DOI: 10.1002/chem.201400296 Communication
& Asymmetric Synthesis Coulomb Explosion Imaged Cryptochiral (R,R)-2,3- Dideuterooxirane: Unambiguous Access to the Absolute Configuration of (+)-Glyceraldehyde Kerstin Zawatzky,[a] Philipp Herwig,[b] Manfred Grieser,[b] Oded Heber,[c] Brandon Jordon- Thaden,[b] Claude Krantz,[b] Oldrˇich Novotny´,[b, d] Roland Repnow,[b] Volker Schurig,[e] Dirk Schwalm,[b] Zeev Vager,[c] Andreas Wolf,[b] Holger Kreckel,[b] and Oliver Trapp*[a]
Abstract: The absolute configuration of (R,R)-2,3-dideu- terooxirane, which has been independently determined using Coulomb explosion imaging, has been unambigu- ously chemically correlated with the stereochemical key reference (+)-glyceraldehyde. This puts the absolute con- figuration of d(+)-glyceraldehyde on firm experimental Figure 1. Rational molecular design of (R,R)-2,3-dideuterooxirane derived grounds. from (+)-glyceraldehyde to determine the absolute configuration by Cou- lomb explosion imaging.
More than 150 years after the discovery of molecular handed- image because the signal intensities only depend on the lattice ness by Louis Pasteur, the determination of absolute configura- planes, but not on the spatial orientation. In 1951 Bijvoet intro- tions is still a non-trivial problem.[1] The knowledge of the ab- duced anomalous single-crystal XRD to determine the absolute solute configuration is of central importance, when looking at configuration of rubidium sodium (+)-tartrate dihydrate crys- processes such as the lock-and-key relationship or structure- tals.[7,8] Here, the anomalous dispersion effect caused by specific targeting in drug development. The configurational a heavy atom in a crystal of an optically active compound is standard of chiral molecules is dextrorotatory (+)-glyceralde- used to determine its absolute configuration. Bijvoet assigned hyde (+)-1[2] (Figure 1), which originally was arbitrarily defined the absolute configuration of rubidium sodium (+)-tartrate to by Emil Fischer as having the d-configuration.[3,4] Already at be (R,R), which matched Fischer’s assignment of (+)-glyceralde- the beginning of the 20th century this triggered many discus- hyde d-1, based on a chemical correlation of Wohl and sions,[5] but even today, configurations of amino acids, sugars, Momber in1917.[9] Despite the fact that Bijvoet’s technique and other natural products are based on his intuitive assign- sometimes leads to false assignments[10,11] mainly due to very ment.[6] Many attempts were made to prove the validity of small intensity differences between enantiomeric forms[12] and Fischer’s definition. Single-crystal X-ray diffraction crystallogra- wrong assignment of the space group, anomalous XRD is still phy (XRD) cannot distinguish between image and mirror the method of choice to determine absolute configurations of crystalline chiral compounds.[13,14] In recent years vibrational [a] Dipl.-Chem. K. Zawatzky, Prof. Dr. O. Trapp circular dichroism (VCD)[15–17] and vibrational Raman optical ac- Ruprecht-Karls Universit t Heidelberg, Organisch-Chemisches Institut tivity (ROA)[18] in combination with quantum-chemical calcula- Im Neuenheimer Feld 270, 69120 Heidelberg (Germany) Fax: (+49) 6221-544904 tions have evolved into mature tools to determine absolute [19,20] E-mail: [email protected] configurations. Limitations are the applicable wavelength [b] Dipl.-Phys. P. Herwig, M. Grieser, Dr. B. Jordon-Thaden, Dr. C. Krantz, range and the theoretical treatment of highly flexible mole- Dr. O. Novotny´, Dr. R. Repnow, Prof. Dr. D. Schwalm, Prof. Dr. A. Wolf, cules.[21] Dr. H. Kreckel New techniques and approaches to determine absolute con- Max-Planck-Institut f r Kernphysik, 69117 Heidelberg (Germany) figurations emerged very recently putting this research area [c] Dr. O. Heber, Prof. Dr. Z. Vager [11,20,22–24] Weizmann Institute, Department of Particle Physics and Astrophysics back into focus. [25] 76100 Rehovot (Israel) Berger and Schçffler et al. reported an approach using [d] Dr. O. Novotny´ cold target recoil ion momentum spectroscopy (COLTRIMS) Columbia University, Columbia Astrophysics Laboratory after laser-induced Coulomb explosion to image both enantio- New York, NY 10027 (USA) mers of racemic mixtures of bromochlorofluoromethane [e] Prof. Dr. V. Schurig (CHBrClF) and isotopically chiral bromodichloromethane Eberhard Karls Universit t T bingen, Institut f r Organische Chemie 37 35 72076 T bingen (Germany) (CHBr Cl Cl). In these experiments, the Coulomb explosion of Supporting information for this article is available on the WWW under molecules in a supersonic gas jet is triggered by 40 fs long http://dx.doi.org/10.1002/chem.201400296. laser pulses to induce multiple ionization by successive remov-
Chem. Eur. J. 2014, 20, 5555 – 5558 5555 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Communication al of the valence electrons. The atoms are detected by a posi- tion- and time-sensitive multichannel plate detector (MCP) giving the structure of both enantiomers. However, this ap- proach can only be applied to molecules of heavier nuclei, which can be considered static to some extent. Besides Bijvoet’s assignment[7] of the absolute configuration of rubidium sodium (+)-tartrate a direct and theory independ- ent method to determine absolute configurations and con- necting it with the configurational standard does not exist to date. A crystal structure of (+)- or (À)-glyceraldehyde has not yet been described, because in contrast to racemic glyceralde- hyde the enantiomerically pure compounds form only highly viscous liquids. We are now able to show the unambiguous chemical corre- lation of the absolute configuration of cryptochiral (R,R)-2,3-di- deuterooxirane determined by Coulomb explosion imaging[26] with the stereochemical key reference (+)-glyceraldehyde, put- Scheme 1. Synthesis of (R,R)-2,3-dideuterooxirane via the key intermediate ting the absolute configuration of (+)-glyceraldehyde on firm 2,3-dideutero-((2S,3S)-3-(triphenylsilyl)oxirane)-2-carbaldehyde (S,S)-6. experimental grounds. We refrained from using (+)-glyceraldehyde in the Coulomb Doering oxidation[32–34] using dimethyl sulfoxide (DMSO) and explosion imaging experiment, due to its limited stereointegri- pyridine sulfur trioxide complex as oxidant in excellent yield ty and the tendency to fragment during the required ioniza- (86.2%) under mild reaction conditions. tion process. A serendipity of this synthesis is that key intermediate (S,S)-6 Therefore, trans-2,3-dideuterooxirane 2 was selected as can be directly correlated with glyceraldehyde, which makes target molecule for the Coulomb explosion imaging experi- unambiguous assignment of the absolute configuration feasi- ment, because it can be directly derived from glyceraldehyde ble. 1 (Figure 1) by formation of an oxirane ring from the two hy- Decarbonylation[35] of (S,S)-6 by stoichiometric reaction with droxyl groups. This constrains the configuration of stereogenic the Wilkinson catalyst RhCl(PPh3)3 gave 2,3-dideutero-(2S,3R)-2- carbon C2 of 1 and reduces the risk of racemization. Substitut- (triphenylsilyl)oxirane (2S,3R)-7 in 86.6 % yield under retention ing hydrogen against deuterium and the carbaldehyde group of the configuration at C2. (R,R)-2 was then released as a gas against hydrogen conserves the configuration and reduces the by removal of the triphenylsilyl group under retention of the molecular weight, which makes acceleration to high speed configuration at C2 by treating with tetraethylammonium fluo- easier. ride in DMSO in 90.7 % yield (7.6 g). This corresponds to an Introducing a second deuterium atom offered the advantage overall yield of 39 % compared to only 10 % reported by [28] that the chiral information is doubled by the resulting C2 sym- Schwab et al. metry, which simplifies the assignment of the absolute config- Very recently, we reported the first assignment of the abso- uration, because even in a four atom event where only two lute configuration of enantiopure (R,R)-2,3-dideuterooxirane carbon atoms, the oxygen atom and one deuterium atom are (R,R)-2[26] by direct visualization of the sense of chirality using detected, assignment of the configuration is still possible. Fur- foil-induced Coulomb explosion imaging (CEI).[36] In this experi- thermore the result is not jeopardized by unintended racemi- ment (Figure 2) a small sample of enantiopure trans-2,3-dideu- zation, which would be detected by the formation of the achi- terooxirane is ionized, accelerated by 2.0 MeV and mass-select- ral cis-isomer. ed. The valence electrons are stripped off within 1 fs by pass- To obtain (R,R)-2 and its precursors as reference material we ing through an ultrathin diamond foil. optimized the synthesis[27,28] in four pivotal steps, including the The Coulomb explosion is triggered which enlarges the mo- trans deuteration, epoxidation, oxidation to the aldehyde, and lecular structure and all relevant atoms are detected by time- deprotection of the silyl group, to improve the overall yield and-position sensitive detection, resulting in a 3D image of the and to achieve a high enantiomeric purity and deuteration molecule (Figure 2). degree (Scheme 1). The configuration of the precursor (S,S)-6 is synthetically di- Triphenylsilyl propargyl alcohol 3 was trans-deuterated by rectly connected with (R,R)-2,3-dideuterooxirane (R,R)-2 [29] reaction with LiAlD4 and quenching with D2O. For the enan- (Scheme 1). However, the correlation with (+)-glyceraldehyde tioselective epoxidation of E-4 a semi-catalytic protocol of the (+)-1 proved to be more challenging as expected, because Sharpless procedure[30,31] was very well suited using 10 mol% except for chiroptical characterization methods there are no TiIV isopropoxide and (+)-diisopropyl tartrate, which gave 2,3- enantioselective separation methods known to directly assign dideutero-((2S,3S)-3-triphenylsilyl)oxiran-2-yl)methanol (S,S)-5 in the configuration by comparison of the elution order of the excellent yield (94 %) and enantiomeric purity (e.r.97.5 %). enantiomers. Oxidation of (S,S)-5 to 2,3-dideutero-((2S,3S)-3-(triphenyl- Therefore we developed a synthetic strategy to convert silyl)oxirane)-2-carbaldehyde (S,S)-6 was achieved by a Parikh– (S,S)-6 and (+)-glyceraldehyde (+)-1 into the same derivative
Chem. Eur. J. 2014, 20, 5555 – 5558 www.chemeurj.org 5556 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Communication
Stereochemical correlation was achieved by enantioselective GC-MS measurements of 2,3-O-isopropylideneglyceraldehydes obtained from racemic glyceraldehyde d,l-1 (Figure 3a) and (+)-glyceraldehyde (+)-1 (Figure 3b), respectively, and
[D2]-(2R,3S)-8 (Figure 3c) with an excellent separation factor a of 1.15.
Figure 2. Schematic experimental setup to determine the absolute configu- ration of enantiopure trans-2,3-dideuterooxirane by foil-induced Coulomb Figure 3. GC-MS traces to assign the elution order of the enantiomers of explosion imaging (CEI). 2,3-O-isopropylideneglyceraldehydes 8 obtained from a) racemic d,l-glycer- aldehyde, b) (+)-glyceraldehyde (+)-1, and c) and d) 2,3-dideutero-((2S,3S)-3- (triphenylsilyl)oxirane)-2-carbaldehyde (S,S)-6. c) Represents the mass trace + at m/z 117 [[D2]MÀCH3] of the dideuterated compound [D2]-(2R,3S)-8 and suitable to be analyzed by enantioselective gas chromatogra- + d) the mass trace at m/z 116 [[D]MÀCH3] of the monodeuterated racemic phy (GC). We first transformed racemic glyceraldehyde d,l- compound [D]-(2RS)-8. Separation conditions: 25 m Chirasil-b-Dex[39] 1 and (+)-glyceraldehyde (+)-1 by ketalization with 2,2-dime- (0.25 mm I.D., 250 nm film thickness), isothermal at 808C, 80 kPa, He as carri- thoxypropane, catalyzed by p-toluenesulfonic acid into the cor- er gas. responding 2,3-O-isopropylideneglyceraldehyde 8, respectively (Scheme 2a).
Epoxyaldehydes can be regioselectively transformed into Apparently, the measured enantiomeric ratio of [D2]-(2R,3S)- their corresponding ketals under retention of the configuration 8 was diminished during the regioselective ring opening and at C2 and inversion of the configuration at C3 by acetone ketalization of the oxirane moiety. Careful interpretation of the [37,38] under catalysis of TiCl4 as Lewis acid. We converted (S,S)-6 electron impact mass spectra of the peaks of the enantiomers into (2S,3R)-2,3-dideutero-3-(triphenylsilyl)-2,3-O-isopropyli- of [D2]-(2R,3S)-8 proved that a proton-deuteron exchange oc- dene-glyceraldehyde [D2]-(2S,3R)-9, which was consecutively curred to about 30%. The electron impact mass spectra show desilylated using tetrabutylammonium fluoride (TBAF) giving that a methyl group of the ketals is abstracted resulting in + (2R,3S)-2,3-dideutero-2,3-O-isopropylideneglyceraldehyde [D2]- a base peak of [MÀ15] at m/z 117 for the dideuterated ketal
(2R,3S)-8 (Scheme 2b). [D2]-(2R,3S)-8 and m/z 116 for the monodeuterated ketal [D]- (2RS,3S)-8. Here, the isotopic labeling allows us to distinguish the reaction product formed by regioselectively ring-opened oxirane (m/z 117; Figure 3c) and ring-opening under keto–enol tautomerization of the adjacent carbaldehyde group (m/z 116 ; Figure 3d), which is accompanied by proton–deuteron ex- change at C2.
It has to be pointed out, that some of the [D2]-(2R,3S)-8 is subjected to a deuteron-deuteron exchange at C2 with a lower probability. This means that the peak of the dideuterated prod- uct with an m/z of 117 is the expected major enantiomer of
[D2]-(2R,3S)-8. The chromatograms show that the ketal derived from
(+)-glyceraldehyde is co-eluted with isotopically labeled [D2]- (2R,3S)-8 obtained from (S,S)-6, which is stereochemically con- nected with (R,R)-2. We have unambiguously connected the sense of chirality of (R,R)-2,3-dideuterooxirane (R,R)-2, which has been determined by direct visualization employing Coulomb explosion imaging, via the synthetically related precursor 2,3-dideutero-((2S,3S)-3- (triphenyl-silyl)oxirane)-2-carbaldehyde (S,S)-6 with (+)-glyceral- dehyde by a careful molecular design as a self-consistent path- Scheme 2. Ketalization of glyceraldehyde 1 and 2,3-dideutero-((2S,3S)-3-(tri- phenylsilyl)oxirane)-2-carbaldehyde (S,S)-6 and transformation into the same way. We are able to prove independently, that Fischer’s assign- derivative for chemical correlation. ment of (+)-glyceraldehyde as D(+)-glyceraldehyde was cor-
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