The absolute configuration of the (+)- and (-)-cis- and (+)- and (-)-trans-1-benzyl-4-hydroxypiperidine-3-methanols: An unusual application of the1H-NMR-mosher method

Article abstract of DOI:10.1002/hlca.200800270

The enantiomerically pure title compounds were prepared and the absolute configurations assigned by the high-field ¹H-NMR application of the Mosher method on the bis-MTPA derivatives (MTPA - a-methoxy-a-(trifluoromethyl) benzeneacetic acid). Th

Full text of DOI:10.1002/hlca.200800270

14
Helvetica Chimica Acta – Vol. 92 (2009)
The Absolute Configuration of the (þ)- and (ꢀ)-cis- and (þ)- and (ꢀ)-trans-1-
Benzyl-4-hydroxypiperidine-3-methanols: An Unusual Application of the
1H-NMR-Mosher Method
by Christian Clerc, Igor Matarazzo, and Peter Rꢀedi*
Organisch-chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41-44-6354241; e-mail: peru@oci.uzh.ch)
The enantiomerically pure title compounds were prepared and the absolute configurations assigned
by the high-field 1H-NMR application of the Mosher method on the bis-MTPA derivatives (MTPA ¼ a-
methoxy-a-(trifluoromethyl)benzeneacetic acid). The final evidence for the adaptability of the
procedure was effected by X-ray crystallographic analyses. The absolute configurations of the cis- and
trans-1-benzyl-4-hydroxypiperidine-3-methanols are as follows: (þ)-(3S,4S) and (ꢀ)-(3R,4R) (cis), and
(þ)-(3R,4S) and (ꢀ)-(3S,4R) (trans), respectively (Scheme 2). Nonfermenting bakersꢂ yeast reduction of
methyl 1-benzyl-4-oxopiperidine-3-carboxylate afforded (þ)-methyl (3R,4S)-1-benzyl-4-hydroxypiper-
idine-3-carboxylate (de > 97%, ee > 99%) which was further reduced to the (þ)-(3S,4S)-diol
(Scheme 3). The result confirms the stereochemical outcome of the biological reduction with re-face
selectivity and cis-diastereoselectivity as predicted for bakersꢂ yeast. The 4-hydroxypiperidine-3-
methanols are the key starting compounds for the synthesis of the enantiomerically pure P(3)-axially and
P(3)-equatorially substituted cis- and trans-configurated 8-benzyl-2,4-dioxa-8-aza-3-phosphadecalin 3-
oxides (¼ 8-benzyl-2,4-dioxa-8-aza-3-phospha-bicyclo[4.4.0]decane 3-oxides) representing g-homo-ace-
tylcholine mimetics.
1. Introduction. – In the course of our studies on the inhibition of acetylcholines-
terase and related serine hydrolases by organophosphates – in particular the
investigation of the stereochemical course of the inhibition reaction [1] and the
physiologically active conformation of acetylcholine [2] – we have prepared several 3-
substituted, cis- and trans-2,4-dioxa-9-aza- (Type I), 2,4-dioxa-8-aza- (Type II), and 2,4-
dioxa-7-aza-3-phosphabicyclo[4.4.0]decane 3-oxides (Type III) as racemates [3]
(Scheme 1). These heterocycles are configuratively fixed and conformationally con-
strained acetylcholine (7-aza- and 9-aza isomers) or g-homo-acetylcholine mimetics (8-
Scheme 1
ꢃ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 92 (2009)
15
aza isomers). Actually, we have completed the syntheses of all these organophosphates
in the enantiomerically pure form (ee > 99%) and established their absolute config-
urations. Key compounds are the respective cis- and trans-diols I – III that are
accessible from suitable starting materials such as appropriately substituted piperidi-
none or pyridine precursors.
During our work on the preparation of the enantiomerically pure piperidineme-
thanols II and the 8-aza-3-phosphadecalins (Type II, Scheme 1) [4], we became aware
that the absolute configurations of the title compounds are not adequately described in
the current literature. In the present report, we conclusively assign the absolute
configurations of the cis- and trans-configurated 4-hydroxypiperidine-3-methanols and
the respective correlation with the chiroptical data.
2. Results and Discussion. – 2.1. Preparation of the (þ)- and (ꢀ)-cis- and (þ)- and
(ꢀ)-trans-4-Hydroxypiperidine-3-methanols ((þ)- and (ꢀ)-3, and (þ)- and (ꢀ)-2,
resp.). Following the protocol for the preparation of the racemic compounds [3], ethyl
1-benzyl-4-oxopiperidine-3-carboxylate (1a) was reduced with NaBH4, the resulting
mixture (ꢁ)-2/(ꢁ)-3 (ca. 1:2) transformed in situ into the acetonides (ꢁ)-4/(ꢁ)-5 and
the diastereoisomers separated by chromatography (SiO2). Prep. HPLC (Chiralcelꢀ
OD) of the pure trans- and cis-isomers (ꢁ)-4 and (ꢁ)-5, respectively, afforded the
optically active acetonides (þ)-4 (k’ ¼ 2.60, ee > 99%), (ꢀ)-4 (k’ ¼ 2.22, ee > 98%)1),
(þ)-5 (k’ ¼ 2.00, ee > 99%), and (ꢀ)-5 (k’ ¼ 3.11, ee > 99%), resp. (Scheme 2) [4].
Hydrolysis of the respective acetonides gave the 1-benzyl-4-hydroxypiperidine-3-
methanols (þ)-2 ([a]D ¼ þ9.2, ee > 98%)1), (ꢀ)-2 ([a]D ¼ ꢀ9.8, ee > 99%), (þ)-3
([a]D ¼ þ16.7, ee > 99%), and (ꢀ)-2 ([a]D ¼ ꢀ16.6, ee > 99%), respectively
(Scheme 2).
2.2. The Absolute Configurations of the Diols (þ)- and (ꢀ)-2 and (þ)- and (ꢀ)-3.
The absolute configurations of the diols (þ)- and (ꢀ)-2 and (þ)- and (ꢀ)-3 were
tentatively inferred from an unusual extension of the high-field NMR application of the
Mosher method [5]. As discussed earlier [6], it was not assured a priori that this
procedure is reliably applicable to our N-heterocyclic compounds. Although the
extension to the bis-(R)-MTPA derivatives 6a – 9a and the bis-(S)-MTPA derivatives
6b – 9b (Scheme 2) renders the concept even more doubtful, the respective MTPA
1
esters were prepared and their H-NMR spectra analyzed (MPTA ¼ a-methoxy-a-
(trifluoromethyl)benzeneacetic acid). Esterification of (þ)- and (ꢀ)-2 with (þ)-(S)-
MTPAꢀCl (¼(þ)-(S)-a-methoxy-a-(trifluoromethyl)benzeneacetyl chloride) afford-
ed the (R)-esters 6a and 7a, and the corresponding (S)-esters 6b and 7b were isolated
after reaction of (þ)- and (ꢀ)-2 with (ꢀ)-(R)-MTPAꢀCl. The same procedure was
performed with (þ)- and (ꢀ)-3 to yield the (R)-MTPA esters 8a and 9a and the (S)-
MTPA esters 8b and 9b (Scheme 2).
1
In the trans-series, the thorough analysis of the H-NMR data led to a provisional
assignment of the absolute configurations such as (þ)-(3R,4S)-2, and (ꢀ)-(3S,4R)-2.
1
)
Although the method had been optimized to afford enantiomerically pure (ꢀ)-4 ([a]D ¼ ꢀ29.3,
ee > 99%) in rather small amounts and the resolution is more than satisfactory (RS > 4), bigger
fractions of (ꢀ)-4 did not exceed ee > 98%. As a consequence, (þ)-2 did not exceed ee > 98%.

16
Helvetica Chimica Acta – Vol. 92 (2009)

Helvetica Chimica Acta – Vol. 92 (2009)
17
The results were self-contained, in particular, the Dd values (¼d(S) – d(R)) of the
diagnostically relevant signals were consistent: For the couple 6a/6b, we observed
Dd(CH2(2) and HꢀC(3)) > 0 and Dd (CH2(5)) < 0, and the inverse was found in the
couple 7a/7b (see Exper. Part)2). But the fact that Dd(HꢀC(4)) ¼ꢁ 0.01 for 6a/6b and
7a/7b is indicative for a deviation from the ideal conformation of the MTPA moiety3),
and, as a consequence, the reliability of the experiment is significantly reduced. Hence,
the assignments of the absolute configurations are arguable and must be verified by an
independent method. The X-ray crystallographic analysis of 6b furnished the definite
evidence (Fig.)4). It fully corroborated the assigned absolute configuration of the
trans-4-hydroxypiperidine-3-methanols: (þ)-(3R,4S)-2 (cf. Fig.) and (ꢀ)-(3S,4R)-2.
Moreover, the crystal structure demonstrated that the conformation of the diagnos-
tically relevant moiety at C(4) coincides with the assumed one3). In contrast, the
MPTA – OCH2 group at C(3) adopts the anti-conformation of C¼O and CF3 that
results in the inversed relative position of the shielding phenyl group, thus suggesting
that the observed Dd(HꢀC(4)) = 0 is due to this additional MTPA moiety.
The situation was more delicate in the conformatively flexible cis-series (8a/8b and
9a/9b), and the experimental data were ambiguous. In particular, the reliability of an
interpretation was significantly reduced due to Dd(HꢀC(4)) ¼ꢁ 0.073) for 8a/8b and
9a/9b, and further considerations had to be made. However, in the absence of an X-ray
crystallographic analysis of a cis-configurated MTPA derivative, the rationale is based
on the comparison of relative differences and remains speculative: According to the
1H-NMR spectra, the MTPAꢀO group at C(4) is axial5), and, under the assumption
that its conformation approximates the idealized one as found for 6b3), the MTPA
phenyl group is situated partly under the piperidine ring. As a consequence, shielding is
expected mainly for HaxꢀC(2), HeqꢀC(5), and CH2(6) (Dd < 0 for 8a/8b), whereas
HeqꢀC(2), HꢀC(3), and HaxꢀC(5) should only be marginally affected (Dd > 0 for 8a/
8b), and vice versa for 9a/9b. Moreover, due to the assumed steric environment for 8b
(2’S,3S,4S) and 9a (2’R,3R,4R)2), the diamagnetic effect is expected to be stronger on
HaxꢀC(5) and HaxꢀC(6) than on HaxꢀC(2) and HeqꢀC(5). The argumentation is
inverse for 8a (2’R,3S,4S) and 9b (2’S,3R,4R)2).
2
)
Since 6a ¼ ent-7b and 6b ¼ ent-7a, 6a (2’R,3R,4S) and 7b (2’S,3S,4R), as well as 6b (2’S,3R,4S) and 7a
(2’R,3S,4R) have identical NMR spectra. The same holds for 8a (2’R,3S,4S) ¼ ent-9b and 8b
(2’S,3S,4S) ¼ ent-9a.
1
3
)
The theoretical prerequisite for the success and reliability of the H-NMR Mosher experiments is
that the MTPA moiety adopts an idealized conformation where the H-atom at the initially OH-
substituted stereogenic center, the C¼O, and the CF3 groups lie in the same plane in a relative syn-
arrangement [5]. Therefore, an essential quality factor for an experiment is the equal chemical shift
(Dd ¼ 0) for the H-atom at the MPTA – O-substituted stereogenic center in both the (R)- and the
(S)-MTPA derivatives.
4
5
)
Originally, 6b crystallized as the piperidinium (S)-MTPA salt 6b · (þ)-(S)-MTPA. For the sake of
simplicity, the carboxylate moiety is omitted in the Figure. The full data set is summarized in the
Table (see Exper. Part). CCDC-694216 contains the supplementary crystallographic data for 6b ·
(þ)-(S)-MTPA. These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre, via http://www.ccdc.cam.ac.uk/data_request/cif.
3
3
3
)
HꢀC(4) is equatorial (q-like, J(4,3) ꢂ J(4,5ax) ꢂ J(4,5eq) ꢂ 3, see Exper. Part).

18
Helvetica Chimica Acta – Vol. 92 (2009)
Figure. The molecular structure of 6b. For reasons of clarity, the systematic atom numbering is restricted
to the piperidine part; 50% probability ellipsoids.
The experimental results observed for the couple 8a/8b (Dd(HaxꢀC(2), HeqꢀC(5),
and CH2(6)) < 0 and Dd(HeqꢀC(2), HꢀC(3), and HaxꢀC(5)) > 0, and vice versa for
the couple 9a/9b see Exper. Part)2), were in accordance with the prediction. The low
quality factor (Dd(HꢀC(4)) reflects the impact of the MTPAꢀOCH2 moiety at C(3)
and the conformational uncertainty. Taking into account the ambiguity of the
differential argumentation, the absolute configurations of the cis-4-hydroxypiperi-
dine-3-methanols were tentatively assigned as (þ)-(3S,4S)-3, and (ꢀ)-(3R,4R)-3.
Finally, X-ray crystallographic analyses with direct determinations of the absolute
configuration of the (þ)- and (ꢀ)-cis-8-aza-3-phosphadecalins, respectively (Type II,
Scheme 1) that were prepared from (þ)- and (ꢀ)-3, fully confirmed the stereochemical
assignments made by the unusual application of the Mosher method with the bis-MTPA
derivatives [4].
2.3. Preparation of (þ)-Methyl (3R,4S)-1-Benzyl-4-hydroxypiperidine-3-carboxy-
late ((þ)-10) by Biological Reduction and Chiroptical Correlation with (þ)-3.
According to the protocol [6][7], methyl 1-benzyl-4-oxopiperidine-3-carboxylate
hydrochloride (1b · HCl) was reduced with bakersꢂ yeast under nonfermenting
conditions to afford the dextrorotatory cis-4-hydroxy ester (þ)-10 ([a]D ¼ þ33.7,
ee > 99%) as the main product (42%, de > 97%) besides the racemic trans-isomer (ꢁ)-

Helvetica Chimica Acta – Vol. 92 (2009)
19
11 (Scheme 3) [8]. Although (þ)-10 turned out to be conformationally very flexible6),
the relative cis-configuration was established according to the 1H-NMR multiplicity of
3
HꢀC(4) that allocates it an equatorial position (d 4.10 (s-like, w1/2 ꢂ 12 Hz, J(4,3) ꢂ
3
3J(4,5ax) ꢂ J(4,5eq) < 3 Hz)).
Scheme 3
a) Bakersꢂ yeast, H2O, 288. b) CC (SiO2, AcOEt). c) (ꢀ)-(R)- or (þ)-(S)-MTPAꢀCl, resp., Et3N,
DMAP, CH2Cl2, r.t. d) CC (SiO2, Et2O). e) LiAlH4, Et2O, r.t.
The (4S)-configuration was anticipated according to the well investigated stereo-
selectivity of the NAD(H) dependent oxido reductions [9][10]. Bakersꢂ yeast is a
representative of the ꢄE3-typeꢂ enzymes [11] that exhibit pro-(R)-H/re-face selectivity
and pronounced cis-diastereoselectivity in the reduction of a-substituted cyclic ketones.
As a consequence, (þ)-10 is expected to have (3R,4S)-configuration. A confirmation
of this assignment was attempted again by the 1H-NMR Mosher method. Esterification
of (þ)-10 with both (þ)-(S)- and (ꢀ)-(R)-MTPAꢀCl afforded the (R)-ester 12a,
and the corresponding (S)-ester 12b (Scheme 3) [8]. However, when examining the
d(S) – d(R) values, all the signals displayed Dd < 0, and the relative differences of
the magnitudes of Dd could not be interpreted straightforwardly. Although
Dd(HꢀC(4)) ¼ 0, an unambiguous conclusion with respect to the configuration at
C(4) was not possible (see Exper. Part). This result reflects the unusual conformational
flexibility of (þ)-106) and contrasts with the successful application of the method for the
positionally isomeric ethyl 1-benzyl-3-hydroxypiperidine-4-carboxylates [6]. The
6
)
The conformational flexibility is evidenced in the NMR spectra (see Exper. Part): HaxꢀC(2) and
HeqꢀC(2) (d 2.65 (m, q-like, w1/2 ꢂ 30 Hz), as well as HaxꢀC(6) and HeqꢀC(6) (d 2.49 m, (dt-like,
1
w1/2 ꢂ 40 Hz) are undistinguishable in the H-NMR. This finding is unprecedented with respect to
our observations with related compounds: Usually, HeqꢀC(2) and HeqꢀC(6) are significantly
paramagnetically shifted with respect to their axial counterparts [3]. Moreover, the signals of C(2)
(d 50.7), C(4) (d 65.6), and C(6) (d 48.7) are broad and hardly exceed the noise in the 13C-NMR
(virtual coalescence).

20
Helvetica Chimica Acta – Vol. 92 (2009)
definite assignment of the absolute configuration at C(4) was effected after reduction
of (þ)-10 to (þ)-3; ([a]D ¼ þ15.6) and comparison with authentic (þ)-(3S,4S)-1-
benzyl-4-hydroxypiperidine-3-methanol ((þ)-3, [a]D ¼ þ16.7, ee > 99%) [4]
(Scheme 3). Hence, methyl (þ)-1-benzyl-4-hydroxypiperidine-3-carboxylate ((þ)-10)
has the (3R,4S)-configuration. This result confirms the predicted stereochemical
outcome of the biological reduction.
3. Remarks. 3.1. The Absolute Configuration of Related 4-Oxypiperidine-3-
carboxylates. The enantiomerically pure 1-benzyl 4-hydroxypiperidine-3-methanols 2
and 3 are not yet described in the literature. But similar investigations are known with
related 4-oxy-substituted piperidine-3-carboxylates. To illustrate the inconsistencies
mentioned in the introduction, the current knowledge is briefly summarized in the
following (Scheme 4): The basis of all assignments of the absolute configuration of this
series is ethyl (ꢀ)-(3R)-piperidine-3-carboxylate ((þ)-20) that has been determined by
a modified quadrant rule [12]. Reduction afforded the virtual key compounds, (þ)-
(3R)-piperidine-3-methanol ((þ)-21a) and the corresponding (þ)-(3R)-N,O-ditosylate
(þ)-21b [13]. Bakersꢂ yeast reduction of 1-(tert-butyl) 3-ethyl 4-oxopiperidine-1,3-
dicarboxylate (22) gave the dextrorotatory cis-configurated 4-hydroxy ester (þ)-23
(de > 99%, ee > 93%) [14], and chemical transformations yielded the laevorotatory
N,O-ditosylate (ꢀ)-21b [14]. Chiroptical correlation led to the assignment of the
(3R,4S)-configuration for (þ)-1-(tert-butyl) 3-ethyl 4-hydroxypiperidine-1,3-dicarbox-
ylate ((þ)-23). On the other hand, studies of the reduction of 22 by bakersꢂ yeast
reported that the reaction proceeded with very low enantioselectivity [15]. The
(3R,4S)-configuration for the main product (þ)-23 was copied from [14], but the
chiroptical data were not consistent7) [15]. Ambiguous results have also been
described by [17], when a series of piperidin-4-ones with different ester components
(Me, Et) and N-substituents (Me, CH(Me)2, COOtBu) was investigated. The
conclusion was that bakersꢂ yeast reduction is not a suitable access for enantiomerically
pure piperidines [17]. However, the (ꢁ)-cis- and (ꢁ)-trans-methyl 4-(benzoyloxy)-1-
methylpiperidine-3-carboxylates ((ꢁ)-24 and (ꢁ)-25, resp.) could be kinetically
resolved by pig-liver esterase (PLE) to afford (ꢀ)-methyl (3S,4R)-4-hydroxy-1-
methylpiperidine-3-carboxylate ((ꢀ)-26); ee 99%) and (ꢀ)-methyl (3R,4R)-4-hy-
droxy-1-methylpiperidine-3-carboxylate ((ꢀ)-27); ee 97%) [17]. The absolute config-
uration of (ꢀ)-26 was assigned chiroptically with reference to its (þ)-enantiomer [14]
and that of (ꢀ)-27 by an X-ray crystallographic analysis of its 4-{{1-[(4-methylphe-
nyl)sulfonyl]-l-prolyl}oxy} derivative [17]. Recently, lipase-catalyzed acylation of the
(ꢁ)-cis- and (ꢁ)-trans-1-(tert-butyl) 3-ethyl 4-hydroxypiperidine-1,3-dicarboxylates
((ꢁ)-23 and (ꢁ)-28, resp.) was reported to afford (þ)-23 and (ꢀ)-28, respectively
7
)
Depending on the reaction conditions, [a]D varied from ꢀ 4 to þ 23. The same research group
reported a reliable result after lipase-catalyzed hydrolysis of 1-(tert-butyl) 3,5-dimethyl 4-
hydroxypiperidine-1,3,5-tricarboxylate [16], chemical transformations to (þ)-cis-1-(tert-butyl) 3-
methyl 4-hydroxypiperidine-1,3-dicarboxylate (ee 79%), and chiroptical correlation referring to
[14]. It is noteworthy that the steric course of the desymmetrization was disputed at that time and
the assignment of the (3R,4S)-configuration for the (þ)-cis-4-hydroxy ester was considered to clear
it [16].

Helvetica Chimica Acta – Vol. 92 (2009)
21
Scheme 4
[18]. The (3R,4S)-configuration for (þ)-23 followed in accordance with [14][17],
whereas the (3S,4S)-configuration for (ꢀ)-28 was guessed on the basis of conclusions
by analogy and speculative handling of chiroptical data [18]. The latter is opposite to
that determined for the related laevorotatory (ꢀ)-methyl 4-hydroxy-1-methylpiper-
idine-3-carboxylate ((ꢀ)-27) [17]. However, as electron-withdrawing N-substituents
can significantly affect the conformation of the piperidine ring8), an assignment of the
8
)
Such influences are significant: Due to the partial double-bond character of the CꢀN carbamate
bond [19], trans-(tert-butyl) 3-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate adopts the
sterically unfavored diaxial conformation [20][21], whereas in the corresponding trans-1-benzyl-3-
hydroxypiperidine-2-methanol, the diequatorial conformer is predominant as expected [3][21].

22
Helvetica Chimica Acta – Vol. 92 (2009)
absolute configuration from merely the sign of the optical rotation is not applicable9).
Hence, it is indispensable to critically check and verify both data and conclusions and,
in doubt, to undertake an independent, reliable determination10).
3.2. Conclusions. During our work with all stereoisomers of the enantiomerically
pure 2-carboxy-3-oxy- [21], 4-carboxy-3-oxy- [6], as well as the present 3-carboxy-4-
oxy-disubstituted piperidines, we encountered significant structural inconsistencies.
Besides obvious errors (see, e.g., [6]), the most important drawback is that there is no
report dealing with a complete set of ꢄequalꢂ compounds (diastereoisomers and
enantiomers of the same derivatives, etc.), a fact that renders direct, reliable
comparisons rather difficult. Moreover, in the majority of cases, isolated reactions of
single derivatives under specific reaction conditions have been described, and most of
the absolute configurations have been assigned by comparison of the chiroptical data.
However, as substituted piperidines are conformationally very flexible, such data are
not only determined by the configuration at the stereogenic centers but also
significantly by their conformations. In spite of this basic knowledge, most of the
assigned absolute configurations have been adopted from precedent articles and lack
an independent determination. This is astonishing since piperidine-based compounds
are pharmaceutically most promising key substances, and the correctness of their
structure is an indispensable prerequisite – not only from the scientific viewpoint but
also with respect to medical applications and legal aspects connected therewith.
We thank PD Dr. A. Linden, head of the X-ray department of our institute, for the X-ray
crystallographic analysis. The financial support of the project by the Swiss National Foundation is
gratefully acknowledged.
Experimental Part
1. General. See [1][3]. Anal. HPLC: the retention is expressed by the capacity ratio k’ ¼ (tR ꢀ t0)/t0,
with tR ¼ retention time and t0 ¼ column dead time (elution time of an unretained component); a ¼
separation factor, RS ¼ resolution. [a]2D5: Perkin-Elmer 241-MC polarimeter with thermostat B. Braun
Thermomix 1441; 10 cm cell; in acetone, c ¼ 1; ee by integration of the peak areas of the anal. HPLC
separations with optimized resolution (Rs > 4) and high sensitivity. 1H-NMR: all assignments of strongly
overlapping 1H-signals by 2D experiments.
2. (þ)-(3R,4S)- and (ꢀ)-(3S,4R)-, and (þ)-(3S,4S)- and (ꢀ)-(3R,4R)-1-Benzyl-4-hydroxypiper-
idine-3-methanols ((þ)- and (ꢀ)-2, and (þ)- and (ꢀ)-3, resp.). 2.1. Ethyl and Methyl 1-Benzyl-4-
oxopiperidine-3-carboxylates (1a and 1b, resp.). The starting piperidin-4-ones were prepared by
Dieckmann condensation of diethyl or dimethyl 3,3’-(benzylimino)bis[propanoate] (¼ N-(3-methoxy- or
-3-ethoxypropyl)-N-(phenylmethyl)-b-alanine methyl or ethyl ester), resp. (obtained after benzylation
of ethyl or methyl 3-bromopropanoate, resp.) by standard procedures [4][8].
2.2. 6-Benzylhexahydro-2,2-dimethyl-4H-1,3-dioxino[5,4-c]pyridines (ꢁ)-4 and (ꢁ)-5 and HPLC
Separation of the Enantiomers. The acetonides (ꢁ)-4 and (ꢁ)-5 were prepared from 1a according to [3].
9
)
Although we had shown in the isomeric 3-hydroxypiperidine-1,4-dicarboxylate [6] and in the 3-
hydroxypiperidine-1,2-dicarboxylate [21] series that the transformation of their carbamate moiety
including N(1) into the corresponding 1-benzyl derivative only affected the magnitude of the optical
rotation but did not change its sign, these particular findings cannot be generalized.
An example illustrating the consequences when data are uncritically copied is the incorrect
assignment of the (3S,4S)-configuration for the isomeric (þ)-1-(tert-butyl) 4-ethyl 3-hydroxypiper-
idine-1,4-dicarboxylate (instead of (þ)-(3R,4R) [6]) [14]. It has been adopted in subsequent
investigations by other authors (e.g., [18]) and has led to further misinterpretations.
10
)

Helvetica Chimica Acta – Vol. 92 (2009)
23
Anal. HPLC of the racemic mixtures (Chiralcelꢅ OD-H, hexane/EtOH 600 :1): (ꢀ)-4 (k’ ¼ 2.22) and (þ)-
4 (k’ ¼ 2.60) with a ¼ 1.17 and RS ¼ 2.4; (þ)-5 (k’ ¼ 2.00) and (ꢀ)-5 (k’ ¼ 3.11) with a ¼ 1.56 and RS ¼ 5.8.
Anal. HPLC (Chiralcelꢅ OD-H, hexane/EtOH 2000 :1): (ꢀ)-4 (k’ ¼ 5.99) and (þ)-4 (k’ ¼ 8.04) with a ¼
1.34 and RS ¼ 4.4; (þ)-5 (k’ ¼ 4.14) and (ꢀ)-5 (k’ ¼ 6.39) with a ¼ 1.54 and RS ¼ 4.2. Prep. HPLC
(Chiralcelꢅ OD, hexane/EtOH 2000 :1) of (ꢁ)-4 (3.45 g) and recrystallization from hexane afforded (þ)-
4 (890 mg) and (ꢀ)-4 (655 mg) as colorless crystals. Prep. HPLC (Chiralcelꢅ OD, hexane/EtOH 600 :1) of
(ꢁ)-5 (2.72 g) and purification by CC (SiO2, Et2O) gave (þ)-5 (885 mg) and (ꢀ)-5 (600 mg) as colorless
crystals.
Data of (þ)-4: Rf (hexane/Et2O 1:1) 0.25. M.p. 62 – 638. [a]D ¼ þ29.2 (ee > 99%). All other data:
identical with those of (ꢁ)-4 [3].
Data of (ꢀ)-4: [a]D ¼ ꢀ29.3 (ee > 99%), [a]D ¼ ꢀ28.7 (ee > 98%)1). All other data: identical with
those of (þ)-4.
Data of (þ)-5: Rf (hexane/Et2O 1:1) 0.04. M.p. 47 – 488. [a]D ¼ þ66.1 (ee > 99%). All other data:
identical with those of (ꢁ)-5 [3].
Data of (ꢀ)-5: [a]D ¼ ꢀ66.5 (ee > 99%). All other data: identical with those of (þ)-5.
2.3. 1-Benzyl-4-hydroxypiperidine-3-methanols 2 and 3. Hydrolysis of 4 and 5 was performed by
suspending each enantiomer in H2O/1n HCl 1:1 (2 ml) and stirring at 608 for 2 h (TLC control). Workup
afforded the piperidine-3-methanols as colorless oils (ca. 100%) that solidified in the refrigerator.
Products: (þ)-4 (120 mg) ! (ꢀ)-2 (101 mg), (ꢀ)-4 (140 mg) ! (þ)-2 (118 mg), (þ)-5 (130 mg) ! (þ)-3
(109 mg), and (ꢀ)-5 (110 mg) ! (ꢀ)-3 (93 mg).
Data of (þ)-2: Rf (Et2O) 0.01. M.p. 69 – 718. [a]D ¼ þ9.2 (ee > 98%)1). All other data: identical with
those of (ꢁ)-2 [3].
Data of (ꢀ)-2: [a]D ¼ ꢀ9.8 (ee > 99%). All other data: identical with those of (þ)-2.
Data of (þ)-3: Rf (Et2O) 0.01. M.p. 134 – 1358. [a]D ¼ þ16.7 (ee > 99%). All other data: identical
with those of (ꢁ)-3 [3].
Data of (ꢀ)-3: [a]D ¼ ꢀ16.6 (ee > 99%). All other data: identical with those of (þ)-3.
3. (R)- and (S)-MTPA Derivatives for the Determination of the Absolute Configuration of (þ)- and
(ꢀ)-2 and (þ)- and (ꢀ)-3. To the soln. of the diols (þ)- or (ꢀ)-2, or (þ)- or (ꢀ)-3 (each 15 mg, 0.07 mmol)
in dry CH2Cl2 (3 ml), Et3N (33 ml, 0.22 mmol) and DMAP (2 mg) were added, and the mixture was
treated with (þ)-(S)-MTPAꢀCl (30 ml, 0.16 mmol, 2.3 equiv.) at r.t. for 16 h. The mixture was poured
onto ice-H2O and thoroughly washed with 0.01n HCl and sat. NaCl soln. Evaporation of the org. solvent
and chromatographic purification (SiO2, AcOEt) of the crude products afforded the (R)-MTPA diesters
6a – 9a. Analogously, (þ)- or (ꢀ)-2 and (þ)- or (ꢀ)-3 were treated with (ꢀ)-(R)-MTPAꢀCl to yield the
(S)-MTPA diesters 6b – 9b. All MTPA derivatives were isolated in pure form as colorless, viscous oils: 6a
(38.9 mg, 89%), 6b (35.9 mg, 82%), 7a (35.4 mg, 81%), 7b (35.9 mg, 82%), 8a (38.1 mg, 87%), 8b
(39.4 mg, 90%), 9a (40.5 mg, 92%), and 9b (35.1 mg, 80%). The fraction containing 6b solidified at ca.
ꢀ 208 to form colorless prisms (from i-PrOH) of 6b · (þ)-(S)-MTPA, m.p. 20 – 258, suitable for an X-ray
crystallographic analysis (see Fig. and Table below).
Data of the (R)- and (S)-MTPA Diesters 6a and 6b of (þ)-2. {(3R,4S)-1-Benzyl-4-[(2R)-3,3,3-
trifluoro-2-methoxy-1-oxo-2-phenylpropoxy]piperidin-3-yl}methyl (aR)-a-Methoxy-a-(trifluoromethyl)-
benzeneacetate (bis-(R)-MTPA ester 6a): 1H-NMR (500 MHz, CDCl3): 7.50 – 7.43, 7.34 – 7.34 (2m, 2 Ph);
7.33 – 7.24 (m, PhCH2); 4.80 (td, 3J(4,3) ¼ 3J(4,5ax) ¼ 10.2, 3J(4,5eq) ¼ 4.5, HꢀC(4)); 4.13, 4.05 (each dd,
3
2
2J ¼ 11.8, 3J ¼ 5.1, J ¼ 2.6, CH2(OMTPA)); 3.63, 3.40 (AB, J ¼ 13.2, PhCH2); 3.52, 3.45 (each s, MeO);
2.98 (br. t-like, w1/2 ꢂ 30, HeqꢀC(2), HeqꢀC(6)); 2.31 (oct.-like, w1/2 ꢂ 22, HꢀC(3)); 2.22 (m, br. td-like,
w1/2 ꢂ 18, HeqꢀC(5), HaxꢀC(6)); 2.08 (t, 2J ¼ 3J(2ax,3) ꢂ 11, HaxꢀC(2)); 1.86 (br. qd-like, 2J ¼ 12.8,
3J(5ax,4) ¼ 10.2, 3J(5ax,6ax) ¼ 11.2, 3J(5ax,6eq) ¼ 3.8, HaxꢀC(5)). 13C-NMR (125.8 MHz, CDCl3): 166.3,
165.9 (CO of MTPA); 137.4 (C(1’)); 132.4, 132.2 (C(1’’), C(1’’’)); 129.9 (C(4’’), C(4’’’)); 129.7 (C(2’),
C(6’)); 128.8, (C(2’’), C(6’’), C(2’’’), C(6’’’)); 128.7 (C(3’), C(5’)); 127.5 (C(3’’), C(3’’’), C(5’’), C(5’’’));
127.2 (C(4’)); 123.5 (q, 1J(C,F) ¼ 289,
2
CF3); 84.8, 84.6 (each q, 2J(C,F) ¼ 28.3,
PhC(MeO)(CF3)C(¼O)); 72.3 (C(4); 64.0 (CH2(OMTPA)); 61.9 (PhCH2); 55.6, 55.5 (2 MeO); 53.2
(C(2)); 50.6 (C(6)); 39.4 (C(3)); 29.3 (C(5)).
{(3R,4S)-1-Benzyl-4-[(2S)-3,3,3-trifluoro-2-methoxy-1-oxo-2-phenylpropoxy]piperidin-3-yl}methyl
(aS)-a-Methoxy-a-(trifluoromethyl)benzeneacetate (bis-(S)-MTPA ester 6b): 1H-NMR (500 MHz,

24
Helvetica Chimica Acta – Vol. 92 (2009)
CDCl3): 7.47 – 7.22 (m, 2 Ph, PhCH2); 4.81 (sext.-like, HꢀC(4)); 4.81 (td, 3J(4,3) ¼ 3J(4,5ax) ¼ 9.8,
2
3
3
2
3J(4,5eq) ¼ 4.2, HꢀC(4)); 4.13 (td-like, J ¼ 12, J ꢂ 5, J ꢂ 3, CH2(OMTPA)); 3.81, 3,76 (AB, J ¼ 13.2,
2
PhCH2); 3.45. 3.44 (each s, 2 MeO); 3.19 (br. s-like, w1/2 ꢂ 20, HeqꢀC(6)); 3.10 (br. d, J ¼ 11, w1/2 ꢂ 20,
HeqꢀC(2)); 2.45 (m, w1/2 ꢂ 18, HꢀC(3)); 2.35 (br. t, 2J ꢂ J (6ax,5ax) ꢂ 12, 3J(6ax,5eq) not resolved,
3
HaxꢀC(6)); 2.23 (t, 2J ꢂ J(2ax,3) ꢂ 11.5, HaxꢀC(2)); 2.19 (dq-like, 2J ¼ 11, 3J(5eq,4) ꢂ J(5eq,6ax) ꢂ
3J(5eq,6ax) ꢂ 4, HeqꢀC(5)); 1.84 (br. qd-like, 2J ¼ 13.5, 3J(5ax,4) ¼ 9.8, 3J(5ax,6ax) ¼ 11.5,
3J(5ax,6eq) ꢂ 4, HaxꢀC(5)). 13C-NMR (125.8 MHz, CDCl3): 166.3, 166.2 (CO of MTPA); 135.0
(C(1’)); 132.0, 131.8 (C1’’), C(1’’’)); 130.4 (C(2’), C(6’)); 130.1 (C(4’’), C(4’’’)); 129.1 (C(3’), C(5’));
128.9, 128.8 (C(2’’), C(6’’), C(2’’’), C(6’’’)); 127.7 (C(4’)); 127.4 (C(3’’), C(5’’), C(3’’’), C(5’’’)); 123.5, 123.4
3
3
1
2
(each q, J(C,F) ¼ 289, CF3); 85.0, 84.9 (each q, J(C,F) ¼ 28.1, PhC(MeO)(CF3)C(¼O)); 71.3 (C(4));
63.5 (CH2(OMTPA)); 61.2 (PhCH2); 55.6, 55.5 (2 MeO); 52.2 (C(2)); 50.0 (C(6)); 38.5 (C(3)); 28.2
(C(5)).
Dd(1H) ¼ d(S) – d(R) (in Hz): HꢀC(4), þ 53); HaxꢀC(2), þ 75; HeqꢀC(2), þ 60; HꢀC(3), þ 70;
HaxꢀC(5), ꢀ 10; HeqꢀC(5), ꢀ 15 ! (4S)-configuration.
Data of the (R)- and (S)-MTPA Diesters 7a and 7b of (ꢀ)-2. Being enantiomeric compounds, 7a and
6b (7a ¼ ent-6b) as well as 7b and 6a (7b ¼ ent-6a) exhibited identical NMR spectra, only the sign of Dd is
inverted: Dd(1H) ¼ d(S) – d(R) (in Hz): HꢀC(4), þ 53); HaxꢀC(2), ꢀ 75; HeqꢀC(2), ꢀ 60; HꢀC(3),
ꢀ 70; HaxꢀC(5), þ 10; HeqꢀC(5), þ 15 ! (4R)-configuration.
Data of the (R)- and (S)-MTPA Diesters 8a and 8b of (þ)-3. {(3S,4S)-1-Benzyl-4-[(2R)-3,3,3-
trifluoro-2-methoxy-1-oxo-2-phenylpropoxy]piperidin-3-yl}methyl (aR)-a-Methoxy-a-(trifluoromethyl)-
benzeneacetate (bis-(R)-MTPA ester 8a): 1H-NMR (500 MHz, CDCl3): 7.51 – 7.48, 7.47 – 7.34 (2m, 2 Ph);
7.32 – 7.23 (m, PhCh2); 5.25 (q-like, 3J(4,3) ꢂ J(4,5ax) ꢂ J(4,5eq) ꢂ 3, HꢀC(4)); 4.09 (m, w1/2 ꢂ 22), 4.02
(dd, 2J ¼ 11.0, 3J ¼ 6.8, CH2(OMTPA)); 3.51, 3.45 (AB, 2J ¼ 13.2, PhCH2); 3.50, 3.42 (each q, 5J(Me,F) ¼
1.1, 2 MeO); 2.64 (m, w1/2 ꢂ 22, HeqꢀC(6)); 2.55 (br. d, 2J ¼ 10, w1/2 ꢂ 22, HeqꢀC(2)); 2.35 (m, w1/2 ꢂ 25,
HꢀC(3)); 2.26 (m, w1/2 ꢂ 30, HaxꢀC(6)); 2.14 (m, w1/2 ꢂ 30, HaxꢀC(2)); 1.93 (br. dq-like, HaxꢀC(5)); 1.92
(m, br. t-like, HeqꢀC(5)). 13C-NMR (125.8 MHz, CDCl3): 166.8, 166.1 (CO of MTPA); 138.8 (C(1’));
132.8, 132.6 (C(1’’), C(1’’’)); 130.21, 130.17 (C(4’’), C(4’’’)); 129.5 (C(2’), C(6’)); 129.1, 129.0 (C(2’’),
C(6’’), C(2’’’), C(6’’’)); 128.9 (C(3’), C(5’)); 127.9 (C(4’)); 127.7 (C(3’’), C(5’’), C(3’’’), C(5’’’)); 123.9,
123.7 (each q, 1J(C,F) ¼ 288, CF3); 85.1, 85.0 (each q, 2J(C,F) ¼ 27.6, PhC(OMe)(CF3)CF3)C(¼O)); 71.3
(C(4)); 64.7 (CH2(OMTPA)); 63.2 (PhCH2); 55.9 (2 MeO); 51.1 (C(2)); 48.3 (C(6)); 39.2 (C(3)); 29.6
(C(5)).
3
3
{(3S,4S)-1-Benzyl-4-[(2S)-3,3,3-trifluoro-2-methoxy-1-oxo-2-phenylpropoxy]piperidin-3-yl}methyl
(aS)-a-Methoxy-a-(trifluoromethyl)benzeneacetate (bis-(S)-MTPA ester 8b): 1H-NMR (500 MHz,
3
CDCl3): 7.48 – 7.43, 7.42 – 7.34 (2 m, 2 Ph); 7.31 – 7.21 (m, PhCH2); 5.18 (q-like, 3J(4,3) ꢂ J(4,5ax) ꢂ
2
3J(4,5eq) ꢂ 3, HꢀC(4)); 4.09 (m, w1/2 ꢂ 24), 4.05 (dd, J ¼ 11.0, 3J ¼ 7.9, CH2(OMTPA)); 3.47, 3.40 (AB,
2J ¼ 13.2, PhCH2); 3.47, 3.44 (each q, 5J(Me,F) ¼ 1.0, 2 MeO); 2.56 (br. t-like, w1/2 ꢂ 25, HeqꢀC(2),
HeqꢀC(6)); 2.36 (m, w1/2 ꢂ 22, HꢀC(3)); 2.09 (br. t-like, w1/2 ꢂ 50, HaxꢀC(2), HaxꢀC(6)); 1.96 (br. dq-
2
2
like, J ꢂ 12, w1/2 ꢂ 24, HaxꢀC(5)); 1.86 (br. t-like, J ꢂ 12, w1/2 ꢂ 24, HeqꢀC(5)). 13C-NMR (125.8 MHz,
CDCl3): 166.6, 165.9 (CO of MTPA); 137.7 (C(1’)); 132.2, 131.2 (C(1’’), C(1’’’)); 130.0, 129.9 (C(4’’),
C(4’’’)); 129.3 (C(2’), C(6’)); 128.8, 128.7 (C(2’’), C(6’’), C(2’’’), C(6’’’)); 128.6 (C(3’), C(5’)); 127.6 (C(3’’),
C(5’’), C(3’’’), C(5’’’)); 127.4 (C(4’)); 123.6, 123.4 ((each q, 1J(C,F) ¼ 289, CF3); 85.0, 84.8 (each q,
2J(C,F) ¼ 27.9, PhC(OMe)(CF3)C(¼O)); 70.9 (C(4)); 64.6 (C(7)); 62.9 (PhCH2); 55.6, 55.5 (2 MeO);
50.5 (C(2)); 48.3 (C(6)); 38.8 (C(3)); 29.1 (C(5)).
Dd(1H) ¼ d(S) – d(R) (in Hz): HꢀC(4), ꢀ 353); HaxꢀC(2), ꢀ 25; HeqꢀC(2), þ 5; HꢀC(3), þ 5;
HaxꢀC(5), þ 15; HeqꢀC(5), ꢀ 30; HaxꢀC(6), ꢀ 85; HeqꢀC(6), ꢀ 40 ! (4S)-configuration.
Data of the (R)- and (S)-MTPA Diesters 9a and 9b of (ꢀ)-3. Being enantiomeric compounds, 9a and
8b (9a ¼ ent-8b) as well as 9b and 8a (9b ¼ ent-8a) exhibited identical NMR spectra, only the sign of Dd is
inverted: Dd(1H) ¼ d(S) – d(R) (in Hz): HꢀC(4), þ 353); HaxꢀC(2), þ 25; HeqꢀC(2), ꢀ 5; HꢀC(3),
ꢀ 5; HaxꢀC(5), ꢀ 15; HeqꢀC(5), þ 30; HaxꢀC(6), þ 85; HeqꢀC(6), þ 40 ! (4R)-configuration.
4. ( þ )-Methyl (3R,4S)-1-Benzyl-4-hydroxypiperidine-3-carboxylate ((þ)-10). 4.1. Methyl (ꢁ)-cis-
and Methyl (ꢁ)-trans-1-Benzyl-4-hydroxypiperidine-3-carboxylates ((ꢁ)-10 and (ꢁ)-11, resp.). To a
cooled soln. of ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride (1a · HCl; 1.01 g, 3.4 mmol)
and anh. Na2CO3 (540 mg, 5.1 mmol) in MeOH (50 ml), NaBH4 (60 mg, 1.7 mmol) was added in portions

Helvetica Chimica Acta – Vol. 92 (2009)
25
and the mixture stirred at ꢀ 158. To complete the transesterification, the mixture was kept at 308 for 2 h.
Workup and continuous extraction with Et2O yielded the mixture of the crude 4-hydroxy esters (ꢁ)-10/
(ꢁ)-11 (585 mg, 69%). Separation of the diastereoisomers (200 mg) by CC (SiO2, hexane/AcOEt 20 :1)
gave (ꢁ)-11 (60 mg) and from the more polar fraction (ꢁ)-10 (30 mg), both as colorless viscous oils.
Anal. HPLC of the racemic mixture (Chiralcelꢅ OD-H, hexane/sec-BuOH 60 :1): (þ)-10 (k’ ¼ 9.1) and
(ꢀ)-10 (k’ ¼ 10.9) with a ¼ 1.20 and RS > 4; (ꢁ)-11 (k’ ¼ 12.7 and 13.8) with a ¼ 1.09 and RS ¼ 1.3.
Data of (ꢁ)-10: Rf (hexane/AcOEt 1:19) 0.15. IR (film): 3434m, 2949m, 2824m, 1736vs, 1659w,
1494w, 1454m, 1436m, 1360m, 1295m, 1204s, 1125m, 1073m, 1056m, 1027m, 979m, 919w, 856w, 797w,
743m, 699s. 1H-NMR (500 MHz, CDCl3): 7.31 – 7.21 (m, PhCH2); 4.10 (s-like, w1/2 ꢂ 12, HꢀC(4)); 3.68 (s,
MeO); 3.56, 3.49 (AB, 2J ¼ 13.2 PhCH2); 2.77 (m, quint.-like, w1/2 ꢂ 15, HꢀC(3)); 2.65 (m, q-like, w1/2
ꢂ
2
30, CH2(2))6); 2.49 (m, dt-like, w1/2 ꢂ 40, CH2(6))6); 1.87, 1.79 (each ddd-like, J ¼ 13.5, 3J ¼ 3.5, 4,5, 5.0,
CH2(5)).13C-NMR (125.8 MHz, CDCl3): 174.2 (COOMe); 138.4 (C(1’)); 129.0 (C(2’), C(6’)); 128.2
(C(3’), C(5’)); 127.1 (C(4’)); 65.6 (br. (C(4))6); 62.8 (PhCH2); 51.7 (MeO); 50.7 (br. (C(2))6); 48.7 (br.
(C(6))6); 46.5 (C(3)); 31.9 (C(5)). EI-MS: 249 (8, Mþ), 231 (15, [M ꢀ H2O]þ), 218 (3), 190 (9), 170 (8),
158 (25), 140 (17), 132 (10), 120 (8), 91 (100, PhCHþ2 ), 65 (11), 55 (2).
Data of (ꢁ)-11: Rf (hexane/AcOEt 1:19) 0.23. IR (film): 3434m, 3062w, 3028w, 2949m, 2823m,
1736vs, 1656w, 1495w, 1453m, 1437m, 1360m, 1296m, 1204s, 1126m, 1095m, 1073m, 1055m, 1027m, 979m,
918w, 856w, 796w, 742m, 799s. 1H-NMR (500 MHz, CDCl3): 7.34 – 7.23 (m, PhCH2); 3.80 (br. tt-like,
3
3
3
3J(4,5ax) ꢂ 12, J(4,3) ¼ 11.5, J(4,5eq) ꢂ 5, J(4,OH) ¼ 3.2, HꢀC(4)); 3.70 (s, MeO); 3.54 (s, PhCH2);
2
3
4
3
3.13 (ddd, J ¼ 11.5, J(2eq,3) ¼ 4.0, J(2eq,6eq) ¼ 2.2, HeqꢀC(2)); 2.98 (d, J(OH,4) ¼ 3.2, OHꢀC(4));
2.89 (br. dt-like, 2J ꢂ 12, 3J(6eq,5ax) ꢂ 4, 3J(6eq,5eq) ꢂ 3, 4J(6eq,2eq) ¼ 2.2, HeqꢀC(6)); 2.63 (td,
3J(3,4) ¼ 3J(3,2ax) ¼ 11.5, 3J(3,2eq) ꢂ 4, HꢀC(3)); 2.08 (t, 2J ¼ 3J(2ax,3) ¼ 11.5, HaxꢀC(2)); 2.07 (br.
td, 2J ꢂ J(6ax,5ax) ꢂ 12, 3J(6ax,5eq) ꢂ 2.5, HaxꢀC(6)); 1.96 (br. ddd, 2J ꢂ 12, 3J(eq,4) ꢂ 5, 3J(5eq,6eq) ꢂ
3
3, 3J(5eq,6ax) ꢂ 2.5, HeqꢀC(5)); 1.65 (br. qd, 2J ꢂ J(5ax,4) ꢂ J(5ax,6ax) ꢂ 12, 3J(5ax,6eq) ꢂ 4,
HaxꢀC(5)). 13C-NMR (125.8 MHz, CDCl3): 172.1 (COOMe); 136.1 (C(1’)); 126.8 (C(2’), C(6’)); 126.1
(C(3’), C(5’)); 125.0 (C(4’)); 67.5 (C(4)); 60.1 (PhCH2); 51.1 (MeO); 49.8 (C(2)); 49.3 (C(6)); 47.4
(C(3)); 30.5 (C(5)). EI-MS: 249 (7, Mþ), 231 (1, [M – H2O]þ), 218 (4), 190 (10), 172 (7), 158 (22), 140
(17), 120 (10), 91 (100, PhCHþ2 ), 82 (4), 65 (9), 55 (8).
3
3
4.2. Reduction of 1b with Bakersꢁ Yeast. Methyl 1-benzyl-4-oxopiperidine-3-carboxylate hydro-
chloride (1b · HCl; 500 mg, 0.17 mmol) was dissolved in tap water (10 ml) and added to a suspension of
commercial (COOP, Zurich) lyophilized bakersꢂ yeast (50 g) in tap water (500 ml) at 288 and the mixture
gently shaken for 60 h. After centrifugation (5000 rpm, 10 min), the supernatant was continuously
extracted with Et2O, and dried after evaporation (508/0.05 Torr) to yield the crude product as a brownish
oil (190 mg, 45%). Anal. HPLC (Chiralcelꢅ OD-H, hexane/sec-BuOH 60 :1): (þ)-10 (k’ ¼ 9.1, de 97%,
ee > 99%) and (ꢁ)-11 (k’ ¼ 12.7 and 13.8, de 3%, ee ca. 0%). CC (SiO2, AcOEt) afforded from the main
fraction pure (þ)-10 (182 mg).
Data of (þ)-10. [a]D ¼ þ33.7 (ee > 99%). All other data identical with those of (ꢁ)-10.
5. (R)- and (S)-MTPA Esters for the Tentative Determination of the Absolute Configuration of (þ)-
10. Following Exper. 3, a mixture of 4-hydroxy ester (þ)-10 (20 mg, 0.08 mmol) in abs. CH2Cl2 (2 ml),
Et3N (25 ml), and DMAP (2 mg) was treated with (þ)-(S)- or (ꢀ)-(R)-MTPAꢀCl (18 ml, 1.2 equiv.) at r.t.
for 4 h. Workup and CC (SiO2, Et2O) of the crude products afforded the MTPA esters 12a (26.2 mg,
70%) and 12b (28.3 mg, 76%), both as colorless, viscous oils.
Data of the (R)- and (S)-MTPA Esters of (þ)-10. Methyl (3R,4S)-1-Benzyl-4-[(2R)-3,3,3-trifluoro-
2-methoxy-1-oxo-2-phenylpropoxy]piperidine-3-carboxylate ((R)-MTPA ester 12a). Rf (Et2O) 0.61.
1H-NMR (500 MHz, CDCl3): 7.42 – 7.20 (m, PhCH2, Ph); 5.61 (s, w1/2 ꢂ 10, HꢀC(4)); 3.84, 3.78 (AB, 2J ¼
5
2
13.0, PhCH2), 3.51 (s, COOMe); 3.35 (q, J(Me,F) ¼ 1.0, MeO); 3.32 (br. d, J ¼ 12.5, HeqꢀC(2)); 3.21
(m, d-like, w1/2 ꢂ 28, HꢀC(3)); 3.02 (br. d, 2J ꢂ 11, w1/2 ꢂ 22, HeqꢀC(6)); 2.55 (t, J ꢂ J(2ax,3) ¼ 12.5,
2
3
HaxꢀC(2)); 2.19 (t, 2J ꢂ J(6ax,5ax) ꢂ 11, HaxꢀC(6)); 2.13 (br. t-like, 2J ꢂ 13, 3J(5ax,6ax) ꢂ 11,
3
HaxꢀC(5)); 1.95 (br. d, J ꢂ 13, w1/2 ꢂ 20, HeqꢀC(5)). 13C-NMR (125.8 MHz, CDCl3): 171.4 (COOMe);
2
169.3 (CO of MTPA); 131.9 (C(1’)); 130.9 (C(1’’)); 130.0 (C(2’), C(6’)); 129.1 (C(3’), C(5’)); 128.8 (C(2’’),
C(6’’)); 128.2 (C(3’’), C(5’’)); 1227.7 (C(4’)); 127.6 (C(4’’)); 123.4 (q, 1J(C,F) ¼ 289, CF3); 84.7 (d,
2J(C,F) ¼ 28, PhC(OMe)(CF3)C(¼O)); 69.5 (C(4)); 61.8 (PhCH2); 55.4 (COOMe); 52.4 (MeO); 48.1
(C(2)); 46.6 (C(6)); 43.2 (C(3)); 27.9 (C(5)).

26
Helvetica Chimica Acta – Vol. 92 (2009)
Methyl (3R,4S)-1-Benzyl-4-[(2S)-3,3,3-trifluoro-2-methoxy-1-oxo-2-phenylpropoxy]piperidine-3-
carboxylate ((S)-MTPA ester 12b): Rf (Et2O) 0.66. 1H-NMR (500 MHz, CDCl3): 7.45 – 7.15 (m, PhCH2,
Ph); 5.61 (s, w1/2 ꢂ 10, HꢀC(4)); 3.53 (s, COOMe); 3.42 (q, 5J(Me,F) ¼ 1.0, MeO); 3.43, 3.40 (AB, 2J ¼
13.0, PhCH2); 2.96 (br. d, 2J ꢂ 10, w1/2 ꢂ 22, HeqꢀC(2)); 2.82 (m, w1/2 ꢂ 28, HꢀC(3)); 2.54 (br. d, 2J ꢂ 10,
3
w1/2 ꢂ 22, HeqꢀC(6)); 2.30 (t, 2J ¼ 3J(2ax,3) ¼ 11.5, HaxꢀC(2)); 1.92 (br. t, 2J ꢂ J(5ax,6ax) ꢂ 11,
3
HaxꢀC(5)); 1.86 (m, t-like, 2J ꢂ J(6ax,5ax) ꢂ 11, HaxꢀC(6)); 1.80 (br. d-like, 2J ꢂ 11, HeqꢀC(5)).
13C-NMR (125.8 MHz, CDCl3): 171.1 (COOMe); 165.7 (CO of MTPA); 132.6 (C(1’)); 132.3 (C(1’’));
129.8 (C(2’), C(6’)); 129.2 (C(3’), C(5’)); 129.0 (C(2’’), C(6’’)), 128.6 (C(3’’), C(5’’)); 128.5 (C(4’)); 127.6
(C(4’’)); 123.5 (q, 1J(C,F) ¼ 289, CF3); 84.8 (d, 2J(C,F) ¼ 27.8, PhC(OMe)(CF3)C(¼O)); 71.2 (C(4));
63.1 (PhCH2); 55.6 (COOMe); 52.1 (MeO); 49.5 (C(2)); 47.4 (C(6)); 45.1 (C(3)); 29.6 (C(5)).
Dd(1H) ¼ d(S) – d(R) (in Hz): HꢀC(4), 03); HaxꢀC(2), ꢀ 125; HeqꢀC(2), ꢀ 180; HꢀC(3), ꢀ 195;
HaxꢀC(5), ꢀ 105; HeqꢀC(5), ꢀ 75; HaxꢀC(6), ꢀ 165; HeqꢀC(6), ꢀ 240. The Dd values do not allow a
configurational assignment.
6. Reduction of (þ)-10 to (þ)-3. The (3R,4S)-carboxylate (þ)-10 (52 mg, 0.198 mmol) in abs. Et2O
(2 ml) was added to LiAlH4 (1.5 mg, 0.38 mmol. 2 equiv.) in abs. Et2O (2 ml) at ca. 58 over 30 min, and the
suspension was stirred at r.t. (3 h). Then 2,2’,2’’-nitrilotris[ethanol] (60 mg) was added slowly at ca. 58,
and after 30 min, H2O (15 ml) was added and the mixture stirred for 15 h at r.t. The resulting suspension
was filtered over Celite, thoroughly washed with Et2O, and dried at 308/0.05 Torr. CC (SiO2, Et2O)
afforded (þ)-3 (40.3 mg, 92%) as colorless crystals ([a]D ¼ þ15.6). All other data: identical with those of
(þ)-3 (see Exper. 2.3) and (ꢁ)-3 [3].
7. X-Ray Crystal Structure Determination of 6b4). All measurements were made on a Nonius-
KappaCCD area-detector diffractometer [22] by using graphite-monochromated MoKa radiation (l
0.71073 ꢆ) and an Oxford-Cryosystems Cryostream-700 cooler. The unit-cell constants and an
orientation matrix for data collection were obtained from a least-squares refinement of the setting
angles of 5170 reflections in the range 48 < 2q < 558. The mosaicity was 0.412(1)8. A total of 219 frames
were collected by using f and w scans with k offsets, 36-s exposure time and a rotation angle of 2.08 per
Table. Crystallographic Data of 6b · (þ)-(S)-MTPA
Crystallized from
Empirical formula
Mr
i-PrOH
C43H42F9NO9
887.79
Scan type
2q(max) [8]
Total reflections measured 60090
f and w
55
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
Crystal system
Space group
colorless, prism Symmetry-independent
5162
0.17 ꢃ 0.28 ꢃ 0.30 reflections
160(1)
Rint
0.070
orthorhombic
P212121 (#19)
4
Reflections with I > 2s(I) 4178
Reflections used in
refinement
5162
Z
Reflections for cell
determination
2 q range for cell
determination [8]
Unit cell parameters: a [ꢆ] 11.0411(1)
b [ꢆ] 17.3020(3)
c [ꢆ] 21.2433(4)
a [8] 90
5170
Parameters refined
Final R(F) (I > 2s(I)
reflections)
567
0.0383
4 – 55
wR(F2) (all data)
Weights
0.0919
w ¼ [s2(F2o ) þ (0.0517P)2
þ 0.0985P]ꢀ1
,
where P ¼ (F2o þ 2 Fc2 )/3
Goodness of fit
Secondary extinction
coefficient
1.092
b [8] 90
g [8] 90
V [ꢆ3] 4058.2(1)
0.030(1)
Final Dmax/s
0.001
F(000)
1840
1453
0.128
D1 (max; min) [e ꢆꢀ3
s (d(CꢀC)) [ꢆ]
]
0.28; ꢀ 0.24
Dx [g cmꢀ3
]
0.003 – 0.004
m(MoKa) [mmꢀ1
]

Helvetica Chimica Acta – Vol. 92 (2009)
27
frame, and a crystal-detector distance of 31.8 mm. Data reduction was performed with HKL Denzo and
Scalepack [23]. The intensities were corrected for Lorentz and polarization effects, but not for
absorption. The space group was uniquely determined by the systematic absences. Equivalent reflections
were merged. The data collection and refinement parameters are compiled in the Table. The structure
was solved by direct methods with SIR92 [24] which revealed the positions of all non-H-atoms. The non-
H-atoms were refined anisotropically. The ammonium H-atom was placed in the position indicated by a
difference-electron-density map, and its position was allowed to refine together with an isotropic
displacement parameter. All remaining H-atoms were placed in geometrically calculated positions and
refined by using a riding model where each H-atom was assigned a fixed isotropic displacement
parameter with a value equal to 1.2Ueq of its parent C-atom (1.5Ueq for the methyl groups). The
refinement of the structure was carried out on F2 by using full-matrix least-squares procedures, which
minimized the function Sw(F2o ꢀ Fc2 )2. The weighting scheme was based on counting statistics and
included a factor to downweight the intense reflections. Plots of Sw(F2o ꢀ Fc2 )2 vs. Fc/Fc(max) and
resolution showed no unusual trends. A correction for secondary extinction was applied. Neutral-atom
scattering factors for non-H-atoms were taken from [25], and the scattering factors for H-atoms were
taken from [26]. Anomalous dispersion effects were included in Fc [27]; the values for f’ and f’’ were
those of [28]. The values of the mass attenuation coefficients are those of [29]. The SHELXL97 program
[30] was used for all calculations.
REFERENCES
[1] W. Ganci, E. J. M. Meier, F. Merckling, G. Przibille, U. Ringeisen, P. Rꢁedi, Helv. Chim. Acta 1997,
80, 421; S. Furegati, W. Ganci, G. Przibille, P. Rꢁedi, Helv. Chim. Acta 1998, 81, 1127; S. Furegati, O.
Zerbe, P. Rꢁedi, Chem.-Biol. Interact. 2005, 157 – 158, 48; M. J. Stçckli, P. Rꢁedi, Helv. Chim. Acta
2007, 90, 2058.
[2] S. Furegati, F. Gorla, A. Linden, P. Rꢁedi, Chem.-Biol. Interact. 2005, 157 – 158, 415.
[3] S. Furegati, W. Ganci, F. Gorla, U. Ringeisen, P. Rꢁedi, Helv. Chim. Acta 2004, 87, 2629.
[4] C. Clerc, ꢄSynthese und Charakterisierung von enantiomerenreinen N-heterocyclischen Phospha-
decalinen als Inhibitoren von Acetylcholinesteraseꢂ, Ph.D. Thesis, University of Zurich, 2008.
[5] J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34, 2543; G. R. Sullivan, J. A. Dale, H. S.
Mosher, J. Org. Chem. 1973, 38, 2143; J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512; I.
Ohtani, T. Kusumi, Y. Kahman, H. Kakisawa, J. Am. Chem. Soc. 1991, 113, 4092.
[6] P. A. Lorenzetto, A. Strehler, P. Rꢁedi, Helv. Chim. Acta 2006, 89, 3023.
[7] D. Seebach, S. Roggo, T. Maetzke, H. Braunschweiger, J. Cercus, M. Krieger, Helv. Chim. Acta 1987,
70, 1605.
[8] I. Matarazzo, ꢄDer stereochemische Verlauf der Reduktion von 4-Oxopiperidin-3-carboxylaten mit
Bꢀckerhefeꢂ, M.Sc. Thesis, University of Zurich, 2008.
[9] D. Seebach, S. Roggo, J. Zimmermann, ꢄStereochemistry of Organic and Bioorganic Trans-
formationsꢂ, Workshop Conferences, Hoechst, Vol. 17, Eds. W. Bartmann and K. B. Sharpless,
VCH-Verlagsgesellschaft Weinheim, 1987.
[10] C. J. Shi, B. Zhou, A. S. Gopalan, W. R. Shieh, F. Van Middlesworth, in ꢄSelectivity – a Goal for
Synthetic Efficiencyꢂ, Workshop Conferences, Hoechst, Vol. 14, Eds. W. Bartmann and B. M. Trost,
Verlag Chemie, Weinheim, 1983; J. C. Shi, C.-S. Chen, Angew. Chem. 1984, 96, 556; R. Csuk, B.
Glꢀnzer, Chem. Rev. 1991, 91, 49.
[11] C.-H. Wong, G. Whitesides, ꢄEnzymes in Synthetic Organic Chemistryꢂ, Pergamon, Oxford, 1995,
p. 139.
[12] H. Ripperger, K. Schreiber, Ber. Dtsch. Chem. Ges. 1969, 102, 2864.
[13] G. Bettoni, E. Duranti, V. Tortorella, Gazz. Chim. Ital. 1972, 102, 189.
[14] D. W. Knight, N. Lewis, A. C. Share, D. Haigh, Tetrahedron: Asymmetry 1993, 4, 625; D. W. Knight,
N. Lewis, A. C. Share, D. Haigh, J. Chem. Soc., Perkin Trans. 1 1998, 3673.
[15] E. Brygesesn, J. Nielsen, M. Willert, M. Bols, Tetrahedron Lett. 1997, 32, 5697; M. Willert, M. Bols,
Acta Chem. Scand. 1998, 52, 461.

28
Helvetica Chimica Acta – Vol. 92 (2009)
[16] X. Liang, A. Lohse, M. Bols, J. Org. Chem. 2000, 65, 7432.
[17] M. Roberti, R. Rondanin, R. Ferroni, R. Barucchello, F. P. Invidiata, V. Andrisano, C. Bertucci, V.
Bertolasi, S. Grimaudo, M. Tolomeo, D. Simoni, Tetrahedron: Asymmetry 2000, 11, 4397.
´
´
[18] M. Solymar, E. Forro, F. Fꢁlçp, Tetrahedron: Asymmetry 2004, 15, 3281.
[19] R. W. Hoffman, Chem. Rev. 1989, 89, 1841.
[20] A. Jourdant, J. Zhu, Tetrahedron Lett. 2000, 41, 7033.
[21] M. Wꢀchter, P. Rꢁedi, in preparation.
[22] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[23] Z. Otwinowski, W. Minor, in ꢄMethods in Enzymologyꢂ, Vol. 276, ꢄMacromolecular Crystallographyꢂ,
Part A, Eds. C. W. Carter Jr., and R. M. Sweet, Academic Press, New York, 1997, pp. 307 – 326.
[24] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, J.
Appl. Crystallogr. 1994, 27, 435.
[25] E. N. Maslen, A. G. Fox, M. A. OꢂKeefe, in ꢄInternational Tables for Crystallographyꢂ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, pp. 477 – 486.
[26] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[27] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[28] D. C. Creagh, W. J. McAuley, in ꢄInternational Tables for Crystallographyꢂ, Ed. A. J. C. Wilson,
Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, pp. 219 – 222.
[29] D. C. Creagh, J. H. Hubbell, in ꢄInternational Tables for Crystallographyꢂ, Ed. A. J. C. Wilson,
Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3, pp. 200 – 206.
[30] G. M. Sheldrick, ꢄSHELXL97, Program for the Refinement of Crystal Structuresꢂ, University of
Gçttingen, Germany, 1997.
Received July 11, 2008