Synthesis of functionalized 3-hydroxypiperidines

Article abstract of DOI:10.1016/j.tet.2010.05.089

The synthetic versatility of three chemoenzymatically prepared hydroxypiperidine building blocks has been explored, resulting in a library of enantiopure functionalized piperidines. Key steps involved N-acyliminium ion-mediated CC-bond formation and cross-metathesis reactions, after which full deprotection led to the set of free 3-hydroxypiperidines.

Full text of DOI:10.1016/j.tet.2010.05.089

Tetrahedron 66 (2010) 5623e5636
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Synthesis of functionalized 3-hydroxypiperidines
*
Marloes A. Wijdeven, Floris L. van Delft, Floris P.J.T. Rutjes
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, NL-6525 AJ Nijmegen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthetic versatility of three chemoenzymatically prepared hydroxypiperidine building blocks has
been explored, resulting in a library of enantiopure functionalized piperidines. Key steps involved
N-acyliminium ion-mediated CC-bond formation and cross-metathesis reactions, after which full
deprotection led to the set of free 3-hydroxypiperidines.
Received 5 January 2010
Received in revised form 29 April 2010
Accepted 24 May 2010
Available online 31 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
approach can be divided in two main pathways as depicted in
Scheme 1. In the first pathway, 2,3-disubstituted piperidines will be
The 3-hydroxypiperidine moiety constitutes a key structural
element in various biologically relevant molecules and natural
products.1 Some examples of the latter include the relatively simple
substituted 3-hydroxypiperidines such as 5-hydroxypipecolic acid
(1),2 1,3,4-trideoxynojirimycin (2),3 and pseudoconhydrine (3,
Fig. 1).4 Pipecolic acid 1 is found in various plants and microor-
ganisms and is a potentially useful scaffold for incorporation into
conformationally restricted peptidomimetics.5 Recently, the aza-
sugar 2 was isolated from the pods of the Angylocalyx pynaertii.
Pseudoconhydrine (3) was isolated from the poisonous hemlock
(Conium maculatum) and a first total synthesis was already repor-
ted in 1949.6
prepared via cross-metathesis (CM) onto the allyl-substited piper-
idine 5. The second pathway should give access to piperidines 6 and
7 with different substitution patterns via N-acyliminium ion
chemistry starting from hemiaminals 8. In case of the 3,5-dihy-
droxy compounds 7 this N,O-acetal is first converted in the
enamide followed by diol formation to deliver the N-acyliminium
ion precursor. Hemiaminals 8 can be formed via Cbz-protection of
the piperidines 5, followed by partial reduction of the lactam. In
turn, the lactams 5 can be formed from an enantiopure cyanohydrin
via a reductive cyclization as previously described.8
HO
TBSO
R
CM
R1
N
H
N
H
O
R = allyl
HO
HO
HO
5
4
OH
HO
R
N
H
N
H
CO2H
N
H
Reduction
R = H,
N
H
R1
N-acyliminium ion
1
2
3
chemistry
Me, allyl
6
Figure 1.
TBSO
R
HO
OH
R1
Although several syntheses of these natural products and
related 3-hydroxypiperidines are known,7 efficient pathways to
diversely substituted 3-hydroxypiperidines still form an attractive
objective. Earlier in our group a strategy for the synthesis of
a 3-hydroxypiperidine moiety was developed and applied in total
syntheses of (þ)-epiquinamide8 and (þ)-febrifugine.9 Herewith we
wish to report an extension of this methodology resulting in the
synthesis of a modest library of diversely substituted piperidines.
elimination/oxidation
N
OH
N
H
N-acyliminium ion
Cbz
chemistry
7
8
Scheme 1. Retrosynthesis.
2. Synthesis of the three building blocks
We devised
a new strategy that would give access to
In earlier investigations we disclosed the efficient formation of
the enantiopure cyanohydrin 9 using the hydroxynitrile lyase
HbHNL and its conversion into the corresponding N,N-acetal under
reductive conditions.8 Diazotation in acetic acid gave the N,O-acetal
10, which turned out to be suitable for N-acyliminium ion-medi-
ated reactions with, for example, allyltrimethylsilane to afford the
functionalized 3-hydroxypiperidines in a straightforward way. The
* Corresponding author. Tel.: þ31 24 365 3202; fax: þ31 24 365 3393; e-mail
address: f.rutjes@science.ru.nl (F.P.J.T. Rutjes).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.089

5624
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
allylated product 13 in 82% over three steps (Scheme 2). In order to
extend the scope, N,O-acetal 10 was now subjected to methyl
cuprate to afford product 12 in a moderate yield of 40% over three
steps (starting from 9) as a single diastereoisomer.10 Varying the
conditions (e.g., changing the nucleophile or copper source) gave
no improvement in yield. Furthermore, cyclization of the cyano-
hydrin under influence of Raney nickel and Et3N gave lactam 11 in
95% yield. With these three building in hand, the stage was set for
the diversifications.
performed with LiAlH4 and proceeded with concomitant desilyla-
tion to the free hydroxy substituent. Next, the amine was Cbz-
protected in view of its anticipated incompatibility with the CM
reaction. Treatment with CbzeOSu in the presence of triethylamine
provided the CM substrate 14 in 72% yield over two steps.
The first cross-metathesis was performed with methyl acrylate
under influence of Grubbs-II to give the desired product 15 in 62%
yield (Table 1, entry 1). Prompted by this result, other olefins were
also subjected to the CM reaction such as 4-chlorostyrene affording
olefin 16 in a moderate yield of 55% (entry 3). CM with a more
electron-rich alkene, allyltrimethylsilane, gave CM product 17 in
a good yield of 70% (entry 4). Next, allyl ethyl carbonate was used to
afford olefin 18 in 72% yield (entry 5). In entry 6, the allyl precursor
was reacted with 6-bromohex-1-ene to provide bromide 19 in 53%
yield. In conclusion, a range of olefins with different functionalities
could be successfully coupled to precursor 14 via cross-metathesis.
Next, Cbz deprotection of the CM products was in order. The first
attempt to remove the Cbz protecting group was carried out with
HBr in acetic acid, but the reactions did not proceed in a clean
manner. Therefore, we switched to a hydrogenolysis approach
under the influence of Pd/C and hydrogen gas, which would also
lead to olefin hydrogenation. The first precursor 15 was subjected
to these reductive conditions and indeed the Cbz group was re-
moved. Analysis showed that the product had partially cyclized via
attack of the liberated nitrogen onto the methyl ester. Subsequent
subjection of the mixture to a basic methanol mixture afforded the
fully cyclized product 20 in 78% yield (Table 1, entry 1). Although,
addition of HCl during the hydrogenation prevented cyclization so
that product 21 was obtained quantitatively (entry 2). Removal of
the Cbz group in case of the halogenated compounds 16 and 19
proceeded smoothly, but also both halogens were removed (entries
3 and 6). Entry 4 shows the deprotected silyl-containing product
23, which was obtained in 79% yield. Surprisingly, hydrogenolysis
Scheme 2. Building block synthesis.
3. Cross-metathesis
A straightforward way to generate a class of 2,3-disubstituted
piperidines proceeds via CM11 of the allylated piperidine derivative
14. Its precursor 13 was reduced prior to the CM reaction to facil-
itate the introduction of more diverse olefins. The reduction was
Table 1
Cross-metathesis of piperidine 14
olefin
1) LiAlH4
THF
HO
HO
TBSO
HO
Grubbs II
deprotection
R
R
N
N
N
H
13
O
N
H
21-25
CH2Cl2
reflux
2) Cbz-OSu
Et3N
Cbz
Cbz
14
72%
15-19
Entry
1
Olefin
R
Product
Yield (%)
62
Conditions
Product
Yield (%)
78
deprotectiona
HO
O
O
15
A
20
N
MeO
MeO
O
HO
2
3
4
5
15
16
17
B
B
C
21
22
23
100
66
MeO2C
N
·HCl
H
HO
55
70
N
Cl
Cl
H
HO
79
Me3Si
Me3Si
O
Me3Si
N
H
HO
O
18
19
72
53
B
C
24
25
100
95
N
H
EtO
O
EtO
O
HO
Br
6
Br
N
H
a
Conditions: (A) (1) Pd/C, 20 bar H2 (H-Cube) 25 ꢀC, 1 mL/min MeOH; (2) K2CO3 (2 equiv), MeOH, 2 h. (B) Pd/C, H2 (1 atm), HCl (1 equiv), MeOH, 2 h. (C) Pd/C, 20 bar H2,
(H-Cube) 25 ꢀC, 1 mL/min MeOH.

M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
5625
of carbonate 18 led to complete reduction of the carbonate group.
Cbz-OSu
LiHMDS
TBSO
R
TBSO
R
LiEt3BH
In the literature, removal of the carbonate group has been de-
scribed with Pd(0) via a mechanism similar to the acetate elimi-
11 13
-
N
Cbz
O
N
Cbz
OH
THF
THF, –78 °C
nation sequence.12 Presumably, the
p-allyl complex is formed
–78 °C → rt
under influence of Pd/C, followed by
b-hydride elimination and
26
29
, R = H 56%
(2 steps)
, R = H
subsequent hydrogenation of the double bond. The reaction pro-
ceeded cleanly and afforded product 24 in quantitative yield
(entry 5). Thus, a series of 2-alkylated 3-hydroxypiperidines were
efficiently prepared in reasonable overall yields.
30, R = Me
31
27
, R = allyl
, R = Me 65%
28, R = allyl 80%
TBSO
TBSO
OH
OH
NMO, OsO4,
NH4Cl
N
Cbz
32
N
Cbz
33
water, acetone
MeCN
130 °C
R = H
4. N-Acyliminium ion chemistry
The three building blocks 11e13 were protected with a Cbz
group to facilitate reduction to the N,O-acetals. Treatment of 11
with CbzeOSu and LiHMDS gave the Cbz-protected piperidone 26
in 56% over two steps. In the same fashion the methyl substituted
(12) and the allyl substituted piperidone (13) were Cbz-protected in
65 and 80% yield, respectively (Scheme 3). Initially, the formation of
the N,O-acetal was troublesome: performing the reduction with
Scheme 3. Synthesis of hemiaminals 29e31 and 33.
did not lead to the desired product either. The outcome was most of
the time unclear due to complex NMR spectra and unstable com-
pounds. Luckily, diol formation under influence of NMO and
osmium tetroxide instead afforded triol 33, which was used in
crude form in the subsequent N-acyliminium ion reaction.
13
NaBH4 gave only the linear amino alcohol due to overreduction.
Gratifyingly, use of LiEt3BH gave the hemiaminal 29 in a clean
conversion.14 Encouraged by this result, the same reaction was
performed on the other two building blocks 27 and 28 to produce
the N-acyliminium ion precursors 30 and 31. Due to the instability
of the hemiaminals, they were used directly without column
chromatography in the next N-acyliminium ion steps. In all cases,
the hemiaminals were obtained as mixtures of diastereoisomers,
but exact determination of the ratios appeared impossible due to
the presence of rotamers and therefore complex NMR spectra.
We envisioned that extension of the library of substituted pi-
peridines could be realized via enamide formation and subsequent
dihydroxylation of hemiaminal 29. Heating in the presence of
NH4Cl smoothly afforded enamide 32.15 Subsequent epoxidation
was attempted with Oxone, but no product was observed. A one-
pot epoxidation-ring opening sequence (Oxone, NaHCO3, MeOH)
Having set the stage for the N-acyliminium ion reactions, pre-
cursor 29 was reacted with allyltrimethylsilane and BF3$OEt2 to
give the allyl-substituted product 35 in 72% yield over two steps as
a single diastereoisomer (Table 2, entry 1).16 Next, different nu-
cleophiles were used to determine the scope of the reaction and
prepare a small set of 2,5-disubstituted piperidines. The in-
troduction of an allene via reaction with propargyltrimethylsilane
proceeded in a moderate yield of 44% (entry 2). Unfortunately, the
reaction with a silyl enol ether did not show any product formation
at all (entry 3). Entry 4 shows that it was possible to introduce
a cyanide group in a yield of 41%. Finally, a last variation was in-
troduced via reacting 2-(chloromethyl)allyltrimethylsilane with
hemiaminal 29 to give 39 in a yield of 68%. In all cases the reaction
was completely diastereoselective, with the trans-isomer as the
Table 2
N-Acyliminium ion reactions of hemiaminal 29
TBSO
TBSO
TBSO
HO
nucleophile
BF3·OEt2
deprotection
N
Cbz
OH
N
Cbz
N
Cbz
R
N
H
R
29
34
35 39
-
1 3
(ent)- ,
40 42
-
Entry
1
Nucleophile
R
Product
Yielda (%)
Conditions
Product
Yield (%)
78
deprotectionb
HO
HO
SiMe3
35
72
A
40
N
H
2
3
36
37
44
B
3
52
SiMe3
·
N
H
OSiMe3
O
n.r.
d
d
d
d
Ph
Ph
HO
R
N
H
4
SiMe3CN
38
39
41
68
A
C
41
42
100
80
NC
O
KOH
61%
41, R = NH2
(ent)-1, R = OH
HO
5
Cl
SiMe3
Cl
N
a
Yield determined over two steps.
b
Conditions: (A) HBr/acetic acid, 0 ꢀC, 5 min. (B) Pd/C, H2 (1 atm), HCl (1 equiv), MeOH, 2 h. (C) (1) HBr/acetic acid, 0 ꢀC, 5 min; (2) K2CO3 (2 equiv), MeOH, 2 h.

5626
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
only product.7a,17 The stereochemistry was elucidated via 2D-NMR
experiments on the deprotected compounds.18
To further apply the successful N-acyliminium ion coupling and
expand the variety of piperidines, we subjected hemiaminal 30 to
A pool of 2,5-trans-disubstituted piperidines was formed via
deprotection of compounds 35e39. To facilitate TBS and Cbz
deprotection in a single operation, the compounds were subjected
to HBr in acetic acid. First, the allyl-substituted precursor 35 was
stirred in HBr/acetic acid, followed by evaporation to afford the
desired product 40 in 78% yield (Table 2, entry 1). The Cbz depro-
several p-nucleophiles in the presence of BF3$OEt2. First, allyl-
trimethylsilane was successfully used providing the desired prod-
uct 44a in 56% over two steps as a single diastereoisomer (Table 3,
entry 1). Second, an allene was introduced in a low yield of 32%,
including partial removal of the TBS group (45b, 25%). Introduction
of two other nucleophiles was somewhat disappointing; reaction
Table 3
N-Acyliminium ion reactions of hemiaminals 30 and 43
XO
Me
XO
Me
HO
Me
HO
Me
HO
Me
nucleophile
BF3·OEt2
deprotection
N
OH
N
R
N
Cbz
c
R
N
H
R
N
H
R
Cbz
Cbz
a, X = TBS
30
, X = TBS
, X = H
TBAF
b, X = H
43
44-47
48-51
Entry
s.m.
30
Nucleophile
R
Product/ratio
A/B/C
Yield (%)
Deprotection
substrate
Conditionsc
Product
Yield (%)
100
HO
Me
HO
Me
HO
Me
·HBr
1
2
3
SiMe3
44/1:0:0
45/1:3.5:0
46/1:2:0
56a
32a
40a
44a
45a
46a
A
B
A
48
49
50
N
H
30
81
SiMe3
·
N
H
·HBr
NH2
30
Me3SiCN
100
NC
N
H
O
·HCl
HO
Me
HO
Me
4
5
30
43
47/1:0:0
44/0:2:1
30a
63b
47a
44c
B
51
52
100
74
Cl
SiMe3
Cl
N
H
·HBr
SiMe3
A
N
H
6
7
43
43
43
45/0:1:1
58b
28b
66b
45c
C
d
d
d
93
SiMe3
·
NC
Cl
Me3SiCN
46/0:>99:0
47/0:1.4:1
46ad
47c
d
C
d
HO
8
53
Cl
SiMe3
Me
N
H
a
Yield determined over two steps.
Yield determined over three steps.
Conditions: (A) HBr/acetic acid, 0 ꢀC, 5 min. (B) Pd/C, H2 (1 atm), HCl (1 equiv), MeOH, 2 h. (C) Pd/C, H2 (1 atm), MeOH, 2 h.
For deprotection results, see entry 3.
b
c
d
tection with HBr/acetic acid in the presence of an allene was more
troublesome, since HBr probably reacted with the allene to gener-
ate multiple side products. Therefore, in this case Pd/C in combi-
nation with hydrogen gas was used to remove the Cbz group and
concomitantly reduce the allene to a propyl side chain. Further-
more, via the addition of HCl, the TBS was removed in the same pot
to afford pseudoconhydrine (3) in 52% yield (entry 2).7a The ana-
lytical data were identical to those in literature, thereby supporting
our stereochemical assignment. Deprotection of the cyanide
substituted product 38 proceeded smoothly with HBr in acetic acid,
but also the cyanide was converted into the amide 41 (entry 4).
Upon treatment with aqueous KOH, amide 41 was converted (61%)
into the corresponding acid, the natural product 5-hydroxy-
pipecolic acid (ent-1).19 Stirring the 2-(chloromethyl)allyl precursor
39 in HBr/acetic acid afforded a mixture of deprotected compound
and cyclized product 42 (entry 5). After the addition of basic
methanol, the cyclization was completed to give 42 as a single
product in 80% yield.
with Me3SiCN proceeded in 40% yield, again as a mixture with and
without protecting group. The introduction of 2-(chloromethyl)al-
lyl afforded only the TBS-protected product 47a, but in a relatively
low 30% yield. More encouraging was the diastereoselectivity of the
process, in all cases leading to the cis-isomer (with respect to the
methyl) as the sole product.20 The isolation of TBS-deprotected
products was taken as an incentive to remove the TBS group prior
to the N-acyliminium ion reactions. Due to the instability of the
hemiaminal, the TBS group was initially removed before the lactam
reduction. Interestingly, the TBS turned out to be crucial in the
reduction, since applying the successful LiEt3BH conditions on the
free alcohol only led to overreduction. Inversely, reduction followed
by TBS deprotection appeared a better alternative providing pre-
cursor 43, which was used in crude form in the N-acyliminium ion
reactions. As depicted in Table 3, entry 5, the yield of the reaction
with allyltrimethylsilane was slightly improved, 63 versus 56%.
Unfortunately, the reaction was no longer completely diaster-
eoselective: the products were formed in a 2:1 ratio in favor of the

M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
5627
cis-product. In case of propargyltrimethylsilane the yield was
slightly better, 58 versus 32%, but this time there was virtually no
selectivity (entry 6). Introduction of the cyanide was problematic,
since a complex reaction mixture was formed and a low yield of the
cis-product 46b was obtained (entry 7). More successful was the
reaction with 2-(chloromethyl)allyltrimethylsilane providing
product 47 in 66% yield and a 1.4:1 diastereomeric ratio (entry 8).
Fortunately, the separation of the diastereoisomers was straight-
forward in all cases and the single diastereoisomers were used in
the deprotection step.
a moderate 50% yield, while the 2-(chloromethyl)allyl was in-
troduced in 62% yield (entries 3 and 4, respectively). In all cases, the
trans-isomers were formed as the exclusive products.
Subsequent removal of the protecting groups afforded the 2-
allyl-3-hydroxypiperidines as shown in Table 4. Deprotection of the
diallylated compound 55 proceeded in 92% yield using HBr in acetic
acid (entry 1). The reductive removal of the Cbz group in case of the
allene substituent afforded the dipropyl-substituted product 60 in
quantitative yield (entry 2). In entry 3, the cyanide-containing
compound 57 was deprotected to afford amide 61 in 68% yield.
Next, the 2-(chloromethyl)allyl compound was deprotected under
reductive conditions to afford the completely reduced product 62 in
a yield of 93%.
The last set of substituted piperidines was generated via N-
acyliminium ion-mediated reactions with precursor 33. First, an
allyl substituent was introduced in a diastereoselective manner in
40% yield over four steps (Table 5, entry 1). Somewhat disap-
pointing was the yield of the formation of the allene-substituted
compound 64, where only 9% product was isolated. The cyanide
and the 2-(chloromethyl)allyl were both introduced in moderate
yields of 21 and 24%, respectively. Thus, the protocol was success-
fully applied for these four nucleophiles to give the products in
a fully diastereoselective manner.
Next, the compounds were deprotected in the same fashion as
described earlier in this section. Allylated compound 63 was stirred in
HBr/acetic acid to liberate the piperidine 67 in 85% (Table 5, entry 1).
The allene was hydrogenated together with hydrogenolysis of the Cbz
group to afford piperidine 68 in 95% (entry 2). Next, the Cbz and TBS
groups of 65 were removed under the influence of HBr in acetic acid
with concomitant conversion of the cyanide into the corresponding
amide 69 in 68% yield (entry 3). In entry 4, the 2-(chloromethyl)
allylated piperidine was deprotected and after stirring in basic
methanol afforded the cyclized product 70 in 59%.
Creation of a set of 2-methyl-3-hydroxypiperidines commenced
with deprotection of the two allyl-substituted compounds 44a and
44c. In both cases, the desired piperidine was obtained in high yield
as depicted in Table 3, entries 1 and 5. Removal of the protecting
groups in the case of the allene substituent was performed with Pd/
C and H2 in methanol, combined with addition of HCl. The 2,6-cis-
disubstituted product 49 was obtained in 81% yield (entry 3). Sadly,
deprotection of the trans-product 45c did not provide sufficient
material for complete spectroscopic analysis. Next, the cyanide
substituted product 46a was deprotected and converted at the
same time into the corresponding amide 50 in quantitative yield
(entry 3). Cbz-removal with HBr in acetic acid in case of the 2-
(chloromethyl)allyl side chain appeared more troublesome, giving
again rise to a mixture of open and cyclized product. This time,
however, we were unsuccessful in converting the open product into
the corresponding cyclic product upon stirring in basic methanol.
On the other hand, reductive removal of the Cbz group was more
successful, providing both isomers 47a and 47c, and the corre-
sponding products 51 and 53, respectively, in high yields (entries 4
and 8). In case of the allylated substrate 31, the yields were disap-
pointing and only TBS-deprotected product was observed. Thus,
hemiaminal 31 was subjected to TBAF and the deprotected com-
pound 54 was used in the N-acyliminium ion reactions (Table 4).
We were delighted to observe a significant improvement in re-
activity: for example, the reaction with allyltrimethylsilane
proceeded in a yield of 68% with selective formation of the trans-
product 55 (entry 1). Again, a small library was generated by
reacting hemiaminal 54 with different nucleophiles. The reaction
with propargyltrimethylsilane proceeded in 62% yield over the
three steps (entry 2). Next, the cyanide was introduced in
5. Mechanistic considerations
The stereochemical observations of the previous section can be
analyzed via the intermediate N-acyliminium ion conformations.21
By considering, such N-acyliminium ions can form two half chair
conformations as shown for N-acyliminium ion precursor 29 in
Table 4
N-Acyliminium ion reactions of hemiaminal 54
XO
HO
HO
nucleophile
BF3·OEt2
deprotection
N
OH
N
R
N
H
R
Cbz
Cbz
55 58
-
59 62
-
31
, X = TBS
, X = H
TBAF
54
Entry
1
Nucleophile
R
Product
Yielda (%)
68
Conditions deprotectionb
Product
Yield (%)
92
HO
HO
·HBr
SiMe3
55
A
B
A
59
60
61
N
H
2
3
56
57
62
50
100
68
SiMe3
·
N
H
HO
HO
Me3SiCN
NH2
NC
N
H
O
4
58
62
B
62
93
Cl
SiMe3
Cl
N
H
a
Yield determined over three steps.
b
Conditions: (A) HBr/acetic acid, 0 ꢀC, 5 min. (B) Pd/C, H2 (1 atm), MeOH, 2 h.

5628
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
Table 5
N-Acyliminium ion reactions of hemiaminal 33
TBSO
OH
OH
TBSO
OH
R
HO
OH
R
nucleophile
BF3·OEt2
deprotection
N
Cbz
33
N
N
H
Cbz
63 66
67 70
-
-
Entry
1
Nucleophile
R
Product
Yielda (%)
40
Conditions deprotectionb
A
Product
Yield (%)
78
HO
HO
HO
OH
SiMe3
63
67
68
69
N
H
OH
2
3
64
65
9
B
52
SiMe3
·
N
H
OH
SiMe3CN
21
A
100
NH2
NC
N
H
O
HO
OH
4
66
24
C
70
80
Cl
SiMe3
Cl
N
a
Yield determined over four steps.
b
Conditions: (A) HBr/acetic acid, 0 ꢀC, 5 min. (B) Pd/C, H2 (1 atm), HCl (1 equiv), MeOH, 2 h. (C) (1) HBr/acetic acid, 0 ꢀC, 5 min; (2) K2CO3 (2 equiv), MeOH, 2 h.
Scheme 4. The pseudoaxial intermediate 71 is favored due to sta-
bilizing electrostatic attraction between the partially negatively
charged oxygen atom at the C-4 position and the positively charged
carbocation. The nucleophile preferentially attacks from the pseu-
doaxial side, giving rise to the trans-substituted product 73. Semi-
empirical calculations (MOPAC AM1) of the energy differences
between the two intermediates 71 and 72 showed a significant
difference of 10.8 kcal/mol in favor of the pseudoaxial product 71.
This is in line with the experimental outcome, in which the trans-
products are formed.
Nu¯ (trans)
TBSO
Me
Me
Cbz
N
TBSO
N
Me
N
OH
Cbz
OTBS
Cbz
Nu¯ (cis)
76
30
75
favored
Nu
Me
TBSO
Me
N
N
Cbz
Nu
OTBS
77
Cbz
Nu¯ (trans)
78
TBSO
Cbz
Scheme 5. Stereochemical rationale II.
TBSO
Cbz
Nu¯ (cis)
N
N
N
Cbz
OH
OTBS
71
The 6-allyl-substituted building block was less reactive with the
TBS protecting group present. Possibly, the N-acyliminium ion is in
this case formed with more difficulty due to steric hindrance. This is
no longer the case after TBS removal so that the trans-products can
be formed. This is also in line with the expectations, in which the
pseudoaxial conformer 79 is favored due to the previously de-
scribed stabilization (Scheme 6). This is confirmed by calculations,
showing a 10.5 kcal/mol difference in favor of the pseudoaxial
conformer 79. Due to the cis-relationship between allyl and hy-
droxyl, both blocking the bottom side of the molecule, there is no
interference with the preferred axial attack of the nucleophile.
72
29
favored
Nu
TBSO
Cbz
74
N
N
Nu
OTBS
73
Cbz
Scheme 4. Stereochemical rationale I.
In the case of the 6-methyl substituted building block, the TBS
protecting group turned out be crucial. Due to the trans-sub-
stitution pattern of the 6-methyl substituted N-acyliminium ion,
the two conformers depicted in Scheme 5 are possible. One has
both substituents in the axial (75) and the other one in the equa-
torial position (76). The axial conformer 75 is favored due to the
stabilization of the oxygen substituent, which is confirmed by
MOPAC AM1 calculations (conformer 75 is 11.8 kcal/mol lower in
energy). With the TBS group present, the nucleophile prefers to
attack in a pseudoaxial fashion so that the trans-isomer was
formed. After deprotection, the stereoselectivity was lost albeit that
there was still a considerable difference in energy between both
conformers of 10.8 kcal/mol. Presumably, the nucleophile now re-
acts from both sides in the pseudoaxial conformer due to compa-
rable steric hindrance from both sides.
Nu¯ (trans)
HO
Cbz
N
HO
N
N
OH
Cbz
OH
Cbz
Nu¯
79
80
31
(cis)
favored
Nu
HO
N
N
Cbz
Nu
OH
81
Cbz
82
Scheme 6. Stereochemical rationale III.

M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
5629
The stereochemical outcome in case of the 3,5-dihydroxy-
7.3. (5S,6R)-5-(tert-Butyldimethylsilyloxy)-6-
piperidine building blocks can be explained in a similar fashion. The
substituent in the 3-position prefers the pseudoequatorial and the
oxygen in the 5-position the pseudoaxial position, while in both
cases the N-acyliminium ion is stabilized by orbital interactions
(Scheme 7). Calculations (MOPAC AM1) showed indeed an energy
difference of 12.2 kcal/mol in favor of conformer 83. Together with
the preferred axial attack, this will give rise to selective formation
of the cis-product 85 (with respect to the 3-hydroxy substituent).
methylpiperidin-2-one (12)
A solution of methyl lithium (40 mL 1 M solution in Et2O,
40.0 mmol) and dimethylsulfide copper bromide (8.1 g, 39.6 mmol)
in THF (130 mL) was cooled to ꢁ40 ꢀC for 20 min. After cooling to
ꢁ78 ꢀC, 10 (3.8 g, 13.2 mmol) and BF3$OEt2 (5 mL, 39.6 mmol) were
added, the reaction mixture was warmed to rt and stirred over-
night. Saturated aqueous NH4Cl solution (150 mL) and Et2O
(150 mL) were added and the aqueous layer was extracted with
Et2O (3ꢂ100 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. Flash column chro-
Nu¯ (trans)
TBSO
OH
OH
Cbz
N
OH
OH
TBSO
N
matography (2:1 to 8:1 EtOAc/heptane) afforded piperidone 12
N
Cbz
20
(1.30 g, 5.3 mmol, 40%). [
a]
þ17 (c 3.8, CH2Cl2); IR (film) 2958,
OTBS
D
Cbz
Nu¯
(cis)
2859, 1675, 1100, 836 cmꢁ1. 1H NMR (CDCl3, 300 MHz)
d 6.99 (br s,
33
83
84
1H), 3.50e3.38 (m, 1H), 3.30e3.25 (m, 1H), 2.46e2.41 (m, 1H),
2.27e2.21 (m, 1H), 1.96e1.95 (m, 1H), 1.84e1.83 (m, 1H), 1.21 (d,
J¼6 Hz, 3H), 0.82 (s, 9H), 0.01 (s, 6H); 13C NMR (CDCl3, 75 MHz)
favored
OH
d
170.5, 70.2, 54.4, 27.5, 25.1, 19.7,17.4, 13.6, ꢁ5.0, ꢁ5.4; HRMS (ESIþ)
Nu
TBSO
OH
calcd for C12H25NaNO2Si (MþNaþ) 266.1552, found 266.1555.
N
N
Cbz
Nu
OTBS
85
Cbz
86
7.4. (2S,3S)-2-Allyl-1-benzyloxycarbonyl-3-hydroxypiperidine
Scheme 7. Stereochemical rationale IV.
(14)
6. Conclusions
To a solution of 13 (296 mg, 1.1 mmol) in THF (30 mL) was added
LiAlH4 (105 mg, 2.8 mmol) and the reaction mixture was stirred
overnight at 70 ꢀC. The reaction was carefully quenched by addition
of H2O (137 mg, 1.3 mg/mg LiAlH4), aqueous NaOH (15% in H2O,
137 mg, 1.3 mg/mg LiAlH4), and again H2O (341 mg, 3.25 mg/mg
LiAlH4). The resulting suspension was stirred vigorously for 10 min,
filtered, and the filtrate was concentrated in vacuo. The amine was
dissolved in CH2Cl2 (10 mL) and CbzeOSu (530 mg, 2.2 mmol) and
In conclusion, a synthetically versatile approach was developed
for the synthesis of diversely substituted piperidines. The first set
was achieved via cross-metathesis on the allyl-substituted pre-
cursor, followed by subsequent deprotection. The second pathway
was based on the formation of the hemiaminals and subsequent
introduction of different
p-nucleophiles, mostly in a diaster-
eoselective fashion. An extension of this method was realized via
the formation of a set of 3,5-dihydroxy trisubstituted piperdines.
Thus, a modest library of diversely functionalized piperidines was
synthesized in a straightforward manner.
Et3N (304 mL, 2.2 mmol) were added. The mixture was stirred
overnight followed by the addition of water (10 mL), the organic
layer was washed with water (2ꢂ10 mL) and dried over Na2SO4,
filtered, and concentrated in vacuo. Purification via flash column
chromatography (3:1 to 1:3 heptane/EtOAc) afforded hydroxy-
piperidine 14 (220 mg, 0.79 mmol, 72%). [
a
]
D
20 þ28.9 (c 2.0, CH2Cl2);
7. Experimental section
7.1. General information
IR (film) 3455, 2945, 1748, 1203, 693 cmꢁ1
.
1H NMR (CDCl3,
300 MHz)
d 7.98e7.33 (m, 5H), 5.74e5.70 (m, 1H), 5.08 (s, 2H),
5.02e4.95 (m, 2H), 4.51e4.48 (m, 1H), 4.01e3.97 (m,1H), 3.84e3.80
(m, 1H), 2.79e2.75 (m, 1H), 2.45e2.32 (m, 2H), 1.79e1.56 (m, 4H);
Solvents were distilled from appropriate drying agents prior to
use and stored under nitrogen. Reactions were carried out under an
inert atmosphere of dry nitrogen or argon. IR spectra were recorded
on an ATI Mattson Genesis Series FTIR spectrometer, or a Bruker
Tensor 27 FTIR spectrometer. NMR spectra were recorded on
a Bruker DMX 300 (300 MHz), and a Varian 400 (400 MHz) spec-
trometer in CDCl3 solutions (unless otherwise reported). Chemical
shifts are given in parts per million with respect to tetramethylsi-
lane (TMS) as internal standard. If stated hydrogenation reactions
were conducted in the H-cube hydrogenation reactor from Tha-
lesnano. Optical rotations were determined with a Perkin Elmer
241 polarimeter. High resolution mass spectra were recorded on
a JEOL AccuTOF (ESI), or a MAT900 (EI, CI, and ESI).
13C NMR (CDCl3, 75 MHz)
d 155.3, 134.6, 128.7, 128.3, 127.5, 127.3,
116.4, 72.3, 68.4, 66.6, 54.8, 37.2, 27.6, 25.0; HRMS (ESI) calcd for
C16H21NNaO3 (MþNaþ) 298.1419, found 298.1414.
7.5. General procedure for the cross-metathesis reactions
Compound 14 was dissolved in CH2Cl2 (0.05 M) and argon was
bubbled through the solution for 15 min after which Grubbs-II
(10 mol %) and the olefin (2 equiv) were added. The solution was
heated at reflux overnight followed by concentration in vacuo. The
crude product was purified by column chromatography using the
indicated solvent mixture.
7.5.1. (2S,3S)-1-Benzyloxycarbonyl-3-hydroxy-2-((E)-4-methoxy-4-
oxobut-2-enyl)piperidine (15). Compound 14 (25 mg, 0.09 mmol)
was reacted with methyl acrylate according to the general pro-
cedure. Flash column chromatography (3:1 to 1:2 heptane/EtOAc)
7.2. (S)-5-(tert-Butyldimethylsilyloxy)piperidin-2-one (11)
To a solution of cyanohydrin 9 (500 mg, 1.94 mmol) in MeOH
(70 mL) were added Et3N (536
mL, 3.88 mmol) and Raney nickel
afforded piperidine 15 (20 mg, 0.056 mmol, 62%). [
a]
20 þ34.2 (c 0.7,
D
(50% solution in water, 50 mg) and the resulting suspension was
stirred under hydrogen pressure (1 atm) for 3 h. Filtration through
Celite and concentration in vacuo afforded the piperidone ring 11.
CH2Cl2); IR (film) 3455, 2958, 1731, 1683, 1160, 702 cmꢁ1. 1H NMR
(CDCl3, 300 MHz)
d 7.33e7.30 (m, 5H), 6.95e6.89 (m, 1H),
5.89e5.84 (m, 1H), 5.07 (dd, J¼12.3, 3.0 Hz, 2H), 4.57e4.55 (m, 1H),
1H NMR (CDCl3, 300 MHz)
d 4.04e3.98 (m, 1H), 3.2e3.12 (m, 2H),
3.99e3.97 (m, 1H), 3.84e3.81 (m, 1H), 3.69 (s, 3H), 2.72e2.48 (m,
2.52e2.44 (m, 1H), 2.26e2.09 (m, 1H), 1.80e1.78 (m, 2H), 0.83 (s,
3H), 1.83e1.25 (m, 4H); 13C NMR (CDCl3, 75 MHz)
d
166.0, 155.0,
9H), 0.01 (s, 6H).
145.4, 136.0, 128.0, 127.5, 127.4, 122.5, 68.3, 66.9, 54.4, 51.0, 37.3,

5630
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
27.2, 26.4, 23.6; HRMS (ESI) calcd for C18H23NNaO5 (MþNaþ)
addition of water (2 mL) and CH2Cl2 (4 mL) followed by extraction
356.1474, found 356.1488.
of the aqueous layer with CH2Cl2 (3ꢂ4 mL). The combined organic
layers were dried, filtered, and concentrated in vacuo to afford
20
7.5.2. (2S,3S)-1-Benzyloxycarbonyl-2-((E)-3-(4-chlorophenyl)allyl)-
3-hydroxypiperidine (16). According to the general method, sub-
strate 14 (25 mg, 0.09 mmol) was reacted with 4-chlorostyrene.
quinolizinone 20 (20 mg, 0.12 mmol, 78%). [
a
]
ꢁ18.6 (c 0.59,
1H NMR
4.81e4.74 (m, 1H), 3.71e3.66 (m, 2H),
3.34e3.30 (m, 1H), 2.47e2.21 (m, 2H), 1.95e1.87 (m, 4H), 1.72e1.58
D
CH2Cl2); IR (film) 3360, 2954, 2867, 1610, 1009 cmꢁ1
(CDCl3, 300 MHz)
;
d
Flash column chromatography (3:1 to 1:2 heptane/EtOAc) afforded
20
the hydroxypiperidine 16 (19 mg, 0.05 mmol, 55%). [
a
]
þ8.2 (c
(m, 4H); 13C NMR (CDCl3, 75 MHz)
d 170.6, 67.6, 59.5, 41.5, 32.5,
D
0.5, CH2Cl2); IR (film) 3433, 2954, 1744, 1692, 1203, 957 cmꢁ1
.
1H
31.2, 25.6, 18.9, 18.5; HRMS (ESI) calcd for C9H16NO2 (MþHþ)
NMR (CDCl3, 300 MHz) 7.39e7.20 (m, 9H), 6.38e6.32 (m, 1H),
d
170.1181, found 170.1173.
6.12e6.09 (m, 1H), 5.11e5.10 (m, 1H), 5.03 (s, 2H), 4.59e4.55 (m,
1H), 4.04e3.99 (m, 1H), 3.89e3.85 (m, 1H), 2.64e2.48 (m, 2H),
7.7. Methyl 4-((2S,3S)-3-hydroxypiperidin-2-yl)butanoate
hydrochloride (21)
1.83e1.54 (m, 4H); 13C NMR (CDCl3, 75 MHz)
d
168.0, 155.2, 130.3,
128.8, 128.3, 128.1, 128.0, 127.5, 137.4, 127.3, 126.8, 72.4, 68.7, 66.7,
55.0, 37.4, 27.4, 26.9; HRMS (ESI) calcd for C22H24NCl35NaO3
(MþNaþ) 408.1342, found 408.1351.
Olefin 15 (40 mg, 0.12 mmol) was dissolved in MeOH (2 mL) and
Pd/C (2 mg, 0.019 mmol) and concentrated HCl (4 mL) were added
and the mixture was stirred under H2 (1 atm) pressure for 2 h. The
mixture was filtered over Celite and the solvent was evaporated
under reduced pressure followed by addition of water (4 mL) and
toluene (4 mL). The aqueous layer was washed with toluene
(2ꢂ4 mL) and concentrated under reduced pressure (azeotropically
evaporated twice with toluene) to afford hydroxypiperidine 21
7.5.3. (2S,3S)-1-Benzyloxycarbonyl-3-hydroxy-2-((E)-4-(trime-
thylsilyl)but-2-enyl)piperidine (17). Substrate 14 (25 mg, 0.09 mmol)
was reacted with allyltrimethylsilane according to the general
method. Flash column chromatography (3:1 to 1:2 heptane/EtOAc)
afforded hydroxypiperidine 17 (20 mg, 0.06 mmol, 70%). [
a
]
20 þ49.6
D
(c 0.32, CH2Cl2); IR (film) 3420, 2949, 1748, 1247, 849 cmꢁ1; 1H NMR
(28 mg, 0.12 mmol, 100%). [
a
]
20 þ7.1 (c 0.46, MeOH); IR (film) 3370,
D
(CDCl3, 300 MHz)
d
7.39e7.33 (m, 5H), 5.47e5.44 (m, 1H), 5.16e5.09
2932, 1726, 1437, 1212, 1001 cmꢁ1
;
1H NMR (D2O, 300 MHz)
(m, 3H), 4.48e4.42 (m, 1H), 4.02e3.96 (m, 1H), 3.84e3.79 (m, 1H),
2.74e2.73 (m, 1H), 2.38e2.32 (m, 2H), 1.93e1.23 (m, 6H), 0.08 (s,
d
4.02e3.99 (m, 1H), 3.57 (s, 3H), 3.26e3.22 (m, 1H), 3.09e305 (m,
1H), 2.92e2.84 (m, 1H), 2.34e2.30 (m, 2H), 1.86e1.82 (m, 2H),
1.71e1.52 (m, 6H); 13C NMR (D2O, 75 MHz)
177.5, 62.6, 58.4, 51.7,
9H); 13C NMR (CDCl3, 75 MHz)
d
155.1, 136.4, 127.9, 127.4, 127.3, 123.8,
d
122.5, 68.9, 66.6, 66.6, 55.3, 37.3, 27.4, 26.7, 25.0, ꢁ2.2, ꢁ2.5; HRMS
44.0, 32.5, 28.0, 27.9, 19.1, 15.7; HRMS (ESI) calcd for C10H20NO3
(ESI) calcd for C20H32NO3Si (MþHþ) 362.2151, found 362.2152.
(MþHþ) 202.1443, found 202.1445.
7.5.4. (2S,3S)-1-Benzyloxycarbonyl-2-((E)-4-(ethoxycarbonyloxy)-
but-2-enyl)-3-hydroxypiperidine (18). According to the general
procedure, substrate 14 (25 mg, 0.09 mmol) was reacted with allyl
ethyl carbonate. Flash column chromatography (3:1 to 1:2 heptane:
7.8. (2S,3S)-2-(3-Phenylpropyl)piperidin-3-ol (22)
Substrate 16 (23 mg, 0.059 mmol) was reacted with Pd/C, fol-
lowing the same procedure as for 21 to afford piperidinol 22 (9 mg,
20
EtOAc) afforded hydroxypiperidine 18 (24 mg, 0.065 mmol, 72%).
0.041 mmol, 66%). [
a]
þ7.7 (c 0.35, MeOH); IR (film) 3343, 2941,
D
20
[
a
]
þ28.2 (c 0.7, CH2Cl2); IR (film) 3438, 2958, 1731, 1692, 1251,
1454, 702, 598 cmꢁ1; 1H NMR (D2O, 300 MHz)
d 7.26e7.16 (m, 5H),
D
603 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.32e7.30 (m, 5H),
3.99 (m, 1H), 3.25e3.20 (m, 1H), 3.04e3.02 (m, 1H), 2.92e2.84 (m,
5.70e5.60 (m, 2H), 5.13e5.09 (m, 2H), 4.44e4.42 (m, 2H), 4.16 (q,
J¼7.2 Hz, 2H), 4.01e3.96 (m, 1H), 3.83e3.79 (m, 1H), 2.79e2.63 (m,
2H), 2.46e2.33 (m, 2H), 1.81e1.26 (m, 4H), 1.28 (t, J¼7.2 Hz, 3H); 13C
1H), 2.59e2.55 (m, 2H), 1.86e1.82 (m, 2H), 1.67e1.48 (m, 6H); 13C
NMR (D2O, 75 MHz) d 141.7,128.2, 128.0, 125.7, 62.7, 58.6, 44.0, 34.0,
28.0, 28.0, 25.5, 15.8; HRMS (ESI) calcd for C14H22NO (MþHþ)
NMR (CDCl3, 75 MHz)
d
170.6, 155.1, 132.6, 129.4, 128.9, 128.1, 127.5,
220.1701, found 220.1698.
125.3, 72.3, 68.5, 67.5, 66.7, 63.4, 54.7, 37.2, 27.2, 26.2, 13.8; HRMS
(ESI) calcd for C20H27NNaO6 (MþNaþ) 400.1436, found 400.1749.
7.9. (2S,3S)-2-(4-(Trimethylsilyl)butyl)piperidin-3-ol (23)
7.5.5. (2S,3S)-Benzyloxycarbonyl-2-((E)-7-bromohept-2-enyl)-3-hy-
droxypiperidine (19). Substrate 14 (25 mg, 0.09 mmol) was reacted
with 6-bromohex-1-ene following the general procedure. Flash
column chromatography (3:1 to 1:2 heptane/EtOAc) afforded
A solution of 17 (26 mg, 0.072 mmol) in MeOH (4 mL) was
pumped through the H-cube (20 bar, 25 ꢀC, 1 mL/min) followed by
evaporation of the solvent under reduced pressure to afford
20
piperidinol 23 (13 mg, 0.057 mmol, 79%). [
a
]
þ27.3 (c 0.29,
1H NMR
3.64 (m, 1H), 2.98e2.97 (m, 1H), 2.62e2.61 (m,
1H), 2.49e2.47 (m, 1H), 1.86e1.71 (m, 4H), 1.68e1.29 (m, 8H), ꢁ0.04
D
hydroxypiperidine 19 (20 mg, 0.048 mmol, 53%). [
a
]
20 þ18.3 (c 1.0,
CH2Cl2); IR (film) 2928, 1696, 1419, 1242, 827, 616 cmꢁ1
(CDCl3, 300 MHz)
;
D
CH2Cl2); IR (film) 3494, 2941, 1735, 1679, 1216 cmꢁ1
;
1H NMR
d
(CDCl3, 300 MHz)
d 7.39e7.33 (m, 5H), 5.40e5.35 (m, 1H),
5.10e5.09 (m, 3H), 4.46e4.44 (m, 1H), 4.00e3.95 (m, 1H),
3.83e3.79 (m, 1H), 3.33 (t, J¼6.6 Hz, 2H), 2.77e2.68 (m, 1H),
2.37e2.33 (m, 2H), 1.94e1.25 (m, 10H); 13C NMR (CDCl3, 75 MHz)
(s, 9H); 13C NMR (CDCl3, 75 MHz)
d 66.3, 60.3, 46.7, 31.9, 31.7, 29.4,
23.6, 20.1, 16.2, ꢁ2.1; HRMS (ESI) calcd for C12H28NOSi (MþHþ)
230.1940, found 230.1931.
d
155.2, 132.8, 131.7, 128.8, 128.1, 127.5, 126.4, 72.3, 68.7, 66.6, 54.9,
37.2, 33.4, 31.1, 27.3, 26.4, 25.0, 23.7; HRMS (ESI) calcd for
7.10. (2S,3S)-2-Butylpiperidin-3-ol (24)
C20H28BrNNaO3 (MþNaþ) 432.1150, found 432.1159.
Substrate 18 (25 mg, 0.066 mmol) was reacted with Pd/C, fol-
7.6. (9S,9aS)-9-Hydroxyhexahydro-1H-quinolizin-4(6H)-one
(20)
lowing the same procedure as for 23 to afford piperidinol 24
20
(13 mg, 0.066 mmol, 100%). [
a
]
þ25.9 (c 0.27, CH2Cl2); IR (film)
D
32.56, 2945, 2850, 1476, 1026, 866 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 3.65e3.64 (m, 1H), 3.01e2.97 (m, 1H), 2.66e2.58 (m, 1H),
A solution of 15 (50 mg, 0.15 mmol) in MeOH (4 mL) was
pumped through the H-cube (20 bar, 25 ꢀC, 1 mL/min) followed by
evaporation of the solvent under reduced pressure. The mixture of
products was dissolved in MeOH (2 mL) and K2CO3 (41 mg,
0.30 mmol) was added. The reaction was quenched after 2 h by the
2.49e2.48 (m, 1H), 1.92e1.85 (m, 1H), 1.78e1.67 (m, 2H), 1.50e1.31
(m, 7H), 0.90 (t, J¼6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 66.2,
60.3, 46.7, 31.9, 31.6, 27.7, 22.4, 20.1, 13.6; HRMS (ESI) calcd for
C9H20NO (MþHþ) 158.1545, found 158.1545.

M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
5631
7.11. (2S,3S)-2-Heptylpiperidin-3-ol (25)
(m, 1H), 1.96e1.92 (m, 2H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13
C
NMR (CDCl3, 75 MHz)
d
170.3, 153.7, 135.2, 134.4, 128.5, 128.2, 128.1,
A solution of 19 (85 mg, 0.21 mmol) was reacted with Pd/C,
117.6, 68.4, 67.6, 59.1, 33.8, 31.7, 25.7, 25.6, 17.9, 5.1, 5.4; HRMS (ESI)
following the same procedure as for 23 to afford piperidinol 25
calcd for C22H33NNaO4Si (MþNaþ) 426.2077, found 426.2093.
20
(39 mg, 0.19 mmol, 95%). [
a]
þ20.5 (c 0.19, CH2Cl2); IR (film)
D
2,910, 2854, 1450, 992 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
3.66 (m,
7.15. (S)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyloxy)-
3,4-(2H)-dihydropyridine (32)
1H), 3.04e2.99 (m, 1H), 2.64e2.60 (m, 1H), 2.52e2.50 (m, 1H),
1.94e1.90 (m, 2H), 1.88e1.74 (m, 2H), 1.50e1.28 (m, 12H), 0.92 (t,
J¼6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
62.7, 58.7, 43.9, 34.8, 31.5,
To a solution of amide 26 (100 mg, 0.28 mmol) in THF (2 mL)
was added LiEt3BH (280 mL of a 1 M solution in THF, 0.28 mmol) at
30.5, 30.4, 28.0, 23.5, 21.5, 17.0, 15.8, 12.9; HRMS (ESI) calcd for
C12H26NO (MþHþ) 200.2014, found 200.1996.
ꢁ78 ꢀC. The solution was slowly warmed to ꢁ40 ꢀC and quenched
after 2 h with water (2 mL) and CH2Cl2 (4 mL). The aqueous layer
was extracted with CH2Cl2 (3ꢂ5 mL) and the combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The hemiaminal was heated with NH4Cl to
130 ꢀC for 2 h. After cooling down the mixture, CH2Cl2 (5 mL) was
added and the suspension was filtered followed by concentration
under vacuo to afford the desired enamide 32, which was used
without further purification.
7.12. (S)-1-Benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)-
2-oxopiperidine (26)
The crude amide 11 was dissolved in THF (20 mL) and LiHMDS
(1.94 mL of a 1 M solution in heptane, 1.94 mmol) was added at
ꢁ78 ꢀC. After stirring for 30 min, CbzeOSu (485 mg, 1.94 mmol)
was added and the resulting mixture was stirred overnight. The
reaction was quenched with water (30 mL) and CH2Cl2 (30 mL) and
the aqueous layer was extracted with CH2Cl2 (2ꢂ30 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. Flash column chromatography (9:1 to 6:1
7.16. General procedure for reduction/N-acyliminium ion
reaction
heptane/EtOAc) afforded piperidine 26 (395 mg, 1.09 mmol, 56%) as
A solution of the Cbz-protected lactam in THF (0.1 M) was cooled
to ꢁ78 ꢀC and LiEt3BH (1 equiv,1 M solution in THF) was added. After
stirring for 2 h, the reaction was quenched with water and CH2Cl2,
followed by an extraction of the aqueous layer with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. The crude product was dissolved
in CH2Cl2 (0.1 M), cooled to 0 ꢀC, and BF3$OEt2 (3 equiv) and the
Me3Si-nucleophile (5 equiv) were added. The mixture was stirred
overnight and water and CH2Cl2 were added followed by an extrac-
tion of the aqueous layer with CH2Cl2. The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography as indicated.
20
a colorless oil, which solidified upon standing. [
a
]
þ6.5 (c 1.0,
CH2Cl2); IR (film) 2945, 2854,1718,1296, 832 cmꢁ1; 1DH NMR (CDCl3,
300 MHz)
3.73e3.67 (m, 1H), 2.75e2.71 (m, 1H), 2.47e2.43 (m, 1H), 1.93e1.84
(m, 2H), 0.85 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 75 MHz)
170.2,
d 7.39e7.31 (m, 5H), 5.26 (s, 2H), 4.15e4.13 (m, 1H),
d
153.6, 135.0, 128.0, 127.7, 127.5, 67.9, 63.7, 52.4, 30.4, 28.4, 25.2, 17.5,
ꢁ5.3, ꢁ5.4; HRMS (ESI) calcd for C19H29NNaO4Si (MþNaþ)
386.1764, found 386.1787.
7.13. (2R,3S)-1-Benzyloxycarbonyl-3-(tert-
butyldimethylsilyloxy)-2-methyl-6-oxopiperidine (27)
Substrate 12 (325 mg, 1.33 mmol) was reacted with CbzeOSu,
following the same procedure as for 26. Purification via column
7.16.1. (2R,5S)-2-Allyl-1-benzyloxycarbonyl-5-(tert-butyldimethylsi-
lyloxy)piperidine (35). Lactam 26 (25 mg, 0.065 mmol) was treated
with allyltrimethylsilane as described in the general procedure.
Purification via flash column chromatography (18:1 to 8:1 heptane/
chromatography (3:1 to 1:1 heptane/EtOAc) afforded piperidine 32
20
(330 mg, 0.86 mmol, 65%) as a colorless oil. [
a
]
D
ꢁ7.0 (c 0.9,
CH2Cl2); IR (film) 2958, 2854, 1779, 1731, 1264, 832, 776, 690 cmꢁ1
;
EtOAc) afforded piperidine 35 (18 mg, 0.07 mmol, 72%). [
a
]
20 þ21.2
D
1H NMR (CDCl3, 300 MHz)
d
7.35e7.26 (m, 5H), 5.27 (s, 2H),
(c 0.41, CH2Cl2); IR (film) 2949, 2850, 1709, 1428, 1238, 849 cmꢁ1
;
4.27e4.25 (m,1H), 3.89e3.88 (m,1H), 2.83e2.71 (m,1H), 2.46e2.37
(m, 1H), 2.05e1.98 (m, 1H), 1.82e1.78 (m, 1H), 1.20 (d, J¼7 Hz, 3H),
0.84 (s, 9H), 0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 75 MHz)
1H NMR (CDCl3, 300 MHz)
d 7.33e7.25 (m, 5H), 5.75e5.69 (m, 1H),
5.14e5.00 (m, 4H), 4.42e4.40 (m, 1H), 3.99e3.98 (m, 1H),
3.86e3.84 (m, 1H), 2.97e2.92 (m, 1H), 2.41e2.16 (m, 2H), 1.70e1.65
d
170.5, 154.0, 135.1, 128.0, 127.6, 127.3, 67.8, 67.7, 58.5, 29.1, 25.1,
(m, 4H), 0.83 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d 155.6,
24.2, 18.9, 17.4, ꢁ5.4, ꢁ5.5; HRMS (ESI) calcd for C20H31NNaO4Si
136.7, 134.9, 134.5, 127.9, 127.2, 116.3, 66.3, 64.2, 49.5, 45.0, 33.7,
26.0, 25.3, 20.9, 17.6, ꢁ5.5; HRMS (ESI) calcd for C22H35NNaO3Si
(MþNaþ) 412.2284, found 412.2302.
(MþNaþ) 400.1920, found 400.1930.
7.14. (2S,3S)-2-Allyl-1-benzyloxycarbonyl-3-(tert-
butyldimethylsilyloxy)-6-oxopiperidine (28)
7.16.2. (2R,5S)-1-Benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)-2-
(propa-1,2-dienyl)piperidine (36). Substrate 26 (106 mg, 0.26 mmol)
was reacted with propargyltrimethylsilane, following the general
procedure. Flash column chromatography (100:0 to 8:1 heptane/
To a solution of amide 13 (500 mg, 1.85 mmol) in THF (20 mL)
was added n-butyllithium (1.28 mL of a 1.6 M solution in hexane,
2.05 mmol) at ꢁ78 ꢀC. After 30 min, CbzeOSu (1.12 g, 4.63 mmol)
was added and the resulted solution was stirred overnight. The
reaction was quenched with water (30 mL) and CH2Cl2 (30 mL) and
the aqueous layer was extracted with CH2Cl2 (2ꢂ30 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. Purification via column chromatography
(2:1 to 1:2 heptane/EtOAc) afforded piperidine 28 (602 mg,
EtOAc) afforded piperidine 36 (44 mg, 0.11 mmol, 44%). [
a
]
20 þ25.7
D
(c 0.18, CH2Cl2); IR (film) 2954, 2850, 1696, 1247, 1043, 823 cmꢁ1; 1H
NMR (CDCl3, 300 MHz)
d 7.31e7.25 (m, 5H), 5.14e5.04 (m, 4H),
4.78e4.75 (m, 2H), 3.98e3.86 (m, 2H), 3.04e3.01 (m, 1H), 1.76e1.49
(m, 4H), 0.85 (s, 9H), 0.07 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3,
75 MHz) d 197.8, 155.2, 136.5, 127.9, 127.8, 127.3, 90.1, 71.6, 66.5, 64.2,
48.4, 45.6, 29.3, 26.5, 25.3, 21.4, ꢁ5.4; HRMS (ESI) calcd for
1.49 mmol, 80%) as a colorless oil, which solidified upon standing.
C22H33NNaO3Si (MþNaþ) 410.2127, found 410.2126.
20
[
a]
þ30.7 (c 2.48, CH2Cl2); IR (film) 2949, 2919, 1774, 1713, 1252,
D
1104, 832, 771 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.35e7.26 (m,
7.16.3. (2R,5S)-Benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)-2-
cyanopiperidine (38). According to the general procedure, substrate
26 (106 mg, 0.26 mmol) was reacted with Me3SiCN. Flash column
5H), 5.76e5.68 (m, 1H), 5.24 (br s, 2H), 5.04e4.91 (m, 2H),
4.35e4.31 (m, 1H), 4.16e4.08 (m, 1H), 2.66e2.55 (m, 3H), 2.23e2.16

5632
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
chromatography (100:0 to 8:1 heptane/EtOAc) afforded piperidine
(s, 6H); 13C NMR (CDCl3, 75 MHz)
d 154.5, 135.6, 128.1, 127.7, 127.4,
119.6, 67.5, 67.2, 54.1, 39.9, 25.3, 25.2, 22.5, 21.3, 17.5, 16.0, ꢁ5.4,
ꢁ5.6; HRMS (ESI) calcd for C21H32N2NaO3Si (MþNaþ) 411.2080,
found 411.2087.
20
38 (40 mg, 0.11 mmol, 41%). [
2958, 2837, 1718, 1247, 1039, 849 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
7.34e7.26 (m, 5H), 5.46e5.45 (m, 1H), 5.21e5.10 (m, 2H),
4.05e3.94 (m, 1H), 3.20e3.16 (m, 1H), 2.32e2.22 (m, 1H), 1.90e1.72
(m, 4H), 0.83 (s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3, 75 MHz)
155.0,
a]
þ45.1 (c 1.1, CH2Cl2); IR (film)
D
d
d
7.16.8. (2R,3S,6R)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyl-
oxy)-6-(2-(chloromethyl)allyl)-2-methylpiperidine (47A). Substrate
27 (80 mg, 0.20 mmol) was reacted with 2-(chloromethyl)allyl-
trimethylsilane, following the general procedure. Flash column
135.4, 128.0, 127.8, 127.6, 117.0, 67.6, 63.0, 47.2, 43.5, 27.3, 25.1, 22.0,
17.5, ꢁ5.5; HRMS (ESI) calcd for C20H30N2NaO3Si (MþNaþ)
397.1923, found 397.1934.
chromatography (100:0 to 8:1 heptane/EtOAc) afforded piperidine
20
7.16.4. (2R,5S)-1-Benzyloxycarbonyl-5-(tert-butyldimethylsilyloxy)-
2-(2-(chloromethyl)allyl)piperidine (39). Lactam 26 (106 mg,
0.26 mmol) was reacted with 2-(chloromethyl)allyltrimethylsilane,
following the general procedure. Flash column chromatography
47A (20 mg, 0.06 mmol, 30%). [
a
]
þ3.3 (c 0.72, CH2Cl2); IR (film)
D
2949, 2919, 1696, 1078, 853, 780 cmꢁ1
7.36e7.31 (m, 5H), 5.16e5.13 (m, 3H), 4.96 (m, 1H), 4.35e4.33 (m,
;
1H NMR (CDCl3, 300 MHz)
d
1H), 4.21e4.19 (m, 1H), 4.06e4.00 (m, 2H), 3.71e3.70 (m, 1H),
2.41e2.37 (m, 2H), 2.14e2.11 (m,1H),1.85e1.79 (m,1H),1.41e1.36 (m,
2H), 1.17 (d, J¼7.2 Hz, 3H), 0.85 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3,
(100:0 to 8:1 heptane/EtOAc) afforded piperidine 39 (78 mg,
20
0.18 mmol, 68%). [
a
]
þ15.6 (c 1.7, CH2Cl2); IR (film) 2949, 2846,
D
1700, 1424, 1234, 840 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.32e7.25
75 MHz) d 155.7,142.4,136.5,127.9,127.5,127.4,116.5, 68.3, 66.4, 53.3,
(m, 5H), 5.11e5.07 (m, 4H), 4.93e4.50 (m, 1H), 4.11e3.86 (m, 3H),
2.98e2.94 (m, 1H), 2.58e2.19 (m, 3H), 1.72e1.57 (m, 3H), 1.36e1.31
47.9, 47.3, 38.4, 25.3, 21.2, 19.2, 17.6, ꢁ5.4, ꢁ5.5; HRMS (ESI) calcd for
C24H38Cl35NNaO3Si (MþNaþ) 474.2207, found 474.2204.
(m, 1H), 0.84 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d 155.6,
142.0, 136.5, 127.9, 127.7, 127.2, 116.5, 66.4, 64.1, 47.7, 47.4, 44.9, 32.8,
26.1, 25.3, 25.2, 21.6, ꢁ5.5, ꢁ5.5; HRMS (ESI) calcd for
C23H37Cl35NO3Si (MþHþ) 438.2231, found 438.2234.
7.17. General procedure for reduction/TBS removal/N-
acyliminium ion reaction
To a solution of the Cbz-protected lactam in THF (0.1 M) was
added LiEt3BH (1 equiv 1 M solution in THF) at ꢁ78 ꢀC. After stir-
ring for 2 h, the reaction was quenched with water and CH2Cl2,
followed by an extraction of the aqueous layer with CH2Cl2. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The resulting oil was dis-
solved in THF (0.1 M) and TBAF (2 equiv 1 M solution in THF) was
added. After stirring for 2 h, water and CH2Cl2 were added and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was dissolved in CH2Cl2
(0.1 M) and BF3$OEt2 (3 equiv) and the Me3Si-nucleophile (5 equiv)
were added. After stirring overnight, the mixture was quenched
with saturated aqueous NaHCO3 and the solution was extracted
with CH2Cl2. The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified
by column chromatography as indicated.
7.16.5. (2R,3S,6R)-6-Allyl-1-benzyloxycarboxylate-3-(tert-butyldi-
methylsilyloxy)-2-methylpiperidine (44A). Amide 27 (70 mg,
0.19 mmol) was reacted with allyltrimethylsilane as described in
the general method. Flash column chromatography (100:0 to 3:1
heptane/EtOAc) afforded piperidine 44A (39 mg, 0.10 mmol, 56%).
20
[
a
]
þ7.0 (c 0.8, CH2Cl2); IR (film) 2958, 2846, 1697, 1415, 1065,
D
836 cmꢁ1
; d 7.33e7.25 (m, 5H),
1H NMR (CDCl3, 300 MHz)
5.79e5.70 (m, 1H), 5.14 (dd, J¼12.3, 5.7 Hz, 2H), 5.04e4.89 (m, 2H),
4.31e4.25 (m, 1H), 4.22e4.16 (m, 1H), 3.70e3.69 (m, 1H), 2.33e2.25
(m, 2H), 1.82e1.62 (m, 4H), 1.15 (d, J¼7.2 Hz, 3H), 0.85 (s, 9H), 0.02
(s, 6H); 13C NMR (CDCl3, 75 MHz)
d 155.7, 136.7, 135.6, 127.9, 127.2,
127.1, 116.3, 68.4, 66.3, 53.2, 49.4, 39.2, 25.3, 21.3, 17.6, ꢁ5.3, ꢁ5.5;
HRMS (ESI) calcd for C23H38NO3Si (MþHþ) 404.2634, found
404.2621.
7.16.6. (2R,3S,6R)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyl-
oxy)-2-methyl-6-(propa-1,2-dienyl)piperidine (45A). According to
the general procedure, substrate 27 (80 mg, 0.20 mmol) was reac-
ted with propargyltrimethylsilane. Flash column chromatography
(100:0 to 8:1 heptane/EtOAc) afforded piperidine 45A (5 mg,
7.17.1. (2R,3S,6R)-6-Allyl-benzyloxycarbonyl-3-hydroxy-2-methyl-
piperidine (44B) and (2R,3S,6S)-6-allyl-benzyloxycarbonyl-3-hy-
droxy-2-methylpiperidine (44C). According to the general method,
substrate 27 (100 mg, 0.25 mmol) was reacted with allyl-
trimethylsilane. Flash column chromatography (5:1 to 1:1 heptane/
EtOAc) afforded the product as a separable mixture of dia-
stereoisomers in a ratio of 2:1 (1H NMR), hydroxypiperidine 44B
(33 mg, 0.11 mmol, 43%) and hydroxypiperidine 44C (15 mg,
0.05 mmol, 20%).
0.01 mmol, 7%) together with the deprotected piperidine 45B
20
(14 mg, 0.05 mmol, 25%, analytical data see below). [
a
]
þ50.6 (c
D
0.22, CH2Cl2); IR (film) 2949, 2846, 1696, 1303, 1087, 620, 421 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.37e7.26 (m, 5H), 5.17e5.14 (m, 3H),
4.97e4.94 (m, 1H), 4.77e4.75 (m, 2H), 4.21e4.17 (m, 1H), 3.71e3.70
(m, 1H), 2.19e2.12 (m, 1H), 1.92e1.82 (m, 1H), 1.64e1.60 (m, 1H),
1.60e1.59 (m,1H),1.13 (t, J¼7.2 Hz, 3H), 0.85 (s, 9H), 0.03 (s, 6H); 13C
Compound 44B: [
a
]
20 þ1.2 (c 1.16, CH2Cl2); IR (film) 3394, 1661,
D
NMR (CDCl3, 75 MHz)
d
206.4, 155.7, 146.8, 127.9, 127.3, 127.2, 93.7,
1432, 1324, 1078, 1018, 703 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
68.4, 66.4, 53.5, 47.0, 25.7, 21.85, 19.7, 18.1, 15.4, ꢁ5.4, ꢁ5.5; HRMS
d 7.34e7.33 (m, 5H), 5.73e5.67 (m, 1H), 5.12e4.98 (m, 4H),
(ESI) calcd for C23H35NNaO3Si (MþNaþ) 424.2284, found 424.2273.
4.29e4.25 (m, 2H), 3.77 (m, 1H), 2.31e2.25 (m, 2H), 2.04e1.86 (m,
2H), 1.63e1.46 (m, 2H), 1.19 (d, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
7.16.7. (2R,3S,6R)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyl-
oxy)-6-cyano-2-methylpiperidine (46A). Substrate 27 (80 mg,
0.20 mmol) was reacted with Me3SiCN according to the general
procedure. Flash column chromatography (100:0 to 1:1 heptane/
EtOAc) afforded piperidine 46A (10 mg, 0.03 mmol, 13%) together
with the deprotected piperidine 46B (15 mg, 0.05 mmol, 27%, an-
75 MHz) d 155.9, 135.3, 128.0, 127.4, 127.3, 116.6, 67.8, 66.6, 63.0,
49.5, 39.1, 25.3, 20.4, 18.9; HRMS (ESI) calcd for C17H23NNaO3
(MþNaþ) 312.1576, found 312.1578.
20
Compound 44C: [
a
]
D
þ14.9 (c 0.56, CH2Cl2); IR (film) 3317,
2936, 1692, 1532, 1260, 1039 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.34e7.33 (m, 5H), 5.83e5.73 (m, 1H), 5.23e5.02 (m, 4H),
alytical data see below). [
a
]
D
20 þ38.9 (c 0.37, CH2Cl2); IR (film) 2962,
3.98e3.94 (m, 2H), 3.78e3.71 (m, 1H), 2.33e2.19 (m, 2H), 1.99e1.96
(m, 2H), 1.65e1.54 (m, 2H), 1.13 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3,
2854, 1705, 1415, 1281, 1074, 832, 784 cmꢁ1
;
1H NMR (CDCl3,
300 MHz)
d
7.37e7.34 (m, 5H), 5.28e5.20 (m, 1H), 5.18 (s, 2H),
75 MHz) d 155.4, 136.1, 134.3, 128.0, 127.6, 116.4, 81.0, 78.7, 66.1,
4.24e4.21 (m, 1H), 3.80e3.78 (m, 1H), 2.36e2.25 (m, 1H), 2.11e2.01
(m, 1H), 1.76e1.63 (m, 2H), 1.33 (d, J¼7.5 Hz, 3H), 0.83 (s, 9H), 0.03
49.8, 39.6, 30.8, 27.8, 15.4; HRMS (ESI) calcd for C17H23NNaO3
(MþNaþ) 312.1576, found 312.1565.

M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
5633
7.17.2. (2R,3S,6R)-1-Benzyloxycarbonyl-3-hydroxy-2-methyl-6-
(propa-1,2-dienyl)piperidine (45B) and (2R,3S,6S)-1-benzyloxy-
carbonyl-3-hydroxy-2-methyl-6-(propa-1,2-dienyl)piperidine (45C).
Substrate 27 (70 mg, 0.18 mmol) was reacted with propargyl-
trimethylsilane according to the general method. Flash column
chromatography (5:1 to 1:1 heptane/EtOAc) afforded the product
as a separable mixture of diastereoisomers in a ratio of 1:1 (1H
NMR), hydroxypiperidine 45B (16 mg, 0.05 mmol, 29%) and
hydroxypiperidine 45C (15 mg, 0.05 mmol, 29%).
(5:1 to 1:1 heptane/EtOAc) afforded hydroxypiperidine 55 (32 mg,
20
0.10 mmol, 68%). [
a]
ꢁ9.8 (c 0.30, CH2Cl2); IR (film) 2945, 1714,
D
1506, 1256, 1044, 906, 703 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.34
(m, 5H), 5.84e5.71 (m, 2H), 5.11e5.03 (m, 6H), 3.99e3.97 (m, 2H),
3.74e3.72 (m, 1H), 2.34e2.10 (m, 4H), 1.99e1.90 (m, 2H), 1.73e1.54
(m, 2H); 13C NMR (CDCl3, 75 MHz)
d 156.1, 136.2, 134.3, 134.2, 128.0,
127.6, 127.5, 117.1, 116.4, 78.8, 66.2, 52.8, 52.8, 39.7, 37.9, 30.9, 28.4;
HRMS (ESI) calcd for C19H25NNaO3 (MþNaþ) 338.1732, found
338.1726.
Compound 45B: [
a
]
D
20 þ63.8 (c 0.42, CH2Cl2); IR (film) 3403, 2988,
1696,1424, 1285, 1078 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.34e7.33
7.17.6. (2S,3S,6R)-2-Allyl-benzyloxycarbonyl-3-hydroxy-6-(propa-
1,2-dienyl)piperidine (56). Substrate 28 (100 mg, 0.25 mmol) was
reacted with propargyltrimethylsilane, following the general pro-
(m, 5H), 5.21e5.09 (m, 3H), 4.96e4.93 (m, 1H), 4.81e4.75 (m, 2H),
4.31e4.28 (m, 1H), 3.78e3.77 (m, 1H), 2.07e1.49 (m, 4H), 1.21 (d,
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
207.4, 155.4, 136.1, 128.1,
cedure. Flash column chromatography (5:1 to 1:1 heptane/EtOAc)
20
127.3, 127.2, 92.0, 81.6, 81.0, 69.2, 66.1, 54.4, 31.3, 27.6, 15.3; HRMS
afforded hydroxypiperidine 56 (48 mg, 0.15 mmol, 62%). [a]
D
(ESI) calcd for C17H21NNaO3 (MþHþ) 310.1419, found 310.1415.
ꢁ20.2 (c 1.5, CH2Cl2); IR (film) 3356, 2928, 1692, 1506, 1195, 1056,
664 cmꢁ1 1H NMR (CDCl3, 300 MHz)
7.36e7.34 (m, 5H),
Compound 45C: [
a
;
]
20 þ9.1 (c 0.68, CH2Cl2); IR (film) 3407, 1718,
;
d
D
1268, 1043, 728 cmꢁ1
1H NMR (CDCl3, 300 MHz)
d
7.34e7.33 (m,
5.84e5.73 (m, 1H), 5.19e5.03 (m, 5H), 4.82e4.78 (m, 2H),
4.52e4.41 (m, 1H), 4.03e3.99 (m, 1H), 3.77e3.74 (m,1H), 2.35e2.33
(m, 2H), 2.06e1.96 (m, 2H), 1.81e1.68 (m, 2H); 13C NMR (CDCl3,
5H), 5.17e5.16 (m, 3H), 4.81e4.86 (m, 2H), 4.70 (m, 1H), 4.56e4.54
(m, 1H), 4.09e3.98 (m, 1H), 2.06e1.99 (m, 2H), 1.75e1.61 (m, 2H),
1.15 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
206.3, 155.9,
75 MHz) d 207.3, 156.1, 136.2, 134.1, 128.0, 127.5, 127.4, 11.7, 92.1,
136.2, 127.9, 127.5, 127.3, 93.3, 76.7, 67.9, 66.7, 53.4, 47.0, 20.9, 19.5,
18.1; HRMS (ESI) calcd for C17H21NNaO3 (MþHþ) 310.1419, found
310.1409.
79.8, 78.8, 66.2, 52.8, 52.4, 37.9, 31.5, 28.0; HRMS (ESI) calcd for
C19H23NNaO3 (MþNaþ) 336.1576, found 336.1584.
7.17.7. (2S,3S,6R)-2-Allyl-1-benzyloxycarbonyl-6-cyano-3-hydroxy-
piperidine (57). According to the general procedure, substrate 28
(100 mg, 0.25 mmol) was reacted with Me3SiCN. Flash column
chromatography (5:1 to 1:1 heptane/EtOAc) afforded hydroxy-
7.17.3. (2R,3S,6R)-1-Benzyloxycarbonyl-6-cyano-3-hydroxy-2-meth-
ylpiperidine (46B). Substrate 27 (70 mg, 0.18 mmol) was reacted
with Me3SiCN according to the general procedure. Flash column
chromatography (5:1 to 1:1 heptane/EtOAc) afforded hydroxy-
piperidine 57 (37 mg, 0.12 mmol, 50%). [
a
]
20 ꢁ27.0 (c 0.76, CH2Cl2);
D
20
piperidine 46B (14 mg, 0.05 mmol, 28%). [
a]
þ14.7 (c 0.61,
IR (film) 3386, 2945, 1696, 1411, 1303, 698 cmꢁ1
;
1H NMR (CDCl3,
D
CH2Cl2); IR (film) 3317, 2954, 1709, 1537, 1256, 1082 cmꢁ1; 1H NMR
(CDCl3, 300 MHz) 7.34e7.33 (m, 5H), 5.19 (s, 2H), 4.76e4.72 (m,
300 MHz)
5H), 4.54e4.56 (m, 1H), 3.85e3.81 (m, 1H), 2.72e2.61 (m, 2H),
2.07e1.84 (m, 4H); 13C NMR (CDCl3, 75 MHz)
155.1, 134.1, 133.5,
d 7.36e7.35 (m, 5H), 5.78e5.72 (m, 1H), 5.30e5.01 (m,
d
2H), 4.10e4.08 (m, 1H), 3.85e3.78 (m, 1H), 2.27e2.21 (m, 2H),
d
1.84e1.80 (m, 1H), 1.60e1.58 (m, 1H), 1.13 (d, J¼6.6 Hz, 3H); 13C
128.2, 127.9, 127.8, 118.9, 117.9, 68.2, 67.9, 55.6, 39.1, 29.2, 27.3, 24.0;
HRMS (ESI) calcd for C17H21N2O3 (MþHþ) 301.1552, found
301.1556.
NMR (CDCl3, 75 MHz)
d 155.3, 135.9, 128.1, 127.7, 127.6, 118.5, 82.7,
66.4, 66.3, 48.9, 30.7, 26.5, 15.7; HRMS (ESI) calcd for C15H18N2NaO3
(MþNaþ) 297.1215, found 297.1219.
7.17.8. (2S,3S,6R)-2-Allyl-1-benzyloxycarbonyl-6-(2-(chloromethyl)-
allyl)-3-hydroxypiperidine (58). Substrate 28 (100 mg, 0.25 mmol)
was reacted with 2-(chloromethyl)allyltrimethylsilane according to
the general method. Flash column chromatography (5:1 to 1:1
7.17.4. (2R,3S,6S)-1-Benzyloxycarbonyl-6-(2-(chloromethyl)allyl)-3-
hydroxy-2-methylpiperidine (47B) and (2R,3S,6R)-1-benzyloxy-
carbonyl-6-(2-(chloromethyl)allyl)-3-hydroxy-2-methylpiperidine
(47C). Substrate 27 (70 mg, 0.18 mmol) was reacted with 2-(chlor-
omethyl)allyltrimethylsilane according to the general method. Flash
column chromatography (5:1 to 1:1 heptane:EtOAc) afforded the
product as a separable mixture of diastereoisomers in a ratio of 1.4:1
(1H NMR), hydroxypiperidine 47B (24 mg, 0.07 mmol, 39%) and
hydroxypiperidine 47C (17 mg, 0.05 mmol, 27%).
heptane/EtOAc) afforded hydroxypiperidine 58 (56 mg, 0.15 mmol,
20
62%). [
a
]
D
ꢁ2.2 (c 0.56, CH2Cl2); IR (film) 3356, 2936, 1713, 1506,
1225, 944 cmꢁ1
; d 7.35 (m, 5H),
1H NMR (CDCl3, 300 MHz)
5.84e5.75 (m, 1H), 5.18e5.00 (m, 6H), 4.14e4.00 (m, 4H),
3.75e3.73 (m, 1H), 2.37e2.30 (m, 4H), 2.05e1.93 (m, 2H), 1.73e1.56
(m, 2H); 13C NMR (CDCl3, 75 MHz)
d 156.1, 142.3, 136.2, 134.0, 128.0,
Compound 47B: [
a]
20 ꢁ4.6 (c 0.69, CH2Cl2); IR (film) 3407, 2954,
127.6, 127.5, 117.2, 116.0, 78.7, 78.2, 66.2, 52.6, 52.6, 48.2, 38.8, 37.8,
31.6, 28.2; HRMS (ESI) calcd for C20H27CI35NO3 (MþHþ) 364.1680,
found 364.1706.
D
1692, 1297, 1019, 712 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 7.34e7.33
(m, 5H), 5.16e4.96 (m, 4H), 4.32e4.29 (m, 1H), 4.00e3.95 (m, 2H),
3.80e3.78 (m, 1H), 2.43e2.38 (m, 2H), 2.00e1.61 (m, 4H), 1.21 (d,
J¼8.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d
155.9, 142.1, 136.1, 135.9,
7.18. (2R,3R,5S)-2-Allyl-1-benzyloxycarbonyl-5-(tert-
butyldimethylsilyloxy)-3-hydroxypiperidine (63)
128.0, 127.6, 127.5, 116.8, 116.1, 67.7, 66.9, 53.1, 48.1, 47.1, 38.6, 20.3,
19.2, 18.9; HRMS (ESI) calcd for C18H24Cl35NNaO3 (MþNaþ)
360.1342, found 360.1332.
To a solution of 32 (40 mg, 0.1 mmol) in a mixture of acetone,
water, and acetonitrile (0.5 mL each) were added NMO (18 mg,
0.15 mmol) and OsO4 (5 mol %, 17 mL of a solution of 4 wt % in H2O).
Compound 47C: [
a
]
D
20 þ8.3 (c 0.71, CH2Cl2); IR (film) 3757, 2936,
1701, 1550, 1269 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.34e7.33 (m,
5H), 5.16e5.09 (m, 4H), 4.15e3.94 (m, 5H), 3.38e2.34 (m, 2H),
The resulting slurry was stirred overnight followed by the addition
of CH2Cl2 (3 mL) and water (2 mL), the aqueous layer was extracted
with CH2Cl2 (3ꢂ5 mL). The combined organic layers were dried,
filtered, and concentrated in vacuo. The crude product was dis-
2.05e1.97 (m, 2H), 1.65e1.60 (m, 2H), 1.14 (d, J¼6.9 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) d 155.4, 142.2, 136.1, 134.8, 128.0, 127.8, 127.6,
116.0, 81.0, 69.2, 66.2, 54.4, 48.2, 38.7, 31.6, 27.7, 15.6; HRMS (ESI)
calcd for C18H24Cl35NNaO3 (MþNaþ) 360.1342, found 360.1333.
solved in CH2Cl2 (3 mL) and BF3$OEt2 (38
mL, 0.3 mmol) and allyl-
trimethylsilane (80 L, 0.5 mmol) were added. After stirring
m
7.17.5. (2S,3S,6R)-2,6-Diallyl-1-benzyloxycarbonyl-3-hydroxypiper-
idine (55). Amide 28 was reacted with allyltrimethylsilane
according to the general procedure. Flash column chromatography
overnight, water (5 mL) was added and the aqueous layer was
extracted with CH2Cl2 (2ꢂ5 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced

5634
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
pressure. Purification via flash column chromatography (3:1 to 1:3
combined and concentrated in vacuo to afford the deprotected
compound.
heptane/EtOAc) afforded hydroxypiperidine 63 (16 mg, 0.04 mmol,
20
40%). [
a
]
þ10.0 (c 0.57, CH2Cl2); IR (film) 2954, 2859, 1700, 1247,
837 cmꢁ1D
;
1H NMR (CDCl3, 300 MHz)
d
7.35e7.30 (m, 5H),
7.23. General procedure for deprotection B
5.74e5.71 (m, 1H), 5.15e5.01 (m, 5H), 4.58e4.54 (m, 1H), 4.33e4.28
(m, 1H), 3.99e3.95 (m, 2H), 2.88e2.84 (m, 1H), 2.44e2.42 (m, 1H),
2.32e2.25 (m, 2H), 0.88 (s, 9H), 0.03 (s, 6H); 13C NMR (CDCl3,
The protected piperidine was dissolved in MeOH (0.1 M) and Pd/
C (10%) was added and the mixture was stirred under H2 (1 atm)
pressure until completion according to TLC. The mixture was fil-
tered through Celite and the solvent was evaporated under reduced
pressure.
75 MHz)
d 155.8, 136.4, 134.7, 127.9, 127.4, 127.3, 116.5, 66.6, 65.8,
63.9, 54.5, 43.9, 35.2, 27.1, 25.3, 22.2, ꢁ5.6; HRMS (ESI) calcd for
C22H36NO4Si (MþHþ) 406.2414, found 406.2422.
7.19. (2S,3S,5S)-1-Benzyloxycarbonyl-5-(tert-
butyldimethylsilyloxy)-3-hydroxy-2-(propa-1,2-dienyl)
piperidine (64)
7.24. General procedure for deprotection C
The protected piperidine was dissolved in MeOH (0.1 M), Pd/C
(10%) and HCl (concentrated, 1 equiv) were added and the mixture
was stirred under H2 (1 atm) pressure until completion according
to TLC. The suspension was filtered through Celite and the solvent
was evaporated under reduced pressure.
Substrate 32 (100 mg, 0.28 mmol) was reacted with propargyl-
trimethylsilane, following the same procedure as for 63. Flash
column chromatography (3:1 to 1:3 heptane/EtOAc) afforded
20
hydroxypiperidine 64 (10 mg, 0.02 mmol, 9%). [
a
]
ꢁ12.6 (c 0.48,
D
CH2Cl2); IR (film) 3408, 2954, 2842, 1701, 1424, 1264, 1109,
7.24.1. (3S,6R)-6-Allylpiperidin-3-ol (40). Piperidine 35 (305 mg,
0.78 mmol) was deprotected according to general procedure A. After
concentration of the aqueous layers, aqueous NaOH (1 M, 1 mL) and
CH2Cl2 (5 mL) were added. The aqueous layer was extracted with
CH2Cl2 (3ꢂ5 mL) and the combined organic layers were dried over
840 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
7.37e7.34 (m, 5H),
5.29e5.05 (m, 3H), 4.84e4.79 (m, 2H), 4.29e4.27 (m, 1H),
4.09e3.94 (m, 2H), 3.75e3.72 (m, 1H), 2.76e2.70 (m, 1H),
2.58e2.54 (m, 1H), 2.01e1.99 (m, 1H), 0.84 (s, 9H), 0.07 (s, 6H); 13C
NMR (CDCl3, 75 MHz)
d
205.9, 158.0, 130.6, 128.0, 127.6, 127.4, 87.5,
Na2SO4, filtered, and concentrated under reduced pressure to afford
20
83.6, 68.5, 67.2, 66.9, 49.2, 46.6, 36.2, 25.3, 17.6, ꢁ5.2; HRMS (ESI)
the free amine 40 (97 mg, 0.68 mmol, 78%). [
a]
þ12.9 (c 0.16,
D
calcd for C22H33NNaO4Si (MþNaþ) 426.2077, found 426.2062.
CH2Cl2); IR (film) 3286, 2932, 1445, 1030, 909, 607 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz) 5.81e5.69 (m, 1H), 5.11e5.05 (m, 2H), 3.67e3.61
d
7.20. (2S,3S,5S)-1-Benzyloxycarbonyl-5-(tert-
butyldimethylsilyloxy)-2-cyano-3-hydroxypiperidine (65)
(m, 1H), 3.25e3.20 (m, 1H), 2.49e2.35 (m, 2H), 2.21e2.02 (m, 3H),
1.76e1.70 (m, 1H), 1.33e1.16 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d
134.9, 117.0, 67.8, 54.6, 53.5, 40.3, 33.7, 30.6; HRMS (ESI) calcd for
Substrate 32 (100 mg, 0.28 mmol) was reacted with Me3SiCN,
following the same procedure as for 63. Flash column chromatog-
C8H16NO (MþHþ) 142.1232, found 142.1236.
raphy (3:1 to 1:3 heptane/EtOAc) afforded hydroxypiperidine 65
7.24.2. (3S,6R)-6-Propylpiperidin-3-ol (3). Allene 36 (45 mg,
0.16 mmol) was deprotected following procedure C followed by
addition of aqueous NaOH (1 M, 2 mL) and CH2Cl2 (2 mL) and the
aqueous layer was extracted with CH2Cl2 (2ꢂ5 mL). The combined
organic layers were dried over Na2SO4, filtered, and the solvent was
removed under vacuo to give (þ)-pseudoconhydrine (3) (12 mg,
20
(23 mg, 0.08 mmol, 21%). [
a]
þ23.1 (c 0.85, CH2Cl2); IR (film)
D
3425, 2911, 2850, 1700, 1424, 1264, 841, 784 cmꢁ1; 1H NMR (CDCl3,
300 MHz) 7.35e7.34 (m, 5H), 5.59e5.40 (m, 1H), 5.22e5.08 (m,
d
2H), 4.24e4.17 (m, 1H), 4.11e4.02 (m, 2H), 3.14e3.09 (m, 1H),
2.11e2.06 (m, 1H), 1.82e1.73 (m, 1H), 0.82 (s, 9H), 0.06 (s, 6H); 13C
20
29
NMR (CDCl3, 75 MHz)
d
155.0, 135.0, 128.1, 127.9, 127.7, 115.1, 67.9,
0.08 mmol, 52%). [
a
]
þ10.3 (c 0.17, EtOH) (lit. [
a
]
þ11.1 (c 1.0,
D
54.6, 62.0, 50.4, 46.5, 36.7, 25.1, 17.4, ꢁ5.5; HRMS (ESI) calcd for
EtOH)); IR (film) 3144, 2923, 1454, 1070, 616 cmꢁ1; 1DH NMR (CDCl3,
C20H31N2O4Si (MþHþ) 391.2053, found 391.2048.
300 MHz)
2.47e2.40 (m, 2H), 2.07e2.00 (m, 1H), 1.73e1.71 (m, 3H), 1.63e1.30
(m, 4H), 1.09e0.90 (m, 3H); 13C NMR (CDCl3, 75 MHz)
68.0, 55.1,
d
3.61 (dt, J¼10.2, 4.8 Hz, 1H), 3.24e3.18 (m, 1H),
7.21. (2S,3S,5S)-1-Benzyloxycarbonyl-5-(tert-
butyldimethylsilyloxy)-2-(2-(chloromethyl)allyl)-3-
hydroxypiperidine (66)
d
53.6, 38.1, 33.7, 30.8, 18.9, 13.7; HRMS (ESI) calcd for C8H18NO
(MþHþ) 144.1388, found 144.1382. Analytical data are in compar-
ison with literature.7a
Substrate 32 (100 mg, 0.28 mmol) was reacted with 2-(chloro-
methyl)allyltrimethylsilane, following the same procedure as for
7.24.3. (2R,5S)-5-Hydroxypiperidine-2-carboxamide hydrobromide
63. Flash column chromatography (3:1 to 1:3 heptane/EtOAc)
(41). Deprotection of compound 38 (40 mg, 0.11 mmol) was per-
formed according to procedure A to afford the desired amine 41
20
afforded hydroxypiperidine 66 (30 mg, 0.07 mmol, 24%). [
a
]
D
20
þ14.6 (c 1.4, CH2Cl2); IR (film) 3404, 2967, 2846, 1662, 1558, 1242,
(25 mg, 0.11, mmol, 100%). [
a
]
þ2.6 (c 0.58, MeOH); IR (film)
D
1048, 845 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
7.32e7.30 (m, 5H),
3390, 3023, 1683, 1441, 1091, 590 cmꢁ1
3.91e3.86 (m, 2H), 3.47e3.41 (m, 1H), 2.83e2.76 (m, 1H),
2.29e2.22 (m, 1H), 2.11e2.02 (m, 1H), 1.83e1.70 (m, 1H), 1.60e1.51
;
1H NMR (D2O, 300 MHz)
5.13e4.95 (m, 4H), 4.70e4.59 (m, 1H), 4.35e4.29 (m, 1H), 4.18e3.95
(m, 4H), 2.92e2.88 (m, 1H), 2.68e2.62 (m, 1H), 2.38e2.35 (m, 1H),
1.84e1.82 (m, 1H), 1.68e1.65 (m, 1H), 0.84 (s, 9H), 0.07 (s, 6H); 13C
d
(m, 1H); 13C NMR (D2O, 75 MHz)
d 170.9, 62.4, 55.9, 46.7, 29.2,
NMR (CDCl3, 75 MHz)
d
155.8, 141.8, 136.2, 128.1, 127.9, 127.5, 116.5,
24.2; HRMS (ESI) calcd for C6H13N2O2 (MþHþ) 145.0985, found
66.7, 65.8, 63.6, 53.0, 47.4, 43.8, 34.9, 25.7, 25.2, 17.5, ꢁ5.5; HRMS
145.0977.
(ESI) calcd for C23H37Cl35NO4Si (MþHþ) 454.2180, found 454.2168.
7.24.4. (2R,5S)-5-Hydroxypipecolic acid (ent-1). Amide 41 (20 mg,
0.09 mmol) was dissolved in MeOH (1 mL), aqueous KOH (2 M,
1 mL) was added and the mixture was stirred overnight followed
by concentration under reduced pressure. The residue was sus-
7.22. General procedure for deprotection A
HBr (33 wt % in acetic acid, 0.1 M) was added to protected pi-
peridine at 0 ꢀC and the mixture was stirred for 5 min followed by
concentration in vacuo. Toluene and water were added and the
organic layer was extracted with water. The aqueous layers were
pended in MeOH, filtered, and concentrated in vacuo to afford
20
hydroxypipecolic acid ent-1 (8 mg, 0.056 mmol, 61%). [
a]
þ31.0
D
20
(c 0.1, MeOH); (lit. (other enantiomer) [
a
]
D
ꢁ33.0 (c 2.2, H2O));19

M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
5635
1H NMR (D2O, 400 MHz)
2.52e2.46 (m, 1H), 2.07e2.02 (m, 1H), 1.95e1.91 (m, 1H),
d
3.68e3.64 (m, 1H), 3.24e3.14 (m, 2H),
25.3, 14.1; HRMS (ESI) calcd for C7H15N2O2 (MþHþ) 159.1134, found
159.1136.
1.49e1.34 (m, 2H); 13C NMR (CD3OD, 75 MHz)
d 178.9, 66.6, 60.0,
51.6, 33.2, 28.9; HRMS (ESI) calcd for C6H12NO3 (MþHþ) 146.0817,
7.24.10. (2R,3S,6R)-6-Isobutyl-2-methylpiperidin-3-ol hydrochloride
(51). Compound 47A (20 mg, 0.06 mmol) was deprotected
found 146.0816.
according to procedure
C to afford piperidinol 51 (10 mg,
7.24.5. (6S,8aR)-2-Methyleneoctahydroindolizin-6-ol (42). Piperi-
dine 39 (78 mg, 0.18 mmol) was deprotected according to procedure
A. The resulting mixture was dissolved in MeOH (2 mL) followed by
the addition of K2CO3 (35 mg, 0.36 mmol). After stirring for 2 h,
water (3 mL) and CH2Cl2 (3 mL) were added and the aqueous layer
was extracted with CH2Cl2 (3ꢂ5 mL). The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. Flash
0.06 mmol, 100%). [
a
]
20 þ11.7 (c 0.67, MeOH); IR (film) 3960, 2971,
D
1640, 1454, 1052, 538 cmꢁ1
;
1H NMR (D2O, 300 MHz)
d
3.45e3.44
(m, 1H), 3.33e3.29 (m, 1H), 2.85e2.76 (m, 1H), 1.89e1.86 (m, 2H),
1.46e1.44 (m, 1H), 1.24e1.19 (m, 4H), 1.12 (d, J¼6.3 Hz, 3H),
0.68e0.62 (m, 6H); 13C NMR (D2O, 75 MHz)
d 69.1, 56.6, 54.7, 41.0,
30.2, 26.2, 23.3, 21.8, 20.2, 14.5; HRMS (ESI) calcd for C10H22NO
(MþHþ) 172.1701, found 172.1707.
column chromatography (100:0 to 95:5 EtOAc/MeOH) afforded the
20
title compound 42 (22 mg, 0.14 mmol, 80%). [
a
]
ꢁ27.4 (c 0.13,
7.24.11. (2R,3S,6S)-6-Isobutyl-2-methylpiperidin-3-ol
(53). Com-
D
CH2Cl2); IR (film) 2932, 2785, 1553, 1450, 1014, 573 cmꢁ1
;
1H NMR
pound 47C (16 mg, 0.05 mmol) was reacted with Pd/C, following
20
(CDCl3, 300 MHz) 4.89e4.88 (m, 2H), 3.88e3.84 (m,1H), 3.59e3.54
d
procedure B to afford piperidinol 53 (8 mg, 0.04 mmol, 93%). [a]
(m, 1H), 3.27e3.22 (m, 1H), 2.92e2.91 (m, 1H), 2.50e2.45 (m, 1H),
ꢁ6.6(c0.32, CH2Cl2);IR(film)3347, 2945,1666,1264,1009, 845 cmꢁD1
;
2.16e1.85 (m, 5H), 1.34e1.29 (m, 2H); 13C NMR (CDCl3, 75 MHz)
1H NMR (CDCl3, 300 MHz)
d 4.12e4.08 (m, 1H), 3.41e3.36 (m, 1H),
d
146.1, 105.2, 67.4, 63.1, 59.2, 58.8, 37.2, 33.4, 28.0; HRMS (ESI) calcd
3.22e3.18 (m, 1H), 2.61e2.52 (m, 1H), 2.37e2.29 (m, 2H), 1.90e1.86
(m, 2H), 1.51e1.42 (m, 2H), 1.32 (d, J¼6.6 Hz, 3H), 0.92e0.86 (m, 6H);
for C9H16NO (MþHþ) 154.1232, found 154.1242.
13C NMR (CDCl3, 75 MHz)
d 32.0, 28.4, 27.0, 22.6, 22.2, 14.6; HRMS
7.24.6. (2R,3S,6R)-6-Allyl-2-methylpiperidin-3-ol
(48). Compound 44A (24 mg, 0.06 mmol) was deprotected
hydrobromide
(ESI) calcd for C10H22NO (MþHþ) 172.1701, found 172.1696.
according procedure A to afford deprotected piperidinol 48 (14 mg,
7.24.12. (2S,3S,6R)-2,6-Diallylpiperidin-3-ol hydrobromide (59). Sub-
20
0.06 mmol, 100%). [
a
]
þ10.3 (c 0.76, MeOH); IR (film) 2941, 1687,
strate 55 (36 mg, 0.12 mmol) was deprotected following procedure A
D
1640, 1445, 1061, 603, 499 cmꢁ1
;
1H NMR (D2O, 300 MHz)
to afford the desired piperidinol 59 (29 mg, 0.11 mmol, 92%). [a]
20
d
5.76e5.64 (m, 1H), 5.18e5.12 (m, 2H), 3.49e3.41 (m, 1H),
þ6.0 (c 0.40, MeOH); IR (film) 3317, 2954, 2828,1406,1001, 667 cmꢁD1
;
3.17e3.12 (m, 1H), 2.96e2.91 (m, 1H), 2.33e2.29 (m, 2H), 2.05e1.98
(m, 2H), 1.49e1.42 (m, 2H), 1.28 (d, J¼6.6 Hz, 3H); 13C NMR (D2O,
1H NMR (D2O, 300 MHz)
d 5.79e5.71 (m, 2H), 5.22e5.00 (m, 4H),
4.06e3.95 (m, 2H), 3.21e3.18 (m, 1H), 2.47e2.41 (m, 1H), 2.31e1.95
75 MHz)
d
131.3, 119.4, 68.9, 56.8, 55.6, 36.6, 30.2, 26.2, 14.4; HRMS
(m, 4H), 1.65e1.63 (m, 3H); 13C NMR (D2O, 75 MHz)
d
134.6, 131.0,
(ESI) calcd for C9H18NO (MþHþ) 156.1388, found 156.1396.
120.0,116.7, 78.9, 77.6, 54.0, 38.3, 33.1, 30.3, 28.0; HRMS (ESI) calcd for
C11H20NO (MþHþ) 182.1545, found 182.1535.
7.24.7. (2R,3S,6S)-6-Allyl-2-methylpiperidin-3-ol
hydrobromide
(52). According to general procedure A, 44C (13 mg, 0.04 mmol)
7.24.13. (2S,3S,6R)-2,6-Dipropylpiperidin-3-ol (60). Compound 56
was deprotected to afford piperidinol 52 (7 mg, 0.03 mmol, 74%).
(13 mg, 0.04 mmol) was reacted with Pd/C, following procedure B
20
[
a]
þ4.3 (c 0.16, MeOH); IR (film) 3420, 2949, 1627, 1070,
to afford piperidinol 60 (8 mg, 0.04 mmol,100%). [
a
]
20 ꢁ17.3 (c 0.38,
D
D
850 cmꢁ1
;
1H NMR (D2O, 300 MHz)
d
5.81e5.72 (m, 1H),
CH2Cl2); IR (film) 3260, 2971, 1649, 1368, 1091, 845 cmꢁ1; 1H NMR
5.09e4.99 (m, 2H), 4.09e4.06 (m, 2H), 3.43e3.41 (m, 1H),
2.24e2.21 (m, 2H), 2.04e1.99 (m, 2H), 1.64e1.62 (m, 2H), 1.16 (d,
(CDCl3, 300 MHz)
3.29e3.28 (m, 1H), 2.42e1.91 (m, 6H), 1.61e1.32 (m, 6H), 0.95e0.89
(m, 6H); 13C NMR (CDCl3, 75 MHz)
82.8, 64.8, 55.0, 37.5, 36.0, 32.5,
d 4.04e4.01 (m, 1H), 3.90e3.85 (m, 1H),
J¼6.9 Hz, 3H); 13C NMR (D2O, 75 MHz)
d
134.4, 116.7, 79.6, 78.1,
d
49.4, 38.5, 30.2, 25.5, 12.7; HRMS (ESI) calcd for C9H18NO (MþHþ)
28.6, 19.0, 18.8, 18.2, 17.6; HRMS (ESI) calcd for C11H23NNaO
156.1388, found 156.1387.
(MþNaþ) 208.1677, found 208.1670.
7.24.8. (2R,3S,6R)-2-Methyl-6-propylpiperidin-3-ol (49). Compound
45A (19 mg, 0.047 mmol) was deprotected according to procedure C.
After concentration in vacuo, aqueous NaOH (1 M, 2 mL) and CH2Cl2
(2 mL) were added and the aqueous layer was extracted with CH2Cl2
(2ꢂ5 mL). The combined organic layers were dried over Na2SO4,
concentrated, and the solvent was removed under vacuo to give
7.24.14. (2R,5S,6S)-6-Allyl-5-hydroxypiperidine-2-carboxamide hy-
drobromide (61). Substrate 57 (17 mg, 0.056 mmol) was deprotected
following procedure A to afford the desired hydroxypiperidine 61
(11 mg, 0.038 mmol, 68%). [
a
]
20 þ2.4 (c 0.53, MeOH); IR (film) 3403,
D
1692,1398,1022, 624 cmꢁ1; 1H NMR (D2O, 300 MHz)
d
5.77e5.68 (m,
1H), 5.25e5.17 (m, 2H), 4.19e4.18 (m, 1H), 3.90e3.77 (m, 1H),
piperidinol 49 (6 mg, 0.037 mmol, 81%). [
a
]
20 þ15.3 (c 0.07 CH2Cl2);
3.31e3.26(m,1H), 2.52e1.92 (m, 6H); 13C NMR (D2O,75 MHz)
d
173.9,
D
IR (film) 2854, 2928, 1458, 1043, 840 cmꢁ1
;
1H NMR (CDCl3,
131.0, 119.6, 69.4, 62.2, 54.8, 33.0, 28.6, 20.7; HRMS (ESI) calcd for
400 MHz)
d
3.18e3.11 (m,1H), 2.54e2.45 (m, 2H), 2.06e2.00 (m,1H),
C12H16N2NaO2 (MþNaþ) 207.1110, found 207.1100.
1.76e1.71 (m, 1H), 1.24e1.33 (m, 6H), 1.19 (d, J¼4.5 Hz, 3H),
0.93e0.89 (m, 3H); 13C NMR (CDCl3, 75 MHz)
d
73.8, 58.1, 55.6, 38.4,
7.24.15. (2S,3S,6R)-6-Isobutyl-2-propylpiperidin-3-ol
(62). Com-
33.6, 31.3, 18.9, 13.8; HRMS (ESI) calcd for C9H20NO (MþHþ)
pound 58 (26 mg, 0.07 mmol) was deprotected according pro-
20
158.1545, found 158.1552.
cedure B to afford piperidinol 62 (13 mg, 0.065 mmol, 93%). [
ꢁ10.7 (c 0.65, CH2Cl2); IR (film) 3407, 2963, 1640, 1394, 1091,
417 cmꢁ1 1H NMR (CDCl3, 300 MHz)
4.14e4.08 (m, 1H),
3.92e3.87 (m, 1H), 3.05e3.03 (m, 1H), 1.74e1.26 (m, 11H),
1.00e0.88 (m, 9H); 13C NMR (CDCl3, 75 MHz)
77.7, 55.3, 44.2, 32.2,
a]
D
7.24.9. (2R,5S,6R)-5-Hydroxy-6-methylpiperidine-2-carboxamide
hydrobromide (50). Substrate 46A (25 mg, 0.064 mmol) was
deprotected following procedure A to provide piperidine 50 (15 mg,
;
d
d
0.064 mmol, 100%). [
a
]
20 þ15.5 (c 0.44, MeOH); IR (film) 3377, 2937,
31.6, 28.7, 25.4, 25.3, 25.0, 22.5, 22.4, 13.6; HRMS (ESI) calcd for
D
1683, 1424, 1035, 547 cmꢁ1
;
1H NMR (D2O, 300 MHz)
d
3.91 (dd,
C12H25NNaO (MþNaþ) 222.1834, found 222.1835.
J¼3.2, 12.7 Hz, 1H), 3.55 (dt, J¼10.8, 4.6 Hz, 1H), 3.05e2.99 (m, 1H),
2.26e2.11 (m, 2H), 1.85e1.67 (m, 1H), 1.62e1.48 (m, 1H), 1.33 (d,
7.24.16. (2S,3S,5S)-2-Allylpiperidine-3,5-diol (67). Piperidine 63
(117 mg, 0.29 mmol) was deprotected according to general
J¼6.6 Hz, 3H); 13C NMR (D2O, 75 MHz)
d
170.8, 68.2, 56.9, 56.0, 30.2,

5636
M.A. Wijdeven et al. / Tetrahedron 66 (2010) 5623e5636
procedure A. After concentration of the aqueous layers, aqueous
NaOH (1 M,1 mL) and CH2Cl2 (5 mL) were added. The aqueous layer
was extracted with CH2Cl2 (3ꢂ5 mL) and the combined organic
layers were dried over Na2SO4, filtered, and concentrated under
71.3, 61.6, 53.0, 50.9, 37.4, 35.4; HRMS (ESI) calcd for C9H16NO2
(MþHþ) 170.1181, found 170.1159.
Acknowledgements
reduced pressure to afford the free amine 67 (39 mg, 0.25 mmol,
20
85%). [
a
]
þ5.8 (c 0.46, MeOH); IR (film) 3282, 2923, 1558, 1090,
603 cmꢁ1D
;
1H NMR (CD3OD, 400 MHz)
d
5.84e5.76 (m, 1H),
Dr. G. Schaftenaar (CMBI, Radboud University Nijmegen) is kindly
acknowledged for assistance with the MOPAC AM1 calculations.
5.16e5.06 (m, 2H), 4.02e3.96 (m, 1H), 3.95e3.89 (m, 1H), 3.18e3.14
(m, 1H), 2.74e2.70 (m, 1H), 2.49e2.43 (m, 1H), 2.32e2.22 (m, 4H);
13C NMR (CD3OD, 75 MHz)
d 133.5, 116.7, 64.9, 61.4, 58.0, 50.6, 39.4,
Supplementary data
34.1; HRMS (ESI) calcd for C8H16NO2 (MþHþ) 158.1181, found
158.1191.
The 2D-NMR data of compounds 42, 50, 59, 67. Supplementary
data associated with this article can be found in the online version,
at doi:10.1016/j.tet.2010.05.089. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
7.24.17. (2S,3S,5S)-2-Propylpiperidine-3,5-diol (68). Compound 64
(10 mg, 0.02 mmol) was deprotected according to procedure C.
After concentration in vacuo, aqueous NaOH (1 M, 2 mL) and CH2Cl2
(2 mL) were added and the aqueous layer was extracted with
CH2Cl2 (2ꢂ5 mL). The combined organic layers were dried over
References and notes
Na2SO4, concentrated, and the solvent was removed under vacuo to
20
give piperidinol 68 (3 mg, 0.02 mmol, 95%). [
a
]
D
þ25.0 (c 0.06,
1. See, e.g. Strunz, G. M.; Findlay, J. A. In The Alkaloids; Brossi, A., Ed.; Acadamic:
San Diego, CA, 1986; Vol. 26, p 89.
2. Witkop, B.; Foltz, C. M. J. Am. Chem. Soc. 1957, 79, 192e197.
3. Yasuda, K.; Kizu, H.; Yamashita, T.; Kameda, Y.; Kato, A.; Nash, R. J.; Fleet, G. W.
J.; Molyneux, R. J.; Asano, N. J. Nat. Prod. 2002, 65, 198e202.
4. Engler, C.; Kronstein, A. Ber. Dtsch. Chem. Ges. 1894, 27, 1779e1784.
5. Quibell, M.; Benn, A.; Flinn, N.; Monk, T.; Ramjee, M.; Wang, Y.; Watts. J. Bioorg.
Med. Chem. 2004, 12, 5689e5710.
MeOH); IR (film) 3230, 2812, 1666, 1066, 603 cmꢁ1
(CD3OD, 400 MHz) 4.08e3.95 (m, 2H), 3.21e3.14 (m, 1H),
2.77e2.73 (m, 1H), 2.55e2.48 (m, 1H), 2.24e2.15 (m, 1H), 1.60e1.27
(m, 5H), 0.98e0.93 (m, 3H); 13C NMR (CD3OD, 75 MHz)
65.0, 61.5,
;
1H NMR
d
d
58.0, 50.7, 39.4, 31.9, 18.2, 12.5; HRMS (ESI) calcd for C8H18NO2
(MþHþ) 160.1338, found 160.1338.
6. Marion, L.; Cockburn, W. F. J. Am. Chem. Soc. 1949, 71, 3402e3404.
7. (a) Sakagami, H.; Kamikubo, T.; Ogasawara, K. J. Chem. Soc., Chem. Commun.
1996, 1433e1434; (b) Moody, C. J.; Lightfoot, A. P.; Gallagher, P. T. J. Org. Chem.
7.24.18. (2R,3S,5S)-3,5-Dihydroxypiperidine-2-carboxamide
(69).
€
€
1997, 62, 746e748; Lofstedt, J.; Pettersson-Fasth, H.; Backvall, J.-E. Tetrahedron
2000, 56, 2225e2230; (c) Botman, P. N. M.; Dommerholt, F. J.; de Gelder, R.;
Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett.
2004, 6, 4941e4944; (d) Haddad, M.; Imogai, H.; Larcheveque, M. J. Org. Chem.
1998, 63, 5680e5683; (e) Jung, J.-C.; Avery, M. A. Tetrahedron: Asymmetry 2006,
17, 2479e2486; (f) Kim, I. S.; Ji, Y. J.; Jung, Y. H. Tetrahedron Lett. 2006, 47,
7289e7293.
Piperidine 65 (23 mg, 0.08 mmol) was deprotected according to
general procedure A. After concentration of the aqueous layers,
aqueous NaOH (1 M, 1 mL) and CH2Cl2 (5 mL) were added. The
aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL) and the com-
bined organic layers were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. Purification with an IsoluteÒ
Flash SCX-2 ion exchange column (eluents: CH2Cl2, MeOH, NH3/
8. Wijdeven, M. A.; Wijtmans, R.; van den Berg, R. J. F.; Noorduin, W.; Schoemaker,
H. E.; Sonke, T.; van Delft, F. L.; Blaauw, R. H.; Fitch, R. W.; Spande, T. F.; Daly, J.
W.; Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001e4003.
9. Wijdeven, M. A.; van den Berg, R. J. F.; Wijtmans, R.; Botman, P. N. M.; Blaauw,
R. H.; Schoemaker, H. E.; van Delft, F. L.; Rutjes, F. P. J. T. Org. Biomol. Chem. 2009,
7, 2976e2980.
MeOH (1 M)) gave dihydroxypiperidine 69 (10 mg, 0.05 mmol,
20
68%). [
a
]
þ25.3 (c 0.08, MeOH); IR (film) 3364, 1640, 1286,
D
858 cmꢁ1
;
1H NMR (CD3OD, 400 MHz)
d
4.52e4.51 (m, 1H),
10. Braekman, J.-C.; Charlier, A.; Daloze, D.; Heilporn, S.; Pasteels, J.; Plasman, V.;
Wang, S. Eur. J. Org. Chem. 1999, 1, 1749e1755.
4.22e4.16 (m, 1H), 3.93e3.85 (m, 1H), 2.78e2.70 (m, 1H), 2.28e2.15
(m, 1H), 1.71e1.62 (m, 1H), 1.29e1.27 (m, 1H); 13C NMR (CD3OD,
11. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953e956.
12. (a) Comins, D. L.; Dinsmore, J. M.; Marks, L. R. Chem. Commun. 2007, 4170e4171;
(b) Matsushita, H.; Negishi, E. J. Org. Chem. 1982, 47, 4161e4165.
13. Vink, M. K. S.; Schortinghuis, C. A.; Luten, J.; van Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2002, 67, 7869e7871.
14. Marin, J.; Didierjean, C.; Aubry, A.; Casimir, J. R.; Briand, J. P.; Guichard, G. J. Org.
Chem. 2003, 69, 130e141.
75 MHz)
d 171.2, 75.0, 64.4, 59.4, 59.0, 38.0; HRMS (ESI) calcd for
C6H12NNaO2 (MþNaþ) 183.0746, found 183.0746.
7.24.19. (6S,8S,8aS)-2-Methyleneoctahydroindolizine-6,8-diol (70).
Piperidine 66 (30 mg, 0.07 mmol) was deprotected according to
procedure A. The resulting mixture was dissolved in MeOH (1 mL)
followed by the addition of K2CO3 (14 mg, 0.14 mmol). After stirring
for 2 h, water (3 mL) and CH2Cl2 (3 mL) were added and the
aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. Flash column chromatography (100:0 to 95:5 EtOAc/MeOH)
15. Furukubo, S.; Moriyama, N.; Onomura, O.; Matsumura, Y. Tetrahedron Lett. 2004,
45, 8177e8181.
16. For excellent reviews on N-acyliminium ion chemistry, see, e.g.: (a) Speckamp,
W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817e3856; (b) Royer, J.; Bonin,
M.; Micouin, L. Chem. Rev. 2004, 104, 2311e2352; (c) Yazici, A.; Pyne, S. G.
Synthesis 2009, 339e368; (d) Yazici, A.; Pyne, S. G. Synthesis 2009, 513e541.
17. For N-acyliminium ion reactions with similar diastereoselectivity, see: Shono,
T.; Matsumura, Y.; Onomura, O.; Sato, M. J. Org. Chem. 2002, 53, 4118e4121.
18. For 2-D NMR data, see Supplementary data.
19. Kristensen, I.; Olesen Larsen, P.; Erik Olsen, C. Tetrahedron 1976, 32, 2799e2804.
20. For examples of the formation of 2,6-cis-disubstituted piperidines via N-acy-
liminium ion chemistry, see: Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K.
J. Org. Chem. 1986, 51, 2590e2592.
afforded indolizidine 70 (7 mg, 0.04 mmol, 59%). [
a
]
20 ꢁ20.0 (c 0.10,
D
CH2Cl2); IR (film) 3369, 2928, 1657, 1087, 1026, 629 cmꢁ1; 1H NMR
(CD3OD, 400 MHz)
d 4.95e4.93 (m, 2H), 4.21e4.16 (m, 1H),
3.99e3.96 (m,1H), 3.84e3.77 (m, 2H), 3.14e3.07 (m,1H), 2.87e2.86
(m, 1H), 2.64e2.62 (m, 1H), 2.45e2.38 (m, 2H), 2.19e2.09 (m, 1H),
21. (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 1,
168e169; (b) Strunz, G. M.; Finlay, J. A. In The Alkaloids; Brossi, A., Ed.; Aca-
demic: New York, NY, 1985; Vol. 26, pp 89e183.
1.56e1.47 (m, 1H); 13C NMR (CD3OD, 75 MHz)
d 138.8, 111.3, 73.1,