Resolution of Thiele's acid

Article abstract of DOI:10.1139/cjc-2016-0125

Thiele's acid has been resolved for the first time by diastereomeric salt formation with brucine. Determination of absolute stereochemistry was accomplished by X-ray crystallography of the corresponding diester. We anticipate that access to optically resolved Thiele's acid will stimulate its use in a diverse range of applications requiring chiral molecular clefts.

Full text of DOI:10.1139/cjc-2016-0125

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Resolution of Thiele’s Acid
Authors:
Jun Chen
Department of Chemistry, University of Victoria,
PO Box 3065 STN CSC, Victoria, BC, Canada, V8W 3V6
XuXin Sun
Department of Chemistry, University of Victoria,
PO Box 3065 STN CSC, Victoria, BC, Canada, V8W 3V6
Allen G. Oliver
Molecular Structure Facility, Department of Chemistry and Biochemistry,
University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN, USA, 46556
Jeremy E. Wulff* (author to whom correspondence should be addressed)
Department of Chemistry, University of Victoria,
PO Box 3065 STN CSC, Victoria, BC, Canada, V8W 3V6
email: wulff@uvic.ca
phone: (250) 721-7179
fax: (250) 721-7147
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Abstract:
Thiele’s acid has been resolved for the first time by diastereomeric salt formation with brucine.
Determination of absolute stereochemistry was accomplished by Xꢀray crystallography of the
corresponding diester. We anticipate that access to optically resolved Thiele’s acid will stimulate
its use in a diverse range of applications requiring chiral molecular clefts.
Keywords:
Thiele’s acid, resolution, molecular cleft, Xꢀray structure, diastereomeric salt formation.
Dedication:
This authors dedicate this article to Professor Reg Mitchell, who first taught the PI how to
interpret an NMR spectrum, and to Professor Tom Fyles, who taught undergraduates to properly
interpret stereochemistry from Fischer projections by saying: “Just think of Reg Mitchell in his
pink bow tie.”
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Introduction:
Thiele’s acid, 1, is the principal DielsꢀAlder dimer of cyclopentadiene carboxylate. Its
synthesis from metalated cyclopentadiene and carbon dioxide has been known for over a
century,1,2 although applications for 1 have been limited by the fact that the insoluble diacid can
be somewhat difficult to purify away from minor regioisomeric coꢀproducts.3
Out of a desire to broaden the scope of Thiele’s acid chemistry, and inspired by an earlier
publication from Dive and coꢀworkers,4 we recently developed an improved preparation of
Thiele’s esters 2 (Scheme 1).5 The soluble ester derivative can be isolated as a single
regioisomer, on multigram scale, following chromatographic purification. Furthermore, the
ability to use a broad range of commercially available carbonates as the electrophile facilitates
access to an equally broad range of functionalized Thiele’s ester products. When the free acid is
desired for use, the ester precursor can be easily hydrolyzed provided that one employs a
hindered alcohol solvent to minimize unwanted conjugate additions6,7 to the strained alkene.5
Insoluble. Difficult to separate
from minor regioisomers.
CO2
1. base
2. CO2
H
H
(see refs 1 & 2)
HO2C
CO2
CO2
(±)-1
CO2H
KOH
iPrOH
1. (COCl)2
2. ROH
CO2R
H
H
1. base
O
RO2C
CO2R
CO2R
2.
RO
OR
(±)-2
CO2R
3. acidification
(see refs 4 & 5)
Soluble. Easy to separate
from minor regioisomers.
Scheme 1. Synthetic approaches to Thiele’s acid and esters.
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From a structural perspective, Thiele’s acid is a molecular cleft: a rigid molecule
containing a chemically inert framework that projects functionality outward from its central core
at a wellꢀcontrolled angle.8 In this regard, 1 may be compared to the widely studied compound
Tröger’s base (Figure 1A),9,10,11 and should be similarly useful for a broad range of applications
in supramolecular, biological and materials chemistry.
Figure 1. Comparison of Thiele’s acid to Tröger’s base. A: Structures and
stereochemical assignment for each compound. B: Overlay of Tröger’s base
(gray) and Thiele’s acid methyl ester (cyan), revealing a narrower cleft angle
for the latter compound.
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In fact, Thiele’s acid supports a considerably narrower cleft angle than does Tröger’s base
(Figure 1B), which may make it complementary for applications that require modified projection
vectors. Moreover, previous work from our lab resulted in a suite of “Thieleꢀlike” scaffolds that
have a range of cleft angles spanning from Thiele’s acid itself all the way to 180° reverse turns
that could potentially be used in the design of βꢀhairpin mimics.5
Naturally, many applications that could be envisioned for these molecular clefts
(particulary for biological chemistry) would require enantiopure material. But while racemic
Tröger’s base (and analogues thereof) has been successfully resolved into its constituent
enantiomers using several different methods,12,13,14,15,16,17,18,19 the resolution of Thiele’s acid has
never been reported. We sought to remedy this deficiency by developing a resolution of 1 via
diastereomeric salt formation, and report here the results of our studies.
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Results and Discussion:
Pure racemic Thiele’s acid was prepared using our previously developed methodology
(Scheme 2).5 With (±)ꢀ1 in hand, we began attempts to form a crystaline diastereomeric salt,
using a variety of chrial amines. As illustrated in Chart 1, (S)ꢀ(–)ꢀmethylbenzylamine (7),
Lꢀtryptophan ethyl ester (8), Lꢀtyrosine hydrazide (9), and (–)ꢀcinchonidine (10) all failed to
produce diastereomerically enriched crystals, despite our evaluating a range of crystallization
solvents. Fortunately, however, the bisꢀbrucine salt of 1 formed readily and could be at least
partially enriched by crystallization from alcoholic solvents. Methanol proved superior to ethanol
and isopropanol for this purpose.
Scheme 2. Synthesis of racemic Thiele’s acid.
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Chart 1. Formation of Diastereomeric Salts from Thiele’s Acid.
a No crystals were observed from ethanol.
bAfter three successive recrystallizations from methanol.
Measurement by NMR methods of the diastereomeric ratio in the crystallized salt formed
from 1 and brucine (11) was more challenging than expected. After evaluating several different
unary and binary solvent combinations, we eventually found that an 8.3:1 mixture of benzeneꢀd6
and CDCl3 provided sufficient resolution of the Hꢀ5 proton on the Thiele acid scaffold to permit
accurate integration (Figure 2). Using this method, we determined that the solid 1•112 salt
precipitated from methanol had a diastereomeric ratio (dr) of approximately 3.6:1. Three further
recrystallizations from methanol improved the dr to >18:1. Starting from 1.1 g of racemic acid (5
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mmol), we were thereby able to obtain a respectable yield of 1.9 g (37%) diastereomerically pure
salt.
1
Figure 2. H NMR spectrum of the bisꢀbrucine salt of 1 after the first
recrystalization from methanol, recorded in 8.3:1 C6D6:CDCl3. Signals
corresponding to the two vinyl CꢀH protons are labeled. The peaks indicated by
13
the single and double asterisks correspond to a C satellite from benzene and
an aromatic CꢀH from brucine, respectively.
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The purified salt was acidified to remove the brucine, and the desired diacid was extracted
into ethyl acetate. The organic solution was dried and evaporated, affording a nearꢀquantitative
recovery of (–)ꢀ1 (Scheme 3). The overall yield of (–)ꢀThiele’s acid from the initial racemic
mixture was 72%.
Scheme 3. Resolution of Thiele’s acid.
Attempts to determine which enantiomer of 1 had been produced (either using Xꢀray
crystallography or VCD/ECD) were thwarted by the poor solubility of the compound. We were
aware, however, of a prior report describing an Xꢀray structure of the racemic methyl ester
derivative.20 Hypothesizing that we could likewise obtain an Xꢀray quality crystal of the ester as
a means of solving its absolute stereochemistry, we converted (–)ꢀ1 to (–)ꢀ2a (Scheme 4).
Gratifyingly, crystals produced from (–)ꢀ2a diffracted well, and high quality Xꢀray dffraction
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data were obtained. A copper microfocus source was used in order to reliably determine the
absolute stereochemistry despite the absence of heavy atoms in the crystal.
Scheme 4. Esterification of resolved Thiele’s acids.
Because (–)ꢀ2a crystallized in a chiral space group, Flack x and Hooft y parameters
[0.04(8) and 0.03(7), respectively] were obtained for the structure, confirming the correct
absolute stereochemistry to be that shown in Figure 3.21 These data thus allowed us to
unambiguously assign the structure of (–)ꢀ2a and (–)ꢀ1 as (3aR,4R,7S,7aR).22,23
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Figure 3. Xꢀray structure for (–)-2a. Thermal elipsoids are shown at 50%
probability.
To demonstrate access to the opposite enantiomeric series, the mother liquor containing the
bisꢀbrucine salt of (+)ꢀ1 was concentrated to a brown oil. This was acidified to provide the crude
free acid, which was then subjected to identical esterification conditions to those employed
above. Ester (+)ꢀ2a was thereby obtained without incident. The spectra for (–)ꢀ2a and (+)ꢀ2a
were identical, and the magnitudes of their optical rotations were equal within experimental error
(Scheme 4).
Conclusions:
In summary, we have achieved the optical resolution of Thiele’s acid for the first time, and
have correlated the absolute stereochemistry for each enantiomer to the sign of the optical
rotation. We hope and anticipate that the availability of these new chiral building blocks will
stimulate their use by other research groups.
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Experimental:
All reactions were performed in singleꢀneck, flameꢀdried, roundꢀbottom flasks fitted with
rubber septa under a positive pressure of argon, unless otherwise noted. Liquid reagents were
transferred via glass microsyringe. Solvents were transferred via syringe with a stainless steel
needle. Organic solutions were concentrated at 40 °C by rotary evaporation under vacuum.
Analytical thinꢀlayer chromatography (TLC) was performed using aluminum plates preꢀcoated
with silica gel (0.20 mm, 60 Å poreꢀsize, 230ꢀ400 mesh, MachereyꢀNagel) impregnated with a
fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light.
Flashꢀcolumn chromatography was performed over silica gel 60 (63ꢀ200 µM, Caledon).
Commercial solvents and reagents were used as received, except that dichloromethane was dried
before use by passage through alumina in a commercial solvent purification system (SPS).
Proton nuclear magnetic resonance spectra (1H NMR) were recorded at 300 MHz and 500
MHz at ambient temperature. Proton chemical shifts are expressed in parts per million (ppm, δ
scale) downfield from tetramethylsilane, and are referenced to residual protium in the NMR
solvent. Carbon nuclear magnetic resonance spectra (13C NMR) were recorded at 75 MHz at
ambient temperature. Carbon chemical shifts are reported in parts per million downfield from
tetramethylsilane and are referenced to the carbon resonances of the solvent. Melting points were
obtained using a MelꢀTemp II apparatus, and are uncorrected.
General Procedure for the Preparation of Racemic Thiele’s Ester.5 A flameꢀdried
round bottomed flask fitted with an ovenꢀdried condensor was charged with sodium
cyclopentadienylide solution (SigmaꢀAldrich cat. no. 304026, 2 M in THF, 1.0 equiv). To this
solution was added dimethyl carbonate in THF, at room temperature with stirring. The reaction
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mixture was heated to reflux for six h, then cooled to room temperature and concentrated in
vacuo. The resulting solid was suspended in ether and collected by vacuum filtration. The
collected solid was washed with ether until the washings became colorless and then dried in
vacuo to give intermediate salt (4) as a tanꢀbrown air sensitive solid. In a separate step, the
partiallyꢀpurified salt (1 equiv) was added to a fresh round bottomed flask, where it was
combined with iPrOH (to 0.33 M) and sulfuric acid (0.55 equiv) at room temperature with
stirring. Acidification was marked by a brown to orange color change. The solution was heated
to 50 °C overnight. The reaction mixture was concentrated in vacuo and the resulting oil was
dissolved in toluene, and loaded onto a silica gel column. Elution with hexanesꢀethyl acetate
provided the desired Thiele's ester, (±)ꢀ2a. Spectral data were identical to those reported
previously,5 while yields were consistently in the range of 60–65%.
General Procedure for the Preparation of Racemic Thiele’s Acid.5 To a solution of
Thiele’s ester in iPrOH was added 10% KOH solution (10 mL / g of Thiele’s ester) dropwise.
After 5 h, iPrOH was removed in vacuo. The mixture was acidified to pH=1 by the addition of
2M HCl, then extracted twice with ethyl acetate. The combined organic layers were dried over
MgSO4 and concentrated in vacuo to afford Thiele’s acid, (±)ꢀ1, as a white powder without
further purification. Spectral data were identical to those reported previously,5 while yields were
consistently >90%.
Resolution of Thiele’s acid. A 100 mL round bottomed flask was charged with racemic
Thiele’s acid (1, 1.10 g, 5.00 mmol) and methanol (20 mL). The suspension was warmed to 80
°C to provide a clear solution. To this hot solution was added brucine (11, 3.94 g, 10.0 mmol).
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An additional 10 mL of methanol was added to facilitate complete dissolution. The resulting
solution was filtered to remove a small amount of residual insolubles, and then cooled in a
freezer at 0 °C. Brown crystals of crude 1•112 were formed within 2 h. NMR analysis of the
crude salt revealed a ~3.6:1 ratio of diastereomers. This ratio varied only slightly across multiple
trials. The crude salt was filtered from the mother liquor, added to 25 mL of methanol, and
warmed until all of the solid dissolved. The solution was then cooled in the freezer. Crystals of
purified 1•112 were formed within 2 h. This recrystallization was repeated twice more, and the
final, thrice recrystallized solid was obtained by suction filtration to provide 1.86 g (1.84 mmol,
37%) of 1•112 as a pale brown solid after drying in vacuo. MP = 147 °C (dec).
1H NMR (500 MHz, CDCl3: C6D6 = 1:8.3) δ 8.22 (s, 2H), 7.07 (d, J = 2.9 Hz, 0.95H, Major),
7.02 (d, J = 2.9 Hz, 0.05H, Minor), 6.90 (s, 2H), 6.63 (s, 1H), 5.40 (s, 2H), 4.16 (s, 2H), 3.74
(dd, J = 14.0, 7.1 Hz, 2H), 3.69 (d, J = 14.4, 2H), 3.58ꢀ3.64 (m, 8H), 3.53ꢀ3.57 (m, 8H), 3.47
(dd, J = 13.5, 6.0 Hz, 2H), 3.12ꢀ3.22 (m, 3H), 3.01ꢀ3.09 (m, 2H), 2.81 (s, 1H), 2.66ꢀ2.77 (m,
3H), 2.61 (dd, J = 17.5, 2.2 Hz, 2H), 2.35ꢀ2.46 (m, 4H), 2.32 (s, 2H), 2.09 (d, J = 14.7 Hz, 2H),
1.89 (dt, J = 13.0, 7.9 Hz, 2H), 1.60 (d, J = 8.1 Hz, 1H), 1.42 (dd, J = 12.8, 5.9 Hz, 2H), 1.10 (d,
J = 8.4 Hz, 1H), 0.97 (d, J = 14.4 Hz, 2H), 0.49 (d, J = 10.3 Hz, 2H); 13C NMR (75 MHz,
CDCl3:C6D6 = 1:8.3) δ 171.3, 169.9, 168.7, 150.8, 147.3, 144.6, 142.4, 141.4, 137.9, 136.9,
130.3, 122.3, 107.3, 101.9, 77.7, 64.2, 60.1, 59.9, 54.6, 52.2, 52.1, 50.4, 50.3, 48.9, 47.7, 47.6,
42.6, 41.8, 41.6, 34.1, 31.1, 26.0; IR (cmꢀ1, film) 3400, 2939, 1641, 1602, 1555, 1501, 1448,
1398, 1198, 987, 847; HRMS (ESI) calcd for [1•11+H]+ C35H39N2O8 615.2706, found 615.2702.
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The isolated salt was added to 30 mL of 10% aqueous HCl, and extracted with 60 mL of ethyl
acetate three times. The combined organic layers were dried over MgSO4. After removal of the
solvent in vacuo, (–)ꢀThiele’s acid was isolated as a light brown solid (398 mg, 1.81 mmol, 98%
from the intermediate salt; 72% recovery of (–)ꢀ1 from the initial racemic mixture). Spectral data
were consistent with the racemic compound that has been described previously in the literature.5
[α]D28.6 = –228 deg mL dmꢀ1 gꢀ1 (c = 0.25, 1 M KOH solution). MP = 180–182 °C.
Esterification of Optically Active Thiele’s acids. To a solution of (–)ꢀ1 (220 mg; 1.00
mmol) in CH2Cl2 (20 mL) was added DMAP (24 mg, 0.2 mmol) and MeOH (0.4 mL, 10 mmol).
DCC (460 mg, 2.2 mmol) was then added at 0 °C. The mixture was allowed to warm to room
temperature, and was stirred overnight. The next day, the product mixture was washed with 1M
HCl and saturated NaHCO3, dried over MgSO4, and concentrated in vacuo. Chromatography
(hexanesꢀethyl acetate, 4:1) afforded (–)ꢀThiele’s ester 2a as a white solid (200 mg, 81%).
Spectral data were consistent with the racemic compound that has been described previously in
the literature.5 [α]D25 = –216 deg mL dmꢀ1 gꢀ1 (c = 0.25, ethanol solution). MP = 87–89 °C.
(+)ꢀThiele’s ester 2a was prepared by the same procedure, beginning from crude (+)ꢀ1 recovered
from the crystalization mother liquor. Spectral data were identical, but a lower melting point
(51–53 °C) was attributed to the presence of minor impurities. [α]D24 = +269 deg mL dmꢀ1 gꢀ1 (c
= 0.25, ethanol solution).
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Supplementary Material:
Supplementary material is available with the article through the journal Web site at
http://nrcresearchpress.com/doi/suppl/xx.xxxx/cjcꢀ2016ꢀxxxx. These data include NMR spectra
for both Thiele’s acid and the corresponding brucine salt, as well as Xꢀray data for (–)ꢀ2a.21
Acknowledgements:
We are grateful to the Cancer Research Society of Canada for operating funds, and to the
Michael Smith Foundation for Health Research and the Canada Research Chairs program for
salary support (to J. W.), as well as incentive funds used to support this research. We would also
like to thank the Office of the Vice President of Research at the University of Notre Dame for
financial support for the purchase of the copper microfocus source used herein.
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