re-
sult shows that both yield and (E)-stereoselectivity are diminished
when NaOH replaces KOH as base for initiating the coupling. We
also attempted, under analogous treatment, the Julia olefination
between sulfone 5c and benzaldehyde using KOH/toluene or
LiOH/THF instead of KOH/THF. However, neither gave the ethenyl
ether 8g, presumably due to the poor solubility of the reagents in
toluene and the lower basicity of LiOH, respectively. In both in-
stances, the starting materials were recovered upon aqueous
workup.
hand, we suggest that the smaller (harder) sodium cation has a
stronger tendency to form a chelated (or closed) transition state
A0 proceeding to the syn adduct B0, which decomposes stereospecif-
ically to the (Z)-vinyl ether 8. Thus, the use of NaOH in the place of
KOH lowers E/Z stereoselectivity in the olefin formation.
2.3. Reactions with enol ethers 8: hetero-Diels–Alder
Enol ethers have an electron-rich functionality, and are well
documented to participate in electrophilic additions or cycloaddi-
tions. Simple enol ethers of glycosidic substrates have been pre-
pared by acid-catalyzed elimination of orthoformates and acetals,
Tebbe reaction with a glycosidic acetate, base-promoted addition
of a glycosidic alcohol to propiolate, and metal-catalyzed trans-
vinylation of glycosidic acetates.7–17 The enol ether functionality
has been introduced onto the carbohydrate most commonly as a
means to facilitate the stereocontrolled introduction of carbon sub-
stituents at the anomeric center, and for glycosylation reactions.
There are a few other instances involving the use of glycosidic vinyl
ethers, such as for polymerization processes or as dienophiles in
[2+2] and hetero-Diels–Alder reactions.16–18 It is the latter applica-
tions that we considered of most immediate interest to us, given
the propensity and popularity of hetero-Diels–Alder methodology
to prepare structurally complex frameworks. In order to establish
some preliminary indications on the synthetic utility of these b-
substituted enol ether glycosides, we explored their reactivity as
dienophiles in hetero-Diels–Alder reactions as illustrated in
Scheme 4. In the first example, ethenyl ether 8c (X = H, 10:1 mix-
ture of E/Z isomers) in a 10:1 mixture of benzene/CH2Cl2 at 82 °C
(sealed tube) led, after two days, to the 20,50-dideoxydisaccharide
aldehyde 25 (X = H) in 77% yield and as an 2:1 mixture of two dia-
stereoisomers (25a and 25b).19,20 Along with adducts 25, 15% of
starting enol ether 8c was observed in the crude mixture after
workup, as a 1.5:1 mixture of E/Z isomers. Compounds 25 and 8c
were separated by flash column chromatography. The analogous
reaction carried out with alkenyl ethers 8f (X = F, E/Z 6.3:1), 8g
(E/Z 7.5:1), and 8b (E/Z 3:1) produced the corresponding annulated
adducts 26 (67%), 27 (73%), and 28 (36%), respectively, also as non-
separable 2:1, 1.2:1, and 8:1 mixtures of diastereomers, respec-
tively. In each case, we also recovered the corresponding starting
enol ethers 8f (25%, E/Z 1:1.1), 8g (20%, E/Z 1.2:1), and 8b (57%,
E/Z 2:1) from the reaction mixture after workup. The structure
A possible mechanistic explanation for these differences in E/Z
stereoselectivities is depicted in Scheme 3. Initially the sulfonyl
carbanion, generated with KOH, reacts with the aldehyde through
a non-chelated (or open) transition state A, which is favored for po-
lar solvents and large counter cations such as potassium. This
kinetically controlled addition preferentially generates the anti-b-
alkoxysulfone B, which decomposes stereospecifically via Smiles
rearrangement with spontaneous expulsion of sulfur dioxide and
2-hydroxypyridine to yield the (E)-vinyl ether 8. On the other
O
O
H
H
(CH2O)n
H
X
Y
X
EtO
15
H
O
O
O
O
9, 10
11, 12
X = OCOPh
13
14
X = S, Y = Ph
X = OCH2OMe
X = O, Y = OMe
O
O
H
O
NC
O
H
OMe
H
H
O
H
N
O2N
O
OMe
N
16
17
18
19
20
N
BnO
O
O
O
O
O
OMe
O
O
BnO
N
O
O
O
O
O
O
O
21
22
23
Figure 1. Limitations of the one-pot Julia–Lythgoe–Kocienski olefination with sulfones 5a–d.

1650
I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
O
SO2PYR
H
OK
H
N
PYR
R1O
R1O
R
S
K
SO2PYR
H
O
R
R1O
=
H
or
S
K
R
O
O
R1O
O
OK
R
H
O
B
H
A
N
OPYR
H
H
O
H
K
R1O
R
R
R1O
R
R1O
PYRO
SO2
H
SO2K
SO2K
or
H
R
R1O
(E)-8
H
C
D
{ R1O = carbohydrate moiety }
O
SO2PYR
R
ONa
H
H
N
PYR
R1O
R
S
Na
SO2PYR
H
O
R1O
=
R1O
H
or
S
Na
O
O
O
R1O
R
ONa
O
H
R
B'
H
A'
N
O
OPYR
R
R1O
Na
R1O
H
R1O
H
R1O
R
SO2
SO2Na
SO2Na
or
PYRO
R
H
R
H
H
H
(Z)-8
C'
D'
Scheme 3. Proposed mechanism for the origin of E/Z selectivity.
and relative stereochemistry of the cycloaddition products 25, 26,
27, and 28 were confirmed by 1D and 2D NMR spectroscopic
experiments.21
2.4. Reactions with enol ethers 8: [2+2] cycloaddition
Chlorosulfonyl isocyanate (CSI) is a highly reactive participant
in [2+2]-cycloadditions with vinyl ethers, providing an attractive
and direct route to substituted b-lactams.22 Recently, sugar-de-
rived vinyl ethers have been used as chiral starting materials in
these cycloadditions for the asymmetric synthesis of b-lactams.23
Our group has had a longstanding interest in b-lactam chemistry,
and in particular, the microbiological activity of N-thiolated b-lac-
tams as mechanistically novel antibiotics.24 The water solubility of
these compounds however is very low, and thus we had hoped to
prepare glycosylated b-lactam derivatives for examination. This led
us to consider the reaction of the glycosylated enol ethers prepared
above for stereocontrolled [2+2]-cycloaddition reactions leading to
C4-glycosylated b-lactams.22,25
We first investigated the reaction of chlorosulfonyl isocyanate
with galactosyl ethenyl ether 8c (used as a 40:1 mixture of E/Z iso-
mers) in toluene in the presence of pulverized anhydrous sodium
carbonate (Scheme 6).26 We noted that the formation of the de-
sired b-lactam and the N-chlorosulfonyl group was then removed
by Red-Al reduction at 70 °C. After hydrolytic workup, we obtained
3,4-disubstituted b-lactam 29 in 77% yield as a 1.3:1 mixture of
diastereomers, which unfortunately could not be separated by
flash column chromatography.
It is interesting that the E/Z ratios of the recovered starting enol
ethers 8 from each of the cycloaddition reactions had an increased
amount of Z-isomer: 8b, E/Z 3:1 (initial) versus 2:1 (recovered); for
8c, E/Z 10:1 (initial) versus 1.5:1 (recovered); for 8f, E/Z ratio 6.3:1
(initial) versus 1:1 recovered); for 8g, E/Z 7.5:1 (initial) versus 1.2:1
(recovered). We attribute this to the strong preference for the E-
isomer to undergo cycloaddition much more readily than the Z-iso-
mer, which remains unreactive in the reaction mixture. This is cor-
roborated with the finding that only the cis-disubstituted
stereoisomers of cycloadducts 25, 26, 27, and 28 are obtained, all
coming from the E-enol ether. The [4+2] cycloaddition reactions
proceed with complete regio- and endo-selectivity and with good
yields (67–77%) when primary enol ethers are employed, but the
yield drops noticeably when secondary ethenyl ether 8b (36%) is
used. The high endo stereocontrol (with respect to the carbohy-
drate-O moiety) is the result of an expected strong donor–acceptor
p-interaction between the oxygen non-bonding electrons of the
enol ether and the carbonyl of the aldehyde function (Scheme 5).
The corresponding transition states endo-I and endo-II lead to the
two possible endo adducts 25a (or 26a) and 25b (or 26b). Similar
transition states would explain the respective formation of the het-
ero-Diels–Alder products 27a, 27b, 28a, and 28b. The higher facial
diastereoselectivity provided by the enol ethers of secondary alco-
hol glycosides 8b versus those of the primary alcohols 8c,f,g is
likely due to greater steric interactions manifested within these
The analogous treatment of glycosylated enol ethers 8g (2.3:1 E/
Z), 8o (2.3:1 E/Z), and 8q (E/Z 1.2:1) with CSI followed by Red-Al
reduction resulted in the formation of the corresponding b-lactams
30, 31, and 32, respectively.27 While the yields of the latter reac-
tions are similar to that with 8c, the diastereoselectivity of the cyc-
p-stacked transition states.

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1651
O
O
X
H
HO
O
H
O
H
O
O
O
O
O
O
O
O
O
O
O
H
conditions
O
O
O
O
O
O
and
HO
O
(eq. a)
+
H
O
O
O
X
X
24
8c X = H 10:1 (E:Z )
25a,b X = H 77%, 2:1
8f X = F 6.3:1 (E:Z)
26a,b X = F
67%, 2:1
O
O
H
HO
O
H
O
H
O
O
O
O
H
conditions
OMe
O
O
O
OMe
OMe
+
O
HO
O
(eq. b)
and
H
O
O
O
O
O
O
24
8g 7.5:1 (E:Z)
27a,b 73%, 1.15:1
O
O
O
O
O
O
O
O
O
O
H
O
H
O
O
H
O
O
O
H
conditions
(eq. c)
O
O
O
and
O
O
O
+
H
O
HO
HO
O
O
F
24
F
F
8b 3:1 (E:Z)
28a,b 36%, 8:1
Scheme 4. 20,50-Dideoxydisaccharides 25–28 prepared by hetero-Diels–Alder of enol ethers 8b,c,f, and g and 2-formyl-1-malondialdehyde. Reaction conditions: sealed tube,
benzene/CH2Cl2 (10:1), 70–82 °C, two days.
O
O
O
OH
O
O
Ar
H
O
O
O
O
H
O
O
O
O
HO
O
RO
O
Ar
O
Ar
endo-I
8c,8f
25a,26a
+
O
H
O
H
O
O
RO
O
O
O
O
O
HO
H
Ar
O
Ar
O
O
H
O
OH
H
24
endo-II
25b,26b
{ RO = carbohydrate moiety }
Scheme 5. Proposed explanation for the endo-selectivity of the hetero-Diels–Alder cycloadditions of glycosidic enol ethers 8.
loadditions once again varies depending on the enol ether used. For
gen enhances stereoregulation. NMR experiments carried out on
the lactam product 31, and on the diastereomeric mixture of ad-
ducts 29 and 30, confirmed the trans stereochemistry of the C3
and C4 ring substituents.21
Our study indicates that the stereochemical outcome of the
[2+2]-cycloaddition is independent of the geometric structure or
E/Z ratio of the glycosylated enol ethers used. This was further
demonstrated in using a different mixture of ethenyl ethers 8g
(E/Z 4:1), which also gave b-lactam 30 as a 1.2:1 mixture of diaste-
reomers (Scheme 6). This finding, coupled to the exclusive forma-
instance, vinyl ethers of primary hydroxylated carbohydrates (gal-
actose and ribose) led to an almost equimolar mixture of diastere-
oisomers of b-lactams 29 (1.3:1) and 30 (1.2:1), respectively, while
for the enol ether at a secondary hydroxyl position (glucose), b-lac-
tams 31 and 32 were obtained as single diastereomers. We attri-
bute this high stereofacial-differentiation for 31 and 32 to the
enhanced steric bias arising from the C4 substituent of the furanoid
ring in 8o and 8q. This confirms the results of the [4+2] cycloaddi-
tions (Scheme 4), in which more steric crowding near the enol oxy-

1652
I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
H
SMe
H
N
N
N
O
O
O
Ph
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
1.
2.
O
O
1.
2.
O
O
O
O
8c 40:1 (E:Z)
29
77%, 1.3:1
29 1.3:1
33
62%, 1.3:1
H
N
SMe
H
O
O
O
Ph
O
N
N
OMe
OMe
O
O
1.
2.
O
O
O
1.
2.
OMe
OMe
O
O
O
O
O
O
O
O
O
O
8g
30
30
2.25:1 (E:Z)
4:1 (E:Z)
71%, 1.2:1
72%, 1.2:1
8g
30 1.2:1
34 46%, 1.2:1
BnO
BnO
BnO
BnO
BnO
BnO
H
O
BnO
H
BnO
SMe
N
O
O
O
O
O
O
O
O
1.
2.
1.
2.
N
O
N
O
O
O
O
O
O
O
O
O
X
8q X = H
2.3:1 (E:Z )
8s X = F 1.2:1 (E:Z )
X
X
X
31 X = H 67%, >98:2
32 X = F
31 X = H >98:2
32 X = F
35 X = H 65%, >98:2
36 X = F
65%, >98:2
>98:2
68%, >98:2
Scheme 6. Carbohydrated b-lactams 29–32 prepared by [2+2] cycloaddition of enol
ethers 8c,g,q,s and chlorosulfonyl isocyanate. Reaction conditions: (1) ClSO2NCO
(3 equiv), Na2CO3 (4 equiv), toluene, ꢀ70 °C, then ꢀ25 °C, 5 h; (2) Red-Al (4 equiv),
ꢀ70 °C, 45 min, then H2O, 0 °C, 15 min.
Scheme 7. Synthesis of N-(methylthio)-b-lactams 33–36. Reaction conditions: (1)
n-BuLi, THF, hexanes, ꢀ78 to ꢀ60 °C, 1 h; (2) MeSSO2Me, ꢀ78 °C to rt, 7 h.
for lactam 34 was 15 mm, with equal effectiveness against MSSA
and MRSA. This is a moderate bioactivity although greater than
that of the reference drug, penicillin, against MRSA (12 mm) and
slightly lower than the activity of another reference drug, vanco-
mycin, against MRSA (18 mm). b-Lactam 35 showed a broth mini-
tion of only the trans-disubstituted b-lactams, suggest a stepwise
addition–cyclization reaction mechanism proceeding through a
resonance-stabilized zwitterion (Fig. 2).
Earlier studies in our laboratories on N-alkylthiolated b-lactams
established that the N-organothio substituent is essential for anti-
microbial activity of these highly lipophilic molecules.23 Thus, we
wanted to investigate the antibacterial properties of the carbohy-
drated b-lactams by converting them to the corresponding N-
methylthio-substituted derivatives 33–36. This was done by
deprotonation of the N-protio precursors 29–32 with n-butyllith-
ium, followed by trapping of the lithium amide anion with methyl
methanethiolsulfonate (Scheme 7).
mum inhibitory concentration (MIC) value of 32 to 64 lg/mL
against all the Staphylococcus microbes. This likewise represents
a moderate, but stronger in vitro activity against MRSA compared
to that of penicillin G (MIC >64 l
g/mL).22
3. Conclusion
In conclusion, we have reported the preparation of glycosidic
enol ethers by Julia–Lythgoe–Kocienski coupling of b-glycoside-
substituted pyridinylsulfones with aldehydes using solid KOH as
a base. Yields and stereoselectivities for this olefination are moder-
ate to excellent depending on the nature of the carbohydrate (pri-
mary alcohols vs secondary alcohols) and the steric and electronic
properties of the aldehyde. These glycosylated enol ethers serve as
convenient starting materials for the synthesis of O-linked disac-
charides and carbohydrated b-lactams. Facial selectivity of the enol
ethers expressed during the cycloadditions is highly dependent on
the steric constraints and conformation effects exerted by the car-
bohydrate moiety.
2.5. Microbiological testing of lactams 34 and 35
The b-lactams 34 and 35 derived from protected
D
-(ꢀ)-ribose
and -(+)-glucose, respectively, were individually tested for anti-
D
bacterial activity against methicillin-susceptible and methicillin-
resistant strains of Staphylococcus aureus Kirby–Bauer well diffu-
sion assays on agar plates for 34 was first done against one MSSA
strain and ten MRSA isolates, all of which were b-lactamase pro-
ducing strains having high resistance to penicillins. The average
diameter (from three experiments) of the growth inhibition zones
carbohydrate
4. Experimental
4.1. General
O
Ph
N
O
Cl
HO
S
O
All reactions were carried out in an oven-dried (90 °C) or flame-
dried glassware under an inert atmosphere with the use of stan-
dard techniques for handling air-sensitive materials. All common
Figure 2. Zwitterion intermediate in the b-lactam formation.

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1653
reagents and solvents were obtained from commercial suppliers
and used without any further purification. Solvents used for the
reactions requiring an inert atmosphere were dried before their
use:28 THF and diethyl ether were refluxed over sodium/benzophe-
none ketyl and distilled immediately prior to use; dichloromethane
was refluxed over phosphorus pentoxide (P4O10) for 24 h and dis-
tilled immediately prior to use. Unless otherwise noted, reaction
mixtures were magnetically stirred and reactions were monitored
by thin layer chromatography (TLC) using on aluminum-backed
analytical TLC plates coated with silica gel 60 with F254 indicator
(Merck Kieselgel 60F254 plates); the chromatograms were visual-
ized under ultraviolet light and/or by staining with a Ce/Mo or DNP
(for aldehydes) reagent and subsequent heating. Rf values are re-
ported on silica gel. Flash column chromatography was carried
The crude was purified by column chromatography on silica gel
(Hx/EtOAc 15:1) to afford the corresponding sulfide 2.
Compound 2a: Colorless oil in 89% yield. Rf = 0.34 (Hx/EtOAc,
8:1); 1H NMR (400 MHz, CDCl3): d 1.30 (s, 3H), 1.31 (s, 3H), 1.40
(s, 3H), 1.48 (s, 3H), 2.16 (s, 3H), 3.96 (dd, J = 8.4, 5.6, 1H), 4.00–
4.13 (m, 2H), 4.22 (td, J = 5.8, 1.5, 1H), 4.30 (d, J = 2.5, 1H), 4.53
(d, J = 3.5, 1H), 4.67 (d, J = 11.5, 1H), 4.77 (d, J = 11.7, 1H), 5.86 (d,
J = 3.5, 1H); 13C NMR (100 MHz, CDCl3): d 13.7 (CH3), 25.2 (CH3),
26.0 (CH3), 26.6 (CH3), 26.7 (CH3), 67.4 (CH2), 72.2 (CH), 74.5
(CH2), 78.8 (CH), 81.0 (CH), 82.6 (CH), 105.1 (CH), 108.9 (C),
111.7 (C); HRMS (ESI): calcd for C14H25O6S [M++H]: 321.1365;
found: 321.1357.
Compound 2b: Colorless oil in 77% yield. Rf = 0.35 (Hx/EtOAc,
8:1); 1H NMR (250 MHz, CDCl3): d 1.34 (s, 3H), 1.35 (s, 3H), 1.46
(s, 3H), 1.54 (s, 3H), 2.16 (s, 3H), 3.67 (dd, J = 10.3, 7.1, 1H), 3.79
(dd, J = 10.3, 5.2, 1H), 3.99 (ddd, J = 7.0, 5.4, 1.8, 1H), 4.26 (dd,
J = 7.9, 1.9, 1H), 4.33 (dd, J = 5.1, 2.4, 1H), 4.61 (dd, J = 7.9, 2.5,
1H), 4.66 (d, J = 11.5, 1H), 4.75 (d, J = 11.5, 1H), 5.55 (d, J = 5.1,
1H); 13C NMR (63 MHz, CDCl3): d 13.7 (CH3), 24.3 (CH3), 24.8
(CH3), 25.8 (CH3), 25.9 (CH3), 66.6 (CH), 66.6 (CH2), 70.3 (CH),
70.5 (CH), 71.1 (CH), 75.4 (CH2), 96.2 (CH), 108.4 (C), 109.1 (C);
HRMS (ESI): calcd for C14H25O6S [M++H]: 321.1365; found:
321.1363.
out on J. T. Baker flash chromatography silica gel (40 lm) or on AC-
ROS aluminum oxide, activated, neutral (50–200 micron). Product
yields refer to chromatographically and spectroscopically pure
compounds, unless otherwise noted. Proton NMR spectra were
recorded with the use of an internal deuterium lock at ambient
temperature with a Bruker DPX-250 or Varian INOVA-400 spec-
trometers. Chemical shifts are given in d units, using the signal at
d = 7.27 for residual CHCl3 in CDCl3 as an internal standard. Chem-
ical shifts are reported in d units (downfield to dTMS = 0 ppm), with
the signal multiplicity (s = singlet, d = doublet, t = triplet, q = quar-
tet, quint. = quintuplet, m = multiplet, br = broad, app = apparent),
coupling constant(s) (J in Hz) and integration area in parentheses.
13C NMR spectra were determined using the signal for residual
CHCl3 in CDCl3 at d = 77.16 as an internal standard. Multiplicities
were determined by DEPT, COSY, HMQC, HMBC, and NOESY exper-
iments. Standard pulse sequences were employed for the DEPT
experiments. Mass spectra were determined at 70 eV with a Agi-
lent Technologies LC–MSD VL and LC-–MSD TOF for low resolution
mass spectra (LRMS), and high resolution mass spectra (HRMS),
respectively; the intensities are reported as a percentage relative
to the base peak after the corresponding m/z value. ESI Electron
spray ionization technique was employed. Infrared spectra were
obtained with Thermo Electron Corporation-Nicolet IR 100. Optical
rotations were measured with an AutopolÒ IV polarimeter
equipped with a sodium lamp. The concentration c to calculate
specific rotation is given in g/100 mL. Melting points were deter-
mined on a Mel-Temp II apparatus and are uncorrected.
Compound 2c: Colorless oil in 72% yield. Rf = 0.45 (Hx/EtOAc,
8:1); 1H NMR (250 MHz, CDCl3): d 1.33 (s, 3H), 1.49 (s, 3H), 2.16
(s, 3H), 3.34 (s, 3H), 3.52 (dd, J = 9.7, 8.1, 1H), 3.60 (dd, J = 9.8,
7.5, 1H), 4.33 (td, J = 7.0, 0.6, 1H), 4.59 (d, J = 6.0, 1H), 4.66–4.69
(m with s at 4.68, 3H), 4.98 (s, 1H); 13C NMR (63 MHz, CDCl3): d
13.8 (CH3), 24.8 (CH3), 26.3 (CH3), 54.7 (CH3), 68.7 (CH2), 75.4
(CH2), 82.0 (CH), 84.9 (CH), 85.0 (CH), 109.1 (CH), 112.2 (C); HRMS
(ESI): calcd for C11H21O5S [M++H]: 265.1104; found: 265.1110.
4.3.1. Synthesis of diol 630
Diacetonide 2a (6.30 g, 19.7 mmol) was dissolved in a mixture
of CH2Cl2/isopropyl alcohol (4:1, 100 mL) and then NaHSO4?SiO2
(1.97 g) was added at room temperature.31 The reaction mixture
was stirred for two days. The mixture was then filtered, and con-
centrated under vacuum. The crude was chromatographed on a sil-
ica gel column (CH2Cl2/EtOAc 1:1) to give diol
6 (4.74 g,
16.94 mmol, 86%) as a colorless oil. Rf = 0.26 (CH2Cl2/EtOAc 1:1);
1H NMR (400 MHz, CDCl3): d 1.32 (s, 3H), 1.50 (s, 3H), 2.24 (s,
3H), 2.29 (br s, 1H, CHOH), 2.98 (d, J = 5.3, 1H, CH2OH), 3.70–3.79
(m, 1H), 3.83–4.00 (m, 2H), 4.15 (dd, J = 8.1, 2.9, 1H), 4.26 (d,
J = 3.0, 1H), 4.57 (d, J = 3.8, 1H), 4.67 (d, J = 11.8, 1H), 4.85 (d,
J = 11.8, 1H), 5.91 (d, J = 3.8, 1H); 13C NMR (63 MHz, CDCl3): d
14.7 (CH3), 26.5 (CH3), 26.9 (CH3), 64.4 (CH2), 69.0 (CH), 75.5
(CH2), 79.9 (CH), 80.2 (CH), 82.8 (CH), 105.4 (CH), 112.1 (C); HRMS
(ESI): calcd for C11H21O6S [M++H]: 281.1053; found: 281.1047.
4.2. Materials
Commercially available
D
-(ꢀ)-ribose,
D-(+)-galactose, D-(+)-glu-
cose, BuLi (1.6 m in hexane), and chlorine (g) were used as re-
ceived. 2-Formyl-1-malondialdehyde was prepared according to
the literature procedures.29
4.3. General procedure for the preparation of methylthiomethy-
lidene derivatives 2
4.3.2. Synthesis of compound 7
Over a stirred suspension of NaH (591 mg, 24.6 mmol; washed
with hexane) in THF (40 mL) under argon was added a solution of
diol 6 (2.3 g, 8.2 mmol) in THF (30 mL). The mixture was then stir-
red for 45 min. Then, a solution of benzyl bromide (4.92 mL,
41.0 mmol, 7.03 g) in THF (20 mL) was added to the mixture. Stir-
ring was continued at room temperature overnight. The reaction
was quenched with NH4Cl (40 mL), THF was removed under re-
duced pressure, and the residue was extracted with CH2Cl2
(2 ꢂ 40 mL) and with ether (1 ꢂ 40 mL). The extracts were dried
over Na2SO4 and concentrated in vacuo. The crude product mixture
was chromatographed on a silica gel column (Hx/EtOAc 5:1) to
To a stirring suspension of NaH (1.56 g, 65 mmol; pre-washed
with anhydrous hexane to remove the mineral oil dispersant) in
THF (60 mL) under argon was added dropwise a solution of the cor-
responding alcohol 1 (50 mmol) in THF (65 mL). The mixture was
then stirred for 45 min. After the mixture was cooled with an ice
bath, a solution of chloromethyl methyl sulfide (4.95 mL, 60 mmol)
in THF (65 mL) was added slowly followed by NaI (8.99 g,
60 mmol). The ice bath was removed and stirring was continued
overnight at room temperature (the product starts to decompose
after 12 h of reaction). The reaction was quenched with 5% aqueous
NH4Cl (100 mL), THF was removed under reduced pressure, and
the residue was washed with saturated aqueous sodium thiosul-
fate (2 ꢂ 40 mL) and extracted with diethyl ether (3 ꢂ 40 mL).
The extracts were dried over Na2SO4 and concentrated in vacuo.
give compound
7 (3.52 g, 7.64 mmol, 93%) as a yellow oil.
Rf = 0.44 (Hx/EtOAc 4:1); 1H NMR (250 MHz, CDCl3): d 1.33 (s,
3H), 1.50 (s, 3H), 2.12 (s, 3H), 3.72 (dd, J = 10.8, 5.8, 1H), 3.93–
4.03 (m, 2H), 4.25 (d, J = 3.3, 1H), 4.34 (dd, J = 9.3, 3.3, 1H), 4.55–
4.69 (m with s at 4.60, 6H), 4.88 (d, J = 11.3, 1H), 5.90 (d, J = 3.8,

1654
I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1H), 7.23–7.40 (m, 10H); 13C NMR (63 MHz, CDCl3): d 14.4 (CH3),
26.1 (CH3), 26.5 (CH3), 70.6 (CH2), 71.8 (CH2), 73.1 (CH2), 75.0
(CH2), 75.1 (CH), 78.5 (CH), 80.4 (CH), 82.1 (CH), 104.7 (CH),
111.6 (C), 127.2 (CH), 127.3 (CH), 127.4 (5 ꢂ CH), 128.1 (3 ꢂ CH),
138.3 (C), 138.3 (C); HRMS (ESI): calcd for C27H33O6S [M++H]:
485.1989; found: 485.1996.
(CH3), 54.3 (OCH3), 69.3 (CH2), 71.6 (CH2), 81.6 (CH), 84.3 (CH),
84.7 (CH), 108.8 (CH), 111.8 (C), 119.8 (CH), 122.3 (CH), 136.0
(CH), 149.0 (CH), 157.2 (C); HRMS (ESI): calcd for C15H22NO5S
[M++H]: 328.1212; found: 328.1216.
Compound 4d: Colorless oil in 86% yield after two steps. Rf = 0.25
(Hx/EtOAc, 4:1); 1H NMR (250 MHz, CDCl3): d 1.34 (s, 3H), 1.51 (s,
3H), 3.69 (dd, J = 10.6, 5.6, 1H), 3.91 (dd, J = 10.6, 2.1, 1H), 3.96–
4.02 (m, 1H), 4.34 (dd, J = 9.1, 2.9, 1H), 4.40 (d, J = 3.3, 1H), 4.47
(d, J = 11.3, 1H), 4.60 (s, 2H), 4.74 (d, J = 3.3, 1H), 4.77 (d, J = 4.5,
1H), 5.42 (d, J = 11.5, 1H), 5.52 (d, J = 11.5, 1H), 5.89 (d, J = 3.8,
1H), 7.13 (m, 1H), 7.26–7.39 (m, 11H), 7.58–7.67 (m, 1H), 8.48
(dddd, J = 10.8, 4.9, 1.8, 0.9, 1H); 13C NMR (63 MHz, CDCl3): d
26.1 (CH3), 26.5 (CH3), 70.1 (CH2), 70.8 (CH2), 72.1 (CH2), 73.1
(CH2), 74.9 (CH), 78.2 (CH), 80.4 (CH), 81.7 (CH), 104.7 (CH),
111.5 (C), 120.1 (CH), 122.4 (CH), 127.2 (CH), 127.3 (CH), 127.5
(2 ꢂ CH), 128.0 (3 ꢂ CH), 128.1 (3 ꢂ CH), 136.2 (CH), 138.3 (C),
138.5 (C), 149.3 (CH), 156.4 (C); HRMS (ESI): calcd for C31H34NO6S
[M++H]: 548.2097; found: 548.2103.
4.4. General procedure for the preparation of chloromethyl
derivatives 3
Into a solution of sulfide 2a–c or 7 (30 mmol) in CCl4 (100 mL)
was slowly bubbled Cl2 gas for 1 min at room temperature. After
this period, CCl4 was removed under reduced pressure. The residue
was washed with water (40 mL) and extracted with CH2Cl2
(3 ꢂ 40 mL). The extracts were dried over Na2SO4 and concentrated
in vacuo. Due to the instability of chloromethyl ethers, the crude
product 3 was used for the next step without further purification.
NMR of the crude mixture show yields estimated to be over 95%.
Compound 3d: Rf = 0.50 (Hx/EtOAc, 4:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H), 1.51 (s, 3H), 2.12 (s, 3H), 3.70 (dd, J = 11.0,
5.5, 1H), 3.87–3.96 (m, 2H), 4.35 (s, 1H), 4.36 (dd, J = 10.5, 2.8,
1H), 4.57 (d, J = 11.4, 1H), 4.61 (s, 2H), 4.72 (d, J = 3.8, 1H), 4.85
(d, J = 11.4, 1H), 5.32 (d, J = 5.9, 1H), 5.43 (d, J = 5.9, 1H), 5.90 (d,
J = 3.8, 1H), 7.29–7.40 (m, 10H); 13C NMR (63 MHz, CDCl3): d 26.2
(CH3), 26.6 (CH3), 70.4 (CH2), 72.0 (CH2), 73.3 (CH2), 74.7 (CH),
78.1 (CH), 81.5 (CH2), 82.2 (CH), 82.4 (CH), 104.8 (CH), 112.0 (C),
127.4 (CH), 127.5 (2 ꢂ CH), 127.6 (CH), 127.8 (2 ꢂ CH), 128.2
(2 ꢂ CH), 128.3 (2 ꢂ CH), 138.2 (C), 138.3 (C).
4.6. General procedures for the preparation of (2-pyridinyl)sul-
fonylmethylidene derivatives 5
Method A: To a cooled solution of sulfide 4 (20 mmol) in CH2Cl2
(300 mL) at 0 °C were added 3-chloroperoxybenzoic acid (70%,
14.8 g, 60 mmol) and then sodium phosphate dibasic (21.3 g,
150 mmol). The ice bath was removed and stirring was continued
at room temperature for 5 h. The reaction mixture was filtered and
concentrated in vacuo. The crude was purified by flash column
chromatography (Hx/EtOAc 3:1 and then Hx/EtOAc 3:2) to give
the corresponding sulfone 5.
4.5. General procedure for the preparation of (2-pyridinyl)thio-
methyl derivatives 4
Method B:4h To a solution of the sulfide 4 (20 mmol) in metha-
nol (180 mL) at 0 °C was added sodium tungstate dihydrate (0.66 g,
2.0 mmol), followed by slow addition of 30% aqueous H2O2
(20.6 mL, 0.2 mol). The reaction mixture was allowed to warm to
room temperature and was stirred for 8 h. The reaction mixture
was then diluted with CH2Cl2 (180 mL) and a solution of 10% aque-
ous NaHSO3 was added. The biphasic mixture was stirred for
15 min and the layers were separated. The aqueous layer was
washed with CH2Cl2 (2 ꢂ 70 mL) and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The crude was purified by col-
umn chromatography (Hx/EtOAc 3:1 and then Hx/EtOAc 3:2) to
give the corresponding sulfone 5.
Compound 5a: White solid in 86% yield. Rf = 0.35 (Hx/EtOAc,
4:3); 1H NMR (250 MHz, CDCl3): d 1.28 (s, 3H), 1.32 (s, 3H), 1.41
(s, 3H), 1.46 (s, 3H), 3.89 (app d, J = 4.9, 2H), 4.00–4.13 (m, 2H),
4.41 (d, J = 1.7, 1H), 4.50 (d, J = 3.5, 1H), 5.06 (d, J = 12.8, 1H), 5.19
(d, J = 12.8, 1H), 5.76 (d, J = 3.5, 1H), 7.64 (ddd, J = 7.6, 4.6, 1.0,
1H), 8.05 (td, J = 7.7, 1.6, 1H), 8.20 (dt, J = 7.9, 0.6, 1H), 8.80 (dt,
J = 3.8, 0.8, 1H); 13C NMR (63 MHz, CDCl3): d 24.8 (CH3), 25.8
(CH3), 26.3 (2 ꢂ CH3), 66.6 (CH2), 72.0 (CH), 80.4 (CH), 81.6 (CH2),
82.6 (CH), 84.6 (CH), 104.6 (CH), 108.8 (C), 111.6 (C), 123.1 (CH),
127.5 (CH), 137.9 (CH), 150.1 (CH), 155.3 (C); HRMS (ESI): calcd
for C18H26NO8S [M++H]: 416.1371; found: 416.1369.
Compound 5b: Colorless oil in 77% yield. Rf = 0.27 (Hx/EtOAc,
3:2); 1H NMR (250 MHz, CDCl3): d 1.31 (s, 6H), 1.42 (s, 3H), 1.46
(s, 3H), 3.85–3.94 (m, 2H), 3.99–4.05 (m, 1H), 4.12 (dd, J = 7.8,
1.5, 1H), 4.29 (dd, J = 5.1, 2.5, 1H), 4.57 (dd, J = 7.9, 2.5, 1H), 4.94
(d, J = 12.6, 1H), 5.07 (d, J = 12.6, 1H), 5.49 (d, J = 5.1, 1H), 7.56
(ddd, J = 7.7, 4.7, 1.1, 1H), 7.97 (td, J = 7.7, 1.7, 1H), 8.15 (app d,
J = 7.9, 1H), 8.78 (ddd, J = 4.6, 1.6, 0.8, 1H); 13C NMR (63 MHz,
CDCl3): d 23.9 (CH3), 24.4 (CH3), 25.4 (2 ꢂ CH3), 66.4 (CH), 69.8
(CH), 70.0 (CH), 70.2 (CH), 71.7 (CH2), 83.0 (CH2), 95.6 (CH),
108.1 (C), 108.9 (C), 123.4 (CH), 127.3 (CH), 137.8 (CH), 149.9
(CH), 155.1 (C); HRMS (ESI): calcd for C18H26NO8S [M++H]:
416.1371; found: 416.1365.
To a stirred suspension of NaH (0.93 g, 39 mmol; pre-washed
with hexane) in THF (80 mL) under argon was added a solution
of 2-mercaptopyridine (4.00 g, 36 mmol) in THF (80 mL). The mix-
ture was then stirred for 45 min. After the mixture was cooled with
an ice bath, there was added dropwise a solution of the chloro-
methyl glycoside 3 (30 mmol) and NaI (5.39 g, 36 mmol) in THF
(80 mL). The ice bath was then removed and stirring was continued
at room temperature for overnight. The reaction was quenched
with NH4Cl (100 mL), THF was removed under reduced pressure,
and the residue washed with saturated aqueous sodium thiosulfate
(2 ꢂ 40 mL) and extracted with ether (3 ꢂ 40 mL). The extracts
were dried over Na2SO4 and concentrated in vacuo. The crude
was chromatographed on a silica gel column (Hx/EtOAc 5:1) to
give the corresponding pyridinylthiomethyl derivative 4.
Compound 4b: Orange oil in 73% yield after two steps. Rf = 0.27
(Hx/EtOAc, 4:1); 1H NMR (250 MHz, CDCl3): d 1.31 (s, 3H), 1.32 (s,
3H), 1.44 (s, 3H), 1.51 (s, 3H), 3.75 (dd, J = 10.4, 7.1, 1H), 3.83 (dd,
J = 10.4, 5.5, 1H), 4.02 (app td, J = 6.2, 1.5, 1H), 4.20 (dd, J = 7.9, 1.6,
1H), 4.30 (dd, J = 5.1, 2.4, 1H), 4.39 (d, J = 3.0, 1H), 4.58 (dd, J = 7.9,
2.3, 1H), 5.36 (d, J = 11.5, 1H), 5.49 (d, J = 11.5, 1H), 5.53 (d, J = 5.4,
1H), 7.00–7.05 (m, 1H), 7.33 (d, J = 8.1, 1H), 7.51 (td, J = 7.8, 1.6,
1H), 8.45 (ddd, J = 4.9, 2.0, 1.0, 1H); 13C NMR (63 MHz, CDCl3): d
24.2 (CH3), 24.7 (CH3), 25.8 (CH3), 25.8 (CH3), 66.3 (CH), 67.4
(CH2), 70.3 (CH), 70.4 (CH), 70.8 (CH), 72.1 (CH2), 96.1 (CH),
108.3 (C), 109.0 (C), 120.0 (CH), 122.5 (CH), 136.2 (CH), 149.2
(CH), 157.8 (C); HRMS (ESI): calcd for C18H26NO6S [M++H]:
384.1473; found: 384.1471.
Compound 4c: Orange oil in 86% yield after two steps. Rf = 0.35
(Hx/EtOAc, 2:1); 1H NMR (250 MHz, CDCl3): d 1.27 (s, 3H), 1.45
(s, 3H), 3.24 (s, 3H), 3.56 (dd, J = 9.7, 8.1, 1H), 3.65 (dd, J = 9.7,
6.4, 1H), 4.32 (app t, J = 7.1, 2H), 4.54 (d, J = 6.0, 1H), 4.61 (d,
J = 4.9, 1H), 4.93 (s, 1H), 5.40 (s, 2H), 7.03 (ddd, J = 7.4, 4.9, 1.1,
1H), 7.30 (d, J = 7.9, 1H), 7.52 (td, J = 7.4, 1.9, 1H), 8.44 (ddd,
J = 4.9, 1.9, 0.8, 1H); 13C NMR (63 MHz, CDCl3): d 24.5 (CH3), 26.0

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1655
Compound 5c: White solid in 78% yield. Rf = 0.12 (Hx/EtOAc,
2:1); 1H NMR (250 MHz, CDCl3): d 1.21 (s, 3H), 1.37 (s, 3H), 3.21
(s, 3H), 3.75 (dd, J = 10.0, 7.9, 1H), 3.81 (dd, J = 10.0, 6.6, 1H), 4.14
(app t, J = 7.1, 1H), 4.46 (d, J = 7.0, 1H), 4.49 (d, J = 6.5, 1H), 4.85
(s, 1H), 4.91 (d, J = 3.3, 2H), 7.54 (ddd, J = 7.6, 4.7, 1.1, 1H), 7.94
(td, J = 7.7, 1.6, 1H), 8.08 (d, J = 7.9, 1H), 8.71 (ddd, J = 4.7, 1.6, 0.8,
1H); 13C NMR (63 MHz, CDCl3): d 24.6 (CH3), 26.1 (CH3), 54.7
(CH3), 73.7 (CH2), 81.3 (CH), 82.9 (CH2), 84.2 (CH), 84.7 (CH),
109.1 (CH), 112.2 (C), 123.3 (CH), 127.5 (CH), 138.0 (CH), 150.2
(CH), 155.6 (C); HRMS (ESI): calcd for C15H22NO7S [M++H]:
360.1110; found: 360.1115.
Compound 5d: White solid in 84% yield. Rf = 0.23 (Hx/EtOAc,
2:1); 1H NMR (400 MHz, CDCl3): d 1.29 (s, 3H), 1.47 (s, 3H), 3.65
(dd, J = 10.5, 4.8, 1H), 3.77–3.83 (m, 1H), 3.89 (dd, J = 10.6, 1.4,
1H), 4.28–4.32 (m with s at 4.32, 2H), 4.46 (d, J = 11.5, 1H), 4.56
(s, 2H), 4.58 (d, J = 4.0, 1H), 4.80 (d, J = 11.3, 1H), 4.82 (d, J = 12.5,
1H), 4.98 (d, J = 12.3, 1H), 5.75 (d, J = 3.8, 1H), 7.28–7.36 (m,
10H), 7.51 (ddd, J = 7.3, 4.8, 0.5, 1H), 7.89 (td, J = 7.8, 1.3, 1H),
8.06 (d, J = 7.8, 1H), 8.71 (d, J = 4.3, 1H); 13C NMR (63 MHz, CDCl3):
d 25.9 (CH3), 26.3 (CH3), 69.6 (CH2), 71.2 (CH2), 72.8 (CH2), 74.6
(CH), 78.0 (CH), 81.8 (CH2), 82.1 (CH), 84.7 (CH), 104.2 (CH),
111.5 (C), 122.7 (CH), 127.1 (CH), 127.1 (2 ꢂ CH), 127.3 (CH),
127.4 (2 ꢂ CH), 127.9 (2 ꢂ CH), 128.0 (2 ꢂ CH), 137.8 (C), 137.9
(CH+C), 149.9 (CH), 155.3 (C); HRMS (ESI): calcd for C31H34NO8S
[M++H]: 580.1995; found: 580.1999.
(CH), 105.1 (CH), 107.7 (CH), 109.3 (C), 112.1 (C), 115.4 (d,
J = 21.6, 2 ꢂ CH), 126.5 (d, J = 7.8, 2 ꢂ CH), 130.2 (d, J = 8.3, C),
145.8 (d, J = 1.4, CH), the fluorinated carbon was not resolved. Re-
solved signals for the minor isomer: 1H NMR (250 MHz, CDCl3): d
5.23 (d, J = 6.9, 1H), 5.88 (d, J = 3.9, 1H), 6.18 (d, J = 7.0, 1H); HRMS
(ESI) of the mixture: calcd for C20H25O6FNa [M++Na]: 403.1526;
found: 403.1532.
Compound 8c: White solid in 71% yield and as a 96:4 mixture of
E/Z diastereomers. Rf = 0.47 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.35 (s, 3H), 1.37 (s, 3H), 1.49 (s, 3H), 1.55 (s, 3H),
3.93–4.15 (m with d at 4.03, J = 3.5, and d at 4.10, J = 6.8, 3H),
4.32 (dd, J = 7.9, 1.7, 1H), 4.36 (dd, J = 5.0, 2.5, 1H), 4.66 (dd,
J = 7.9, 2.4, 1H), 5.58 (d, J = 4.9, 1H), 5.89 (d, J = 13.0, 1H), 7.04 (d,
J = 13.0, 1H), 7.13–7.26 (m with s at 7.23, 5H); 13C NMR (63 MHz,
CDCl3): d 24.4 (CH3), 24.9 (CH3), 25.9 (CH3), 26.0 (CH3), 66.3 (CH),
68.3 (CH2), 70.5 (CH), 70.6 (CH), 71.0 (CH), 96.3 (CH), 106.3 (CH),
108.7 (C), 109.5 (C), 125.1 (2 ꢂ CH), 125.6 (CH), 128.5 (2 ꢂ CH),
136.2 (C), 147.7 (CH). Resolved signals for the minor isomer: 1H
NMR (250 MHz, CDCl3): d 5.26 (d, J = 7.1, 1H), 6.26 (d, J = 7.1,
1H); HRMS (ESI) of the mixture: calcd for C20H26O6Na [M++Na]:
385.1620; found: 385.1622.
Compound 8d: Colorless oil in 91% yield and as a 89:11 mixture
of E/Z diastereomers. Rf = 0.37 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.35 (s, 3H), 1.37 (s, 3H), 1.48 (s, 3H), 1.55 (s, 3H), 3.79 (s,
3H), 3.96–4.13 (m, 3H), 4.31 (dd, J = 8.0, 1.8, 1H), 4.35 (dd, J = 5.1,
2.5, 1H), 4.65 (dd, J = 7.9, 2.5, 1H), 5.57 (d, J = 5.1, 1H), 5.86 (d,
J = 13.0, 1H), 6.82 (d, J = 8.7, 2H), 6.92 (d, J = 13.0, 1H), 7.15 (d,
J = 8.7, 2H); 13C NMR (63 MHz, CDCl3): d 24.4 (CH3), 24.8 (CH3),
25.9 (CH3), 26.0 (CH3), 55.2 (CH3), 66.2 (CH), 68.2 (CH2), 70.4
(CH), 70.6 (CH), 70.9 (CH), 96.3 (CH), 105.9 (CH), 108.6 (C), 109.4
(C), 114.0 (2 ꢂ CH), 126.1 (2 ꢂ CH), 128.8 (C), 146.4 (CH), 157.8
(C). Resolved signals for the minor isomer: 1H NMR (250 MHz,
CDCl3): d 3.80 (s, 3H), 5.21 (d, J = 7.0, 1H), 6.18 (d, J = 7.0, 1H),
6.83 (d, J = 8.8, 2H), 7.54 (d, J = 8.8, 2H); 13C NMR (63 MHz, CDCl3):
d 24.3 (CH3), 55.1 (CH3), 66.8 (CH), 70.5 (CH), 70.8 (CH), 96.2 (CH),
105.7 (CH), 109.3 (C), 113.5 (2 ꢂ CH), 128.7 (C), 144.8 (CH), 157.5
(C); HRMS (ESI) of the mixture: calcd for C21H28O7Na [M++Na]:
415.1725; found: 415.1717.
Compound 8e: Colorless oil in 78% yield and as a 89:11 mixture
of E/Z diastereomers. Rf = 0.28 (Hx/EtOAc, 6:1); 0.18 (Hx/CH2Cl2,
6:1); 1H NMR (250 MHz, CDCl3): d 1.35 (s, 3H), 1.38 (s, 3H), 1.49
(s, 3H), 1.56 (s, 3H), 3.84 (s, 3H), 3.98–4.16 (m, 3H), 4.33 (dd,
J = 7.9, 1.7, 1H), 4.36 (dd, J = 5.2, 2.5, 1H), 4.66 (dd, J = 7.9, 2.5,
1H), 5.58 (d, J = 4.9, 1H), 6.11 (d, J = 13.0, 1H), 6.83–6.91 (m, 2H),
7.01–7.18 (m with d at 7.15, J = 12.9, 2H), 7.24 (dd, J = 7.6, 1.4,
1H); 13C NMR (63 MHz, CDCl3): d 24.3 (CH3), 24.8 (CH3), 25.8
(CH3), 25.9 (CH3), 55.2 (CH3), 66.2 (CH), 67.9 (CH2), 70.4 (CH),
70.5 (CH), 70.9 (CH), 96.2 (CH), 101.8 (CH), 108.6 (C), 109.3 (C),
110.5 (CH), 120.5 (CH), 125.0 (C), 126.0 (CH), 126.4 (CH), 148.4
(CH), 155.8 (C). Resolved signals for the minor isomer: 1H NMR
(250 MHz, CDCl3): d 3.82 (s, 3H), 4.63 (dd, J = 7.6, 2.5, 1H), 5.56
(d, J = 4.9, 1H), 5.69 (d, J = 7.1, 1H), 6.31 (d, J = 7.1, 1H); 13C NMR
(63 MHz, CDCl3): d 24.2 (CH3), 55.3 (CH3), 66.6 (CH), 70.7 (CH),
71.6 (CH), 96.1 (CH), 99.1 (CH), 109.2 (C), 110.0 (CH), 120.3 (CH),
126.6 (CH), 146.4 (CH); HRMS (ESI) of the mixture: calcd for
C21H28O7Na [M++Na]: 415.1725; found: 415.1719.
4.7. General procedure for the preparation of enol ethers 8
To a stirred solution of sulfone 5 (1.0 mmol) and tetrabutylam-
monium bromide (65 mg, 0.2 mmol) in THF (30 mL) at room tem-
perature was added the corresponding aldehyde (1.8 mmol). After
10 min, pulverized potassium hydroxide (0.85 g, 15.0 mmol) was
added at room temperature. The solution was stirred for 24 h
and then THF was removed under reduced pressure. The crude
was washed with water (40 mL) and extracted with ethyl acetate
(3 ꢂ 30 mL). The organic layers were combined and dried over
Na2SO4 and concentrated in vacuo. The crude was purified by col-
umn chromatography (Al2O3) (Hx and then Hx/EtOAc 15:1 or Hx/
CH2Cl2 3:2) to give the corresponding enol ether 8. Enol ethers 8
are relatively unstable on SiO2.
Compound 8a: Pale yellow oil in 63% yield and as a 75:25 mix-
ture of E/Z diastereomers. Rf = 0.48 (Hx/EtOAc, 6:1); 1H NMR
(250 MHz, CDCl3): d 1.24 (s, 3H), 1.25 (s, 3H), 1.36 (s, 3H), 1.45
(s, 3H), 3.96 (dd, J = 8.6, 5.3, 1H), 4.04 (dd, J = 8.6, 6.0, 1H), 4.12
(dd, J = 8.1, 2.9, 1H), 4.23–4.32 (m, 1H), 4.36 (d, J = 2.9, 1H), 4.57
(d, J = 3.7, 1H), 5.84 (d, J = 3.8, 1H), 5.92 (d, J = 13.0, 1H), 6.86 (d,
J = 13.0, 1H), 7.12–7.21 (m, 5H); 13C NMR (63 MHz, CDCl3): d 25.2
(CH3), 26.1 (CH3), 26.6 (CH3), 26.8 (CH3), 67.2 (CH2), 71.9 (CH),
80.5 (CH), 82.0 (CH), 82.3 (CH), 105.0 (CH), 108.6 (CH), 109.2 (C),
112.0 (C), 125.1 (CH), 128.2 (2 ꢂ CH), 128.4 (2 ꢂ CH), 135.8 (C),
146.0 (CH). Resolved signals for the minor isomer: 1H NMR
(250 MHz, CDCl3): d 1.23 (s, 3H), 3.97 (dd, J = 8.5, 5.1, 1H), 4.56
(d, J = 3.6, 1H), 5.25 (d, J = 7.0, 1H), 5.89 (d, J = 3.7, 1H), 6.19 (d,
J = 7.0, 1H), 7.42 (d, J = 7.6, 2H); 13C NMR (63 MHz, CDCl3): d 25.1
(CH3), 67.3 (CH2), 72.0 (CH), 80.7 (CH), 105.1 (CH), 109.3 (C),
112.1 (C), 126.0 (CH), 128.5 (2 ꢂ CH), 135.5 (C), 144.8 (CH); HRMS
(ESI) of the mixture: calcd for C20H26O6Na [M++Na]: 385.1620;
found: 385.1614.
Compound 8f: Colorless oil in 40% yield and as a 93:7 mixture of
E/Z diastereomers. Rf = 0.34 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H), 1.37 (s, 3H), 1.48 (s, 3H), 1.55 (s, 3H),
3.94–4.14 (m, 3H), 4.30 (dd, J = 7.9, 1.8, 1H), 4.35 (dd, J = 5.1, 2.5,
1H), 4.65 (dd, J = 7.9, 2.5, 1H), 5.57 (d, J = 5.0, 1H), 5.85 (d,
J = 13.0, 1H), 6.91–6.98 (m with d at 6.95, J = 13.0, 3H), 7.16 (dd,
J = 8.7, 5.4, 2H); 13C NMR (63 MHz, CDCl3): d 24.3 (CH3), 24.8
(CH3), 25.9 (CH3), 25.9 (CH3), 66.2 (CH), 68.3 (CH2), 70.4 (CH),
70.5 (CH), 70.9 (CH), 96.2 (CH), 105.2 (CH), 108.7 (C), 109.4 (C),
115.4 (d, J = 21.6, 2 ꢂ CH), 126.4 (d, J = 7.4, 2 ꢂ CH), 132.2 (d,
Compound 8b: Colorless oil in 54% yield and as a 75:25 mixture
of E/Z diastereomers. Rf = 0.39 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.25 (s, 6H), 1.36 (s, 3H), 1.45 (s, 3H), 3.96 (dd, J = 8.7, 5.2,
1H), 4.04 (dd, J = 8.7, 6.0, 1H), 4.11 (dd, J = 8.1, 2.8, 1H), 4.21–4.31
(m, 1H), 4.34 (d, J = 2.8, 1H), 4.56 (d, J = 3.6, 1H), 5.84 (d, J = 3.6,
1H), 5.89 (d, J = 12.8, 1H), 6.78 (d, J = 12.8, 1H), 6.84–7.42 (m,
4H); 13C NMR (63 MHz, CDCl3): d 25.2 (CH3), 26.1 (CH3), 26.6
(CH3), 26.8 (CH3), 67.2 (CH2), 71.9 (CH), 80.5 (CH), 82.1 (CH), 82.4

1656
I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
J = 3.2, C), 147.5 (d, J = 1.4, CH), 161.1 (d, J = 244.1, C). Resolved sig-
nals for the minor isomer: 1H NMR (250 MHz, CDCl3): d 1.53 (s,
3H), 5.22 (d, J = 7.0, 1H), 6.23 (d, J = 7.0, 1H), 7.56 (dd, J = 8.8, 5.7,
2H); 13C NMR (63 MHz, CDCl3): d 24.3 (CH3), 24.8 (CH3), 66.8
(CH), 70.5 (CH), 70.8 (CH), 71.9 (CH), 96.2 (CH), 105.0 (CH), 114.8
(d, J = 21.1, 2 ꢂ CH), 129.7 (d, J = 7.4, 2 ꢂ CH), 146.0 (d, J = 1.4,
CH), 161.0 (d, J = 212.8, C); HRMS (ESI) of the mixture: calcd for
C20H25O6FNa [M++Na]: 381.1706; found: 381.1714.
84.3 (CH), 84.9 (CH), 103.0 (CH), 109.2 (CH), 112.5 (C), 125.4
(2 ꢂ CH), 126.9 (CH), 129.5 (CH), 129.7 (CH), 132.0 (C), 134.1 (C),
148.9 (CH). Resolved signals for the minor isomer: 1H NMR
(250 MHz, CDCl3): d 1.33 (s, 3H), 1.50 (s, 3H), 3.35 (s, 3H), 4.62
(d, J = 6.2, 1H), 4.71 (d, J = 6.2, 1H), 5.01 (s, 1H), 5.69 (d, J = 7.2,
1H), 6.31 (d, J = 7.2, 1H); 13C NMR (63 MHz, CDCl3): d 54.7 (CH3),
85.0 (CH), 101.7 (CH), 109.3 (CH); HRMS (ESI) of the mixture: calcd
for C17H21O5ClNa [M++Na]: 365.0940; found: 365.0941.
Compound 8g: Colorless oil in 72% yield and as a 96:4 mixture of
E/Z diastereomers. Rf = 0.38 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.35 (s, 3H), 1.51 (s, 3H), 3.37 (s, 3H), 3.82 (dd, J = 9.9,
8.1, 1H), 3.89 (dd, J = 9.9, 6.8, 1H), 4.46 (app t, J = 7.4, 1H), 4.63
(d, J = 6.0, 1H), 4.74 (d, J = 5.9, 1H), 5.02 (s, 1H), 5.87 (d, J = 13.0,
1H), 7.01 (d, J = 13.0, 1H), 7.23 (s, 2H), 7.24 (s, 3H); 13C NMR
(63 MHz, CDCl3): d 24.9 (CH3), 26.4 (CH3), 54.9 (CH3), 70.1 (CH2),
81.8 (CH), 84.4 (CH), 85.0 (CH), 106.5 (CH), 109.3 (CH), 112.6 (C),
125.1 (2 ꢂ CH), 125.8 (CH), 128.5 (2 ꢂ CH), 136.0 (C), 147.4 (CH).
Resolved signals for the minor isomer: 1H NMR (250 MHz, CDCl3):
d 5.27 (d, J = 7.0, 1H), 6.20 (d, J = 7.0, 1H); HRMS (ESI) of the mix-
ture: calcd for C17H22O5Na [M++Na]: 329.1359; found: 329.1366.
Compound 8h: Colorless oil in 88% yield and as a 78:22 mixture
of E/Z diastereomers. Rf = 0.33 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H), 1.51 (s, 3H), 3.36 (s, 3H), 3.76–3.93 (m with s
at 3.79, 5H), 4.45 (app t, J = 7.4, 1H), 4.62 (d, J = 5.8, 1H), 4.73 (d,
J = 5.7, 1H), 5.02 (s, 1H), 5.84 (d, J = 12.9, 1H), 6.82 (d, J = 8.8, 2H),
6.89 (d, J = 12.9, 1H), 7.15 (d, J = 8.8, 2H); 13C NMR (63 MHz, CDCl3):
d 24.9 (CH3), 26.3 (CH3), 54.8 (CH3), 55.2 (CH3), 70.1 (CH2), 81.8
(CH), 84.4 (CH), 85.0 (CH), 106.1 (CH), 109.3 (CH), 112.5 (C),
114.0 (2 ꢂ CH), 126.1 (2 ꢂ CH), 128.5 (C), 146.0 (CH), 157.9 (C). Re-
solved signals for the minor isomer: 1H NMR (250 MHz, CDCl3): d
5.22 (d, J = 7.0, 1H), 6.11 (d, J = 7.0, 1H), 7.55 (d, J = 8.8, 2H); 13C
NMR (63 MHz, CDCl3): d 55.1 (CH3), 81.6 (CH), 84.7 (CH), 85.1
(CH), 106.0 (CH), 109.4 (CH), 112.4 (C), 113.6 (2 ꢂ CH), 128.4 (C),
129.5 (2 ꢂ CH), 144.3 (CH); HRMS (ESI) of the mixture: calcd for
C18H24O6Na [M++Na]: 359.1464; found: 359.1460.
Compound 8i: Colorless oil in 83% yield and as a 71:29 mixture
of E/Z diastereomers. Rf = 0.35 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H), 1.51 (s, 3H), 3.36 (s, 3H), 3.85 (s, 3H), 3.87–
3.94 (m, 2H), 4.43–4.51 (m, 1H), 4.63 (d, J = 5.9, 1H), 4.75 (d, J = 6.0,
1H), 5.02 (s, 1H), 6.06 (d, J = 13.0, 1H), 6.83–6.97 (m, 2H), 7.09–7.18
(m with d at 7.11, J = 13.0, 2H), 7.23 (dd, J = 7.8, 1.6, 1H). Resolved
signals for the minor isomer: 1H NMR (250 MHz, CDCl3): d 1.33 (s,
3H), 3.35 (s, 3H), 3.84 (s, 3H), 5.00 (s, 1H), 5.69 (d, J = 7.1, 1H), 6.23
(d, J = 7.1, 1H); HRMS (ESI) of the mixture: calcd for C18H24O6Na
[M++Na]: 359.1464; found: 359.1460.
Compound 8j: Colorless oil in 48% yield and as a 92:8 mixture of
E/Z diastereomers. Rf = 0.41 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H), 1.51 (s, 3H), 3.36 (s, 3H), 3.82 (dd, J = 10.0,
8.2, 1H), 3.89 (dd, J = 10.0, 6.5, 1H), 4.45 (app t, J = 6.8, 1H), 4.63
(d, J = 5.8, 1H), 4.73 (d, J = 5.8, 1H), 5.02 (s, 1H), 5.82 (d, J = 12.9,
1H), 6.98 (d, J = 13.0, 1H), 7.14 (d, J = 8.6, 2H), 7.23 (d, J = 8.6,
2H); 13C NMR (63 MHz, CDCl3): d 24.9 (CH3), 26.4 (CH3), 54.9
(CH3), 70.3 (CH2), 81.8 (CH), 84.4 (CH), 85.0 (CH), 105.5 (CH),
109.3 (CH), 112.6 (C), 126.2 (2 ꢂ CH), 128.6 (2 ꢂ CH), 134.5 (C),
147.8 (CH), 149.3 ppm (C). Resolved signals for the minor isomer:
1H NMR (250 MHz, CDCl3): d 5.23 (d, J = 7.0, 1H), 6.21 (d, J = 7.0,
1H); 13C NMR (63 MHz, CDCl3): d 129.2 (2 ꢂ CH), 131.2 (2 ꢂ CH);
HRMS (ESI) of the mixture: calcd for C17H21O5ClNa [M++Na]:
365.0940; found: 365.0941.
Compound 8l: Pale yellow oil in 70% yield and as a 81:19 mix-
ture of E/Z diastereomers. Rf = 0.29 (Hx/EtOAc, 6:1); 1H NMR
(250 MHz, CDCl3): d 1.37 (s, 3H), 1.53 (s, 3H), 3.36 (s, 3H),
3.87–4.02 (m with s at 4.00, 5H, CH2+CH3), 4.52 (app t, J = 7.2,
1H), 4.66 (d, J = 6.0, 1H), 4.80 (d, J = 5.9, 1H), 5.05 (s, 1H), 6.44
(d, J = 12.6, 1H), 6.77 (d, J = 8.1, 1H), 6.84 (d, J = 12.6, 1H), 7.31
(d, J = 7.9, 1H), 7.45–7.57 (m, 2H), 8.01 (dd, J = 7.4, 2.0, 1H), 8.29
(dd, J = 7.4, 1.9, 1H); 13C NMR (63 MHz, CDCl3): d 24.9 (CH3),
26.4 (CH3), 54.9 (CH3), 55.4 (CH3), 70.3 (CH2), 81.9 (CH), 84.6
(CH), 85.1 (CH), 103.7 (CH), 103.8 (CH), 109.3 (CH), 112.6 (C),
122.3 (CH), 123.3 (CH), 124.0 (CH), 125.1 (CH), 125.4 (C), 126.1
(C), 126.3 (CH), 132.3 (C), 147.7 (CH), 154.5 (C). Resolved signals
for the minor isomer: 1H NMR (250 MHz, CDCl3): d 1.33 (s, 3H),
1.51 (s, 3H), 3.40 (s, 3H), 4.02 (s, 3H), 4.62 (d, J = 5.9, 1H), 4.74
(d, J = 6.0, 1H), 5.01 (s, 1H), 5.87 (d, J = 7.3, 1H), 6.36 (d, J = 7.3,
1H); 13C NMR (63 MHz, CDCl3): d 54.9 (CH3), 84.7 (CH), 103.7
(CH), 109.4 (CH), 112.4 (C), 145.5 (CH); LRMS (ESI): m/z (%):
405.2 (26), 404.2 (100) [M++NH4], 349.2 (15), 297.1 (10), 265.1
(8), 237.1 (8), 215.1 (24), 201.1 (17), 187.1 (9); HRMS (ESI) of
the mixture: calcd for C22H26O6Na [M++Na]: 409.1620; found:
409.1629.
Compound 8m: Pale yellow liquid in 81% yield and as a 86:14
mixture of E/Z diastereomers. Rf = 0.40 (Hx/EtOAc, 4:1); 1H NMR
(250 MHz, CDCl3): d 1.36 (s, 3H), 1.53 (s, 3H), 2.94 (s, 6H), 3.37
(s, 3H), 3.76–3.92 (m, 2H), 4.47 (app t, J = 7.3, 1H), 4.64 (d, J = 6.0,
1H), 4.75 (d, J = 6.0, 1H), 5.03 (s, 1H), 5.85 (d, J = 12.9, 1H), 6.69
(d, J = 8.7, 2H), 6.88 (d, J = 12.9, 1H), 7.14 (d, J = 8.7, 2H); 13C NMR
(63 MHz, CDCl3): d 24.8 (CH3), 26.2 (CH3), 40.5 (2 ꢂ CH3), 54.7
(CH3), 69.8 (CH2), 81.7 (CH), 84.4 (CH), 84.9 (CH), 106.4 (CH),
109.1 (CH), 112.3 (C), 112.8 (2 ꢂ CH), 124.2 (C), 125.8 (2 ꢂ CH),
144.7 (CH), 148.9 (CH). Resolved signals for the minor isomer: 1H
NMR (250 MHz, CDCl3): d 2.95 (s, 6H), 5.21 (d, J = 7.0, 1H), 6.07
(d, J = 7.0, 1H), 6.73 (d, J = 8.5, 2H), 7.54 (d, J = 8.8, 2H); 13C NMR
(63 MHz, CDCl3): d 40.4 (2 ꢂ CH3), 81.6 (CH), 84.6 (CH), 85.0
(CH), 109.2 (CH), 112.2 (2 ꢂ CH), 129.1 (2 ꢂ CH), 143.1 (CH),
148.6 (CH); LRMS (ESI): m/z (%): 351.2 (21), 350.2 (100) [M++H],
349.2 (10) [M+], 282.1 (7); HRMS (ESI) of the mixture: calcd for
C19H27NO5Na [M++Na]: 372.1779; found: 372.1780.
Compound 8n [(E)-major]: Pale yellow oil in 61% yield. Rf = 0.48
(Hx/EtOAc, 6:1); 1H NMR (250 MHz, CDCl3): d 1.33 (s, 3H), 1.49 (s,
3H), 3.34 (s, 3H), 3.74–3.87 (m, 2H), 4.43 (app t, J = 7.2, 1H), 4.61 (d,
J = 5.9, 1H), 4.70 (d, J = 5.9, 1H), 5.00 (s, 1H), 5.71 (d, J = 12.8, 1H),
6.01 (d, J = 3.2, 1H), 6.32 (dd, J = 3.2, 1.9, 1H), 7.03 (d, J = 12.8,
1H), 7.24 (d, J = 1.5, 1H); 13C NMR (63 MHz, CDCl3): d 24.8 (CH3),
26.3 (CH3), 54.8 (CH3), 70.2 (CH2), 81.7 (CH), 84.3 (CH), 84.9 (CH),
96.7 (CH), 104.4 (CH), 109.2 (CH), 110.9 (CH), 112.4 (C), 140.2
(CH), 147.2 (CH), 151.1 (C); HRMS (ESI): calcd for C15H20O6Na
[M++Na]: 319.1152; found: 319.1150.
Compound 8n [(Z)-(minor)]: Pale yellow oil in 31% yield.
Rf = 0.39 (Hx/EtOAc, 6:1); 1H NMR (250 MHz, CDCl3): d 1.34 (s,
3H), 1.51 (s, 3H), 3.35 (s, 3H), 3.95 (app d, J = 7.4, 2H), 4.47 (app
t, J = 7.2, 1H), 4.63 (d, J = 6.0, 1H), 4.75 (d, J = 5.9, 1H), 5.01 (s,
1H), 5.42 (d, J = 6.8, 1H), 6.15 (d, J = 6.8, 1H), 6.41 (dd, J = 3.2, 1.9,
1H), 6.59 (d, J = 3.2, 1H), 7.29 (d, J = 1.6, 1H); 13C NMR (63 MHz,
CDCl3): d 24.9 (CH3), 26.4 (CH3), 54.9 (CH3), 73.8 (CH2), 81.6 (CH),
84.6 (CH), 85.0 (CH), 97.0 (CH), 108.2 (CH), 109.4 (CH), 111.4
(CH), 112.5 (C), 139.8 (CH), 144.3 (CH), 150.5 (C); HRMS (ESI): calcd
for C15H20O6Na [M++Na]: 319.1152; found: 319.1141.
Compound 8k: Colorless oil in 45% yield and as a 78:22 mixture
of E/Z diastereomers. Rf = 0.49 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H), 1.51 (s, 3H), 3.36 (s, 3H), 3.86 (dd, J = 10.0,
7.9, 1H), 3.93 (dd, J = 10.0, 7.1, 1H), 4.47 (app t, J = 7.2, 1H), 4.64
(d, J = 6.1, 1H), 4.74 (d, J = 6.1, 1H), 5.02 (s, 1H), 6.16 (d, J = 13.0,
1H), 6.98 (d, J = 13.0, 1H), 7.10–7.30 (m, 4H); 13C NMR (63 MHz,
CDCl3): d 24.8 (CH3), 26.3 (CH3), 54.8 (CH3), 70.0 (CH2), 81.7 (CH),

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1657
Compound 8o: Colorless oil in 78% yield and as a 71:29 mixture
of E/Z diastereomers. Rf = 0.39 (Hx/EtOAc, 5:1); 1H NMR (400 MHz,
CDCl3): d 1.30 (s, 3H), 1.49 (s, 3H), 3.68 (dd, J = 10.8, 5.6, 1H), 3.88–
3.93 (m, 1H), 3.95–4.00 (m, 1H), 4.39 (ddd, J = 16.6, 9.6, 2.8, 1H),
4.43 (d, J = 3.6, 1H), 4.50 (d, J = 3.6, 1H), 4.59–4.62 (m with s at
4.60, 3H), 4.79 (d, J = 11.2, 1H), 5.91 (d, J = 4.0, 1H), 5.99 (d,
J = 12.8, 1H), 6.81 (d, J = 12.8, 1H), 7.15 (d, J = 7.2, 2H), 7.22–7.37
(m with s at 7.23, 12H), 7.51 (d, J = 7.2, 1H); 13C NMR (100 MHz,
CDCl3): d 26.0 (CH3), 26.4 (CH3), 70.5 (CH2), 72.4 (CH2), 73.1
(CH2), 74.8 (CH), 78.1 (CH), 82.0 (CH), 85.2 (CH), 104.8 (CH),
108.3 (CH), 111.8 (C), 124.9 (2 ꢂ CH), 125.8 (CH), 127.2 (CH),
127.3 (CH), 127.7 (2 ꢂ CH), 128.0 (2 ꢂ CH), 128.0 (4 ꢂ CH), 128.3
(2 ꢂ CH), 135.1 (C), 138.0 (C), 138.1 (C), 145.8 (CH). Resolved sig-
nals for the minor isomer: 1H NMR (400 MHz, CDCl3): d 1.29 (s,
3H), 1.49 (s, 3H), 4.48 (d, J = 5.6, 1H), 4.71 (d, J = 11.2, 1H), 5.31
(d, J = 7.0, 1H), 5.97 (d, J = 3.8, 1H), 6.20 (d, J = 7.0, 1H); 13C NMR
(100 MHz, CDCl3): d 26.1 (CH3), 26.4 (CH3), 70.4 (CH2), 72.4
(CH2), 73.1 (CH2), 75.3 (CH), 78.1 (CH), 82.0 (CH), 82.7 (CH),
104.9 (CH), 107.3 (CH), 111.9 (C), 125.9 (CH), 127.3 (2 ꢂ CH),
127.3 (CH), 127.6 (2 ꢂ CH), 128.1 (CH), 128.1 (2 ꢂ CH), 135.3 (C),
138.1 (C), 138.2 (C), 144.6 (CH); HRMS (ESI) of the mixture: calcd
for C31H34O6Na [M++Na]: 525.2244; found: 525.2251.
Compound 25a,b: Colorless oil in 77% yield and as a 2:1 mixture
of diastereomers. Rf = 0.22 (Hx/EtOAc, 4:3); 1H NMR (250 MHz,
CDCl3): d 1.27 (s, 3H), 1.33 (s, 3H), 1.41 (s, 3H), 1.47 (s, 3H), 2.59
(br s, 1H, OH), 3.10 (dd, J = 9.0, 3.8, 1H), 3.81–3.90 (m, 2H), 3.95
(dd, J = 5.8, 4.2, 2H), 4.27 (app quint, J = 2.6, 1H), 4.48 (dd, J = 7.7,
2.4, 1H), 4.74 (d, J = 3.8, 1H), 5.51 (d, J = 5.1, 1H), 5.80 (d, J = 9.1,
1H), 7.28–7.37 (m with s at 7.32, 6H), 9.36 (s, 1H); 13C NMR
(63 MHz, CDCl3): d 24.2 (CH3), 24.8 (CH3), 25.8 (CH3), 26.0 (CH3),
48.3 (CH), 61.7 (CH), 66.7 (CH), 68.4 (CH2), 70.3 (CH), 70.4 (CH),
70.5 (CH), 96.1 (CH), 102.7 (CH), 108.5 (C), 109.2 (C), 121.6 (C),
127.1 (CH), 128.4 (2 ꢂ CH), 129.2 (2 ꢂ CH), 135.8 (C), 162.9 (CH),
189.4 (CH). Resolved signals for the minor isomer: 1H NMR
(250 MHz, CDCl3): d 3.06 (dd, J = 9.3, 3.6, 1H), 4.50 (dd, J = 7.9,
2.4, 1H), 4.71 (d, J = 3.6, 1H), 5.48 (d, J = 5.1, 1H), 5.73 (d, J = 9.3,
1H); 13C NMR (63 MHz, CDCl3): d 24.4 (CH3), 24.8 (CH3), 48.4
(CH), 61.8 (CH), 65.6 (CH), 68.7 (CH2), 70.2 (CH), 70.5 (CH), 70.7
(CH), 102.6 (CH), 108.5 (C), 109.1 (C), 127.2 (CH), 128.2 (2 ꢂ CH),
129.1 (2 ꢂ CH), 135.9 (C), 162.9 (CH), 189.3 (CH); LRMS (ESI) of
the mixture: m/z (%): 485 (56) [M++Na], 480 (23) [M++NH4], 446
(17), 445 (70) [M+ꢀOH], 363 (15), 317 (14), 279 (12), 278 (100);
HRMS (ESI) of the mixture: calcd for C24H28O8 [M+ꢀH2O]:
444.1776; found: 444.1766.
Compound 8p: Colorless oil in 31% yield and as a single Z diaste-
reomer. Rf = 0.58 (Hx/EtOAc, 4:1); 1H NMR (250 MHz, CDCl3): d
1.12 (s, 9H), 1.32 (s, 3H), 1.48 (s, 3H), 3.68 (dd, J = 10.6, 5.7, 1H),
3.89–3.99 (m, 2H), 4.25 (d, J = 2.7, 1H), 4.31 (dd, J = 9.6, 2.8, 1H),
4.37 (d, J = 7.0, 1H), 4.53 (d, J = 7.1, 1H), 4.56–4.61 (m with s at
4.61, 3H), 4.80 (d, J = 10.9, 1H), 5.78 (d, J = 7.0, 1H), 5.90 (d, J = 3.6,
1H), 7.27–7.36 (m with s at 7.31, 10H); HRMS (ESI) of the mixture:
calcd for C29H38O6Na [M++Na]: 505.2556; found: 505.2557.
Compound 26a,b: Colorless oil in 67% yield and as a 2:1 mixture
of diastereomers. Rf = 0.27 (Hx/EtOAc, 1:1); 1H NMR (250 MHz,
CDCl3): d 1.29 (s, 3H), 1.34 (s, 3H), 1.43 (s, 3H), 1.44 (s, 3H), 2.49
(br s, 1H, OH), 3.09 (dd, J = 8.7, 3.6, 1H), 3.78–3.96 (m, 4H), 4.29
(app quint. d, J = 2.5, 1.0, 1H), 4.52 (d, J = 7.7, 1H), 4.72 (d, J = 3.8,
1H), 5.53 (d, J = 5.1, 1H), 5.76 (d, J = 9.0, 1H), 6.98–7.07 (m, 2H),
7.25–7.37 (m, 3H), 9.36 (s, 1H); 13C NMR (63 MHz, CDCl3): d 24.2
(CH3), 24.8 (CH3), 25.8 (CH3), 25.9 (CH3), 47.5 (CH), 61.7 (CH),
67.1 (CH), 68.6 (CH2), 70.2 (CH), 70.4 (CH), 70.7 (CH), 96.1 (CH),
102.7 (CH), 108.5 (C), 109.3 (C), 115.3 (d, J = 21.1, 2 ꢂ CH), 121.6
(C), 130.9 (d, J = 8.3, 2 ꢂ CH), 131.4 (d, J = 3.2, C), 161.9 (d,
J = 245.9, C), 162.8 (CH), 189.5 (CH). Resolved signals for the minor
isomer: 1H NMR (250 MHz, CDCl3): d 3.05 (dd, J = ?, 3.6, 1H), 4.53
(d, J = 7.7, 1H), 4.69 (d, J = 3.6, 1H), 5.48 (d, J = 4.9, 1H), 5.66 (d,
J = 9.3, 1H); 13C NMR (63 MHz, CDCl3): d 24.4 (CH3), 24.8 (CH3),
47.6 (CH), 68.7 (CH2), 70.2 (CH), 70.3 (CH), 102.4 (CH), 108.6 (C),
109.2 (C), 115.1 (d, J = 21.1, 2 ꢂ CH), 121.6 (C), 130.7 (d, J = 8.3,
2 ꢂ CH), 162.8 (CH), 189.4 (CH); LRMS (ESI): m/z (%): 503 (29)
[M++Na], 463 (6) [M+ꢀOH], 204 (14), 203 (100); HRMS (ESI) of
the mixture: calcd for C24H27O8F [M+ꢀH2O]: 462.1682; found:
462.1673.
Compound 27a,b: White crystals in 73% yield and as a 1.15:1
mixture of diastereomers. Rf = 0.22 (Hx/EtOAc, 4:3); 1H NMR
(250 MHz, CDCl3): d 1.23 (s, 3H, major), 1.23 (s, 3H, minor), 1.43
(s, 3H, minor), 1.44 (s, 3H, major), 2.42 (br s, 2H, OH), 3.09 (dd,
J = 9.3, 3.6, 2H), 3.23 (s, 3H, major), 3.25 (s, 3H, minor), 3.59 (app
t, J = 9.3, 1H), 3.70 (dd, J = 9.8, 6.2, 1H), 3.86 (dd, J = 9.6, 8.2, 1H),
3.95 (dd, J = 9.6, 6.0, 1H), 4.24 (dd, J = 7.6, 6.6, 2H), 4.29 (d, J = 6.2,
1H), 4.45–4.48 (m with s at 4.46, 3H), 4.74 (d, J = 3.3, 1H, major),
4.75 (d, J = 4.3, 1H, minor), 4.91 (s, 2H), 5.68 (d, J = 9.3, 1H, minor),
5.74 (d, J = 9.3, 1H, major), 7.26–7.39 (m with s at 7.38, 12H), 9.38
(s, 2H); 13C NMR (63 MHz, CDCl3): d 24.6 (CH3, minor), 24.8 (CH3,
major), 26.2 (CH3, minor), 26.3 (CH3, major), 48.1 (CH, major),
48.2 (CH, minor), 54.8 (CH, minor), 54.8 (CH, major), 61.6 (CH, min-
or), 61.7 (CH, major), 69.8 (CH2, major), 70.6 (CH2, minor), 81.5 (CH,
minor), 81.7 (CH, major), 84.2 (CH, major), 84.4 (CH, minor), 84.8
(CH, minor), 84.9 (CH, major), 101.7 (CH, major), 102.4 (CH, minor),
109.3 (2 ꢂ CH), 112.2 (C, minor), 112.3 (C, major), 121.6 (2 ꢂ C),
127.4 (2 ꢂ CH), 128.4 (2 ꢂ CH, minor), 128.5 (2 ꢂ CH, major),
129.1 (2 ꢂ CH, major), 129.1 (2 ꢂ CH, minor), 135.5 (2 ꢂ CH, ma-
jor), 135.7 (2 ꢂ CH, minor), 162.8 (2 ꢂ CH), 189.3 (2 ꢂ CH); LRMS
(ESI): m/z (%): 430 (8) [M++Na+H], 429 (30) [M++Na], 275 (15),
217 (100), 185 (40); HRMS (ESI) of the mixture: calcd for
C21H27O8 [M++H]: 407.1698; found: 407.1712.
Compound 8q: Colorless oil in 58% yield and as a 69:31 mixture
of E/Z diastereomers. Rf = 0.37 (Hx/EtOAc, 6:1); 1H NMR (250 MHz,
CDCl3): d 1.32 (s, 3H), 1.52 (s, 3H), 3.72 (dd, J = 10.7, 5.5, 1H), 3.91–
4.02 (m, 2H), 4.00–4.52 (m, 3H), 4.61–4.63 (m with s at 4.62, 3H),
4.84 (d, J = 11.4, 1H), 5.94 (d, J = 3.9, 1H), 5.97 (d, J = 12.8, 1H), 6.74
(d, J = 12.8, 1H), 6.90–7.11 (m, 4H), 7.25–7.40 (m with s at 7.26,
10H); 13C NMR (63 MHz, CDCl3): d 26.2 (CH3), 26.5 (CH3), 70.5
(CH2), 72.3 (CH2), 73.2 (CH2), 75.0 (CH), 78.1 (CH), 82.1 (CH), 82.3
(CH), 104.9 (CH), 107.3 (CH), 111.9 (C), 115.1 (CH), 115.5 (CH),
126.3 (CH), 126.5 (CH), 127.3 (CH), 127.4 (2 ꢂ CH), 127.6
(2 ꢂ CH), 128.1 (3 ꢂ CH), 128.2 (3 ꢂ CH), 131.4 (C), 138.2 (C),
138.3 (C), 145.8 (d, J = 1.4, CH), 161.2 (d, J = 245.0, C). Resolved sig-
nals for the minor isomer: 1H NMR (250 MHz, CDCl3): d 1.31 (s,
3H), 1.52 (s, 3H), 4.61–4.63 (m with s at 4.61, 3H), 4.75 (d,
J = 11.2, 1H), 5.29 (d, J = 7.0, 1H), 5.99 (d, J = 3.8, 1H), 6.19 (d,
J = 7.0, 1H), 7.50 (dd, J = 8.7, 5.5, 2H); 13C NMR (63 MHz, CDCl3): d
70.3 (CH2), 75.3 (CH), 82.8 (CH), 85.3 (CH), 105.0 (CH), 106.3
(CH), 112.0 (C), 114.9 (CH), 115.2 (CH), 127.4 (CH), 127.5
(2 ꢂ CH), 127.7 (2 ꢂ CH), 129.6 (CH), 129.7 (CH), 131.5 (C), 138.1
(C), 138.2 (C), 144.3 (d, J = 2.3, CH), 160.9 (d, J = 245.9, C); HRMS
(ESI) of the mixture: calcd for C31H33O6FNa [M++Na]: 543.2150;
found: 543.2149.
4.8. General procedure for the preparation of hetero-Diels–
Alder products 25–28
In a sealed tube, a mixture of the corresponding enol ether 8
(0.2 mmol) and freshly sublimed and finely ground 2-formyl-1-
malondialdehyde2 24 (30.0 mg, 0.3 mmol) in a 10:1 mixture of
benzene/CH2Cl2 (2.0 mL) (previously deoxygenated by ‘freeze-vac-
uum-thaw’ treatment) was heated at 70–82 °C for two days. The
mixture was diluted with CH2Cl2 (7 mL) and the solvents were re-
moved under vacuum. The resulting residue was purified by col-
umn chromatography (silica gel, Hx/EtOAc 1:1) or (aluminum
oxide, Hx/EtOAc 1:2) to afford the hetero-Diels–Alder products
25–28, along with the corresponding enol ether 8 (see Scheme 4).

1658
I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
Compound 28a,b: White solid in 36% yield and as a 8:1 mixture
NMR (250 MHz, C6D6): d 1.18 (s, 3H), 1.49 (s, 3H), 2.98 (s, 3H),
3.12–3.24 (m, 2H), 4.09 (br s, 1H), 4.36–4.48 (m, 3H), 4.58 (s,
1H), 5.03 (s, 1H), 6.73 (br s, 1H, NH), 7.03–7.19 (m, 5H). Resolved
signals for the minor isomer: 1H NMR (250 MHz, CDCl3): d 1.33
(s, 3H); 13C NMR (63 MHz, CDCl3): d 55.2 (CH3), 63.1 (CH), 70.0
(CH2), 84.9 (CH), 85.4 (CH), 86.0 (CH), 109.5 (CH), 112.7 (C),
166.9 (C); 1H NMR (250 MHz, C6D6): d 1.17 (s, 3H), 1.48 (s, 3H),
2.99 (s, 3H), 4.12 (br s, 1H), 4.36–4.48 (m, 2H), 4.53 (d, J = 5.8,
1H), 4.58 (s, 1H), 5.01 (s, 1H), 5.81 (br s, 1H, NH), 7.03–7.19 (m,
5H); LRMS (ESI) of the mixture: m/z (%): 367.1 (23) [M++NH4],
350.1 (100) [M++H], 319.2 (30), 219.1 (33); HRMS (ESI) of the mix-
ture: calcd for C18H24NO6 [M++H]: 350.1596; found: 350.1606.
Compound 31: Colorless oil in 67% yield and as a single diaste-
of diastereomers. Rf = 0.20 (Hx/EtOAc, 4:3); mp.: 153–156 °C; 1H
NMR (250 MHz, CDCl3): d 1.33 (s, 6H), 1.42 (s, 3H), 1.50 (s, 3H),
2.43 (br s, 1H, OH), 3.04 (dd, J = 9.2, 3.6, 1H), 3.56 (ddd, J = 8.4,
6.2, 3.8, 1H), 3.75 (dd, J = 8.8, 6.2, 1H), 3.91 (dd, J = 8.8, 3.8, 1H),
4.01 (dd, J = 8.4, 2.8, 1H), 4.30 (d, J = 2.8, 1H), 4.69 (d, J = 3.6, 1H),
4.74 (d, J = 3.6, 1H), 5.79 (d, J = 9.2, 1H), 5.82 (d, J = 3.6, 1H), 7.03
(app t, J = 8.7, 2H), 7.32 (d, J = 8.7, 1H), 7.34 (d, J = 8.7, 1H), 7.39
(s, 1H), 9.41 (s, 1H); 13C NMR (63 MHz, CDCl3): d 25.1 (CH3), 26.2
(CH3), 26.7 (CH3), 27.0 (CH3), 48.1 (CH), 61.6 (CH), 66.7 (CH2),
71.8 (CH), 80.5 (CH), 83.1 (CH), 84.0 (CH), 102.9 (CH), 105.1 (CH),
109.1 (C), 112.0 (C), 115.1 (d, J = 20.9, 2 ꢂ CH), 121.8 (C), 131.1
(d, J = 7.8, 2 ꢂ CH), 161.8 (d, J = 245.5, C), 162.0 (CH), 189.3 (CH).
Resolved signals for the minor isomer: 1H NMR (250 MHz, CDCl3):
d 1.40 (s, 3H), 3.07 (dd, J = 9.3, 3.9, 1H), 9.39 (s, 1H); 13C NMR
(63 MHz, CDCl3): d 26.6 (CH3), 48.2 (CH); LRMS (ESI): m/z (%):
503 (28) [M++Na], 463 (28) [M+ꢀOH], 233 (26), 203 (100); HRMS
(ESI) of the mixture: calcd for C24H28O8F [M+ꢀOH]: 463.1760;
found: 463.1761.
reomer. Rf = 0.17 (Hx/EtOAc, 3:2); IR (CH2Cl2): [
m]
(cmꢀ1) =
max
3512 (br), 3265 (br), 1960, 1770, 1499, 1458, 1382, 1107, 1032,
743, 709; 1H NMR (250 MHz, CDCl3): d 1.29 (s, 3H), 1.46 (s, 3H),
3.34 (dd, J = 8.7, 5.0, 1H), 3.52 (dd, J = 10.9, 5.1, 1H), 3.70 (dd,
J = 10.8, 1.7, 1H), 3.98 (d, J = 11.8, 1H), 4.13 (d, J = 3.2, 1H), 4.21–
4.31 (m, 1H), 4.37 (dd, J = 4.3, 2.0, 1H), 4.44 (d, J = 3.6, 1H), 4.49
(s, 2H), 4.55 (d, J = 11.7, 1H), 5.19 (dd, J = 4.4, 1H), 5.79 (d, J = 3.7,
1H), 6.81 (br s, 1H), 7.18–7.39 (m with s at 7.31, 15H); 13C NMR
(63 MHz, CDCl3): d 26.3 (CH3), 26.7 (CH3), 62.1 (CH), 70.0 (CH2),
71.6 (CH2), 73.1 (CH2), 75.4 (CH), 78.5 (CH), 82.1 (CH), 82.2 (CH),
82.7 (CH), 104.9 (CH), 112.0 (C), 127.2 (2 ꢂ CH), 127.4 (CH),
127.4 (2 ꢂ CH), 127.6 (CH), 127.9 (CH), 128.2 (4 ꢂ CH), 128.4
(2 ꢂ CH), 129.7 (2 ꢂ CH), 130.9 (C), 138.3 (C), 138.6 (C), 168.2 (C).
LRMS (ESI) of the mixture: m/z (%): 568.1 (25) [M++Na], 546.2
(26) [M++H], 421.2 (20), 392.0 (16), 391.2 (42), 375.0 (26), 370.2
(20), 318.9 (29), 264.1 (21), 246.0 (19), 241.9 (35), 221.0 (88),
216.1 (67), 215.0 (100); HRMS (ESI): calcd for C32H36NO7 [M++H]:
546.2481; found: 546.2487.
Compound 32: Colorless oil in 65% yield and as a single diaste-
reomer. Rf = 0.22 (Hx/EtOAc, 3:2); 1H NMR (250 MHz, CDCl3): d
1.31 (s, 3H), 1.49 (s, 3H), 3.72 (dd, J = 10.4, 5.0, 1H), 3.90–3.99 (m
with s at 3.95, 2H), 4.11 (d, J = 3.0, 1H), 4.17 (s, 1H), 4.22 (d,
J = 11.4, 1H), 4.36 (dd, J = 9.5, 2.8, 1H), 4.57 (d, J = 3.8, 1H), 4.60
(s, 2H), 4.84 (d, J = 11.4, 1H), 4.97 (d, J = 1.1, 1H), 5.93 (d, J = 3.7,
1H), 6.90 (br s, 1H), 6.94–7.10 (m, 6H), 7.23–7.38 (m, 8H); 13C
NMR (63 MHz, CDCl3): d 26.2 (CH3), 26.6 (CH3), 62.9 (CH), 70.2
(CH2), 71.8 (CH2), 73.4 (CH2), 75.6 (CH), 78.2 (CH), 80.8 (CH), 82.7
(CH), 85.5 (CH), 105.0 (CH), 112.1 (C), 115.8 (d, J = 21.6, 2 ꢂ CH),
127.0 (2 ꢂ CH), 127.5 (CH), 127.5 (CH), 127.6 (2 ꢂ CH), 128.3
(4 ꢂ CH), 128.6 (d, J = 3.2, C), 129.1 (d, J = 8.3, 2 ꢂ CH), 138.0 (C),
138.1 (C), 166.8 (C), the quaternary carbon C–F was not resolved;
LRMS (ESI): m/z (%): 564.2 (7) [M++H], 414.3 (5), 359.1 (10),
338.2 (15), 293.0 (32), 280.1 (18), 279.1 (100), 263.1 (62); HRMS
(ESI): calcd for C32H35FNO7 [M++H]: 564.2387; found: 564.2406.
4.9. General procedure for the preparation of b-lactams 29–32
To a suspension of pulverized anhydrous sodium carbonate
(280 mg, 2.6 mmol) in anhydrous toluene (5 mL), chlorosulfonyl
isocyanate (0.17 mL, 2.0 mmol, 280 mg) was added. The mixture
was stirred and upon cooling to ꢀ70 °C, a solution of enol ether su-
gar 8 (0.65 mmol) in dry toluene (7.5 mL) was added dropwise.
Subsequently, the temperature of the mixture was allowed to rise
to ꢀ25 °C and maintained for 5 h. The mixture was then cooled to
ꢀ70 °C, diluted with toluene (17 mL), treated with sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Al) (0.82 mL, 2.6 mmol,
65 wt % solution in toluene), and left for 45 min whereas the tem-
perature was maintained (ꢀ70 °C). Subsequently, the temperature
was allowed to rise to 0 °C, water (2 mL) was added, and the mix-
ture was intensively stirred for 15 min. The suspension was filtered
through Celite, the solvent was evaporated and the residue was
purified by flash column chromatography (Hx/EtOAc 2:1, then
Hx/EtOAc 1:1) to give b-lactams 29–32.
Compound 29: Pale yellow oil in 77% yield and as a 1.3:1 mix-
ture of diastereomers. Rf = 0.28 (Hx/EtOAc, 3:2); 1H NMR
(250 MHz, CDCl3): d 1.35 (s, 6H), 1.45 (s, 3H), 1.55 (s, 3H), 3.75
(dd, J = 10.9, 5.2, 1H), 3.84–4.00 (m, 2H), 4.25 (dd, J = 7.9, 1.7,
1H), 4.28 (br s, 1H), 4.36 (dd, J = 4.8, 2.5, 1H), 4.64 (dd, J = 7.9,
2.5, 1H), 5.05 (d, J = 1.1, 1H), 5.57 (d, J = 4.8, 1H), 6.82 (br s, 1H),
7.29–7.38 (m, 5H); 13C NMR (63 MHz, CDCl3): d 24.2 (CH3), 24.8
(CH3), 25.8 (CH3), 25.9 (CH3), 62.3 (CH), 66.1 (CH), 68.0 (CH2),
70.4 (CH), 70.6 (CH), 70.8 (CH), 85.7 (CH), 96.2 (CH), 108.7 (C),
109.5 (C), 127.5 (2 ꢂ CH), 128.2 (CH), 128.8 (2 ꢂ CH), 133.4 (C),
167.2 (C). Resolved signals for the minor isomer: 1H NMR
(250 MHz, CDCl3): d 1.47 (s, 3H), 4.59 (dd, J = 7.3, 2.7, 1H), 4.97
(d, J = 1.4, 1H); 13C NMR (63 MHz, CDCl3): d 24.4 (CH3), 24.7
(CH3), 25.8 (CH3), 25.9 (CH3), 63.1 (CH), 67.4 (CH2), 70.2 (CH),
70.7 (CH), 87.2 (CH), 96.4 (CH), 108.6 (C), 109.4 (C); LRMS (ESI)
of the mixture: m/z (%): 428.2 (20) [M++Na], 406.2 (33) [M++H],
179.1 (32), 145.2 (100); HRMS (ESI) of the mixture: calcd for
C21H28NO7 [M++H]: 406.1857; found: 406.1861.
4.10. General procedure for the preparation of N-methylthio b-
lactams 33–36
To a solution of the corresponding b-lactam 29–32 (0.25 mmol)
in THF (10 mL) at ꢀ78 °C was added n-BuLi (0.69 mL, 1.11 mmol,
1.6 M in hexanes); 4.5 equiv due to the presence of ca. 3 equiv of
H2O with the b-lactam 29–32. After 1 h, methyl methanethiosulfo-
nate (0.11 mL, 1.11 mmol, 140 mg) was added at ꢀ78 °C and the
reaction mixture was stirred for 7 h while warming to room tem-
perature. The mixture is poured into aqueous NH4Cl (20 mL) and
extracted with ethyl acetate (3 ꢂ 30 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy using Hx/EtOAc 4:1 and CH2Cl2/Hx 7:1 for compounds 33
and 34, and by flash column chromatography (Hx/EtOAc 4:1) for
compounds 35 and 36.
Compound 30: Colorless oil in 72% yield and as a 1.2:1 mixture
of diastereomers. Rf = 0.20 (Hx/EtOAc, 2:1); Rf = 0.46 (Hx/EtOAc,
1:1); 1H NMR (250 MHz, CDCl3): d 1.35 (s, 3H), 1.50 (s, 3H), 3.34
(s, 3H), 3.57 (dd, J = 10.1, 7.9, 1H), 3.66 (dd, J = 10.1, 6.2, 1H), 4.25
(br s, 1H), 4.34 (app q, J = 7.4, 1H), 4.59 (dd, J = 6.0, 2.4, 1H), 4.64
(d, J = 6.3, 1H), 4.71 (d, J = 6.3, 1H), 4.98 (br s, 1H), 5.00 (s, 1H),
6.65 (br s, 1H, NH), 7.29–7.40 (m, 5H); 13C NMR (63 MHz, CDCl3):
d 24.9 (CH3), 26.4 (CH3), 55.3 (CH3), 63.3 (CH), 69.1 (CH2), 81.5
(CH), 84.7 (CH), 84.9 (CH), 86.1 (CH), 109.5 (CH), 112.8 (C), 127.5
(2 ꢂ CH), 127.8 (CH), 128.9 (2 ꢂ CH), 133.1 (C), 167.0 (C). 1H
Compound 33: Colorless oil in 62% yield and as a 1.3:1 mixture
of diastereomers. Rf = 0.28 (Hx/EtOAc, 4:1); 1H NMR (250 MHz,

I. P. Sánchez, E. Turos / Tetrahedron: Asymmetry 20 (2009) 1646–1660
1659
CDCl3): d 1.35 (s, 6H), 1.45 (s, 3H), 1.53 (s, 3H), 2.58 (s, 3H), 3.87
(dd, J = 9.5, 6.2, 1H), 4.00–4.22 (m, 2H), 4.29 (dd, J = 7.9, 1.6, 1H),
4.34 (dd, J = 5.0, 2.5, 1H), 4.37 (br s, 1H), 4.64 (dd, J = 7.9, 2.5,
1H), 5.08 (d, J = 1.4, 1H), 5.52 (d, J = 5.2, 1H), 7.28 (d, J = 7.6, 2H),
7.34 (t, J = 7.5, 3H); 13C NMR (63 MHz, CDCl3): d 23.0 (CH3), 24.4
(CH3), 24.9 (CH3), 25.9 (CH3), 26.0 (CH3), 63.0 (CH), 66.8 (CH),
68.4 (CH2), 70.4 (CH), 70.6 (CH), 70.9 (CH), 93.2 (CH), 96.2 (CH),
108.6 (C), 109.4 (C), 127.3 (2 ꢂ CH), 127.7 (CH), 128.8 (2 ꢂ CH),
133.0 (C), 165.6 (C). Resolved signals for the minor isomer: 1H
NMR (250 MHz, CDCl3): d 2.54 (s, 3H), 4.54 (dd, J = 7.7, 2.4, 1H),
5.54 (d, J = 5.2, 1H), 7.55 (app td, J = 7.9, 1.6, 5H); LRMS (ESI) of
the mixture: m/z (%): 474.2 (16) [M++Na], 452.0 (100) [M++H],
394.2 (14), 325.2 (15), 303.1 (25); HRMS (ESI) of the mixture: calcd
for C22H29NO7SNa [M++Na]: 474.1554; found: 474.1563.
4.11. Testing of antimicrobial susceptibilities (Kirby–Bauer well
diffusion)
S. aureus (ATCC 25923) and MRSA (ATCC 43300, ATCC 33591)
were purchased from American Type Culture Collection sources.
Culture preparation: from a freezer stock in tryptic soy broth (Difco
Laboratories, Detroit, MI) and 20% glycerol, a culture of each micro-
organism was transferred with a sterile Dacron swab to Trypti-
caseÒ Soy Agar (TSA) plates (Becton–Dickinson Laboratories,
Cockeysville, MD), streaked for isolation, and incubated at 37 °C
for 24 h. A 108 standardized cell count suspension was then made
in sterile phosphate-buffered saline (pH 7.2) and swabbed across
fresh TSA plates. Prior to swabbing with the culture solution,
20 lL of a 1 mg/mL stock solution of the test compound in dimeth-
Compound 34: Colorless oil in 57% yield and as a 1.2:1 mixture
of diastereomers. Rf = 0.30 (Hx/EtOAc, 4:1); 1H NMR (250 MHz,
CDCl3): d 1.34 (s, 3H, major.), 1.35 (s, 3H, minor.), 1.51 (s, 6H),
2.59 (s, 3H, major.), 2.59 (s, 3H, minor.), 3.30 (s, 3H, minor.),
3.32 (s, 3H, major.), 3.65–3.67 (m, 2H), 3.87–4.00 (m, 2H), 4.32
(d, J = 1.6, 1H, minor.), 4.33 (d, J = 1.6, 1H, major.), 4.38 (app q,
J = 7.2, 2H), 4.60 (d, J = 5.9, 1H, minor.), 4.62 (d, J = 5.9, 1H, major.),
4.69 (d, J = 5.9, 1H, major.), 4.75 (d, J = 5.9, 1H, minor.), 4.98 (d,
J = 1.6, 2H), 4.99 (s, 1H, major.), 5.00 (s, 1H, minor.), 7.22 (d,
J = 7.6, 4H), 7.34 (t, J = 7.5, 6H); 13C NMR (63 MHz, CDCl3): d 23.2
(CH3, minor.), 23.2 (CH3, major.), 24.9 (2 ꢂ CH3), 26.4 (2 ꢂ CH3),
55.0 (2 ꢂ CH3), 63.7 (CH, major.), 63.9 (CH, minor.), 70.4 (CH2, ma-
jor.), 70.5 (CH2, minor.), 81.7 (2 ꢂ CH), 84.8 (CH, major.), 84.9 (CH,
minor.), 85.0 (CH, major.), 85.0 (CH, minor.), 86.0 (CH, major.), 86.1
(CH, minor.), 109.3 (CH, major.), 109.4 (CH, minor.), 112.6 (2 ꢂ C),
127.2 (4 ꢂ CH), 128.0 (2 ꢂ CH), 129.0 (4 ꢂ CH), 132.8 (C, major.),
132.8 (C, minor.), 166.0 (2 ꢂ C). LRMS (ESI) of the mixture: m/z
(%): 418.2 (18) [M++Na], 396.2 (38) [M++H], 364.1 (77), 279.2
(29), 246.0 (36), 224.0 (58), 194.2 (100); HRMS (ESI) of the mix-
ture: calcd for C19H25NO6SNa [M++Na]: 418.1293; found:
418.1301.
ylsulfoxide (DMSO) was added to a 6-mm diameter well bored into
the agar. The plates were swabbed uniformly with the test microbe
compound mentioned above and then incubated for 24 h at 37 °C.
The antimicrobial susceptibilities were determined by measuring
the diameter of the growth inhibition zone appearing around each
well.
4.12. Determination of minimum inhibitory concentrations
The minimum inhibitory concentration (MIC) values of the lac-
tams were determined for S. aureus and MRSA by serial dilution in
agar, according to NCCLS protocols.32 The test medium was pre-
pared in 24-well plates (Costar 3524, Cambridge, MA) by adding
the test drug in DMSO to Mueller–Hinton II agar (Becton–Dickin-
son Laboratories, Cockeysville, MD) to bring the total volume in
each well to 1.0 mL. Starting with an initial well concentration of
256 lg of drug/mL, each sequential dilution contained half the con-
centration of the drug. The medium was allowed to solidify at
room temperature for 24 h before inoculation with the bacteria.
Using a sterilized inoculating loop, a small amount of each stan-
dardized Staphylococcus strain cultured on TSA plates for 24 h
was transferred into sterile test tubes containing 5 mL of TSA broth
and was incubated at 37 °C for 24 h. One microliter of each culture
was then applied to the appropriate well of Mueller–Hinton agar
and was incubated at 37 °C overnight. After 24 h, the MICs were
determined as the lowest concentration of the drug where bacte-
rial growth was visibly inhibited.
Compound 35: Colorless oil in 65% yield and as a single diaste-
reomer. Rf = 0.28 (Hx/EtOAc, 4:1); ½a D18
ꢃ
¼ ꢀ7:6 (c 0.5, CH2Cl2); 1H
NMR (250 MHz, CDCl3): d 1.41 (s, 6H), 1.57 (s, 3H), 2.58 (s, 3H),
3.76 (dd, J = 10.6, 4.9, 1H), 3.92–4.02 (m, 2H), 4.15 (d, J = 11.5,
1H), 4.29 (br s, 1H), 4.40–4.44 (m with s at 4.44, 2H), 4.64 (s,
2H), 4.82 (d, J = 9.0, 1H), 4.85 (s, 1H), 5.10 (d, J = 1.3, 1H), 6.03 (d,
J = 3.7, 1H), 7.03–7.13 (m, 4H), 7.28–7.41 (m, 11H); 13C NMR
(63 MHz, CDCl3): d 22.8 (CH3), 26.3 (CH3), 26.6 (CH3), 64.6 (CH),
70.2 (CH2), 71.4 (CH2), 73.3 (CH2), 75.5 (CH), 78.2 (CH), 81.9 (CH),
83.2 (CH), 92.1 (CH), 104.9 (CH), 112.1 (C), 126.9 (2 ꢂ CH), 127.2
(2 ꢂ CH), 127.3 (CH), 127.5 (CH), 127.5 (2 ꢂ CH), 128.0 (CH),
128.2 (2 ꢂ CH), 128.3 (2 ꢂ CH), 129.0 (2 ꢂ CH), 132.5 (C), 138.1
(C), 138.2 (C), 169.5 (C); LRMS (ESI): m/z (%): 614.1 (6) [M++Na],
609.2 (43) [M++NH4], 592.2 (11) [M++H], 535.2 (5), 418.1 (25),
279.0 (19), 277.0 (100); HRMS (ESI): calcd for C33H37NO7SNa
[M++Na]: 614.2178; found: 614.2168.
Acknowledgments
We gratefully acknowledge the National Institutes of Health
(AI05135) for financial support. We also thank Sonja Dickey of
the Department of Biology, University of South Florida, for antibac-
terial testing of the b-lactams 34 and 35.
References
Compound 36: Colorless oil in 68% yield and as a single diaste-
reomer. Rf = 0.25 (Hx/EtOAc, 4:1); 1H NMR (250 MHz, CDCl3): d
1.39 (s, 6H), 1.55 (s, 3H), 2.57 (s, 3H), 3.74 (dd, J = 10.6, 4.9, 1H),
3.92 (dd, J = 9.9, 4.9, 1H), 3.99 (dd, J = 10.6, 1.4, 1H), 4.16 (d,
J = 11.7, 1H), 4.21 (d, J = 1.3, 1H), 4.39–4.44 (m with s at 4.40,
2H), 4.62 (s, 2H), 4.82 (d, J = 3.8, 1H), 4.85 (d, J = 11.7, 1H), 5.04
(d, J = 1.3, 1H), 6.01 (d, J = 3.6, 1H), 6.93 (app d, J = 7.1, 4H), 7.12
(d, J = 5.5, 1H), 7.13 (d, J = 7.3, 1H), 7.27–7.39 (m with s at 7.37,
8H); 13C NMR (63 MHz, CDCl3): d 22.9 (CH3), 26.3 (CH3), 26.6
(CH3), 63.8 (CH), 70.1 (CH2), 71.3 (CH2), 73.4 (CH2), 75.6 (CH),
78.1 (CH), 81.9 (CH), 83.2 (CH), 92.1 (CH), 104.9 (CH), 112.2 (C),
115.9 (d, J = 21.6, 2 ꢂ CH), 126.6 (2 ꢂ CH), 127.5 (3 ꢂ CH), 128.2
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138.1 (C), 160.9 (d, J = 249.1, C), 169.3 (C); HRMS (ESI): calcd for
C33H37NO7FS [M++H]: 578.2543; found: 578.2552.
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