Enantioselective synthesis of (R)-and (S)-1-2H-1-octanol and their corresponding amines

Article abstract of DOI:10.1080/00397911.2010.527422

Both enantiomers of 1-²H-1-octanol were obtained by the enzymatic reduction of deuterated octanal in the presence of alcohol dehydrogenases (ADH) (ADH-T or ADH-LB) as the biocatalyst in good yield, purity, and enantiomeric excess (<95%). The cofactor nicotinamide adenine dinucleotide phosphate was regenerated by the addition of isopropanol. To simplify the synthetic route, the direct reduction of octanal using the same enzymes and the same cofactor but adding deuterated isopropanol was evaluated. This provided a one-step procedure from a commercially available starting compound to both enantiomers of 1-²H-1-octanol in good yields (<80%) and good enantiomeric excess (～97%). The (S)-alcohols were converted to their corresponding (R)-amines, which showed ee's around 90%. Taylor & Francis Group, LLC.

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Enantioselective Synthesis of (R)-
and (S)-1-2H-1-Octanol and Their
Corresponding Amines
Diederik W. R. Balkenende a , Seda Cantekin a , Christopher J.
Duxbury b , Marcel H. P. van Genderen a , E. W. Meijer a & Anja R. A.
Palmans a
a Laboratory of Macromolecular and Organic Chemistry, Eindhoven
University of Technology, Eindhoven, the Netherlands
b DSM Research B. V., Geleen, the Netherlands
Accepted author version posted online: 04 Aug 2011.Published
online: 17 Oct 2011.
To cite this article: Diederik W. R. Balkenende , Seda Cantekin , Christopher J. Duxbury , Marcel
H. P. van Genderen , E. W. Meijer & Anja R. A. Palmans (2012) Enantioselective Synthesis of
(R)- and (S)-1-2H-1-Octanol and Their Corresponding Amines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:4, 563-573, DOI:
10.1080/00397911.2010.527422
To link to this article: http://dx.doi.org/10.1080/00397911.2010.527422
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Synthetic Communications1, 42: 563–573, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.527422
ENANTIOSELECTIVE SYNTHESIS OF (R)-
AND (S)-1-2H-1-OCTANOL AND THEIR
CORRESPONDING AMINES
Diederik W. R. Balkenende,1 Seda Cantekin,1
Christopher J. Duxbury,2 Marcel H. P. van Genderen,1
E. W. Meijer,1 and Anja R. A. Palmans1
1Laboratory of Macromolecular and Organic Chemistry, Eindhoven
University of Technology, Eindhoven, the Netherlands
2DSM Research B. V., Geleen, the Netherlands
GRAPHICAL ABSTRACT
Abstract Both enantiomers of 1-2H-1-octanol were obtained by the enzymatic reduction
of deuterated octanal in the presence of alcohol dehydrogenases (ADH) (ADH-T
or ADH-LB) as the biocatalyst in good yield, purity, and enantiomeric excess (>95%).
The cofactor nicotinamide adenine dinucleotide phosphate was regenerated by the addition
of isopropanol. To simplify the synthetic route, the direct reduction of octanal using the
same enzymes and the same cofactor but adding deuterated isopropanol was evaluated. This
provided a one-step procedure from a commercially available starting compound to both
enantiomers of 1-2H-1-octanol in good yields (>80%) and good enantiomeric excess
(ꢀ97%). The (S)-alcohols were converted to their corresponding (R)-amines, which
showed ee’s around 90%.
Keywords Asymmetric synthesis; biocatalysis; deuterium; NMR spectroscopy
INTRODUCTION
Chiral, deuterated compounds are useful mechanistic probes to elucidate
chemical and biological pathways.[1,2] Recently we became interested in chiral
Received June 14, 2010.
Address correspondence to E. W. Meijer or Anja R. A. Palmans, Laboratory of Macromolecular
and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600, MB Eindhoven, the
Netherlands. E-mail: e.w.meijer@tue.nl; a.palmans@tue.nl
563

564
D. W. R. BALKENENDE ET AL.
deuterated alkyl amines to prepare chiral C3-symmetrical benzene-1,3,5-tricarboxa-
mides (BTAs).[3] BTAs have received a lot of interest because of their highly coop-
erative self-assembly and strong chiral amplification effects in dilute solution.[4–6] In
our ongoing quest to understand BTA self-assembly, we found it desirable to synthe-
size both enantiomers of a deuterated BTA derivative. For this, we required an easy
and fast route to chiral (R)- and (S)-1-2H-1-octylamine of high enantiomeric purity.
Several chemical reductions are known to afford deuterated alcohols enantio-
selectively and the ee’s are usually moderate to good (typically ee < 92%).[2,7–12] In
addition, the biocatalytic synthesis of enantioenriched (S)-1-2H-1-hexanol via the
reduction of 1-2H-hexanal with Baker’s yeast, a well-known alcohol dehydrogenase,
was described but the ee of the product was not determined.[13] Later, Baker’s yeast
was applied for the reduction of 1-2H-octanal, affording (S)-1-2H-1-octanol with an
ee > 99%.[14] An alternative approach to obtain enantiopure deuterated alcohols was
found by reducing hexanal with alcohol dehydrogenases from horse liver (HL-ADH)
and Pseudomonas (PADH) using a deuterated cofactor to the corresponding (R)-1-
2H-1-hexanol and (S)-1-2H-1-hexanol, respectively.[15] The deuterated cofactor was
regenerated by the deuterium transfer from a deuterated solvent such as isopropanol
or ethanol. The ee’s of the deuterated alcohols were >97%, but the conversions were
far from quantitative and long reaction times were required.
Recently, new alcohol dehydrogenases from Lactobacillus brevis (ADH-LB, R-
selective) and Thermoanaerobacter sp. (ADH-T, S-selective), which are highly active
and show excellent enantioselectivity in the reduction of ketones (ee > 99%),[16] have
become commercially available. These enzymes depend on nicotinamide adenine
dinucleotide phosphate (NADPH) as a cofactor, which serves as reduction equiva-
lent. Both enzymes are able to oxidize isopropanol for cofactor regeneration, and
therefore only catalytic amounts of NADPH are needed. The reaction equilibrium
is driven by using an excess of isopropanol in buffer. To date, these ADHs have
not been explored to access optically pure deuterated alcohols.
Here we report the use of ADH-T and ADH-LB in the reduction of 1-2H-
octanal and (by applying a deuterated cofactor) of octanal to (R) and (S)-1-2H-1-
octanol with high ee and in good yields. The ee’s of all (R)- and (S)-1-2H-1-octanol
obtained were determined by using (R)-a-methoxy-a-trifluoromethylphenylacetyl
chloride (MTPA-Cl) derivatization, a useful chemical reagent for determining the
ee’s of the chiral alcohols via the formation of diastereomeric esters.[7,8] Finally, we
converted the (S)-alcohols into the corresponding (R)-amines and evaluated how this
procedure affects the enantiomeric excess.
RESULTS AND DISCUSSION
We first evaluated the reductions of deuterated octanal employing ADH-T and
ADH-LB (Scheme 1). Deuterated octanal was obtained following a previously
described three-step synthesis.[13] Reductions were performed in isopropanol and
potassium phosphate buffer (pH ¼ 7, 23–29% v=v) at substrate concentrations of
46–48 mM (Table 1). The reactions were monitored by gas chromatography–mass
spectrometry (GC-MS), and after 4 days the conversions were >98%. The alcohols
(R)-1 and (S)-1 were isolated in good yields (93–97%) and high purity as evidenced
by NMR spectroscopy and GC-MS.

ENANTIOSELECTIVE SYNTHESIS
565
Scheme 1. (a) Synthesis of (R)-1: ADH-LB, isopropanol, NADPH, phosphate buffer solution, MgCl2
solution, 36 ꢂC, 48 h, 97%; (S)-1: ADH-T, isopropanol, NADPH, phosphate buffer solution, 36 ꢂC,
48 h, 93%. (b) Synthesis of (R)-2: ADH-T, NADPH, isopropanol-d8, phosphate buffer solution, 36 ꢂC,
4 d, 81%; (S)-2: ADH-LB, NADPH, isopropanol-d8, phosphate buffer solution, 36 ꢂC, 4 d, 83%.
To avoid the lengthy synthesis of deuterated octanal, the reduction of octanal
using isopropanol-d8 to regenerate the cofactor was performed (Scheme 1). In this
case, ADH-LB affords (S)-2 while ADH-T affords (R)-2. We performed the reaction
at a lower isopropanol concentration and at a two times higher substrate concen-
tration. Within 4 days, quantitative conversions were obtained and the isolated yields
were >80% (Table 1). Both enantiomers were of high purity as evidenced by NMR
spectroscopy and GC-MS.
Subsequently, alcohols (R)-1, (S)-2, and (R)-2 were converted to their corre-
sponding chiral amines (S)-3, (R)-4, and (S)-4, respectively, following a previously
described procedure by tosylation, azidation, and reduction (Scheme 2).[13] All steps
proceeded in good yields and high purity as evidenced by NMR and GC-MS.
The optical purity of all alcohols and amines (S)-3 and (S)-4 was assessed by
derivatization employing MTPA-Cl (Scheme 3).[7,8] The NMR spectra of the diaster-
eomeric compounds were quantified to determine the ee’s. To facilitate the interpret-
ation of the NMR spectra of the enantiomers, we synthesized the racemic alcohol
(rac)-5 and its amine derivative (rac)-6, which were converted to their MTPA ester
and amide derivatives.
In the 1H NMR spectrum of MTPA ester of rac-5, the –OCH– proton resonates
as two overlapping triplets with equal intensity (Fig. 1). Deconvolution of the
overlapping peaks gave an ee of 0% (Table 2, entry 1). Following this procedure,
the ee’s of (R)-1, (S)-1 and (R)-2, (S)-2 (Table 2, entries 2–5) were found to be
97 ꢁ 1%, 97 ꢁ 1%, 97 ꢁ 1%, and 89 ꢁ 1%, respectively. Alcohol (R)-2 (synthesized
via reduction with a deuterated cofactor) shows the same ee as (R)-1 synthesized
Table 1. Enzymatic reduction of (deuterated) octanal
Substrate
Solvent (%v=v)a
Concentration (mM)
Enzyme
Alcohol
Isolated yield (%)
D-octanal
D-octanal
Octanal
IPA=H2O, 23
IPA=H2O, 29
46
48
ADH-LB
ADH-T
ADH-T
ADH-LB
(R)-1
(S)-1
(R)-2
(S)-2
97
93
81
83
IPA-d8=H2O, 11
IPA-d8=H2O, 12
93
103
Octanal
aIPA, isopropanol.

566
D. W. R. BALKENENDE ET AL.
Scheme 2. Synthesis of (R)- and (S)-1-2H-1-octylamine. Experimental conditions: (a) TsCl, pyridine, 4 ꢂC,
5 h, 89%; (b) NaN3, DMF, 70 ꢂC, overnight, 85%; and (c) LiAlH4, ether, reflux, 2 h, 85%.
Scheme 3. Synthesis of diastereomeric MTPA-esters and amides.
via the normal enzymatic reduction process. The slightly lower ee of 89% measured
for (S)-2 is presumably the result of nonoptimal reduction conditions. The high
concentration (103 mM) employed in this reaction may have negatively influenced
its enantioselectivity.
We then analyzed the MTPA amides of (rac)-6, (S)-3, and (S)-4 (Fig. 2). Two
(overlapping) quartet peaks with equal intensities at 3.32 and 3.28 ppm were
identified for the MTPA amide of (rac)-6 which, after deconvoluting the spectra,
1
gave an ee of 0% (Table 2, entry 6). The H NMR spectra of the MTPA amide of
(S)-3 and (S)-4 show a large quartet at 3.32 ppm and a small partially overlapping
quartet at 3.28 ppm. In these cases, the ee’s were around 90%, indicating that the
inversion of configuration that takes place when converting the chiral alcohol into
the chiral amine proceeds with high selectivity.
Figure 1. 1H NMR spectra of MTPA esters of (a) (R)-1, (b) (S)-2, and (c) (rac)-5.

ENANTIOSELECTIVE SYNTHESIS
567
Table 2. The ee’s of chiral deuterated alcohols and amines
Entry
Alcohol=aminea
Eeb,c (%)
1
2
3
4
5
6
7
8
(rac)-5
(R)-1
(S)-1
(R)-2
(S)-2
(rac)-6
(S)-3
(S)-4
0
97 ꢁ 1
97 ꢁ 1
97 ꢁ 1
89 ꢁ 1
0
89 ꢁ 1
90 ꢁ 1
aAll compounds were converted into their MTPA ester or amide
derivatives.
bEe [¼(R ꢃ S)=(R þ S)] was calculated from the intensities of
–XCH– signals in the 1H NMR spectra of the diastereomeric MTPA
derivatives by using deconvolution to resolve overlapping peaks.
cThe error on the ee by deconvolution of the spectra was determined
by performing an error propagation analysis assuming that the inten-
sity of the 1H NMR signals possesses an uncertainty of 10%.
Figure 2. 1H NMR spectra of MTPA amides of (a) (S)-3, (b) (S)-4, and (c) (rac)-6.
CONCLUSIONS
Both enantiomers of 1-2H-1-octanol are accessible in good yields and purity by
applying alcohol dehydrogenases ADH-T or ADH-LB in the reduction step. More-
over, the use of a deuterated cofactor allows the one-step synthesis of (R)-1-2H-1-
octanol and (S)-1-2H-1-octanol starting from octanal whereby the synthesis of deut-
erated octanal can be avoided. In all cases, excellent ee’s of ꢀ97% were achieved. The
conversion of (R)-1-2H-1-octanol to (S)-1-2H-1-octylamine proceeded in good yields
and enantiomeric excess (ꢀ90%). This biocatalytic route provides a simple and fast

568
D. W. R. BALKENENDE ET AL.
access to stereoselectively labeled deuterated amines from commercially available
aldehydes.
EXPERIMENTAL
1H NMR (400 MHz and 500 MHz) and 13C NMR (100 MHz) spectra were
recorded on Varian spectrometers (Varian Mercury Vx 400 or Varian Unity Inova
2
500) in deuterated chloroform unless stated otherwise. H NMR was measured on
a Varian Unity Inova 500 spectrometer by dissolving the sample in chloroform and
adding 10 mL of deuterated chloroform in the NMR tube. The spectra were referenced
to deuterated chloroform (7.26 ppm). Chemical shifts are reported in parts per million
(ppm) and referenced to tetramethylsilane (TMS). Peaks are noted as singlet (s),
doublet (d), triplet (t), quartet (q), quintet (qui), or heptet (h), and broadened peaks
are noted as (br). Deconvolution was performed by using the linefit in MestReNova
version 6.0.3-5604. To verify to upper and lower values of the ee’s, considering the
1
uncertainty of the H NMR signals, an error propagation analysis was performed.
GC-MS was performed on a Shimadzu GC-MS-QP5000 equipped with a Zebron
ZB-5 column and an autosampler. All GC-MS measurements were done with injector
temperature at 300 ꢂC and detector temperature at 300 ꢂC. Infrared (IR) spectra were
recorded on a Perkin-Elmer spectrum 1 using a universal attenuated total reflectance
(ATR).
Deuterated octanal was prepared according to Ref. 13. Octanal, ethyl octanoate,
LiAlD4, phosphate buffered saline, and isopropanol-d8 were obtained from Sigma-
Aldrich. Cofactor NADPH and alcohol dehydrogenases from Lactobacillus brevis
[ADH-LB, (R)-selective, 4100 U=mL] and Thermoanaerobacter sp. [ADH-T, (S)-
selective, 331 U=mL] were purchased from Julich Chiral Solutions GmbH. (R)-(ꢃ)-
a-Methoxy-a-trifluoromethylphenylacetyl chloride [(R)-(–)-MTPA-Cl] was purchased
from Acros. All other chemicals were purchased from Sigma-Aldrich and used as
received unless otherwise noted. All solvents were purchased from Biosolve. Ether
was dried over molsieves. Phosphate buffered saline was dissolved in deionized water
to prepare phosphate buffer solution (pH 7.4, 50 mM) and was used for the enzymatic
reduction reactions. All alcohols and amines [except (R)-1 and 2] were converted to
their diastereomeric MTPA ester and amide derivatives by treating with commercially
available (R)-(–)-MTPA-Cl following a modified literature procedure.[8]
(R)-1-2H-1-Octanol [(R)-1]
Deuterated octanal (1.16 g, 9 mmol) was dissolved in isopropanol (45 mL). To
this mixture, phosphate buffer solution (150 mL) and NADPH (265 mg) were added.
A few drops of MgCl2 solution in distilled water (0.1 M) was added to the reaction mix-
ture. When the temperature was set to 36 ꢂC, the enzyme ADH-LB (308 U) was added
to the reaction mixture. The mixture was left stirring at that temperature for 48 h. The
mixture was washed with ether (3 ꢄ 50 mL), and the combined organic layers were
dried with MgSO4. After the solvent was evaporated, (R)-1 was obtained as a colorless
oil (1.14 g, 97%). ee ¼ 97 ꢁ 1%. 1H NMR (400 MHz, CDCl3): d ¼ 3.56 (tt, J ¼ 6.8 and
1.2 Hz, 1H, -CH2CHDOH), 1.51 [q, J ¼ 6.8 Hz, 2H, -(CH2)5CH2CHDOH], 1.27 [m,
10H, CH3(CH2)5CH2-], 0.85 [t, J ¼ 7.2 Hz, 3H, CH3(CH2)5-] ppm. 2H NMR

ENANTIOSELECTIVE SYNTHESIS
569
(500 MHz, CDCl3): d ¼ 3.65 (s, -CD) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 62.0 (t),
32.5, 31.7, 29.3, 26.1, 25.6, 22.5, 14.0 ppm. GC-MS temperature program:
50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 2.64 min, purity >99.5%, major peaks:
[Mþ-CHDOH] ¼ 99,
[Mþ-CH2CHDOH] ¼ 84,
[Mþ-CH4CHDOH] ¼ 70,
[Mþ-CH6CHDOH] ¼ 57, [Mþ-CH8CHDOH] ¼ 43. FT-IR: n ¼ 3336 (br), 2956 (s),
2856 (s), 2157 (w), 1711 (s), 1466 (m), 1069 (m), 939 (m), 723 (w).
(S)-1-2H-1-Octanol [(S)-1]
Deuterated octanal (1.29 g, 10 mmol) was dissolved in isopropanol (60 mL). To
this mixture, phosphate buffer solution (150 mL) and NADPH (326 mg) were added.
Instead of using ADH-LB for the reduction, ADH-T (155 U) was used. MgCl2
solution was not required for this enzyme. (S)-1 was obtained as a colorless oil
1
(1.22 g, 93%). ee ¼ 97 ꢁ 1%. H NMR (400 MHz, CDCl3): d ¼ 3.56 (tt, J ¼ 6.8 and
1.2 Hz, 1H, -CH2CHDOH), 1.51 [q, J ¼ 6.8 Hz, 2H, -(CH2)5CH2CHDOH], 1.27
2
[m, 10H, CH3(CH2)5CH2-], 0.85 [t, J ¼ 7.2 Hz, 3H, CH3(CH2)5-] ppm. H NMR
(500 MHz, CDCl3): d ¼ 3.65 (s, -CD) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 62.0
(t), 32.5, 31.7, 29.3, 26.1, 25.6, 22.5, 14.0 ppm. GC-MS temperature program:
50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 2.64 min, purity >99.5%, major peaks:
[Mþ-CHDOH] ¼ 99, [Mþ-CH2CHDOH] ¼ 84, [Mþ-CH4CHDOH] ¼ 70, [Mþ-
CH6CHDOH] ¼ 57, [Mþ-CH8CHDOH] ¼ 43. FT-IR: n ¼ 3336 (br), 2956 (s), 2856
(s), 2157 (w), 1711 (s), 1466 (m), 1069 (m), 939 (m), 723 (w).
(S)-1-2H-1-Octylamine [(S)-3]
(R)-1-2H-Octyl 4-methylbenzenesulfonate. p-Toluenesulfonyl chloride
(1.56 g, 8.4 mmol) was dissolved in dry pyridine (10 mL) in a round-bottom flask
and cooled down to 0 ꢂC. (R)-1 (1.0 g, 7.6 mmol) was added dropwise to this mixture.
The reaction mixture was left stirring overnight at 4 ꢂC. The mixture was quenched
with ice and extracted with ether (3 ꢄ 50 mL). The combined organic layers were
washed sequentially with 1 M HCl solution, water, and brine. The organic layer
was dried over MgSO4. The solvent was removed by in vacuo at 50 ꢂC. The isolated
1
product yielded a yellowish oil (1.95 g, 89%). H NMR (400 MHz, CDCl3): d ¼ 7.78
[d, J ¼ 8.4 Hz, 2H, -SO2C(CHCH)2CCH3], 7.33 [d, J ¼ 8.4 Hz, 2H, -SO2C(CHCH)2
CCH3], 3.99 (t, J ¼ 6.6 Hz, 1H, -CH2CHDO-), 2.45 [s, 3H, -SO2C(CHCH)2CCH3],
1.66 [q, J ¼ 6.6 Hz, 2H, (CH2)5CH2CHDO], 1.23 [m, 10H, CH3(CH2)5CH2], 0.86 [t,
J ¼ 7.2 Hz, 3H, CH3(CH2)5-] ppm. 13C NMR (100 MHz, CDCl3): d ¼ 144.6, 133.2,
129.8, 71.5 (t), 31.7, 29.0, 28.8, 28.5, 25.3, 127.8, 22.5, 21.6, 14.0 ppm. GC-MS
temperature program: 50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 7.39 min, purity ¼
>99.5%, major peaks: [Mþ-C7H15CDH] ¼ 127, [Mþ-OTs] ¼ 113, [Mþ-C4H9] ¼ 99,
[Mþ-CH2CHDOTs] ¼ 84, [Mþ-CH4CHDOTs] ¼ 70, [Mþ-CH6CHDOTs] ¼ 57, [Mþ-
CH8CHDOTs] ¼ 43.
(S)-1-2H-1-Azidooctane. The tosylate (1.95 g, 6.8 mmol) was dissolved in
DMF (30 mL). While stirring the reaction mixture at room temperature, NaN3
(4.4 g, 68 mmol) was added as a solid in proportions to this solution. The reaction
mixture was left stirring at 70 ꢂC overnight. Subsequently the mixture was poured

570
D. W. R. BALKENENDE ET AL.
into ice water (200 mL) and extracted with ether (3 ꢄ 50 mL). The combined organic
layers were washed with water and brine. The organic layer was dried over MgSO4.
1
After removal of solvent, the product was obtained as clear oil (0.9 g, 85%). H
NMR (400 MHz, CDCl3): 3.23 (tt, J ¼ 7.2 and 1.6 Hz, 1H, -CH2CDHN3), 1.56 [q,
J ¼ 7.2 Hz, 2H, -(CH2)5CH2CDHN3], 1.28 [m, 10H, CH3(CH2)5CH2-], 0.85 [t,
J ¼ 7.2 Hz, 3H, CH3(CH2)5-] ppm. 13C NMR (100 MHz, CDCl3): 51.1 (t), 31.7,
29.2, 26.6, 22.5, 15.2, 14.0 ppm. GC-MS temperature program: 50 ꢂC j 15 min !
300 ꢂC, 10 ꢂC=min. tR ¼ 2.73 min, purity ¼ 88%, major peaks: [Mþ-N2] ¼ 127,
[Mþ-N3] ¼ 113, [Mþ-C4H9] ¼ 99, [Mþ-CH2CHDN3] ¼ 84, [Mþ-CH4CHDN3] ¼ 70,
[Mþ-CH6CHDN3] ¼ 57, [Mþ-CH8CHDN3] ¼ 43. FT-IR: 2956 (s), 2856 (s), 2157
(w), 2092 (s), 1677 (m), 1466 (m), 1069 (m), 939 (m), 723 (w).
(S)-1-2H-1-Octylamine. LiAlH4 solution (9.9 mL, 1.0 M in ether) was placed
in a round-bottom flask under argon atmosphere and diluted with additional ether
(10 mL). The mixture was cooled down to 0 ꢂC. To this solution, (S)-1-2H-octylazide
(0.7 g, 4.5 mmol) in ether (40 mL) was added dropwise. The mixture was refluxed for
2 h, cooled down using an ice bath, and quenched slowly with ice water. The mixture
was extracted with ether (3 ꢄ 50 mL). The combined organic layers were washed with
water and dried over MgSO4. The solvent was removed under reduced pressure. The
1
product was isolated as a clear oil (0.5 g, 85%). Ee ¼ 89 ꢁ 1%. H NMR (400 MHz,
CDCl3): 2.62 (t, J ¼ 6.8 Hz, 1H, -CH2CDHNH2), 1.60 (br. s, 2H, -CH2CDHNH2),
1.40 [q, J ¼ 6.8 Hz, CH3(CH2)5CH2CDHNH2], 1.20 [m, 10H, CH3(CH2)5CH2
CDHNH2], 0.85 [t, J ¼ 7.2, 3H, CH3(CH2)5CH2CDHNH2] ppm. 13C NMR
(100 MHz, CDCl3): 41.7 (t), 33.6, 31.7, 29.2, 26.8, 22.6, 15.2, 14.0 ppm. GC-MS
temperature program: 50 ꢂC j 15 min
!
300 ꢂC, 10 ꢂC=min. tR ¼ 2.00 min,
purity ¼ 94%, major peaks: [Mþ] ¼ 130, [Mþ-NH2] ¼ 113, [Mþ-C2H5] ¼ 101, [Mþ-
CH2CHDNH2] ¼ 84, [Mþ-CH4CHDNH2] ¼ 70, [Mþ-CH6CHDNH2] ¼ 57, [Mþ-
CH8CHDNH2] ¼ 43. FT-IR: 2956 (s), 2856 (s), 2157 (w), 1466 (m), 1069 (m), 939
(m), 723 (w).
(R)-1-2H-1-Octanol [(R)-2]
Octanal (3.0 g, 23 mmol) was dissolved in isopropanol-d8 (28 mL). To this sol-
ution, phosphate buffer solution (220 mL) and NADPH (1.0 g) were added. Then,
the temperature was set to 36 ꢂC; ADH-T (331 U) was added to the reaction mixture,
which was left stirring at 36 ꢂC for 4 days. The reaction was monitored by GC-MS
and NMR spectroscopy. The mixture was extracted with ether (3 ꢄ 50 mL), and the
organic layer was dried over MgSO4. The solvent was evaporated, and the desired
alcohol (R)-2 was obtained as a colorless oil (2.50 g, 81%). The alcohol was used
1
without further purification. Ee ¼ 97 ꢁ 1%. H NMR (400 MHz, CDCl3): d ¼ 3.56
(tt, J ¼ 6.8 and 1.2 Hz, 1H, -CH2CHDOH), 1.51 [q, J ¼ 6.8 Hz, 2H, -(CH2)5CH2
CHDOH], 1.27 [m, 10H, CH3(CH2)5CH2-], 0.85 [t, J ¼ 7.2 Hz, 3H, CH3(CH2)5-]
ppm. 13C NMR (100 MHz, CDCl3): d ¼ 62.0 (t), 32.5, 31.7, 29.3, 26.1, 25.6, 22.5,
14.0 ppm. GC-MS temperature program: 50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼
2.64 min, purity >99.5%, major peaks: [Mþ-CHDOH] ¼ 99, [Mþ-CH2CHDOH] ¼
84, [Mþ-CH4CHDOH] ¼ 70, [Mþ-CH6CHDOH] ¼ 57, [Mþ-CH8CHDOH] ¼ 43.

ENANTIOSELECTIVE SYNTHESIS
571
FT-IR: n ¼ 3336 (br), 2956 (s), 2856 (s), 2157 (w), 1711 (s), 1466 (m), 1069 (m), 939
(m), 723 (w).
(S)-1-2H-1-Octylamine [(S)-4]
The desired amine (S)-4 was obtained from (R)-2 by following the same
procedure as described previously. Ee ¼ 90ꢁ1%. 1H NMR (400 MHz, CDCl3):
d ¼ 2.62 (t, J ¼ 6.8 Hz, 1H, -CH2CDHNH2), 1.60 (br. s, 2H, -CH2CDHNH2), 1.40
[q, J ¼ 6.8 Hz, CH3(CH2)5CH2CDHNH2], 1.2 [m, 10H, CH3(CH2)5CH2CDHNH2],
0.85 [t, J ¼ 7.2, 3H, CH3(CH2)5CH2CDHNH2] ppm. 13C NMR (100 MHz, CDCl3):
d ¼ 41.7 (t), 33.6, 31.7, 29.2, 26.8, 22.6, 15.2, 14.0 ppm. GC-MS temperature
program: 50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 2.00 min, purity ¼ 94%, major
peaks: [Mþ] ¼ 130, [Mþ-NH2] ¼ 113, [Mþ-C2H5] ¼ 101, [Mþ-CH2CHDNH2] ¼ 84,
[Mþ-CH4CHDNH2] ¼ 70, [Mþ-CH6CHDNH2] ¼ 57, [Mþ-CH8CHDNH2] ¼ 43.
FT-IR: n ¼ 2956 (s), 2856 (s), 2157 (w), 1466 (m), 1069 (m), 939 (m), 723 (w).
(S)-1-2H-1-Octanol [(S)-2]
Octanal (1.5g, 11.7 mmol) was dissolved in isopropanol-d8 (14 mL). To this sol-
ution, phosphate buffer solution (100mL), NADPH (0.5 g), and a few drops of MgCl2
(0.1 M in distilled water) were added. The temperature was set to 36ꢂC, ADH-LB
(380U) was added, and the reaction mixture was left stirring at 36ꢂC for 4 days.
The same procedure was followed to obtain alcohol (S)-2 as colorless oil (1.25 g,
1
83%). Ee ¼ 89ꢁ 1%. H NMR (400MHz, CDCl3): d ¼ 3.56 (tt, J ¼ 6.8 and 1.2 Hz,
1H, -CH2CHDOH), 1.51 [q, J ¼ 6.8 Hz, 2H, -(CH2)5CH2CHDOH], 1.27 [m, 10H,
CH3(CH2)5CH2-], 0.85 [t, J ¼ 7.2 Hz, 3H, CH3(CH2)5-] ppm. 13C NMR (100MHz,
CDCl3): d ¼ 62.0 (t), 32.5, 31.7, 29.3, 26.1, 25.6, 22.5, 14.0 ppm. GC-MS temperature
program: 50ꢂC j 15min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 2.64min, purity >99.5%, major
peaks: [Mþ-CHDOH] ¼ 99, [Mþ-CH2CHDOH] ¼ 84, [Mþ-CH4CHDOH]¼ 70, [Mþ-
CH6CHDOH] ¼ 57, [Mþ-CH8CHDOH] ¼ 43. FT-IR: n ¼ 3336 (br), 2956 (s), 2856
(s), 2157 (w), 1711 (s), 1466 (m), 1069 (m), 939 (m), 723 (w).
(R)-1-2H-1-Octylamine [(R)-4]
The desired amine (R)-4 was obtained from (S)-2 by following the same pro-
cedure as described previously. 1H NMR (400 MHz, CDCl3): d ¼ 2.62 (t, J ¼ 6.8 Hz,
1H, -CH2CDHNH2), 1.60 (br. s, 2H, -CH2CDHNH2), 1.40 [q, J ¼ 6.8 Hz, CH3(CH2)5
CH2CDHNH2], 1.2 [m, 10H, CH3(CH2)5CH2CDHNH2], 0.85 [t, J ¼ 7.2, 3H,
CH3(CH2)5CH2CDHNH2] ppm. 13C NMR (100 MHz, CDCl3): d ¼ 41.7 (t),
33.6, 31.7, 29.2, 26.8, 22.6, 15.2, 14.0 ppm. GC-MS temperature program:
50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 2.00 min, purity ¼ 94%, major peaks:
[Mþ] ¼ 130, [Mþ-NH2] ¼ 113, [Mþ-C2H5] ¼ 101, [Mþ-CH2CHDNH2] ¼ 84, [Mþ-
CH4CHDNH2] ¼ 70, [Mþ-CH6CHDNH2] ¼ 57, [Mþ-CH8CHDNH2] ¼ 43. FT-IR:
n ¼ 2956 (s), 2856 (s), 2157 (w), 1466 (m), 1069 (m), 939 (m), 723 (w).
(rac)-1-2H-1-Octanol [(rac)-5]
Octanal (2.0 g, 16.5 mmol) in ether (20 mL) was added dropwise to a solution of
LiAlD4 (0.43 g, 10.1 mmol) in ether (10 mL) at 0 ꢂC. The reaction mixture was

572
D. W. R. BALKENENDE ET AL.
refluxed for 2 h and then quenched with ice water (10 mL) slowly. The mixture was
extracted with ether (3 ꢄ 50 mL). The combined organic layers were washed with
HCl (1 M) solution, water, and dried over MgSO4. The solvent was removed under
1
reduced pressure. The product was isolated as clear oil (1.95 g, 95%). H NMR
(400 MHz, CDCl3): d ¼ 3.56 (tt, J ¼ 6.8 and 1.2 Hz, 1H, -CH2CHDOH), 1.51 [q,
J ¼ 6.8 Hz, 2H, -(CH2)5CH2CHDOH], 1.27 [m, 10H, CH3(CH2)5CH2-], 0.85 [t,
J ¼ 7.2 Hz, 3H, CH3(CH2)5-] ppm. 13C NMR (100 MHz, CDCl3): d ¼ 62.0 (t),
32.5, 31.7, 29.3, 26.1, 25.6, 22.5, 14.0 ppm. GC-MS temperature program:
50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min. tR ¼ 2.64 min, purity >99.5%, major peaks:
[Mþ-CHDOH] ¼ 99, [Mþ-CH2CHDOH] ¼ 84, [Mþ-CH4CHDOH] ¼ 70, [Mþ-
CH6CHDOH] ¼ 57, [Mþ-CH8CHDOH] ¼ 43.
(rac)-1-2H-1-Octylamine [(rac)-6]
The desired racemic amine was obtained from (rac)-5 (3.53 g, 27 mmol) as a yel-
lowish oil (3.50 g, 99%) by following the same procedure as described previously. 1H
NMR (400 MHz, CDCl3): d ¼ 2.62 (t, J ¼ 6.8 Hz, 1H, -CH2CDHNH2), 1.60 (br. s,
2H, -CH2CDHNH2), 1.40 [q, J ¼ 6.8 Hz, CH3(CH2)5CH2CDHNH2], 1.2 [m, 10H,
CH3(CH2)5CH2CDHNH2], 0.85 [t, J ¼ 7.2, 3H, CH3(CH2)5CH2CDHNH2] ppm.
13C NMR (100 MHz, CDCl3): d ¼ 41.7 (t), 33.6, 31.7, 29.2, 26.8, 22.6, 15.2,
14.0 ppm. GC-MS temperature program: 50 ꢂC j 15 min ! 300 ꢂC, 10 ꢂC=min.
tR ¼ 2.00 min, purity ¼ 94%, major peaks: [Mþ] ¼ 130, [Mþ-NH2] ¼ 113, [Mþ-
C2H5] ¼ 101, [Mþ-CH2CHDNH2] ¼ 84, [Mþ-CH4CHDNH2] ¼ 70, [Mþ-CH6
CHDNH2] ¼ 57, [Mþ-CH8CHDNH2] ¼ 43.
General Synthesis Procedure for MTPA Derivatives
The desired alcohol or amine (0.10 mmol) was dissolved in dry chloroform
(300 mL) under an argon atmosphere. To this solution, dry pyridine (300 mL) and
(R)-(ꢃ)-a-methoxy-a-trifluoromethylphenylacetyl chloride [(R)-(ꢃ)-MTPA-Cl]
(26 mL, 0.14 mmol) were injected using a syringe. The reaction mixture was stirred
overnight at room temperature. A few drops of water were added, and the mixture
was left stirring for 10 min. The mixture was diluted with ether (10 mL) and washed
with cold HCl (1 M), Na2CO3, and saturated brine solution. The combined organic
layers were dried on MgSO4, and subsequently the solvent was removed under
reduced pressure. The desired ester or amide was obtained as a colorless oil in quan-
titative yield. The NMR spectra of these samples were recorded, and the relative
proportions of the diastereomers were determined from the integrals of the proton
signals.
ACKNOWLEDGMENTS
The authors would like to thank the Dutch National Research School Combi-
nation Catalysis Controlled by Chemical Design (NRSC-C) and the Dutch Science
Foundation (NWO) for financial support. The authors thank Andreas Heise and
Bahar Yeniad for helpful discussions on enzymatic reductions of (deuterated)
octanal.

ENANTIOSELECTIVE SYNTHESIS
573
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