Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

Article abstract of DOI:10.1039/b808644c

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH ₂Cl₂ at -78 °C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94: 6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl₂ in CH₂Cl₂ or CHCl₃ at temperatures of between 20-60 °C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99: 1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl₂ proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.

Full text of DOI:10.1039/b808644c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene
and Prins cyclisations†
Claire A. M. Cariou, Benson M. Kariuki‡ and John S. Snaith*
Received 21st May 2008, Accepted 13th June 2008
First published as an Advance Article on the web 28th July 2008
DOI: 10.1039/b808644c
An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or
carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated
hydrochloric acid in CH2Cl2 at −78 ◦C afforded good yields of two of the four possible diastereomeric
piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94 : 6. The
diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming
unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl2 in CH2Cl2 or
CHCl3 at temperatures of between 20–60 ◦C, favoured the 4,5-trans diastereomer 8, in a diastereomeric
ratio of up to 99 : 1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control
via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis
cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The
cyclisations catalysed by MeAlCl2 proceed under thermodynamic control, affording the product in
which both the 4- and 5-substituents are equatorial.
a tunicate,7 with an ascidian later providing other members of the
Introduction
family,8 and have recently been the focus of synthetic attention.9
Functionalised piperidines occur widely in natural products1 and
We now describe in full our efforts towards the synthesis of
feature in a number of successful pharmaceuticals, with the ring
2,4,5-trisubstituted piperidines, using cyclisation precursors in the
system being regarded as an important scaffold for drug discovery.2
The biological importance of piperidines has led to the develop-
ment of numerous synthetic approaches,3 but the wide variety
of functionality and substitution patterns present in piperidine
targets continues to drive the search for new methodologies.4
We recently published an approach to 3,4-disubstituted
piperidines using a carbonyl ene reaction as the key ring-
closing step.5 The Type I intramolecular carbonyl ene reaction
is a very attractive method of ring closure, forming a carbon–
carbon bond with the concomitant generation of two contiguous
stereocentres.6 In our case, the Brønsted acid-catalysed reaction
at low temperatures strongly favoured a cis relationship between
the two new stereocentres, while the Lewis acid-catalysed reaction
at elevated temperatures gave the corresponding trans product,
providing a useful stereocontrol feature.
main derived from a-amino acids.10
Results and discussion
Our key cyclisation precursors were the aldehydes 1a–1g
(Fig. 1), and we envisaged that in most cases these could be pre-
pared from the N-tosyl b-amino acids, obtained by homologation
of the readily available a-amino acids or the corresponding a-
amino alcohols. Given that 3-aminobutyric acid is commercially
available, a simple N-tosylation of this material proved to be the
most expeditious route to the N-tosyl b-amino acid, although
nitrile 3a was also prepared for later studies (vide infra). The
preparation of 1g used homoserine as a starting material (vide
infra). Reduction of the corresponding amino acids according to
the procedure of Meyers et al. afforded the a-amino alcohols 2b–c
and 2e–f;11 we found reduction of alanine by this means to be
low-yielding, and so commercially available alaninol was used.
Bis-tosylation followed by treatment with NaCN in DMF gave
Extending our approach to 2,4,5-trisubstituted piperidines is an
important goal, since they form the core of a number of important
natural products, including the pseudodistomin family of anti-
tumour compounds. These were isolated by Kobayashi et al. from
School of Chemistry, The University of Birmingham, Edgbaston, Birming-
ham, UK B15 2TT. E-mail: j.s.snaith@bham.ac.uk
† Electronic supplementary information (ESI) available: Experimental
procedures, NMR spectra and full characterisation for all compounds,
as well as CIF files and ORTEP diagrams for the X-ray structures. CCDC
reference numbers 689102–689105. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b808644c
‡ Author to whom correspondence regarding the X-ray crystallography
should be addressed. Current address: School of Chemistry, Cardiff
University, Main Building, Park Place, Cardiff, UK, CF10 3AT. Email:
KariukiB@cardiff.ac.uk
Fig. 1 Cyclisation precursors.
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good yields of the N-tosyl b-amino nitriles 3a–c and 3e–f
(Scheme 1).12
Scheme 5 Route to cyclisation precursors from N-tosyl b-amino nitriles.
Scheme 1 Synthesis of nitriles 3a–c and 3e–f.
cyclisation precursors were used, although the Dibal-H reduction
route was shorter and generally higher-yielding.
Preparation of nitrile 3d was achieved by a slightly modified
route (Scheme 2). Reduction of 1-aminocyclohexane carboxylic
acid by BH3·THF in refluxing THF gave an excellent yield of the
corresponding b-amino alcohol, but bis-tosylation was very low-
yielding and gave a complex mixture of products. Instead, methyl
ester formation, N-tosylation and subsequent LiAlH4 reduction
gave the N-tosyl amino alcohol 2d, which could be O-tosylated in
near-quantitative yield; treatment with NaCN in DMF smoothly
led to the desired nitrile 3d in 97% yield.
With the nitriles in hand, we explored two different routes to
the target aldehydes. Acid-catalysed hydrolysis of nitriles 3b–c and
3e–f to give the N-tosyl b-amino acids 4b–c and 4e–f (Scheme 3)
proceeded smoothly for 3b–c and 3e, but for 3f the inseparable
elimination product 5 was visible in the 1H NMR spectrum.
Conversion of the N-tosyl b-amino acids 4a–c into the cycli-
sation precursors was readily achieved by a three-step sequence
(Scheme 4) involving N,O-alkylation by prenyl bromide, LiAlH4
reduction to alcohols 6a–c and Swern oxidation to give 1a–c in
excellent overall yield.
With a range of cyclisation precursors in hand, we turned our
attention to their cyclisation. Initially, the cyclisation was catalysed
by three equivalents of concentrated HCl in CH2Cl2 at −78 ◦C. In
our earlier work on 3,4-disubstituted piperidines,5 these conditions
had favoured formation of the kinetic product, in which there is a
cis relationship between the hydroxyl and isopropenyl substituents.
For aldehydes 1a–f the results are summarised in Table 1.
In all cases except 1f, only two of the four possible stereoisomers
were observed, in excellent combined yields. Small amounts (0–
10%) of the HCl addition products 11 and 12 (vide infra) were
often present; although generally separable from the alkene, it
was also possible to treat the mixture with aqueous ammonia in
THF to effect elimination of HCl and return the pure alkene. The
identities of the cis, cis and trans, trans products were secured by
X-ray diffraction on single crystals grown from 7c and 8a (Fig. S1
and S2 in the ESI†).
As can be seen from Table 1, the diastereoselectivities were
generally good, and the reaction favoured the cis, cis product 7
for small- and medium-sized 2-substituents, although the reaction
became unselective for very bulky 2-substituents (entries 5 and 6).
The stereoselectivities can be rationalised by considering two
factors. Firstly, there is a strong preference for the 2-substituent
to adopt an axial disposition in the chair-like transition state,
thus avoiding the pseudo A1,3 strain with the sulfonamide
Whilst the route was efficient for the preparation of 1a–c, it was
unsatisfactory for 1f, and we believed that the same compounds
should be accessible by a more direct route (Scheme 5). N-
Alkylation of N-tosyl amino nitriles 3a–f proceeded in excellent
yield, and Dibal-H reduction of the products proceeded smoothly
to afford the cyclisation precursors 1a–f. Both routes to the
Scheme 2 Preparation of nitrile 3d.
Scheme 3 Hydrolysis of nitriles.
Scheme 4 Route to cyclisation precursors from N-tosyl b-amino acids.
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Table 1 Cyclisations of aldehydes 1a–f with concentrated hydrochloric acid
Entry
Aldehyde
R
7 : 8a
Yield (%)b
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Me
78 : 22
94 : 6
89 : 11
89 : 11
47 : 53
54 : 46c
70 (22)
81 (0)
75 (5)
68 (11)
42 (37)
41 (40)
Bn
iPr
–(CH2)5–
tBu
Ph
a Ratio was determined by integration of crude 1H NMR spectra. b Isolated yield of major (minor) isomers after chromatography. c Traces of two other
isomers were observed—see main text.
(Scheme 6); this stereochemical preference in N-acyl and N-
sulfonamido piperidines has been shown to be pronounced in a
number of cases.13 The second factor is the kinetic preference for
the ene component and the aldehyde to adopt a cis relationship in
the cyclisation transition state, as observed in our earlier work.5
According to our proposal, any carbocationic character developed
Fig. 2 The two additional diastereomers isolated from cyclisation of 1f.
on the 5-substituent in the transition state (or a carbocationic
intermediate formed during cyclisation through a fully stepwise
mechanism) can be stabilised by interaction with the lone pair of
the oxygen when these two substituents adopt a cis relationship.
This cis relationship is achieved with the aldehyde lying in an
axial position in the transition state, and the more bulky ene
component lying equatorial. More bulky 2-substituents lead to
a lowering of the diastereoselectivity as a result of increased 1,3-
diaxial interactions with the aldehyde, forcing the aldehyde into
an equatorial position to give 8.
structural analysis. The equatorial 2-substituent in 9 is interesting.
Normally there is a very strong preference for the 2-substituent
of N-tosyl and N-acyl piperidines to lie in an axial position to
minimise the pseudo A1,3 strain with the nitrogen substituent. It
would appear that in this example the energetic penalty of placing
both the phenyl and the isopropenyl groups axial is greater than
the pseudo A1,3 strain, meaning that this conformer is not observed
for 9.
The rather modest selectivity observed for 1a appears to be
a result of equilibration of the initially formed kinetic isomer
7a to the thermodynamic product 8a due to the fact that the
reaction required 48 h to reach completion, compared with
around 18 h for the other examples. Later studies (vide infra)
supported the fact that Brønsted acid-catalysed isomerisation
to the thermodynamically more stable trans, trans piperidine
occurred readily for these compounds. This contrasts with our
previous work where Brønsted acid-catalysed isomerisation was
very slow for 3,4-disubstituted piperidines, reflecting the much
smaller 1,3-diaxial interactions with the hydroxyl group that are
present in these molecules.
In the case of 1f, two other isomers were isolated in very
small amounts: 9 in 4% yield and 10 in 2% yield. Compound
9 was confirmed by single-crystal X-ray analysis as the trans, cis
piperidine in which the 2-substituent is equatorial, Fig. 2 and
Fig. S3 in the ESI.† Compound 10 is presumed to be the fourth
diastereomer, although there was insufficient material for a full
The successful results achieved with concentrated hydrochloric
acid led us to explore the cyclisation of 1a–f in dichloromethane
saturated with hydrogen chloride gas. Typically, hydrogen chlo-
ride gas was bubbled through a solution of the aldehyde in
dichloromethane at −78 ◦C for 1 h and the reaction mixture was
stirred for a further 4 h at −78 ◦C to complete the cyclisation. The
reaction mixture was then stirred for 24 h at room temperature to
ensure complete addition of HCl across the double bond in the
product. The results are presented in Table 2.
The cis/trans selectivities are broadly in line with those obtained
using concentrated hydrochloric acid, although the reactions are
slightly less cis selective. Although the cyclisations were more
rapid than those with concentrated hydrochloric acid, with starting
material consumed within 2–4 h rather than 18 h, the reactions had
to be left for around 24 h to get complete addition of HCl across
the double bond, and it appeared that this prolonged contact
with acid led to some equilibration to the trans, trans isomer. For
example, cyclisation of 1b to a mixture of alkenes and chlorides
Scheme 6 Stereocontrol model for Brønsted acid-catalysed cyclisations.
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Table 2 Cyclisations of aldehydes 1a–f in CH2Cl2 saturated with HCl
Entry
Aldehyde
R
11 : 12a
Yield (%)a
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
Me
72 : 28
88 : 12
81 : 19
87 : 13
46 : 54
57 : 43c
55 (20)
83 (11)
68 (12)
65 (10)
28 (36)
42 (34)
Bn
iPr
–(CH2)5–
tBu
Ph
a Ratio was determined by integration of crude 1H NMR spectra. b Isolated yield of major (minor) isomers after chromatography. c Traces of two other
isomers were observed in the crude NMR spectra, but were not isolated—see main text.
was complete after 3 h with an overall cis : trans ratio of 93 : 7.
After 24 h, conversion to the chlorides was complete, but the cis :
trans ratio had dropped to 88 : 12.
stereoselectivities, although in some cases, a small loss in stere-
oselectivity occurred on switching from dichloromethane at 40 ◦C
to chloroform at 60 ◦C.
Addition of HCl to the 4,5-trans alkenes was noticeably slower
than addition to the 4,5-cis alkenes, supporting our assertion that
overlap between the oxygen lone pair of the hydroxyl and the
empty p-orbital of the cationic centre stabilises the 4,5-cis cation
but not the 4,5-trans cation, in which such overlap is geometrically
unfavourable.
Turning to the Lewis acid-catalysed reaction, aldehydes 1a–f
were treated with one equivalent of methylaluminium dichloride,
which had been found to be the optimal Lewis acid in our earlier
studies;5 the results are summarised in Table 3.
Under these Lewis acid conditions, equilibration to the ther-
modynamic trans, trans product is favoured to minimise the
large 1,3-diaxial interactions that result in the transition state
between the axial 2-substituent and the Lewis acid-coordinated
oxygen, Scheme 7. This accounts for the increased prefer-
ence for the trans, trans isomer as the 2-substituent becomes
larger.
Pipecolic acid derivatives
The stereoselectivities for the Lewis acid-catalysed cyclisation
ranged from good to excellent (up to 99 : 1), with good overall
yields (typically over 70% of the major isomer was isolated
after chromatography). Generally 40–60 ◦C afforded the best
Pipecolic acid (piperidine 2-carboxylic acid) is an important non-
proteinogenic amino acid and one of the constituents of a variety
of natural products such as rapamycin and FK506. A variety of
substituted pipecolic acids feature in natural products, as well as
Table 3 Cyclisations of aldehydes 1a–f with MeAlCl2
Entry
Aldehyde
R
Temp/◦Ca
7 : 8b
Yield (%)c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1c
1c
1c
1d
1e
1f
Me
Me
Me
Bn
20
40
60
20
40
60
20
40
60
20d
60
60
12 : 88
7 : 93
4 : 96
10 : 90
5 : 95
9 : 91
4 : 96
2 : 98
3 : 97
3 : 97
1 : 99
2 : 98e
76 (5)
60 (4)
71 (4)
61 (10)
64 (5)
73 (9)
74 (2)
82 (2)
83 (0)
76 (3)
88 (1)
80 (2)
Bn
Bn
iPr
iPr
iPr
10
11
12
–(CH2)5–
tBu
Ph
a Reactions were carried out in dichloromethane (20 ◦C and 40 ◦C) or chloroform (60 ◦C). b Ratio was determined by integration of crude H NMR
spectra. c Isolated yield of major (minor) isomers after chromatography. d Carrying out the reaction in refluxing chloroform resulted in very low yields of
product. e Traces of two other isomers were observed—see main text.
1
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Scheme 7 Stereocontrol model for Lewis acid-catalysed cyclisations.
in pharmaceuticals such as the HIV protease inhibitor Palinavir,
and synthetic work in this area continues apace.14 We believed that
substituted pipecolic acids or their derivatives should be accessible
using our chemistry, starting from the readily available amino acid
homoserine.
amounts, allowing us to confirm the structure of 11g by X-ray
diffraction (Fig. S5, ESI†). In contrast, lactone 15 proved to be
completelyunreactive towards HCladdition, so that an unchanged
mixture of 15 and 16 was returned after stirring for two days in
dichloromethane saturated with hydrogen chloride gas.
O-tert-Butyldimethylsilylhomoserine methyl ester 13, prepared
in two steps from homoserine by the method of Kline et al.,15 was
N-tosylated and N-alkylated using prenyl bromide to give 14 in
80% overall yield (Scheme 8). Removal of the TBDMS group
by pyridinium p-toluenesulfonate in methanol and subsequent
Swern oxidation gave the aldehyde cyclisation precursor 1g in
near-quantitative yield.
Given that alkene 7g readily underwent HCl addition, and that
chlorolactone 16 appeared to be completely stable, the failure of
lactone 15 to add HCl is interesting. Addition of HCl to both
compounds would be considered to proceed through a carbocation
(Scheme 10).
In the case of 7g, addition of HCl will proceed via cation
17, in which the lone pair of the hydroxyl provides a stabilising
interaction with the empty p-orbital. In contrast, the delocalised
oxygen lone pair in 18 will have little, if any, overlap with the empty
p-orbital, and it would appear that without this stabilisation, 18
does not form.
The facile lactonisation of 1g on treatment with MeAlCl2 meant
that isomerisation to the trans, trans isomer would not be possible
under these conditions. Instead, lactone 15 was reduced to diol 19
by LiBH4, but this proved resistant to isomerisation by MeAlCl2 in
refluxing CHCl3, presumably due to chelation of the Lewis acid by
the two hydroxyl groups. Protection of the primary hydroxyl as a
TBDPS ether overcame this problem, and treatment of the cis, cis
silyl ether 20 with one equivalent of MeAlCl2 in refluxing CHCl3
afforded an 86 : 14 ratio of 21 : 20 after 1 h, from which 21 was
isolated in 61% yield (Scheme 11). Longer reaction times resulted
in a lower recovery of 21, along with unidentified side-products.
The success of the cyclisations of the substrates containing a
prenyl ene moiety led us to investigate the corresponding crotyl
Stirring 1g at −78 ◦C in dichloromethane saturated with
hydrogen chloride gas (Scheme 9) resulted in a completely
stereoselective reaction and afforded a mixture of four products,
all of which had the cis, cis stereochemistry: the expected carbonyl
ene product 7g and the HCl addition product 11g, along with
lactones 15 and 16. None of the corresponding trans products was
detected. In contrast, treating 1g with one equivalent of MeAlCl2
at room temperature gave solely the lactone 15 in 79% yield after
chromatography; the structure of 15 was confirmed by single
crystal X-ray diffraction (Fig. S4, ESI†).
Although the two lactones 15 and 16 could be separated from the
two esters 7g and 11g, these pairs of compounds were inseparable
from one another, and so we attempted to convert the two mixtures
entirely to the corresponding chlorides. Stirring the mixture of
esters in dichloromethane saturated with hydrogen chloride gas
resulted in complete HCl addition and partial lactonisation to
afford a separable mixture of 11g and 16 in roughly equal
Scheme 8 Preparation of cyclisation precursor 1g.
Scheme 9 Brønsted acid-catalysed cyclisation of 1g.
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Scheme 10 Proposed HCl addition pathway.
Scheme 11 Lactone opening and isomerisation.
compounds 23a,b,e. These were prepared via nitriles 22a,b,e
(Scheme 12) using commercial crotyl chloride, which afforded the
products as roughly 5 : 1 mixtures of E : Z isomers. In our earlier
work on the synthesis of 3,4-disubstituted piperidines, we found
that the geometry of the crotyl double bond did not influence
the stereochemical outcome of the reaction, with both the E
and Z crotyl compounds giving the cis piperidine on cyclisation
with MeAlCl2 at room temperature.5 Aldehydes 23a,b,e, chosen to
provide a range of steric demands at the 2-position, were treated
with three equivalents of MeAlCl2 in CH2Cl2 at room temperature;
the results are summarised in Table 4.
The major product was identified by NOE studies as the trans,
cis piperidine 26, and this was subsequently confirmed by X-ray
diffraction in the case of 26b (Fig. S6, ESI†). The other two
products, formed in roughly equal amounts, were the cis, cis and
trans, trans products 24 and 25, respectively. Small amounts of the
product of b-elimination 27 were also observed, as well as some
trace products from dimerisation (vide infra).
Scheme 12 Preparation of crotyl cyclisation precursors 23a,b,e.
Table 4 Cyclisations of aldehydes 23a,b,e with MeAlCl2
Entry
Aldehyde
R
Temp/◦Ca
Time/h
24b
25b
26b
1
2
3
4
5
6
7
23a
23a
23a
23a
23a
23b
23e
Me
Me
Me
Me
Me
Bn
−78
20
16
3
16
22
3
16
16
10
8
12
8
8
18
7
8
22
35
33
25
33
44
18
11
10
8
11
16
27
20
20c
40
20
20
tBu
a Reactions were carried out in dichloromethane with 3 equiv of MeAlCl2 unless otherwise stated. b Isolated yield after chromatography. c Reaction carried
out with 1 equiv of MeAlCl2.
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It is interesting that the cyclisation of 23 should favour
formation of the previously unobserved 26. Assuming cyclisation
via a cationic mechanism (although the arguments hold for a
more concerted mechanism in which partial cationic character is
generated), in intermediate 28 (leading to 24) and intermediate 29
(leading to 26) the hydroxyl can stabilise the carbocation (Fig. 3).
However, in 29 the relatively sterically undemanding ethyl cation
can adopt an axial disposition, allowing the cis relationship to be
maintained with the Lewis acid-coordinated oxygen, which now
lies in an equatorial position to avoid the 1,3-diaxial interaction
with the 2-substituent.
for four days; only in the case of 24 did any isomerisation occur,
with small amounts of 25 (4%) and 26 (9%) produced, along with
recovered starting material (60%) and decomposition products
(accounting for the remaining mass).
The cyclisation of 23a,b,e was also screened using the
Lewis acids AlCl3, Me2AlCl, TiCl4, SnCl4, Sc(OTf)3 and
BF3·Et2O. Me2AlCl gave product ratios similar to MeAlCl2, but
the reactions were not as clean. AlCl3, TiCl4 and BF3·Et2O
gave rather less of the three piperidines 24–26 and led to the
formation of significant amounts of dimerisation products 30–
32 (Scheme 13), analogous to those isolated in our earlier work,
which were identified by mass spectrometry.
The attempted cyclisation of 23a in dichloromethane saturated
with hydrogen chloride gas (Scheme 14) gave chiefly the b-
elimination product 27, along with small amounts of three
piperidines: 26a and two chlorine-containing compounds, iden-
tified as 33 and 34, both as mixtures of epimers at the carbon
bearing the chlorine.
Fig. 3 Stabilising interactions in intermediates 28 and 29.
Removal of the p-toluenesulfonyl protecting group
The product ratio was rather insensitive to reaction time, tem-
perature and the amount of Lewis acid used. The three products
were separated and re-subjected to MeAlCl2 at room temperature
Removal of the p-toluenesulfonyl protecting group was carried
out on a representative range of examples by stirring the N-
tosylpiperidines with sodium naphthalenide in THF at −78 ◦C
Scheme 13 Proposed route to dimerisation products.
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Scheme 14 Cyclisation of 23a in CH2Cl2 saturated with HCl.
(Scheme 15). The yields were good to excellent in most cases, with
some loss of material noted for the alanine derivatives 35a and 36a
due to their significant polarity and water solubility.
and the aqueous phase re-extracted with CH2Cl2. The combined
organic phases were washed with aqueous CuSO4, brine, dried
over MgSO4 and concentrated in vacuo to give the crude product
as a solid. Purification by flash column chromatography (silica;
eluent 1 : 2 EtOAc–petroleum ether, Rf = 0.36) afforded the title
compound as a white powder (15.93 g, 75%): mp 96–98 ◦C (from
EtOAc–petroleum ether); [a]2D3 −42.7 (c 1.0 in CHCl3); (Found: C,
60.19; H, 5.49; N, 2.99. C23H25NO5S2 requires C, 60.11; H, 5.48; N,
3.05%); mmax (KBr)/cm−1 3290 (NH), 3067 (CH aromatic), 2953 (mas
Conclusion
In summary, we have discovered a diastereoselective synthesis
of cis, cis and trans, trans 2,4,5-trisubstituted piperidines from
simple acyclic precursors. Cyclisation catalysed by HCl at low
temperature affords predominantly the kinetic cis, cis product
resulting from the preferred axial disposition of the 2- and 4-
substituents. The 2-substituent adopts an axial orientation to
minimise pseudo A1,3 strain with the N-tosyl group, while the axial
4-hydroxyl group is able to provide a stabilising interaction with
the carbocationic centre attached to the 5-position. The diastere-
oselectivity of the reaction is good for small and medium sized
2-substituents, although an unfavourable 1,3-diaxial interaction
with the 4-hydroxyl results in a loss of stereoselectivity for larger
2-substituents. Cyclisation catalysed by MeAlCl2 at 20–60 ◦C
affords the thermodynamically more stable trans, trans isomer
with good to excellent diastereoselectivity. The method should
find application in the synthesis of more complex molecules.
=
=
CH2), 2892 (ms CH2), 1598 (C C aromatic), 1495 (C C aromatic),
=
1456 (C C aromatic), 1160 (ms SO2); dH (300 MHz, CDCl3) 2.40
(3H, s, Ph-CH3), 2.46 (3H, s, Ph-CH3), 2.65 (1H, dd, J 13.9 and
7.2, Ph-CHH), 2.80 (1H, dd, J 13.9 and 7.4, Ph-CHH), 3.52–3.60
(1H, m, CH), 3.84 (1H, dd, J 10.1 and 5.3, CHH-OPh), 3.97 (1H,
dd, J 10.1 and 3.5, CHH-OPh), 4.71 (1H, d, J 7.7, NH), 6.86
(2H, d, J 7.2, Ar CH), 7.11–7.18 (5H, m, Ar CH), 7.35 (2H, d, J
8.5, Ar CH), 7.51 (2H, d, J 8.1, Ar CH), 7.75 (2H, d, J 8.1, Ar
CH); dC (75 MHz, CDCl3) 21.6 (Ph-CH3), 21.8 (Ph-CH3), 37.7
(Ph-CH2), 53.7 (CH), 70.3 (CH2-OPh), 127.0 (Ar CH), 128.1 (Ar
CH), 128.8 (Ar CH), 129.2 (Ar CH), 129.8 (Ar CH), 130.1 (Ar
CH), 132.4 (Cq), 135.8 (Cq), 136.9 (Cq), 143.6 (Cq), 145.3 (Cq);
m/z (ES+) 482.1 (100%, [M + Na]+), 310.1 (85) [HRMS Found:
(M + Na)+ 482.1060. C23H25NNaO5S2 requires M, 482.1072].
Experimental section
Typical procedure for preparation of nitriles:
Typical procedure for tosylation: (2S)-O-(p-toluenesulfonyl)-N-(p-
(3S)-(p-toluenesulfonyl)amino-4-phenylbutyronitrile (3b)
toluenesulfonyl)phenylalaninol
To a suspension of NaCN (2.24 g, 45.70 mmol) in DMF
(90 mL) was added a solution of (2S)-O-(p-toluenesulfonyl)-N-
(p-toluenesulfonyl)phenylalaninol (7.00 g, 15.25 mmol) in DMF
(60 mL), and stirring was continued until the reaction was judged
to be complete by TLC analysis (24 h). The reaction mixture
was diluted with water and extracted with Et2O. The combined
organic phases were washed with water, brine, dried over MgSO4
and concentrated in vacuo to give nitrile 3b as colourless crystals
(4.32 g, 90%), which were used without further purification:
To a solution of p-toluenesulfonyl chloride (19.43 g, 101.99 mmol)
and pyridine (26.2 mL, 324.50 mmol) in CH2Cl2 (50 mL) at 0 ◦C
was added a solution of (S)-phenylalalinol (7.00 g, 46.36 mmol) in
CH2Cl2 (50 mL). The resulting solution was warmed to ambient
temperature and stirred until the reaction was judged to be
complete by TLC analysis (ca. 24 h). The reaction mixture was
poured into a separating funnel containing cold aqueous HCl
(1 M, 60 mL) and CH2Cl2. The organic phase was separated
Scheme 15 Removal of the p-toluenesulfonyl protecting group.
3344 | Org. Biomol. Chem., 2008, 6, 3337–3348 This journal is
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Rf = 0.38 (silica; eluent 2 : 1 toluene–diethyl ether); mp 82–84 ◦C
(from toluene–diethyl ether) (lit.16 oil); [a]D23 −65.5 (c 1.0 in CHCl3)
(lit.16 [a]D −58.6 (c 4.0 in CHCl3)); (Found: C, 64.79; H, 5.84;
N, 8.81. C17H18N2O2S requires C, 64.94; H, 5.77; N, 8.91%); mmax
(KBr)/cm−1 3350 (NH), 2920 (mas CH2), 2850 (ms CH2), 2246 (CN),
by TLC analysis (12 h). The solvent was removed in vacuo to give
a white solid, which was partitioned between water and Et2O (4 ×
100 mL). The combined organic phases were washed with water
and brine, dried over MgSO4 and concentrated in vacuo to give
the crude product. Purification by flash column chromatography
(silica; eluent 5 : 1 hexane–EtOAc, Rf = 0.3) afforded the title
compound as a colourless oil (1.02 g, 83%): [a]2D1 −6.7 (c 1.0 in
CHCl3); (Found: C, 69.00; H, 7.44; N, 2.92. C27H35NO4S requires
=
1597 (C C aromatic), 1380 (mas SO2), 1160 (ms SO2); dH (300 MHz,
CDCl3) 2.42 (3H, s, Ph-CH3), 2.56 (1H, dd, J 16.8 and 3.9, CHH-
CN), 2.67 (1H, dd, J 16.8 and 6.3, CHH-CN), 2.77 (1H, dd, J
14.0 and 7.7, Ph-CHH), 2.90 (1H, dd, J 14.0 and 7.0, Ph-CHH),
3.58–3.69 (1H, m, CH), 4.85 (1H, d, J 7.0, NH), 6.99 (2H, m, Ar
CH), 7.20–7.22 (5H, m, Ar CH), 7.55 (2H, d, J 8.1, Ar CH); dC
(75 MHz, CDCl3) 21.6 (Ph-CH3), 24.3 (CH2-CN), 39.9 (Ph-CH2),
51.5 (CH), 116.9 (CN), 127.0 (2 × Ar CH), 127.4 (Ar CH), 129.0
(2 × Ar CH), 129.1 (2 × Ar CH), 129.9 (2 × Ar CH), 135.3
(Cq), 136.6 (Cq), 143.8 (Cq); m/z (ES+) 337.1 (100%, [M + Na]+)
[HRMS Found: (M + Na)+ 337.0993. C17H18N2NaO2S requires
M, 337.0987].
C, 69.05; H, 7.51; N, 2.98%); mmax (film)/cm−1 3028 ( CH), 2971
=
=
=
(mas CH3), 2929 (mas CH2), 1731 (C O), 1675 (C C aliphatic), 1600
=
=
=
(C C aromatic), 1496 (C C aromatic), 1453 (C C aromatic),
1338 (mas SO2), 1155 (ms SO2); dH (300 MHz, CDCl3) 1.64 (9H, s,
=
=
3 × C C(CH3)2), 1.72 (3H, s, C C(CH3)2), 2.38 (3H, s, Ph-CH3),
2.52 (1H, dd, J 15.8 and 6.6, CHH-COO), 2.71 (1H, dd, J 15.8
and 7.7, CHH-COO), 2.87 (1H, dd, J 13.6 and 8.1, Ph-CHH),
2.97 (1H, dd, J 13.6 and 6.6, Ph-CHH), 3.81 (2H, d, J 6.8, N-
CH2), 4.35–4.38 (1H, m, N-CH), 4.41 (2H, d, J 7.3, O-CH2), 5.08
(1H, t, J 6.8, N-CH2-CH), 5.24 (1H, t, J 7.3, O-CH2-CH), 7.12–
7.27 (7H, m, Ar CH), 7.59 (2H, d, J 8.1, Ar CH); dC (75 MHz,
Typical procedure for nitrile hydrolysis: (3S)-(p-toluenesulfonyl)-
amino-4-phenylbutyric acid (4b)
=
=
CDCl3) 17.9 (C C(CH3)2), 18.1 (C C(CH3)2), 21.6 (Ph-CH3),
=
=
25.8 (C C(CH3)2), 25.9 (C C(CH3)2), 38.4 (CH2-COO), 40.8
(Ph-CH2), 44.0 (N-CH2), 57.5 (Ph-CH2-CH), 61.7 (CH2-O-CO),
118.6 (O-CH2-CH), 121.5 (N-CH2-CH), 126.7 (Ar CH), 127.5
(2 × Ar CH), 128.6 (2 × Ar CH), 129.41 (2 × Ar CH), 129.45
(2 × Ar CH), 135.4 (Cq), 138.2 (Cq), 138.5 (Cq), 139.1 (Cq),
A mixture of nitrile 3b (1.01 g, 3.2 mmol), glacial acetic acid
(3.2 mL), water (3.2 mL) and concentrated sulfuric acid (3.2 mL)
was stirred at 110 ◦C overnight under a reflux condenser. After
cooling, the reaction mixture was diluted with water and the
aqueous phase extracted with CH2Cl2. The combined organic
phases were washed with brine, dried over MgSO4 and concen-
trated in vacuo to afford the crude acid. Purification by flash
column chromatography (silica; eluent 1 : 1 petroleum ether–ethyl
acetate, Rf = 0.33) afforded acid 4b as a grey powder (0.87 g,
+
+
=
142.9 (Cq), 171.2 (C O); m/z (ES ) 492.3 (100%, [M + Na] )
[HRMS Found: (M + Na)+ 492.2169. C27H35NNaO4S requires
492.2185].
Typical procedure for reduction of the ester: (3S)-[N-(3-methylbut-
2-enyl)-N-(p-toluenesulfonyl)amino]-4-phenylbutanol (6b)
◦
81%): mp 63–65 C (from petroleum ether–EtOAc) (lit.17 85 ◦C
(from petroleum ether–EtOAc)); [a]2D0 −21.2 (c 1.0 in CHCl3)
(lit.18 [a]D23 −14.6 (c 0.9 in CH2Cl2)); (Found: C, 61.16; H, 5.84;
N, 4.01. C17H19NO4S requires C, 61.24; H, 5.74; N, 4.20%); mmax
(KBr)/cm−1 3500 (OH), 3280 (NH), 2926 (mas CH2), 2875 (ms CH2),
To
a solution of 3-methylbut-2-enyl (3S)-[N-(3-methylbut-
2-enyl)-N-(p-toluenesulfonyl)amino]-4-phenylbutanoate (0.34 g,
0.72 mmol) in THF (1.6 mL) at 0 C was added LiAlH4 (1.0 M
◦
in Et2O, 0.59 mL, 0.59 mmol) dropwise. The ice bath was
removed and stirring continued for 3 h. After cooling to 0 ◦C,
the reaction mixture was carefully acidified with 2 M aqueous
HCl and the aqueous phase extracted with EtOAc. The combined
organic phases were washed with brine, dried over MgSO4 and
concentrated in vacuo to afford the crude alcohol. Purification by
flash column chromatography (silica; eluent 2 : 1 petroleum ether–
EtOAc, Rf = 0.32) afforded alcohol 6b as a colourless oil (0.22 g,
78%): [a]2D3 −43 (c 1.0 in CHCl3); (Found: C, 68.19; H, 7.31; N, 3.62.
C22H29NO3S requires C, 68.18; H, 7.54; N, 3.61%); mmax (neat)/cm−1
3436 (OH), 2928 (mas CH2), 1651 (C C aliphatic), 1599 (C C
aromatic), 1495 (C C aromatic), 1454 (C C aromatic), 1331 (mas
SO2), 1153 (ms SO2), 1050 (C–O); dH (500 MHz, CDCl3) 1.57 (1H, tt,
J 12.9 and 3.3, CHH-CH2-OH), 1.65–1.72 (7H, stack, C C(CH3)2
and CHH-CH2-OH), 2.41 (3H, s, Ph-CH3), 2.50–2.63 (2H, m, Ph-
CH2), 3.55 (1H, ddd, J 11.7, 4.8 and 3.3, CHH-OH), 3.78 (1H, td,
J 11.7 and 3.3, CHH-OH), 3.83 (1H, dd, J 16.2 and 5.5, N-CHH),
3.94 (1H, dd, J 16.2 and 8.1, N-CHH), 4.14–4.24 (1H, m, N-CH),
5.17 (1H, t, J 6.5, CH C), 6.95–7.0 (2H, m, Ar CH), 7.18–7.23
(5H, m, Ar CH), 7.61 (2H, d, J 8.1, Ar CH); dC (125 MHz,
=
=
=
1712 (C O), 1599 (C C aromatic), 1496 (C C aromatic), 1454
=
(C C aromatic), 1325 (mas SO2), 1157 (ms SO2); dH (300 MHz,
CDCl3) 2.40 (3H, s, Ph-CH3), 2.54 (2H, d, J 5.2, CH2-COOH),
2.78 (1H, dd, J 13.6 and 7.0, Ph-CHH), 2.87 (1H, dd, J 13.6
and 7.7, Ph-CHH), 3.70–3.81 (1H, m, CH), 5.59 (1H, br d, J
5.9, NH), 7.01–7.03 (2H, m, Ar CH), 7.19–7.23 (5H, m, Ar CH),
7.62 (2H, d, J 8.6, Ar CH); dC (75 MHz, CDCl3) 21.7 (Ph-CH3),
37.8 (CH2-COOH), 40.7 (Ph-CH2), 51.8 (CH), 127.0 (Ar CH),
127.1 (2 × Ar CH), 128.9 (2 × Ar CH), 129.4 (2 × Ar CH),
129.8 (2 × Ar CH), 136.8 (Cq), 137.4 (Cq), 143.6 (Cq), 175.9
(COOH); m/z (EI+) 334 (9%, [M + H]+), 242 (52), 155 (38), 91 (100)
[HRMS Found: (M + H)+ 334.1110. C17H20NO4S requires M,
334.1113].
=
=
=
=
=
Typical procedure for alkylation of the acid: 3-methylbut-2-enyl
(3S)-[N-(3-methylbut-2-enyl)-N-(p-toluenesulfonyl)amino]-4-
phenylbutanoate
=
Caesium carbonate (1.70 g, 5.2 mmol) was added to a solution of
acid 4b (0.87 g, 2.6 mmol) in acetonitrile (110 mL). The reaction
mixture was stirred at ambient temperature for 30 min before
1-bromo-3-methylbut-2-ene (0.60 mL, 5.2 mmol) was added and
stirring was continued until the reaction was judged to be complete
=
=
CDCl3) 17.9 ( C-CH3), 21.5 (Ph-CH3), 25.7 ( C-CH3), 34.6
(CH2-CH2-OH), 40.1 (Ph-CH2), 41.6 (N-CH2), 56.4 (N-CH), 58.4
=
(CH2-OH), 121.6 (CH C), 126.5 (Ar CH), 127.1 (2 × Ar CH),
128.6 (2 × Ar CH), 129.1 (2 × Ar CH), 129.6 (2 × Ar CH),
Org. Biomol. Chem., 2008, 6, 3337–3348 | 3345
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=
134.9 (CH C(CH3)2), 137.9 (Cq), 138.1 (Cq), 143.2 (Cq); m/z
2.40 (3H, s, Ph-CH3), 2.52 (1H, dd, J 17.1 and 5.7, CHH-CHO),
2.71–2.80 (2H, stack, Ph-CHH and CHH-CHO), 2.89 (1H, dd, J
13.6 and 5.9, Ph-CHH), 3.84 (2H, d, J 6.6, N-CH2), 4.43–4.53 (1H,
(ES+) 410 (100%, [M + Na]+) [HRMS Found: (M + Na)+ 410.1761.
C22H29NNaO3S requires M, 410.1766].
=
m, N-CH), 5.08 (1H, t, J 6.6, CH), 7.08–7.11 (2H, m, Ar CH),
Typical procedure for alkylation of the nitrile: (3S)-[N-(3-
methylbut-2-enyl)-N-(p-toluenesulfonyl)amino]-4-
phenylbutyronitrile
Caesium carbonate (0.23 g, 0.70 mmol) was added to a solution
of nitrile 3b (0.20 g, 0.64 mmol) in CH3CN (15 mL). The reaction
mixture was stirred at ambient temperature for 30 min before
1-bromo-3-methylbut-2-ene (74 lL, 0.64 mmol) was added. The
resulting mixture was stirred until the reaction was judged to be
complete by TLC analysis (12 h), before the solvent was removed
in vacuo. The resulting solid was partitioned between water and
Et2O. The combined organic phases were washed with water (2 ×
50 mL), brine (50 mL), dried over MgSO4 and concentrated in
vacuo to afford the crude alkylated product. Purification by flash
column chromatography (silica; eluent 5 : 1 hexane–EtOAc, Rf =
0.24) afforded the title compound as a yellow powder (0.20 g, 82%):
mp 65–67 ◦C (from hexane–EtOAc); [a]D21 −24.6 (c 0.5 in CHCl3);
(Found: C, 68.91; H, 6.80; N, 7.27. C22H26N2O2S requires C, 69.08;
H, 6.85; N, 7.32%); mmax (film)/cm−1 3029 ( CH aliphatic), 2927
=
=
=
(mas CH2), 2249 (CN), 1599 (C C aromatic), 1496 (C C aromatic),
=
1454 (C C aromatic), 1379 (ds CH3), 1340 (mas SO2), 1157 (ms SO2),
1092 (C-N); dH (300 MHz, CDCl3) 1.67 (3H, s, C-CH3), 1.70
(3H, s, C-CH3), 2.41 (3H, s, Ph-CH3), 2.52 (1H, dd, J 16.9 and
5.5, CHH-CN), 2.83 (1H, dd, J 16.9 and 8.5, CHH-CN), 2.94–
3.08 (2H, m, Ph-CH2), 3.85 (2H, br d, J 6.8, N-CH2), 4.10–4.20
=
=
=
(1H, m, N-CH), 5.10 (1H, br t, J 6.8, CH), 7.10–7.14 (2H, m,
Ar CH), 7.23–7.30 (7H, m, Ar CH), 7.66 (2H, d, J 8.1, Ar CH); dC
Typical procedure for Lewis acid-catalysed cyclisation:
(2S,4S,5S)-2-benzyl-4-hydroxy-5-isopropenyl-1-(p-
toluenesulfonyl)piperidine (8b)
=
(75 MHz, CDCl3) 18.0 ( C-CH3), 21.6 (Ph-CH3), 22.2 (CH2-CN),
=
25.9 ( C-CH3), 39.6 (Ph-CH2), 43.8 (N-CH2), 56.9 (N-CH), 117.8
=
(CN), 120.6 ( CH), 127.3 (Ar CH), 127.5 (2 × Ar CH), 129.0 (2 ×
Ar CH), 129.1 (2 × Ar CH), 129.8 (2 × Ar CH), 136.6 (Cq), 136.9
(Cq), 137.5 (Cq), 143.7 (Cq); m/z (ES+) 405.4 (100%, [M + Na]+)
[HRMS Found: (M + Na)+ 405.1611. C22H26N2NaO2S requires
M, 405.1613].
Toasolutionof aldehyde 1b (100 mg, 0.26mmol) inCHCl3 (10 mL)
was added methylaluminium dichloride (1.0 M in hexane, 260 lL,
0.26 mmol). The solution was stirred overnight at reflux, after
which it was quenched by addition of water and the aqueous
phase was extracted with CH2Cl2. The combined organic phases
were washed with brine, dried over MgSO4 and concentrated in
vacuo to afford the crude piperidine. Purification by flash column
chromatography (silica; eluent 1 : 2 EtOAc–hexane, Rf = 0.19)
afforded piperidine 8b as a colourless oil (73 mg, 73%): [a]2D7 −16.1
Typical procedure for oxidation of the alcohol: (3S)-[N-(3-methyl-
but-2-enyl)-N-(p-toluenesulfonyl)amino]-4-phenylbutanal (1b)
Distilled DMSO (88 lL, 1.24 mmol) was added dropwise at a
rapid rate to a solution◦of oxalyl chloride (54 lL, 0.62 mmol) in
CH2Cl2 (8 mL) at −60 C. After 5 min a solution of alcohol 6b
(0.20 g, 0.52 mmol) in CH2Cl2 (5 mL) was added dropwise. The
mixture was stirred for another 20 min before dry Et3N (362 lL,
2.59 mmol) was added dropwise and then the solution was stirred
for a further 3 h at −60 ◦C. The mixture was allowed to warm to
room temperature before addition of water (25 mL). The aqueous
phase was separated and extracted with CH2Cl2 (4 × 25 mL). The
combined organic phases were washed with aqueous HCl (1 M,
50 mL), water (50 mL), brine (50 mL), dried over MgSO4 and
concentrated in vacuo to afford aldehyde 1b as a colourless oil
(0.20 g, 100%), which was used without further purification: [a]D20
(c 0.18 in CHCl3); mmax (film)/cm−1 3498 (OH), 3058 (mas CH2),
=
=
=
2925 (mas CH2), 2855 (ms CH2), 1644 (C C aliphatic), 1599 (C C
=
=
aromatic), 1495 (C C aromatic), 1454 (C C aromatic), 1378 (ds
CH3), 1337 (mas SO2), 1155 (ms SO2), 1087 (C–O); dH (500 MHz,
=
CDCl3) 1.30–1.40 (1H, m, N-CH-CHH), 1.77 (3H, s, C-CH3),
1.88–2.02 (2H, stack, N-CH-CHH and N-CH2-CH), 2.08 (1H,
br s, OH), 2.40 (3H, s, Ph-CH3), 2.80–2.83 (2H, m, Ph-CH2), 2.99
(1H, dd, J 14.3 and 11.7, N-CHH), 3.82 (1H, dd, J 14.3 and
4.1, N-CHH), 3.95 (1H, td, J 10.8 and 4.4, CH-OH), 4.40–4.47
=
=
(1H, m, N-CH), 4.90 (1H, s, CHH), 5.03 (1H, s, CHH), 7.14–
7.31 (7H, m, Ar CH), 7.56 (2H, d, J 8.5, Ar CH); dC (125 MHz,
=
CDCl3) 20.3 ( C-CH3), 21.3 (Ph-CH3), 34.1 (N-CH-CH2-CH),
−20 (c 0.5 in CHCl3); mmax (neat)/cm−1 3028 ( CH aliphatic), 2965
37.9 (Ph-CH2), 44.2 (N-CH2), 51.9 (N-CH2-CH), 55.2 (N-CH),
=
=
=
(mas CH3), 2925 (mas CH2), 2863 (ms CH3), 1724 (CHO), 1599 (C C
65.8 (CH-OH), 114.9 ( CH2), 127.1 (Ar CH), 127.4 (2 × Ar CH),
=
=
aromatic), 1495 (C C aromatic), 1454 (C C aromatic), 1337 (mas
SO2), 1156 (ms SO2); dH (300 MHz, CDCl3) 1.69 (6H, s, C(CH3)2),
129.2 (2 × Ar CH), 129.6 (2 × Ar CH), 130.2 (2 × Ar CH), 138.4
(Cq), 143.0 (Cq), 143.8 (Cq); m/z (ES+) 408.1 (40%, [M + Na]+),
3346 | Org. Biomol. Chem., 2008, 6, 3337–3348
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386.1 (100, [M + H]+), 376.1 (26), 368.1 (11), 270.1 (64), 226.1 (42)
[HRMS Found: (M + Na)+ 408.1601. C22H27NNaO3S M, requires
408.1609].
(1H, td, J 9.4 and 4.1, CH-OH), 4.94 (1H, s, CHH), 4.98 (1H, s,
=
=
CHH), 7.16–7.33 (5H, m, Ar CH); dC (75 MHz, CDCl3) 21.2
(CH3), 37.0 (N-CH-CH2-CH), 38.8 (Ph-CH2), 43.7 (N-CH2), 53.4
=
(N-CH2-CH), 54.4 (N-CH), 66.4 (CH-OH), 113.3 ( CH2), 126.4
(Ar CH), 128.7 (2 × Ar CH), 129.1 (2 × Ar CH), 139.6 (Cq),
144.4 (Cq); m/z (ES+) 232.1 (65%, [M + H]+), 214.1 (100) [HRMS
Found: (M + H)+ 232.1700. C15H22NO requires M, 232.1701].
Typical procedure for Brønsted acid-catalysed cyclisation:
(2S,4R,5S)-2-benzyl-4-hydroxy-5-isopropenyl-1-
(p-toluenesulfonyl)piperidine (7b)
Concentrated hydrochloric acid (37%, 130 lL, 1.54 mmol) was
added to a solution of aldehyde 1b (197 mg, 0.51 mmol) in CH2Cl2
(15 mL) at −78 ◦C. The solution was stirred at −78 ◦C overnight,
after which water was added and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were washed with
brine, dried over MgSO4 and concentrated in vacuo to afford the
crude piperidine. Purification by flash column chromatography
(silica; eluent 1 : 2 EtOAc–hexane, Rf = 0.36) afforded piperidine
7b as a colourless thick oil (160 mg, 81%): [a]2D7 −16.1 (c 0.18
Acknowledgements
We thank the Engineering and Physical Sciences Research Council
for a studentship to C. A. M. C., the University of Birmingham
for financial support and Dr J. T. Williams for some preliminary
experiments.
References
1 J. A. Findlay in The Alkaloids, ed. A. Brossi, Academic Press, London,
1985, vol. 26, pp. 89–183; A. R. Pinder, Nat. Prod. Rep., 1986, 3, 171–
180; A. R. Pinder, Nat. Prod. Rep., 1987, 4, 527–537; A. R. Pinder, Nat.
Prod. Rep., 1989, 6, 67–78; A. R. Pinder, Nat. Prod. Rep., 1990, 7, 447–
455; A. R. Pinder, Nat. Prod. Rep., 1992, 9, 491–504; A. O. Plunkett,
Nat. Prod. Rep., 1994, 11, 581–590; D. O’Hagan, Nat. Prod. Rep., 1997,
14, 637–651; D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435–446.
2 P. S. Watson, B. Jiang and B. Scott, Org. Lett., 2000, 2, 3679–3681.
3 For reviews see: S. Laschat and T. Dickner, Synthesis, 2000, 1781–
1813; P. M. Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding,
Tetrahedron, 2003, 59, 2953–2989; M. G. P. Buffat, Tetrahedron, 2004,
60, 1701–1729.
in CHCl3); mmax (neat)/cm−1 3530 (OH), 3027 ( CH), 2923 (mas
=
=
=
=
CH2), 1644 (C C aliphatic), 1599 (C C aromatic), 1495 (C C
=
aromatic), 1453 (C C aromatic), 1340 (mas SO2), 1157 (ms SO2),
1105 (C–O); dH (300 MHz, CDCl3) 1.55–1.68 (2H, stack, N-CH-
=
CHH and OH), 1.76 (3H, s, C-CH3), 1.93 (1H, dd, J 14.3 and
2.0, N-CH-CHH), 2.23 (1H, br d, J 11.8, N-CH2-CH), 2.39 (3H, s,
Ph-CH3), 2.87 (1H, dd, J 13.0 and 6.6, Ph-CHH), 3.19 (1H, dd, J
13.0 and 9.6, Ph-CHH), 3.43 (1H, dd, J 13.6 and 12.1, N-CHH),
3.64 (1H, dd, J 13.6 and 3.9, N-CHH), 4.04 (1H, app d, J 2.0, CH-
=
4 (a) T. A. Johnson, M. D. Curtis and P. Beak, J. Am. Chem. Soc., 2001,
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10337.
OH), 4.20–4.30 (1H, m, N-CH), 4.74 (1H, s, CHH), 5.05 (1H, s,
=
CHH), 7.17–7.29 (7H, m, Ar CH), 7.53 (2H, d, J 8.1, Ar CH);
=
dC (75 MHz, CDCl3) 21.6 (Ph-CH3), 22.9 ( C-CH3), 31.5 (N-CH-
CH2), 38.3 (CH2), 38.9 (CH2), 46.2 (N-CH2-CH), 53.3 (N-CH),
=
64.8 (CH-OH), 112.5 ( CH2), 126.3 (Ar CH), 127.2 (2 × Ar CH),
128.5 (2 × Ar CH), 129.7 (2 × Ar CH), 129.8 (2 × Ar CH), 138.2
(Cq), 139.4 (Cq), 143.1 (Cq), 144.2 (Cq); m/z (ES+) 408.1 (90%, [M
+ Na]+), 386.1 (26, [M + H]+), 368.1 (9), 286.0 (27), 274.0 (100)
[HRMS Found: (M + Na)+ 408.1598. C22H27NNaO3S M, requires
408.1609].
Typical detosylation procedure: (2S,4S,5S)-2-benzyl-4-hydroxy-5-
isoproprenyl piperidine (36b)
5 J. T. Williams, P. S. Bahia, B. Kariuki, N. Spencer, D. Philp and J. S.
Snaith, J. Org. Chem., 2006, 71, 2460–2471.
To a solution of piperidine 8b (99 mg, 0.26 mmol) in THF (1.5 mL)
at −78 ◦C was added a freshly prepared solution of sodium
naphthalenide (1.0 M in THF, 1.18 mL, 1.18 mmol). After 5 min
the reaction was quenched with MeOH (0.3 mL), warmed up to
room temperature, diluted with water and acidified to pH 1 with
aqueous HCl. The aqueous phase was washed with Et2O, basified
to pH 9 with aqueous NaOH (2 M) and extracted with EtOAc.
The combined organic phases were washed with brine, dried over
MgSO4 and concentrated in vacuo to afford piperidine 36b as a
white powder (52 mg, 87%): [a]2D3 −49 (c 0.98 in CHCl3); mp 119–
121 ◦C (from CH2Cl2–hexane); (Found: C, 77.80; H, 9.22; N, 6.19.
C15H21NO requires C, 77.88; H, 9.15; N, 6.05%); mmax (film)/cm−1
6 For a review see: B. B. Snider in Comprehensive Organic Synthesis,
ed. B. M. Trost and I. Fleming, Pergamon, Oxford, 1991, vol. 2,
pp. 527–561.
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9 Y. Doi, M. Ishibashi and J. Kobayashi, Tetrahedron, 1996, 52, 4573–
4580; D. Ma and H. Sun, J. Org. Chem., 2000, 65, 6009–6016; N.
Langlois, Org. Lett., 2002, 4, 185–187; B. M. Trost and D. R. Fandrick,
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K. Tanaka, T. Maesoba and H. Sawanishi, Heterocycles, 2006, 68, 183–
192.
=
=
3306 (OH, NH), 2917 (mas CH2), 1641 (C C aliphatic), 1602 (C C
=
=
aromatic), 1493 (C C aromatic), 1455 (C C aromatic), 1090 (C–
O); dH (300 MHz, CDCl3) 1.63 (1H, ddd, J 12.9, 9.9 and 5.1,
N-CH-CHH), 1.79 (3H, s, CH3), 1.91 (1H, br s, OH and NH),
1.97 (1H, dt, J 12.9 and 3.7, N-CH-CHH), 2.07–2.15 (1H, m,
N-CH2-CH), 2.72 (1H, dd, J 13.4 and 6.4, N-CHH), 2.86–2.94
(3H, stack, N-CHH and Ph-CH2), 3.32–3.41 (1H, m, N-CH), 3.99
10 A preliminary account of this work has been published: C. A. M. Cariou
and J. S. Snaith, Org. Biomol. Chem., 2006, 4, 51–53.
11 M. McKennon, A. Meyers, K. Drauz and M. Schwarm, J. Org. Chem.,
1993, 58, 3568–3571.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3337–3348 | 3347
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12 We are grateful to Dr J. T. Williams for carrying out development
work on this synthetic route. J. T. Williams, PhD Thesis, University of
Birmingham, 2003.
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3348 | Org. Biomol. Chem., 2008, 6, 3337–3348
This journal is
The Royal Society of Chemistry 2008
©