Stereochemical course of the reductive spiroannulations of N-Boc and N-benzyl 2-cyanopiperidines

Article abstract of DOI:10.1016/j.tet.2005.01.099

The stereochemical outcome of spiroannulations of N-protected 2-lithiopiperidines (generated by lithium di-tert-butyl biphenylide (LiDBB) mediated reductive lithiation of 2-cyanopiperidines) was investigated using deuterium labeled side-chains containing phosphate leaving groups. High stereoselectivity was observed when benzyl (Bn) protected 2-cyanopiperidines were employed, while tert-butoxycarbonyl (Boc) protected 2-cyanopiperidines afforded lower selectivity. Models are proposed to rationalize the results of this study.

Full text of DOI:10.1016/j.tet.2005.01.099

Tetrahedron 61 (2005) 3371–3381
Stereochemical course of the reductive spiroannulations of N-Boc
and N-benzyl 2-cyanopiperidines
*
Scott A. Wolckenhauer and Scott D. Rychnovsky
Department of Chemistry, 516 Rowland Hall, University of California-Irvine, Irvine, CA 92697-2025, USA
Received 1 November 2004; revised 7 December 2004; accepted 21 January 2005
Abstract—The stereochemical outcome of spiroannulations of N-protected 2-lithiopiperidines (generated by lithium di-tert-butyl
biphenylide (LiDBB) mediated reductive lithiation of 2-cyanopiperidines) was investigated using deuterium labeled side-chains containing
phosphate leaving groups. High stereoselectivity was observed when benzyl (Bn) protected 2-cyanopiperidines were employed, while tert-
butoxycarbonyl (Boc) protected 2-cyanopiperidines afforded lower selectivity. Models are proposed to rationalize the results of this study.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Sequential nitrile alkylation and reductive decyanation/
lithiation with subsequent intramolecular electrophile dis-
placement (‘reductive annulation’) represents a powerful
method for the synthesis of carbocyclic molecules.1 Work in
our laboratory has demonstrated the utility of this strategy in
the stereoselective synthesis of complex spirocyclic tetra-
hydrofuran derivatives2 and in an enantioselective synthesis
of cyclopentane rings.3 This approach is convergent and
Figure 1. Naturally-occurring 2-spiropiperidine alkaloids.
possesses the potential for the stereoselective generation of
quaternary centers. As an extension of this chemistry, we
have also applied this sequence towards 2-cyanopiperidines
(Scheme 1).4,5 The resulting 2-spiropiperidine ring systems
can be found in a small but structurally and biologically
interesting selection of naturally-occurring alkaloids such as
histrionicotoxin6 (5) and pinnaic acid7 (6) (Fig. 1).
generated in the simple examples in Scheme 1. We chose
to probe the stereoinduction imparted by additional
stereocenters on the piperidine ring. At the onset of these
studies, we recognized that the protecting group on nitrogen
could have a profound effect in directing the resulting
stereochemistry of the quaternary spiro center. For example,
Husson8 has shown that N-benzyl (benzylZBn) 2-cyano-
piperidine 7 undergoes highly stereoselective reductive
decyanation under dissolving metal conditions to produce 8
as a single diastereomer while Nagasaka9 has revealed that
under similar conditions, the related N-carbethoxy com-
pound 9 produces decyanated products 10 and 11 with low
stereoselectivity (Scheme 2).
Scheme 1. Reductive spiroannulation approach to 2-spiropiperidines.
For our studies, we targeted N-benzyl and N-tert-butoxy-
carbonyl (Boc) protected cyanopiperidines 12 and 13.
Alkylation with deuterium labeled iodide 14 and reductive
spiroannulation should produce the diastereomeric products
N-benzyl trans/cis-17 and N-Boc trans/cis-18 (Scheme 3).
The relative configuration of the generated quaternary spiro
centers could then be determined using nuclear Overhauser
effect (NOE) studies to establish the position of the
The efficiency of these spiroannulations, especially in
forming the five-membered ring product 3, encouraged
further development of this approach in the context of the
2-spiropiperidine alkaloids. New stereocenters are not
Keywords: Lithiation; Alkylation; Electrophilic addition.
* Corresponding author. E-mail: srychnov@uci.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.099

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S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
diastereomers following chromatographic purification. For
ease of characterization, typically only trans-21 was carried
forward, although the relative stereochemistry at this stage
was ultimately irrelevant.
Protection of the relatively unreactive 2-cyanopiperidines
was accomplished by treatment with BnBr/KI/Na2CO3 in
refluxing acetone or with neat di-tert-butyl dicarbonate
(Boc2O) at 60 8C for several hours to afford N-benzyl
derivative trans-12 and N-Boc derivative trans-13,
respectively (Scheme 5).
The 2-cyanopiperidines trans-12 and trans-13 are readily
alkylated by treatment with lithium diisopropylamide
Scheme 2. Representative reductive decyanations.
Scheme 3. Proposed deuterium-labelled spiroannulations.
Scheme 4. Synthesis of unprotected 2-cyanopiperidines.
deuterium labels. This study would provide information
regarding the stereoselectivity of the reductive lithiations
and would indicate the most appropriate protecting group
for more complex spiroannulations leading to the 2-spiro-
piperidine cores of histrionicotoxin and pinnaic acid.
(LDA) at K78 8C in the presence of N,N-dimethyl-
propyleneurea (DMPU) followed by addition of an alkyl
iodide electrophile (Scheme 6). Alkylation of N-benzyl
derivative trans-12 with MeI or EtI affords axial nitriles 22
and 23 along with their minor diastereomers in a ratio of ca.
10:1. Relative configuration of the major diastereomer was
2. Results and discussion
2.1. Synthesis of substrates
A flexible approach to either N-benzyl or N-Boc cyano-
piperidines was desired. Our attention was drawn to work by
Davis, who showed that imine formation by base-induced
elimination of cyclic N-chloro amines could be rendered
regioselective by choice of base.10 Trapping of these cyclic
imines with a nucleophilic cyanide source would produce
the unprotected 2-cyanopiperidines.11,12 Starting with
2-methylpiperidine (19), N-chlorination using N-chloro-
succinimide (NCS) produced N-chloro-2-methylpiperidine
(20), which was reacted in unpurified form in a regio-
selective elimination mediated by lithium 2,2,6,6-tetra-
methylpiperidide (LTMP) (Scheme 4). Direct addition of an
aqueous solution of KCN and gradual warming to room
temperature produces diastereomeric 2-cyanopiperidines
trans- and cis-21 in 52% overall yield from 19. Analysis
of the crude products by 1H NMR indicates a diastereomer
ratio of ca. 3:1 trans/cis (relative stereochemistry assigned
by NOE studies), however facile epimerization on silica gel
produces ratios on the order of 9:1 of the separable
Scheme 5. Protection of 2-cyanopiperidine 21.
Scheme 6. Alkylation of N-protected 2-cyanopiperidines.

S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
3373
assigned based on the known anomeric-type effect in
2-cyanopiperidines.13 N-Benzyl 2-alkyl-2-cyanopiperidines
such as 22 and 23 are rather labile compounds and
decompose in the presence of acid and on silica gel,
presumably due to facile iminium ion formation and ensuing
side reactions. Purification is best performed on basic
alumina and long-term storage (O6 months) can be
accomplished at low-temperature (K20 8C) in the presence
of small amounts of triethylamine as an acid scavenger.
Alkylation of N-Boc 2-cyanopiperidine trans-13 under
similar conditions produces single detectable diastereomers
24 and 25. The relative configuration of 24 was assigned by
X-ray crystallography and products from similar alkylations
were assigned by analogy. In contrast to the N-benzyl
compounds, N-Boc 2-alkyl-2-cyanopiperidines are very
stable compounds, readily purified by silica gel chromato-
graphy and storable at room temperature for extended
periods of time (O1 year).
(single diastereomer) without evidence of competing
phosphate displacement (Scheme 9).
Scheme 9. Preparation of deuterium-labeled cyclization precursors.
2.2. Preliminary reductive lithiations
Prior to exploring the reductive spiroannulations of 15 and
16, we conducted some preliminary reductive decyanation/
lithiations on N-benzyl 2-cyanopiperidine 22 and N-Boc
2-cyanopiperidine 24 in order to explore the stereo-
selectivity of reductive lithiation in these simpler systems.
The intermediate a-aminoorganolithiums were typically
generated by addition of the cyanopiperidines to solutions of
lithium di-tert-butylbiphenylide (LiDBB) in THF at low
temperature. After a given time period, CD3OD was added
and the reaction was worked up and crude mixtures were
The highly stereoselective alkylation of N-Boc 2-cyano-
piperidine trans-13 is a useful demonstration of a stereo-
control element found in amide and carbamate protected
piperidines. The presence of such carbonyl groups on
nitrogen forces substituents at the 2- or 6-positions to adopt
axial dispositions to relieve severe A1,3-strain.14 This effect
has been elegantly exploited by Beak in stereoselective
lithiations of N-Boc piperidines.15 While we are unsure of
the precise nature of the intermediate involved in the N-Boc
2-cyanopiperidine alkylations, reasonable possibilities
include 1) N-lithiated ketene iminate16 26, where equatorial
electrophile incorporation results due to blocking of the
bottom face by the axial methyl group or 2) C-lithiated
nitrile17 27, stabilized by Boc–Li coordination, which
undergoes electrophilic substitution with retention of
configuration to afford equatorial products 24 and 25
(Scheme 7).
1
analyzed by GC to determine diastereomer ratios and H
NMR (for 22) or GC–MS (for 24) to determine deuterium
incorporation.
The reductive lithiations of N-benzyl 2-cyanopiperidine 22
were problematic, with low crude yields and the presence of
small amounts of several unidentified by-products.
Additionally, deuterium incorporation was often low
despite extensive efforts to exclude proton sources. These
results are indicative of the high basicity of the a-aminoor-
aminoorganolithium derived from 22, where THF is likely
acting as a proton donor.18 Efforts to utilize Cohen’s THF-
free conditions19 (lithium 1-(dimethylamino)naphthalenide
(LDMAN), Me2O, K78 8C) produced no reduced product.
Reasonably useful yields and deuterium incorporations
were ultimately achieved using N,N,N0,N0-tetramethyl-
ethylene diamine (TMEDA) as an additive20 in a pentane/
THF (1:1) solvent system (Scheme 10). The reductive
lithiations of 22 occur with high stereoselectivity (R95:5)
to produce cis piperidine 31.21 While higher temperatures
are not conducive to the chemical stability of the
intermediate a-aminoorganolithiums, they appear to be
configurationally stable at K78 8C for at least 60 min.
Scheme 7. Possible rationales for stereoselective nitrile alkylations.
The deuterium labeled bis-electrophile 14 was prepared
starting with LiAlD4 reduction of ester 28. Phosphorylation,
TIPS removal and iodination produced 14 in good overall
yield (Scheme 8). Alkylation of trans-12 and trans-13 as
described previously for 22–25 afforded the deuterium
labeled cyclization precursors 15 (drZca. 9:1) and 16
Scheme 10. Reductive lithiation/deuteriation of 22.
In accord with Husson’s work, the major stereoisomer
isolated from these reactions displays axial incorporation of
the proton or electrophile. We interpret these results with
the following explanation: (1) single-electron transfer to 22
Scheme 8. Synthesis of deuterated bis-electrophile 14.

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diastereomers trans/cis-35 (Scheme 12).24 These are pre-
sumed to be in rapid equilibrium due to a low-lying barrier
to radical inversion.22 A cursory inspection of the radical
diastereomers suggests that a strong thermodynamic
preference does not exist. Unlike the N-benzyl derivative,
Scheme 11. Rationale for stereoselective reductive lithiation.
Table 1. Reductive lithiation/deuteriation of 22
Entry
Reduction temperature (8C)
Time
Ratio (cis-34: trans-34)
Total yield (%)
1
2
3
K78
K78
K40
5 min
12.5 h
5 min
62 (91% D): 38 (89% D)
78 (92% D): 22 (79% D)
94 (84% D): 6 (72% D)
88
83
67
leads to carbon–CN bond cleavage, predominantly generat-
ing anomerically-stabilized axial radical22 32; (2) sub-
sequent single-electron transfer occurs with retention of
configuration, leading to formally axial 2-lithiopiperidine
33, which reacts with CD3OD with retention of configur-
ation to produce 31 (Scheme 11). Attempts to utilize
electrophiles other than DC (i-PrCHO, PhCHO, MeI and
Me2SO4) produced complex reaction mixtures. While our
work with this class (N-benzyl) of a-aminoorganolithiums
has not demonstrated broad synthetic utility in inter-
molecular reactions with electrophiles, this route does
provide a means of accessing axial 2-lithiopiperidines.
Gawley has reported failed Sn–Li exchange in attempted
generation of an axial N-methyl 2-lithiopiperidine from the
corresponding axial 2-stannylpiperidine.23
anomeric stabilization of an axially disposed radical (trans-
35) would be expected to be diminished due to significant
delocalization of the nitrogen lone pair into the carbonyl
moiety. Additionally, A1,3-strain between the Boc group and
the equatorial methyl group in trans-35 serves to destabilize
this conformation.15 Further single-electron reduction of the
diastereomeric radical intermediates leads to a-amino-
organolithiums trans/cis-36. trans-36 is destabilized by
the axial disposition of the carbon–lithium bond, a
manifestation of an anti-anomeric (HOMO–HOMO)
effect,25 and by A1,3-strain arising from interactions
between the Boc group and the equatorial methyl group.
This stereoelectronic interaction is absent in cis-36, which
may also benefit from coordinative stabilization between the
Boc group and the equatorial lithium.15 These factors appear
to override the 1,3-diaxial (Me–Me) interactions in cis-
36.15c Deuterium incorporation with retention of configur-
ation produces the observed products, trans/cis-34. Despite
the presumed thermodynamic preference for cis-36, a
substantial energy barrier still exists, resulting in slow
equilibration at K78 8C. Computational work by Haeffner,
Brandt and Gawley suggests an inversion barrier of ca.
16 kcal/mol for related N-Boc 2-lithiopyrrolidines.26 At
Reductive lithiations of N-Boc 2-cyanopiperidine 24
initially proved to be less stereoselective than those of the
N-benzyl derivative. However, several features of these
reductive lithiations are noteworthy. The a-aminoorgano-
lithiums derived from 24 were far more robust than the
a-aminoorganolithium derived from 22, as evidenced by
generally high yields and levels of deuterium incorporation
(Table 1). While rapid (!1 h) CD3OD quenches afforded
low ratios of diastereomeric products cis/trans-34 (entry 1),
maintaining a solution of the a-aminoorganolithiums
derived from 24 at K78 8C for extended time periods
demonstrated slow equilibration of the intermediate dia-
stereomeric organolithiums (entry 2). Conducting the
reductive lithation at K40 8C provided superior dia-
stereomer ratios, albeit at the expense of yield and
deuterium incorporation (entry 3).
To account for these results, we suggest the following
possibilities. Single-electron transfer produces radical
Scheme 12. Possible rationale for stereoselectivity in reductive lithiation of
24.
Scheme 13. Reductive spiroannulation of 15.

S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
3375
below). The cyclization of N-benzyl derivative 15 is
presumably rapid enough to outcompete the side reactions
which plagued the intermolecular reactions of 22, leading to
high yields of the spirocyclic products. From these results,
we conclude that reductive lithiation generated a predomi-
Scheme 14. Intermolecular addition of a phosphate electrophile.
Table 2. Reductive spiroannulation of 16
Entry
Reduction temperature (8C)
Ratio (cis-34: trans-34)
Total yield (%)
1
2
K78
K40
72:28
74:26
85
90
nantly axially lithiated a-aminoorganolithium intermediate
corresponding to 33 (Scheme 11). Cyclization with reten-
tion of configuration then produces the major diastereomer
trans-17. Further evidence for retentive electrophilic
addition was shown by conducting reductive lithiation on
N-benzyl 2-cyanopiperidine 23 in the presence of a large
excess (20 equiv) of trimethyl phosphate (Scheme 14). The
sole detectable isomer (37) by GC–MS again displays axial
incorporation of the electrophile as determined by NOESY.
Figure 2. Relevant NOESY signals.
As we had previously observed with N-Boc 2-cyano-
piperidine 24, reductive spiroannulation of 16 was not
highly stereoselective (Table 2). Proton assignments of the
non-deuterated compound 38 were assigned using COSY,
HMQC and NOESY experiments (Fig. 2) and relative
stereochemistry and diastereomeric ratios of the deuterated
compounds cis/trans-18 were made using 1H NMR. We also
observed that spiroannulation stereoselectivity was
independent of temperature, providing nearly identical
results at K78 8C (entry 1) or K40 8C (entry 2). Whereas
the major diastereomer from reductive lithiation/deuteration
of 24 displayed equatorial electrophile incorporation
(Table 1), the major spirocycle diastereomer (cis-18) results
from axial electrophile incorporation. Subjecting N-Boc 2-
cyanopiperidine 25 to reductive lithiation conditions at
K40 8C, at which temperature the equatorially lithiated
a-aminoorganolithium (40) is presumed to be present in
excess, followed by addition of trimethyl phosphate affords
cis/trans-39 in a ratio of 87:13 (Scheme 15). As with
CD3OD, the phosphate electrophile is predominantly
Scheme 15. Intermolecular addition of a phosphate electrophile to 25.
K40 8C, we may be observing faster equilibration of these
species, however the lower yield may indicate selective
decomposition of the axially lithiated trans-36.
2.3. Reductive spiroannulations
With the above information in hand, cyclization precursors
15 and 16 were subjected to LiDBB in THF at K78 8C. As
anticipated from our preliminary studies, the reductive
spiroannulation of 15 was highly stereoselective producing
trans/cis-17 in a ratio of 92:8 (Scheme 13). Relative
configurations of the diastereomeric products were assigned
by conversion to the corresponding N-Boc compounds (see
Scheme 16. Possible raation pathways leading to cis-18.

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S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
incorporated equatorially, resulting in major diastereomer
cis-39.
was used from freshly opened bottles following the
indicated molarity or was titrated using N-benyzlbenza-
mide.30 Diisopropylamine and 2,2,6,6-tetramethylpiper-
idine was distilled from CaH2. DMPU was distilled
An explanation for the disparity in stereoselection between
the reductive spiroannulations of N-Boc 2-cyanopiperidine
16 and the intermolecular reactions of 24 and 25 is not
readily apparent. Fast deuterium quenches (Table 1, entry 1)
indicate that a mixture of equatorially and axially lithiated
intermediates are initially produced following single
electron reduction of the radical intermediates. If the
diastereomer ratios of cis/trans-34 are representative of
the diastereomer ratios of the lithiated intermediates through
a retentive electrophilic addition pathway, an equatorially
lithiated intermediate such as 43 would be expected to
predominate. This scenario in the reductive spiroannulation
of 16 would lead to trans-18 as the major diastereomer,
which is not the observed result. The major diastereomer,
cis-18, may arise through retentive cyclization of an axially
lithiated intermediate (41) or through an invertive cycliza-
tion of an equatorially lithiated intermediate (43)
(Scheme 16). While retentive electrophilic addition occurs
in the intermolecular cases, competing invertive electro-
philic addition of the presumed major equatorially lithiated
43 may be responsible for the generation of cis-18 as the
major diastereomer. The constrained transition states that
must be operative in these cyclizations (e.g., 42 and 44)
would appear to include a different set of interactions when
compared to the intermolecular reactions.
˚
from CaH2 and stored over microwave-activated 4 A
molecular sieves. d4-Methanol was utilized from freshly
opened (!1 week old) bottles. Iodomethane and iodoethane
were filtered through oven-dried basic alumina prior to use.
Trimethylphosphate was vacuum-distilled from CaH2 onto
˚
microwave-activated 4 A molecular sieves. LiDBB was
prepared as described previously.4 All other reagents were
used as received from commercial suppliers. Thin layer
chromatography was performed on Whatman silica gel PE
SIL G/UV (0.25 mm) plates. Flash chromatography was
performed using the indicated solvent system on Sorbent
Technologies 230–400 mesh silica gel. Melting points were
determined using an Electrothermal apparatus and are
reported uncorrected. Infrared spectra were recorded on a
MIDAC Prospect FT-IR. NMR spectra were recorded on
Bruker instruments. 1H NMR spectra are reported
in ppm relative to tetramethylsilane or residual solvent
(CDCl3: d 7.26 ppm; C6D6: d 7.16 ppm). Data are presented
as follows: chemical shift, multiplicity (sZsinglet, dZ
doublet, tZtriplet, qZquartet, pZpentet, brZbroad),
coupling constant(s) in Hertz (Hz), and integration. 13C
NMR spectra were reported in ppm relative to the solvent
signal (CDCl3: 77.2 ppm; C6D6: d 128.0 ppm). Capillary
GC analysis was performed on a Hewlett Packard Model
6890 instrument with a 30 m X 0.25 mM Alltech EC-5 (SE-
54) or Restek RTX-1701 capillary column equipped with a
flame ionization detector. Mass spectral data was obtained
on a MicroMass Autospec E spectrometer or a MicroMass
LCT Electrospray spectrometer. Combustion analyses were
performed by M-H-W Laboratories (Phoenix, AZ).
3. Conclusion
Clearly, the missing piece of the puzzle in these reductive
lithiations remains the exact structure and stereochemistry
of the a-aminoorganolithium intermediates. Nevertheless,
we have demonstrated several interesting features associ-
ated with this chemistry. As Gawley has reported with
secondary N-methyl 2-lithiopiperidines, tertiary N-benzyl
2-lithiopiperidines such as 33 possess high configurational
stability.20,27 While chemical lability remains an issue for
intermolecular reactions, the methods reported herein allow
for their stereoselective generation and use in intra-
molecular electrophilic additions. The N-Boc 2-lithio-
piperidines present an unresolved synthetic dichotomy.
They possess superior chemical stability when compared to
the N-benzyl derivatives. However, their generation in
stereochemically homogenous form and understanding the
stereoselectivity of their reactions with electrophiles require
further study. Exploration of the fascinating chemistry and
synthetic potential of these reactive intermediates will
continue in our laboratory.28
4.1.1. trans/cis-6-Methyl-piperidine-2-carbonitrile (21).
To a 0 8C suspension of N-chlorosuccinimide (14.8 g,
111 mmol) in Et2O (100 mL) was added 2-methylpiperidine
(11.8 mL, 101 mmol) over 5 min. After 1.5 h, the reaction
was diluted with hexanes (250 mL), washed with water
(3x50 mL), satd aq NaCl (50 mL), dried (MgSO4) and
concentrated to afford 1-chloro-2-methylpiperidine10
(12.5 g, 92%) as a pale yellow oil that was dissolved in
THF (200 mL) and cooled to K78 8C. To a 0 8C solution of
2,2,6,6-tetramethylpiperidine (22.5 g, 159 mmol) in THF
(100 mL) was added n-BuLi (2.50 M, 58.4 mL, 146 mmol)
over 30 min. The cooling bath was removed and the orange
solution was allowed to warm to room temperature at which
time it was added to the 1-chloro-2-methylpiperidine
solution via cannula over 1 h. After 30 min, a solution of
KCN (17.3 g, 266 mmol) in MeOH (100 mL)/water
(30 mL) was added over 10 min. The reaction was stirred
for 14 h with gradual warming to room temperature. Water
(500 mL) was added and the mixture was extracted with
EtOAc (3!100 mL) and CH2Cl2 (3!100 mL). The
combined organic phases were washed with satd aq NaCl
(50 mL), dried (Na2SO4) and concentrated. 1H NMR
revealed a diastereomeric ratio of ca. 5.5 trans-21: 1 cis-
21. Flash chromatography (30–50% EtOAc/hexanes)
afforded less polar cyanopiperidine cis-21 (1.01 g, 6%)
and more polar cyanopiperidine trans-21 (8.43 g, 51%) as
pale yellow oils.
4. Experimental
4.1. General experimental details
Unless otherwise noted, all reactions were carried out under
positive argon pressure in flame- or oven-dried glassware
using standard syringe/septum techniques. THF, Et2O and
CH2Cl2 were degassed with argon and dried by vacuum
filtration through activated alumina columns purchased
from GlassContour, Laguna Beach, CA.29 n-Butyllithium

S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
3377
1
Analytical data for cis-21. H NMR (500 MHz, CDCl3) d
(15 mL) over 15 min. After 30 min, iodomethane (3.9 mL,
62 mmol) was added over 5 min and the solution was stirred
for 1 h. Buffer solution (pH 7.0, 50 mL) was added and the
reaction was warmed to room temperature and extracted
with EtOAc (3!50 mL). The combined organic phases
were washed with satd aq NaCl (50 mL), dried (Na2SO4)
and concentrated. Flash chromatography (10% triethyl-
amine/hexanes to 5% EtOAc/10% triethylamine/85%
hexanes) afforded cyanopiperidine 22 (6.56 g, 92%) as an
3.62 (dd, JZ11.6, 2.6 Hz, 1H), 2.62 (dqd, JZ12.4, 6.2,
2.5 Hz, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 1.68–1.60 (m, 3H),
1.37 (qt, JZ13.2, 3.8 Hz, 1H), 1.08 (d, JZ6.2 Hz, 3H), 1.08
(m, 1H); 13C NMR (125 MHz, CDCl3) d 120.6, 52.4, 47.5,
33.2, 30.3, 23.9, 22.7.
Analytical data for trans-21. 1H NMR (500 MHz, CDCl3) d
4.12 (m, 1H), 3.02 (dqd, JZ12.4, 6.2, 2.5 Hz, 1H), 1.87–
1.64 (m, 6H), 1.12 (m, 1H), 1.06 (d, JZ6.2, 3H); 13C NMR
(125 MHz, CDCl3) d 120.4, 48.2, 46.9, 33.4, 28.2, 22.7,
21.2; IR (thin film) 3332, 2223 cmK1; MS (CI) m/z 125
(MCH, 100%).
1
orange oil: H NMR (500 MHz, CDCl3) d 7.38 (d, JZ
7.3 Hz, 2H), 7.30 (t, JZ7.7 Hz, 2H), 7.20 (t, JZ7.3 Hz,
1H), 3.95 (d, JZ17.7 Hz, 1H), 3.77 (d, JZ17.7 Hz, 1H),
2.72 (m, 1H), 1.95 (m, 1H), 1.76–1.56 (m, 5H), 1.40 (s, 3H),
1.35 (m, 1H), 0.99 (d, JZ6.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 142.6, 128.4, 126.8, 126.5, 120.9, 60.1, 56.8, 55.1,
4.1.2. trans-1-Benzyl-6-methyl-piperidine-2-carbonitrile
(trans-12). To a solution of trans-21 (4.88 g, 39.3 mmol) in
acetone (50 mL) was added NaI (5.89 g, 39.3 mmol) and
K2CO3 (8.15 g, 59.0 mmol). Benzyl bromide (5.6 mL,
47 mmol) was added over 2 min and the mixture was
heated at 50 8C for 9 h. The reaction was cooled to room
temperature, diluted with water (250 mL) and extracted
with Et2O (3!50 mL). The combined organic phases were
washed with satd aq NaCl (25 mL), dried (Na2SO4) and
concentrated. Flash chromatography (3% EtOAc/hexanes)
afforded cyanopiperidine trans-12 (6.70 g, 78%) as an
38.9, 35.0, 28.1, 22.5, 21.7; IR (thin film) 2216 cmK1
;
HRMS (ESI) calcd for C14H20N [MKCN]C 202.1596,
found 202.1591. Additional purification could be performed
using flash chromatography on basic Al2O3 (30% CH2Cl2/
hexanes). Long term storage (O24 h) was conducted by
concentrating the cyanopiperidine down from Al2O3-
filtered NEt3 several times and low-temperature (K20 8C)
storage under argon.
4.1.5. cis-1-Benzyl-2-ethyl-6-methyl-piperidine-2-carbo-
nitrile (23). To a K78 8C solution of diisopropylamine
(0.657 mL, 4.69 mmol) in THF (15.0 mL) was added
n-BuLi (1.46 M, 2.98 mL, 4.36 mmol) over 5 min. After
15 min, DMPU (0.810 mL, 6.70 mmol) was added followed
by dropwise addition of a solution of 12 (0.718 g,
3.35 mmol) in THF (3.0 mL) over 5 min. After 1 h,
iodoethane (0.804 mL, 6.70 mmol) was added over 2 min
and the solution was stirred for 1 h. Water (50 mL) was
added and the reaction was warmed to room temperature
and extracted with EtOAc (3!20 mL). The combined
organic phases were washed with satd aq NaCl (10 mL),
dried (Na2SO4) and concentrated. Flash chromatography
(basic Al2O3, 30% CH2Cl2/hexanes) afforded cyano-
1
orange oil: H NMR (500 MHz, CDCl3) d 7.36–7.26 (m,
5H), 4.25 (d, JZ13.3 Hz, 1H), 3.65 (m, 1H), 3.21 (d, JZ
13.3 Hz, 1H), 2.66 (dqd, JZ12.1, 6.0, 2.5 Hz, 1H), 1.81–
1.59 (m, 5H), 1.34 (m, 1H), 1.22 (d, JZ6.1, 3H); 13C NMR
(125 MHz, CDCl3) d 138.0, 129.2, 128.8, 127.6, 117.5,
55.5, 53.6, 51.5, 34.7, 28.9, 21.3, 21.3; IR (thin film) 2937,
1454 cmK1; HRMS (ESI) calcd for C14H19N2 [MCH]C
215.1548, found 215.1553.
4.1.3. trans/cis-2-Cyano-6-methyl-piperidine-1-car-
boxylic acid tert-butyl ester (trans/cis-13). A mixture of
diastereomers 21 (5.14 g, 41.4 mmol) and Boc2O (9.03 g,
41.4 mmol) was heated at 60 8C for 10 h. Flash chromato-
graphy (10% to 15% to 20% EtOAc/hexanes) afforded
inseparable cyanopiperidines trans/cis-13 (7.78 g, 84%) as a
pale yellow oil.
1
piperidine 23 (0.667 g, 82%) as a colorless oil: H NMR
(500 MHz, CDCl3) d 7.36 (d, JZ7.2 Hz, 2H), 7.29 (t, JZ
7.6 Hz, 2H), 7.19 (t, JZ7.3 Hz, 1H), 3.98 (d, JZ18.0 Hz,
1H), 3.75 (d, JZ18.0 Hz, 1H), 2.73 (dqd, JZ12.2, 6.12,
2.74 Hz, 1H), 2.07 (ddd, JZ13.3, 5.6, 3.1 Hz, 1H), 1.86 (dq,
JZ14.9, 7.5 Hz, 1H), 1.77–1.62 (m, 3H), 1.55–1.48 (m,
2H), 1.32 (m, 1H), 0.99 (d, JZ6.1 Hz, 3H), 0.94 (t, JZ
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 142.5, 128.3,
126.8, 126.4, 120.3, 65.2, 57.2, 55.3, 35.0, 34.7, 32.6, 22.8,
21.3, 8.8; IR (thin film) 2216 cmK1; HRMS (ESI) calcd for
C15H22N [MKCN]C 216.1752, found 216.1761. Long term
storage (O24 h) was effected by concentrating the cyano-
piperidine down from Al2O3-filtered NEt3 several times and
low-temperature (K20 8C) storage under argon.
1
Analytical data for cis diastereomer. H NMR (500 MHz,
CDCl3) d 5.05 (m, 1H), 4.33 (m, 1H), 2.01 (m, 1H), 1.90 (m,
1H), 1.71–1.61 (m, 4H), 1.48 (s, 9H), 1.33 (d, JZ7.0, 3H);
13C NMR (125 MHz, CDCl3) d 154.4, 120.5, 81.5, 47.1,
40.8, 29.4, 28.7, 28.5, 17.5, 15.3.
Analytical data for trans diastereomer. 1H NMR (500 MHz,
CDCl3) d 4.80 (app t, JZ4.2 Hz, 1H), 4.00 (m, 1H), 2.10
(m, 1H), 2.04–2.00 (m, 2H), 1.88–1.73 (m, 2H), 1.64–1.57
(m, 1H), 1.48 (s, 9H), 1.24 (d, JZ6.7, 3H); 13C NMR
(125 MHz, CDCl3) d 154.6, 119.8, 81.4, 48.3, 42.7, 28.5,
27.1, 25.7, 20.8, 14.6; IR (thin film) 1704 cmK1; HRMS
(ESI) calcd for C12H20N2O2Na [MCNa]C 247.1420, found
247.1420.
4.1.6. trans-2-Cyano-2,6-dimethyl-piperidine-1-car-
boxylic acid tert-butyl ester (24). To a K78 8C solution
of diisopropylamine (8.6 mL, 61 mmol) in THF (200 mL)
was added n-BuLi (1.6 M, 35.6 mL, 57 mmol) over 10 min.
After 30 min, DMPU (10.6 mL, 88 mmol) was added
followed by dropwise addition of a solution of 13 (9.82 g,
43.8 mmol) in THF (50 mL) over 20 min. After 1.5 h,
iodomethane (8.2 mL, 131 mmol) was added over 5 min
and the solution was stirred for 1.5 h. Half-saturated NH4Cl
solution (500 mL) was added and the reaction was warmed
4.1.4. cis-1-Benzyl-2,6-dimethyl-piperidine-2-carbo-
nitrile (22). To a K78 8C solution of diisopropylamine
(6.2 mL, 44 mmol) in THF (50 mL) was added n-BuLi
(2.31 M, 16.2 mL, 37.4 mmol) over 10 min. After 30 min,
DMPU (7.5 mL, 62 mmol) was added followed by dropwise
addition of a solution of 12 (6.69 g, 31.2 mmol) in THF

3378
S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
to room temperature and extracted with Et2O (3!150 mL).
The combined organic phases were washed with satd aq
NaCl (100 mL), dried (MgSO4) and concentrated. Flash
chromatography (5% EtOAc/hexanes) afforded cyano-
piperidine 24 (9.03 g, 86%) as a pale yellow solid. Low-
temperature (K20 8C) recrystallization from EtOH/MeOH/
H2O provided crystals (colorless cubes) suitable for X-ray
satd aq NaCl (ca. 10 mL) was added dropwise and the
resulting mixture was stirred vigorously for 15 min and then
filtered through a thin Celite pad, washing with Et2O (ca.
200 mL). Concentration of the filtrate and flash chromato-
graphy (30% EtOAc/hexanes) afforded alcohol 29 (4.27 g,
94%) as a colorless oil: 1H NMR (500 MHz, CDCl3) d 3.74
(t, JZ4.5 Hz, 2H), 2.55 (br s, 1H), 1.66 (m, 4H), 1.09 (s,
21H); 13C NMR (125 MHz, CDCl3) d 63.8, 30.3, 30.2, 18.4,
12.4; IR (thin film) 3337 cmK1; HRMS (CI/NH3) calcd for
C14H28D2O2Si [MCH]C 249.2217, found 249.2222.
1
diffraction. Mp 38–40 8C; H NMR (500 MHz, CDCl3) d
4.34 (m, 1H), 4.00 (m, 1H), 2.21 (m, 1H), 1.94–1.84 (m,
1H), 1.81 (s, 3H), 1.79–1.59 (m, 5H), 1.52 (s, 9H), 1.24 (d,
JZ6.9, 3H); 13C NMR (125 MHz, CDCl3) d 155.9, 122.8,
81.7, 49.8, 49.7, 38.9, 29.3, 29.0, 28.5, 18.8, 15.3; IR (thin
film) 1708 cmK1; HRMS (ESI) calcd for C13H22N2O2Na
[MCNa]C 261.1579, found 261.1580; Anal. calcd for
C13H22N2O2: C 65.51, H 9.30, N 11.75; found C 65.70, H
9.23, N 11.93.
4.1.10. Phosphoric acid diethyl ester 1,1-dideuterio-4-
triisopropylsilanyloxy-butyl ester (30). To a 0 8C solution
of alcohol 29 (2.01 g, 8.09 mmol) in Et2O (30 mL) was
added pyridine (0.98 mL, 12 mmol) followed by dropwise
addition of diethyl chlorophosphate (1.40 mL, 9.71 mmol)
over 5 min. A catalytic amount of DMAP (5 crystals) was
added and the reaction was allowed to stir at room
temperature for 24 h. Water (100 mL) was added, the
mixture was stirred for 15 min and the layers were
separated. The aqueous phase was extracted with Et2O
(2!30 mL) and the combined organic phases were washed
with satd aq NaCl (3!20 mL), dried (MgSO4) and
concentrated. Flash chromatography (gradient elution: 10
to 50% EtOAc/hexanes) afforded phosphate 30 (2.60 g,
84%) as a colorless oil: 1H NMR (500 MHz, CDCl3) d 4.09
(dp, JZ7.2, 1.4 Hz, 4H), 3.70 (dt, JZ6.2, 1.2 Hz, 2H), 1.74
(t, JZ8.0 Hz, 2H), 1.60 (m, 2H), 1.32 (t, JZ7.0 Hz, 6H),
1.04 (s, 21H); 13C NMR (125 MHz, CDCl3) d 64.0 (JZ
5.8 Hz), 63.2, 29.3, 27.2 (JZ7.0 Hz), 18.4, 16.6 (JZ
6.8 Hz), 12.4; IR (thin film) 1281, 1035 cmK1; HRMS (ESI)
calcd for C17H37D2O5PSiNa [MCNa]C 407.2326, found
407.2308.
4.1.7. trans-2-Cyano-2-ethyl-6-methyl-piperidine-1-car-
boxylic acid tert-butyl ester (25). To a K78 8C solution
of diisopropylamine (0.240 mL, 1.72 mmol) in THF
(10.0 mL) was added n-BuLi (1.46 M, 1.09 mL,
1.59 mmol) over 5 min. After 15 min, DMPU (0.297 mL,
2.46 mmol) was added followed by dropwise addition of a
solution of 13 (0.275 g, 1.23 mmol) in THF (1.0 mL
C0.5 mL rinse) over 5 min. After 2 h, iodoethane
(0.295 mL, 3.69 mmol) was added over 2 min and the
solution was stirred for 2 h. Half-saturated NH4Cl solution
(40 mL) was added and the reaction was warmed to room
temperature and extracted with EtOAc (3!15 mL). The
combined organic phases were washed with satd aq NaCl
(10 mL), dried (Na2SO4) and concentrated. Flash chroma-
tography (5% EtOAc/hexanes) afforded cyanopiperidine 25
(0.257 g, 83%) as a colorless oil: 1H NMR (500 MHz,
CDCl3) d 4.32 (m, 1H), 2.28 (dq, JZ14.7, 7.4 Hz, 1H),
2.16–2.06 (m, 2H), 1.92–1.82 (m, 2H), 1.76–1.60 (m, 3H),
1.52 (s, 9H), 1.30 (d, JZ6.9 Hz, 3H), 0.94 (t, JZ7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 155.5, 122.4, 81.5,
53.9, 49.4, 33.6, 32.2, 28.6, 28.5, 19.5, 14.6, 8.5; IR (thin
film) 1708 cmK1; HRMS (ESI) calcd for C14H24N2O2Na
[MCNa]C 275.1736, found 275.1725.
4.1.11. Phosphoric acid diethyl ester 1,1-dideuterio-4-
iodo-butyl ester (14). To a chilled (0 8C) flask containing
phosphate 30 (1.96 g, 5.10 mmol) was added TBAF solution
(1.0 M in THF, 5.6 mL, 5.6 mmol) and the solution was
stirred for 30 min. The cooling bath was removed and the
reaction was allowed to stir for an additional 30 min.
Solvent was removed by rotary evaporation and the
resulting pale brown oil was dissolved in CH2Cl2 (10 mL)
and cooled to 0 8C. Imidazole (2.28 g, 33.5 mmol) was
added followed by PPh3 (8.00 g, 30.5 mmol) and the
mixture was stirred until dissolution at which time iodine
(7.74 g, 30.5 mmol) was added in portions over 5 min. After
1 h, Et2O (50 mL) was added and the mixture was washed
with 1 M aq HCl (2!10 mL), satd aq NaHCO3 (2!10 mL)
and 10% aq Na2S2O3 (2!10 mL). The combined aqueous
phases were extracted with Et2O (3!10 mL) and the
combined organic phases were then washed with satd aq
NaCl (10 mL), dried (Mg2SO4) and concentrated. Flash
chromatography (Et2O) afforded iodide 14 (1.21 g, 70%
4.1.8. 4-(Triisopropylsiloxy)butyric acid methyl ester
(28). To a solution of g-hydroxybutyric acid methyl ester
(4.30 g, 36.4 mmol (contaminated with 2.21 g of
g-butyrolactone)) in DMF (20 mL) was added imidazole
(2.98 g, 43.7 mmol) followed by dropwise addition of TIPS-
Cl (9.4 mL, 44 mmol) over 5 min. After 24 h, water
(200 mL) was added and the mixture was extracted with
Et2O (4!50 mL) and the combined organic phases were
washed with satd aq NaCl (3!50 mL), dried (MgSO4)- and
concentrated. Flash chromatography (10% Et2O/hexanes)
afforded ester 28 (9.99 g, 100%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) d 3.71 (t, JZ6.1 Hz, 2H), 3.66 (s, 3H),
2.43 (t, JZ7.5 Hz, 2H), 1.85 (p, JZ6.9 Hz, 2H), 1.03 (s,
21H); 13C NMR (100 MHz, CDCl3) d 173.8, 62.1, 51.4,
30.4, 28.0, 17.9, 11.8; IR (thin film) 1743 cmK1; HRMS
(CI/NH3) calcd for C15H30O3Si [MCH]C 275.2042, found
275.2054.
1
over 2 steps) as a pale yellow oil: H NMR (400 MHz,
CDCl3) d 4.11 (m, 4H), 3.22 (t, JZ6.8 Hz, 2H), 1.94 (m,
2H), 1.78 (t, JZ8.1 Hz, 2H), 1.34 (dt, JZ7.1, 0.95 Hz, 6H);
13C NMR (125 MHz, CDCl3) d 64.2 (JZ5.8 Hz), 31.3 (JZ
6.9 Hz), 29.8, 16.6 (JZ6.6 Hz), 6.3; IR (thin film) 1267,
1030 cmK1; HRMS (CI/NH3) calcd for C8H16D2IO4P
338.0111, found 338.0110. Comparison to the correspond-
ing non-deuterated compound4 confirmed the position of the
deuterium labels. Deuterium incorporation was quantitative
4.1.9. 1,1-Dideuterio-4-triisopropylsilanyloxybutan-1-ol
(29). To a 0 8C suspension of LiAlD4 (0.576 g, 13.7 mmol)
in Et2O (40 mL) was added a solution of ester 28 (5.02 g,
18.3 mmol) in Et2O (10 mL) over 15 min. After 30 min,
1
within the limits of H NMR.

S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
3379
4.1.12. Phosphoric acid 3-(cis-1-benzyl-2-cyano-6-
methyl-piperidin-2-yl)-1,1-dideuterio-propyl ester
diethyl ester (15). To a K78 8C solution of diisopropyl-
amine (0.297 mL, 2.12 mmol) in THF (5.0 mL) was added
n-BuLi (1.38 M, 1.42 mL, 1.96 mmol) over 2 min. After
15 min, DMPU (0.394 mL, 3.26 mmol) was added followed
by dropwise addition of a solution of trans-12 (0.350 g,
1.63 mmol) in THF (2.0 mL C0.5 mL flask rinse) over
10 min. After 1.5 h, a solution of 14 (0.552 g, 1.63 mmol) in
THF (1.5 mL C0.5 mL rinse) was added over 2 min. After
1.5 h, water (15 mL) was added and the mixture was
warmed to room temperature and extracted with EtOAc
(3!8 mL). The combined organic extracts were washed
with satd aq NaCl (2!5 mL), dried (Na2SO4) and
concentrated. Flash chromatography (basic Al2O3, CH2Cl2
to 10% Et2O/CH2Cl-2 to Et2O to 10% MeOH/Et2O)
afforded cyanopiperidine 15 (0.550 g, 79%) as a pale
yellow oil. Additional chromatography (basic Al2O3, 50%
EtOAc/hexanes to EtOAc) afforded an analytical sample:
1H NMR (500 MHz, C6D6) d 7.22 (d, JZ7.6 Hz, 2H), 7.16
(m, 2H), 7.05 (t, JZ7.2 Hz, 1H), 3.94 (m, 4H), 3.89 (d, JZ
17.9 Hz, 1H), 3.55 (d, JZ17.9 Hz, 1H), 2.58 (m, 1H), 1.65–
1.49 (m, 4H), 1.36–1.27 (m, 5H), 1.24–1.09 (m, 3H), 1.05 (t,
JZ7.0 Hz, 6H), 1.00–0.92 (m, 2H), 0.78 (d, JZ6.1 Hz,
3H); 13C NMR (125 MHz, C6D6) d 142.6, 128.6, 127.0,
126.6, 119.9, 64.2, 63.4 (d, JZ5.5 Hz), 57.0, 55.5, 39.0,
35.0, 34.8, 30.0 (d, JZ6.7 Hz), 22.7, 21.4, 20.3, 16.2 (d, JZ
6.4 Hz); IR (thin film) 1275, 1031 cmK1; HRMS (ESI)
calcd for C21H33D2NO4P [MKCN]C 398.2215, found
398.2208. Long term storage (O24 h) was effected by
concentrating the cyanopiperidine down from Al2O3-
filtered NEt3 several times and low-temperature (K20 8C)
storage under argon.
hex. This solution was transferred over 15 s via cannula
down the chilled wall of a flask containing a solution of
LiDBB (1.05 mmol) and TMEDA (0.141 mL, 0.936 mmol)
in THF (2.0 mL)/pentane (2.0 mL). After 5 min, CD3OD
(0.3 mL) was added down the flask wall over 15 s. After
15 min, water (10 mL) was added and the mixture was
extracted with EtOAc (3!5 mL). The combined organic
phases were washed with satd aq NaCl solution (3 mL),
dried (Na2SO4) and concentrated. GC analysis of the crude
reaction mixture indicated a dr of 98:2 cis/trans. Flash
chromatography (10% i-PrOH/CH2Cl2) afforded piperidine
31 (0.0457 g, 52%) as a pale brown oil. 1H NMR was
consistent with literature data21 and indicated 77% D.
4.1.15. Representative reductive lithiation/deuterium
quench (inverse addition). To a K40 8C solution of 24
(0.0534 g, 0.224 mmol) and 1,10-phenanthroline (1 crystal)
in THF (5.0 mL) was added n-BuLi/hexanes (2 drops)
followed by addition of LiDBB solution (ca. 0.50 M,
0.986 mL, 0.493 mmol) over 15 s. After 5 min, CD3OD
(0.3 mL) was added and the reaction was stirred for 5 min.
Half-saturated NH4Cl (20 mL) was added and the mixture
was extracted with EtOAc (3!5 mL). The combined
organic extracts were washed with satd aq NaCl (3 mL),
dried (Na2SO4). A sample was analyzed by GC, indicating a
dr of 94:6 cis-34/trans-34. GC–MS (EI) analysis of a sample
indicated deuterium incorporations of 84% D (cis-34) and
72% D (trans-34). Flash chromatography (20% CH2Cl2/
hexanes to 10% Et2O/hexanes) afforded an inseparable
mixture of cis/trans-34 (0.0321 g, 67%) as a colorless oil.
1H NMR was consistent with literature data.15b,31
4.1.16. trans/cis-Dideuterio-6-benzyl-7-methyl-6-aza-
spiro[4.5]decane (trans/cis-17). To a 0 8C solution of 15
(0.0140 g, 0.0330 mmol) and 1,10-phenanthroline
(1 crystal) in THF (0.25 mL) was added n-BuLi/hexanes
(1 drop). This solution was added via syringe down the
chilled flask wall over 1 min to a K78 8C solution of LiDBB
solution (ca. 0.50 M, 0.165 mL, 0.0824 mmol) in THF
(2.0 mL) followed by a syringe/flask rinse of THF
(0.25 mL). After 1.5 h, MeOH (0.1 mL) was added followed
by water (6 mL) and the mixture was warmed to room
temperature and extracted with EtOAc (3!2 mL). The
combined organic phases were washed with satd aq NaCl
(1 mL), dried (Na2SO4) and concentrated. Flash chroma-
tography (20% CH2Cl2/hexanes to 7.5% EtOAc/hexanes)
afforded spirocycles trans/cis-17 (0.0063 g, 85%) as a pale
yellow oil: 1H NMR (500 MHz, C6D6) d 7.42 (d, JZ7.2 Hz,
2H), 7.27 (m, 2H), 7.15 (t, JZ7.3 Hz, 1H), 3.79 (d, JZ
17.1 Hz, 1H), 3.50 (d, JZ17.1 Hz, 1H), 2.75 (dqd, JZ9.6,
6.5, 3.1 Hz, 1H), 1.71–1.19 (m, 12H), 0.81 (d, JZ6.5 Hz,
3H); 13C NMR (125 MHz, C6D6) d 145.4, 128.1, 127.2,
125.9, 67.9, 55.0, 51.5, 39.5, 36.7, 32.9, 25.6, 25.1, 22.0,
21.4; IR (thin film) 2930, 1453 cmK1; HRMS (ESI) calcd
for C17H24D2N [MCH]C 246.2189, found 246.2175. For
correlation purposes, the product from a larger scale
experiment (ca. 0.300 g) was transformed without purifi-
cation to the corresponding N-Boc compounds (cis/trans-
18) through the following sequence: (1) LiDBB, THF,
K78 8C; (2) Pd(OH)2/C, H2 (1 atm), 1 N HCl/MeOH, 6 h
4.1.13. trans-2-Cyano-2-[4-(diethoxy-phosphoryloxy)-
4,4-dideuterio-butyl]-6-methyl-piperidine-1-carboxylic
acid tert-butyl ester (16). To a K78 8C solution of
diisopropylamine (0.195 mL, 1.39 mmol) in THF (5.0 mL)
was added n-BuLi (1.52 M, 0.845 mL, 1.28 mmol) over
2 min. After 15 min, DMPU (0.259 mL, 2.14 mmol) was
added followed by dropwise addition of a solution of 13
(0.264 g, 1.18 mmol) in THF (1.0 mL) over 5 min. After
1 h, a solution of 14 (0.362 g, 1.07 mmol) in THF (1.0 mL)
was added over 3 min. After 3 h, half-saturated aq NH4Cl
(25 mL) was added and the mixture was warmed to room
temperature and extracted with EtOAc (3!10 mL). The
combined organic phases were washed with satd Na2S2O3
(10 mL), brine (10 mL), dried (Na2SO4) and concentrated.
Flash chromatography (25% hexanes/EtOAc) afforded
cyanopiperidine 16 (0.349 g, 75%) as a pale yellow oil:
1H NMR (500 MHz, CDCl3) d 4.30 (m, 1H), 4.11 (m, 4H),
2.31 (td, JZ12.5, 5.1 Hz, 1H), 2.17–2.12 (m, 1H), 2.04 (td,
JZ12.7, 4.3 Hz, 1H), 1.92–1.81 (m, 2H), 1.75–1.59 (m,
5H), 1.51 (s, 9H), 1.39 (m, 1H), 1.34 (m, 6H), 1.30 (d, JZ
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 155.5, 122.2,
81.6, 63.9 (d, JZ6.2 Hz), 53.2, 49.5, 38.6, 34.4, 30.1 (d, JZ
6.8 Hz), 28.6, 28.5, 20.2, 19.4, 16.4 (d, JZ6.7 Hz), 14.7; IR
(thin film) 1705 cmK1
;
HRMS (ESI) calcd for
C20H36N2O6PD2 [MCH]C 435.2595, found 435.2606.
4.1.14. cis-1-Benzyl-2,6-dimethyl-piperidine (31). To a
K78 8C solution of 22 (0.0972 g, 0.426 mmol) in THF
(0.5 mL)/pentane (0.5 mL) was added 3 drops of n-BuLi/
1
and (3) Boc2O, 60 8C, 48 h (34% yield, 3 steps). H NMR
indicated a dr of 92:8 trans/cis-18.

3380
S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
4.1.17. cis-1-Benzyl-2-ethyl-2,6-dimethyl-piperidine (37).
To a K78 8C solution of 23 (0.0799 g, 0.330 mmol),
trimethyl phosphate (0.777 mL, 6.60 mmol) and 1,10-
phenanthroline (1 crystal) in THF (1.0 mL) was added
n-BuLi/hexanes (3 drops). This solution was transferred via
cannula over 5 min down the chilled flask wall of an LiDBB
solution (ca. 0.50 M, 2.64 mL, 1.32 mmol) in THF (4.0 mL)
at K78 8C. The reaction was stirred for 15 h with gradual
warming to room temperature at which time it was diluted
with Et2O (25 mL) and extracted with 1 N HCl (3!
7.5 mL). The combined acidic aqueous phases were washed
with Et2O (3!5 mL), basified to pHZ12 with solid KOH
and extracted with Et2O (3!5 mL). The combined organic
phases were washed with satd aq NaCl (3 mL), dried
(K2CO3) and concentrated. GC analysis of a sample
indicated the presence of a single major component with
several minor components. GC–MS (CI) confirmed the
identity of the major component as 37 but failed to detect
the minor components. Flash chromatography (5% EtOAc/
hexanes) afforded 37 (0.0203 g, 26%) as a pale yellow oil:
1H NMR (500 MHz, CDCl3) d 7.43 (d, JZ7.7 Hz, 2H), 7.25
(t, JZ7.6 Hz, 2H), 7.14 (t, JZ7.3 Hz, 1H), 3.99 (d, JZ
17.4 Hz, 1H), 3.34 (d, JZ17.4 Hz, 1H), 2.69 (dqd, JZ12.5,
6.2, 2.3 Hz, 1H), 1.59–1.43 (m, 8H), 1.26 (m, 2H), 0.99 (s,
3H), 0.81–0.78 (m, 6H); 13C NMR (125 MHz, CDCl3) d
145.3, 127.9, 127.2, 125.7, 57.6, 54.5, 52.5, 36.6, 36.1, 35.4,
23.5, 20.4, 15.6, 8.7; IR (thin film) 2929, 1459 cmK1; MS
(CI) m/z 232 (MCH, 100%).
added LiDBB solution (ca. 0.50 M, 1.81 mL, 0.907 mmol)
rapidly via syringe. After 5 min, the solution was cooled to
K78 8C and trimethyl phosphate (0.970 mL, 8.24 mmol)
was added over 2 min. The solution was allowed to stir for
15 h with gradual warming to room temperature. Satd aq
NH4Cl (15 mL) was added and the mixture was extracted
with EtOAc (3!5 mL). The combined organic phases were
washed with satd aq NaCl (3 mL), dried (Na2SO4) and
concentrated. GC analysis indicated a diastereomeric ratio
of 87:13 cis/trans. Flash chromatography (20% CH2Cl2/
hexanes to 2.5% EtOAc/hexanes) afforded a mixture of cis/
trans-39 (0.0370 mg, 37%) as a colorless oil.
1
Analytical data for cis-39. H NMR (500 MHz, CDCl3) d
4.28 (m, 1H), 2.16 (dq, JZ15.0, 7.5 Hz, 1H), 2.03 (ddd, JZ
14.3, 9.6, 6.9 Hz, 1H), 1.86 (m, 1H), 1.73–1.40 (m, 4H),
1.46 (s, 9H), 1.37 (s, 3H), 1.20 (m, 1H), 1.18 (d, JZ7.0 Hz,
3H), 0.78 (d, JZ7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 155.8, 79.0, 57.0, 47.9, 33.1, 33.0, 28.8, 27.3, 26.9,
22.2, 14.2, 9.1; IR (thin film) 1688 cmK1; MS (CI) m/z 242
(MCH, 100%).
References and notes
1. For related methods, see: (a) Zeller, E.; Grierson, D. S.
Heterocycles 1988, 27, 1575–1578. (b) Zeller, E.; Sajus, H.;
Grierson, D. S. Synlett 1991, 44–46. (c) Zeller, E.; Grierson,
D. S. Synlett 1991, 878–880. (d) Broka, C. S.; Shen, T. J. Am.
Chem. Soc. 1989, 111, 2981–2984. (e) Deng, K.; Bensari, A.;
Cohen, T. J. Am. Chem. Soc. 2002, 124, 12106–12107.
2. (a) Rychnovsky, S. D.; Hata, T.; Kim, A. I.; Buckmelter, A. J.
Org. Lett. 2001, 3, 807–810. (b) Rychnovsky, S. D.; Takaoka,
L. R. Angew. Chem. Int. Ed. 2003, 42, 818–820.
4.1.18. cis/trans-Dideuterio-7-methyl-6-aza-spiro[4.5]-
decane-6-carboxylic acid tert-butyl ester (cis/trans-18).
To a K78 8C solution of 16 (0.0522 g, 0.120 mmol) and
1,10-phenanthroline (1 crystal) in THF (0.5 mL) was added
n-BuLi/hex (1 drop) to form a brown solution. This solution
was transferred via syringe to a K78 8C solution of LiDBB
solution (ca. 0.50 M in THF, 0.529 mL, 0.264 mmol) in
THF (2.0 mL) down the chilled flask wall over 3 min
followed by a flask/syringe rinse with THF (0.25 mL). After
2.5 h, half-saturated NH4Cl (10 mL) was added and the
mixture was warmed to room temperature and extracted
with EtOAc (3!4 mL). The combined organic phases were
washed with satd aq NaCl (3 mL), dried (Na2SO4) and
concentrated. Flash chromatography (20% CH2Cl2/hexanes
to 5% Et2O/hexanes) afforded diastereomers cis/trans-18
(0.0236 mg, 77%) as a colorless oil. 1H NMR indicated a dr
of 72:28 cis/trans-18; HRMS (ESI) calcd for C15H25D2-
NO2Na [MCNa]C 278.2063, found 278.2061.
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5. A conceptually similar approach can be found in the work of
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1
Analytical data for non-deuterated compound. H NMR
(500 MHz, C6D6) d 4.38 (m, 1H), 2.75 (ddd, JZ13.0, 8.9,
4.6 Hz, 1H), 2.28–2.15 (m, 2H), 1.94 (dtt, JZ11.1, 7.0,
3.4 Hz, 1H), 1.59–1.48 (m, 4H), 1.44 (s, 9H), 1.43–1.35 (m,
3H), 1.31–1.17 (m, 3H), 1.08 (d, JZ6.8 Hz, 3H); 13C NMR
(125 MHz, C6D6) d 155.9, 78.8, 64.8, 49.2, 41.0, 39.8, 38.7,
9. Nagasaka, T.; Hayashi, H.; Kumakawa, M.; Sakamoto, M.;
Mizuno, M.; Hamaguchi, F. Heterocycles 1989, 29,
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30.1, 29.0, 27.3, 26.2, 21.5, 16.4; IR (thin film) 1698 cmK1
;
HRMS (ESI) calcd for C15H27NO2Na [MCNa]C 276.1939,
found 276.1949.
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4.1.19. cis/trans-2-Ethyl-2,6-dimethyl-piperidine-1-car-
boxylic acid tert-butyl ester (cis/trans-39). To a K40 8C
solution of 25 (0.104 g, 0.412 mmol) and 1,10-phenanthro-
line (1 crystal) in THF (5.0 mL) was added n-BuLi/hex
(3 drops) to form a brown solution. To this solution was

S. A. Wolckenhauer, S. D. Rychnovsky / Tetrahedron 61 (2005) 3371–3381
3381
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24. These conformations likely represent an oversimplification.
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pyramidalization at the radical center.
15. (a) Beak, P.; Lee, W. K. J. Org. Chem. 1990, 55, 2578–2580.
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