Enantiopure 2,9-Dideuterodecane – Preparation and Proof of Enantiopurity

Article abstract of DOI:10.1002/ejoc.202100360

(R,R)- and (S,S)-(2,9-²H₂)-n-Decane were prepared regio- and stereospecifically in 25–26 % yield over five steps from commercially available enantiopure (R)- and (S)-propylene oxide, respectively. The synthetic procedure involved nucleophilic displacement of (R)- and (S)-4-toluenesulfonic acid 1-methyl-4-pentenyl ester with LiAlD₄ to furnish the respective (5-²H)-1-hexenes. Subsequent olefin metathesis and reduction of the double bond furnished the title compounds. The optical purity of (R,R)- and (S,S)-(2,9-²H₂)-n-decane could not be determined by chromatography or polarimetry. Therefore, (R,R)- and (R,S)-(5-²H)-3-hydroxy-2-hexanone were prepared from their respective hexenes by Wacker oxidation, followed by enantioselective α-hydroxylation. The enantiopurity could then be determined by NMR spectroscopy because the stereospecifically deuterated hydroxyketones showed separated signals for the subterminal carbon atom (C-5) in the ¹³C NMR spectrum.

Full text of DOI:10.1002/ejoc.202100360

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Enantiopure 2,9-Dideuterodecane – Preparation and Proof of
Enantiopurity
Authors: Nico Mitschke, Gülsera Eruçar, Miriam H. Fsadni, Amy
R. Roberts, Majid M. Sadeghi, Bernard T. Golding, Jens
Christoffers, and Heinz Wilkes
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
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to ensure accuracy of information. The authors are responsible for the
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100360
Link to VoR: https://doi.org/10.1002/ejoc.202100360
01/2020

10.1002/ejoc.202100360
European Journal of Organic Chemistry
Enantiopure 2,9-Dideuterodecane – Preparation and Proof of Enantiopurity
Nico Mitschke,[a,b] Gülsera Eruçar,[a] Miriam H. Fsadni,[c] Amy R. Roberts,[c] Majid M.
Sadeghi,[c] Bernard T. Golding,*[c] Jens Christoffers,*[a] Heinz Wilkes*[b]
In memoriam Prof. Wittko Francke
[a] N. Mitschke, G. Eruçar, Prof. Dr. J. Christoffers
Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg (Germany)
E-mail: jens.christoffers@uol.de
Homepage: https://uol.de/chemie/oc-christoffers
[b] N. Mitschke, Prof. Dr. H. Wilkes
Institut für Chemie und Biologie des Meeres (ICBM), Carl von Ossietzky
Universität Oldenburg, 26111 Oldenburg (Germany)
E-mail: heinz.wilkes@uni-oldenburg.de
Homepage: https://uol.de/icbm/ogc/
[c] M. H. Fsadni, Dr. A. R. Roberts, Prof. Dr. M. M. Sadeghi, Prof. Dr. B. T. Golding
School of Natural & Environmental Sciences, Bedson Building; Newcastle
University, NE1 7RU Newcastle upon Tyne (UK)
E-mail: bernard.golding@ncl.ac.uk
Homepage:
https://www.ncl.ac.uk/nes/staff/profile/bernardgolding.html#background
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Abstract: (R,R)- and (S,S)-(2,9-2H2)-n-decane were prepared regio- and
stereospecifically in 25-26% yield over five steps from commercially available
enantiopure (R)- and (S)-propylene oxide, respectively. The synthetic procedure
involved nucleophilic displacement of (R)- and (S)-4-toluenesulfonic acid 1-methyl-4-
pentenyl ester with LiAlD4 to furnish the respective (5-2H)-1-hexenes. Subsequent
olefin metathesis and reduction of the double bond furnished the title compounds. The
optical purity of (R,R)- and (S,S)-(2,9-2H2)-n-decanes could not be determined by
chromatography or polarimetry. Therefore, (R,R)- and (R,S)-(5-2H)-3-hydroxy-2-
hexanones were prepared from their respective hexenes by Wacker oxidation,
followed by enantioselective α-hydroxylation. The enantiopurity could then be
determined by NMR spectroscopy because the stereospecifically deuterated
hydroxyketones showed separated signals for the subterminal carbon atom C-5 in the
13C NMR spectrum.
Graphical Abstract: Optically active (S,S)-(2,9-2H2)-n-decane was prepared in five
steps from (R)-propylene oxide. Its optical purity was determined at the stage of (S)-
(5-2H2)-1-hexene, being an intermediate of the synthetic approach, by NMR
spectroscopy after Wacker oxidation and enantioselective α-hydroxylation. (R,R)-(2,9-
2H2)-n-decane was prepared analogously.
Keywords: Hydrocarbons, Deuteration, Biodegradation, Chirality
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Introduction
With the discovery of deuterium in 1932[1] the question arose whether optically active
compounds could be prepared whose activity is only based on the differences between
deuterium and hydrogen.[2] Two types of compounds could meet this requirement:
those that feature a hydrogen and a deuterium atom attached to the same carbon
atom, or those in that the isotopically different substituents are not attached directly to
a stereocenter.[2]
Several early attempts were made to prepare optically active compounds chiral solely
by virtue of deuteration.[2] Notably, already in 1936 Clemo and McQuillen reported the
resolution of racemic 1-phenyl-1-(phenyl-d5)ethan-1-amine by multiple fractional
crystallizations of the tartrate salt giving enantiomers with finite optical rotations.[3,4]
Although this claim was meticulously questioned,[5] it cannot be dismissed that a skillful
experimentalist could not achieve such a resolution. The first clear example of an
optically active deuterium compound per se was reported in 1949 by Alexander and
Pinkus, who reduced (+)-trans-2-menthene (Scheme 1, 1) with D2 in the presence of
Raney nickel to yield the optically active (–)-2,3-dideutero-trans-menthane (Scheme 1,
2).[6]
Scheme 1. Preparation of (–)-2,3-dideutero-trans-menthane (2) from (+)-trans-2-
menthene (1) by Alexander and Pinkus.[6] Reagents: (a) D2, Raney-Ni. The main
diastereoisomer of the product is tentatively assigned according to Verbit.[2]
The first undisputed example of an optically active deuterium compound with only one
stereocenter was reported by Eliel who prepared (R)-(1-2H)ethylbenzene [(R)-3] by
reduction of α‐chloroethylbenzene with LiAlD4.[7] Today, the descriptor optically active
deuterium compound not only refers to deuterium compounds with measurable optical
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activity, but also to deuterated compounds whose chirality exclusively depends on the
differences between hydrogen and deuterium.[2]
Deuterium labeling has become one of the most important and powerful tools in the
investigation of reaction mechanisms. As emphasized in several reviews, deuterium-
labeled compounds are invaluable for the elucidation of enzymatic reaction
mechanisms.[8–10] For mechanistic studies, the regio- and stereospecific incorporation
of deuterium into an organic compound is often required. Measuring the optical rotation
of deuterated optical isomers is challenging due to their often-low values, which may
fall below the detection limit, and their associated large errors.
Therefore, other approaches for determining the enantiomeric excess with sufficient
precision are required. One major strategy for the determination of the enantiomeric
excess of optically active deuterated compounds is NMR spectroscopy. While some
approaches make use of chiral shift reagents or chiral solvating agents, others pursue
the strategy of chiral derivatization.[11,12] Recently, the enantiopurity of (S)-(1-
2H)ethylbenzene [(S)-3] was determined by NMR spectroscopy after chiral
derivatization with (R)‐α‐phenethylamine (Scheme 2).[13]
Scheme 2. Synthesis of bis-sulfonamide 5 from (1-2H)ethylbenzene (S)-3. Reagents:
(a) ClSO3H, (b) (R)-PhCH(NH2)Me.[13]
As shown for the anaerobic degradation of n-hexane (6a) by the denitrifying
betaproteobacterium Aromatoleum aromaticum HxN1, stereospecific deuterium-
labeling can provide stereochemical information and profound mechanistic insights into
enzyme mechanisms.[14] Activation of n-hexane (6a) occurs at the subterminal carbon
atom (C-2) by the addition to fumarate (7) via a radical mechanism to furnish (1-
methylpentyl)succinate (MPS, 8b).[15] This reaction is catalyzed by the enzyme (1-
methylpentyl)succinate synthase (Mas).[16] Stereospecifically labeled 2,5-dideuterated
hexanes (R,R)- and (S,S)-6b (Figure 1) were used to demonstrate that the formation
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of MPS (8b) proceeds with inversion at C-2 and that exclusively the pro-S hydrogen
atom is abstracted from n-hexane (6a).[14] Based on these findings, a concerted
reaction mechanism for the formation of MPS (8b) was proposed that would avoid the
formation of a reactive 2-hexyl radical (Scheme 3). By combining incubation
experiments with deuterium-labeled and non-labeled substrates with gas
chromatographic, mass spectrometric and EPR analyses, the entire pathway of n-
hexane (6a) degradation by strain HxN1 has been elucidated.[15,17,18]
Scheme 3: Proposed stereochemical course for the activation of n-hexane (6a) in
strain HxN1 (modified from Jarling et al.).[14]
The mesophilic denitrifying betaproteobacterium strain OcN1 and the thermophilic
sulfate-reducing deltaproteobacterium strain TD3 activate C8-C12 and C6-C16 alkanes,
respectively, in an analogous manner to strain HxN1 by addition of C-2 of the alkane
to fumarate yielding the corresponding alkylsuccinic acid derivatives.[19–22] To obtain
mechanistic insights into the initial activation reactions of n-decane by strains OcN1
and TD3, stereospecifically 2,9-dideuterated n-decanes (R,R)- and (S,S)-9a are ideal
model substrates. We speculate, based on evolutionary considerations, that addition
of any n-alkane to fumarate by the (1-methylalkyl)succinate synthases in different
anaerobic bacteria will show the same stereochemistry, although this still has to be
proven.
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Figure 1. Model substrates for mechanistic investigations into the initial activation
reaction in anaerobic degradation of n-alkanes: (A) 6 for n-hexane degradation by
bacterial strain HxN1; (B) 9a for n-decane degradation by bacterial strains OcN1 and
TD3.
A literature survey yielded only examples of vicinal dideuterated n-decanes that were
prepared by catalytic deuteration of an alkene precursor as shown, for example, by
Morandi and Jensen.[23] However, to the best of our knowledge no access to the
stereospecifically 2,9-dideuterated decanes (R,R)- and (S,S)-9a has been reported. As
outlined above, the determination of the enantiomeric excess of deuterated optically
active compounds is often difficult. Therefore, the objective of this study was the
preparation of 2,9-dideuterated n-decanes (R,R)- and (S,S)-9a, as well as the
development of a facile, reliable method for the determination of their enantiopurity.
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Results and Discussion
Our retrosynthetic analysis of racemic and enantiopure (2,9-2H2)-n-decanes, rac-,
(R,R)- and (S,S)-9a, is based upon olefin metathesis of hexene 13a and hydrogenation
of the metathesis product 10a (Scheme 4). The preparation of hexene 13a may be
realised by reduction of tosylate 12 with LiAlD4, which is expected to proceed with
inversion of the stereocenter at C-5.[14,24] The tosylate 12 can be prepared from the
corresponding alcohol 11. This, in turn, is easily obtained from commercially available
racemic or enantiopure propylene oxides rac-, (R)- and (S)-14, by epoxide opening
with an allylcuprate.
Scheme 4. Retrosynthetic analysis of (2,9-2H2)-n-decane (9a).
Since the stereocenter of deuterated hexene 13a is not assumed to be affected by the
metathesis or hydrogenation reactions, the enantiomeric excess of the final deuterated
decane 9a can be determined at the stage of this compound. We envisaged that
Wacker oxidation of hexene 13a to hexanone 16a followed by enantioselective α-
hydroxylation to hydroxyketone (R)-17a would lead to diastereotopic splitting of the
protons at C-5. The enantiomeric excess could then be determined by integration of
the 1H or 2H NMR signals. Prior to adopting this approach we synthesized (2,9-2H2)-n-
decane 9a by metathesis of the (R)- and (S)-enantiomers of the O-benzyl ether of
compound 11, followed by reduction to 2,9-dihydroxydecane, conversion to the di-
tosylate and reduction with LiAlD4 or LiEt3BD (see Scheme S1, Supplementary
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information). However, this method does not enable the optical purity of either
enantiomer of (2,9-2H2)-n-decane 9a to be established.
To test our strategy, the synthesis was initially carried out without the incorporation of
deuterium using racemic propylene oxide (rac-14) as the starting material (Scheme 5).
Scheme 5. Synthesis of non-deuterated n-decane (9b). Reagents and conditions: (a)
i: 1.4 equiv. C3H5MgBr, 1.4 equiv. CuCN, dry Et2O, –78 °C, 17 h; ii: 0.2 equiv. TEMPO,
0.2 equiv. Bu4NCl, 2.6 equiv. NCS, CH2Cl2/aq. NaHCO3/aq. K2CO3, 23 °C, 1.5 h; (b)
3.5 equiv. TosCl, dry pyridine/dry CH2Cl2 1:1.3, 0 °C to 23 °C, 16 h; (c) 1.5 equiv.
LiAlH4, tetraglyme, 0 °C to 23 °C, 4 h; (d) 1 mol% Grubbs I catalyst, dry CH2Cl2, 23 °C,
68 h; (e) 0.1 equiv. 10 wt% Pd/C, H2 (1 atm), n-pentane, 23 °C, 20 h.
The conversion of propylene oxide (rac-14) with diallylcuprate prepared from catalytic
amounts of copper iodide and allylmagnesium bromide led to a mixture of the primary
alcohol 15 and the secondary alcohol rac-11 (Scheme 6).[25] After some
experimentation, the use of stoichiometric amounts of copper cyanide was found to
improve the yield of the secondary alcohol rac-11 up to 95% (established by 1H NMR).
However, the primary alcohol 15 was still formed in 5% yield as the undesired by-
product. Unfortunately, alcohols rac-11 and 15 were not separable by column
chromatography or distillation.
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Scheme 6. Product mixture of secondary alcohol rac-11 and primary alcohol 15, from
the ring-opening reaction of propylene oxide rac-14 with an allylcuprate.
Therefore, the mixture of alcohols rac-11 and 15 was submitted to selective TEMPO
oxidation of the primary alcohol 15 to furnish 2-methyl-4-pentenal,[26] which was easily
removed by column chromatography (Scheme 5, step a). The secondary alcohol rac-
11 was subsequently converted into its tosylate rac-12, using tosyl chloride (step b).[27]
The tosylate rac-12 in tetraglyme was reduced using LiAlH4 to give 1-hexene (13b,
step c), which was continuously distilled from the reaction flask by vacuum distillation.
By attaching a cold trap (–196 °C) to the distillation apparatus, 1-hexene 13a was
isolated in 88–94% yield in later attempts. The olefin metathesis was performed using
Grubbs I catalyst (step d) and decene 10b was isolated by vacuum distillation using a
cold trap (–196 °C).[28] Hydrogenation with Pd/C catalyst and 1 atm of hydrogen
furnished the targeted n-decane (9b, step e).
The route developed for n-decane (9b) was modified for the synthesis of 2,9-
dideuterated n-decane rac-9a. The tosylate rac-12 was reduced with LiAlD4 to give 2,9-
dideuterated 5-decene rac-10a in 33% yield over four steps (Scheme 7, steps a–d).
This type of reaction is known to proceed with inversion of configuration.[24] Decene
10a was obtained as a mixture of (E)- and (Z)-isomers (cf. experimental section).
However, the double bond geometry does neither influence the absolute configuration
of the deuterated carbon atoms nor the enantiomeric excess of decane 9a, because
hydrogenation of (E)- and (Z)-10a yields the same product and the pre-existing
stereocenters are not affected by this reaction. Note that while decene 10a and decane
9a exist as a mixture two diastereoisomers (rac and meso, cf. Scheme 7), they are
denoted as rac-10a and rac-9a. The hydrogenation of decene rac-10a with a palladium
on carbon catalyst was found to be more problematic than that of its unlabeled
analogue 10b, resulting in a mixture of products ranging from non-deuterated decanes
to decanes with more than two deuterium atoms incorporated into the molecule.
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This is best displayed by the distribution of the molecular ions in the electron impact
mass spectrum (EIMS) of the decane product as shown in Figure 2. As hydrogenation
reactions employing transition metal catalysts are known to be reversible,[29] the finding
of a distributed deuterium incorporation could be explained by continuous
hydrogenation and dehydrogenation reactions. Once hydrogenated, dehydrogenation
followed by hydrogenation can occur at any position of the alkane, which may result in
the formation of decanes with more than two deuterium atoms incorporated. In
addition, random α,β-dideuterodecanes might occur along with the desired 2,9-
dideuterodecane. In an attempt to reduce the randomization of deuterium in the final
product, we initially investigated the effect of shortening the reaction time. However,
mass spectrometry showed that after 1 h nearly the same deuterium pattern was
obtained as after 20 h.
Due to the apparently microscopic reversibility of the system, we thought that catalytic
hydrogenation reactions using transition metal catalysts would always lead to similar
problems. Diimide reduction was found to be a suitable alternative for the reduction of
dideuterated decene rac-10a.[30] The reaction conditions were optimized, generating
the diimide by slow addition of acetic acid to a suspension of decene rac-10a and
potassium azodicarboxylate in methanol over a period of 20 h (Scheme 7, steps e).
The targeted dideuterated decane rac-9a could be obtained in 82% yield (27% overall
yield over five steps). The reaction product rac-9a showed the well-defined expected
isotopic pattern of the molecular ion in the EIMS (Figure 2, B).
The stereospecifically dideuterated decanes (R,R)- and (S,S)-9a were obtained
analogously (cf. Scheme 7) starting with the commercially available enantiopure
propylene oxides (R)- and (S)-14, respectively. The optical rotations of the
stereospecifically deuterated hydrocarbons 9a, 10a and 13a were found to be zero (c
= 1 g L–1 in DCM) and could, therefore, not be used to determine their enantiopurity.
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Scheme 7. Synthesis of dideuterated n-decane rac-9a. Reagents and conditions:(a) i:
1.4 equiv. C3H5MgBr, 1.4 equiv. CuCN, dry Et2O, –78 °C, 17 h; ii: 0.2 equiv. TEMPO,
0.2 equiv. Bu4NCl, 2.6 equiv. NCS, CH2Cl2/aq. NaHCO3/aq. K2CO3. 23 °C, 1.5 h; (b)
3.5 equiv. TosCl, dry pyridine/dry CH2Cl2 1:1, 0 °C to 23 °C, 16 h; (c) 1.5 equiv. LiAlD4,
tetraglyme, 0 °C to 23 °C, 10 h; (d) 0.8 mol% Grubbs I catalyst, dry CH2Cl2, 23 °C, 48
h; (e) 14 equiv. potassium azodicarboxylate, 43 equiv. AcOH, MeOH, 23 °C, 20 h.
Yields are given for the racemic decane rac-9a. For the yields of the (R,R)- and the
(S,S)-series see experimental section.
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Figure 2. Distribution of the molecular ions of dideuterated decane 9a (m/z 144)
obtained by: (A) catalytic hydrogenation of (2,9-2H2)decene (rac-10a) after 20 h using
palladium on carbon as the catalyst; (B) reduction with diimide.
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As outlined above, determining the enantiopurity of deuterated 1-hexenes (R)- and (S)-
13a would also establish that of the stereospecifically dideuterated decanes (R,R)- and
(S,S)-9a. A literature survey revealed that the protons of the methylene group at C-5
of 3-hydroxy-2-hexanone (17b) show the desired diastereotopic splitting in the 1H NMR
spectrum.[31] Enantioselective hydroxylation of 2-hexanone (16b) can easily be
achieved by α-aminoxylation with nitrosobenzene using L- or D-proline as the catalyst,
followed by cleavage of the N–O-bond with copper sulfate.[31–33] The enantiopurity of
stereospecifically deuterated hexenes (R)- and (S)-13a could therefore be determined
2
based on H NMR of their corresponding hydroxyketones (R,R)- and (3R,5S)-17a,
synthesized via Wacker oxidation to hexanones (R)- and (S)-16a followed by
enantioselective hydroxylation.
Following this concept, initially the hydroxylation reaction was optimized using
commercially available non-deuterated 2-hexanone (16b). Dropwise addition of excess
of nitrosobenzene (2 equiv.) over a period of 24 h, followed by treatment with catalytic
amounts of copper sulfate and excess methanol furnished the 3-hydroxy-2-hexanone
(17b) in 52% yield. The Wacker oxidation of 1-hexene (13b) occurred smoothly to give
2-hexanone (16b) in 81% yield (established by 1H NMR) using standard conditions.[34]
Hydroxylation of crude 2-hexanone (16b) obtained by Wacker oxidation of 1-hexene
(13b) was found to be problematic. Therefore, 2-hexanone (16b) was submitted to
column chromatography prior to α-hydroxylation using diethyl ether and pentane as
the eluents. However, yields of 2-hexanone (16b) decreased due to this purification
step, as 2-hexanone (16b) is relatively volatile (b.p. = 127°C, 1 atm).[35] Applying these
optimized reaction conditions, hydroxyketone (R)-17b was obtained in 11% overall
yield with 99% ee as established by GLC on a chiral phase (Scheme 8). Following this
approach but using racemic deuterated 1-hexene (rac-13a), hydroxyketone (R)-17a
was obtained, which showed unexpectedly but gratifyingly, two sets of signals for C-5
in the 13C NMR (Figure 3, A). Therefore, the enantiopurity of deuterated hexenes (R)-
and (S)-13a can easily and directly be determined by integration of the 13C NMR
signals. As expected, in case of deuterated hexene rac-13a no isomeric excess at the
subterminal C-5 was observed (Figure 3, A). With these promising preliminary results,
we turned to the preparation of both enantiomers of deuterated hexenes (R)- and (S)-
13a starting with commercially available enantiopure propylene oxides (R)- and (S)-
14, respectively.
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Hexenes (R)- and (S)-13a were converted into hydroxyketones (R,R)- and (3R,5S)-
17a, which displayed only one set of signals for C-5 in the 13C NMR spectrum (Figure
4, B and C). Considering the accuracy of NMR spectroscopy, quantitative
stereoselectivity is assumed for the reaction introducing the deuterium atom into the
precursors of hydroxyketones (R,R)- and (3R,5S)-17a since the other diastereoisomer
is not detectable. This finding actually establishes the enantiopurity of hexenes (R)-
and (S)-13a and consequently also of the deuterated decanes (R,R)- and (S,S)-9a.
Therefore, the nucleophilic displacement from tosylates (S)- and (R)-12 to hexenes
(R)- and (S)-13a proceeds with almost full inversion at C-5 following a SN2 reaction
mechanism. It follows that the alternative synthetic approach to the enantiomeric (2,9-
2H2)-n-decanes 9a (see Supplementary Information) also gave optically pure materials.
Scheme 8. Synthesis of (R)-3-hydroxy-2-hexanone [(R)-17b, R = H] and deuterated
(3R,5R*)-3-hydroxy-2-hexanone [(R)-17a, R = D]. Reagents and conditions: (a) 0.1
equiv. Pd(OAc)2, 1.0 equiv. TFA, O2 (1 atm), DMSO/H2O 10:1, 70 °C, 7 h; (b) i: 2.0
equiv. C6H5NO, 0.2 equiv. L-proline, DMSO, 23 °C, 26 h; ii: 0.3 equiv. CuSO4, MeOH,
23 °C, 7 h. For the yields of the (R,R)- and the (R,S)-series of compound 17a see
experimental section.
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A
B
C
13
Figure 3. C signals of C-5 of the hydroxyketones (A) (3R,5R*)-17a, (B) (R,R)-17a
and (C) (3R,5S)-17a.
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Conclusion
Enantiopure (2,5-2H2)-n-hexane 6b was reported to be an excellent model substrate
for the mechanistic investigation of the activation reaction of n-hexane (6a) catalyzed
by the (1-methylpentyl)succinate synthase of the bacterium Aromatoleum aromaticum
strain HxN1.[14] The activation mechanisms of n-alkanes in the mesophilic denitrifying
betaproteobacterium strain OcN1 and the thermophilic sulfate-reducing
deltaproteobacterium strain TD3 are expected to occur in a similar manner. Therefore
we envisioned stereospecifically 2,9-dideuterated decanes (R,R)- and (S,S)-9a to be
ideal model substrates for investigating the activation mechanisms in the bacterial
strains OcN1 and TD3. Starting from commercially available propylene oxide 14, we
developed a reliable synthetic approach to dideuterated decane rac-9a in 27% yield
over five steps. The synthetic approach involved nucleophilic substitution of tosylate
rac-12 with LiAlD4 in order to introduce the deuterium, followed by olefin metathesis
and reduction of the double bond. Starting from enantiopure propylene oxide the
stereospecifically dideuterated decanes (R,R)- and (S,S)-9a were obtained in a similar
manner and in 25% and 26% overall yield, respectively. As compounds (R,R)- and
(S,S)-9a should be prepared in optically pure form for mechanistic investigations an
analytical tool was needed in order to prove their optical purity. Since the
chromatographic separation of enantiomers of optically active deuterated compounds
is quite challenging, and the optical rotation values of decanes (R,R)- and (S,S)-9a
were determined to be zero (c = 1 g L–1 in DCM), an alternative approach was required
for the determination of the optical purity. Therefore, we describe a method for the
determination of enantiopurity by NMR spectroscopy after Wacker oxidation of
hexenes (R)- and (S)-13a followed by enantioselective hydroxylation to furnish
hydroxyketones (R,R)- and (3R,5S)-17a with 99% ee. These products showed a triplet
for subterminal C-5 in the 13C NMR spectrum with different chemical shifts. No residual
signals arising from the other epimer were detected. Thus, the nucleophilic
displacement from tosylates (S)- and (R)-12 must have proceeded with, based on the
detection limit of NMR spectroscopy, complete inversion of configuration at C-5.
16
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
Experimental Section
General: Unless otherwise noted, all synthetic transformations were performed under
inert conditions (nitrogen atmosphere, exclusion of air and moisture). Preparative
column chromatography was carried out using Merck SiO2 (40–63 μm, type 60 A) with
hexanes (mixture of isomers, bp. 64–71 °C), n-pentane, tert-butyl methyl ether (MTBE)
and Et2O as eluents. TLC was performed on aluminum plates coated with SiO2 F254.
GLC analyses were performed on a Thermo Scientific Focus GC gas chromatograph
equipped with a flame ionization detector using a CP-Sil 19 CB fused silica capillary
column (30 m length, 0.25 mm internal diameter, 0.25 μm film thickness). GC-MS
analyses were performed on a Shimadzu GCMS-QP2020 using a Macherey-Nagel
OPTIMA 5 HT fused silica capillary column (30 m length, 0.25 mm internal diameter,
0.25 μm film thickness). Helium was used as carrier gas. Gas chromatographic
separation of both enantiomers of 3-hydroxy-2-hexanone [(R)-17b and (S)-17b] was
performed using a Shimadzu GC-2010 Plus gas chromatograph equipped with a flame
ionization detector using a Hydrodex β-6TBDM column (25 m length, 0.25 mm internal
1
2
diameter). Hydrogen was used as carrier gas. H, H and 13C NMR spectra were
recorded on Bruker Avance DRX 500 and 300 instruments. Multiplicities of carbon
signals were determined with DEPT experiments. HRMS spectra of products were
obtained with a Waters Q-TOF Premier (ESI) or Thermo Scientific DFS (EI)
spectrometer. IR spectra were recorded on a Shimadzu IRSpirit spectrometer
equipped with a diamond ATR unit. All starting materials were commercially available.
17
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10.1002/ejoc.202100360
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rac-5-Hexen-2-ol (rac-11). According to a modified procedure reported previously in
the literature,[25] allylmagnesium bromide (1.0 mol/L solution in Et2O, 135 mL, 135
mmol, 1.4 equiv.) was added dropwise over a period of 50 min to a suspension of
degassed CuCN (12.1 g, 135 mmol, 1.4 equiv.) in dry Et2O (25 mL) at –78 °C. After
stirring for 90 min at this temperature, rac-propylene oxide (rac-14, 5.54 g, 95.4 mmol)
was added dropwise over a period of 25 min and stirring was continued for 17 h. The
reaction mixture was warmed to ambient temperature, diluted with saturated, aqueous
NH4Cl solution (200 mL) and extracted with Et2O (3 x 200 mL). The combined organic
layers were washed with saturated, aqueous NaCl solution (2 x 200 mL), dried over
MgSO4 and filtered. The solvent was evaporated to furnish a mixture (11.5 g)
containing the title compound rac-11 (9.07 g, 90.5 mmol, 95%, established by 1H NMR)
and the regioisomeric compound 15 (483 mg, 4.82 mmol, 5%, established by 1H NMR)
as a yellow liquid. Because product rac-11 and the regioisomeric primary alcohol 15
were not separable by column chromatography or distillation, the mixture was
submitted to a TEMPO oxidation as reported previously in the literature.[26] TEMPO
(150 mg, 960 μmol, 0.2 equiv.), Bu4NCl (267 mg, 961 μmol, 0.2 equiv.), CH2Cl2 (50
mL) and an aqueous buffer solution (50 mL, containing 2.10 g NaHCO3 and 346 mg
K2CO3) were added to the mixture of regioisomers containing the primary alcohol 15
(483 mg, 4.82 mmol). Subsequently, NCS (1.67 g, 12.5 mmol, 2.6 equiv.) was added
and the reaction mixture was stirred for 90 min. The reaction mixture was diluted with
H2O (50 mL), the organic layer separated and the aqueous layer extracted with CH2Cl2
(3 x 100 mL). The combined organic layers were washed with saturated, aqueous NaCl
solution (1 x 200 mL), dried over MgSO4, filtered and evaporated. The crude product
was submitted to column chromatography (SiO2, pentane/Et2O 3:2, Rf = 0.26) to
furnish the title compound rac-11 (7.12 g, 71.1 mmol, yield over two steps 75%, based
on 82% purity established by 1H NMR) as a colorless liquid. 1H NMR (300 MHz, CDCl3):
δ = 1.20 (d, J = 6.2 Hz, 3H), 1.44–1.47 (m, 1H), 1.49–1.63 (m, 2H), 2.06–2.25 (m, 2H),
3.83 (sex, J = 6.2 Hz, 1H), 4.94–4.99 (m, 1H), 5.05 (dq, J = 17.2 Hz, J = 1.6 Hz, 1H),
5.84 (ddt, J = 16.9 Hz, J = 10.2 Hz, J = 6.7 Hz, 1H) ppm. 13C{1H} NMR (75 MHz, CDCl3):
δ = 23.41 (CH3), 30.17 (CH2), 38.28 (CH2), 67.45 (CH), 114.64 (CH2), 138.53 (CH)
ppm. All spectroscopic data were in accordance with the literature.[36] C6H12O (100.16).
18
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
(R)-5-Hexen-2-ol [(R)-11]. According to the procedure reported above for the racemic
compound rac-11 allymagnesium bromide (1.0 mol/L solution in Et2O, 107 mL, 107
mmol, 1.4 equiv.), CuCN (9.60 g, 107 mmol, 1.4 equiv.) and (R)-propylene oxide [(R)-
14, 4.37 g, 75.2 mmol] were converted in dry Et2O (25 mL) to furnish a mixture
1
containing primary alcohol 15 (449 mg, 4.48 mmol, 6% established by H NMR) and
1
secondary alcohol (R)-11 (7.09 g, 70.8 mmol, 94%, established by H NMR). The
mixture was submitted to TEMPO oxidation as reported above using TEMPO (141 mg,
902 μmol, 0.2 equiv.), Bu4NCl (250 mg, 900 μmol, 0.2 equiv.), CH2Cl2 (50 mL),
aqueous buffer solution (50 mL, containing 2.10 g NaHCO3 and 346 mg K2CO3) and
NCS (1.56 g, 11.7 mmol, 2.6 equiv.) to furnish the title compound (R)-11 (4.90 g, 48.9
mmol, 65%, based on 90% purity established by 1H NMR) after column
chromatography (SiO2, pentane/Et2O 3:2, Rf = 0.26) as a colorless liquid. The
spectroscopic data are in accordance with the literature and with those of the racemic
compound.[37] [α]D20 = –20 (CH2Cl2, 1.0 g L−1). Lit. [α]D21.7 = –15.9 (Et2O, 0.48 g L−1).[38]
(S)-5-Hexen-2-ol [(S)-11]. According to the procedure reported above for the racemic
compound rac-11 allymagnesium bromide (1.0 mol/L solution in Et2O, 107 mL, 107
mmol, 1.3 equiv.), CuCN (9.60 g, 107 mmol, 1.3 equiv.) and (S)-propylene oxide [(S)-
14, 4.73 g, 81.4 mmol] were converted in dry Et2O (25 mL) to furnish a mixture
1
containing primary alcohol 15 (485 mg, 4.84 mmol, 6% established by H NMR) and
1
secondary alcohol (S)-11 (7.67 g, 76.6 mmol, 94%, established by H NMR). The
mixture was submitted to TEMPO oxidation as reported above using TEMPO (151 mg,
966 μmol, 0.2 equiv.), Bu4NCl (270 mg, 972 μmol, 0.2 equiv.), CH2Cl2 (50 mL),
aqueous buffer solution (50 mL, containing 2.10 g NaHCO3 and 346 mg K2CO3) and
NCS (1.68 g, 12.6 mmol, 2.6 equiv.) to furnish the title compound (S)-11 (5.51 g, 55.0
mmol, 68%, based on 82% purity established by 1H NMR) after column
chromatography (SiO2, pentane/Et2O 3:2, Rf = 0.26) as a colorless liquid. The
spectroscopic data are in accordance with the literature and with those of the racemic
compound.[39] [α]D20 = +13 (CH2Cl2, 1.0 g L−1). Lit. [α]D24.2 = +17.3 (CH2Cl2, 2.9 g L−1).[40]
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
4-Toluenesulfonic acid 1-methyl-4-pentenyl ester (rac-12). According to a slightly
modified procedure reported previously in the literature,[27] TosCl (48.6 g, 255 mmol,
3.5 equiv.) was added in portions over a period of 30 min to a solution of alcohol rac-
11 (7.30 g, 72.9 mmol) in pyridine (50 mL) and dry CH2Cl2 (65 mL) at 0 °C. The mixture
was warmed to ambient temperature and stirred for 16 h. The reaction mixture was
diluted with saturated, aqueous NH4Cl solution (150 mL), the layers were separated
and the aqueous layer was extracted with CH2Cl2 (3 x 150 mL). The combined organic
layers were washed with hydrochloric acid (1.0 mol/L, 200 mL), saturated, aqueous
NaHCO3 (200 mL) and saturated, aqueous NaCl (200 mL) solutions, dried over MgSO4
and the solvent was evaporated. The crude product was submitted to column
chromatography (SiO2, hexanes/MTBE 2:3 Rf = 0.58) to furnish the title compound rac-
1
12 (14.0 g, 55.0 mmol, 75%) as a colorless oil. H NMR (300 MHz, CDCl3): δ = 1.25
(d, J = 6.3 Hz, 3H), 1.51–1.63 (m, 1H), 1.65–1.77 (m, 1H), 1.88–2.09 (m, 2H), 2.43 (s,
3H), 4.62 (sex, J = 6.3 Hz, 1H), 4.88–4.91 (m, 1H), 4.93–4.96 (m, 1H), 5.66 (ddt, J =
17.5 Hz, J = 9.8 Hz, J = 6.5 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 20.84 (CH3), 21.70 (CH3), 29.10 (CH2), 35.71
(CH2), 79.97 (CH), 115.42 (CH2), 127.77 (2 x CH), 129.82 (2 x CH), 134.57 (CH),
137.11 (C), 144.57 (C) ppm. All spectroscopic data were in accordance with the
literature.[27] C13H18O3S (254.35)
(R)-4-Toluenesulfonic acid 1-methyl-4-pentenyl ester [(R)-12]. According to the
procedure reported above for the racemic compound rac-12, alcohol (R)-11 (4.81 g,
48.0 mmol) and TosCl (32.0 g, 168 mmol, 3.5 equiv.) were converted in dry pyridine
(50 mL) and dry CH2Cl2 (50 mL) to furnish the title compound (R)-12 (10.4 g, 41.1
mmol, 86%) as a colorless oil. The spectroscopic data are in accordance with those of
the racemic compound. [α]D20 = –7 (CH2Cl2, 1.0 g L−1).
(S)-4-Toluenesulfonic acid 1-methyl-4-pentenyl ester [(S)-12]. According to the
procedure reported above for the racemic compound rac-12, alcohol (S)-11 (5.52 g,
55.1 mmol) and TosCl (36.8 g, 193 mmol, 3.5 equiv.) were converted in dry pyridine
(50 mL) and dry CH2Cl2 (50 mL) to furnish the title compound (S)-12 (11.2 g, 44.0
mmol, 80%) as a colorless oil. The spectroscopic data are in accordance with those of
the racemic compound. [α]D20 = +7 (CH2Cl2, 1.0 g L−1).
20
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1-Hexene (13b). LiAlH4 (300 mg, 7.91 mmol, 1.5 equiv.) was added to a solution of
tosylate rac-12 (1.34 g, 5.27 mmol) in tetraglyme (7 mL) at 0 °C. The reaction mixture
was warmed to ambient temperature and stirred for 4 h. The product was purified and
isolated by vacuum distillation into a cold trap (–196 °C) to yield the title compound
1
13b as a colorless liquid (244 mg, 2.90 mmol, 55%). H NMR (300 MHz, CDCl3): δ =
0.90 (t, J = 6.2 Hz, 3H), 1.26–1.42 (m, 4H), 2.02–2.09 (m, 2H), 4.93 (ddt, J = 10.2 Hz,
J = 2.2 Hz, J = 1.3 Hz, 1H), 5.00 (ddt, J = 17.1 Hz, J = 2.2 Hz, J = 1.6 Hz, 1H), 5.82
(ddt, J = 16.9 Hz, J = 10.2 Hz, J = 6.7 Hz, 1H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ
= 14.09 (CH3), 22.34 (CH2), 31.25 (CH2), 33.65 (CH2), 114.24 (CH2), 139.37 (CH) ppm.
All spectroscopic data were in accordance with the literature.[41] C6H12 (84.16).
rac-(5-2H)-1-Hexene (rac-13a). According to the procedure reported above for the
non-deuterated compound 13b, LiAlD4 (1.98 g, 47.2 mmol, 1.5 equiv.) and tosylate
rac-12 (8.00 g, 31.5 mmol) were converted in tetraglyme (38 mL). After warming the
reaction mixture to room temperature, the product was continuously distilled into a cold
trap (–196 °C) over a period of 10 h to furnish the title compound rac-13a as a colorless
liquid (2.36 g, 27.7 mmol, 88%). 1H NMR (500 MHz, CDCl3): δ = 0.91 (dt, J = 7.2 Hz,
JHD = 1.1 Hz, 3H), 1.28–1.40 (m, 3H), 2.04–2.09 (m, 2H), 4.94 (ddt, J = 10.2 Hz, J =
2.2 Hz, J = 1.2 Hz, 1H), 5.01 (ddt, J = 17.1 Hz, J = 2.2 Hz, J = 1.6 Hz, 1H), 5.83 (ddt,
13
J = 17.0 Hz, J = 10.2 Hz, J = 6.7 Hz, 1H) ppm. C{1H} NMR (75 MHz, CDCl3): δ =
13.98 (CH3), 21.95 (t, J = 19.2 Hz, CHD), 31.16 (CH2), 33.64 (CH2), 114.22 (CH2),
139.37 (CH) ppm. 2H NMR (77 MHz, CDCl3): δ = 1.29–1.40 (m, 1D) ppm. 1H NMR data
2
were in accordance with the literature.[42] HRMS (EI): calcd. 85.0996 (for C6H11 H+),
2
found 85.1000 [M+]. C6H11 H (85.17).
(S)-(5-2H)-1-Hexene [(S)-13a]. According to the procedure reported above for the non-
deuterated compound rac-13a, LiAlD4 (2.56 g, 61.0 mmol, 1.5 equiv.) and tosylate (R)-
12 (10.3 g, 40.5 mmol) were converted in tetraglyme (50 mL) and continuously distilled
over a period of 18 h to furnish the title compound (S)-13a as a colorless liquid (3.24
g, 38.0 mmol, 94%). The spectroscopic data are in accordance with those of the
racemic compound. [α]D20 = ±0 (CH2Cl2, 1.0 g L−1).
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10.1002/ejoc.202100360
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(R)-(5-2H)-1-Hexene [(R)-13a]. According to the procedure reported above for the non-
deuterated compound rac-13a, LiAlD4 (2.72 g, 64.8 mmol, 1.5 equiv.) and tosylate (S)-
12 (11.0 g, 43.2 mmol) were converted in tetraglyme (50 mL) and continuously distilled
over a period of 14 h to furnish the title compound (R)-13a as a colorless liquid (3.36
g, 39.5 mmol, 91%). The spectroscopic data are in accordance with those of the
racemic compound. [α]D20 = ±0 (CH2Cl2, 1.08 g L−1).
5-Decene (10b). Grubbs I catalyst (395 mg, 0.480 mmol, 1.0 mol%) was added to a
degassed solution (one cycle of freeze, pump, thaw) of 1-hexene (13b, 4.00 g, 47.5
mmol) in dry CH2Cl2 (20 mL). The resulting suspension was degassed (one cycle of
freeze, pump, thaw) and stirred for 64 h in the dark. The solvent was evaporated and
the crude product was submitted to vacuum distillation into a cold trap (–196°C) to yield
the title compound 10b (2.17 g, 15.5 mmol, 65%, based on 96% purity established by
1H NMR) as a colorless liquid. According to 13C NMR the compound exists as a mixture
of two diastereoisomers (E/Z = 84:16). 1H NMR (300 MHz, CDCl3), both
diastereoisomers: δ = 0.84–0.93 (m, 12H), 1.23–1.40 (m, 16H), 1.92–2.06 (m, 8H),
5.33–5.36 (m, 2H), 5.37–5.45 (m, 2H) ppm. 13C{1H} NMR (75 MHz, CDCl3), (E)-isomer:
δ = 14.13 (2 x CH3), 22.36 (2 x CH2), 32.00 (2 x CH2), 32.45 (2 x CH2), 130.46 (2 x CH)
ppm; (Z)-isomer: δ = 14.16 (2 x CH3), 22.51 (2 x CH2), 27.06 (2 x CH2), 32.13 (2 x
CH2), 130.00 (2 x CH) ppm. All spectroscopic data were in accordance with the
literature.[41,43] C10H20 (140.27)
(2,9-2H2)-5-Decene (rac-10a). According to the procedure reported above for the non-
deuterated compound 10b, Grubbs I catalyst (92 mg, 0.11 mmol, 0.8 mol%) and 1-(5-
2H)-hexene (rac-13a, 1.20 g, 14.0 mmol) were converted in dry CH2Cl2 (10 mL) for 48
h to furnish the title compound rac-10a (671 mg, 4.72 mmol, 67%) as a colorless liquid.
According to 13C NMR the compound exists as a mixture of two diastereoisomers (E/Z
= 81:19). 1H NMR (300 MHz, CDCl3), both diastereoisomers: δ = 0.84–0.94 (m, 12H),
1.22–1.36 (m, 12H), 1.92–2.06 (m, 8H), 5.32–5.36 (m, 2H), 5.37–5.45 (m, 2H) ppm.
13C{1H} NMR (75 MHz, CDCl3), (E)-isomer: δ = 14.01 (2 x CH3), 21.97 (t, J = 19.2 Hz,
2 x CHD), 31.92 (2 x CH2), 32.44 (2 x CH2), 130.47 (2 x CH) ppm; (Z)-isomer: δ = 14.04
(2 x CH3), 22.12 (t, J = 19.1 Hz, 2 x CHD), 27.05 (2 x CH2), 32.05 (2 x CH2), 130.00 (2
x CH) ppm. 2H NMR (77 MHz, CDCl3): δ = 1.28–1.39 (m, 2D) ppm. IR (ATR): ν
̃ = 2957
(m), 2917 (s), 2873 (m), 2853 (m), 2152 (w), 1457 (m), 1439 (w), 1377 (w), 1140 (w),
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2
966 (m), 890 (w), 691 (w), 661 (w) cm–1. HRMS (EI): calcd. 142.1685 (for C10H18 H2),
2
found 142.1684 [M+]. C10H18 H2 (142.28).
(S,S)-(2,9-2H2)-5-Decene [(S,S)-10a]. According to the procedure reported for the non-
deuterated compound 10b, Grubbs I catalyst (164 mg, 0.20 mmol, 1.0 mol%) and (S)-
(5-2H)-1-hexene [(S)-13a, 1.70 g, 20.0 mmol] were converted in dry CH2Cl2 (10 mL) for
89 h to furnish the title compound (S,S)-10a (833 mg, 5.85 mmol, 59%, based on 83%
1
purity established by H NMR) as a colorless liquid. According to 13C NMR the
compound exists as a mixture of two diastereoisomers (E/Z = 81:19). The
spectroscopic data are in accordance with those of the racemic compound. [α]D20 = ±0
(CH2Cl2, 1.09 g L−1).
(R,R)-(2,9-2H2)-5-Decene [(R,R)-10a]. According to the procedure reported for the
non-deuterated compound 10b, Grubbs I catalyst (239 mg, 0.29 mmol, 1.0 mol%) and
(R)-(5-2H)-1-hexene [(R)-13a, 2.44 g, 28.6 mmol] were converted in dry CH2Cl2 (10
mL) for 74 h to furnish the title compound (R,R)-10a (1.22 g, 8.57 mmol, 60%, based
on 87% purity established by 1H NMR) as a colorless liquid. According to 13C NMR the
compound exists as a mixture of two diastereoisomers (E/Z = 80:20). The
spectroscopic data are in accordance with those of the racemic compound. [α]D20 = ±0
(CH2Cl2, 1.01 g L−1).
n-Decane (9b). (a) Through catalytic hydrogenation of 5-decene (10b) using Pd/C.
5-Decene (10b, 200 mg, 1.43 mmol) was added to a degassed (three cycles of freeze,
pump, thaw) suspension of 10 wt% Pd/C (152 mg, 143 μmol) in n-pentane (10 mL).
The resulting mixture was degassed again and stirred for 20 h at ambient temperature
under an atmosphere of H2 (balloon). Subsequently, the reaction mixture was filtered
through a plug of SiO2 (2 cm, rinsed with n-pentane) and the solvent was evaporated
to yield the title compound 9b (171 mg, 1.20 mmol, 84%, based on 92% purity
established by 13C NMR) as a colorless liquid. 1H NMR (300 MHz, CDCl3): δ = 0.88 (t,
J = 6.7 Hz, 6H), 1.18–1.36 (m, 16H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 14.29 (2
x CH3), 22.86 (2 x CH2), 29.53 (2 x CH2), 29.83 (2 x CH2), 32.09 (2 x CH2) ppm. All
spectroscopic data were in accordance with the literature.[44] C10H22 (142.29) (b)
Through diimide reduction of 5-decene (10b). Dipotassium azodicarboxylate was
freshly prepared according to a modified procedure reported previously in the
literature:[30,45] Azodicarboxamide (2.32 g, 20.0 mmol) was added in ten portions over
23
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European Journal of Organic Chemistry
a period of 1 h to a solution of KOH (8.00 g, 143 mmol, 7.1 equiv.) in H2O (12 mL) at 0
°C. The resulting suspension was stirred for 1.5 h at 0 °C, filtered, washed with ice-
cold MeOH and dried in high vacuum to furnish potassium azodicarboxylate (3.56 g,
18.3 mmol, 92%) as a yellow solid. A solution of AcOH (3.30 g, 54.9 mmol, 30 equiv.)
in MeOH (9 mL) was added dropwise over a period of 12 h to a suspension of
dipotassium azodicarboxylate (3.56 g, 18.3 mmol, 10 equiv.) and 5-decene (10b, 257
mg, 1.83 mmol) in MeOH (20 mL). Subsequently, stirring was continued for 6 h. The
reaction mixture was diluted with aqueous H2O2 solution (20 mL 10 wt% and 10 mL 30
wt%) and extracted with cyclopentane (3 x 30 mL). The combined organic layers were
washed with hydrochloric acid (1 mol/L, 90 mL), dried over MgSO4 and evaporated to
yield the title compound 9b (225 mg, 1.58 mmol, 86%, based on 42% purity based on
1H NMR) as a colorless liquid The spectroscopic data are in accordance with the
literature and with those of the product of the catalytic hydrogenation.[44]
(2,9-2H2)-n-Decane (rac-9a). According to the procedure reported above for the non-
deuterated compound 9b, a solution of AcOH (8.00 mL, 8.40 g, 140 mmol, 43 equiv.)
in MeOH (14 mL) was added dropwise over a period of 20 h to a suspension of (2,9-
2H2)-5-decene (rac-10a, 469 mg, 3.25 mmol) and potassium azodicarboxylate (8.99 g,
46.3 mmol, 14 equiv.) in MeOH (65 mL) to furnish the title compound rac-9a (387 mg,
1
2.68 mmol, 82%, based on 63% purity established by H NMR) as a colorless liquid.
1H NMR (300 MHz, CDCl3): δ = 0.83–0.91 (m, 6H), 1.19–1.34 (m, 14H) ppm. 13C{1H}
NMR (75 MHz, CDCl3): δ = 14.17 (2 x CH3), 22.46 (t, J = 19.1 Hz, 2 x CHD), 29.50 (2
2
x CH2), 29.83 (2 x CH2), 31.99 (2 x CH2) ppm. H NMR (77 MHz, CDCl3): δ = 1.25–
1.39 (m, 2D) ppm. IR (ATR): ν̃ = 2957 (m), 2920 (s), 2873 (w), 2853 (m), 2154 (w),
1644 (w), 1459 (w), 1400 (w), 1377 (w), 1273 (w), 1139 (w), 1073 (w), 967 (w), 891
(w), 724 (w), 661 (w) cm–1. GC-MS (EI, 70 eV): m/z (%) 144 (6.5), 143 (0.74), 114 (6),
100 (10), 99 (7), 86 (36), 85 (15), 72 (45), 71 (34), 70 (11), 58 (100), 57 (95), 56 (30),
2
2
55 (16). HRMS (EI): calcd. 144.1842 (for C10H20 H2), found 144.1844 [M+]. C10H20 H2
(144.30).
(S,S)-(2,9-2H2)-n-Decane [(S,S)-9a]. According to the procedure reported above for
the non-deuterated compound 9b, a solution of AcOH (6.60 mL, 6.93 g, 115 mmol, 48
equiv.) in MeOH (13 mL) was added dropwise over a period of 20 h to a suspension
of (S,S)-(2,9-2H2)-decene [(S,S)-10a, 341 mg, 2.40 mmol] and potassium
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azodicarboxylate (7.45 g, 38.4 mmol, 16 equiv.) in MeOH (60 mL) to furnish the title
compound (S,S)-9a (296 mg, 2.05 mmol, 85%, based on 56% purity established by 1H
NMR) as a colorless liquid. The spectroscopic data are in accordance with those of the
racemic compound. [α]D20 = ±0 (CH2Cl2, 1.01 g L−1).
(R,R)-(2,9-2H2)-n-Decane [(R,R)-9a]. According to the procedure reported above for
the non-deuterated compound 9b, a solution of AcOH (7.20 mL, 7.56 g, 126 mmol, 41
equiv.) in MeOH (13 mL) was added dropwise over a period of 20 h to a suspension
of (R,R)-(2,9-2H2)-decene [(R,R)-10a, 437 mg, 3.07 mmol] and potassium
azodicarboxylate (8.17 g, 42.1 mmol, 14 equiv.) in MeOH (60 mL) to furnish the title
compound (R,R)-9a (376 mg, 2.61 mmol, 85%, based on 57% purity established by 1H
NMR) as a colorless liquid. The spectroscopic data are in accordance with those of the
racemic compound. [α]D20 = ±0 (CH2Cl2, 1.06 g L−1).
2-Hexanone (16b). According to a procedure reported previously in the literature,[34]
TFA (813 mg, 7.13 mmol, 1 equiv.) was added over a period of 3 min to a solution of
1-hexene (13b, 600 mg, 7.13 mmol) and Pd(OAc)2 (159 mg, 708 μmol, 0.1 equiv.) in
DMSO (14 mL) and H2O (1.4 mL) under an atmosphere of O2 (balloon). The mixture
was warmed to 70 °C and stirred for 7 h. The reaction mixture was diluted with Et2O
(15 mL), filtered through a plug of SiO2 (2 cm, rinsed with Et2O), washed with H2O (50
mL), aqueous, saturated NaCl (50 mL), dried over MgSO4 and filtered. The crude
product was submitted to column chromatography (SiO2, pentane/Et2O 9:1) to furnish
the title compound 16b (269 mg, 2.69 mmol, 38%, based on 26% purity established by
1H NMR) as a slightly yellow liquid which was directly used in the next step without
further purification or characterization. 1H NMR (300 MHz, CDCl3): δ = 1.51–1.61 (m,
2H), 2.14 (s, 3H), 2.42 (t, J = 7.4 Hz, 2H) ppm; not all signals could be identified with
1
certainty due to overlapping solvent signals. The H NMR data were in accordance
with the literature.[46] C6H12O (100.16).
(R)-3-Hydroxy-2-hexanone [(R)-17b]. According to a modified procedure reported
previously in the literature,[31-33] a solution of nitrosobenzene (576 mg, 5.38 mmol, 2
equiv.) in DMSO (6.5 mL) was added over a period of 24 h to a solution of 2-hexanone
(16b, 269 mg, 2.69 mmol) and L-proline (62 mg, 0.54 mmol, 0.2 equiv.) in DMSO (3.4
mL) at ambient temperature. After stirring was continued for 2 h, anhydrous CuSO4
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
(129 mg, 808 μmol, 0.3 equiv.) and MeOH (4.2 mL) were added and stirring was
continued for further 7 h. The reaction mixture was diluted with aqueous, saturated
NH4Cl (30 mL) and the aqueous layer extracted with Et2O (3 x 30 mL). The combined
organic layers were washed with aqueous, saturated NaCl (60 mL), dried over MgSO4
and the solvent was evaporated. The crude product was submitted to column
chromatography (SiO2, pentane/MTBE 2:1, Rf = 0.21) to furnish the title compound (R)-
17b (88 mg, 0.76 mmol, 28%, based on 37% purity established by 1H NMR, 99% ee)
as a yellow liquid. 1H NMR (300 MHz, CDCl3): δ = 0.96 (t, J = 7.1 Hz, 3H), 1.31–1.44
(m, 1H), 1.45–1.60 (m, 2H), 1.74–1.86 (m, 1H), 2.20 (s, 3H), 3.45 (d, J = 4.6 Hz, 1H),
4.16–4.21 (m, 1H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ = 14.03 (CH3), 18.25 (CH2),
25.32 (CH3), 35.77 (CH2), 76.83 (CH), 210.16 (C) ppm. All spectroscopic data were in
accordance with the literature.[47] C6H12O2 (116.16).
(S)-3-Hydroxy-2-hexanone [(S)-17b]. According to the procedure reported above for
the preparation of the non-deuterated compound (R)-17b, 2-hexanone (16b, 400 mg,
3.99 mmol), a solution of nitrosobenzene (428 mg, 4.00 mmol, 1 equiv.) in DMSO (4.8
mL), D-proline (92 mg, 0.80 mmol, 0.2 equiv.), anhydrous CuSO4 (192 mg, 1.20 mmol,
0.3 equiv.) and MeOH (6 mL) were converted in DMSO (5 mL) to furnish the title
compound (S)-17b (148 mg, 1.28 mmol, 32% based on 75% purity established by 1H
NMR, 99% ee) after column chromatography (SiO2, pentane/MTBE 2:1, Rf = 0.22) as
a yellow liquid. All spectroscopic data were in accordance with those of the (R)-
enantiomer.
(5-2H)-2-Hexanone (rac-16a). According to the procedure reported above for the non-
deuterated compound 16b, hexene rac-13a (821 mg, 9.64 mmol), Pd(OAc)2 (319 mg,
1.42 mmol, 0.15 equiv.) and TFA (1.11 g, 9.74 mmol, 1.0 equiv.) were converted in
DMSO (28 mL) and H2O (2.8 mL) to furnish the title compound rac-16a (472 mg, 4.67
mmol, 48%, based on 37% purity established by 1H NMR) after column
chromatography (SiO2, pentane/Et2O 9:1) as a slightly yellow liquid which was directly
used in the next step without further purification or characterization. 1H NMR (300 MHz,
CDCl3): δ = 0.89 (dt, J = 7.3 Hz, JHD = 1.0 Hz, 3H), 1.50–1.58 (m, 2H), 2.13 (s, 3H),
2.42 (t, J = 7.5 Hz, 2H) ppm; not all signals could be identified with certainty due to
overlapping solvent signals. All spectroscopic data were in accordance with the
2
literature.[48] C6H11 HO (101.17).
26
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
(3R)-(5-2H)-3-Hydroxy-2-hexanone [(3R,5R*)-17a]. According to the procedure
reported above for the preparation of the non-deuterated compound (R)-17b,
hexanone rac-16a (472 mg, 4.67 mmol), a solution of nitrosobenzene (999 mg, 9.33
mmol, 2 equiv.) in DMSO (11 mL), L-proline (107 mg, 929 μmol, 0.2 equiv.), CuSO4
(223 mg, 1.40 mmol, 0.3 equiv.) and MeOH (7.2 mL) were converted in DMSO (5.8
mL) to furnish the title compound (3R,5R*)-17a (95 mg, 0.81 mmol, 17% based on 52%
1
purity established by H NMR, 99% ee) after column chromatography (SiO2,
pentane/MTBE 2:1, Rf = 0.22) as a yellow liquid. According to 13C NMR, the compound
exists as two epimers (er 1:1). 1H NMR (500 MHz, CDCl3), both epimers: δ = 0.95 (dt,
J = 7.2 Hz, JHD = 1.0 Hz, 2 x 3H), 1.34–1.42 (m, 1H), 1.43–1.55 (m, 3H), 1.77–1.82 (m,
2 x 1H), 2.19 (s, 2 x 3H), 3.42 (brs, 2 x 1H), 4.15–4.21 (m, 2 x 1H) ppm. 13C{1H} NMR
(125 MHz, CDCl3), both epimers: δ = 13.82 (2 x CH3), 17.85 (t, J = 19.5 Hz, CHD),
17.88 (t, J = 19.4 Hz, CHD), 25.21 (2 x CH3), 35.66 (CH2), 35.68 (CH2), 76.80 (CH),
2
76.82 (CH), 210.12 (2 x C) ppm. H NMR (77 MHz, CDCl3), both epimers: δ = 1.30–
1.42 (m, 1D), 1.42–1.53 (m, 1D) ppm. [α]D20 = –133 (CH2Cl2, 1.09 g L−1). IR (ATR): ν
̃ =
3466 (w), 2959 (w), 2932 (w), 2874 (w), 2166 (w), 1710 (s), 1457 (w), 1419 (w), 1397
(w), 1380 (w), 1357 (m), 1289 (w), 1249 (w), 1219 (w), 1187 (w), 1116 (m), 1083 (w),
1060 (w), 1016 (w), 999 (w), 966 (w), 756 (w), 696 (w), 670 (w), 624 (w), 599 (w), 546
2
+
(w), 509 (w) cm–1. HRMS (ESI, pos. mode): calcd. 140.0792 (for C6H11 HNaO2 ), found
2
140.0791 [M+]. C6H11 HO2 (117.17).
(R)-(5-2H)-2-Hexanone [(R)-16a]. According to the procedure reported above for the
non-deuterated compound 16b, hexene (R)-13a (600 mg, 7.05 mmol), Pd(OAc)2 (157
mg, 699 μmol, 0.1 equiv.) and TFA (804 mg, 7.05 mmol, 1.0 equiv.) were converted in
DMSO (14 mL) and H2O (1.4 mL) to furnish the title compound (R)-16a (318 mg, 3.14
mmol, 45%, based on 41% purity established by 1H NMR) after column
chromatography (SiO2, pentane/Et2O 9:1) as a slightly yellow liquid which was directly
used in the next step without further characterization. 1H NMR (300 MHz, CDCl3): δ =
0.90 (dt, J = 7.4 Hz, JHD = 1.0 Hz, 3H), 1.51–1.59 (m, 2H), 2.14 (s, 3H), 2.43 (t, J = 7.5
Hz, 2H) ppm; not all signals could be identified with certainty due to overlapping solvent
signals. The spectroscopic data were in accordance with those of the racemic
compound.
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
(R,R)-(5-2H)-3-Hydroxy-2-hexanone [(R,R)-17a]. According to the procedure
reported above for the preparation of the non-deuterated compound (R)-17b,
hexanone (R)-16a (318 mg, 3.14 mmol), a solution of nitrosobenzene (673 mg, 6.28
mmol, 2 equiv.) in DMSO (7.6 mL), L-proline (73 mg, 0.63 mmol, 0.2 equiv.), CuSO4
(150 mg, 0.94 mmol, 0.3 equiv.) and MeOH (4.9 mL) were converted in DMSO (4 mL)
to furnish the title compound (R,R)-17a (23 mg, 0.20 mmol, 6% based on 34% purity
established by 1H NMR, 99% ee) after column chromatography (SiO2, pentane/MTBE
2:1, Rf = 0.22) as a yellow liquid. 1H NMR (500 MHz, CDCl3): δ = 0.93 (dt, J = 7.2 Hz,
JHD = 1.0 Hz, 3H), 1.41–1.53 (m, 2H), 1.74–1.80 (m, 1H), 2.17 (s, 3H), 4.15 (dd, J =
7.5, 3.7 Hz, 1H) ppm; the signal of the hydroxy group could not be identified with
certainty. 13C{1H} NMR (125 MHz, CDCl3): δ = 13.84 (CH3), 17.90 (t, J = 19.4 Hz, CHD),
25.22 (CH3), 35.70 (CH2), 76.83 (CH), 210.10 (C) ppm. 2H NMR (77 MHz, CDCl3): δ =
1.31–1.46 (m, 1D) ppm. [α]D20 = –67 (CDCl3, 1.15 g L−1). IR (ATR): ν
̃ = 3466 (w), 2959
(w), 2929 (w), 2874 (w), 2856 (w), 2162 (w), 1712 (s), 1642 (w), 1602 (w), 1499 (w),
1457 (w), 1443 (w), 1419 (w), 1399 (w), 1356 (w), 1314 (w), 1290 (w), 1249 (w), 1216
(w), 1189 (w), 1113 (m), 1083 (w), 1061 (w), 1016 (w), 966 (w), 869 (w), 796 (w), 754
(w), 694 (w), 670 (w), 624 (w), 544 (w), 509 (w) cm–1.
(S)-(5-2H)-2-Hexanone [(S)-16a]. According to the procedure reported above for the
non-deuterated compound 16b, hexene (S)-13a (600 mg, 7.04 mmol), Pd(OAc)2 (157
mg, 699 μmol, 0.1 equiv.) and TFA (804 mg, 7.05 mmol, 1.0 equiv.) were converted in
DMSO (14 mL) and H2O (1.4 mL) to furnish the title compound (S)-16a (400 mg, 3.95
mmol, 56%, based on 46% purity established by 1H NMR) after column
chromatography (SiO2, pentane/Et2O 9:1) as a slightly yellow liquid which was directly
used in the next step without further characterization. 1H NMR (500 MHz, CDCl3): δ =
0.90 (dt, J = 7.4 Hz, JHD = 1.0 Hz, 3H), 1.53–1.58 (m, 2H), 2.13 (s, 3H), 2.42 (t, J = 7.5
Hz, 2H) ppm; not all signals could be identified with certainty due to overlapping solvent
signals. The spectroscopic data were in accordance with those of the racemic
compound.
(3R,5S)-(5-2H)-3-Hydroxy-2-hexanone [(3R,5S)-17a]. According to the procedure
reported above for the preparation of the non-deuterated compound (R)-17b,
hexanone (S)-16a (400 mg, 3.95 mmol), a solution of nitrosobenzene (846 mg, 7.90
mmol, 2 equiv.) in DMSO (9.7 mL), L-proline (92 mg, 0.79 mmol, 0.2 equiv.), CuSO4
28
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10.1002/ejoc.202100360
European Journal of Organic Chemistry
(189 mg, 1.18 mmol, 0.3 equiv.) and MeOH (6.2 mL) were converted in DMSO (5 mL)
to furnish the title compound (3R,5S)-17a (100 mg, 0.85 mmol, 22% based on 87%
1
purity established by H NMR, 99% ee) after column chromatography (SiO2,
pentane/MTBE 2:1, Rf = 0.22) as a yellow liquid. 1H NMR (500 MHz, CDCl3): δ = 0.93
(dt, J = 7.4 Hz, JHD = 0.9 Hz, 3H), 1.32–1.41 (m, 1H), 1.48–1.54 (m, 1H), 1.78 (ddd, J
= 14.0, 10.4, 3.8 Hz, 1H), 2.18 (s, 3H), 3.43 (d, J = 4.3 Hz, 1H), 4.16 (dt, J = 7.2, 3.3
Hz, 1H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 13.85 (CH3), 17.86 (t, J = 19.5 Hz,
2
CHD), 25.24 (CH3), 35.68 (CH2), 76.82 (CH), 210.10 (C) ppm. H NMR (77 MHz,
CDCl3): δ = 1.42–1.54 (m, 1D) ppm. [α]D20 = –108 (CH2Cl2, 1.06 g L−1). IR (ATR): ν
̃ =
3467 (w), 2959 (w), 2933 (w), 2874 (w), 2162 (w), 1710 (s), 1457 (w), 1357 (m), 1289
(w), 1250 (w), 1222 (w), 1187 (w), 1117 (m), 1083 (w), 1059 (w), 1016 (w), 967 (w),
667 (w), 626 (w), 596 (w), 546 (w) cm–1.
Acknowledgment
We are grateful to Elisabeth Jaskulska for her assistance. This work was funded by
the Deutsche Forschungsgemeinschaft (GRK2226). MTBE was obtained as generous
gift from Evonik Industries, Marl, Germany.
Conflict of interest
The authors declare no conflict of interest.
29
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