Synthesis of a Chiral Auxiliary Family from Levoglucosenone and Evaluation in the Diels-Alder Reaction

Article abstract of DOI:10.1055/s-0037-1610148

A new family of chiral auxiliaries has been developed based on the lignocellulosic biomass pyrolysis product levoglucosenone. A promising single stereoisomer with an alcohol and π-stacking phenyl substituents was prepared in excellent yield in two steps from dihydrolevoglucosenone without chromatography on >50 g scale. Acrylate esters prepared from the auxiliaries underwent diastereoselective Lewis acid promoted Diels-Alder reactions with cyclopentadiene (endo / exo 98:2, endo d. r. up to 98:2), dimethylbutadiene (d.r. 93:7), and isoprene (d.r. > 98:2).

Full text of DOI:10.1055/s-0037-1610148

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
J. Klepp et al.
Letter
Synlett
Synthesis of a Chiral Auxiliary Family from Levoglucosenone and
Evaluation in the Diels–Alder Reaction
Julian Kleppa
Christopher J. Sumbyb
Ben W. Greatrex*a
chiral auxiliary
1. esterification
OH
O
2. Diels–Alder
reaction
O
0
0
0
0
0-
0
0
2
0-
3
5
6
4-
9
6
6
O
O
3 steps
O
O
O
Ph
O
O
Ph
a School of Science and Technology, University of New
England, Armidale, New South Wales, 2351, Australia
ben.greatrex@une.edu.au
b Department of Chemistry, School of Physical Sciences,
University of Adelaide, North Terrace, Adelaide, South
Australia, 5005, Australia
Ph
Ph
one stereoisomer
no chromatography
> 50 g scale
from cellulose
pyrolysis
endo/exo up to 98:2
endo d.r. up to 98:2
Received: 14.02.2018
Accepted after revision: 17.04.2018
Published online: 25.05.2018
Newer chiral auxiliaries have been developed which also
utilize a rigid substituted cyclohexanol ring and include 2
and trityl-substituted 3 (Figure 1).5b,11 While most of these
auxiliaries are cheaper than 1 to produce, their synthesis
usually involves the separation of diastereomers and the
resolution of enantiomers.
DOI: 10.1055/s-0037-1610148; Art ID: st-2018-b0104-l
Abstract A new family of chiral auxiliaries has been developed based
on the lignocellulosic biomass pyrolysis product levoglucosenone. A
promising single stereoisomer with an alcohol and π-stacking phenyl
substituents was prepared in excellent yield in two steps from di-
hydrolevoglucosenone without chromatography on >50 g scale. Acry-
late esters prepared from the auxiliaries underwent diastereoselective
Lewis acid promoted Diels–Alder reactions with cyclopentadiene
(endo/exo 98:2, endo d.r. up to 98:2), dimethylbutadiene (d.r. 93:7), and
isoprene (d.r. > 98:2)
OH Ph
OH Ph
OH
Ph
Ph
Ph
3
2
1
O
This work
Ph
HO
HO
O
O
HO
Key words chiral auxiliary, chiral pool, levoglucosenone, Diels–Alder
reaction, diastereoselectivity
O
O
O
O
Ph
O
O
4
5
6a, R = Me
6b, R = Ph
R
O
7a
Chiral auxiliaries are widely used in the production of
enantiopure compounds to control the formation of new
stereocenters and for the separation of the resultant dia-
stereomers.1 The major advantages of choosing them over
other asymmetric approaches include stability and re-
usability, while drawbacks include the low atom-efficiency
and resultant cost, as a stoichiometric quantity of reagent is
required by definition. Issues of cost have meant that auxil-
iaries are a nonpreferred option when scaling the synthesis
of a chiral target.
One of the most successful chiral auxiliaries is (–)-8-
phenylmenthol (1),2 which generates diastereoselectivity
via π-stacking interactions. It has been used to control the
stereochemical outcome of an array of reactions including
cycloadditions,2,3 1,2-additions,3,4 1,4-additions,5 oxida-
tions,6 reductions,7 photochemical/radical reactions8 and
can be used as a chiral resolution agent.9 A major limitation
of 1 is its cost, due to the use of (–)-pulegone as a starting
material for its synthesis and because the reduction step
yields two diastereomers which have to be separated.10
Figure 1 Known chiral auxiliaries utilizing cyclohexyl rings (1–3),
previous auxiliaries (5, 6a/6b) derived from levoglucosenone (4) and
this work
Carbohydrates are an abundant source of chirality, and a
number of chiral auxiliaries have been developed using
carbohydrate derivatives.12 One such derivative is levo-
glucosenone (4, LGO), which is a product of cellulose pyrol-
ysis and along with the dihydro derivative 8 (Cyrene™), is
now readily available from biomass.13 Suárez and co-work-
ers developed a series of auxiliaries from LGO including
6a/6b (Figure 1) which achieved excellent diastereoselectiv-
ity in the Diels–Alder reaction. The selectivity was generat-
ed by a pendant ether which blocked one face of an
attached α,β-unsaturated ester.14 Conversion into the
anthracene adduct was required as auxiliary 5, based on the
unsubstituted 6,8-dioxabicyclooctane ring system, gave
only moderate control of the Diels–Alder reaction.15
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
J. Klepp et al.
Letter
Synlett
To achieve diastereoselective Diels–Alder reactions
through π-stacking interactions, an aryl group must be suit-
ably positioned to interact with the alkene. In our recent
work, α-benzyl derivatives of LGO such as 12 were prepared
from the reduced adduct 8 by an aldol reaction then fol-
lowed by a reduction/epimerization strategy (Scheme 1).16
The attempted α-alkylation with benzyl bromide to gener-
ate the same compounds resulted in a high yield of di-
alkylated adduct 14a.16 In the current work, these products
have been used as starting points to develop chiral auxilia-
ries and the effects of substitution have been examined.
(i)
1. NaBH4
MeOH
2. (i)
DCC
DMAP
CH2Cl2
O
O
O
O
O
OH
Cl
O
O
NEt3
CH2Cl2
(ii)
O
O
4
16 (59%)
R1
HO
O
R2
R1
17, R1 = H, R2 = Bn, (i) (64%)
18, R1 = Bn, R2 = H, (i) (88%)
19a, R1 = R2 = Bn, (ii) (83%)
19b, R1 = R2 = 2-MeC6H4CH2,
(i) (100%)
19c, R1 = R2 = 2,4-Cl2C6H3CH2
(i) (59%)
O
(i) or (ii)
O
R2
O
O
O
11, 13, 7a–c
Ph
HO
O
O
Ph
Ph
NaBH4
ZnCl2
Scheme 2 Formation of acrylate esters 16–19
1. H2, Pd/C
EtOAc
O
O
O
O
O
O
MeOH
2. i-Pr2NEt
The selective reductions of the hindered 6,8-dioxabi-
cyclo[3.2.1]octan-4-one ring system should be highlighted.
The stereochemical outcome of these reactions is con-
trolled by the methyleneoxy bridge with approach of the
nucleophile from the face opposite the bridge. This conveys
an advantage over other cyclohexanone-derived chiral aux-
iliaries, which usually yield mixtures upon reduction and
then require chromatographic separation.5b Furthermore,
the bicyclic ring system often affords highly crystalline de-
rivatives; crystalline alcohol 7a and ester 19a (Figure 2)
could be prepared starting from cellulose without any chro-
matography.
13 (72%)
9 (69%)
12 (77%)
PhCHO
TMG
(neat)
NaBH4
CeCl3
HO
HO
O
Ph
Ph
H2, Pd/C
EtOAc
O
O
O
O
O
O
10 (96%)
11 (91%)
8
ArCH2X, X = Br,Cl
t-BuOK, THF
R
R
HO
R
O
NaBH4
MeOH
O
R
R
R
+
O
O
O
O
O
O
14a, R = Ph, (88%)
14b, R = 2-MePh, (54%)
14c, R = 2,4-Cl2Ph, (24%)
7a, R = Ph, (94%)
7b, R = 2-MePh, (55%)
7c, R = 2,4-Cl2Ph, (63%)
15
Scheme 1 Preparation of chiral auxiliaries from dihydrolevoglucose-
none (8)
The syn-relationship between the alcohol and neighbor-
ing benzyl group was constructed from aldol adduct 9,16
which was reduced to the alcohol 10 using NaBH4 and then
hydrogenated to give 11. To generate the anti-relationship
between the alcohol and pendant benzyl group, the ketone
1216 was reduced using NaBH4/ZnCl2 to give diastereomer
13 in 72% yield. The dibenzylated products 14a–c were pre-
pared from 8 by reaction with 2.2 equiv of substituted ben-
zyl halide and t-BuOK. O-Benzylation resulting in 15 was
also observed in these reactions, in particular with the
more hindered 2-methylbenzyl chloride and 2,4-dichloro-
benzyl chloride. The ketones 14a–c were then reduced with
NaBH4 to give alcohols 7a–c. The alcohols were converted
through into the acrylate esters 17, 18, and 19b,c by DCC
coupling with acrylic acid while 19a was prepared using
freshly prepared acryloyl chloride and NEt3 in good yield
(Scheme 2).17 As a reference compound lacking the aryl
group, unsubstituted acrylate 16 was synthesized from 4
via reduction and acylation.
Figure 2 X-ray crystal structures of 19a (left), showing the accessible
acrylate group in the solid state, and (R)-22a (right)
The Diels–Alder reactions of the acrylate esters and
cyclopentadiene were performed with and without Lewis
acids which are usually required for selectivity with chiral
auxiliaries (Table 1).17,18 Acrylate ester 18 which had an
anti-relationship between the alkene and benzyl group
afforded 21 with little selectivity when the reaction was
catalyzed by SnCl4 at –13 °C, while the syn-configured 17
gave an encouraging 82:18 ratio of diastereomers in 20 un-
der the same conditions (Table 1, entries 1, 2). The gem-
dibenzyl acrylate ester 19a gave excellent diastereoselectiv-
ity (97:3) using SnCl4 at −13 °C (entry 3). The substitution
of the pendant aromatic rings in 19 was found to influence
the selectivity of the reaction. The addition of steric bulk by
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
J. Klepp et al.
Letter
Synlett
incorporating an ortho-methyl substituent in 19b gave bet-
ter results compared to the unsubstituted ring (endo d.r.
98:2), while the bis-2,4-dichlorobenzyl auxiliary 19c gave
lower selectivity (Table 1, entries 3–5). The ability to use
substituted aromatics in these auxiliaries is intriguing as it
allows for the possibility of selecting groups which can co-
ordinate reagents and influence reactivity, even if only
minor improvement in Diels–Alder selectivity was ob-
served in this system.
A series of reactions were performed to probe the reac-
tion conditions using ester 19a. In the absence of Lewis
acid, an approximate 1:1 mixture of diastereomers was
formed in the reaction (Table 1, entry 6). This is consistent
with the documented requirement for Lewis acid to gener-
ate the s-trans geometry,18c,d although a direct temperature
comparison was not possible as no reaction was observed
at –13 °C in the absence of Lewis acid. Both AlCl3 and
BF3·OEt2 gave slightly inferior diastereoselectivities com-
pared to SnCl4, while EtAlCl2 was the most selective (d.r.
98:2, Table 1, entries 3, 8, 14, 15). Using more than 1.0 equiv
of Lewis acid reduced the diastereoselectivity for the reac-
tion (Table 1, entries 8, 11). No advantage was seen by de-
creasing the temperature past –13 °C and the reactions
were significantly slowed (Table 1, entry 7).
The reaction of dimethylbutadiene with the chiral dieno-
phile 19a was highly selective giving 23 while diastereo-
mers of 24 could not be detected in the crude mixtures
from the reaction of 19a with isoprene (Table 1, entries 16
and 17). The excellent diastereoselectivities were encourag-
ing as some known auxiliaries are less selective with these
two dienes.14f Diels–Alder reactions of cinnamate and cro-
tonate esters of 7a with cyclopentadiene did not proceed at
–13 °C and higher temperatures and extended times led to
decomposition (not shown).
The stereocenters α to the ester group in the products
22a, 23, and 24 were assigned as R after saponification
using NaOH and comparison of the optical rotations of the
acids to the literature values.14b,f The auxiliary was recov-
Table 1 Diels–Alder Reactions of Acrylate Esters 17, 18, and 19a–c with Cyclopentadiene, Isoprene, or Dimethylbutadiene
R3
R3
S
O
or
O
O
O
R1
R2
R3 = H, Me
R
AuxO
17, 18, 19a–c
AuxO
O
AuxO
Aux =
conditions
AuxO
O
O
20, R1 = H, R2 = Bn
21, R1 = Bn, R2 = H
22, R1 = R2 = CH2Ar
23, R1 = R2 = Bn, R3 = Me
24, R1 = R2 = Bn, R3 = H
Entrya
Diene
Lewis acid (equiv)
Time (h)
Temp (°C)
Conv. (%)b
Product
endo/exob
d.r. R/Sc
1
2
17
SnCl4(1.0)
SnCl4(1.0)
SnCl4(1.0)
SnCl4 (1.0)
SnCl4 (1.0)
–
36
36
36
36
36
42
18
18
18
18
18
36
36
24
24
24
24
–13
–13
–13
–13
–13
22
>99
20
93:7
93:7
97:3
96:4
95:5
84:16
96:4
88:12
86:14
96:4
93:7
97:3
82:18
54:46
97:3
18
>99
21
3
19a
19b
19c
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
19a
>99
22a
22b
22c
22a
22a
22a
22a
22a
22a
22a
4
>99 (84)
>99
98:2
5
84:16
51:49
95:5
6
92
7
AlCl3 (1.0)
AlCl3(1.0)
AlCl3(1.0)
AlCl3(0.5)
AlCl3(2.0)
SnCl4(0.5)
TiCl4(1.0)
BF3·OEt2(1.0)
EtAlCl2 (1.0)
EtAlCl2 (1.0)
EtAlCl2 (1.0)
–75
–13
0
68
8
91
94:6
9
>99
73:27
95:5
10
11
12
13
14
15d
16e
17e
–13
–13
–13
–13
–13
–13
–13
–13
>99
55
75:25
96:4
>99
–
decomposition
35
22a
22a
23
92:8
98:2
–
95:5
98:2
>99 (89)
>99 (96)
>99 (97)
93:7
24
–
>98:2
a Reactions performed on 20 mg of acrylate (0.2 M) in CH2Cl2.
b Conversion and exo/endo ratios determined by 1H NMR spectroscopy and confirmed by GC.
c Ratio of stereoisomers in the endo isomer determined by 1H NMR spectroscopy.
d1.0 g scale.
e 200 mg scale.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
J. Klepp et al.
Letter
Synlett
ered unchanged after saponification in 92–95% yield. The
endo/exo ratios in the products were determined using
NMR spectroscopy and confirmed by transesterifying the
product with methanol and analyzing using GC–MS. Resid-
ual trace diastereomers were removed from the major
product (R)-22a by recrystallization and the crystals ob-
tained were suitable for X-ray structure determination,
which showed the configuration of the product with auxil-
iary attached (Figure 2).
Table 2 Comparison of 1H NMR and 13C NMR Chemical Shift Changes
of Acrylates with SnCl4
O
H
12E
O
R
R
9
O
3
H
O
H
10
HO
Bn
2
O
O
11
H
8
O
4
5
O
1
H
O
12Z
Ph
O
H
7
O
6
R = H, CH2Ar
SnCl4
25
19a⋅SnCl4
Ester
SnCl4(equiv) Temp
(°C)
Δδa
The selectivity observed with these chiral auxiliaries
was surprising on the basis of the NMR analysis of the acry-
late ester. When aromatic rings are aligned parallel to an
H12E
+0.23
H12Z
H4
C10
+3.53
MAb
MA
16
1.0
2.0
1.0
1.0
1.0
0.5
1.0
2.0
1.0
–13
–13
–13
–13
–13
–13
–13
–13
–3
+0.35
+0.40
+0.07
+0.01
+0.11
–0.03
–0.02
–0.01
+0.01
–
–
1
acrylate ester, an upfield shift is expected in the H NMR
spectrum for the olefinic protons of up to ca. 0.8 ppm.3a,19
Relative to the unsubstituted acrylate ester 16, there was no
change in the chemical shifts of the alkene protons in 17 or
19a in the absence of Lewis acid (see electronic Supporting
Information). The lack of shift in 19a is consistent with
other α-arylmethylene cyclohexanols which are not effec-
tive chiral controlling agents.20
+0.28
+0.11
+0.12
+0.20
+0.01
+0.07
+0.11
+0.03
+3.91
+1.12
+1.85
+2.14
+1.00
+1.12
+1.76
–
+0.04
+0.03
+0.04
–0.04
–0.03
–0.02
+0.01
17
18
19a
19a
19a
19a
Furthermore, a crystal structure obtained for the acry-
late ester 19a (Figure 2) and the precursor alcohol 7a (see
electronic Supporting Information) showed that the aro-
matic ring was directed away from the ring and not aligned
with the acrylate ester. Therefore, to investigate the origins
of the selectivity in these reactions, the acrylate esters were
aDifferences are calculated from the same compound at the same
temperature without Lewis acid.
bMA = methyl acrylate, numbered to match the other acrylate esters.
Shading indicates upfield shift.
1
mixed with different proportions of SnCl4 and the H NMR
and 13C NMR chemical shifts studied at the temperatures
where selectivity was observed (Table 2).
shielding, consistent with the reduced selectivity at higher
temperatures while a further increase to 7 °C caused a slow
rearrangement over two days giving rise to 25. The confor-
mation 19a·SnCl4 (Table 2) with the aromatic ring aligned
with the acrylate ester was only obtained in the presence of
Lewis acid at low temperature, a key finding when consid-
ering the application of this auxiliary family to other reac-
tion types.
In conclusion, we have developed a chiral auxiliary
family that displays excellent selectivity in a Diels–Alder
reaction. It demonstrates that readily introduced geminal
dibenzyl functionality can promote facial selectivity
whereas most auxiliaries employ larger single substituents
such as trityl or 2-phenylprop-2-yl. The saponified Diels–
Alder adducts prepared in this study have been used for the
preparation of drug building blocks such as (+)-bornan-2-
one.22 Large scale uses are also possible as compound 8 can
be synthesized from cellulose in two steps and is currently
commercially available (see electronic Supporting Informa-
tion). Its ease of synthesis means that this cheap auxiliary
could potentially be used as an adjunct for transformations
promoted by asymmetric catalysts, which could then en-
able removal of minor diastereomers via crystallization.
The development of conditions suitable for less reactive
dienophiles and other applications are under investigation
and will be reported in due course.
The reference compound methyl acrylate showed a
downfield shift of all olefinic protons in the 1H NMR and the
carbonyl in the 13C NMR upon addition of 1.0 equiv of SnCl4
consistent with previous literature.21 In comparison, the
downfield shifts of the olefinic protons for unsubstituted
ester 16 were much smaller. This was attributed to inter-
actions of the O6 and O8 ether oxygens with the Lewis acid
which reduced binding to the carbonyl oxygen. A downfield
shift of 0.12 ppm was observed for the hemiacetal proton
H5 and 0.09 ppm for H7α on the bicyclic ring which sup-
ported this interpretation.
In the presence of SnCl4, the olefinic protons in ester 17
had a smaller downfield shift in the 1H NMR spectrum com-
pared to 16 even though the carbonyl was shifted further
downfield in the 13C NMR spectrum due to coordination to
the Lewis acid. The relatively small shift of the olefinic pro-
tons was attributed to π-interactions of the aromatic ring
with the acrylate ester. The effect in 17 was larger than that
seen for 18 which matches the selectivity observed in Table 1.
Auxiliary 19a had an upfield shift for the H4 and H12Z
resonance in the presence of SnCl4 while H11 and H12E had
small downfield shifts. Extrapolating the results from 16,
this represents a modest upfield shift of ca. 0.1 ppm for all
olefinic protons in 19a. The NOESY NMR spectrum also
showed crosspeaks between H12 and the aromatic protons.
Raising the temperature by 10 °C resulted in reduced
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

E
J. Klepp et al.
Letter
Synlett
Funding Information
Duhayon, C.; Tuchagues, J.-P.; Suárez, A. G. Tetrahedron 2007,
63, 241. (e) Sarotti, A. M.; Spanevello, R. A.; Suárez, A. G. Tetra-
hedron Lett. 2005, 46, 6987. (f) Sarotti, A. M.; Spanevello, R. A.;
Suárez, A. G. Tetrahedron 2009, 65, 3502.
JK thanks UNE for an IPRA scholarship. This work was financially
supported by the University of New England.
)(
(15) Zanardi, M. M.; Suárez, A. G. Tetrahedron Lett. 2009, 50, 999.
(16) Ledingham, E. T.; Stockton, K. P.; Greatrex, B. W. Aust. J. Chem.
2017, 70, 1146.
Acknowledgment
(17) Experimental Procedure for the Synthesis of the Auxiliary
19a and Diels–Alder Reactions: (1S,5R)-3,3-Dibenzyl-6,8-
dioxabicyclo[3.2.1]octan-4-one (14a)16
The authors thank Mr. Tony Duncan and Dr. Warwick Raverty (Circa
Group, Melbourne, Australia) for supplying LGO and 8 and Assoc. Prof.
Chris Fellows (UNE) for helpful discussions related to the NMR study.
To a stirred solution of ketone 8 (30.0 g, 1.0 equiv, 234 mmol)
and BnBr (88.2 g, 59.7 mL, 2.2 equiv, 515.1 mmol) in dry THF
(250 mL) cooled using a water/ice bath was added t-BuOK (21.3
g, 2.2 equiv, 171.7 mmol) portion wise, such that the tempera-
ture of the reaction did not exceed 30 °C. The mixture was
stirred until complete by TLC (3 h), then 1 M HCl (250 mL) and
EtOAc (600 mL) were added. The organic phase was separated
and washed with sat. NaHCO3 (300 mL) then brine (300 mL),
dried over MgSO4, filtered, and concentrated under reduced
pressure. If spontaneous crystallization did not occur, residual
benzyl bromide was removed using a high-vacuum pump with
gentle warming of the mixture. The residue was then dissolved
in MeOH (400 mL) and allowed to crystallize for 24 h over
which time some solvent evaporated to give a final volume of
ca. 100 mL. The crystals were collected by vacuum filtration and
washed with cold MeOH to give 14a as colorless crystals (50.4 g,
70%). Evaporation of the mother liquor and flash chromatogra-
phy (EtOAc/hexanes = 1:4) afforded an additional portion of 14a
(13.2 g, 18%). 1H NMR (500 MHz, CDCl3): δ = 7.30–7.22 (m, 6 H,
Ar-H), 7.12–7.07 (m, 4 H, Ar-H), 5.04 (s, 1 H, 5-H), 4.53 (br dd,
J = 6.0, 5.5 Hz, 1 H, 1-H), 3.53 (dd, J = 6.9, 5.5 Hz, 1 H, 7-Hα), 3.27
(d, J = 13.3 Hz, 1 H, 9-H), 3.26 (d, J = 13.3 Hz, 1 H, 9-H), 3.10 (d,
J = 7.20 Hz, 1 H, 7-Hβ), 2.75 (d, J = 13.3 Hz, 1 H, 9-H), 2.58 (d, J =
13.3 Hz, 1 H, 9-H), 2.39 (dd, J = 14.7, 6.0 Hz, 1 H, 2-H), 1.75 (d, J =
14.7 Hz, 1 H, 2-H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610148.
S
u
p
p
ortioInfgrmoaitn
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p
ortiInfogrmoaitn
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Chemicals; CRC Press: Boca Raton, FL, 2005. (d) Roos, G. Key
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(1S,4S,5R)-3,3-Dibenzyl-6,8-dioxabicyclo[3.2.1]-octan-4-ol
(7a)
The ketone 14a (60.0 g, 1.0 equiv, 195 mmol) was dissolved in
CH2Cl2 (100 mL), MeOH (180 mL) was added and the solution
cooled to –15 °C. Finely powdered NaBH4 (6.0 g, 0.8 equiv, 156
mmol) was then added at a rate such that the temperature of
the reaction did not exceed 0 °C. After stirring for 2 h, the reac-
tion was allowed to warm to ambient temperature and the
reaction monitored by TLC. When no starting material
remained, the reaction mixture was concentrated under
reduced pressure and 1.0 M HCl (100 mL) was added. The
aqueous phase was extracted with CH2Cl2 (3 × 100 mL) ensuring
that no product remained in the aqueous layer by TLC, then the
organic layers were combined, dried with MgSO4, filtered, and
concentrated under reduced pressure. The residue was recrys-
tallized using an EtOAc/hexanes (1:4) mixture by slow evapora-
tion to give 7a as colorless crystals (56.9 g, 94%); mp 126–127 °C
(from (i-Pr)2O); [α]D25–43 (c 1.1, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 7.36–7.33 (m, 2 H, Ar-H), 7.30–7.26 (m, 6 H, Ar-H),
7.08–7.07 (m, 2 H, Ar-H), 5.34 (d, J = 2.0 Hz, 1 H, 5-H), 4.43–4.41
(ddd, J = 5.4, 2.8, 2.8, 1 H, 1-H), 4.29 (d, J = 7.5 Hz, 1 H, 7-Hβ),
3.82 (dd, J = 7.5, 5.4 Hz, 1 H, 7-Hα), 3.71 (dd, J = 10.0, 2.1 Hz, 1 H,
4-H), 3.17 (d, J = 13.9 Hz, 1 H, 9-H), 3.02 (d, J = 13.9 Hz, 1 H, 9-
H), 2.88 (d, J = 13.4 Hz, 1 H, 9-H), 2.38 (d, J = 13.5 Hz, 1 H, 9-H),
(6) Muñiz, K.; Lesato, A.; Nieger, M. Chem. Eur. J. 2003, 9, 5581.
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22, 6552.
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Anderson, J.; Johnson, K. M. ChemMedChem 2006, 1, 58.
(10) Buschmann, H.; Scharl, H.-D. Synthesis 1988, 827.
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Angew. Chem., Int. Ed. Engl. 1992, 31, 1190. (b) Mezrhab, B.;
Dumas, F.; d'Angelo, J.; Riche, C. J. Org. Chem. 1994, 59, 500.
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C.-H.; Chen, K. J. Org. Chem. 1999, 64, 6993. (d) Al Hazmi, A. M.;
Sheikh, N. S.; Bataille, C. J.; Al-Hadedi, A. A.; Watkin, S. V.; Luker,
T. J.; Camp, N. P.; Brown, R. C. Org. Lett. 2014, 16, 5104. (e) Gelat,
F.; Richard, V.; Berger, O.; Montchamp, J.-L. Org. Lett. 2015, 17,
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2011.
(14) (a) Sarotti, A. M.; Joullié, M. M.; Spanevello, R. A.; Suárez, A. G.
Org. Lett. 2006, 8, 5561. (b) Sarotti, A. M.; Spanevello, R. A.;
Suárez, A. G. Org. Lett. 2006, 8, 1487. (c) Sarotti, A. M.;
Fernández, I.; Spanevello, R. A.; Sierra, M. A.; Suárez, A. G. Org.
Lett. 2008, 10, 3389. (d) Sarotti, A. M.; Spanevello, R. A.;
1.87–1.84 (m, 1 H, OH), 1.74 (app. br d, J = 2.9 Hz, 2 H, 2-H). 13
C
NMR (126 MHz, CDCl3): δ = 138.2, 137.7, 131.9, 131.6, 128.40,
128.38, 126.74, 126.67, 103.0, 73.7, 71.6, 68.1, 44.4, 41.4, 39.4,
31.1. FT-IR (neat): 3514, 2969, 1365, 1229, 897, 701 cm–1. MS
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
J. Klepp et al.
Letter
Synlett
(ESI): m/z = 332.9 [M + Na]+; ESI-HRMS: m/z calcd for [M + Na]+:
20H22O3Na: 333.1467; found: 333.1473.
General Procedure for the Diels–Alder Reactions of Acrylates
with Cyclopentadiene
Ar-H), 6.33 (dd, J = 5.7, 3.1 Hz, 1 H, 15-H), 6.11 (dd, J = 5.7, 2.8
Hz, 1 H, 16-H), 5.35 (d, J = 1.9 Hz, 1 H, 5-H), 4.91 (d, J = 1.9 Hz,
1 H, 4-H), 4.40 (ddd, J = 5.5, 5.2, 3.1 Hz, 1 H, 1-H), 4.34 (d, J = 7.5
Hz, 1 H, 7-Hβ), 3.81 (dd, J = 7.5, 5.2 Hz, 1 H, 7-Hβ), 3.46 (d, J =
14.5 Hz, 1 H, 18-H), 3.37 (br s, 1 H, 11-H), 3.15–3.11 (m, 1 H, 12-
H), 3.12–3.08 (d, J = 14.5 Hz, 1 H, 18-H), 2.98 (br s, 1 H, 14-H),
2.60 (d, J = 14.0 Hz, 1 H, 18-H), 2.48 (d, J = 14.0 Hz, 1 H, 18-H),
1.98 (ddd, J = 11.8, 9.3, 3.7 Hz, 1 H, 13-H), 1.76 (app. d, J = 2.9 Hz,
2 H, 2-H), 1.57–1.50 (m, 2 H, 13-H, 17-H), 1.35 (d, J = 8.3 Hz, 1 H,
17-H). 13C NMR (126 MHz, CDCl3): δ = 174.2, 138.7, 138.2,
136.7, 132.1, 132.0, 131.6, 128.31, 128.29, 126.8, 126.6, 100.1,
73.3, 72.7, 68.0, 50.2, 46.2, 43.8, 42.7, 40.48, 40.45, 30.9, 29.9,
29.2. FT-IR (neat): 2958, 1746, 1356, 1231, 899, 708 cm–1. MS
(ESI): m/z = 453.1 [M + Na]+. ESI-HRMS: m/z calcd for [M + Na]+
C28H30O4Na: 453.2042; found: 453.2042.
C
The acrylic ester 19a (1.0 equiv) was dissolved in dry CH2Cl2
(0.2 M final concentration) under N2 and then cooled to the
temperature indicated in Table 1. The Lewis acid was added
under N2 and stirred for 20 min at the indicated temperature,
then freshly distilled cyclopentadiene (5 mmol) was added
dropwise, and the reaction was stirred at the temperature indi-
cated in Table 1 for the appropriate time. After 18 h, if the reac-
tion was incomplete a further portion of cyclopentadiene
(5 mmol) was added. The reactions without Lewis acid were
concentrated after completion. The reactions where Lewis acids
were used were quenched by the addition of water and 1 M HCl,
then extracted with CH2Cl2(3×). The combined organic extracts
were dried over MgSO4, filtered, and then concentrated under
reduced pressure. For all reactions, the residues were absorbed
onto a pad of silica (10 g/g ester), and the remaining cyclopen-
tadiene and its corresponding dimer were washed from the
silica using hexanes. Then the product was eluted with EtOAc.
(1S,4S,5R)-3,3-Dibenzyl-6,8-dioxabicyclo[3.2.1]octan-4-yl
(1R,4R)-bicyclo[2.2.1]hept-5-ene-2-carboxylate ((R)-22a)
Following the general procedure, acrylate ester 19a (1.0 g, 1.0
equiv, 2.8 mmol) was treated with cyclopentadiene (1.81 mg, 10
equiv, 28.0 mmol) catalyzed by 1.8 M EtAlCl2 in toluene (1.50
mL, 1.0 equiv, 2.8 mmol). The product was recrystallized by
slow evaporation from dry MeOH to afford (R)-22a as colorless
crystals (1.05 g, 89%); mp 96–98 °C; [α]D25 –23 (c 1.0, CH2Cl2). 1H
NMR (500 MHz, CDCl3): δ = 7.37–7.34 (m, 2 H, Ar-H), 7.30–7.26
(m, 4 H, Ar-H), 7.22–7.20 (m, 2 H, Ar-H), 6.97–6.95 (m, 2 H,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F