Synthesis of a novel chiral cubane-based Schiff base ligand and its application in asymmetric nitro-aldol (Henry) reactions

Article abstract of DOI:10.1055/s-0029-1217083

The first reported cubane-based chiral Schiff base ligand has been successfully synthesized. This ligand has been evaluated on the nitro-aldol (Henry) reaction. The reactions were performed in the presence of four different copper salts, using eight different solvents, and five different temperatures. The highest enantioselectivity obtained for this novel ligand was ～39% ee.

Full text of DOI:10.1055/s-0029-1217083

98
PAPER
Synthesis of a Novel Chiral Cubane-Based Schiff Base Ligand and Its
Application in Asymmetric Nitro-Aldol (Henry) Reactions
Synthesis of
a
Novel
C
i
hira
l
C
c
ubane-Base
h
d Schiff Ba
s
e
e
L
igand lle L. Ingalsbe,a Jeffrey D. St. Denis,b James L. Gleason,b G. Paul Savage,c Ronny Priefer*a
a
Department of Chemistry, Biochemistry, and Physics, Niagara University, Niagara, NY 14109, USA
Fax +1(716)2868254; E-mail: rpriefer@niagara.edu
b
c
Department of Chemistry, McGill University, Montreal, QC, H3A 2K6, Canada
CSIRO Molecular and Health Technologies, Clayton South MDC 3169, Australia
Received 16 July 2009; revised 9 September 2009
ole),18 and Schiff base ligands.19 Herein, we report the
synthesis of a cubane-based chiral Schiff base ligand and
its use in the enantioselective Henry reaction.
Abstract: The first reported cubane-based chiral Schiff base ligand
has been successfully synthesized. This ligand has been evaluated
on the nitro-aldol (Henry) reaction. The reactions were performed
in the presence of four different copper salts, using eight different
solvents, and five different temperatures. The highest enantioselec-
tivity obtained for this novel ligand was ~39% ee.
In order to synthesize our desired cubane-based chiral
Schiff base ligand, we required the dimethyl-1,4-cubane
dicarboxylate (5), which was synthesized according to
Tsanaktsidis’ procedure (Scheme 1).20 Initially, we start-
ed with cyclopentanone (1), which was ketalized to 2 with
ethane-1,2-diol in the presence of Dowex 50W-X8 (H)
cation-exchange resin. After treatment with bromine in
1,4-dioxane, the unpurified tribromide was dimerized to 3
in refluxing methanol. The formation of the dione 4 was
accomplished with concentrated sulfuric acid, which was
irradiated, hydrolyzed, induced to undergo two consecu-
tive Favorskii ring contractions, and subsequently esteri-
fied to afford the dimethyl-1,4-cubane dicarboxylate (5).
After addition of one equivalent of sodium hydroxide, cu-
bane 5 was converted into the corresponding acid ester 6.
A subsequent Moriarty reaction,21 followed immediately
by another base-mediated hydrolysis yielded the iodo acid
7. Borane reduction of the carboxylic acid, then a Swern
oxidation afforded aldehyde 9. Finally, the cubane-based
chiral ligand 10 was formed by reacting two equivalents
of 9 with trans-(1R,2R)-(–)-1,2-cyclohexanediamine. All
Key words: cubane, aldol reactions, chirality, Schiff base, catalysis
In 1964, the first successful synthesis of pentacy-
clo[4.2.0.02,5.03,8.04,7]octane, more commonly known as
cubane, was accomplished at the University of Chicago
by Philip E. Eaton and Tom Cole Jr.1 Since this first syn-
thesis, much work has been performed on a large number
of its derivatives. Octanitrocubane has been classified as
the most powerful non-nuclear explosive,2 cubylamines
have shown antiviral acitivity,3 dicubyl disulfide4 and its
derivatives5 have revealed unique bond lengths and in-
tramolecular hydrogen-bonding. Cubanes have also been
shown to rearrange with silver(I)6 and rhodium(I)7 ions to
cuneane and syn-tricyclooctadiene, respectively. Recent-
ly, it was reported that 4-iodo-1-vinylcubane rearranged
under heat, and/or in the presence of a Lewis acid, to yield
4-vinyl-trans-b-iodostyrene.8 Polymers of cubane have
also been synthesized9,10 and some have undergone cage-
opening once incorporated within the polymer.10 One area
of cubane chemistry that has not been examined is its ap-
plication in asymmetric synthesis. The bulkiness of the
cubane makes it an attractive moiety for incorporation
into a chiral ligand.
1
intermediates were characterized by H NMR and com-
pared to literature values.8,20,22 Ligand 10 was fully char-
acterized through 1H and 13C NMR as well as HRMS.
Ligand 10 was evaluated in the Henry reaction described
by Jiang and Shi.23 Typical conditions were 10 mol%
ligand 10 and 5 mol% copper(I) triflate in methanol at
room temperature for 48 hours. This provided a high con-
version (>99%) with only 13% ee. We next compared dif-
ferent copper salt sources (entries 1–4, Table 1).
Copper(II) triflate gave both poor conversion and poor
enantiomeric excess (entry 2, Table 1). When using cop-
per(I) triflate tetrakisacetonitrile or copper(I) chloride, we
obtained near quantitative conversion and an increase in
enantiomeric excess to 27 and 32% ee, respectively. Next,
we focused on the use of these two copper salts with
ligand 10, in a range of solvents. After screening eight sol-
vents with copper(I) chloride, we found near quantitative
conversion in each case (entries 4–11, Table 1). Only a
moderate increase in enantiomeric excess was observed
with diethyl ether (entry 8) and dichloromethane (entry 9).
The same solvent systems were also examined with cop-
per(I) triflate tetrakisacetonitrile (entries 12–18, Table 1).
A classical C–C bond forming reaction is the nitro-aldol
(Henry) reaction. This reaction was first reported in
1895;11 however, the first asymmetric version was only
accomplished in 1992.12 This reaction couples a nitroal-
kane with a carbonyl compound in the presence of a base,
yielding b-nitroalcohols. This methodology has been suc-
cessfully used in the stereoselective synthesis of several
b-blockers, including (S)-metoprolol,13 (S)-pindolol,14
and (S)-propranolol.15 Numerous chiral ligands have been
used in this copper- and zinc-catalyzed reaction, including
bis(oxazoline),16 amino alcohols,17 tridentate-bis(thiaz-
SYNTHESIS 2010, No. 1, pp 0098–0102
x
x
.
x
x
.2
0
0
9
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217083; Art ID: M04209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of a Novel Chiral Cubane-Based Schiff Base Ligand
99
O
O
Br
O
O
O
ethane-1,2-diol, benzene
1. Br2 (3 equiv), 1,4-dioxane
Dowex 50W-X8 (H) resin
90%
2. NaOH, MeOH
75%
O
Br
2
1
O
3
concd H2SO4
98%
O
CO2Me
CO2Me
Br
1. hν, MeOH, concd H2SO4
1. NaOH, MeOH, THF
2. HCl
2. H2O, heat
3. 25% NaOH, heat
4. MeOH, Dowex 50W-X8 (H) resin
79%
HO2C
6
73%
MeO2C
5
4
Br
O
1. IBDA, I2, benzene
2. NaOH, MeOH
3. HCl
74%
CH2OH
CHO
CO2H
1. BH3⋅SMe2, THF
2. HCl
68%
oxalyl chloride, CH2Cl2
DMSO, Et3N
81%
I
8
I
I
9
7
trans-(1R,2R)-(–)-1,2-cyclohexanediamine
EtOH, 4 Å MS
75%
N
N
10
I
I
Scheme 1 Synthesis of the cubane-based chiral Schiff base ligand
Purchased chemicals were reagent grade. 1,4-Dioxane was distilled
over potassium benzophenone ketyl immediately prior to use. Melt-
ing points were obtained on a Gallenkamp apparatus and are uncor-
rected. 1H (400 MHz) and 13C (100 MHz) NMR spectra were
obtained on a Varian instrument with the indicated solvent. HPLC
measurements were performed with Varian Polaris HPLC model
325. Separations were carried out on a Diacel Chiralcel AD column
(hexane–i-PrOH, 65:35; 0.7 mL/min; 230 nm; tminor = 10.595 min,
tmajor = 13.106 min).
Only diethyl ether (entry 15) provided a higher enantio-
meric excess compared to the initial study in methanol
(entry 3), but gave a lower conversion after 48 hours.
Ligand 10, with copper(I) triflate tetrakisacetonitrile in
dichloromethane gave the lowest conversion (72.2%) as
well as yielding the opposite enantiomer in 11% ee (entry
16).
Finally, we examined the reaction in the presence of
ligand 10 and copper(I) chloride in methanol at different
temperatures (entries 4 and 19–22, Table 1). Surprisingly,
the highest enantiomeric excess (39% with >99.0% con-
version) was observed at 65 °C. The enantiomeric excess
as well as the level of conversion decreased with temper-
ature, which was unexpected, however within experimen-
tal error, excluding the –80 °C data point.
Synthesis of Cubane-Based Chiral Schiff Base
Cyclopentanone Ethylene Ketal (2)
Cyclopentanone (1; 250 ml, 3.0 mol), ethane-1,2-diol (200 mL, 3.59
mol), and Dowex 50W-X8 (H) cation-exchange resin (3 g) were re-
fluxed in benzene (500 mL) with simultaneous azeotropic removal
of H2O over 30 h. The yellow solution that remained was cooled to
r.t., filtered, and washed with aq NaOH (4%, 250 mL) and brine
(500 mL), dried with MgSO4 and concentrated by distillation
through a Vigreux column (35 cm). Simple distillation of the resi-
due (59–63 °C/23 mmHg; Lit.24 57 °C/18 mmHg) yielded the ketal
2.
In conclusion, we have successfully synthesized the first
reported cubane-based chiral Schiff base ligand and have
demonstrated its use in the enantioselective copper-cata-
lyzed Henry reaction. Further applications of this novel
ligand are currently underway.
Yield: 326.2 g (90%); colorless liquid.
1H NMR (400 MHz, CDCl3): d = 1.58–1.81 (m, 8 H), 3.87 (s, 4 H).
Synthesis 2010, No. 1, 98–102 © Thieme Stuttgart · New York

100
M. L. Ingalsbe et al.
PAPER
was added slowly, so as to maintain the temperature below 10 °C.
After half the NaOH solution had been added, the mixture turned a
dark-green color. After ~4 h, the addition was complete with the
color having turned to brown. The mixture was then heated to reflux
and left stirring for 16 h then subsequently cooled to r.t. and pumped
out of the reactor into ice water (80 L). The precipitate was then col-
lected by vacuum filtration, washed with deionized H2O (90 L) and
cold MeOH (5 L). The solid was then air-dried to yield the bisketal
3.
Table 1 Optimization of the Copper-Catalyzed Asymmetric Henry
Reaction between p-Nitrobenzaldehyde and Nitromethane
HO
CHO
NO2
NO2
*
Cu salt (5% mol)
MeNO2
+
10 (10% mol)
4 Å MS
NO2
Yield: 7.46 kg (74.7%); solid; mp 174–176 °C (Lit.25 172–174 °C).
Entry Metal
Temp Solvent Conv. ee
(°C)
(%)a
(%)b
1H NMR (400 MHz, CDCl3): d = 2.69–2.76 (m, 1 H), 3.02–3.13 (m,
1 H), 3.46–3.55 (m, 1 H), 3.83–4.30 (m, 8 H), 5.84 (d, J = 6.5 Hz,
1 H), 6.07 (d, J = 2.3 Hz, 1 H), 6.19 (dd, J = 3.5, 6.5 Hz, 1 H).
1
2
3
4
5
6
7
8
9
Cu(OTf) toluene complex
Cu(OTf)2
25
MeOH >99.0 13 (R)
25
MeOH
MeOH
MeOH
EtOH
THF
54.2
2 (R)
endo-2,4-Dibromodicyclopentadiene-1,8-dione (4)
The bisketal 3 (14 kg, 34.5 mol) was slowly added to concd H2SO4
(45 L) keeping the temperature below 25 °C. The mixture was then
stirred at r.t. for 24 h, then pumped from the reactor onto ice water
(~120 L) while stirring. The precipitate was then collected by vac-
uum filtration washed with H2O (2 × 20 L) and air-dried, yielding
the dione 4.
Yield: 10.8 kg (98.4%); colorless solid; mp 156–157 °C (Lit25 155–
155.5 °C).
1H NMR (400 MHz, CDCl3): d = 3.15–3.25 (m, 1 H), 3.48–3.63 (m,
2 H), 6.24–6.36 (m, 2 H), 7.67 (d, J = 2.9 Hz, 1 H).
Cu(OTf) tetrakisacetonitrile 25
97.9 27 (R)
97.8 32 (R)
>99.0 20 (R)
>99.0 31 (R)
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
25
25
25
25
25
25
25
25
Toluene 96.3 17 (R)
Et2O >99.0 36 (R)
CH2Cl2 >99.0 34 (R)
iPrOH 95.2 25 (R)
MeCN >99.0 25 (R)
Dimethyl 1,4-Cubanedicarboxylate (5)
10 CuCl
11 CuCl
The dione 4 (4.00 kg, 12.6 mol) was dissolved in MeOH (68 L),
deionized H2O (12 L) and concd H2SO4 (103 mL) in a 100 L reactor.
The solution was circulated through the Symantec large-scale pho-
tolysis unit irradiating the solution with UV light (2 kW Hg vapor
lamp). Cooling was applied to the reactor to maintain a temperature
of ~25 °C. Conversion into the caged dione was quite slow, with a
12 Cu(OTf) tetrakisacetonitrile 25
13 Cu(OTf) tetrakisacetonitrile 25
14 Cu(OTf) tetrakisacetonitrile 25
15 Cu(OTf) tetrakisacetonitrile 25
16 Cu(OTf) tetrakisacetonitrile 25
17 Cu(OTf) tetrakisacetonitrile 25
18 Cu(OTf) tetrakisacetonitrile 25
EtOH
THF
93.0 26 (R)
97.1 5 (R)
1
maximum conversion rate of ~10 g per hour (monitored by H
Toluene 91.1 13 (R)
NMR). When conversion was complete, the reaction solution was
concentrated to dryness under reduced pressure. The crude solid
caged dione was dissolved in aq NaOH (30%, 38 L) and the mixture
was heated to reflux for 3 h. The solution was then cooled to 0 °C
and acidified by the slow addition of concd HCl (24 L) with vigor-
ous stirring while maintaining the temperature below 10 °C. The re-
sulting precipitate of crude cubane diacid, was collected by vacuum
filtration and washed with ice-cold H2O (2 × 2 L). The solid cake
was again washed with ice-cold H2O (2 × 5 L) and then air-dried.
The cubane diacid was dissolved in MeOH (15 L), washed Dowex
50W-X8 ion-exchange resin [75 g; pre-washed with MeOH (500
mL)] was added and the solution was heated at reflux overnight.
The mixture was cooled to r.t., filtered, and evaporated to dryness
under reduced pressure. The crude product was then purified by
sublimation (100–120 °C/0.01 mmHg) to afford 5.
Et2O
73.1 30 (R)
72.2 11 (S)
CH2Cl2
iPrOH >99.0 19 (R)
MeCN 98.0 15 (R)
MeOH >99.0 39 (R)
19 CuCl
20 CuCl
21 CuCl
22 CuCl
65
5
MeOH
MeOH
27.9 32 (R)
23.3 31 (R)
–5
–80 MeOH
16.2
8 (R)
Yield: 563 g (78.7%); white solid; mp 161–162 °C (Lit.26 161–
162 °C).
a Determined by 1H NMR analysis of the crude reaction mixture.
b Determined by chiral HPLC using Diacel Chiralcel AD column.
1H NMR (400 MHz, CDCl3): d = 3.70 (s, 6 H, CH3), 4.24 (s, 6 H,
cubyl H).
endo-2,4-Dibromodicyclopentadiene-1,8-dione Bisethylene
Ketal (3)
4-Methoxycarbonyl-cubanecarboxylic Acid (6)
Anhydrous 1,4-dioxane (25 kg) was transferred into a 100 L reac-
tion vessel under nitrogen. To this was added cyclopentanone eth-
ylene ketal (2; 6.3 kg, 49.2 mol) and the mixture was stirred under
nitrogen. The system was cooled to ~10 °C while stirring at ~200
rpm. Anhydrous liquid bromine (25 kg, 156 mol) was added slowly
under nitrogen to the vigorously stirred reaction mixture keeping
the temperature between 10–15 °C and ensuring the bromine was
added directly into the stirred solution. Addition of bromine was
complete after ~6 h. The mixture was stirred at r.t. with nitrogen
blowing through the delivery vessel and over the reaction mixture
to ensure removal of HBr. NaOH (11 kg, 275 mol) in MeOH (55 L)
To a solution of dimethyl 1,4-cubane dicarboxylate (5; 2.498 g, 11.3
mmol) dissolved in THF (85 mL) at r.t., was added dropwise a so-
lution of NaOH (0.438 g, 10.9 mmol) dissolved in MeOH (7.1 mL).
The mixture was stirred overnight and evaporated to dryness. The
resulting white solid was dissolved in H2O (100 mL), extracted with
CHCl3 (3 × 25 mL), dried with MgSO4, filtered and evaporated to
afford the excess starting material (0.125 g, 5.5%). The aqueous
layer from the extraction was acidified with concd HCl to pH ~1,
extracted with CHCl3 (3 × 50 mL), dried with MgSO4, filtered and
Synthesis 2010, No. 1, 98–102 © Thieme Stuttgart · New York

PAPER
Synthesis of a Novel Chiral Cubane-Based Schiff Base Ligand
101
evaporated to afford 4-methoxycarbonyl cubane carboxylic acid
in EtOH (1.1 mL) at r.t. and stirred for 30 min. The mixture was
(6).
evaporated to dryness, affording an off-white solid. The solid was
collected and washed with cold EtOH under vacuum filtration,
yielding 10.
Yield: 1.70 g (73.0%); mp 181–183 °C (Lit.22a 182–183 °C).
1H NMR (400 MHz, CD3OD): d = 3.71 (s, 3 H, CH3), 4.20 (s, 6 H,
cubyl H).
Yield: 195 mg (75.0%); white solid; mp 95–97 °C.
1H NMR (400 MHz, CDCl3): d = 1.36–1.40 (m, 2 H), 1.61–1.84 (m,
6 H) 3.06–3.09 (m, 2 H), 4.21–4.32 (m, 6 H), 7.66 (s, 2 H).
4-Iodocubanecarboxylic Acid (7)
A suspension of 4-methoxycarbonyl-cubanecarboxylic acid (6;
1.94 g, 9.38 mmol) was prepared in anhydrous benzene (150 mL)
under argon. To it, iodobenzenediacetate (9.06 g, 28.1 mmol) and I2
(7.14 g, 28.1 mmol) were added and the mixture was refluxed for 7
h. The mixture was then cooled to r.t. and hexanes (75 mL) was add-
ed. The solution was washed with sat. Na2SO3 (2 × 25 mL), H2O (25
mL), and brine (25 mL), dried with MgSO4, filtered, and evaporated
to near dryness. The resulting red-brown liquid was dissolved in
THF (50 mL) and a mixture of NaOH (3.75 g, 93.8 mmol) dissolved
in MeOH (40 mL) and H2O (15 mL) was added. The mixture was
stirred overnight then the solution was evaporated to near dryness.
The residue was dissolved in H2O (25 mL), and acidified with concd
HCl to pH <1, whereby a white precipitate formed which was col-
lected under vacuum filtration, yielding 4-iodocubanecarboxylic
acid (7).
13C NMR (100 MHz, CDCl3): d = 162.0, 73.7, 59.0, 54.7, 49.9, 37.5,
32.6, 24.4.
HRMS (ESI): m/z [M + H+] calcd for C24H25N2I2: 595.0102; found:
595.01074.
General Procedure for Henry Reaction
To the solvent (1.5 mL) at r.t., 4 Å molecular sieves (20 mg), the
copper salt (0.00841 mmol), and cube ligand 10 (10 mg, 0.0168
mmol) were added and the mixture was stirred for 10 min. 4-Ni-
trobenzaldehyde (25.4 mg, 0.168mmol) and excess MeNO2 (1 mL)
were added and the reaction was stirred for 48 h. The mixture was
evaporated to near dryness, dissolved in CH2Cl2 (10 mL) and 1 M
HCl (10 mL) was added until the mixture became clear. Work-up
with CH2Cl2 (2 × 10 mL), washing with H2O (2 × 10 mL) and brine
(10 mL), drying with MgSO4, filtering and evaporating to dryness
afforded the dark-yellow glutinous product which was used directly
to determine conversion and enantioselectivity.
Yield: 1.91 g (74.3%); mp 212 °C (dec.) [Lit.22a 215 °C (dec.)].
1H NMR (400 MHz, CD3OD): d = 4.24 (m, 3 H, cubyl H), 4.36 (m,
3 H, cubyl H).
1H NMR (400 MHz, CDCl3): d = 4.49–4.60 (m, 2 H, CH2), 5.62 (dd,
J = 4.4, 8.0 Hz, 1 H, CH), 7.63 (d, J = 9.2 Hz, 2 H, Ar), 8.28 (d,
J = 9.2 Hz, 2 H, Ar).
1-Iodo-4-(hydroxymethyl)cubane (8)
4-Iodocubanecarboxylic acid (7; 676 mg, 2.46 mmol) was dissolved
in anhydrous THF (25 mL) under argon and cooled to 0 °C. To it,
borane dimethyl sulfide complex (0.78 mL, 3.91 mmol) was added
and the mixture was stirred for 20 min at 0 °C, then at r.t. for 4 h.
The reaction was quenched with H2O (20 mL) and stirred overnight.
After adding EtOAc (20 mL), the solution was washed with H2O
(2 × 15 mL) and brine (20 mL), dried with MgSO4, filtered, and
evaporated to dryness. Column chromatography (CHCl3–EtOAc,
1:1) afforded 1-iodo-4-(hydroxymethyl)cubane (8).
Acknowledgment
The authors thank the Niagara University Academic Center for
Integrated Science and the Rochester Academy of Science for their
financial support. M.L.I. would like to thank the Barbara S. Zimmer
Memorial Research Award for financial aid. R.P. would also like to
thank Dr. David Llewellyn for helpful discussions.
Yield: 438 mg (68.4%); white solid; mp 109–111 °C (Lit.22a 109–
111 °C).
1H NMR (400 MHz, CDCl3): d = 3.80 (s, 2 H, CH2), 4.07 (m, 3 H,
cubyl H), 4.23 (m, 3 H, cubyl H).
References
(1) Eaton, P. E.; Cole, T. W. Jr. J. Am. Chem. Soc. 1964, 96, 962
and 3157.
(2) (a) Service, R. F. Science 2000, 287, 564. (b)Zhang, M.-X.;
Eaton, P. E.; Gilardi, R. Angew. Chem. 2000, 39, 401.
(c) Kortus, J.; Pederson, M. R.; Richardson, S. L. Chem.
Phys. Lett. 2000, 322, 224. (d) Hrovat, D. A.; Borden, W.
T.; Eaton, P. E.; Kahr, B. J. Am. Chem. Soc. 2001, 123, 1289.
(3) Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1421.
(4) Priefer, R.; Lee, Y. J.; Barrios, F.; Wosnick, J. H.; Lebuis,
A.-M.; Farrell, P. G.; Harpp, D. N.; Sun, A.; Wu, S.; Snyder,
J. P. J. Am. Chem. Soc. 2002, 124, 5626.
1-Iodocubane-4-carboxaldehyde (9)
A stirring solution of oxalyl chloride (0.16 mL, 1.89 mmol) in an-
hydrous CH2Cl2 (4 mL) was prepared under argon at –78 °C. To it,
anhydrous DMSO (0.28 mL, 3,86 mmol) in anhydrous CH2Cl2 (4
mL) was added dropwise. After 20 min at –78 °C, 1-iodo-4-(hy-
droxymethyl)cubane (8; 403 mg, 1.56 mmol) dissolved in anhy-
drous CH2Cl2 (17 mL) under argon was added to the system
dropwise. The system was maintained at –78 °C for 1.5 h and anhy-
drous Et3N (7.02 mmol) was added via syringe. The mixture was
warmed to r.t. and quenched with H2O (15 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 15 mL) and the organic layers were
combined and washed with H2O (15 mL) and brine (15 mL), dried
with MgSO4, filtered, and evaporated to dryness. Column chroma-
tography (CH2Cl2) afforded 1-iodocubane-4-carboxaldehyde (9).
(5) Priefer, R.; Martineau, E.; Harpp, D. N. J. Sulfur Chem.
2007, 28, 529.
(6) Cassar, L.; Eaton, P. E.; Halpern, J. J. Am. Chem. Soc. 1970,
92, 6366.
(7) Cassar, L.; Eaton, P. E.; Halpern, J. J. Am. Chem. Soc. 1970,
92, 3515.
(8) Carroll, V. M.; Harpp, D. N.; Priefer, R. Tetrahedron Lett.
2008, 49, 2677.
Yield: 326 mg (80.9%); white solid; mp 106–109 °C (Lit.27 108–
110 °C).
1H NMR (400 MHz, CDCl3): d = 4.31 (m, 3 H, cubyl H), 4.53 (m,
(9) Priefer, R.; Nguyen, S.; Farrell, P. G.; Harpp, D. N.
Macromolecules 2003, 36, 5435.
(10) McGonagle, A. E.; Savage, G. P. Aust. J. Chem. 2009, 62,
145.
(11) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
(12) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418.
3 H, cubyl H), 9.76 (s, 1 H, CHO).
Cubane-Based Chiral Schiff Base Ligand (10)
trans-(1R,2R)-(–)-1,2-Cyclohexanediamine (50.3 mg, 0.438 mmol)
and 1-iodocubane-4-carboxaldehyde (9; 226 mg, 0.876 mmol) and
oven-dried 4 Å molecular sieves (0.05 g) were combined together
Synthesis 2010, No. 1, 98–102 © Thieme Stuttgart · New York

102
M. L. Ingalsbe et al.
PAPER
(21) (a) Moriarty, R. M.; Khosrowshahi, J. S.; Dalecki, T. M.
J. Chem. Soc., Chem. Commun. 1987, 675. (b) Concepcion,
J. I.; Francisco, C. G.; Freire, R.; Hernandez, R.; Salazar, J.
A.; Suarez, E. J. Org. Chem. 1986, 51, 402.
(22) (a) Priefer, R.; Farrell, P. G.; Harpp, D. N. Synthesis 2002,
2671. (b) Priefer, R.; Farrell, P. G.; Harpp, D. N.
Tetrahedron Lett. 2002, 43, 8781.
(23) Jiang, J.-J.; Shi, M. Tetrahedron: Asymmetry 2007, 18,
1376.
(24) Salmi, E. J. Chem. Ber. 1938, 71, 1803.
(25) Chapman, N. B.; Key, J. M.; Toyne, K. J. J. Org. Chem.
1970, 35, 3860.
(13) Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M.
Tetrahedron Lett. 1993, 34, 2657.
(14) Sasai, H.; Yamada, Y. M. A.; Suzuki, T.; Shibasaki, M.
Tetrahedron 1994, 50, 12313.
(15) Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. Tetrahedron
Lett. 1993, 34, 855.
(16) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J.
T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692.
(17) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. Int. Ed.
2005, 44, 3881.
(18) Lu, S. F.; Du, D. M.; Zhang, S. W.; Xu, J. Tetrahedron:
Asymmetry 2004, 15, 3433.
(19) Gan, C.; Lai, G.; Zhang, Z.; Wang, Z.; Zhou, M.-M.
Tetrahedron: Asymmetry 2006, 17, 3315.
(20) Bliese, M.; Tsanaktsidis, J. Aust. J. Chem. 1997, 50, 189.
(26) Stock, L. M.; Luh, T.-Y. J. Org. Chem. 1972, 37, 338.
(27) Eaton, P. E.; Galoppini, E.; Gilardi, R. J. Am. Chem. Soc.
1994, 116, 7588.
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