Second generation levoglucosenone-derived chiral auxiliaries. Scope and application in asymmetric Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2009.02.020

Chiral alcohols were designed and easily prepared from levoglucosenone, a biomass-derived valuable synthon. These alcohols were tested as chiral auxiliaries in asymmetric Diels-Alder reactions between the corresponding acrylates with acyclic and cyclic di

Full text of DOI:10.1016/j.tet.2009.02.020

Tetrahedron 65 (2009) 3502–3508
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Second generation levoglucosenone-derived chiral auxiliaries. Scope and
application in asymmetric Diels–Alder reactions
*
´
Ariel M. Sarotti, Rolando A. Spanevello, Alejandra G. Suarez
Instituto de Qu´ımica Rosario, Facultad de Ciencias Bioqu´ımicas y Farmace´uticas, Universidad Nacional de Rosario-CONICET, Suipacha 531, S2002LRK Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral alcohols were designed and easily prepared from levoglucosenone, a biomass-derived valuable
synthon. These alcohols were tested as chiral auxiliaries in asymmetric Diels–Alder reactions between
the corresponding acrylates with acyclic and cyclic dienes. The regio, stereo, and facial selectivity varied
from very good to excellent, depending upon the benzylic substitution of the auxiliary and the diene
employed. As a consequence, after removal of the auxiliary, the resulting carboxylic acid derivatives were
obtained in 72–99% ee.
Received 20 November 2008
Received in revised form 11 February 2009
Accepted 11 February 2009
Available online 20 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
auxiliaries such menthol derivatives, camphor derivatives10 and
oxazolidinones are available.11 Carbohydrate compounds have also
Chirality at the molecular level has emerged as one of the major
issues in the development of chemical technology, especially in the
areas of drug synthesis and advanced materials. The transfer of
chirality through the use of chiral auxiliaries has been demon-
strated as an effectual means for preparing enantiopure materials.1
Most chiral auxiliaries reported in the literature are derived from
natural occurring compounds.
Among the plethora of natural molecules, carbohydrates are
the most prominent members of the chiral pool since they are
major constituents of all foremost structural molecules in living
been reported, although the stereoselectivity was not always good.1
A systematic study was made in order to investigate the re-
lationship between the structure of the synthetic chiral auxiliaries
and their effectiveness in asymmetric Diels–Alder transformations.
We found that the introduction of a substituent at the benzylic
position closer to the ester group (Scheme 1), established a new key
element of steric control, therefore imposing an additional re-
striction to the transition state. This structural modification
allowed us to obtain excellent diastereoisomeric ratios (up to 98%
de) in the cycloaddition reaction of the corresponding acrylic ester
and cyclopentadiene (Scheme 1).7,8
systems. Levoglucosenone (1,6-anhydro-3,4-dideoxy-b-D-glycero-
hex-3-enopyranos-2-ulose) (1) is a versatile and easily available
chiral building block from the carbohydrate family.2,3 Conventional
pyrolysis of cellulose-containing materials such as waste paper is
typically used to generate 1,2–4 but microwave irradiation of mi-
crocrystalline cellulose was recently found to be also effective.5 The
highly functionalized structure of 1 makes it an attractive chiral
synthon for the synthesis of a wide variety of natural and unnatural
compounds.2,3
In the context of our ongoing interest in the development new
tools for asymmetric synthesis, we have recently reported the
design and application of novel chiral auxiliaries derived from
levoglucosenone and their application in Diels–Alder reactions.6–8
Both stoichiometric (chiral auxiliaries) and catalytic (chiral
Lewis acids) approaches to asymmetric Diels–Alder reaction have
been developed with success.9 For acrylates, several chiral
The high levels of asymmetric induction achieved with the use
of cyclopentadiene encouraged us to test the scope of this system
with other dienes. Additionally, in an effort to develop new struc-
turally related inductors we envisaged the synthesis of other two
chiral auxiliaries bearing bulky groups at the benzylic position of
the molecule. We considered that the presence of a tert-butyldi-
methylsilyloxy (OTBS) or a tert-butyldiphenylsilyloxy (OTPS) group
would induce enhanced selectivity resulting from a larger differ-
ence in the steric environment of the two diastereofaces of the
acrylate moiety.
O
O
O
O
O
O
H
CO2R*
O
1
R
R=OMe, OPh
* Corresponding author. Tel./fax: þ54 341 437 0477.
´
Scheme 1.
E-mail address: suarez@iquir-conicet.gov.ar (A.G. Suarez).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.020

A.M. Sarotti et al. / Tetrahedron 65 (2009) 3502–3508
3503
2. Results and discussion
O
H
O
H
O
O
O
O
OH
Cl
Our strategy toward the preparation of the chiral auxiliaries 6a–
d was achieved using a general procedure, which started with
a Diels–Alder reaction between levoglucosenone and the corre-
O
CH2Cl2, NEt3
0 °C
7 (R=OMe)
8 (R=OPh)
9 (R=OTBS)
10 (R=OTPS)
R
R
6a-d
79-84%
sponding 9-substituted anthracene, followed by
a diaster-
eoselective reduction of the ortho adduct (Scheme 2). The 9-derived
anthracenes 2a–d were synthesized in a simple and efficient way
from commercially available 9-anthracenemethanol.12 Attempts to
perform the cycloaddition step using Lewis acids as catalyst did not
afford the desired product. However, this chemical transformation
was accomplished in refluxing toluene with very good yields and
ortho selectivity. Separation of both ortho 3a–d and meta 4a–d ad-
ducts was easily achieved by flash chromatography.
Scheme 3.
interplay between stabilizing secondary orbital interactions and
steric effects in the transition state.13
As shown in Table 1 (entries 1–4), an interesting
p-facial se-
lectivity favoring the endo S-adduct was observed (up to 76% de). It
is generally accepted that the s-cis/s-trans conformation of the
enoate moiety is not fixed in the absence of Lewis acids. However,
the higher selectivity shown by these chiral auxiliaries compared to
the one obtained with structurally related systems without a sub-
stituent at the benzylic position could be ascribed to the steric
hindrance exerted by the substituent.6a
In order to improve the selectivity, the reactions were next
carried out in the presence of Lewis acids. After extensive survey,
Et2AlCl and EtAlCl2 demonstrated to be the most effective in this
system and with structurally related dienophiles in terms of re-
activity and selectivity.6–8,14 All cycloaddition reactions of acrylates
7–10 with cyclopentadiene (entries 5–8) proceeded in very good
R
O
O
O
O
O
R
O
+
O
O
2a-d
PhMe, reflux
>90% yield
O
3a-d
4a-d
R
3/4=4:1 to >25:1
1
O
O
H
O
NaBH4; >90%
5/6=1:2
O
O
O
OH
+
O
H
OH
5a-d
R
R
6a-d
3a-d
R
yields with high endo/exo and p-facial selectivity (endo R/S ratio up
a: R = OMe; b: R = OPh
to 99:1). It is important to point out that when employing Lewis
acids a striking reversal of the stereoselectivity was obtained
compared to the thermal conditions. This observation was inter-
preted in terms that the metal coordination plays a key role in the
conformational preference of the enoate moiety, toward the attack
of the diene.
With the high selectivity established in the Diels–Alder re-
actions of cyclopentadiene, our challenge was to test the effec-
tiveness to less reactive cyclic dienes, such as cyclohexadiene
(entries 9–12). Not unexpectedly, this reaction could not be carried
out under thermal conditions. However, the addition of 3 equiv of
Lewis acids proved to be effective in terms of reaction rate and
yields. In all cases, the cycloaddition reaction showed excellent
endo selectivity (endo/exo >99:1). The endo R/S ratios were very
good (up to 92% de), except with the use of chiral acrylate 9
(R¼OTBS), which was slightly decreased.
PCC, CH2Cl2, rt
>90%
c: R = OTBS; d: R = OTPS
Scheme 2. Synthesis of chiral auxiliaries.
The reduction of ketones 3a–d led to the formation of two
epimeric alcohols 5a–d and 6a–d. Even though these com-
pounds have the appropriate functionality to be tested as chiral
auxiliaries, after extensive experimentation we found that es-
terification of isomers 5a–d were notably difficult, probably due
to the steric hindrance surrounding the a-alcohol. For this rea-
son, we investigated reducing conditions toward the formation
of 6a–d. Reducing agents like DIBAL or L-Selectride afforded
exclusively the a-alcohols 5a–d due to the steric effect produced
by the aromatic ring that overcomes the one exerted by the 1,6-
anhydro bridge. With NaBH4 instead, the outcome of the re-
duction was function of the MeOH/CH2Cl2 ratio employed. A low
proportion of MeOH favored the product obtained from the at-
tack of the hydride from the more crowded face of the carbonyl
group at low MeOH concentration. This experimental result can
be understood considering a coordination between the boron
atom of the reducing agent and the oxygen at the homobenzylic
position. The reaction of ketones 3a–d with NaBH4 in a mixture
CH2Cl2/MeOH 95:5 at 0 ꢀC afforded 5a–d/6a–d in a 1:2 ratio,
with excellent yields. The epimeric products were simply sepa-
rated by flash chromatography. In order to improve the overall
yield of 6a–d, alcohols 5a–d can be recycled by oxidation with
PCC almost quantitatively to regenerate starting material.
Once the syntheses of inductors 6a–d were achieved in
a straightforward manner, the corresponding acrylates were pre-
pared and tested as chiral dienophiles in asymmetric Diels–Alder
cycloadditions. The acylation step was easily performed in good
yields by reaction of acryloyl chloride with the corresponding al-
cohol in the presence of triethylamine at 0 ꢀC (Scheme 3).
Chiral acrylates 7–10 were also found to accomplish high levels
of regio- and diastereoselectivity when representative acyclic di-
enes were investigated (entries 13–24). Of the eight possible
products, which might have been anticipated from the reaction
using piperylene as diene, to our delight we found that only two of
them were obtained, namely ortho-endo adducts (entries 13–16).
The excellent regiocontrol was also achieved when isoprene was
employed (para/meta >99:1, entries 17–20). The levels of
p-facial
selectivity with both dienes were high, particularly when using
acrylates 7 (R¼OMe) and 8 (R¼OPh) (up to 92% de with piperylene,
94% de with isoprene). These experimental findings suggest that
substitution at the benzylic position of chiral auxiliaries is a key
element for facial discrimination, but the effectiveness does not
rely on the bulkiness of the substituent group. In the case of 2,3-
dimethyl-1,3-butadiene (entries 21–24) a lower
p-facial selectiv-
ities were achieved (up to 72% de) than the ones observed for
previous dienes. The lack of high selectivity in this case was not
surprising, since it has already been reported a similar behavior
when using this diene in asymmetric cycloaddition reactions.15
It is noteworthy to mention that the Diels–Alder reactions of the
chiral acrylates with all dienes when tested at 25 ꢀC in this study
maintained almost the same diastereoselectivity observed at low
temperatures.
The Diels–Alder reactions between acrylates 7–10 and cyclo-
pentadiene were first carried out under thermal conditions (Table
1, entries 1–4), affording the four expected diastereoisomers, two
endo and two exo adducts. All cycloadditions were endo selective, as
predicted by Alder’s rule, which has been rationalized in terms of

3504
A.M. Sarotti et al. / Tetrahedron 65 (2009) 3502–3508
Table 1
Diels–Alder reactions of chiral acrylates 7–10 with different dienesa
R2
R3
R3
R1
O
H
O
H
O
R1
n
O
O
O
R
n
n
O
O
O
R2
+
S
n = 0, 1, 2
R1, R2, R3 = H, CH3
R1
O
O
O
R3
R2
H
R
R
11b-30b
R
11a-30a
Entry
Diene
Chiral acrylate
Lewis acid (equiv)
T (ꢀC)
t (h)
Yield (%)b
Regio-selectivityc
endo/exoc
endo R/Sc
Major productd
1
2
3
4
5
6
7
8
7
8
9
10
7
8
9
10
7
8
9
10
7
8
9
10
7
8
9
10
7
d
25
25
25
25
ꢁ80
ꢁ80
ꢁ80
ꢁ80
0
0
0
0
0
0
0
0
0
0
0
0
0
48
48
48
48
1
1
1
1
6
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
95
91
91
99
80
82
85
87
90
92
89
86
82
86
85
86
87
89
87
83
86
80
81
79
d
76:24
78:22
78:22
76:24
98:2
96:4
97:3
97:3
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
d
23:77
13:87
12:88
16:84
99:1
97:3
91:9
96:4
96:4
94:6
84:16
93:7
95:5
96:4
89:11
83:17
97:3
97:3
93:7
11b (R¼OMe)
d
d
12b (R¼OPh)
13b (R¼OTBS)
14b (R¼OTPS)
11a (R¼OMe)
12a (R¼OPh)
13a (R¼OTBS)
14a (R¼OTPS)
15a (R¼OMe)
16a (R¼OPh)
17a (R¼OTBS)
18a (R¼OTPS)
19a (R¼OMe)
20a (R¼OPh)
21a (R¼OTBS)
22a (R¼OTPS)
23a (R¼OMe)
24a (R¼OPh)
25a (R¼OTBS)
26a (R¼OTPS)
27a (R¼OMe)
28a (R¼OPh)
29a (R¼OTBS)
30a (R¼OTPS)
d
d
d
d
S
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (2)
Et2AlCl (3)
EtAlCl2 (3)
EtAlCl2 (3)
Et2AlCl (3)
EtAlCl2 (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
Et2AlCl (3)
d
COXc
d
R
d
d
COXc
9
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
d
R
d
COXc
COXc
d
>99:1e
>99:1e
>99:1e
>99:1e
>99:1f
>99:1f
>99:1f
>99:1f
d
S
R
COXc
COXc
d
R
d
d
92:8
d
86:14
83:17
76:24
69:31
8
9
10
0
0
0
d
d
R
d
d
d
d
a
Reactions run in CH2Cl2 with 10 equiv of diene.
Overall isolated yield after flash column chromatography.
Determined by NMR and HPLC (C-18 column, MeCN/H2O 80/20, flow rate 1 mL/min).
b
c
d
Major product absolute stereochemistry determined by hydrolysis and further comparison of the sign of the specific rotation of the isolated carboxylic acid to those
reported in the literature (Ref. 15).
e
ortho/meta ratio.
para/meta ratio.
f
It is generally accepted that the stereoselectivity in the Diels–
Alder reaction depends upon the s-trans/s-cis conformation of the
enoate.16 Based on literature reports,17 experimental evidences and
detailed NMR studies, we can postulate that in this case, the re-
action promoted with more than 1 equiv of Et2AlCl (or EtAlCl2)
proceeds through the formation of a chelated complex like 36 in
the s-cis conformation.7,8 The addition of diene from the more
accessible face of the Lewis acid–dienophile intermediate affords
For that reason, acids 31–35 could be isolated in high enantio-
meric purity, depending upon the diene employed. For instance,
endo R adducts derived from reaction of acrylates 7–10 and
cyclopentadiene (or cyclohexadiene), can be isolated in pure
diastereoisomeric form after flash chromatography. Thus, the
hydrolytic cleavage affords (2R)-endo-bicyclo[2.2.1]hept-5-ene-
2-carboxylic acid (31) and (2R)-endo-bicyclo[2.2.2]oct-5-ene-2-
carboxylic acid (32) in enantiomerically pure forms.18 On the other
hand, all attempts to separate pure major isomers derived from
Diels–Alder reaction using piperylene, isoprene, and 2,3-dimethyl-
1,3-butadiene met with no success. As a result, the cyclohexene
carboxylic acids (33–35) obtained after hydrolysis could be only
isolated in up to 94% ee.
the predominant
(Scheme 4).
R
isomers, as we observed experimentally
R2
R1
R3
Et2AlCl2
O
n
Al
O
O
"si" face
R3
R2
attack
endo TS
O
R
n
Xc
R3
R2
O
H
O
H
H
O
R1
O
O
n
LiOH
THF-H2O
25 ºC
O
OH
36
R
R1
O
Scheme 4.
>95%
R
R
6a-d
CO2H
CO2H
CO2H
Aside from the excellent regio- and diastereocontrol, a salient
feature of these chiral auxiliaries is their simple removal pro-
cedure. Treatment of adducts 11–30 with LiOH in THF/H2O at
25 ꢀC followed by a quench with 1 N HCl until pH¼4 gave the
corresponding free carboxylic acids 31–35 and allowed quantita-
tive recovery of chiral auxiliaries (Scheme 5). No epimerization
CO2H
CO2H
31
32
33
34
35
up to
72% ee
up to
92% ee
up to
94% ee
>99% ee
>99% ee
Scheme 5.
was observed at the stereogenic center
a to the carboxylic acid.

A.M. Sarotti et al. / Tetrahedron 65 (2009) 3502–3508
3505
3. Conclusion
with CH2Cl2 (100 mL) and then with AcOEt (3ꢂ150 mL). The com-
bined organic extracts were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by flash chro-
matography to afford alcohols 5a–d and 6a–d (major) in >90%
overall yield. To recycle minor compounds 5a–d, they were dis-
solved in CH2Cl2 (c 0.15 M) then PCC (2.7 equiv) was added in one
portion and stirred overnight under argon atmosphere. The re-
action mixture was diluted with CH2Cl2 and filtered through Flo-
risilÒ contained in a sintered glass funnel. The filtrate was
concentrated to give starting ketones 3a–d in >95% yield.
In summary, we have described highly efficient regio- and dia-
stereoselective Diels–Alder reactions using levoglucosenone-de-
rived chiral auxiliaries. A systematic study was performed in order
to investigate the relationship between the nature of the sub-
stituent at the benzylic position of chiral acrylates and its effec-
tiveness in asymmetric Diels–Alder transformations. The sense of
asymmetric induction depended upon the diene and the nature of
the benzylic substituent of the chiral auxiliary, the smallest ones
(R¼OMe, R¼OPh) being the most effective in terms of
p-facial se-
25
lectivity. Saponification of the obtained cycloadducts provided free
carboxylic acids in high yields and enantiomeric purity. Chiral
auxiliaries were recovered quantitatively after hydrolysis and could
be reused.
4.2.1.1. Alcohol 6c. Colorless oil; [
a
]
þ6.4 (c 0.64, CHCl3); IR (film)
D
nmax: 3462 (OH), 3072, 3023, 2953, 2928, 1457, 1254, 1102, 1056,
835, 749 cmꢁ1; 1H NMR (CDCl3)
d
7.53–7.02 (m, 8H, aromatic), 4.98
(d, J1–2¼3.4 Hz, 1H, H-1), 4.86 (d, Jgem¼10.7 Hz, 1H, H-7), 4.73
(d, Jgem¼10.7 Hz, 1H, H-7), 4.65 (d, J5–6exo¼4.7 Hz, 1H, H-5), 4.13
(d, J4–4a¼0.9 Hz, 1H, H-4a), 3.74 (dd, Jgem¼7.1 Hz, J5–6exo¼4.7 Hz, 1H,
H-6exo), 3.66 (d, Jgem¼7.1 Hz, 1H, H-6endo), 2.99–2.91 (m, 1H, H-2),
2.32–2.21 (m, 2H, H-3 and OH), 2.08 (d, J3–4¼10.5 Hz, 1H, H-4), 0.98
(s, 9H, H-10), 0.33 (s, 3H, H-8a), 0.28 (s, 3H, H-8b); 13C NMR (CDCl3)
4. Experimental
4.1. General methods
The melting points were taken on a Leitz Wetzlar Microscope
Heating Stage Model 350 apparatus and are uncorrected. Optical
rotations were recorded with a Jasco DIP 1000 polarimeter. Infrared
spectra were obtained on an IRPrestige-21 Fourier Transform
Spectrophotometer Shimadsu. High resolution mass spectrometry
measurements were performed using a Waters AutoSpect equip-
ment, Applied Biosystems MS, Micromass AutoSpec or Bruker
micrOTOF-Q equipments. HPLC analyses were performed with
a chromatograph Varian ProStar equipped with UV-V detector
ProStar 320 at 270 nm. HPLC was performed on a Beckman C-18,
25 cm column. Acetonitrile and water HPLC grade were used as
eluents in a mixture 80:20, respectively. Flow rate was 1 mL/min.
Nuclear magnetic resonance spectra were recorded on a Bruker AC-
200 or a Bruker Avance-300 DPX spectrometers with tetrame-
thylsilane as internal standard and deuterochloroform as solvent.
The NMR assignments were corroborated by NOE measurements,
H,H- and H,C-correlations.
The reactions were monitored by thin layer chromatography
carried out on 0.25 mm E. Merck silica gel plates (60F254) that were
developed using UV light and anisaldehyde–sulfuric acid–acetic
acid with subsequent heating. Flash column chromatographies
were performed using Merck silica gel 60H, by gradient elution
created by mixtures of hexanes and increasing amounts of ethyl
acetate. All reactions were carried out under argon atmosphere
with dry, freshly distilled solvents under anhydrous conditions
unless otherwise noted. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless oth-
erwise stated.
d 146.5 (C, aromatic), 141.9 (C, aromatic), 141.4 (C, aromatic), 141.2
(C, aromatic), 126.0 (CH, aromatic), 125.4 (CH, 3C, aromatic), 124.9
(CH, aromatic), 123.9 (CH, aromatic), 122.9 (CH, aromatic), 121.8
(CH, aromatic), 99.8 (CH, C-1), 76.7 (CH, C-5), 70.2 (CH2, C-6), 68.7
(CH, C-2), 61.9 (CH2, C-7), 50.8 (C, C-3a), 50.5 (CH, C-4a), 47.6 (CH, C-
4), 41.2 (CH, C-3), 25.8 (CH3, C-10), 18.2 (C, C-9), ꢁ5.5 (CH3, C-8a),
ꢁ5.6 (CH3, C-8b). HRMS calcd for C27H34O4SiNa [MþNa]þ 473.2124;
found 473.2144.
16
4.2.1.2. Alcohol 6d. Colorless oil; [
a]
þ9.7 (c 1.80, CHCl3); IR (film)
D
nmax: 3473 (OH), 3071, 2930, 2857, 1457, 1426, 1103, 1056, 750,
702 cmꢁ1; 1H NMR (CDCl3)
d
7.86–7.81 (m, 4H, aromatic), 7.49–7.41
(m, 6H, aromatic), 7.33–7.30 (m, 1H, aromatic), 7.19–6.87 (m, 7H,
aromatic), 4.98 (d, J1–2¼3.3 Hz, 1H, H-1), 4.88 (s, 2H, H-7), 4.65 (d,
J5–6exo¼4.7 Hz, 1H, H-5), 4.11 (d, J4–4a¼1.0 Hz, 1H, H-4a), 3.74 (dd,
Jgem¼7.1 Hz, J5–6exo¼4.7 Hz, 1H, H-6exo), 3.67 (d, Jgem¼7.1 Hz, 1H, H-
6endo), 2.94 (br s, 1H, H-2), 2.33–2.26 (m, 2H, H-3 and OH), 2.10 (d,
J3–4¼10.4 Hz, 1H, H-4), 1.16 (s, 9H, H-9); 13C NMR (CDCl3)
d 146.3 (C,
aromatic), 141.7 (C, aromatic), 141.3 (C, aromatic), 140.8 (C, aro-
matic), 136.2 (CH, 2C, aromatic), 136.1 (CH, 2C, aromatic), 133.0 (C,
aromatic), 132.9 (C, aromatic), 130.0 (CH, aromatic), 129.8 (CH,
aromatic), 127.7 (CH, 2C, aromatic), 127.6 (CH, 2C, aromatic), 125.9
(CH, aromatic), 125.3 (CH, aromatic), 125.2 (CH, 2C, aromatic), 124.8
(CH, aromatic), 124.3 (CH, aromatic), 123.1 (CH, aromatic), 121.6
(CH, aromatic), 99.8 (CH, C-1), 76.7 (CH, C-5), 70.1 (CH2, C-6), 68.5
(CH, C-2), 62.7 (CH2, C-7), 51.2 (C, C-3a), 50.4 (CH, C-4a), 47.7 (CH, C-
4), 41.4 (CH, C-3), 27.2 (CH3, C-9), 19.3 (C, C-8). HRMS calcd for
C37H38O4SiNa [MþNa]þ 597.2437; found 597.2426.
Levoglucosenone (1) was synthesized according to the pro-
cedure described in literature2,3 or following the procedure de-
veloped in our research group.5
4.3. Synthesis of chiral acrylates
4.3.1. General procedure
4.2. Synthesis of chiral auxiliaries
Each alcohol 6a–d (3 mmol) was dried azeotropically with dry
benzene, dissolved in CH2Cl2 to afford a 0.70 mM solution which
was cooled at 0 ꢀC. Triethylamine (21 mmol) and acryloyl chloride
(13 mmol) were added and stirred for 1 h under argon atmosphere.
The mixture was diluted with water (50 mL) and extracted several
times with 50 mL portions of CH2Cl2. The combined organic ex-
tracts were dried (Na2SO4) and concentrated. The residue was pu-
rified by flash chromatography to afford acrylates 7–10 in 79–84%
yield.
4.2.1. General procedure
Levoglucosenone (1) and the corresponding 9-substituted an-
thracenes 2a–d (2.8 equiv) were dissolved in toluene (c 0.2 M) at
room temperature. The solution was heated under reflux for 7–10
days until completion by TLC analysis. Solvent was evaporated
under reduced pressure and the solid residue was purified by flash
chromatography to give adducts ortho 3a–d and meta 4a–d in >90%
overall yield. The excess of the diene was recovered quantitatively
and reused. Next, the major regioisomers ortho 3a–d were dis-
solved in a CH2Cl2/MeOH 95:5 mixture (c 0.06 M), cooled at 0 ꢀC
and NaBH4 (2.2 equiv) was incorporated. The solution was stirred
4–8 h and then water was added. The aqueous phase was extracted
4.3.1.1. Acrylate 9. Colorless oil; [
a
]
D ꢁ14.3 (c 1.95, CHCl3); IR (film)
nmax: 3074, 2955, 2857, 1722 (C]O), 1464, 1405, 1259, 1194, 1104,
1012, 838, 733 cmꢁ1; 1H NMR (CDCl3)
d 7.57–7.05 (m, 8H, aromatic),
6.48 (dd, Jvic¼17.3 Hz, Jgem¼1.4 Hz, 1H, H-30cis), 6.19 (dd,

3506
A.M. Sarotti et al. / Tetrahedron 65 (2009) 3502–3508
Jvic¼17.3 Hz, Jvic¼10.3 Hz, 1H, H-20), 5.88 (dd, Jvic¼10.3 Hz,
Jgem¼1.4 Hz, 1H, H-30trans), 5.09 (d, J1–2¼3.1 Hz, 1H, H-1), 4.66
(d, J5–6exo¼4.0 Hz, 1H, H-5), 4.55 (d, Jgem¼10.7 Hz, 1H, H-7), 4.42 (d,
Jgem¼10.7 Hz, 1H, H-7), 4.32 (dd, J2–3¼6.1 Hz, J1–2¼3.1 Hz, 1H, H-2),
4.16 (s, 1H, H-4a), 3.75–3.69 (m, 2H, H-6), 2.45 (br s, 1H, H-3), 2.18
(d, J3–4¼10.4 Hz, 1H, H-4), 0.92 (s, 9H, H-10), 0.24 (s, 3H, H-8a), 0.15
Jgem¼7.2 Hz, J5–6exo¼4.4 Hz, 1H, H-6exo), 3.63 (d, Jgem¼7.2 Hz, 1H,
H-6endo), 3.59(s, 3H, H-8), 3.01 (brs,1H, H-70), 2.68(td, J2 –3 exo¼9.9 Hz,
0
0
0
0
0
0
0
0
J2 –3 endo¼5.5 Hz, J2 –7 ¼2.2 Hz, 1H, H-2 ), 2.60 (br s, 1H, H-4 ), 2.35 (dd,
J3–4¼10.4 Hz, J2–3¼6.0 Hz, 1H, H-3), 2.10 (d, J3–4¼10.4 Hz, 1H,0H-4), 1.79
0
0
0
0
(td, Jgem¼12.9 Hz, J2 –3 exo¼9.9 Hz, J3 exo–4 ¼2.6 Hz, 1H, H-3 exo), 1.66
0
0
0
0
0
(td, Jgem¼12.9 Hz, J2 –3 endo¼5.5 Hz, J3 endo–4 ¼2.8 Hz, 1H, H-3 endo),
(s, 3H, H-8b); 13C NMR (CDCl3)
d
165.2 (C, C-10), 146.0 (C, aromatic),
1.60–1.24 (m, 4H, H-80 and H-90); 13C NMR (CDCl3) 174.4 (C, C-10),
d
141.1 (C, aromatic), 141.0 (C, aromatic), 140.8 (C, aromatic), 131.5
(CH2, C-30), 128.2 (CH, C-20), 126.1 (CH, aromatic), 125.8 (CH, aro-
matic), 125.6 (CH, aromatic), 125.3 (CH, aromatic), 124.8 (CH, aro-
matic), 124.6 (CH, aromatic), 123.6 (CH, aromatic), 121.8 (CH,
aromatic), 96.8 (CH, C-1), 76.6 (CH, C-5), 70.8 (CH, C-2), 70.1 (CH2, C-
6), 61.2 (CH2, C-7), 51.5 (C, C-3a), 50.7 (CH, C-4a), 47.8 (CH, C-4), 37.1
(CH, C-3), 25.8 (CH3, C-10),18.0 (C, C-9), ꢁ5.6 (CH3, C-8a), ꢁ5.9 (CH3,
C-8b). HRMS calcd for C30H36O5SiNa [MþNa]þ 527.2230; found
527.2219.
145.6 (C, aromatic), 140.8 (C, aromatic), 140.6 (C, aromatic), 140.4 (C,
aromatic), 135.3 (CH, C-50), 131.1 (CH, C-60), 126.1 (CH, aromatic), 125.9
(CH, aromatic), 125.7 (CH, 2C, aromatic), 124.6 (CH, aromatic), 123.9
(CH, aromatic), 123.5 (CH, aromatic), 121.8 (CH, aromatic), 96.6 (CH,
C-1), 76.3 (CH, C-5), 71.3 (CH2, C-7), 70.1 (CH, C-2), 70.1 (CH2, C-6), 59.0
(CH3, C-8), 50.5 (CH, C-4a), 50.4 (C, C-3a), 47.5 (CH, C-4), 42.7 (CH, C-20),
37.6 (CH, C-3), 32.1 (CH, C-70), 30.0 (CH2,C-30), 29.2 (CH, C-40), 25.3 (CH2,
C-90), 24.0 (CH2, C-80).
4.4.2. Adduct 16a
24
4.3.1.2. Acrylate 10. Colorless oil; [
(film) nmax: 3072, 2929, 2857, 1724 (C]O), 1458, 1405, 1189, 1105,
1011, 749, 702 cmꢁ1; 1H NMR (CDCl3)
7.72–7.66 (m, 4H, aromatic),
a
]
ꢁ17.7 (c 0.78, CHCl3); IR
Colorless oil; [
a]
ꢁ6.5 (c 0.99, CHCl3); IR (film) 3042, 3023,
D
D
2944, 2868, 1728 (C]O), 1599, 1499, 1478, 1244, 1160, 1147, 1052,
753 cmꢁ1; 1H NMR (CDCl3)0 d 7.42–7.01 (m, 13H, aromatic), 6.17 (d0d,
d
0
0
0
0
0
0
0
0
7.49–7.33 (m, 9H, aromatic), 7.21–6.94 (m, 5H, aromatic), 6.31 (dd,
Jvic¼17.2 Hz, Jgem¼1.5 Hz, 1H, H-30cis), 5.99 (dd, Jvic¼17.2 Hz,
Jvic¼10.4 Hz, 1H, H-20), 5.74 (dd, Jvic¼10.4 Hz, Jgem¼1.5 Hz, 1H,
H-30trans), 5.11 (d, J1–2¼3.1 Hz, 1H, H-1), 4.63 (d, J5–6exo¼4.4 Hz, 1H,
H-5), 4.59 (d, Jgem¼11.5 Hz, 1H, H-7), 4.55 (d, Jgem¼11.5 Hz, 1H, H-7),
4.16–4.13 (m, 2H, H-2 and H-4a), 3.69 (dd, Jgem¼7.0 Hz,
J5–6exo¼4.4 Hz, 1H, H-6exo), 3.64 (d, Jgem¼7.0 Hz, 1H, H-6endo), 2.20
(dd, J3–4¼10.6 Hz, J2–3¼6.1 Hz, 1H, H-3), 2.10 (d, J3–4¼10.6 Hz, 1H,
J5 –6 ¼J4 –5 ¼7.2 Hz,1H, H-5 ), 6.05 (dd, J5 –6 ¼J6 –7 ¼7.2 Hz,1H, H-6 ),
5.00 (d, Jgem¼9.8 Hz, 1H, H-7), 4.95 (d, J1–2¼3.2 Hz, 1H, H-1), 4.69 (d,
Jgem¼9.8 Hz, 1H, H-7), 4.65 (dd, J5–6exo¼3.5 Hz, J5–6endo¼2.1 Hz, 1H,
H-5), 4.28 (dd, J2–3¼6.3 Hz, J1–2¼3.2 Hz, 1H, H-2), 4.21 (d,
J4–4a¼1.2 Hz, 1H, H-4a), 3.74–3.69 (m, 2H, H-6), 2.80 (br s, 1H, H-3),
2.44 (br s, 2H, H-40 and H-70), 2.24 (d, J3–4¼10.9 Hz,1H, H-4),1.97 (br
s, 1H, H-20), 1.64 (td, Jgem¼11.6 Hz, J2 –3 exo¼11.6 Hz, J3 exo–4 ¼2.3 Hz,
0
0
0
0
1H, H-30exo), 1.36–1.01 (m, 5H, H-30endo, H-80 and H-90); 13C NMR
(CDCl3) d
174.9 (C, C-10), 158.5 (C, aromatic), 145.9 (C, aromatic),
H-4), 1.12 (s, 9H, H-9); 13C NMR (CDCl3)
d
164.9 (C, C-10), 145.7 (C,
aromatic), 140.7 (C, 2C, aromatic), 140.3 (C, aromatic), 136.0 (CH, 2C,
aromatic), 135.9 (CH, 2C, aromatic), 133.2 (C, aromatic), 132.9
(C, aromatic), 131.2 (CH2, C-30), 129.8 (CH, aromatic), 129.7 (CH,
aromatic), 127.9 (CH, C-20), 127.7 (CH, 2C, aromatic), 127.5 (CH,
2C, aromatic), 126.0 (CH, aromatic), 125.8 (CH, aromatic), 125.6
(CH, aromatic), 125.3 (CH, aromatic), 124.8 (CH, aromatic), 124.7
(CH, aromatic), 124.6 (CH, aromatic), 121.7 (CH, aromatic), 96.6 (CH,
C-1), 76.4 (CH, C-5), 71.1 (CH, C-2), 70.3 (CH2, C-6), 62.7 (CH2, C-7),
52.4 (C, C-3a), 50.6 (CH, C-4a), 48.1 (CH, C-4), 38.3 (CH, C-3), 27.1
(CH3, C-9), 19.5 (C, C-8). HRMS calcd for C40H40O5SiNa [MþNa]þ
651.2543; found 651.2554.
141.0 (C, aromatic), 140.5 (C, 2C, aromatic), 134.3 (CH, C-50), 132.0
(CH, C-60), 129.5 (CH, 2C, aromatic), 126.4 (CH, aromatic), 126.0 (CH,
aromatic), 125.9 (CH, aromatic), 125.8 (CH, aromatic), 125.0 (CH,
aromatic), 124.0 (CH, aromatic), 122.7 (CH, aromatic), 122.0
(CH, aromatic), 121.1 (CH, aromatic), 114.3 (CH, 2C, aromatic), 97.0
(CH, C-1), 76.6 (CH, C-5), 70.3 (CH2, C-6), 69.9 (CH, C-2), 65.5 (CH2,
C-7), 50.6 (CH, C-4a), 49.7 (C, C-3a), 47.4 (CH, C-4), 42.3 (CH, C-20),
36.5 (CH, C-3), 31.2 (CH, C-70), 31.0 (CH2, C-30), 29.2 (CH, C-40), 24.9
(CH2, C-90), 23.8 (CH2, C-80).
4.4.3. Adducts 19a and 19b
Colorless oil; IR (film) 3071, 3021, 2960, 2923, 2892, 1725, 1458,
4.4. Asymmetric Diels–Alder reactions
1305, 1228, 1145, 1115, 1020, 734 cmꢁ1; 1H NMR (CDCl3)
d 7.44–7.34
(m, 2H, aromatic), 7.27–7.06 (m, 6H, aromatic), 5.72–5.48 (m, 2H,
Each acrylic ester 7–10 (0.1 mmol) was dried azeotropically with
dry benzene and dissolved in the CH2Cl2 to give a 0.2 M solution.
When the reaction was promoted by Lewis acid the appropriate
amount was added under nitrogen and stirred for 20 min at the
corresponding temperature. The diene (1 mmol) was added drop-
wise and the mixture was stirred at the temperature and time in-
dicated in Table 1. The cycloaddition reactions carried out without
Lewis acid were concentrated after completion to afford a solid
residue. The reactions promoted by Lewis acids were quenched by
the addition of water (10 mL) and HCl 0.1 N (10 mL), then extracted
with CH2Cl2 (3ꢂ30 mL). The combined organic extracts were dried
(Na2SO4) and concentrated. The solid residue was purified by flash
chromatography to separate the excess of diene and to recover the
product mixture. Diastereoselectivities were determined by HPLC
and NMR analysis.
H-40 and H-50), 5.12 (d, J1–2¼3.5 Hz, 1H, H-1 of 19a), 5.08 (d, J1–
¼3.3 Hz, 1H, H-1 of 19b), 4.64 (d, J5–6exo¼4.4 Hz, 1H, H-5), 4.32–
2
4.23 (m, 3H, H-2 and H-7), 4.17 (d, J4–4a¼1.3 Hz, 1H, H-4a), 3.72 (dd,
Jgem¼7.1 Hz, J5–6exo¼4.4 Hz, 1H, H-6exo), 3.67 (dd, Jgem¼7.1 Hz,
J5–6endo¼1.1 Hz,1H, H-6endo), 3.59 (s, 3H, H-8), 2.77–2.64 (m, 2H, H-
20 and H-30), 2.42 (dd, J¼10.3, 5.9 Hz, 1H, H-3), 2.16 (d, J3–4¼10.5 Hz,
1H, H-4), 2.09–1.75 (m, 4H, H-60 and H-70), 1.09 (d, J3 –8 ¼7.2 Hz, H-
0
0
80 of 19b), 1.06 (d, J3 –8 ¼7.0 Hz, 3H, H-8 of 19a); 13C NMR (CDCl3)
0
0
0
d
174.9 (C, C-10 of 19b), 173.8 (C, C-10 of 19a), 145.6 (C, aromatic),
140.9 (C, aromatic), 140.7 (C, aromatic), 140.5 (C, aromatic), 131.5
(CH, C-40), 126.2 (CH, aromatic), 125.9 (CH, aromatic), 125.8 (CH, 2C,
aromatic), 125.7 (CH, C-50), 124.7 (CH, aromatic), 123.9 (CH, aro-
matic), 123.3 (CH, aromatic), 121.9 (CH, aromatic), 96.6 (CH, C-1),
76.4 (CH, C-5), 71.3 (CH2, C-7), 70.3 (CH, C-2), 70.2 (CH2, C-6), 58.9
(CH3, C-8), 50.6 (CH, C-4a), 50.2 (C, C-3a), 47.5 (CH, C-4), 43.9 (CH, C-
20), 37.4 (CH, C-3), 31.8 (CH, C-30 of 19b), 31.0 (CH, C-30 of 19a), 24.6
(CH2, C-60 of 19a), 24.3 (CH2, C-60 of 19b), 19.4 (CH2, C-70), 16.7 (CH3,
C-80).
4.4.1. Adduct 15a
23
Colorless oil; [
a
]
þ9.8 (c 0.71, CHCl3); IR (film) 3041, 3022,
D
2941, 2868, 1729 (C]O), 1458, 1191, 1160, 1147, 1111, 1053, 1004,
748 cmꢁ1; 1H NMR (CDCl3)0 d 7.44–7.05 (m, 8H, aromatic), 6.36 (d0d,
0
0
0
0
0
0
0
0
4.4.4. Adducts 20a and 20b
J4 –5 ¼J5 –6 ¼7.0 Hz,1H, H-5 ), 6.28 (dd, J5 –6 ¼J6 –7 ¼7.0 Hz,1H, H-6 ),
4.99 (d, J1–2¼3.3 Hz, 1H, H-1), 4.58 (d, J5–6exo¼4.4 Hz, 1H, H-5),
4.26–4.18 (m, 3H, H-2 and H-7), 4.13 (s, 1H, H-4a), 3.67 (dd,
Colorless oil; IR (film) 3065, 3021, 2960, 2893, 1722, 1599,
1478, 1245, 1145, 1020, 909, 752, 734 cmꢁ1 1H NMR (CDCl3)
;

A.M. Sarotti et al. / Tetrahedron 65 (2009) 3502–3508
3507
d
7.43–7.00 (m, 13H, aromatic), 5.50–5.36 (m, 2H, H-40 and H-50),
4.4.7. Adducts 27a and 27b
Colorless oil; IR (film) 3072, 3021, 2923, 1728 (C]O), 1458, 1386,
1316, 1220, 1147, 1114, 1006, 749 cmꢁ1; 1H NMR (CDCl3)
7.43–7.34
5.09 (d, J1–2¼3.2 Hz, 1H, H-1), 4.99 (d, Jgem¼9.7 Hz, 1H, H-7), 4.76
(d, Jgem¼9.7 Hz, 1H, H-7), 4.69 (dd, J5–6exo¼2.8 Hz, J5–6endo
¼2.8 Hz, 1H, H-5), 4.36 (dd, J2–3¼6.2 Hz, J1–2¼3.2 Hz, 1H, H-2 of
20a), 4.33 (dd, J1–2¼3.2 Hz, J2–3¼6.2 Hz, 1H, H-2 of 20b), 4.23 (d,
J4–4a¼1.0 Hz, 1H, H-4a), 3.77–3.72 (m, 2H, H-6), 2.85 (br s, 1H, H-
3), 2.31–2.17 (m, 3H, H-20, H-30 and H-4), 1.088–1.56 (m, 4H, H-60
d
(m, 2H, aromatic), 7.23–7.05 (m, 6H, aromatic), 5.05 (d, J1–2¼3.1 Hz,
1H, H-1), 4.62 (d, J5–6exo¼4.3 Hz, 1H, H-5), 4.31–4.15 (m, 4H, H-2, H-
4a and H-7), 3.71 (dd, Jgem¼7.0 Hz, J5–6exo¼4.3 Hz, 1H, H-6exo), 3.66
(dd, Jgem¼7.0 Hz, J5–6endo¼0.9 Hz, 1H, H-6endo), 3.57 (s, 3H, H-8),
2.65–2.55 (m, 1H, H-20), 2.48 (dd, J3–4¼10.3 Hz, J2–3¼6.0 Hz, 1H, H-
3), 2.35–2.00 (m, 6H, H-4, H-30, H-60 and H-70a), 1.73–1.61 (m, 7H,
and H-70), 0.79 (d, J3 –8 ¼6.8 Hz, 3H, H-8 ); 13C NMR (CDCl3)
0
0
d
174.0 (C, C-10), 158.3 (C, aromatic of 20b), 158.2 (C, aromatic of
20a), 145.9 (C, aromatic), 141.1 (C, aromatic), 140.6 (C, aromatic),
140.4 (C, aromatic), 131.5 (CH, C-40), 129.5 (CH, 2C, aromatic),
126.4 (CH, aromatic), 126.0 (CH, aromatic), 125.9 (CH, C-50),
125.8 (CH, aromatic), 125.4 (CH, aromatic), 125.1 (CH, aromatic),
124.0 (CH, aromatic), 122.6 (CH, aromatic), 122.0 (CH, aromatic),
121.1 (CH, aromatic), 114.2 (CH, 2C, aromatic), 96.9 (CH, C-1),
76.6 (CH, C-5), 70.2 (CH2, C-6), 70.2 (CH, C-2), 65.3 (CH2, C-7),
50.6 (CH, C-4a), 49.69 (C, C-3a), 47.5 (CH, C-4), 43.5 (CH, C-20),
36.3 (CH, C-3), 30.7 (CH, C-30), 24.5 (CH2, C-60 of 20a), 24.0 (CH2,
C-60 of 20b), 20.1 (CH2, C-70 of 20b), 19.2 (CH2, C-70 of 20a), 16.4
(CH3, C-80).
H-70b, H-80 and H-90); 13C NMR (CDCl3) 175.1 (C, C-10), 145.8 (C,
d
aromatic), 141.0 (C, aromatic), 140.8 (C, aromatic), 140.7 (C, aro-
matic), 126.2 (CH, aromatic), 125.9 (CH, aromaticþ), 125.8 (CH, aro-
matic), 125.7 (CH, aromatic), 125.4 (C, C-50 of 27a) , 125.1 (C, C-50 of
27b)þþ, 124.8 (CH, aromatic),þ123.9 (CH, aromatic), 123.8 (C, C-40 of
27b)þþ, 123.5 (C, C-40 of 27a) , 123.1 (CH, aromatic), 121.9 (CH, aro-
matic), 96.9 (CH, C-1), 76.5 (CH, C-5), 71.2 (CH2, C-7), 70.2 (CH2, C-
6), 70.1 (CH, C-2), 59.1 (CH3, C-8), 50.6 (CH, C-4a), 50.1 (C, C-3a), 47.5
(CH, C-4), 40.2 (CH, C-20 of 27b), 40.1 (CH, C-20 of 27a), 37.0 (CH, C-
3), 33.6 (CH2, C-30 of 27b) , 33.4 (CH2, C-30 of 27a)**, 31.0 (CH2, C-60
*
of 27b)
, 30.8 (CH2, C-60 of 27a)**, 25.8 (CH2, C-70 of 27a), 25.6 (CH2,
*
C-70 of 27b), 18.9 (CH3, C-80)***, 18.7 (CH3, C-90)*** (þ,
*
in-
4.4.5. Adducts 23a and 23b
terchangeable signals).
Colorless oil; IR (film) 3072, 3022, 2957, 2925, 2894, 2853,
1729, 1458, 1306, 1222, 1147, 1114, 1013, 735 cmꢁ1
;
1H NMR
4.4.8. Adducts 28a and 28b
(CDCl3)
d
7.43–7.33 (m, 2H, aromatic), 7.21–7.06 (m, 6H, aro-
Colorless oil; IR (film) 3071, 3023, 2925, 1726 (C]O), 1600, 1499,
matic), 5.40 (br s, 1H, H-40), 5.05 (d, J1–2¼3.5 Hz, 1H, H-1), 4.64
(d, J5–6exo¼4.2 Hz, 1H, H-5), 4.31–4.16 (m, 4H, H-2, H-4a and H-
7), 3.72 (dd, Jgem¼7.1 Hz, J5–6exo¼4.2 Hz, 1H, H-6exo), 3.68 (dd,
Jgem¼7.1 Hz, J5–6endo¼1.2 Hz, 1H, H-6endo), 3.56 (s, 3H, H-8),
2.61–2.45 (m, 2H, H-20 and H-3), 2.31–2.29 (m, 2H, H-30), 2.16
(d, J3–4¼10.6 Hz, 1H, H-4), 2.08–1.99 (m, 3H, H-60, H-70), 1.77–
1476, 1243, 1147, 1012, 753 cmꢁ1 1H NMR (CDCl3)
;
d
7.42–6.97 (m,
13H, aromatic), 5.02–4.97 (m, 2H, H-1 and H-7), 4.74–4.68 (m, 2H,
H-5 and H-7), 4.37 (dd, J2–3¼6.0 Hz, J1–2¼3.4 Hz, 1H, H-2), 4.22 (s,
1H, H-4a), 3.77–3.72 (m, 2H, H-6), 2.84 (br s, 1H, H-3), 2.26 (d,
J3–4¼10.5 Hz,1H, H-4), 2.03–1.26 (m,13H, H-20, H-30, H-60, H-70, H-80
and H-90); 13C NMR (CDCl3)
d
175.4 (C, C-10), 158.4 (C, aromatic),
1.69 (m, 1H, H-70), 1.65 (s, 3H, H-80); 13C NMR (CDCl3)
d
175.1 (C,
145.9 (C, aromatic), 141.1 (C, aromatic), 140.6 (C, aromatic), 140.5 (C,
aromatic), 129.5 (CH, 2C, aromatic), 126.4 (CH, aromatic), 126.0 (CH,
aromatic), 125.9 (CH, aromatic), 125.8 (CH, aromatic)þ, 125.0
(CH, aromatic), 125.0 (C, C-50 ofþ28a)þ, 124.6 (C, C-50 of 28b) , 124.0
(CH, aromatic), 123.4 (C, C-40) , 122.6 (CH, aromatic), 122.0 (CH,
aromatic), 121.0 (CH, aromatic), 114.3 (CH, 2C, aromatic), 97.0 (CH,
C-1), 76.6 (CH, C-5), 70.3 (CH2, C-6), 69.8 (CH, C-2), 65.5 (CH2, C-7),
50.6 (CH, C-4a), 49.7 (C, C-3a), 47.4 (CH, C-4), 39.9 (CH, C-20 of 28b),
C-10), 145.7 (C, aromatic), 141.0 (C, aromatic), 140.8 (C, aro-
matic), 140.7 (C, aromatic), 133.8 (C, C-50 of 23a), 133.5 (C, C-50
of 23b), 126.2 (CH, aromatic), 125.9 (CH, aromatic), 125.8 (CH,
aromatic), 125.7 (CH, aromatic), 124.8 (CH, aromatic), 123.9 (CH,
aromatic), 123.1 (CH, aromatic), 121.9 (CH, aromatic), 119.1
(CH, C-40 of 23a), 118.8 (CH, C-40 of 23b), 96.8 (CH, C-1), 76.5
(CH, C-5), 71.2 (CH2, C-7), 70.2 (CH, C-2), 70.1 (CH2, C-6), 59.1
(CH3, C-8), 50.5 (CH, C-4a), 50.1 (C, C-3a), 47.5 (CH, C-4), 39.2
(CH, C-20 of 23b), 39.0 (CH, C-20 of 23a), 37.1 (CH, C-3), 29.3
(CH2, C-60 of 23b), 29.1 (CH2, C-60 of 23a), 27.6 (CH2, C-30 of
23b), 27.3 (CH2, C-30 of 23a), 25.5 (CH2, C-70 of 23a), 25.2 (CH2,
C-70 of 23b), 23.4 (CH3, C-80).
39.7 (CH, C-20 of 28a), 36.4 (CH, C-3), 33.8 (CH2, C-30 of 28b)
(CH2, C-30 of 28a)**, 30.6 (CH2, C-60 of 28a) , 29.5 (CH2, C-60 of
28b)**, 25.9 (CH2, C-70 of 28a), 24.9 (CH2, C-70 of 28b), 18.6 (CH3,
C-80 and C-90) (þ,
interchangeable signals).
*
, 32.8
*
*
4.5. Hydrolysis of Diels–Alder adducts
4.4.6. Adducts 24a and 24b
Colorless oil; IR (film) 3071, 3041, 2958, 2927, 2854, 1729,
Each adduct 11–30 was dissolved in THF/H2O 2:1 and LiOH$H2O
(6 equiv) was added. The reaction was stirred at room temperature
until no starting material was detected by TLC. The solution was
neutralized with HCl 0.1 N to reach pH¼4 and extracted with ether
(5ꢂ40 mL). The combined organic extracts were dried (Na2SO4) and
the solvent was evaporated. The resulting residue was purified by
flash chromatography to obtain the chiral auxiliary 6 (>95%) and
the corresponding carboxylic acid 31–35 (80–90%).
1600, 1499, 1478, 1456, 1305, 1243, 1160, 1012, 910, 753 cmꢁ1
;
1H NMR (CDCl3)
d 7.42–6.98 (m, 13H, aromatic), 5.20 (br s, 1H,
H-40 of 24b), 5.13 (br s, 1H, H-40 of 24a), 5.03–4.98 (m, 2H, H-1
and H-7), 4.72–4.68 (m, 2H, H-5 and H-7), 4.35 (dd, J2–3¼6.2 Hz,
J1–2¼3.3 Hz, 1H, H-2), 4.23 (d, J4–4a¼1.1 Hz, 1H, H-4a), 3.77–3.72
(m, 2H, H-6), 2.85 (br s, 1H, H-3), 2.27 (d, J3–4¼10.4 Hz, 1H, H-
4), 1.93–1.43 (m, 10H, H-20, H-30, H-60, H-70 and H-80); 13C NMR
(CDCl3)
d
175.3 (C, C-10), 158.4 (C, aromatic), 145.9 (C, aromatic),
141.1 (C, aromatic), 140.6 (C, aromatic), 140.5 (C, aromatic),
133.5 (C, C-50 of 24b), 133.1 (C, C-50 of 24a), 129.5 (CH, aro-
matic), 126.5 (CH, aromatic), 126.0 (CH, aromatic), 125.9 (CH,
aromatic), 125.8 (CH, aromatic), 125.1 (CH, aromatic), 124.0
(CH, aromatic), 122.6 (CH, aromatic), 122.0 (CH, aromatic), 121.0
(CH, aromatic), 118.9 (CH, C-40 of 24a), 118.8 (CH, C-40 of 24b),
114.2 (CH, aromatic), 97.0 (CH, C-1), 76.6 (CH, C-5), 70.3 (CH2,
C-6), 69.9 (CH, C-2), 65.5 (CH2, C-7), 50.6 (CH, C-4a), 49.7 (C, C-
3a), 47.4 (CH, C-4), 38.8 (CH, C-20 of 24b), 38.6 (CH, C-20 of 24a),
36.4 (CH, C-3), 28.9 (CH2, C-60), 26.8 (CH2, C-30), 25.4 (CH2, C-
70), 23.3 (CH3, C-80).
Acknowledgements
This research was supported by grants from Consejo Nacional de
Investigaciones Cientıficas y Tecnicas (CONICET), Agencia Nacional
´
´
´
´
´
de Promocion Cientıfica y Tecnologica (ANPCyT), The International
Foundation for Science (IFS) and the Organization for the Pro-
hibition of Chemical Weapons (OPCW), The Netherlands to A.G.S.
´
and R.A.S. A.M.S. thanks CONICET and Fundacion Josefina Prats for
the award of a fellowship. We also thank Dr. Alejandra Rodrıguez,
Uruguay for the HRMS.
´

3508
A.M. Sarotti et al. / Tetrahedron 65 (2009) 3502–3508
10. (a) Tanaka, K.; Uno, H.; Osuga, H.; Suzuki, H. Tetrahedron: Asymmetry 1993, 4,
Supplementary data
629; (b) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876.
11. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238.
12. See Supplementary data.
13. Fringuelli, F.; Taticchi, A. The Diels-Alder Reaction. Selected Practical Methods;
John Wiley & Sons: New York, NY, 2002; Chapter 1.
14. After an extensive screening of Lewis acids (Et2AlCl, EtAlCl2, TiCl4, AlCl3) the
former two were selected based on the yields and selectivities achieved. See
Supplementary data.
Experimental procedures for the synthesis of all compounds,
characterization data, and copies of 1H NMR and 13C NMR spectra of
new compounds. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.02.020.
15. Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.;
Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc.
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