Chiral Br?nsted acid-catalyzed enantioselective ionic [2+4] cycloadditions

Article abstract of DOI:10.1016/j.tet.2013.03.086

The first asymmetric chiral N-triflylphosphoramide-catalyzed ionic [2+4] cycloaddition reaction of unsaturated acetals is described. This reaction proceeds through the intermediacy of a vinyl oxocarbenium/chiral anion pair, and the chiral N-triflylphosphoramide anion controls the stereoselectivity of the cycloaddition step. Moderate enantioselectivities (up to 80:20 e.r.) have been obtained when α,β-unsaturated dioxolanes were employed as the dienophiles. These reactions demonstrate strong dependence on the counterion coordinating properties and solvent polarity, a behavior characteristic of oxocarbenium ions.

Full text of DOI:10.1016/j.tet.2013.03.086

Tetrahedron 69 (2013) 5719e5725
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral Brønsted acid-catalyzed enantioselective ionic [2þ4]
cycloadditions
*
Alina Borovika, Pavel Nagorny
Chemistry Department, University of Michigan, 930 N. University, Ann Arbor, MI 48109, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric chiral N-triflylphosphoramide-catalyzed ionic [2þ4] cycloaddition reaction of un-
saturated acetals is described. This reaction proceeds through the intermediacy of a vinyl oxocarbenium/
chiral anion pair, and the chiral N-triflylphosphoramide anion controls the stereoselectivity of the cy-
Received 22 January 2013
Received in revised form 12 March 2013
Accepted 19 March 2013
cloaddition step. Moderate enantioselectivities (up to 80:20 e.r.) have been obtained when
a,b-un-
Available online 29 March 2013
saturated dioxolanes were employed as the dienophiles. These reactions demonstrate strong dependence
on the counterion coordinating properties and solvent polarity, a behavior characteristic of ox-
ocarbenium ions.
Keywords:
Oxocarbenium ion
Ionic DielseAlder
Cycloaddition
Ó 2013 Elsevier Ltd. All rights reserved.
Chiral counterion
N-Triflyl phosphoramide
1. Introduction
Traditional LUMO activation of α,β−unsaturated carbonyls
LA, H+, R2NH
(catalysts)
H
LA
Numerous protocols involving Lewis acids,1 H-bond donors,2
R
R
R
2
3
O
O
4
O
N
and amines3 as catalysts for
a,b-unsaturated carbonyl (1) activa-
R
R
R
R
R
R
R
tion have been developed and used to gain access to valuable chiral
building blocks. Typically, these catalysts activate the LUMO of the
substrate by coordinating to a carbonyl functionality (2 or 3). Al-
ternatively, LUMO activation could be achieved through the for-
mation of iminium ions (4) (Scheme 1). Such LUMO activation
1
O
This work
R
P
R*O
O
P
R*O
R*O
NHTf
O
RO OR
R
R*O
NTf
R
R
R
results in increased reactivity of the
a,b-unsaturated carbonyl-
6
5
Chiral Ion Pair
containing compounds, and numerous reactions involving the
functionalization of the olefin portion of the molecule could be
accomplished under relatively mild conditions.1e3
Scheme 1.
Chiral versions of these protocols have been developed and
applied to convert simple achiral building blocks to more advanced
chiral products. However, cases in which the structural features of
the a,b-unsaturated carbonyl-containing compound preclude the
aforementioned modes of activations are also common. For ex-
ample, chiral Lewis and Brønsted acids are mostly employed for the
It has been determined that vinyl oxocarbenium ion pairs
(6, Scheme 1) have similar reactivity patterns to and often are more
reactive than 2e4.6 Both
-unsaturated ketals and acetals are
known to provide 6 with equal propensity. Vinyl oxocarbenium
ions (6) can be generated by a reaction of catalytic or stoichiometric
a,b
LUMO activation of a,b-unsaturated aldehydes, and utilizing chiral
quantities of Lewis or Brønsted acids with a,b-unsaturated acetals
Lewis and Brønsted acids to catalyze the reactions of
a,b-un-
5. Acetals 5 can be obtained by various methods including alkene
cross-metathesis, Wittig olefination or direct acetalization of un-
saturated aldehydes or ketones (Scheme 2). Once generated, the
vinyl oxocarbenium intermediates (6) can undergo a variety of
important transformations including conjugate additions,7 [2þ4],
[3þ4], and [5þ2] cycloadditions.6
saturated ketones is often nontrivial.4,5
The first application of
a,b-unsaturated acetals, such as 7 in
* Corresponding author. Tel.: þ1 734 615 2833; fax: þ1 734 615 9852; e-mail
address: nagorny@umich.edu (P. Nagorny).
DielseAlder reaction was reported by Gassman and co-workers in
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.086

5720
A. Borovika, P. Nagorny / Tetrahedron 69 (2013) 5719e5725
Table 1
Gassman's Ionic Diels-Alder Reaction
Preliminary catalyst and solvent screens
TfOH (2 mol%)
O
H
O
O
O
cat. (5 mol%)
solvent (0.3 M)
78%, 11:1 dr
O
CH3
CH3
+
O
O
Ph
7
8
9
O
Ph
(1 equiv)
(2 equiv)
13
14
Sammakia's Asymmetric Ionic Diels-Alder Reaction
Me
Entrya
Catalyst
Solvent
Time, h
Conversion, %b
Me
Me
TiCl4 (2 equiv)
Me
O
Me
Ti(OiPr)4 (2 equiv)
O
1
2
3
4
5
6
7
8
9
15
16
17
18
15
16
17
18
16
18
MeCN
MeCN
MeCN
MeCN
PhMe
PhMe
PhMe
PhMe
5
5
16
5
13
13
16
16
16
16
77
Me
80 (50:50 e.r.)
89
82 (50:50 e.r.)
0
0
0
85 (44:56 e.r.)
0
80 (43:57 e.r.)
85%, 15:1 dr
O
Me
O
Me
10
11
12
Scheme 2.
1987 (Scheme 2).8 Since then, this variant of the DielseAlder reaction
has found widespread application in organic synthesis. The in-
troduction of an acetal functionality could improve the stability of
the dienophiles and products to acids.9,10 At the same time, the re-
activity of dienophiles in ionic DielseAlder (IDA) cycloadditions is
often greater, and cycloadditions with rather unreactive dienes could
be accomplished under relatively mild conditions. However, one of
the major drawbacks of such methods is that relatively few asym-
metric variants of IDA reactions exist. To our knowledge, no catalytic
enantioselective transformations of vinyl oxocarbenium ions 6 have
been reported to date6,11 and only auxiliary-based diastereoselective
approaches are known (cf. Scheme 2, formation of 12).12
Dixoane
Dixoane
10
Ar
Ar
O
O
O
O
O
O
O
O
S
PhO
P
O
OH
P
P
P
PhO
OH
NHTf
OH
15
17
Ar
Ar
16, 3,5-(CF3)2C6H3
18 3,5-(CF3)2C6H3
a
Up to 0.06 mmol scale.
Determined by GCeMS.
b
While designing a catalyst capable of controlling the reactivity
of an oxocarbenium ion still represents a formidable challenge, the
use of chiral catalysts to control enantioselective reactions of oxo-
carbenium ions is well precedented.13 In particular, several reports,
describing chiral phosphoric acid-catalyzed reactions presumably
proceeding through enantioselective nucleophilic addition to oxo-
carbenium ions, have appeared over the past three years.14 Al-
though the precise nature of the catalytic mechanisms and
intermediates in such transformations has yet to be clarified,14f the
existence of an oxocarbenium/chiral phosphate ion pair has been
invoked. The chirality of the phosphate counterion could, in theory,
control not only direct addition of nucleophiles to oxocarbenium
ions, but also reactions at remote sites. Thus, we surmised that the
The observed solvent effect could be attributed to the formation
of a more separated ion pair 6 in acetonitrile perhaps due to the
intermediacy of nitrilium ions.15 Insignificant stereoinduction is
expected for the separated ion pairs, which is consistent with the
observation that the reactions catalyzed by 16 and 18 in acetonitrile
produced racemic products (entries 2 and 4). The higher catalytic
activity of 18 in toluene and dioxane could be attributed to a higher
acidity of this compound relative to the other catalysts16 as well as
to a lower coordinating ability of the resultant anion. A stronger
Brønsted acid is expected to populate larger quantities of the oxo-
carbenium ion, while an ion pair (6) with a less coordinating anion
will be more reactive due to the lower energy of the LUMO.
Based on the unique ability of 18 to catalyze the IDA of 13 and
cyclopentadiene in various solvents, the evaluation of N-sulfonyl-
phosphoramides 19e26 in toluene was executed next (Table 2).
The variation of the aromatic substituents (Ar) on the BINOL
backbone of the catalyst (entries 2e4) helped to identify 21
(Ar¼2,4,6-(i-Pr)3C6H2) as the catalyst of choice (entry 4). Thus, the
formation of 14 proceeded with improved yield (75%) and selec-
tivities (64:36 e.r., 5:1 d.r.) when compared to the catalysts 18e20.
To further improve the conversion for this reaction, more acidic N-
triflylthiophosphoramide 22 was utilized as a catalyst (entry 5).
Although the enantioselectivity and d.r. for those reactions were
similar to the corresponding selectivities observed for 21, the
product yield for the reaction catalyzed by catalyst 22 was found to
be significantly lower (24%). Probably, the diminished activity of 22
results from the lower reactivity of the ion pair 6 due to the stronger
coordination of the N-triflylthiophosphoramide anion derived from
22 to the oxocarbenium ion. In an attempt to affect the coordinating
properties of the N-sulfonylphosphoramide counterion, we decided
to evaluate the effect of the N-sulfonyl group on the cycloaddition
rate and selectivity. Thus N-mesylphosphoramide 23 (entry 6) and
N-pentafluorophenylsulfonylphosphoramide 24 (entry 7) were
synthesized and screened. However, neither 23 nor 24 were found
to promote the IDA reaction leading to 14. This is likely to result from
the significantly lower acidities of 23 and 24 in comparison with N-
triflylphosphoramides (e.g., the pKas of CH3SO2NH2 and CF3SO2NH2
in DMSO are 17.5, and 9.7, respectively).17 Finally, our attempts to
evaluate H8-BINOL and VAPOL-based N-triflylphosphoramides 25
and 26 did not result in improved reactivities or selectivities (entries
protonation of an a,b-unsaturated acetal with a chiral Brønsted acid
would result in the formation of a vinyl oxocarbenium/chiral
counterion pair 6 (Scheme 1), and that the olefinic portion of the
resultant ion pair 6 could undergo various counterion-directed
enantioselective reactions. Our group has obtained experimental
evidence confirming the feasibility of such counterion directed
reactions. This article summarizes our studies in this vein and
provides the first successful example of a catalytic enantioselective
IDA reaction of
a,b-unsaturated acetals and dienes catalyzed by
N-triflylphosphoramides.
2. Results
Our studies commenced with attempts to identify an appro-
priate Brønsted acid catalyst that is capable of promoting a cyclo-
addition reaction between
a,b-unsaturated acetal 13 and
cyclopentadiene (Table 1). Representative Brønsted acids 15e18
were combined with dioxolane 13 and cyclopentadiene (2 equiv) in
acetonitrile (entries 1e4) and toluene (entries 5e8), and the for-
mation of 14 was monitored by GCeMS. While all of the catalysts
promoted the formation of cycloadduct 14 in acetonitrile, only
N-triflylphosphoramide 18 catalyzed the cycloaddition in toluene
(16 h, 85% conversion, 44:56 e.r.). In addition, the reactions cata-
lyzed by 16 and 18 were evaluated in dioxane (entries 9 and 10).
While N-triflylphosphoramide 18 catalyzed the formation of 14
(16 h, 80% conversion, 43:57 e.r.), phosphoric acid 16 did not pro-
mote any cycloaddition.

A. Borovika, P. Nagorny / Tetrahedron 69 (2013) 5719e5725
5721
Table 2
Table 3
Evaluation of various N-triflylphosphoramides
Evaluation of the solvent effect on IDA selectivity
O
O
(5 mol%)
cat. (5 mol%)
PhMe (0.3 M)
16 h
O
O
O
+
O
+
solvent (0.3 M)
16 h
O
Ph
O
Ph
Ph
14
(1 equiv)
(3 equiv)
Yielda
13
Ph
(1 equiv)
(3 equiv)
13
14
Entry
Catalyst
e.r.b
endo/exo
Entry
Catalyst
Solvent
e.r.a
endo/exo
1
2
3
4
5
6
7
8
9
18
19
20
21
22
23
24
25
26
65
47
44:56
63:37
56:44
64:36
61:39
n.d.
n.d.
46:54
50:50
3:1
2:1
2:1
5:1
3:1
n.d.
n.d.
3:1
2:1
1
2
3
4
5
6
7
8
21
21
21
21
21
21
21
21
21
21
18
19
22
25
i-PrOH
CH2Cl2
PhMe
50:50
57:43
64:36
61:39
70:30
69:31
70:30
73:27
76:24
80:20
41:59
68:32
64:36
43:57
3:1
3:1
5:1
6:1
7:1
3:1
4:1
7:1
7:1
7:1
4:1
2.5:1
3:1
4:1
53c
75
Hexanes
PhH
24
<5
<5
61
CCl4
Et2O
EtOAc
54c
9
tBuCO2Me
iPrCO2Et
iPrCO2Et
iPrCO2Et
iPrCO2Et
iPrCO2Et
10
11
12
13
14
Ar
iPr
iPr
O
O
O
P
NHTf
O
Y
O
a
Determined by chiral HPLC.
P
iPr
iPr
iPr
iPr
X
Ar
21 X = O, Y = NHTf
22 X = S, Y = NHTf
23 X = O, Y = NHMs
19 3,5-(tBu)2C6H6
20 9-Anthr
2e4). The hydrolysis of unsaturated 1,3-dioxanes, such as 27a is
known to progress faster than the hydrolysis of the corresponding
dioxolanes.18 Based on this, one would expect a greater reaction
rate for 27a; however, this substrate was found to be a less re-
active dienophile than 13 although both reactions proceeded with
similar levels of stereocontrol. The introduction of the additional
gem-dimethyl substitution to the acetal backbone of 1,3-dioxane
(27b, entry 3) resulted in significant reduction of the reactivity
and no reaction was observed for 27b. This observation is con-
sistent with the experimental results obtained for the hydrolysis
of gem-dimethyl substituted vinyl 1,3-dioxanes and could result
from the both steric and stereoelectronic effects.18 Finally, the
reaction of cinnamaldehyde dimethyl acetal (27c) with cyclo-
pentadiene resulted in the formation of the corresponding prod-
uct (68:32 e.r., 8:1 d.r.). Consistent with the observations made by
Gassman, the cycloadduct yield for the reaction with 27c was
significantly lower than the corresponding yield with the cyclic
acetal 13. This could be ascribed to the higher reactivity of the
intermediate oxocarbenium ion that undergoes competitive olig-
omerization. The possibility of utilizing ketone-derived dioxolane
27d was examined next (entry 5). Although the ionization of 27d
should provide a significantly more stable oxocarbenium ion in
comparison to the corresponding ionization of 13, the reaction of
27d was significantly slower albeit selective (29% yield, 70:30 e.r.,
endo isomer). In addition, significant amounts of the hydrolyzed
starting material and products were also observed. To delineate
the role of the C3 substitution, acetal 27e was synthesized and
evaluated (entry 6). Although the replacement of the phenyl
substituent with the cyclohexyl should result in a less labile ac-
etal, the reactivity of 27e was not significantly different from 13,
(60% yield, 4:1 d.r.).
24 X = O, Y = NHSO2C6F5
Ph Ph
O
O
O
O
O
O
F3C
CF3
P
P
TfHN
CF3
TfHN
F3C
25
26
Determined by 1H NMR with Ph3CH as an internal standard.
Determined by chiral HPLC.
a
b
c
Estimated by 1H NMR without an internal standard.
8 and 9). While both 25 and 26 could promote the formation of the
cycloadduct 14, the selectivities of these reactions were significantly
lower than for the BINOL-derived N-sulfonylphosphoramides
19e24.
With the optimal catalyst (21) identified, the effect of solvent on
the formation of 14 was determined next to optimize the enan-
tioselectivity of the cycloaddition (Table 3). Consistent, with the
results obtained in acetonitrile, the formation of 14 in isopropanol
was completely unselective (entry 1). Reducing the polarity of the
solvents significantly improved the enantioselectivity and diaster-
eoselectivity of the cycloaddition (entries 2e8). Remarkably, the
reaction in weakly coordinating ethyl acetate (entry 8) was the
most selective (73:27 e.r., 7:1 d.r.). Employing other ester-
containing solvents, such as methyl pivalate (entry 9) and ethyl
isobutyrate (entry 10) resulted in increased selectivities. Thus, the
cycloaddition of 13 and cyclopentadiene in ethyl isobutyrate as the
solvent produced enantio- and diastereoenriched 14 (80:20 e.r., 7:1
d.r.). It is noteworthy that the reactions utilizing other catalysts
were also more selective when ethyl isobutyrate was employed as
the solvent (entries 11e14). However, catalyst 21 was still found to
be superior in terms of enantio- and diastereocontrol.
The acrolein-derived acetals 27feh were significantly more re-
active (entries 7e9). Thus, the reaction with vinyl dioxolane pro-
vided corresponding cycloadduct 28 even at ꢀ20 ꢁC (52% yield,
77:23 e.r., 3:1 d.r.). While the cinnamaldehyde-derived 5,50-di-
methyl-1,3-dioxane 27b did not react with cyclopentadiene (vide
supra), the reaction of acrolein-derived 5,50-dimethyl-1,3-dioxane
27g resulted in the formation of the corresponding cycloadduct
(85% yield, 69:31 e.r., 7:1 d.r.). Finally, the reaction of 27h and 2,3-
dimethyl-1,3-butadiene resulted in enantioselective formation of
the corresponding product (43% yield, 70:30 e.r.) indicating that
other dienes could also be employed for this reaction.
The scope and limitation of the catalytic asymmetric ionic
cycloaddition was evaluated next (Table 4). As changes in the
acetal portion of the dienophile could significantly affect the re-
action rates and selectivities, substrates 27aec were synthesized
and subjected to cycloaddition with cyclopentadiene (entries

5722
A. Borovika, P. Nagorny / Tetrahedron 69 (2013) 5719e5725
Table 4
Substrate scope
Ar
R
O
Ar
O
O
O
TfN
O
OR
O
O
O
O
R
P
R3
P
OR'
21 (5 mol%)
H
OR
O
NHTf
R3
iPrCO2Et (0.3 M)
R
OR'
R1
Ar
r.t.
30
Ar
(1 equiv)
(3 equiv)
28
e.r.b
29
27
Entry
Dienophile
Diene Time Yield
(conversion), %a
endo/exo
O
Ar
O
O
R3
O
O
O
TfN
O
P
R1
1
2
16 h 64 (100)
16 h 32 (60)
80:20 7:1
O
O
Ph
Ph
H
13
R
Ar
31
O
81:19 12:1
O
Ar
27a
R3
O
O
O
TfN
O
Me
Me
P
O
O
H
3
16 h
0 (0)
n.d.
n.d.
[2+4]
Ar
R3
Ph
O
R
Ar
32
27b
OMe
4c
5
20 h 33 (100)
16 h 29 (65)d
16 h 60 (100)
68:32 8:1
Ph
Ph
Cy
OMe
Ar
O
O
O
27c
TfN
O
R3
R
+
P
O
O
O
O
H
O
P
R
N
70:30d endo only
68:32e 4:1
H
δ
O
R3
Ar
O
Tf
Me
O
δ
+
27d
O
Ar
34
33
Scheme 3. Proposed reaction mechanism.
6
O
27e
role in this reaction. Further mechanistic and computational stud-
ies will help to shed some light on the nature of the reaction in-
termediates and the transition states (33 vs 34) and aid the design
of superior catalysts for this and related transformations.
O
7f
8
16 h 52 (88)
24 h 85 (95)
24 h 43 (89)
77:23 3:1
69:31 7:1
O
27f
Me
Me
O
4. Conclusion
O
O
27g
In summary, this article describes the first example of an
asymmetric chiral N-triflylphosphoramide-catalyzed ionic DA re-
action. This reaction presumably proceeds through the in-
termediacy of a vinyl oxocarbenium/chiral anion pair, and the chiral
N-triflylphosphoramide anion controls the stereoselectivity of the
cycloaddition step. Moderate enantioselectivities (up to 80:20 e.r.)
n.a
9
70:30
O
Me
Me
27f
Determined by 1H NMR with Ph3CH as an internal standard.
Measured by chiral HPLC.
Conducted at 0 ꢁC.
a
b
c
have been obtained when
a,b-unsaturated dioxolanes were
d
The yield, ee, and endo/exo ratio were determined after hydrolysis to a corre-
employed as the dienophiles. These reactions exhibit a strong de-
pendence on the counterion coordinating properties and solvent
polarity, a behavior characteristic of oxocarbenium ions. The pro-
vided examples demonstrate that chiral Brønsted acid-catalyzed
activation of acetals could be more generally employed as an al-
ternative to Lewis or Brønsted acid-catalyzed LUMO activation of
sponding ketone.
e
Determined after hydrolysis to the corresponding aldehyde.
Conducted at ꢀ20 ꢁC.
f
3. Discussion
the
a,
b-unsaturated carbonyls. Other Brønsted acid-catalyzed
Although a conclusive mechanistic and computational in-
vestigation delineating the nature of the reaction intermediates is
yet to be conducted, a tentative mechanism is summarized in
Scheme 3. Thus, initial protonation of an unsaturated acetal with N-
triflylphosphoramide 29 results in the reversible formation of the
contact ion pair 30. The subsequent reversible ionization results in
the unsaturated oxocarbenium ion 31 that undergoes a rate-
limiting reaction with a diene. The cyclization of the resultant
ionic cycloadduct 32 provides the product and regenerates the
catalyst 29. At the moment, it is not clear whether this reaction
proceeds through a clearly defined oxocarbenium ion-like transi-
tion state 34 or through the transition state 33, in which the
breakage of the CeO bond is coupled with the cycloaddition event.
It is clear that the acidity of the catalyst, coordinating ability of the
counterion and the reactivity of the dienophile play an important
transformations of a,b
mechanistic investigation of the ionic DA reaction reported herein
are the subject of the ongoing studies.
-unsaturated acetals as well as the detailed
5. Experimental section
5.1. General
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without purification. Toluene
(PhMe), tetrahydrofuran (THF), dichloromethane (CH2Cl2), and
diethyl ether (Et2O) were filtered through a column (Innovative
Technology PS-MD-5) of activated alumina under nitrogen atmo-
ꢀ
sphere. Ethyl isobutyrate (iPrCO2Et) was dried with activated 4 A
molecular sieves according to the previously reported procedure by

A. Borovika, P. Nagorny / Tetrahedron 69 (2013) 5719e5725
5723
Burfield et al.19 All reactions were carried out under an atmosphere
of nitrogen in flame- or oven-dried glassware with magnetic stir-
ring. Reactions were cooled via external cooling baths: ice water
(0 ꢁC), Neslab Cryotrol CB-80 immersion cooler (0 to ꢀ60 ꢁC) or
Neslab Cryocool immersion cooler CC-100 II. Purification of the re-
actions mixtures was performed by flash chromatography using
SiliCycleSiliaFlash P60 (230e400 mesh) silica gel. The enantiomeric
ratios (e.r.) were determined on Alliance Waters (separations
module e2695, detector 2998) using CHIRALCEL OD-H column
phosphoryl chloride prepared above in dry THF (0.9 mL) again
at ꢀ78 ꢁC. The resulting reaction mixture was refluxed for 16 h.
After that the reaction mixture was brought to room temperature
and quenched with water. Organic products were extracted with
DCM. Extract was then washed with 4 N HCl and dried over an-
hydrous magnesium sulfate. The desired product was purified via
preparatory TLC (10:1 DCM/Et2O) and washed again with 4 N HCl to
provide a white solid, 42.2 mg, 49% yield; IR (thin film, cmꢀ1) 2961,
2922, 2869, 1595, 1432, 1364, 1203, 1151, 910, 733. 1H NMR
(4.6 mmꢂ250 mm, 5
m
m) by comparing the samples with the ap-
(700 MHz, CDCl3)
d
8.15 (s, 1H), 8.06 (s, 1H), 8.02 (d, J¼8.3 Hz, 1H),
propriate racemic mixtures. 1H NMR spectra were recorded on
Varian vnmrs 700 (700 MHz), Varian vnmrs 500 (500 MHz), Varian
MR400 (400 MHz), Varian Inova 500 (500 MHz) spectrometers and
7.99 (d, J¼8.3 Hz, 1H), 7.58e7.51 (m, 5H), 7.51e7.42 (m, 4H),
7.38e7.30 (m, 3H), 1.37 (s, 18H), 1.34 (s, 18H); 13C NMR (175 MHz,
CDCl3) 151.5, 150.9, 144.0, 143.5, 135.7, 135.2, 134.9, 134.3, 132.3,
132.03, 131.99, 131.96, 128.8, 128.6, 127.4, 127.3, 127.0, 126.6, 124.6,
124.4, 122.9, 122.8, 122.5, 122.2, 35.21, 35.18, 31.6; 31P NMR
chemical shifts (
solvent resonance as the internal standard (CDCl3 at
d
) are reported in parts per million (ppm) with
7.26). Data are
d
reported as (br¼broad, s¼singlet, d¼doublet, t¼triplet, q¼quartet,
qn¼quintet, sext¼sextet, m¼multiplet; coupling constant(s) in
Hertz; integration). Proton-decoupled 13C NMR, as well as 19F and
31P spectra were recorded on Varian vnmrs 500 (500 MHz) or Varian
(283 MHz, CDCl3)
d
ꢀ11.0 (s); 19F NMR (376 MHz, CDCl3)
d
ꢀ77.4;
HRMS (ESIꢀ) (m/z): [MꢀH] calcd for C49H52F3NO5PS 854.3259;
found 854.3259.
vnmrs 700 (700 MHz) spectrometers and chemical shifts (
reported in ppm with solvent resonance as the internal standard
(CDCl3 at 77.2). High resolution mass spectra (HRMS) were
d
) are
5.2.2. N-((2s,11bS)-4-Oxido-2,6-bis(2,4,6-triisopropylphenyl)dinaph-
tho[2,1-d:10,20-f][1,3,2]dioxaphosphepin-4-yl) methanesulfonamide
(23). Following the procedure described by Yamamoto and Naka-
shima,4b the preparation of 23 was conducted on 0.28 mmol scale
from the corresponding BINOL derivative and sulfonamide. The
resultant product, was isolated as a white solid, 60 mg, 26% yield; IR
(thin film, cmꢀ1) 2961, 2870, 1381, 1315, 1171, 912. 1H NMR
d
recorded on MicromassAutoSpecUltima or VG (Micromass) 70-250-
S Magnetic sector mass spectrometers in the University of Michigan
mass spectrometry laboratory. Infrared (IR) spectra were recorded
as thin films on NaCl plates on a Perkin Elmer Spectrum BX FT-IR
spectrometer. Absorption peaks were reported in wavenumbers
(cmꢀ1). All previously reported phosphoramides were prepared
according to published procedures.4b,20 All commercially unavail-
able acetals and ketals were prepared following the procedure re-
ported by Lu and co-workers.21 Racemic DielseAlder reactions were
performed according to the Chavan procedure.22 Products were
then purified by flash chromatography or preparatory HPLC (Waters
(700 MHz, CDCl3) d 8.00e7.94 (m, 4H), 7.58e7.53 (m, 2H), 7.39e7.33
(m, 3H), 7.29e7.26 (m, 1H), 7.15 (dd, J¼3.1, 1.9 Hz, 2H), 7.13
(d, J¼1.7 Hz, 1H), 7.02 (d, J¼1.7 Hz, 1H), 2.98e2.95 (m, 3H),
2.73e2.68 (m, 1H), 2.60e2.52 (m, 2H), 2.42 (s, 3H), 1.43 (s, 1H), 1.30
(d, J¼7.2 Hz, 6H), 1.26 (d, J¼6.9 Hz, 9H), 1.24 (dd, J¼10.0, 6.9 Hz, 6H),
1.21 (dd, J¼6.9, 1.9 Hz, 6H), 1.09 (d, J¼6.9 Hz, 3H), 1.00 (d, J¼6.9 Hz,
3H), 0.96 (d, J¼6.9 Hz, 3H); 13C NMR (175 MHz, CDCl3)
d 149.9,
Delta 600, column Agilent Zorbax RX-SIL, 21.2ꢂ250 mm, 7
m
m) to
149.2, 148.7, 148.3, 147.2, 146.2, 146.0, 144.6, 133.0, 132.9, 132.6,
132.4, 132.3, 131.8, 131.3, 130.9, 130.7, 130.2, 128.6, 128.5, 127.5,
126.9, 126.5, 126.4, 122.1, 121.7, 121.6, 121.3, 120.3, 42.1, 34.6, 31.6,
31.4, 31.2, 30.8, 30.5, 29.9, 27.1, 27.0, 25.6, 25.2, 24.4, 24.2, 23.3, 23.2,
ensure high purity standards for developing chiral HPLC assays.
5.2. Synthesis of catalysts 17e26
23.1; 31P NMR (202 MHz, CDCl3)
d
ꢀ4.5 (s); HRMS (ESIþ) (m/z):
Catalysts 17,23 18,4b 20,20a 21,20b 22,20b 25,20c and 2620d
have been synthesized according to the previously published
procedures.
[MꢀH] calcd for C51H59NO5PS 828.3857; found 828.3854.
5.2.3. 2,3,4,5,6-Pentafluoro-N-(4-oxido-2,6-bis (2,4,6-triisopropyl-
phenyl)dinaphtho[2,1-d:10,20-f][1,3,2] dioxaphosphepin-4-yl)benze-
nesulfonamide (24). Following the procedure described by Yama-
moto and Nakshima,4b the preparation of 24 was conducted on
0.117 mmol scale from the corresponding BINOL derivative and
sulfonamide. The resultant product, 11.6 mg was isolated as a white
solid in 10% yield; IR (thin film, cmꢀ1) 2961, 2928, 2870, 1520, 1504,
1409, 1316, 1302, 1182, 1103, 996, 903, 733. 1H NMR (700 MHz,
5.2.1. N-((11bS)-2,6-Bis(3,5-di-tert-butylphenyl)-4-oxidodinaphtho
[2,1-d:10,20-f] [1,3,2]dioxaphosphepin-4-yl)-1,1,1-trifluoromethane-
sulfonamide (19). 75.2 mg (0.104 mmol) of the corresponding chi-
ral phosphoric acid was dissolved in 0.91 mL of dry 1,2 di-
chloroethane under nitrogen atmosphere. Then 1.0
mL (0.0135 mmol)
of DMF and 44.5 L (0.519 mmol) of oxalyl chloride were added. The
m
resulting mixture was stirred at reflux for 20 h. After reaction com-
pletion volatiles were evaporated, the product was dried under high
vacuum, and subjected to the next step without further purification.
This product was isolated as a yellow solid, 77.1 mg, quantitative
yield; IR (thin film, cmꢀ1) 2962, 2868, 15.95, 1477, 1406, 1363, 1317,
CDCl3) d 8.02e7.91 (m, 4H), 7.60e7.51 (m, 2H), 7.42e7.29 (m, 4H),
7.22 (d, J¼8.9 Hz, 2H), 7.12 (d, J¼1.4 Hz, 1H), 7.06 (d, J¼1.4 Hz),
3.05e2.92 (m, 2H), 2.82e2.73 (m, 1H), 2.68e2.50 (m, 3H), 1.32
(d, J¼6.8 Hz, 12H), 1.26 (d, J¼6.8 Hz, 6H), 1.23e1.15 (m, 9H), 1.04
(d, J¼6.8 Hz, 3H), 0.98 (d, J¼6.8 Hz, 3H), 0.94 (d, J¼6.8 Hz); 13C NMR
1239, 1086, 922, 751. 1H NMR (400 MHz, CDCl3)
d
8.11 (d, J¼9.4 Hz,
(175 MHz, CDCl3) d 150.4, 148.9, 148.5, 147.7, 146.9, 146.3, 133.6,
2H), 8.02 (dd, J¼8.3, 4.8 Hz, 2H), 7.64 (d, J¼1.5 Hz, 2H), 7.58e7.51 (m,
2H), 7.47 (s, 4H), 7.44 (d, J¼8.6 Hz, 1H), 7.38e7.31 (m, 3H), 1.38 (s,
18H), 1.37 (s, 18H); 13C NMR (175 MHz, CDCl3) 151.0, 150.8, 144.52,
144.46,144.4,135.7,135.5,134.9,132.1, 132.0,131.7, 128.8,128.7,127.4,
127.3, 126.94, 126.89, 126.64, 126.62, 124.7, 123.0, 122.7, 121.9, 35.3,
133.2,132.9,132.4,132.2,131.8,131.3,130.3,130.1,129.8,128.6,127.7,
127.6, 126.9, 126.6, 126.5, 122.1, 122.0, 121.5, 121.4, 120.6, 34.6, 34.4,
31.8, 31.3, 31.2, 30.5, 29.9, 27.5, 26.9, 25.6, 25.4, 24.1, 24.0, 23.2, 23.1,
23.0, 22.7; 31P NMR (202 MHz, CDCl3)
d
ꢀ6.0 (s); 19F NMR (376 MHz,
CDCl3)
d
ꢀ135.3 (d, J¼21.9 Hz, 2F), ꢀ144.9 (ꢀ145.2) (m, 1F), ꢀ159.6
35.2, 31.7; 31P NMR (202 MHz, CDCl3)
[MþNa] calcd for C48H52ClO3PNa 765.3235; found 765.3216.
A solution of 16.3 mg (0.110 mmol) of trifluoromethanesulfony-
lamide in 0.5 mL of dry THF was treated with freshly prepared
d
8.4 (s); HRMS (ESIþ) (m/z):
(t, J¼19.1 Hz, 2F); HRMS (ESIꢀ) (m/z): [MꢀH] calcd for
C56H56F5NO5PS 980.3542; found 980.3541.
5.3. Preparation of acetals 27 in Table 4
solution of LDA made from 30.7 mL (0.219 mmol) diisopropylamine,
0.14 mL 1.6 M (0.219 mmol) n-butyllithium and dry THF (0.5 mL)
The unsaturated acetals 13,21 27a,24a 27b,24a 27c,24b 27d,24c and
27g,24d have been synthesized according to previously published
at ꢀ78 ꢁC. The resulting solution was cannulated over a solution of

5724
A. Borovika, P. Nagorny / Tetrahedron 69 (2013) 5719e5725
procedures. Acetal 27e was synthesized from the corresponding
aldehyde following the protocol provided below. Acetal 27f was
purchased from SigmaeAldrich and used as received.
the corresponding ketone that has been synthesized and charac-
terized before.25c The hydrolysis procedure is provided below.
5.5.2. Hydrolysis of cycloadduct 28d. The crude reaction mixture
was obtained following the General procedure A (Section 5.4) de-
scribed above. The reaction was quenched with w10 mol % of
triethylamine. Volatiles were evaporated from the reaction mix-
ture, and then the resultant mixture was dissolved in dioxane
(1.0 mL). To this, 4 N HCl (0.5 mL) was added, the resultant mixture
was stirred at 40 ꢁC for 2 h, then organics were extracted with
diethyl ether. Organic layer was dried with MgSO4 and filtered. The
solvent was removed in vacuo and triphenylmethane was added.
The resultant crude mixture was analyzed by 1H NMR to establish
the yield and d.r.25c
5.3.1. (E)-2-(2-Cyclohexylvinyl)-1,3-dioxolane
hexylacrylaldehyde (768.0 mg, 5.56 mmol) was dissolved in
6.8 mL of dry toluene, followed by addition of -tartaric acid
(27e). (E)-3-Cyclo-
L
(10.2 mg, 0.0680 mmol) and anhydrous magnesium sulfate
(869.4 mg, 7.22 mmol). The setup was flushed with nitrogen and
then ethylene glycol was added (0.81 mL, 14.5 mmol). The reaction
mixture was refluxed with a DeaneStark column overnight. The
reaction was quenched with 0.1 mL of triethylamine and then solids
were quickly filtered off. The filtrate was then concentrated in
vacuo and the desired product was purified by column chroma-
tography. Light yellow oil, 60% yield. IR (thin film, cmꢀ1) 2924,
2852, 1674, 1449, 1400, 1139, 1064, 963. 1H NMR (700 MHz, CDCl3)
5.5.3. 2-(3-Phenylbicyclo[2.2.1]hept-5-en-2-yl)-1,3-dioxane (28a).
Colorless oil, 32% yield (about 60% conversion) 12:1 endo/exo; IR
(thin film, cmꢀ1) 3057, 2964, 2847,1498,1377,1240,1144,1110,1011,
d
5.89 (dd, J¼15.7, 6.5 Hz, 1H), 5.42 (ddd, J¼15.7, 6.7, 1.5 Hz, 1H), 5.17
(d, J¼6.7 Hz, 1H), 4.03e3.97 (m, 2H), 3.92e3.86 (m, 2H), 2.04e1.97
(m, 1H), 1.78e1.68 (m, 4H), 1.67e1.61 (m, 1H), 1.30e1.22 (m, 2H),
1.15 (tt, J¼12.7, 3.4 Hz, 1H), 1.12e1.05 (m, 2H); 13C NMR (175 MHz,
720, 700. endo product: 1H NMR (400 MHz, CDCl3)
d 7.39
(d, J¼7.6 Hz, 2H), 7.28 (t, J¼7.6 Hz, 2H), 7.16 (t, J¼7.3 Hz, 1H), 6.34
(dd, J¼5.6, 3.1 Hz, 1H), 6.15 (dd, J¼5.6, 2.8 Hz), 4.15e4.03 (m, 2H),
4.05 (d, J¼8.3 Hz, 1H), 3.75e3.62 (m, 2H), 3.02 (s, 1H), 2.93 (s, 1H),
2.49e2.45 (m, 1H), 2.45e2.39 (m, 1H), 2.13e1.99 (m, 1H), 1.66
(d, J¼8.6 Hz,1H),1.46 (dq, 8.6,1.7 Hz,1H),1.32e1.26 (m,1H). Distinct
CDCl3)
d 143.8, 123.8, 104.8, 65.1, 40.2, 32.4, 26.3, 26.1; HRMS (EI)
(m/z): [MꢀH] calcd for C11H17O2 181.1229; found 181.1224.
5.4. General procedure A for enantioselective DielseAlder
reactions
peaks for the exo product: 1H NMR (400 MHz, CDCl3)
d 6.29 (dd,
J¼5.5, 3.1 Hz, 1H), 5.92 (dd, J¼5.5, 2.9 Hz, 1H), 5.71e5.60 (m, 1H),
4.55 (d, J¼6.4 Hz, 1H), 3.21 (dd, J¼5.0, 3.5 Hz, 1H), 3.08 (br s, 1H),
2.98 (br s, 1H), 1.94e1.89 (m, 1H), 1.75 (d, J¼8.6 Hz, 1H), 1.34 (br s,
An oven-dried 4-mL scintillation vial was charged with 1 equiv
of a dienophile and 5 mol % of a catalyst, capped with septum and
flushed with nitrogen. Ethyl isobutyrate was then added to ensure
0.3 M concentration of dienophile. Cyclopentadiene (3 equiv) was
then added via micro syringe. The resulting reaction mixture was
stirred at room temperature for 16 h and then the reaction was
1H); endo only: 13C NMR (175 MHz, CDCl3)
d 145.3, 138.1, 135.4,
128.4, 128.1,125.8, 106.8, 67.1, 51.5, 49.4, 47.0, 46.7, 44.3, 26.0; HRMS
(ESIþ) (m/z): [MþNH4] calcd for C17H24NO2 274.1802; found
274.1800.
quenched with about 10 mol
% of triethylamine. Then tri-
phenylmethane was added and volatiles were evaporated from the
reaction vial. The crude mixture was analyzed by quantitative 1H
NMR and HPLC. The 1H NMR yields were calculated using the fol-
5.5.4. 2-(3-Cyclohexylbicyclo[2.2.1]hept-5-en-2-yl)-1,3-dioxolane
(28e). Light yellow oil, 60% yield, 3:1 endo/exo. The nonpolar nature
of 28e precluded ambiguous determination of the e.r. for this re-
action. IR (thin film, cmꢀ1) 2980, 2922, 2851, 1448, 1334, 1098, 1056,
lowing formula: yield (%)¼100%$(
n
(product))/(
n(standard))$n,
where (product))/
n
n
(standard) is the integral ratio of the corre-
990, 719. endo product: 1H NMR (400 MHz, CDCl3)
d 6.18e6.13
sponding 1H NMR peaks and n is the ratio of the standard to
starting material (in mol). The conversions were determined using
the following formula: conversion (%)¼100%ꢀ(yield (starting ma-
terial, %)þyield (hydrolyzed starting material, %).
(m, 1H, endo/exo), 6.09e6.04 (m, 1H, endo/exo), 4.26 (d, J¼7.6 Hz,
1H, endo), 4.03e3.88 (m, 2H, endo/exo), 3.88e3.73 (m, 2H, endo/
exo), 2.88 (br s, 1H, endo/exo), 2.75 (br s, 1H, endo), 1.94e1.85 (2H,
endo/exo), 1.80e1.70 (m, 2H, endo/exo), 1.68e1.53 (m, 2H, endo/exo),
1.41 (d, J¼8.5 Hz, 1H, endo), 1.31 (dd, J¼8.5, 1.4 Hz, 1H, endo/exo),
1.29e1.08 (m, 4H, endo/exo), 1.06e0.86 (m, 3H, endo/exo). Distinct
5.5. General procedure B for enantioselective DielseAlder
reactions
peaks for the exo product: 1H NMR (400 MHz, CDCl3)
d 4.83
(d, J¼5.0 Hz, 1H), 2.80 (br s, 1H); endo only: 13C NMR (175 MHz,
An oven-dried 4-mL scintillation vial was charged with 5 mol % of
a catalyst, capped with septum and flushed with nitrogen. Ethyl
isobutyrate was then added to ensure 0.3 M concentration of dien-
ophile. After that 1 equiv of a dienophile and 3 equiv of diene
were added via micro syringe. The resulting reaction mixture was
stirred at room temperature for 16e24 h and then the reaction
was quenched with about 10 mol % of triethylamine. Then, tri-
phenylmethane was added and the crude mixture was analyzed
by quantitative 1H NMR and HPLC. The 1H NMR yields were calcu-
CDCl3) d 138.1, 134.6, 108.9, 65.0, 64.7, 48.2, 47.6, 46.7, 44.6 (2H),
42.3, 32.9, 32.3, 27.1, 26.9 (2H); HRMS (EI) (m/z): [M] calcd for
C16H24O2 248.1776; found 248.1779.
In a separate experiment, after the reaction was complete, crude
mixture containing 28e was quenched with 1.5 mL of triethylamine
and volatiles were evaporated in vacuo. Then the crude product
was dissolved in 2 mL of acetone and 0.5 mL of 4 N HCl was added.
The resulting mixture was stirred for 2 h at room temperature. Then
the reaction was quenched with saturated sodium bicarbonate
solution and organics were extracted with diethyl ether. Organic
layers were dried over magnesium sulfate, solids were filtered off
and the filtrate was concentrated in vacuo. Crude product was
analyzed on chiral HPLC (100% hex, AD-H column, 1.0 mL/min).
lated using the following formula: yield (%)¼100%$(
n
(product))/
(n
(standard))$n, where ( (product))/(
n
n(standard) is the integral ratio
of the corresponding 1H NMR peaks and n is the ratio of the standard
to starting material (in mol). The conversions were determined us-
ing the following formula: conversion (%)¼100%ꢀ(yield (starting
material, %)þyield (hydrolyzed starting material, %).
5.5.5. 2-(3,4-Dimethylcyclohex-3-en-1-yl)-1,3-dioxolane (28h, entry
9, Table 4). Colorless oil, 43% yield. IR (thin film, cmꢀ1) 2956, 2926,
5.5.1. Characterization data for the cycloadducts 28 in Table 4. The
cycloadducts 14,22 28c,25a 28g,22 and 28h,25b have been previously
characterized. The characterization data for compounds 28a, and
28f is provided below. The crude product 28d was hydrolyzed to
2869, 1456, 1373, 1116, 1051. 1H NMR (500 MHz, CDCl3)
d 4.68
(d, J¼5.3 Hz, 1H), 4.00e3.92 (m, 2H), 3.90e3.82 (m, 2H), 2.08e1.85
(m, 4H), 1.85e1.75 (m, 2H), 1.61 (m, 6H), 1.33 (dd, J¼11.6, 5.9, 1H);
NMR (175 MHz, CDCl3) d 125.7,124.5,107.6, 65.1, 38.8, 32.6, 31.3, 24.4,

A. Borovika, P. Nagorny / Tetrahedron 69 (2013) 5719e5725
5725
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Acknowledgements
P.N. acknowledges University of Michigan for financial support.
This material is based upon work supported by the National Science
Foundation Graduate Student Research Fellowship under Grant No.
DGE 0718128.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.03.086.
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