Asymmetric inverse-electron-demand hetero-diels-alder reaction for the construction of bicyclic skeletons with multiple stereocenters by using a bifunctional organocatalytic strategy: An efficient approach to chiral macrolides

Article abstract of DOI:10.1002/chem.201201102

We have performed the first bifunctional organocatalytic highly enantioselective inverse-electron-demand hetero-Diels-Alder reaction of cyclic ketones with enones to afford densely functionalized bicyclic skeletons that contain three stereocenters (up 82 % yield, 10:1 d.r., and 97 % ee). Unlike the previous IEDDAR catalytic strategy, this method features a double HOMO _dienophile/ LUMO_diene-activated pathway. Moreover, this process provides a promising method for the construction of enantioenriched macrolides. Bicyclic exercises: A highly enantioselective inverse-electron- demand hetero-Diels-Alder reaction of cyclic ketones with enones affords functionalized bicyclic skeletons with three stereocenters that can be used for the construction of macrolides. Copyright

Full text of DOI:10.1002/chem.201201102

FULL PAPER
DOI: 10.1002/chem.201201102
Asymmetric Inverse-Electron-Demand Hetero-Diels–Alder Reaction for the
Construction of Bicyclic Skeletons with Multiple Stereocenters by Using a
Bifunctional Organocatalytic Strategy: An Efficient Approach to Chiral
Macrolides
Xianxing Jiang, Long Wang, Ming Kai, Liping Zhu, Xiaojun Yao, and Rui Wang*[a]
Abstract: We have performed the first bifunctional organocatalytic highly enantio-
selective inverse-electron-demand hetero-Diels–Alder reaction of cyclic ketones
with enones to afford densely functionalized bicyclic skeletons that contain three
stereocenters (up 82% yield, 10:1 d.r., and 97% ee). Unlike the previous
Keywords: asymmetric synthesis ·
bifunctional catalysts · enones · het-
ero-Diels–Alder reactions · ketones
IEDDAR catalytic strategy, this method features
a double HOMOdienophile/
LUMOdiene-activated pathway. Moreover, this process provides
method for the construction of enantioenriched macrolides.
a promising
Introduction
The macrolide core is a privileged structural element that is
found in a large series of bioactive naturally occurring alka-
loids and in pharmaceutically relevant assays.[1]As an impor-
tant skeleton structure in the larger macrocyclic lactone
family; medium-sized lactones not only act as natural chiral
molecules, which often show interesting biological activities,
but they can also act as intermediates in the synthesis of
more-sophisticated macrocyclic frameworks, as well as other
natural alkaloids (Figure 1).[2]Over the past few decades, al-
though a tremendous amount of effort has been made in the
development of synthetic methods owing to their great bio-
logical and synthetic importance,[3] the synthesis of enan-
tioenriched macrocyclic lactones still remains one of the
most-challenging subjects in modern organic synthesis.
The catalytic asymmetric inverse-electron-demand Diels–
Alder reaction (IEDDAR) has emerged as a powerful and
atom-economical tool in organic synthesis.[4] This reaction
has frequently served as a fundamental platform for the
stereoselective construction of cyclic skeletons and, in those
processes, the catalytic activation of the dienophiles and
dienes is crucial for achieving high activity and selectivity.
To date, various catalytic asymmetric methodologies have
Figure 1. Ten-membered-lactone motif in various natural products.
been established, including metal-based- and organocatalytic
methods. These strategies have mainly relied on: 1) the
LUMO-lowering activation of dienes by Lewis acids;[5] or
2) the HOMO-raising activation of electron-rich dienophiles
by an enamine.[6] Recently, Juhl and Jøgensen[7] reported the
first enamine-based organocatalytic asymmetric IEDDAR[8]
with the a characteristic concerted HOMO of the dieno-
philes; moreover, remarkable advances in this field have
been achieved by Chen and co-workers.[9] Whereas the
HOMO-raising activation by the condensation of aldehydes
with amines has been made possible through an in situ en-
amine-based strategy, this catalytic system is not suitable for
the activation of much-less-reactive ketones. A notable ex-
ception is the interesting work of Wang and co-workers,[10]
who performed the enantioselective catalytic IEDHDAR
(inverse-electron-demand hetero-Diels–Alder reaction) of
ketones with enones by using a bifunctional activated ap-
proach with a combination of an enamine and a metal
Lewis acid. Although this approach is efficient, it requires
inconvenient reaction conditions and quenching of the
[a] Dr. X. Jiang,+ L. Wang,+ Dr. M. Kai,+ L. Zhu, Dr. X. Yao,
Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs, Gansu Province
Institute of Biochemistry and Molecular Biology
School of Basic Medical Sciences
Lanzhou University, Lanzhou 730000 (P.R. China)
Fax : (+86)931-8911255
E-mail: wangrui@lzu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201102.
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metal Lewis acid and organic base can easily lead to catalyst
inactivation. In our attempts to try to discover and explore
new reactivity strategies, we questioned whether this asym-
metric IEDHDAR could be initiated by one reactive cata-
lyst through a dual HOMOdienophile/LUMOdiene-controlling
pathway, thereby providing an organocatalytic platform for
highly efficient and convenient bifunctional activation.
Herein, we report the successful execution of these ideals
and present the first highly enantioselective bifunctional cat-
alytic IEDHDAR of cyclic ketones, which proceeds through
a H-bonding dual HOMOdienophile/LUMOdiene-activated path-
way. Moreover, this procedure allows for the rapid construc-
tion of enantioenriched medium-sized lactones.
To explore this proposed cyclization process, we began by
screening several organocatalysts to evaluate their catalytic
activities. The model reaction between b,g-unsaturated a-
keto ester (2a) and 2-nitrocycloketone (3a) was performed
in Et2O at room temperature in the presence of the catalyst
(3 mol% loading, Table 1). Whilst the desired products were
obtained in 42% yield in the presence of bifunctional pri-
mary-amine–thiourea catalyst 1a, only 18% ee was observed
(Table 1, entry 1). Furthermore, a screening of rosin-derived
tertiary-amine–thiourea catalysts 1b–1e indicated that cata-
lyst 1c was the best, thereby furnishing the products in 80%
yield, 80% ee, and 4:1 d.r. (Table 1, entry 3). Subsequently,
various other solvents were tested with catalyst 1c (Table 1,
entries 6-11). These results indicated changing the solvent
had a significant effect on the reaction. Among the solvents
tested, the mixed solvent of methyl tert-butyl ether and 1,2-
dichloroethane (1:1) appeared to be the most-suitable in
terms of yield and stereoselectivity (Table 1, entry 9). To our
delight, the best result was observed when the reaction was
performed at À138C after further optimization of the reac-
tion temperature (76% yield, 93% ee, and 5:1 d.r.; Table 1,
entry 13).
With the optimized conditions in hand, the scope of the
IEDHDAR was investigated (Table 2). The reactions of
range of enones were examined with several six-membered
2-nitrocycloketones for the construction of various chiral bi-
cyclic hemiketals. In general, all of the various substituted
b,g-unsaturated a-keto esters could be well-tolerated, in-
cluding those that contained electron-withdrawing- and elec-
tron-donating substituents at different positions on the aro-
matic ring and heterocyclic groups, thus giving bicyclic hemi-
ketals 4a–4m with excellent enantioselectivities (90% to
>97% ee) and good diastereoselectivities (up to 8:1 d.r.) in
yields of 73–83%. Gratifyingly, bicyclic hemiketal 4n was
smoothly formed with excellent enantioselectivity (93% ee)
and diastereoselectivity (10:1 d.r.) in 79% yield. Notably,
this asymmetric procedure was also efficient for the reaction
of an aromatic dienophile, again leading to compound 4o in
72% yield, albeit with a slight decrease in enantioselectivity
(76% ee). The configurations of the products were deter-
mined by single-crystal X-ray analysis of compound 4c.
To gain a better understanding of the scope of this con-
ceptually new catalytic system, aliphatic b,g-unsaturated a-
keto ester 2 was investigated under the same optimized con-
dition (Scheme 2). As expected, the IEDDAR of aliphatic
b,g-unsaturated a-keto ester 2 with 2-nitrocycloketone re-
acted smoothly, thereby preferably affording endo-selective
product 4p in 62% yield, 82% ee, and 6:1 d.r.
Results and Discussion
The use of tertiary amines as promoters for a range of trans-
formations of carbonyl compounds by exploiting H-bond in-
teraction has been recently explored.[11] Herein, we expected
that the activation of cyclic ketones through the in situ for-
mation of enolates would be more feasible. We envisioned
that the Lewis acid activated LUMOdiene-lowering enones
would be expected undergo nucleophilic attack by the Lewis
base activated HOMOdienophile-controlling cyclic ketones,
thereby leading to the generation of bicyclic hemiketals,
which can then be transformed into ten-membered macro-
lides through a single cleavage step (Scheme 1). Notably, the
Scheme 1. Bifunctional H-bonding approach in the synthesis of macro-
lides.
introduction of electron-withdrawing groups at the a posi-
tion of cyclic ketones would not only be beneficial to test
the catalytic activity of the formation of multiple stereocen-
ters, but it could also facilitate the retro-Henry-type cleav-
age reaction. We recently explored bifunctional catalytic
modes for asymmetric transformations by using rosin-
derived bifunctional amine–thiourea catalysts.[12,13] Encour-
aged by these elegant advances, we surmised that this kind
of bifunctional amine–thiourea catalyst would be suitable
for catalyzing the asymmetric IEDHDAR of ketones with
enones through double-H-bond activation.
Scheme 2. IEDDAR of aliphatic b,g-unsaturated a-keto ester 2.
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An Efficient Approach to Chiral Macrolides
FULL PAPER
Table 1. Optimization of the parameters in the IEDDAR.[a]
Entry
1
Catalyst
Solvent
Et2O
Yield [%][b]
42 (21)
ee [%][c]
d.r.[d]
1:1
18
2
3
Et2O
Et2O
58 (39)
80 (64)
61
80
2:1
4:1
4
5
Et2O
Et2O
79 (64)
75 (56)
À75
4:1
3:1
71
6
7
8
9
10
11
12[e]
13[f]
1c
1c
1c
1c
1c
1c
1c
1c
toluene
MTBE
DCE
MTBE/DCE (1:1)
MTBE/DCE (3:1)
MTBE/DCE (1:3)
MTBE/DCE (1:1)
MTBE/DCE (1:1)
52 (42)
80 (64)
60 (45)
78 (62)
72 (58)
71 (57)
76 (61)
76 (63)
83
82
85
86
83
79
88
93
4:1
4:1
3:1
4:1
4:1
4:1
4:1
5:1
[a] Unless otherwise stated, the reactions were performed with compounds 2a (0.10 mmol) and 3a (0.11 mmol); [b] the reported yields are of the isolated
diastereomeric mixtures and the values in parentheses are those of their corresponding major diastereomers; [c] the ee values of the major diastereomers
were determined by HPLC and the configurations were assigned by comparison with the HPLC data and X-ray crystallographic analysis of compound
4c; [d] determined by 1H NMR spectroscopy; [e] reaction performed at 08C for 20 h; [f] reaction performed at À138C for 36 h. DCE=1,2-dichloro-
ethane, MTBE=methyl tert-butyl ether.
Following the successful construction of these chiral bi-
cyclic skeletons, their conversion into valuable macrolides
was found to be straightforward. In view of the significant
biological activities of fluoro-substituted macrolides, the
prototypical transformation of compound 4d is shown in
Scheme 3. Compound 4d was smoothly converted into ten-
membered lactone 5a in 61% yield by a retro-Henry-type
cleavage with catalytic amounts of nBu4NF in a single step.
This representative example demonstrates the inherent syn-
thetic potential of this kind of bicyclic hemiketals. More-
over, it provides an alternative asymmetric access to enan-
tioenriched macrolides.
Scheme 3. Synthetic transformation to afford chiral macrolides.
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R. Wang et al.
Table 2. Substrate scope in the IEDDAR.[a]
On the basis of our experimental results and
recent studies,[14] we have proposed a possible bi-
functional catalytic mode to account for the ob-
served results (Figure 2). The b,g-unsaturated a-
keto ester is fixed and LUMO-activated by hydro-
gen bonds between the two carbonyl groups in the
enones and the hydrogen atoms on the thiourea
catalyst, whilst the 2-nitrocycloketone could be
HOMO-activated by deprotonation at its a-carbon
atom (enolization) by the tertiary amine. Then, we
used DFT calculations to consider the possible in-
termediates that participate in the reaction, which
indicated that the activated intermediate B is
easier to form and, thus, that it is more likely to be
involved in the reaction (for the DFT calculations
of other intermediates, see the Supporting Infor-
mation). To further identify the reaction intermedi-
ates, we performed MS (ESI) analysis whilst moni-
toring the reaction. The existence of intermediates
A and B in the reaction mixture was confirmed by
MS (Figure 3 and the Supporting Information).
The observed stereochemistry can be best ex-
plained by the proposed reaction models shown in
Figure 4. We carefully studied all of the possible
conformers of the initially found transition-state
structures and selected the conformer with the
lowest energy. In the transition-state structures for
the formation of both conformers Xa and Xb, the
arrangement of the oxygen atoms on the two car-
bonyl groups in the enones relative to the hydro-
gen atoms on the thiourea moiety and the arrange-
ment of the hydrogen atoms on the enol (enoliza-
tion of 2-nitrocycloketone) relative to the nitrogen
atom on the chiral tertiary amine moiety are clear-
ly non-planar. The stereochemical control of 1,2-di-
aminocyclohexane and steric hindrance from the
dehydroabietic amine moiety of the thiourea
would give the endo-selective mode of reaction,
which also matches well with the relative stereo-
Product
t
Yield
[%]
d.r.
5:1
ee
[%]
[h]
36
48
36
36
36
24
76 (63)
72 (62)
81 (65)
83 (71)
80 (67)
81 (69)
93
93
92
94
93
90
6:1
4:1
6:1
5:1
6:1
48
76 (65)
6:1
91
À
À
chemistry of the C7 C17 (3.28 ꢁ) and C12 O3
bonds (3.56 ꢁ; Figure 2). The activated enone at-
tacks from the Re face, which accounts for the ab-
solute configuration of the C12 and C17 chiral cen-
ters in the products. In contrast, the exo selectivity
is suppressed owing to the shielding effect on the
Si face of the enol from the S,S configuration of
1,2-diaminocyclohexane and the big group. Nota-
bly, the formation of the stereochemical C7 center
might lead to two different final products: Xa and
Xb. DFT calculations revealed that the 4-fluorine-
substituted phenyl ring on the enone had almost
no interactions with the nitro group (5.23 ꢁ) under
a trans relationship and had attractive interactions
with hydrophobic ring B (3.86 ꢁ) when (R)-C7 was
formed in product Xa. Conversely, in product Xb
((S)-C7), this 4-fluorine-substituted phenyl ring un-
derwent a steric repulsion with the nitro group
48
72
76 (68)
68 (54)
8:1
4:1
93
93
48
48
73 (63)
75 (60)
6:1
4:1
97
90
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An Efficient Approach to Chiral Macrolides
Table 2. (Continued)
FULL PAPER
the distance of beneficial approach is shorter (by
1.07 ꢁ). Thus, structure Xa is more-favorably
formed over Xb to preferentially give the
4R,4’R,8’S bicyclic product with three stereocen-
ters, in keeping with the experimental results
(Figure 4).
Product
t
Yield
[%]
d.r.
6:1
ee
[%]
[h]
48
79 (68)
90
Conclusion
36
36
72
82 (73)
79 (72)
72 (56)
8:1
10:1
3.5:1
92
93
76
In conclusion, we have reported a highly efficient
bifunctional strategy that has enabled the develop-
ment of the first bifunctional organocatalytic
highly enantioselective inverse-electron demand
hetero-Diels–Alder reaction of cyclic ketones with
enones, thereby affording densely functionalized
bicyclic skeletons that contained three stereocen-
ters (up to 82% yield, 10:1 d.r., and 97% ee).
Unlike the previous IEDDAR catalytic strategy,
this IEDHDAR approach features a dual HO-
MOdienophile/LUMOdiene-activated pathway. Further-
more, this process provides a promising method for
the construction of enantioenriched ten-membered
macrolides and this synthetic route is more conven-
ient for practical use.
[a] Unless otherwise stated, the reactions were performed with compounds
2
(0.10 mmol) and 3 (0.11 mmol). The reported yields are of the isolated diastereomeric
mixtures and the values in parentheses are those of their corresponding major dia-
stereomers. The ee values of the major diastereomers and the d.r. values were deter-
mined by HPLC analysis.
Figure 3. Confirmation of the presence of intermediates A and B by MS
(ESI).
Experimental Section
General methods: All reactions were performed under an argon atmos-
phere unless otherwise stated and solvents were dried according to estab-
lished procedures. Reactions were monitored by thin layer chromatogra-
phy (TLC); purification was performed by column chromatography on
silica gel GF254. 1H NMR spectra were recorded on a Brucker 300 MHz
spectrometer in CDCl3 unless otherwise stated and 13C NMR spectra
were recorded on a Brucker 300 MHz spectrometer in CDCl3, with tetra-
methylsilane (TMS) as an internal standard, unless otherwise stated. Mul-
tiplicity data are presented as follows: br=broad, s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet, cm=complex multiplet; coupling
constants are given in Hertz (Hz). Infrared (IR) spectra were recorded
on an FTIR spectrometer. Optical rotations were recorded on a Perkin–
Elmer 341 polarimeter. HRMS was measured on an APEX II 47e mass
spectrometer. Melting points were measured on an XT-4 melting-point
apparatus and were uncorrected. The ee values were determined by
Figure 2. Catalytic cycle and reaction transition state. The ball and stick
structure shows the DFT calculation of intermediate B.
(3.98 ꢁ) under a cis relationship and pointed away from
ring B (4.93 ꢁ). Compared to compound Xb, the distance of
adverse approach is longer (by 1.25 ꢁ) in product Xa and
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R. Wang et al.
13C NMR (75 MHz, CDCl3): d=
162.2, 140.6, 133.1, 133.0, 132.3, 128.6,
128.3, 127.9, 127.7, 126.6, 126.5, 113.1,
97.2, 92.7, 52.6, 46.5, 35.2, 29.7, 27.6,
˜
21.3, 19.9 ppm; IR (KBr): n=3376.23,
2923.80, 2854.70, 1730.32, 1656.68,
1544.47, 1440.72, 1366.73, 1263.42,
1198.35, 1156.21, 1092.78, 1066.86,
1023.51, 903.09, 861.86, 825.04,
748.04 cmÀ1
C21H21NO6+NH4
;
HRMS (ESI): m/z
+
:
401.1707; found:
401.1708; major diastereomer (Chiral-
cel AD-H, iPrOH/n-hexane=20:80,
1.0 mLminÀ1
,
230 nm):
retention
time: tminor =7.38 min; tmajor =8.58 min;
ee=93%.
(4R,4aR,8aS)-Methyl-4-(4-chloro-
phenyl)-8a-hydroxy-4a-nitro-
4a,5,6,7,8,8a-hexahydro-4H-chro-
mene-2-carboxylate (4c): The diaste-
reomeric mixture was isolated by
column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as
a white solid. Rf =0.3 (major diaste-
reomer), 0.2 (minor diastereomer);
[a]2D0 =À20.0 (c 1.0, CHCl3); 1H NMR
Figure 4. Plausible reaction models for the asymmetric IEDDAR.
(300 MHz, CDCl3): d=7.30–7.33 (dd,
J=2.1 Hz, 6.6 Hz, 2H), 6.98–7.01 (dd,
J=2.1 Hz, 6.6 Hz, 2H), 6.24–6.25 (d,
J=2.4 Hz, 1H), 4.65 (br s, 1H), 4.60–4.61 (d, J=2.4 Hz, 1H), 3.85 (s,
3H), 2.22–2.27 (m, 1H), 1.54–1.86 (m, 7H), 1.35–1.43 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=162.0, 140.7, 134.7, 133.4, 130.5, 128.8,
chiral HPLC with a Daicel Chiracel AD-H column on Waters with
a 2996 UV-detector; d.r. values were determined by H NMR spectrosco-
py (300 Hz).
1
˜
112.3, 97.1, 92.3, 52.6, 45.6, 35.1, 27.4, 21.2, 19.9 ppm; IR (KBr): n=
General procedure for the asymmetric synthesis: A solution of com-
pound 1c (0.003 mmol, 3.0 mol%) and b,g-unsaturated a-keto ester
(0.10 mmol) was stirred in MTBE/DCE (1.0 mL, 1:1) at À138C for 0.5 h
under an argon atmosphere. Then, 2-nitrocycloketones (0.10 mmol) was
slowly added into the mixture. After the reaction was completed (moni-
tored by TLC), the resulting mixture was concentrated under reduced
pressure and the residue was purified by column chromatography on
silica gel (EtOAc/petroleum ether, 1:8 to 20:1) to afford the products,
which were dissolved in Et2O. After filtration, removal of the solvent
under reduced pressure gave the pure products. The enantiomeric purity
of the products were determined by HPLC and the d.r. values were de-
3374.94, 2923.79, 2854.53, 1731.54, 1657.06, 1604.12, 1545.99, 1490.31,
1454.72, 1440.82, 1414.43, 1372.94, 1259.38, 1202.65, 1154.76, 1070.29,
1031.75, 898.14, 828.87 cmÀ1; HRMS (ESI): m/z C17H18ClNO6+NH4
:
+
385.1161; found: 385.1168; major diastereomer (Chiralcel AD-H, iPrOH/
n-hexane=10:90, 1.0 mLminÀ1
230 nm): retention time: tminor
,
=
10.74 min; tmajor =19.98 min; ee=92%.
(4R,4aR,8aS)-Methyl-4-(4-fluorophenyl)-8a-hydroxy-4a-nitro-
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4d): The diastereo-
meric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.3 (major diastereo-
mer), 0.2 (minor diastereomer); [a]2D0 =À10.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=6.99–7.07 (m, 4H), 6.19–6.20 (d, J=2.1 Hz, 1H),
4.07–4.08 (d, J=2.4 Hz, 1H), 4.04 (br s, 1H), 3.85 (s, 3H), 2.47–2.52 (m,
1H), 1.64–2.28 (m, 7H), 1.26–1.42 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): d=164.4, 163.1, 141.6, 131.6, 130.7, 130.6, 115.8, 115.5, 112.4,
96.9, 52.6, 44.4, 33.2, 31.0, 21.3, 20.9 ppm; IR (KBr): n˜ =3391.92, 2924.05,
2854.85, 1805.36, 1731.89, 1659.48, 1604.34, 1545.46, 1510.07, 1440.94,
1351.75, 1277.71, 1230.44, 1198.35, 1159.24, 1100.33, 1074.64, 1023.51,
1
termined by H NMR spectroscopy (300 Hz).
(4R,4aR,8aS)-Methyl-8a-hydroxy-4a-nitro-4-phenyl-4a,5,6,7,8,8a-hexa-
hydro-4H-chromene-2-carboxylate (4a): The diastereomeric mixture was
isolated by column chromatography on silica gel (EtOAc/petroleum
ether, 1:8) as a white solid. Rf =0.3 (major diastereomer), 0.2 (minor dia-
1
stereomer); [a]2D0 =À6.0 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d=
7.33–7.35 (m, 3H), 7.03–7.06 (m, 2H), 6.31–6.32 (d, J=1.8 Hz, 1H), 4.76
(br s, 1H), 4.61–4.62 (d, J=2.4 Hz, 1H), 3.85 (s, 3H), 2.21–2.28 (m, 1H),
1.56–1.89 (m, 7H), 1.29–1.44 ppm (m, 1H); 13C NMR (75 MHz, CDCl3):
d=162.2, 140.5, 134.8, 129.2, 128.6, 128.6, 113.0, 97.1, 92.6, 52.5, 46.3,
904.74, 875.05, 836.93, 752.99, 663.46 cmÀ1
C17H18FNO6+NH4
;
HRMS (ESI): m/z
+
: 369.1456; found: 369.1460; major diastereomer
(Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1, 230 nm): reten-
tion time: tminor =7.48 min; tmajor =10.97 min; ee=94%.
˜
35.2, 27.4, 21.2, 19.9 ppm; IR (KBr): n=3376.77, 2923.70, 2854.44,
1729.51, 1661.79, 1633.81, 1602.47, 1544.89, 1442.20, 1409.48, 1352.88,
1276.86, 1249.48, 1198.35, 1152.16, 1068.87, 1023.51, 827.22, 756.29 cmÀ1
;
(4R,4aR,8aS)-Methyl-4-(4-bromophenyl)-8a-hydroxy-4a-nitro-
+
HRMS (ESI): m/z calcd for C17H19NO6+NH4
: 351.1551; found:
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4e): The diastereo-
meric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.3 (major diastereo-
mer), 0.2 (minor diastereomer); [a]2D0 =À17.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.45–7.48 (d, J=8.4 Hz, 2H), 6.92–6.94 (d, J=
8.4 Hz, 2H), 6.23–6.24 (d, J=2.4 Hz, 1H), 4.64 (br s, 1H), 4.59–4.60 (d,
J=2.4 Hz, 1H), 3.85 (s, 3H), 2.22–2.27 (m, 1H), 1.35–1.86 ppm (m, 8H);
13C NMR (75 MHz, CDCl3): d=162.0, 140.7, 133.9, 131.8, 130.8, 122.8,
351.1544; major diastereomer (Chiralcel AD-H, iPrOH/n-hexane=10:90,
1.0 mLminÀ1, 230 nm): retention time: tminor =7.19 min; tmajor =13.26 min;
ee=93%.
(4R,4aR,8aS)-Methyl-8a-hydroxy-4-(naphthalen-2-yl)-4a-nitro-
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4b): The dia-
stereomeric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.25 (major dia-
stereomer), 0.1 (minor diastereomer); [a]2D0 =À20.0 (c 1.0, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.79–7.86 (m, 3H), 7.49–7.54 (m, 3H),
7.12–7.16 (dd, J=1.8 Hz, 5.4 Hz, 1H), 6.41–6.42 (d, J=2.4 Hz, 1H), 4.79–
4.81 (m, 2H), 3.87 (s, 3H), 2.24–2.34 (m, 1H), 1.57–1.92 ppm (m, 8H);
˜
112.2, 97.1, 92.3, 52.6, 45.7, 35.1, 27.4, 21.2, 19.9 ppm; IR (KBr): n=
3373.21, 2923.30, 2854.46, 1731.61, 1656.62, 1544.71, 1439.57, 1374.44,
1269.04, 1198.33, 1154.45, 1067.12, 1025.85, 895.88, 828.56 cmÀ1; HRMS
(ESI): m/z C17H18BrNO6+NH4+: 429.0656; found: 429.0647; major dia-
&
6
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ÝÝ
These are not the final page numbers!

An Efficient Approach to Chiral Macrolides
FULL PAPER
stereomer (Chiralcel AD-H, iPrOH/n-hexane=20:80, 1.0 mLminÀ1
230 nm): retention time: tminor =7.28 min; tmajor =13.92 min; ee=93%.
,
ether, 1:8) as a white solid. Rf =0.3 (major diastereomer), 0.2 (minor dia-
stereomer); [a]2D0 =À43.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.14–7.24 (m, 2H), 6.83–6.84 (t, J=1.8 Hz, 2H), 6.30–6.31 (d, J=
2.4 Hz, 1H), 4.79 (br s, 1H), 4.56–4.57 (d, J=2.4 Hz, 1H), 3.85 (s, 3H),
2.34 (s, 3H), 2.21–2.31 (m, 1H), 1.56–1.91 (m, 7H), 1.32–1.39 ppm (m,
1H); 13C NMR (75 MHz, CDCl3): d=162.2, 140.4, 138.3, 134.7, 129.3,
128.4, 126.3, 113.2, 97.1, 92.6, 52.5, 46.3, 35.2, 27.4, 21.4, 21.2, 19.9 ppm;
(4R,4aR,8aS)-Methyl-8a-hydroxy-4a-nitro-4-(4-(trifluoromethyl)phen-
yl)-4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4 f): The dia-
stereomeric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.3 (major diastereo-
mer), 0.2 (minor diastereomer); [a]2D0 =À17.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.59–7.62 (d, J=5.4 Hz, 2H), 7.18–7.21 (d, J=
5.1 Hz, 2H), 6.26 (d, J=2.4 Hz, 1H), 4.70 (d, J=2.4 Hz, 1H), 4.57 (br s,
1H), 3.86 (s, 3H), 2.24–2.29 (m, 1H), 1.21–1.85 ppm (m, 8H); 13C NMR
(75 MHz, CDCl3): d=162.0, 140.9, 129.7, 125.6, 125.5, 111.8, 97.1, 92.2,
˜
IR (KBr): n=3400.42, 2952.87, 2923.82, 2854.57, 1728.67, 1662.03,
1633.94, 1603.66, 1545.60, 1441.47, 1408.78, 1382.43, 1277.19, 1252.63,
1196.53, 1154.54, 1093.19, 1070.00, 1029.79, 830.52, 797.53, 774.43, 718.35,
+
672.16, 607.84, 536.91, 465.98 cmÀ1; HRMS (ESI): m/z C18H21NO6+NH4
:
365.1707; found: 365.1710; major diastereomer (Chiralcel AD-H, iPrOH/
n-hexane=20:80, 1.0 mLminÀ1, 230 nm): retention time: tminor =4.78 min;
˜
52.6, 45.9, 35.0, 27.5, 21.2, 19.9 ppm; IR (KBr): n=3381.03, 2923.54,
2854.54, 1732.81, 1659.24, 1546.61, 1458.97, 1442.19, 1374.41, 1325.55,
1257.73, 1159.81, 1117.51, 1066.97, 1025.13, 904.74, 838.76, 663.76 cmÀ1
;
tmajor =5.80 min; ee=97%.
HRMS (ESI): m/z C18H18F3NO6+NH4+: 419.1424; found: 419.1430; major
(4S,4aR,8aS)-Methyl-8a-hydroxy-4a-nitro-4-(thiophen-2-yl)-
diastereomer (Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1
230 nm): retention time: tminor =7.83 min; tmajor =13.79 min; ee=90%.
,
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4k): The diastereo-
meric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.25 (major diastereo-
mer), 0.1 (minor diastereomer); [a]2D0 =À40.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.28–7.30 (dd, J=0.9 Hz, 5.1 Hz, 1H), 6.99–7.01
(dd, J=3.6 Hz, 5.1 Hz, 1H), 6.82–6.84 (d, J=3.3 Hz, 1H), 6.32–6.33 (d,
J=2.7 Hz, 1H), 5.06 (d, J=2.4 Hz, 1H), 4.41 (br s, 1H), 3.85 (s, 3H),
2.17–2.24 (m, 1H), 1.97–1.99 (m, 1H), 1.57–1.77 ppm (m, 7H); 13C NMR
(75 MHz, CDCl3): d=162.0, 140.7, 137.0, 134.6, 129.9, 129.3, 128.8, 127.5,
(4R,4aR,8aS)-Methyl-4-(3-chlorophenyl)-8a-hydroxy-4a-nitro-
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4g): The diastereo-
meric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.3 (major diastereo-
mer), 0.2 (minor diastereomer); [a]2D0 =À30.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.24–7.36 (m, 2H), 7.07–7.08 (t, J=1.8 Hz, 1H),
6.91–6.94 (m, 1H), 6.25 (d, J=2.4 Hz, 1H), 4.61–4.64 (m, 2H), 3.86 (s,
3H), 2.21–2.27 (m, 1H), 1.56–1.89 ppm (m, 8H); 13C NMR (75 MHz,
CDCl3): d=162.0, 139.9, 136.8, 127.7, 127.1, 126.0, 112.5, 97.1, 92.3, 52.6,
˜
112.1, 97.1, 92.2, 52.6, 45.9, 35.0, 27.5, 21.2, 19.9 ppm; IR (KBr): n=
3375.39, 2929.39, 2854.20, 1729.75, 1659.82, 1585.93, 1545.21, 1457.72,
1373.82, 1346.80, 1305.57, 1264.09, 1198.35, 1155.46, 1092.78, 1070.07,
˜
41.6, 35.0, 26.9, 21.1, 20.0 ppm; IR (KBr): n=3377.17, 2923.63, 2854.47,
1025.15,
C15H17NO6S+NH4
904.74,
851.96,
835.52 cmÀ1
;
HRMS
(ESI):
m/z
1729.96, 1661.86, 1630.52, 1602.47, 1545.05, 1437.53, 1356.70, 1275.88,
+
1198.35, 1150.52, 1070.47, 1025.15, 898.14, 830.52, 795.88, 766.19 cmÀ1
;
:
357.1115; found: 357.1117; major diastereomer
(Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1, 230 nm): reten-
tion time: tminor =6.63 min; tmajor =13.86 min; ee=90%.
HRMS (ESI): m/z C17H18ClNO6+NH4+: 385.1161; found: 385.1153; major
diastereomer (Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1
230 nm): retention time: tminor =6.84 min; tmajor =10.04 min; ee=91%.
,
(4R,4aR,8aS)-Ethyl-8a-hydroxy-4a-nitro-4-phenyl-4a,5,6,7,8,8a-hexahy-
dro-4H-chromene-2-carboxylate (4l): The diastereomeric mixture was
isolated by column chromatography on silica gel (EtOAc/petroleum
ether, 1:15) as a white solid. Rf =0.4 (major diastereomer), 0.2 (minor
(4R,4aR,8aS)-Methyl-8a-hydroxy-4a-nitro-4-(p-tolyl)-4a,5,6,7,8,8a-hexa-
hydro-4H-chromene-2-carboxylate (4h): The diastereomeric mixture was
isolated by column chromatography on silica gel (EtOAc/petroleum
ether, 1:8) as a white solid. Rf =0.3 (major diastereomer), 0.2 (minor dia-
stereomer); [a]2D0 =À45.0 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d=7.12–7.15 (d, J=8.1 Hz, 2H), 6.91–6.94 (d, J=8.1 Hz, 2H), 6.29–6.30
(d, J=2.4 Hz, 1H), 4.78 (br s, 1H), 4.56–4.57 (d, J=2.4 Hz, 1H), 3.84 (s,
3H), 2.34 (s, 3H), 2.22–2.28 (m, 1H), 1.54–1.89 (m, 7H), 1.32–1.43 ppm
(m, 1H); 13C NMR (75 MHz, CDCl3): d=162.2, 140.4, 138.4, 131.7,
129.6, 129.3, 129.1, 126.6, 116.5, 113.3, 97.1, 92.7, 52.5, 46.1, 35.2, 27.4,
1
diastereomer); [a]2D0 =À17.0 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3):
d=7.29–7.42 (m, 5H), 6.16 (d, J=1.8 Hz, 1H), 5.90–5.91 (d, J=1.8 Hz,
1H), 5.22–5.28 (q, J=6.0 Hz, 1H), 4.00–4.06 (dd, J=6.9 Hz, 14.1 Hz,
1H), 2.62–2.69 (m, 1H), 2.39–2.54 (m, 3H), 2.01–2.15 (m, 2H),1.74–1.82
(m, 3H), 1.43–1.47 ppm (t, J=6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=167.0, 144.8, 134.7, 128.2, 127.9, 127.6, 126.0, 115.6, 90.9, 78.9, 66.1,
˜
39.8, 30.6, 25.4, 21.6, 13.2 ppm; IR (KBr): n=3402.73, 3064.36, 3031.27,
2933.19, 2871.64, 1771.45, 1727.39, 1655.42, 1545.13, 1494.22, 1451.22,
1373.70, 1337.46, 1274.89, 1247.07, 1194.55, 1129.81, 1097.67, 1053.03,
1024.70, 910.65, 862.06, 832.33, 800.24, 760.14, 703.20 cmÀ1; HRMS (ESI):
m/z C18H21NO6+Na+: 370.1249; found: 370.1245; major diastereomer
(Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1, 230 nm): reten-
tion time: tminor =6.83 min; tmajor =14.40 min; ee=90%.
˜
21.3, 21.1, 19.9 ppm; IR (KBr): n=3377.84, 2924.02, 2855.07, 1777.86,
1729.48, 1657.81, 1597.53, 1549.69, 1440.82, 1241.26, 1200.00, 1124.10,
1067.86, 1028.45, 903.09, 856.91, 822.27, 800.82 cmÀ1; HRMS (ESI): m/z
C18H21NO6+NH4+: 365.1707; found: 365.1709; major diastereomer (Chir-
alcel AD-H, iPrOH/n-hexane=20:80, 1.0 mLminÀ1, 230 nm): retention
time: tminor =6.17 min; tmajor =7.57 min; ee=93%.
(4R,4aR,8aS)-Benzyl-8a-hydroxy-4a-nitro-4-phenyl-4a,5,6,7,8,8a-hexa-
hydro-4H-chromene-2-carboxylate (4m): The diastereomeric mixture
was isolated by column chromatography on silica gel (EtOAc/petroleum
ether, 1:15) as a white solid. Rf =0.3 (major diastereomer), 0.1 (minor
(4R,4aR,8aS)-Methyl-8a-hydroxy-4-(4-methoxyphenyl)-4a-nitro-
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4i): The diastereo-
meric mixture was isolated by column chromatography on silica gel
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.25 (major diastereo-
mer), 0.15 (minor diastereomer); [a]2D0 =À68.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=6.95–6.98 (m, 2H), 6.84–6.87 (d, J=2.4 Hz, 2H),
6.28–6.29 (d, J=2.4 Hz, 1H), 4.80 (br s, 1H), 4.56–4.57 (d, J=2.4 Hz,
1H), 3.84 (s, 3H), 3.80 (s, 3H), 2.22–2.27 (m, 1H), 1.53–1.90 (m, 7H),
1.32–1.43 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=162.2, 159.7,
140.3, 130.3, 126.6, 114.0, 113.4, 97.1, 92.7, 55.3, 52.5, 45.7, 35.1, 27.4, 21.2,
20.0 ppm; IR (KBr): n˜ =3396.76, 2924.19, 2854.11, 1729.92, 1657.04,
1611.96, 1585.98, 1543.10, 1512.82, 1441.26, 1380.20, 1352.08, 1297.69,
1254.01, 1179.05, 1151.58, 1097.47, 1058.52, 1030.46, 964.12, 942.68,
908.04, 876.70, 832.29, 717.13, 700.21, 660.62, 609.48 cmÀ1; HRMS (ESI):
m/z C18H21NO7+NH4+: 381.1656; found: 381.1658; major diastereomer
(Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1, 230 nm): reten-
tion time: tminor =11.52 min; tmajor =20.45 min; ee=93%.
1
diastereomer); [a]2D0 =À29.0 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3):
d=7.31–7.41 (m, 8H), 7.02–7.05 (m, 2H), 6.32–6.33 (d, J=2.4 Hz, 1H),
5.31–5.35 (d, J=12.3 Hz, 1H), 5.20–5.24 (d, J=12.3 Hz, 1H), 4.72 (br s,
1H), 4.61–4.62 (d, J=2.1 Hz, 1H), 2.21–2.28 (m, 1H), 1.57–1.89 (m, 7H),
1.36–1.41 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=161.5, 140.4,
135.3, 134.8, 129.2, 128.6, 128.6, 128.5, 128.4, 113.2, 97.1, 92.6, 46.4, 35.1,
27.4, 21.2, 19.9 ppm; IR (KBr): n˜ =3383.45, 3065.55, 3032.62, 2953.40,
2923.66, 2854.24, 1729.66, 1660.04, 1601.15, 1545.44, 1493.10, 1457.18,
1379.32, 1270.25, 1131.94, 1074.88, 1031.75, 912.81, 827.22, 749.67, 698.61,
+
597.94, 482.47, 402.23 cmÀ1
;
HRMS (ESI): m/z C23H23NO6+NH4
:
427.1864; found: 427.1870; major diastereomer (Chiralcel AD-H, iPrOH/
n-hexane=10:90, 1.0 mLminÀ1, 230 nm): retention time: tminor =7.79 min;
tmajor =15.23 min; ee=92%.
(4R,4aR,8aS)-Methyl-8a-hydroxy-4a-nitro-4-(m-tolyl)-4a,5,6,7,8,8a-hex-
ahydro-4H-chromene-2-carboxylate (4j): The diastereomeric mixture
was isolated by column chromatography on silica gel (EtOAc/petroleum
(4R,4aR,8aS)-Methyl-8a-hydroxy-6-methyl-4a-nitro-4-phenyl-
4a,5,6,7,8,8a-hexahydro-4H-chromene-2-carboxylate (4n): The diastereo-
meric mixture was isolated by column chromatography on silica gel
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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ÞÞ
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R. Wang et al.
(EtOAc/petroleum ether, 1:8) as a white solid. Rf =0.3 (major diastereo-
mer), 0.2 (minor diastereomer); [a]2D0 =À18.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.32–7.36 (m, 3H), 7.03–7.06 (m, 2H), 6.30–6.31
(d, J=2.4 Hz, 1H), 4.76 (br s, 1H), 4.57–4.58 (d, J=2.4 Hz, 1H), 3.85 (s,
3H), 2.21–2.28 (m, 1H), 1.45–1.84 (m, 7H), 1.29–1.34 (m, 1H), 0.86–
0.88 ppm (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=162.2,
140.5, 134.8, 129.3, 128.6, 128.6, 113.0, 97.1, 92.6, 52.5, 46.4, 35.2, 35.0,
samune, G. S. Bates, J. W. Corcoran, Angew. Chem. 1977, 89, 602;
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[2] For selected examples, see: a) A. Gçhrt, A. Zeeck, K. Hꢂtter, R.
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[7] K. Juhl, K. A. Jøgensen, Angew. Chem. 2003, 115, 1536–1539;
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[8] For representative examples of the organocatalytic DAR, see:
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[10] Z. Xu, L. Liu, K. Wheeler, H. Wang, Angew. Chem. 2011, 123, 3546;
Angew. Chem. Int. Ed. 2011, 50, 3484.
[11] For selected examples, see: a) B. Tan, N. R. Candeias, C. F. Barba-
s III, Nat. Chem. 2011, 3, 473; b) B. Tan, N. R. Candeias, C. F. Barba-
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sen, Chem. Rev. 2007, 107, 5713; d) Y. Takemoto, Org. Biomol.
Chem. 2005, 3, 4299.
[12] For selected reviews of bifunctional amine–thiourea catalysts, see:
a) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550;
Angew. Chem. Int. Ed. 2006, 45, 1520; b) S. J. Connon, Chem. Eur. J.
2006, 12, 5418; for selected recent examples, see: c) K. L. Tan, E. N.
Jacobsen, Angew. Chem. 2007, 119, 1337; Angew. Chem. Int. Ed.
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˜
29.8, 26.8, 21.4 ppm; IR (KBr): n=3365.56, 2925.03, 2853.38, 1731.13,
1651.66, 1543.16, 1508.45, 1457.79, 1424.33, 1366.60, 1335.26, 1310.52,
1265.98, 1201.65, 1158.76, 1069.74, 1030.10, 897.85 cmÀ1; HRMS (ESI): m/
z calcd for C18H21NNaO6: 370.1265; found: 370.1261; major diastereomer
(Chiralcel AD-H, iPrOH/n-hexane=10:90, 1.0 mLminÀ1, 230 nm): reten-
tion time: tminor =6.50 min; tmajor =10.68 min; ee=93%.
(4R,4aR,10bS)-Methyl-10b-hydroxy-4a-nitro-4-phenyl-4a,5,6,10b-tetra-
hydro-4H-benzo[h]chromene-2-carboxylate (4o): The diastereomeric
mixture was isolated by column chromatography on silica gel (EtOAc/
petroleum ether, 1:20) as a white solid. Rf =0.45 (major diastereomer),
0.4 (minor diastereomer); [a]2D0 =À52.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=8.00–8.12 (m, 1H), 7.46–7.53 (m, 1H), 7.15–7.37
(m, 7H), 4.29–4.42 (m, 1H), 3.80 (s, 3H), 3.63–3.69 (m, 1H), 3.35–3.39
(m, 1H), 2.95–3.01 (m, 1H), 2.34–2.39 (m, 1H), 2.21–2.29 (m, 1H), 1.98–
2.06 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=160.6, 142.1, 141.8,
136.5, 134.6, 131.6, 130.9, 129.8, 128.9, 128.6, 128.3, 127.4, 95.9, 95.2, 53.1,
˜
49.4, 46.6, 43.3, 41.5, 31.7, 30.7, 29.6, 25.1 ppm; IR (KBr): n=3364.78,
3067.55, 3037.86, 2923.60, 2854.12, 1732.90, 1694.23, 1661.86, 1599.70,
1543.88, 1495.23, 1454.00, 1401.24, 1371.35, 1335.26, 1287.42, 1265.98,
1234.25, 1159.93, 1069.48, 1030.10, 903.09, 856.91, 820.62, 747.43, 742.63,
702.39 cmÀ1; HRMS (ESI): m/z calcd for C21H19NNaO6: 404.1112; found:
404.1105; major diastereomer (Chiralcel AD-H, iPrOH/n-hexane=30:70,
1.0 mLminÀ1, 230 nm): retention time: tminor =14.03 min; tmajor =26.14 min;
ee=76%.
General procedure for synthesis of fluoro-substituted macrolide 5a: To
a solution of compound 4d (70.1 mg, 0.2 mmol) in dry THF (2.0 mL) was
slowly added catalytic amounts of nBu4NF (11 mg, 0.04 mmol, 20 mol%)
at 208C. Next, the mixture was heated to reflux for about 4.0 h under an
argon atmosphere and monitored by TLC analysis. After the reaction
was completed, the mixture was cooled to 08C and quenched with glacial
acetic acid. The mixture was extracted with Et2O and washed sequential-
ly with a saturated solution of sodium bicarbonate, water, and brine. The
collected organic phases were dried over magnesium sulfate and concen-
trated, in vacuo. Purification by column chromatography on silica gel (n-
hexane/EtOAc, 8:1) gave macrolide 5a as a white solid (42 mg, 61%
yield).
ACHTUNGTRENNUNG(7S,8R,Z)-methyl 8-(4-fluorophenyl)-7-nitro-2-oxo-3,4,5,6,7,8-hexahydro-
2H-oxecine-10-carboxylate (5a): [a]2D0 =À50.0 (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.17–7.27 (m, 2H), 6.99–7.11 (m, 2H), 6.48 (s,
0.38H; syn), 6.37 (s, 0.62H; anti), 4.50–4.53 (dd, J=2.1 Hz, 6.3 Hz,
0.63H; anti); 3.80–3.84 (m, 1.37H; anti), 3.74 (s, 2.33H; anti), 3.47 (s,
0.67H; anti), 2.52–2.64 (m, 1H), 2.32–2.41 (m, 2H), 1.50–1.79 (m, 3H),
1.08–1.27 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=175.1, 162.7,
162.6, 140.1, 138.8, 137.8, 136.0, 130.4, 130.1, 129.9, 129.7, 115.5, 115.2,
113.2, 112.7, 100.5, 52.2, 49.4, 44.3, 37.2, 30.7, 29.6, 27.2, 23.9, 23.4,
17.6 ppm; HRMS (ESI): m/z calcd for C17H18FNO6ÀH+: 350.1032; found:
350.1045.
Acknowledgements
We are grateful for grants from the National Natural Science Foundation
of China (nos. 20932003 and 90813012) and from the Key National Sci-
ence and Technology Program “Major New Drug Development” of the
Ministry of Science and Technology of China (2012ZX09504–001–003).
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An Efficient Approach to Chiral Macrolides
FULL PAPER
Jiang, L. P. Liu, F. F. Shen, F. T. Zhang, R. Wang, Angew. Chem.
2011, 123, 9290; Angew. Chem. Int. Ed. 2011, 50, 9124; c) X. X.
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Wang, L. P. Liu, F. F. Shen, R. Wang, J. Am. Chem. Soc. 2010, 132,
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5562.
Received: April 1, 2012
Revised: June 7, 2012
Published online: && &&, 0000
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Angew. Chem. 2012, 124, 2126–2129; Angew. Chem. Int. Ed. 2012,
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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R. Wang et al.
Bifunctional Catalysts
X. Jiang, L. Wang, M. Kai, L. Zhu,
X. Yao, R. Wang* ............ &&&& — &&&&
Asymmetric Inverse-Electron-Demand
Hetero-Diels–Alder Reaction for the
Construction of Bicyclic Skeletons
with Multiple Stereocenters by Using
a Bifunctional Organocatalytic
Strategy: An Efficient Approach to
Chiral Macrolides
Bicyclic exercises: A highly enantiose-
lective inverse-electron-demand
hetero-Diels–Alder reaction of cyclic
ketones with enones affords function-
alized bicyclic skeletons with three
stereocenters that can be used for the
construction of macrolides.
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!