An efficient synthesis of 2- and 2,6-substituted piperidines using Pd II-catalyzed 1,3-chirality transfer reaction

Article abstract of DOI:10.1021/jo801926g

(Chemical Equation Presented) An efficient and general method for 2- and 2,6-substituted piperidine syntheses using Pd^II-catalyzed 1,3-chirality transfer reaction has been developed. The various N-protected ζ-amino allylic alcohols cyclize in the presence of PdCl ₂(CH₃CN)₂ to give substituted piperidines with high stereoselectivities. The syntheses of (S)-(+)- and (R)-(-)-coniine were achieved in 3 steps from the optically pure allylic alcohols (S)-14c and (R)-14c, respectively. Although the rates of reactions were significantly accelerated in CH₂Cl₂, THF gave the highest stereoselectivity. PdCl₂(CH₃CN)₂ was found to be the best catalyst for this transformation. A plausible reaction pathway involving the formation of the Pd π-complex directed by the chiral secondary allylic alcohol followed by syn-azapalladation, and subsequent syn-elimination of PdCl(OH) is proposed.

Full text of DOI:10.1021/jo801926g

An Efficient Synthesis of 2- and 2,6-Substituted Piperidines Using
PdII-Catalyzed 1,3-Chirality Transfer Reaction
Sudhir M. Hande, Nobuyuki Kawai, and Jun’ichi Uenishi*
Kyoto Pharmaceutical UniVersity, Misasagi, Yamashina, Kyoto 607-8412, Japan
juenishi@mb.kyoto-phu.ac.jp
ReceiVed August 30, 2008
An efficient and general method for 2- and 2,6-substituted piperidine syntheses using PdII-catalyzed 1,3-
chirality transfer reaction has been developed. The various N-protected ꢀ-amino allylic alcohols cyclize
in the presence of PdCl2(CH3CN)2 to give substituted piperidines with high stereoselectivities. The syntheses
of (S)-(+)- and (R)-(-)-coniine were achieved in 3 steps from the optically pure allylic alcohols (S)-14c
and (R)-14c, respectively. Although the rates of reactions were significantly accelerated in CH2Cl2, THF
gave the highest stereoselectivity. PdCl2(CH3CN)2 was found to be the best catalyst for this transformation.
A plausible reaction pathway involving the formation of the Pd π-complex directed by the chiral secondary
allylic alcohol followed by syn-azapalladation, and subsequent syn-elimination of PdCl(OH) is proposed.
1. Introduction
(2),3 alkaloid 241D (3),4 and (-)-cassine (4)5 are some of the
representative examples having simple substituted piperidine
rings, which are known to be inhibitors of the neuromuscular,
ganglionic, central neuronal nicotinic acetylcholine receptors
and HIV-protease. Because of the known dependence between
the biological activity of a molecule and its absolute configu-
ration, stereoselective synthesis of various substituted piperidines
have evoked immense interest from a both synthetic and
Piperidine alkaloids and their analogues comprise a large
family of pharmacologically important compounds.1 Particularly,
piperidines bearing the alkyl substituent group at the 2- and/or
2,6-position on the ring can be found as a core structure in many
naturally occurring alkaloids that possess a large spectrum of
interesting biological activities. They serve as attractive scaf-
folding for medicinal agents to bind to biological targets. Among
them, (S)-(+)- and (R)-(-)-coniine (1a) and (1b),2 (-)-lobeline
(2) (a) Wolffenstein, R. Ber. 1894, 27, 2611–2615. (b) Ahrens, F. B. Ber.
1902, 35, 1330–1334. (c) Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H.-P
J. Am. Chem. Soc. 1983, 105, 7754–7755. (d) Sanchez-Sancho, F.; Herradon,
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* To whom correspondence should be addressed.
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A. J. Chem. Soc., Perkin Trans. 1 2000, 2862–2892. (c) Bailey, P. D.; Millwood,
P. A.; Smith, P. D. Chem. Commun. 1998, 633–640. (d) Meyers, A. I.; Brengel,
G. P. Chem. Commun. 1997, 1–8. (e) Husson, H.-P.; Royer, J. Chem. Soc. ReV.
1999, 28, 383–394. (f) Laschat, S.; Dickner, T. Synthesis 2000, 13, 1781–1813.
(g) Groaning, M. D.; Meyers, A. I. Tetrahedron 2000, 56, 9843–9873. (h) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701–1729. (i) Escolano, C.; Amat, M.; Bosch,
J. Chem.sEur. J. 2006, 12, 8198–8202.
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10.1021/jo801926g CCC: $40.75 2009 American Chemical Society
Published on Web 11/14/2008

Synthesis of 2- and 2,6-Substituted Piperidines
SCHEME 1. PdII-catalyzed Cyclizations of Oxygen
Nucleophile to Chiral Allylic Alcohols
FIGURE 1. Structures of some naturally occurring piperidine alkaloids.
SCHEME 2. PdII-catalyzed Cyclizations of Nitrogen
Nucleophile to Chiral Allylic Alcohols
biological standpoint. Although there are many synthetic
methods of piperidines reported in literature,1,6-10 including
Mannich-type reaction,6 Michael addition,7 ring-closing me-
tathesis,8 iminium ion cyclization,9 aza Diels-Alder reaction10
etc. a more efficient, convenient, and highly stereoselective
synthetic method is desired.
PdII-catalyzed C-N bond formation reactions have been
documented well in literature,11 and they proceed under milder
conditions with high functional group tolerance and high
stereoselectivities.12 Both syn- and anti-azapalladation were
discussed with their stereochemistry; however, the exact mecha-
nistic course of this reaction remains unknown. Several reports
have demonstrated the anti-azapalladation process,13 whereas
some recent studies show that the nitrogen nucleophiles bearing
electron-withdrawing groups such as sulfonamides and carbam-
ates undergo oxidative coupling with alkenes through syn-
azapalladation.14 Most recently, Stahl and co-workers illustrated
that, although syn-azapalladation is more favored in such type
of a reaction, anti-azapalladation could occur as well.15 This
depends upon the substrate, the catalyst, and reaction conditions.
Recently we have reported the PdII-catalyzed stereospecific
synthesis of 5-, 6-, and 7-membered oxaheterocycles by 1,3-
chirality transfer reaction using chiral allylic alcohols (Scheme
1).16 In this reaction, the stereochemistry at the newly formed
chiral center is produced by syn-oxypalladation and syn-
elimination processes. The advantages of this method are; (i)
No oxidant such as CuCl2 is required, because the PdII-catalyst
is regenerated during the reaction. This is how it differs from
other oxidative cyclizations to an alkene17 by Wacker-type
reactions. (ii) The reaction proceeds smoothly at 0 °C with
excellent selectivities. Since only a few examples of piperidine
synthesis using PdII-catalyzed cyclization of ꢀ-amino allylic
alcohols were reported in literature,18 there is not much known
about the reaction mechanism. Because of our continuous
interest in this area, we decided to apply this methodology to
the synthesis of chiral 2- and 2,6-disubstituted piperidines
(Scheme 2). To establish this as a general method, we
synthesized various N-protected ꢀ-amino allylic alcohols and
examined the cyclization reaction using different PdII-catalysts
and solvents. Herein, we report the full account of our study in
the synthesis of chiral piperidines and discuss the mechanistic
details of this reaction.
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Tetrahedron: Asymmetry 2004, 15, 1561–1567. (b) Bariau, A.; Jatoi; W, B.;
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2. Results and Discussion
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65, 4435–4439. (b) Agami, C.; Comesse, S.; Kadouri-Puchot, C. J. Org. Chem.
2002, 67, 2424–2428.
2.1. Synthesis of Various N-Protected ꢀ-Amino Allylic
Alcohols. As is mentioned above, the protecting group on amino
functionality is expected to be important in the Pd-catalyzed
cyclization for piperidine synthesis. We planned the synthesis
of precursors 14a-f possessing six protecting groups on the
nitrogen atom via their common intermediate 12. The synthesis
is shown in Schemes 3 and 4.
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3588. (c) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 17, 2913–2916.
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palladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley and
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Soc. 2005, 127, 17778–17788. (d) Sharma, G V. M.; Chander, A. S.; Krishnudu,
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J. Org. Chem. Vol. 74, No. 1, 2009 245

Hande et al.
SCHEME 3. Preparation of 12
SCHEME 4. Preparation of Precursors 14a-f for
Cyclizations
Compound 12 was synthesized from δ-silyloxypentanal 519
in seven steps. Wittig olefination of 5 gave the R,ꢁ-unsaturated
ketone 620 in 85% yield. Reduction of ketone by sodium
borohydride in the presence of CeCl3 and protection of the
resultant allylic alcohol 7 with benzoyl chloride gave benzoate
8 in quantitative yield in two steps. Desilylation of 8 with TBAF
followed by mesylation with methanesulfonyl chloride gave 10
in 87 and 99% yields, respectively. Treatment of 10 with sodium
azide in DMF afforded azide 11 in 92% yield, which on
subsequent reduction with triphenylphosphine in the presence
of H2O gave 12 in 92% yield.
The nitrogen atom of 12 was then protected with methyl
carbonate, Boc, Cbz, Fmoc, Ts, and trifluoroacetyl groups. Using
the standard procedures,21 13a-f were obtained in good yields
as shown in Scheme 4. Basic hydrolysis of benzoates 13a-c
and 13e gave cyclization precursors 14a-c and 14e in 93-97%
yields. In the case of 13d, deprotection of Fmoc group took
place faster than hydrolysis of the benzoate. Therefore, depro-
tection of benzoate by DIBAL-H was carried out to provide
14d in 75% yield. Methanolysis of 13f afforded 14f in 54%
yield along with 30% recovery of starting material. Elongation
of reaction time for this reaction resulted in hydrolysis of
trifluoroacetamide.
2.1.1. Cyclization of 14a-f Using PdII-Catalysts in
Different Solvents. With precursors 14a-f in hand, the
cyclization reaction was investigated. First, we chose the four
most efficient PdII-catalystssPdCl2(CH3CN)2, PdCl2(PhCN)2,
Pd(OAc)2, and Pd(OCOCF3)2sfrom the exhaustive screening
in the study of oxy-palladation for tetrahydropyran synthesis.
Then, we selected some common solvents such as CH2Cl2, THF,
toluene, and acetonitrile. Primary screenings were performed
in a multiple reaction kit using dry solvents under an argon
atmosphere. Among the four catalysts, PdCl2(CH3CN)2 and
PdCl2(PhCN)2 were found to be the best catalysts to give
(18) (a) Hirai, Y.; Watanabe, J.; Nozaki, T.; Yokoyama, H.; Yamaguchi, S.
J. Org. Chem. 1997, 62, 776–777. (b) Yokoyama, H.; Otaya, K.; Kobayashi,
H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Org. Lett. 2000, 2, 2427–2429. (c)
Yokoyama, H.; Ejiri, H.; Miyazawa, M.; Yamaguchi, S.; Hirai, Y. Tetrahedron:
Asymmetry 2007, 18, 852–856.
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121, 700–709.
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Mauduit, M. J. Org. Chem. 2008, 73, 4225–4228.
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Third ed.; John Wiley and Sons: New York, 1999.
246 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2- and 2,6-Substituted Piperidines
TABLE 1. PdII-Catalysed Cyclization of Substrates 14a-f
CH2Cl2
THF
entry
substrate (PG)
time (min)
temp (°C)
yield (%)
time (min)
temp (°C)
yield (%)
product
1
2
3
4
5
6
14a (COOCH3)
14b (Boc)
15
5
0
0
0
0
0
rt
89
93
95
85
83
30
60
rt
0
rt
rt
rt
rt
82
91
15a, see ref 22
15b, see ref 23
14c (Cbz)
10
30
5
45
95a
92
15c
15d
15e
15f
14d (Fmoc)
14e (Ts)
14f (COCF3)
90
30
91
b,c
b,c
30
-
120
-
a The results with the use of 1, 5, and 10 mol % of catalyst, see coniine synthesis in the main text. b No cyclization was observed. c Complex
mixtures were obtained at 40 °C.
SCHEME 5. PdII-Catalyzed Synthesis of (S)-(+)- and (R)-(-)-Coniine
cyclized product 15 in CH2Cl2 or THF in excellent yields. The
reaction with PdCl2(CH3CN)2 was quite slower in toluene at 0
°C because of the reduced solubility of the catalyst. Note that
Pd(OCOCF3)2 was also effective in THF to complete the
reactions, generally in 20 min at room temperature for 14b and
in 5 min at room temperature for 14e, whereas reactions with
Pd(OAc)2 required heating at 40 °C for a longer period of time.
Among the solvents used, CH2Cl2 was found to be the best in
reaction at 0 °C. THF and toluene are the next choice of solvents
in which the transformation is clean but slower than that in
CH2Cl2 at room temperature. Reactions in CH3CN were even
slower, and in most cases, a majority of the starting materials
were recovered. The coordination of CH3CN on the catalyst
might decrease the reaction rate, which can retard the formation
of π-complex or the attack of nucleophile in the azapalladation
reaction. This could be the reason why the rate of reaction in
THF was also slower and far slower in CH3CN.
Table 1 lists selected results. The reactions in THF required
higher temperature and longer period of time than those in
CH2Cl2. Nucleophilicity of nitrogen and stereic factor are
important for the rate of reactions. The results indicate N-
carbamoyl and N-sulfonyl groups can be used for cyclization
(entries 1-5), although the N-trifluoroacetyl group is unsuitable
for this purpose in both solvents (entry 6).
mechanism. For this purpose, we choose the synthesis of (S)-
(+)- and (R)-(-)-coniine2 using (S)-(-)-14c and (R)-(+)-14c
as the chiral starting materials. Although Hirai et al. reported
the synthesis of (R)-coniine from (S)-(-)-14c using
PdCl2(CH3CN)2 catalyst,24 the structure in their report indicated
the (R)-configuration but the (+)-sign was shown. As per our
prediction, the stereospecific attack of the nucleophile based
on the stereochemistry of oxaheterocycles16 should take place
from syn with respect to the chiral alcohol to afford (S)-(+)-
coniine from (S)-(-)-14c, contrary to the results that appeared
in their report. Therefore, re-examinations were carried out. Our
results are depicted in Scheme 5.
Lipase (Candida Antarctica lipase; Novozyme 435) catalyzed
kinetic acetylation of racemic 14c gave (R)-acetate 16 in 40%
yield along with an (S)-14c in 41% yield with >99% ee.
Although methanolysis of 16 gave (R)-14c in 99% yield with
87% ee, the enzymatic acetylation and methanolysis of the
resulted acetate were repeated to raise its ee value up to 99%.
Treatment of enantiomerically pure (S)-(-)-14c with 10 mol
% of PdCl2(CH3CN)2 in THF at room temperature for 75 min
afforded (R)-(+)-15c25 in 92% yield with 93% ee. This result
was reproducible when the reaction of (R)-(+)-14c in THF at
room temperature for 80 min gave (S)-(-)-15c in 93% yield
with 92% ee. When this reaction was carried out in CH2Cl2 at
2.1.2. Enantioselective Synthesis of (S)-(+)- and (R)-(-)-
Coniine. In view of these findings, we now focus on the
stereochemical outcome of this reaction and the related reaction
(22) Wilson, S. R.; Augelli-Szafran, C. E. Tetrahedron 1988, 44, 3983–3995.
(23) Lim, S. H.; Ma, S.; Beak, P. J. Org. Chem. 2001, 66, 9056–9062.
J. Org. Chem. Vol. 74, No. 1, 2009 247

Hande et al.
SCHEME 6. Preparation of 25a, 25b, and 27
0 °C for 30 min, (S)-(-)-15c was obtained with 91% ee. On
the other hand, catalysts can be reducible to 5 mol %. The
reaction took for 2 h in THF at rt leading to the cyclized product
in 89% yield. However, when 1 mol % of PdCl2(CH3CN)2 was
used, the reaction stopped after 3.5 h and the cyclized product
was obtained in 58% yield along with the recovery of starting
material in 39% yield. Having successfully effected the key
chirality transfer step, we then deprotected the Cbz group and
reduced the double bond of (R)-(+)-15c all in one step using
Pearlman’s catalyst under a H2 atmosphere. This gave (S)-(+)-
coniine 1a, which was then treated with HCl gas in ether to
give (S)-(+)-coniine hydrochloride in two steps with 95% yield.
(R)-(-)-Coniine 1b hydrochloride was obtained in 90% yield
from (S)-(-)-15c using the same two steps. The absolute
configurations of 1a and 1b indicated in Scheme 5 were
determined by specific degrees, which were consistent with the
data of (+)- and (-)-coniine reported in literature.2 Therefore,
the stereochemical outcome in the piperidine synthesis is similar
to that in the tetrahydropyran synthesis. Thus, in both the
reactions, the formation of the product was directed by the chiral
secondary allylic hydroxy group. However, it should be noted
that the diastereoselectivity was nearly 92-3% de (96:4 to 97:3
ratio), which meant an occurrence of 3-4% of antiazapallada-
tion. In comparison, the synthesis of the tetrahydropyran ring
was exclusively stereospecific by syn-oxypalladation.16
2.2. Stereocontrolled Synthesis of 2,6-Disubstituted
Piperidine.
The key chiral alcohols were generated by Carreira’s asym-
metric alkynylation.26 Alkynylation of cyclohexanecarboxalde-
hyde with (S)-6-sililoxy-1-heptyne 1727 in the presence of
Zn(OTf)2 and (+)-N-methylephedrine produced (R)-propargyl
alcohol 18a in 89% yield with 96% de.16b Similarly, when (-)-
N-methylephedrine was used instead of (+)-N-methylephedrine,
the diastereomer 18b was obtained in 73% yield with 94% de.
A partial reduction of 18a and 18b with Red-al followed by
benzoylation of the generated allylic alcohols 19a and 19b gave
benzoates 20a in 89% yield and 20b in 81% yield in two steps,
respectively. The O-TBS group of 20 was transformed to a
NHCOOCH3 group in 6 steps. Desilylation of 20a and 20b with
TBAF and the resultant alcohols 21a and 21b were treated with
methanesulfonyl chloride in the presence of triethylamine to
afford 22a and 22b both in 89% yield in two steps, respectively.
The SN2 displacement of the mesylate with NaN3 gave azides
23a in 94% yield and 23b in 90% yield. The reduction of azido
group in 23a was effected by PPh3 in THF/H2O, and the
produced amine was protected in situ with methyl chlorocar-
bonate in the presence of triethylamine, giving 24a in 80% yield.
A similar reaction with 23b afforded 24b in 74% yield.
Hydrolysis of benzoate by NaOH in aq. methanol gave 25a in
96% yield with 96% ee and also gave 25b in 91% yield with
94% ee, respectively. After the reduction of 23a, in situ
protection of the amine with Boc anhydride gave 26 in 85%
yield in 2 steps, and the subsequent hydrolysis of benzoate
provided 27 in 98% yield.
2.2.1. Synthesis of Precursors of Cyclization Bearing
Two Chiral Centers. Knowing the importance of solvent,
catalyst, and protecting group for this cyclization reaction, the
chemistry was developed for the synthesis of optically active
2,6-disustituted piperidines. The preparation of precursors 25a,
25b, and 27 are shown in Scheme 6.
2.2.2. Diastereoselective Synthesis of Cis and Trans
2,6-Disubstituted Piperidine Derivatives. Next, we examined
the cyclization reaction on 25a and 25b. The results are listed
(24) Hirai, Y.; Nagatsu, M. Chem. Lett. 1994, 23, 21–22.
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248 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2- and 2,6-Substituted Piperidines
TABLE 2. Synthesis of Cis and Trans 2,6-Disubstituted Piperidine Derivatives 28
entry
substratea
solvent
THF
time (h)b
product
yield (%)
de (%)c
1
2
3
4
5
6
7
25a
25a
25a
25a
25a
25b
25b
6.5
0.5
0.75
15
28a
28a
28a
28a
28a
28b
28b
81
79
75
83
68
85
82
88
49
69
82
44
86
19
CH2Cl2
ClCH2CH2Cl
toluene
CH3CN
THF
6
3.5
CH2Cl2
11d
a Compounds 25a with 96% de and 25b with 94% de were used. b Reactions were conducted at room temperature except stated otherwise. c The de
values were calculated based on H NMR spectra. d The reaction was conducted at 0 °C.
1
FIGURE 2. Plausible mechanistic and stereochemical pathway for piperidine synthesis by 1,3-chirality transfer process.
in Table 2. First, cyclization of 25a with 96% de was conducted
under the same conditions described for the synthesis of coniine.
proved to be the best for the synthesis of 2,6-disubstituted
piperidines. Using 27 bearing Boc group instead of methoxy-
carbonyl group on the nitrogen atom resulted in no reaction.
The stereochemistry of 28a and 28b was confirmed by NOE
experiments.
2.2.3. Mechanism of the Cyclization. A proposed reaction
mechanism for the PdII-catalyzed stereoselective ring formation
of piperidine by 1,3-chirality transfer is outlined in Figure 2.
Coordination of the PdII-catalyst to both the chiral allylic alcohol
and the double bond forms the palladium π-complex I, from
syn to the chiral secondary allylic alcohol.28
However, the reaction was slow and did not go to the
completion even after 24 h. When PdII-catalyst was increased
to 30 mol%, the cyclization of 25a occurred faster at room
temperature to give 28a in 81% yield with 88% de (entry 1).
The reactions of 25a were faster in halogenated solvents, CH2Cl2
or dichloroethane, and were completed in 30 and 45 min at room
temperature to give 28a in 79 and 75% yields, respectively
(entries 2 and 3). However, surprisingly, the diastereoselectivity
decreased to 49% de and 69% de. The higher selectivity with
82% de obtained in toluene (entry 4) was similar to that in THF
(entry 1). The reaction in CH3CN was not clean, resulting in a
poor yield with less selectivity (entry 5). Similarly, the reaction
of diastereomer 25b with 94% de in THF was completed in
3.5 h to give cis piperidine 28b in 85% yield with 86% de,
whereas that in CH2Cl2 was completed in 11 h at 0 °C to give
28b in 82% yield with only 19% de. It is interesting that the
formation of cis 2,6-substituted piperidine is faster than that of
trans piperidine in both solvents. Overall, the use of THF was
In the next step, a ligand exchange occurs to give complex
II, which is in an equilibrium with I. The step is important for
the chiral induction in which the nitrogen nucleophile attacks
(26) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806–1807.
(27) Drian, C. L.; Greene, A. E. J. Am. Chem. Soc. 1982, 104, 5473–5483.
(28) The possibility of anti-coordination of Pd with respect to the chiral
hydroxy group is not considered here. The argument of this possibility was
discussed well in the case of oxy-palladation reaction in the previous article.
See ref 16c.
J. Org. Chem. Vol. 74, No. 1, 2009 249

Hande et al.
in methanol (300 mL) at 0 °C. The reaction mixture was stirred at
room temperature for 1 h. The reaction was recooled to 0 °C,
quenched with water, acidified with 1N HCl to its pH between 5-6
and extracted with EtOAc. The combined organic layer was dried
over MgSO4. Evaporation of the solvent and purification of the
residue by column chromatography on silica gel eluted with 25%
EtOAc in hexane gave 7 (10.52 g, quant): colorless oil; Rf ) 0.25
the alkenyl carbon from the same side of Pd π-complex. Syn-
azapalladation gives σ-Pd intermediate III by elimination of a
HCl molecule, which on subsequent syn-elimination of Pd-
Cl(OH) delivers the major isomer (trans) in this case. Depending
on the substrate and reaction conditions, the reaction may
proceed partially through the antiazapalladation pathway from
the palladium π-complex I to give the complex IV, which on
syn-elimination of PdCl(OH) gives the minor isomer (cis) in
this case. The catalyst is regenerated by the reaction of
PdCl(OH) with HCl during the reaction sequence. The low
selectivity obtained in solvents like CH2Cl2 can be justified
based on the stability of complex II. If complex II is less stable
than complex I, the antiattack of nucleophile leading to IV (i.e.,
from the opposite side of the Pd π-complex) may take place,
which will give the minor product. When compared, the
corresponding complex II of the 2-substituted piperidine (i.e.,
R1 ) H) is more stable than the complex II of 2,6-disubstituded
piperidine (i.e., R1 ) CH3), because in the latter case it is under
more steric demand. Because of this reason, the better selectivity
was obtained in monosubstituted piperidine (Scheme 5) than
that in the 2,6-disubstituted piperidine (Table 2).
1
(10% EtOAc in hexane); H NMR (300 MHz, CDCl3) δ 5.62 (dt,
1H, J ) 15.4, 6.8 Hz), 5.50 (dd, 1H, J ) 15.4, 6.4 Hz), 4.25 (dq,
1H, J ) 6.4, 6.2 Hz), 3.60 (t, 2H, J ) 6.3 Hz), 2.02 (dt, 2H, J )
7.2, 6.8 Hz), 1.70 (br, 1H), 1.35-1.56 (m, 4H), 1.24 (d, 3H, J )
6.4 Hz), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
134.3, 130.8, 68.9, 63.0, 32.3, 31.8, 25.9, 25.4, 23.4, 18.3, -5.3;
IR (film, cm-1) 3349, 2930, 2857, 1472, 1254, 1102. MS (FAB)
m/z 281 (M + Na+); HRMS calcd for C14H30O2SiNa (M + Na+)
281.1913; Found: m/z 281.1918.
(E)-2-Benzoyloxy-8-(tert-butyldimethylsilyloxy)oct-3-ene (8).
Benzoyl chloride (9.65 mL, 83.03 mmol) was added at 0 °C to a
stirred solution of 7 (10.72 g, 41.5 mmol), Et3N (28.9 mL, 207.6
mmol) and DMAP (0.507 g, 4.15 mmol) in CH2Cl2 (250 mL). The
reaction mixture was stirred at room temperature overnight. The
reaction was quenched with H2O, and the organic layer was
separated. The aqueous layer was extracted (CH2Cl2), and the
combined organic extract was dried over MgSO4. Evaporation of
the solvent and purification of the residue by column chromatog-
raphy on silica gel eluted with 10% EtOAc in hexane gave 8 (14.96
g, 99%): colorless oil; Rf ) 0.75 (20% EtOAc in hexane); 1H NMR
(300 MHz, CDCl3) δ 8.04 (d, 2H, J ) 7.1 Hz), 7.54 (t, 1H, J )
7.1 Hz), 7.42 (t, 2H, J ) 7.1 Hz), 5.73-5.85 (m, 1H), 5.48-5.70
(m, 2H), 3.60 (t, 2H, J ) 6.2 Hz), 2.07 (dt, 2H, J ) 7.2, 7.0 Hz)
1.40-1.57 (m, 4H), 1.42 (d, 3H, J ) 6.0 Hz), 0.89 (s, 9H), 0.04
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 165.8, 133.2, 132.7, 130.9,
129.7, 129.5, 128.2, 71.7, 63.0, 32.3, 31.9, 26.0, 25.2, 20.5, 18.3,
-5.3; IR (film, cm-1) 2930, 2857, 1729, 1451, 1271, 1108; MS
(CI) m/z 363 (M + H+); HRMS calcd for C21H35O3Si (M + H+)
363.2355; Found: m/z 363.2359.
3. Conclusions
In conclusion, we have described a PdII-catalyzed intramo-
lecular cyclization of N-protected ꢀ-amino allylic alcohols
and the stereospecific synthesis of 2-substituted and 2,6-
disubstituted piperidines. The concise syntheses of (S)-(+)-
and (R)-(-)-coniine were achieved using this method. The
reaction gives a syn SN2′ product majorly through syn-
coordination of the PdII-catalyst to the allylic alcohol followed
by syn-azapalladation and syn-elimination of PdCl(OH),
leading to the product. Although the syn-azapalladation is
found to be more favored, the formation of a minor isomer
suggests that the anti-azapalladation is also plausible and it
depends upon the substrate and solvent. The reaction and its
rate suffer in a steric environment with an N-protecting group
and an alkyl group. For the formation of 2,6-disubstituted
piperidine, the reaction rate was slower than that of 2-sub-
stituted piperidine due to the steric hindrance. The reaction
in dichloromethane was generally faster as compared to other
solvents, although THF indicated higher stereoselectivity in
the case of 2,6-disubstituted piperidine. This method will
allow efficient and flexible synthesis of chiral 2- or 2,6-
substituted piperidines.
(E)-2-Benzoyloxy-8-hydroxyoct-3-ene (9). TBAF (1.0 M in
THF, 45.4 mL, 45.4 mmol) was added to a stirred solution of 8
(14.94 g, 41.24 mmol) in THF (196 mL) at room temperature. The
reaction mixture was stirred overnight. After evaporation of the
solvent, the residue was purified by column chromatography on
silica gel eluted with 50% EtOAc in hexane to give 9 (8.86 g, 87%):
1
colorless oil; Rf ) 0.25 (20% EtOAc in hexane); H NMR (300
MHz, CDCl3) δ 8.03 (dd, 2H, J ) 7.7, 1.5 Hz), 7.54 (tt, 1H, J )
7.3, 1.1 Hz), 7.42 (t, 2H, J ) 7.7 Hz), 5.78 (dt, 1H, J ) 14.3, 6.6
Hz), 5.51-5.62 (m, 2H), 3.63 (t, 2H, J ) 6.3 Hz), 2.08 (dt, 2H, J
) 7.1, 6.6 Hz), 1.44-1.62 (m, 5H), 1.42 (d, 3H, J ) 6.4 Hz); 13
C
NMR (75 MHz, CDCl3) δ 165.9, 132.9, 132.7, 130.8, 129.8, 129.5,
128.2, 71.7, 62.7, 32.1, 31.8, 25.0, 20.5; IR (film, cm-1) 3374, 2933,
2861, 1716, 1451, 1273, 1111; MS (CI) m/z 249 (M + H+); HRMS
calcd for C15H21O3 (M + H+) 249.1491; Found: m/z 249.1493.
(E)-2-Benzoyloxy-8-(methanesulfonyloxy)oct-3-ene (10). MsCl
(5.5 mL, 71.2 mmol) was added to a stirred solution of 9 (8.44 g,
35.61 mmol) and Et3N (24.8 mL, 178.1 mmol) in CH2Cl2 (200
mL) at 0 °C. The reaction mixture was stirred for 30 min at room
temperature. The reaction was then quenched with H2O, and the
organic layer was separated. The aqueous layer was extracted
(CH2Cl2), and the combined organic layer was dried over MgSO4.
Filtration and evaporation of the solvent and purification of the
residue by column chromatography on silica gel eluted with 30%
EtOAc in hexane gave 10 (11.52 g, 99%): colorless oil; Rf ) 0.25
4. Experimental Section
(E)-8-(tert-Butyldimethylsilyloxy)oct-3-en-2-one (6). 1-(Triph-
enylphosphoranylidene)-2-propanone (17 g, 53.37 mmol) was added
to a solution of aldehyde 5 (10.5 g, 48.52 mmol) in toluene (240
mL), and the reaction mixture was stirred at 80 °C for 15 h.
Evaporation of the solvent and purification of the residue by column
chromatography on silica gel eluted with 10% EtOAc in hexane
gave 6 (10.62 g, 85%): colorless oil; Rf ) 0.28 (10% EtOAc in
1
hexane); H NMR (300 MHz, CDCl3) δ 6.78 (dt, 1H, J ) 16.0,
6.8 Hz), 6.05 (dt, 1H, J ) 16.0, 1.5 Hz), 3.60 (m, 2H), 2.22 (s,
3H), 2.17-2.25 (m, 2H), 1.40-1.59 (m, 4H), 0.87 (s, 9H), 0.02
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 198.6, 148.2, 131.3, 62.6,
32.2, 32.1, 26.8, 25.9, 24.4, 18.3, -5.4; IR (film, cm-1) 2930, 2854,
1677, 1253, 1100; MS (CI) m/z 257 (M + H+); HRMS calcd for
C14H29O2Si (M + H+) 257.1937; Found: m/z 257.1931.
1
(20% EtOAc in hexane); H NMR (300 MHz, CDCl3) δ 8.04 (d,
2H, J ) 7.2 Hz), 7.55 (t, 1H, J ) 7.3 Hz), 7.43 (t, 2H, J ) 7.3
Hz), 5.75 (dt, 1H, J ) 14.5, 6.7 Hz), 5.52-5.63 (m, 2H), 4.22 (t,
2H, J ) 6.4 Hz), 2.99 (s, 3H), 2.00 (dt, 2H, J ) 7.2, 6.7 Hz),
1.70-1.80 (m, 2H), 1.47-1.57 (m, 2H), 1.42 (d, 3H, J ) 6.2 Hz);
13C NMR (75 MHz, CDCl3) δ 165.8, 132.8, 132.1, 130.7, 130.5,
(E)-8-(tert-Butyldimethylsilyloxy)oct-3-en-2-ol (7). NaBH4 (2.31
g, 61.1 mmol) was added in small portions to a stirred solution of
6 (10.45 g, 40.75 mmol) and CeCl3 ·7H2O (15.18 g, 40.75 mmol)
129.5, 128.3, 71.5, 69.8, 37.4, 31.4, 28.5, 24.7, 20.5; IR (film, cm-1
)
250 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2- and 2,6-Substituted Piperidines
2938, 1714, 1451, 1274, 1112; MS (FAB) m/z 349 (M + Na+);
HRMS calcd for C16H22O5SNa (M + Na+) 349.1086; Found: m/z
349.1091.
6.7 Hz), 5.29 (dq, 1H, J ) 6.7, 6.4 Hz), 5.09 (s, 2H), 4.85 (br,
1H), 3.18 (q, 2H, J ) 6.4), 2.02 (s, 3H), 1.98-2.07 (m, 2H),
1.39-1.49 (m, 4H), 1.28 (d, 3H, J ) 6.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 170.3, 156.3, 136.5, 132.5, 129.9, 128.4, 128.0 (2C), 71.0,
66.5, 40.8, 31.6, 29.3, 25.9, 21.3, 20.3; IR (film, cm-1) 3346, 2934,
1730, 1532, 1243, 1136; MS (FAB) m/z 342 (M + Na+); HRMS
calcd for C18H25NO4Na (M + Na+) 342.1681; Found: m/z 342.1676.
This optically pure (R)-acetate was hydrolyzed again to give pure
(R)-14c in 98% yield with 99% ee.; [R]2D4 +1.7 (c 0.53, CHCl3).
Preparation of (R)-15c and (S)-15c. The reaction was performed
by the general procedure for PdII-catalyzed cyclization. Compound
(R)-15c25 was obtained from (S)-14c in 92% yield with 93% ee;
colorless oil; [R]2D2 +37.3 (c 0.72, CHCl3). Rf ) 0.74 (40% EtOAc
(E)-8-Azido-2-benzoyloxy-oct-3-ene (11). A mixture of 10 (11.5
g, 35.23 mmol) and sodium azide (6.87 g, 105.7 mmol) in dry DMF
(120 mL) was stirred at room temperature for 24 h. After a removal
of DMF under vaccum, water was added and the mixture was
extracted with EtOAc. The extract was dried over MgSO4.
Evaporation of the solvent and purification of the residue by column
chromatography on silica gel eluted with 10% EtOAc in hexane
gave 11 (8.83 g, 92%): colorless oil; Rf ) 0.77 (20% EtOAc in
hexane); 1H NMR (300 MHz, CDCl3) δ 8.05 (dd, 2H, J ) 7.3, 1.5
Hz), 7.55 (tt, 1H, J ) 7.3, 1.5 Hz), 7.43 (dt, 2H, J ) 7.3, 1.5 Hz),
5.77 (dt, 1H, J ) 14.5, 6.8 Hz), 5.52-5.64 (m, 2H), 3.26 (t, 2H, J
) 6.7 Hz), 2.08 (dt, 2H, J ) 7.2, 6.8 Hz), 1.56-1.63 (m, 2H),
1.44-1.52 (m, 2H), 1.43 (d, 3H, J ) 6.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 165.8, 132.7, 132.4, 130.8, 130.2, 129.5, 128.3, 71.5,
51.3, 31.6, 28.3, 26.0, 20.5; IR (film, cm-1) 2935, 1716, 1451, 1271,
1110; MS (CI) m/z 274 (M + H+); HRMS calcd for C15H20N3O2
(M + H+) 274.1555; Found: m/z 274.1554.
1
in hexane); H NMR (300 MHz, CDCl3) δ 7.25-7.35 (m, 5H),
5.41-5.58 (m, 2H), 5.13 (q, 2H, J )12.3 Hz), 4.82 (br s, 1H),
4.01 (d, 1H, J ) 12.8 Hz), 2.91 (dt, 1H, J ) 12.8, 2.7 Hz), 1.68
(dd, 3H, J ) 4.6, 1.5 Hz), 1.37-1.69 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 155.6, 137.0, 129.0, 128.3, 127.7, 127.6, 126.8, 66.8,
52.1, 39.9, 29.3, 25.5, 19.3, 17.7; IR (film, cm-1) 2936, 2857, 1697,
1497, 1255, 1171; MS (EI) m/z 259 (M+); HRMS calcd for
C16H21NO2 (M+) 259.1572; Found: m/z 259.1578. Compound (S)-
15c was obtained from (R)-14c in 93% yield with 92% ee; colorless
oil, [R]2D2 -38.2 (c 0.62, CHCl3). These enantiomeric purities were
determined by chiral HPLC, the details for which are described in
the Supporting Information.
Synthesis of Coniines 1a and 1b Hydrochlorides. A mixture
of (R)-15c (96 mg, 0.3 mmol) and Pd(OH)2/C (8 mg) in methanol
(10 mL) was stirred under H2 atmosphere at room temperature for
24 h. The reaction mixture was then filtered through a ceilite bed.
Then, HCl gas was bubbled into the obtained filtrate. Evaporation
of the solvent gave the corresponding coniine hydrochloride, (S)-
(+)-Coniine 1a hydrochloride, in 95% yield in two steps. White
solid; [R]2D1 +7.1 (c 1.00, EtOH); colorless crystals, mp 214-216
°C (methanol), lit.2d mp 213-215 °C; 1H NMR (300 MHz, CDCl3)
δ 9.48 (br s, 1H), 9.18 (br s, 1H), 3.44 (d, 1H, J ) 10.5 Hz), 2.93
(br s, 1H), 2.83 (br s, 1H), 1.62-1.96 (m, 7H), 1.37-1.52 (m, 3H),
0.94 (t, 3H, J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 57.2, 44.8,
35.3, 28.2, 22.4, 22.2, 18.6, 13.7; MS (EI) m/z 127 (M+); HRMS
calcd for C8H17N (M+) 127.1361; Found: m/z 127.1357. (R)-(-)-
Coniine 1b hydrochloride. HCl was obtained from (S)-15c in 90%
yield in two steps. White solid; [R]2D1 -6.3 (c 1.00, EtOH); colorless
crystals, mp 218-220 °C (methanol); MS (EI) m/z 127 (M+);
HRMS calcd for C8H17N (M+) 127.1361; Found: m/z 127.1353.
(1S,7S)-7-(tert-Butyldimethylsilyloxy)-1-cyclohexyloct-2-yn-1-
ol (18b). Et3N (0.257 mL, 1.8 mmol) was added in one portion to
a stirred suspension of Zn(OTf)2 (618 mg, 1.65 mmol, predried
overnight at 125 °C under vacuum) and (-)-N-methylephedrine
(332 mg, 1.8 mmol) in dry toluene (4.9 mL). After the white slurry
was stirred at room temperature for 3 h, alkyne 17 (350 mg, 1.5
mmol) was added. The mixture was stirred for 30 min and then
treated with freshly distilled cyclohexanecarboxaldehyde (173 mg,
1.5mmol). After the mixture was stirred for 3 h at room temperature,
a saturated NH4Cl solution was added to the mixture, and the
aqueous layer was extracted (EtOAc). After filtration and evapora-
tion of the solvent, the residue was purified by column chroma-
tography on silica gel eluted with 5% of EtOAc in hexane to give
product 18b (382 mg, 73%): colorless oil; [R]2D3 +11.6 (c 1.08,
CHCl3) (>94% de, based on chiral HPLC); Rf ) 0.32 (10% EtOAc
in hexane); 1H NMR (300 MHz, CDCl3) δ 4,13 (br, 1H), 3.81 (qt,
1H, J ) 6.0, 5.5 Hz), 2.19-2.24 (m, 2H), 1.43-1.85 (m, 10H),
1.13 (d, 3H, J ) 6.0 Hz), 1.02-1.26 (m, 5H), 0.88 (s, 9H), 0.05
(s, 6H); 13C NMR (75 MHz, CDCl3) δ 86.2, 80.3, 68.2, 67.4, 44.4,
38.8, 28.6, 28.1, 26.4, 25.9, 25.9, 25.0, 23.8, 23.7, 18.8, 18.1, -4.4,
-4.7; IR (film, cm-1) 3367, 2927, 1450, 1374, 1254, 1186, 1136,
1023, 892, 835, 774; MS (FAB) m/z 361 (M + Na+). HRMS calcd
for C20H38O2SiNa (M + Na+): 361.2539; Found: m/z 361.2544.
The enantiomeric purities were determined by chiral HPLC, the
details for which are described in the Supporting Information.
(E)-8-Amino-2-benzoyloxy-oct-3-ene (12). A mixture of 11 (4
g, 12.8 mmol) and triphenylphosphine (7.68 g, 25.61 mmol) in H2O
(6 mL) and THF (120 mL) was stirred at room temperature for
24 h. Evaporation of solvents and purification of the residue by
column chromatography on silica gel eluted with 20% MeOH in
chloroform gave 12 (3.34 g, 92%): colorless oil; Rf ) 0.33 (10%
1
MeOH in chloroform); H NMR (300 MHz, CDCl3) δ 8.04 (dd,
2H, J ) 7.1, 1.3 Hz), 7.54 (tt, 1H, J ) 7.3, 1.3 Hz), 7.42 (dt, 2H,
J ) 7.1, 1.3 Hz), 5.78 (dt, 1H, J ) 14.5, 6.6 Hz), 5.30-5.63 (m,
2H), 2.69 (t, 2H, J ) 6.6 Hz), 2.06 (dt, 2H, J ) 6.8, 6.6 Hz), 1.88
(br s, 2H), 1.42 (d, 3H, J ) 6.0 Hz), 1.40-1.57 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 165.8, 133.0, 132.7, 130.8, 129.8, 129.5, 128.2,
71.7, 41.8, 32.8, 31.9, 26.2, 20.5; IR (film, cm-1) 3370, 2979, 1715,
1451, 1272, 1111; MS (EI) m/z 247 (M+); HRMS calcd for
C15H21NO2 (M+) 247.1572; Found: m/z 247.1577.
General Procedure for PdII-Catalyzed Cyclization. A mixture
of precursor 14a-f (0.1 mmol) and PdCl2(CH3CN)2 (10 or 20 mol
%) was stirred in dry solvent (2.5 mL) at 0 °C to room temperature.
Evaporation of the solvent and purification of the residue by column
chromatography on silica gel eluted with 10% EtOAc in hexane
gave the corresponding 15a-f. The chemical yields and their
characteristic data are indicated in Table 1 and in the Supporting
Information.
Lipase Catalyzed Kinetic Acetylation of Racemic 14c. MS 4
Å (1.78 g), Novozyme 435 (0.45 g), and vinyl acetate (3.04 mL,
44.55 mmol) were added to a solution of 14c (1.5 g, 8.91 mmol)
in diisopropyl ether (175 mL) at room temperature. The mixture
was stirred for 20 h and filtered through a celite pad. The filtrate
was condensed, and the residue was purified by column chroma-
tography on silica with 15% EtOAc in hexane as an eluent to give
(S)-14c (621 mg, 41%) with 99% ee and with 25% EtOAc in hexane
as an eluent to give 16 (811 mg, 40%) with 87% ee. Compound
(S)-14c: amorphous solid, mp 28-29 °C; [R]2D3 -2.9 (c 0.51,
CHCl3); other spectroscopic data were all matched with those in
racemic 14c described above. The enantiomeric purities were
determined by chiral HPLC, the details for which are described in
the Supporting Information.
Preparation of (R)-14c. A solution of 16 (811 mg, 2.54 mmol)
with 87% ee in methanol (20 mL) and aq. K2CO3 (702 mg, 5.08
mmol) in H2O (1 mL) was stirred overnight at room temperature.
After removal of solvent under vaccum, water was added to the
residue and the mixture was extracted with EtOAc. The organic
layer was dried over MgSO4 and purified by column chromatog-
raphy on silica gel eluted with 50-60% EtOAc in hexane to give
(R)-14c (695 mg, 99%) with 87% ee. This was subjected to the
above lipase catalyzed kinetic acetylation to give 16 in 84% yield
with 99% ee: colorless oil; [R]2D0 +38.0 (c 0.2, CHCl3): Rf ) 0.65
(40% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 7.26-7.36
(m, 5H), 5.65 (dt, 1H, J ) 15.2, 6.6 Hz), 5.45 (dd, 1H, J ) 15.2,
J. Org. Chem. Vol. 74, No. 1, 2009 251

Hande et al.
(E,1S,7S)-7-(tert-Butyldimethylsilyloxy)-1-cyclohexyloct-2-en-1-
ol (19b). Red-al (70% in toluene solution, 1.27 mL, 4.37 mmol)
was added to a solution of 18b (370 mg, 1.09 mmol) in THF (39
mL). The mixture was refluxed for 2 h, quenched with a saturated
NH4Cl and was extracted with EtOAc. The extract was dried over
MgSO4 and evaporated. The residue was purified by column
chromatography on silica gel eluted with 5% of EtOAc in hexane
gave 19b (311 mg, 84%): colorless oil [R]2D3 +8.90 (c 1.10, CHCl3);
Rf ) 0.32 (10% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ
5.59 (dt, 1H, J ) 15.4, 6.6 Hz), 5.45 (dd, 1H, J ) 15.4, 7.3 Hz),
3.78 (m, 2H), 2.03 (m, 2H), 1.63-1.87 (m, 5H), 1.31-1.51 (m,
6H), 1.11 (d, 3H, J ) 6.0 Hz), 0.95-1.24 (m, 5H), 0.88 (s, 9H),
0.04 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 132.8, 131.6, 77.7,
68.4, 43.7, 39.2, 32.2, 28.8, 28.7, 26.5, 26.1, 26.0, 25.9, 25.4, 23.8,
18.1, -4.4, -4.7; IR (film, cm-1) 3366, 2927, 2855, 1450, 1374,
1254, 1135, 1005, 891, 835, 774; MS (FAB) m/z 363 (M + Na+).
HRMS calcd for C20H40O2SiNa (M + Na+): 363.2696; Found: m/z
363.2689.
Benzoylation of 19. Et3N (1.08 mL, 7.79 mmol), DMAP (9.5 mg,
0.078 mmol), and benzoyl chloride (0.271 mL, 2.34 mmol) were
succesively added to a stirred solution of 19a16b (265 mg, 0.78 mmol)
in CH2Cl2 (15 mL) at 0 °C. The reaction mixture was stirred at room
temperature for 14 h and was quenched with water. The mixture was
extracted with CH2Cl2, and the extract was dried over MgSO4.
Evaporation of the solvent and purification of the residue by column
chromatography on silica gel eluted with 3% EtOAc in hexane gave
20a (337 mg; 98%): colorless oil; [R]2D3 -3.53 (c 0.65, CHCl3); Rf )
0.5 (5% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.06 (dd,
2H, J ) 7.8, 1.5 Hz), 7.54 (tt, 1H, J ) 7.3, 1.5 Hz), 7.43 (dt, 2H, J )
7.8, 7.3 Hz), 5.76 (dt, 1H, J ) 15.2, 6.4 Hz), 5.49 (dd, 1H, J ) 15.2,
7.7 Hz), 5.26 (dd, 1H, J ) 7.2, 6.9 Hz), 3.77 (m, 1H), 2.05 (m, 2H),
1.65-1.85 (m, 5H), 1.04-1.53 (m, 10H), 1.09 (d, 3H, J ) 6.0 Hz),
0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 165.8, 135.1, 132.6, 130.9, 129.5, 128.3, 126.8, 79.5, 68.4, 42.0,
39.1, 32.2, 28.8, 28.7, 26.4, 26.0, 25.9, 25.8, 25.2, 23.8, 18.1, -4.4,
-4.7; IR (film, cm-1) 2928, 2855, 1719, 1270, 1109; MS (FAB) m/z
467 (M + Na+). HRMS calcd for C27H44O3SiNa (M + Na+):
467.2958; Found: m/z 467.2963. The diastereoisomer 20b was obtained
from 19b in 97% yield: colorless oil; [R]2D3 +11.00 (c 1.29, CHCl3);
Rf ) 0.5 (5% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.06
(dd, 2H, J ) 7.7, 1.5 Hz), 7.54 (m, 1H), 7.43 (t, 2H, J ) 7.7 Hz),
5.76 (dt, 1H, J ) 15.2, 6.8 Hz), 5.49 (dd, 1H, J ) 15.2, 7.7 Hz), 5.27
(dd, 1H, J ) 7.2, 7.0 Hz), 3.75 (m, 1H), 2.04 (m, 2H), 1.60-1.81 (m,
5H), 1.31-1.51 (m, 5H), 1.04-1.26 (m, 5H), 1.11 (d, 3H, J ) 6.0
Hz), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 165.8, 135.1, 132.7, 132.6, 129.4, 129.5, 128.3, 128.2, 126.9,
79.5, 68.4, 42.0, 39.1, 32.2, 28.7, 28.6, 26.4, 26.0, 25.9, 25.8, 25.2,
23.8, 18.1, -4.4, -4.8; IR (film, cm-1) 2928, 2855, 1720, 1272, 1109;
MS (FAB) m/z 467 (M + Na+). HRMS calcd for C27H44O3SiNa (M
+ Na+): 467.2958; Found: m/z 467.2965.
Deprotection of TBDMS Ether of 20. A mixture of 20a (322
mg, 0.72 mmol) and TBAF (1.0 M in THF, 5.73 mL, 5.79 mmol)
in THF (8 mL) was stirred at room temperature overnight. After
evaporation of the solvent, the residue was purified by column
chromatography on silica gel eluted with ether to give 21a (230
mg, 96%): colorless oil; [R]2D4 -9.07 (c 0.65, CHCl3); Rf ) 0.33
(40% Et2O in hexane); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 2H,
J ) 7.0 Hz), 7.53 (t, 1H, J ) 7.3 Hz), 7.43 (t, 2H, J ) 7.0 Hz),
5.75 (dt, 1H, J ) 15.4, 6.8 Hz), 5.49 (dd, 1H, J ) 15.4, 7.5 Hz),
5.24 (dd, 1H, J ) 7.3, 7.0 Hz), 3.77 (m, 1H), 2.07 (m, 2H),
1.64-1.84 (m, 6H), 1.16 (d, 3H, J ) 6.2 Hz), 0.86-1.52 (m, 10H);
13C NMR (75 MHz, CDCl3) δ 165.8, 134.8, 132.6, 130.8, 129.5,
128.2, 127.0, 79.5, 67.8, 41.8, 38.7, 32.2, 28.7, 28.6, 26.3, 25.8,
25.9, 25.1, 23.4; IR (film, cm-1) 3387, 2927, 2854, 1716, 1272,
1112; MS (FAB) m/z 331 (M + H+). HRMS calcd for C21H31O3
(M + H+): 331.2273; Found: m/z 331.2265. The diastereoisomer
21b was obtained from 20b in quantitative yield: colorless oil; [R]2D2
+13.2 (c 1.05, CHCl3); Rf ) 0.33 (40% Et2O in hexane); 1H NMR
(300 MHz, CDCl3) δ 8.05 (d, 2H, J ) 7.0 Hz), 7.54 (t, 1H, J )
7.3 Hz), 7.42 (t, 2H, J ) 7.0 Hz), 5.75 (dt, 1H, J ) 15.4, 6.8 Hz),
5.49 (dd, 1H, J ) 15.4, 7.5 Hz), 5.24 (dd, 1H, J ) 7.3, 7.0 Hz),
3.78 (m, 1H), 2.07 (m, 2H), 1.49-1.85 (m, 6H), 1.16 (d, 3H, J )
6.2 Hz), 0.86-1.46 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 165.8,
134.8, 132.6, 130.8, 129.5, 128.2, 127.0, 79.5, 67.8, 41.9, 38.7,
32.2, 28.7, 28.6, 26.4, 25.9, 25.8, 25.0, 23.4; IR (film, cm-1) 3385,
2928, 2854, 1718, 1271, 1111; MS (FAB) m/z 331 (M + H+).
HRMS calcd for C21H31O3 (M + H+): 331.2273; Found: m/z
331.2266.
Mesylation of Alcohol 21. MsCl (0.34 mL, 4.4 mmol) was added
to a stirred solution of 21a (940 mg, 2.93 mmol) and Et3N (1.22
mL, 8.8 mmol) in CH2Cl2 (69 mL) at 0 °C. The mixture was stirred
for 30 min at room temperature and then poured into water and
extracted with CH2Cl2. The extract was dried over MgSO4.
Evaporation of the solvent and purification of the residue by column
chromatography on silica gel eluted with 10% EtOAc in hexane
gave 22a (1.08 g; 93%): colorless oil; [R]2D3 -8.26 (c 0.52, CHCl3);
1
Rf ) 0.41 (40% Et2O in hexane); H NMR (300 MHz, CDCl3) δ
8.05 (dd, 2H, J ) 7.2, 1.5 Hz), 7.54 (tt, 1H, J ) 7.5, 1.5 Hz), 7.43
(dt, 2H, J ) 7.5, 7.2 Hz), 5.72 (dt, 1H, J ) 15.4, 6.8 Hz), 5.50
(dd, 1H, J ) 15.4, 7.3 Hz), 5.24 (dd, 1H, J ) 7.2, 7.0 Hz), 4.78
(tq, 1H, J ) 6.4, 5.8 Hz), 2.96 (s, 3H) 2.09 (m, 2H,), 1.42-1.85
(m, 10H), 1.39 (d, 3H, J ) 6.4 Hz), 1.03-1.40 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 165.8, 133.9, 132.7, 130.8, 129.5, 128.3, 127.7,
79.9, 79.3, 41.8, 38.6, 35.9, 31.7, 28.8, 28.6, 26.3, 25.9, 25.8, 24.3,
21.1; IR (film, cm-1) 2930, 2854, 1714, 1272, 1112; MS (FAB)
m/z 409 (M + H+). HRMS calcd for C22H33O5S (M + H+):
409.2048; Found: m/z 409.2040. Diastereoisomer 22b was obtained
from 21b in 89% yield: colorless oil; [R]2D2 +14.7 (c 1.03, CHCl3);
1
Rf ) 0.41 (40% Et2O in hexane); H NMR (300 MHz, CDCl3) δ
8.05 (dd, 2H, J ) 7.1, 1.5 Hz), 7.54 (tt, 1H, J ) 7.5, 1.5 Hz), 7.43
(dt, 2H, J ) 7.5, 7.1 Hz), 5.72 (dt, 1H, J ) 15.4, 6.6 Hz), 5.51
(dd, 1H, J ) 15.4, 7.5 Hz), 5.24 (dd, 1H, J ) 7.2, 7.0 Hz), 4.78
(tq, 1H, J ) 6.2, 5.5 Hz), 2.96 (s, 3H) 2.09 (m, 2H,), 1.37-1.85
(m, 10H), 1.39 (d, 3H, J ) 6.2 Hz), 1.03-1.25 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 165.8, 134.0, 132.7, 130.8, 129.5, 128.3, 127.7,
79.9, 79.3, 41.8, 38.6, 35.9, 31.7, 28.8, 28.6, 26.3, 25.9, 25.8, 24.3,
21.1; IR (film, cm-1) 2929, 2854, 1714, 1272, 1112; MS (FAB)
m/z 431 (M + Na+). HRMS calcd for C22H33O5SNa (M + Na+):
431.1868; Found: m/z 431.1861.
Substitution of Methanesulfonate with Azide. A mixture of
22a (1.036 g, 2.53 mmol) and sodium azide (989 mg, 15.22 mmol)
was stirred in dry DMF (25 mL) at room temperature for 24 h.
After removal of DMF under vaccum, water was added and the
mixture was extracted with EtOAc. The extract was dried on MgSO4
and condensed. The residue was purified by column chromatography
on silica gel eluted with 5% ether in hexane to give 23a (847 mg;
94%): colorless oil; [R]D23 -35.2 (c 1.14, CHCl3); Rf ) 0.66 (10%
EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.06 (dd, 2H, J
) 7.0, 1.5 Hz), 7.55 (tt, 1H, J ) 7.3, 1.5 Hz), 7.44 (dt, 2H, J )
7.3, 7.0 Hz), 5.74 (dt, 1H, J ) 15.2, 6.8 Hz), 5.50 (dd, 1H, J )
15.2, 7.5 Hz), 5.26 (dd, 1H, J ) 7.3, 7.0 Hz), 3.42 (m, 1H), 2.08
(m, 2H,), 1.40-1.85 (m, 10H), 1.23 (d, 3H, J ) 6.6 Hz), 1.04-1.28
(m, 5H); 13C NMR (75 MHz, CDCl3) δ 165.8, 134.3, 132.7, 130.8,
129.5, 128.3, 127.4, 79.4, 57.7, 41.9, 35.5, 31.9, 28.8, 28.6, 26.4,
25.9, 25.8, 25.3, 19.4; IR (film, cm-1) 2928, 2854, 1716, 1270,
1111; MS (FAB) m/z 378(M + Na+). HRMS calcd for
C21H29N3O2Na (M + Na+): 378.2157; Found: m/z 378.2163.
Diastereomer 23b was obtained from 22b in 90% yield: colorless
oil; [R]2D4 -7.8 (c 1.00, CHCl3); Rf ) 0.66 (10% EtOAc in hexane);
1H NMR (300 MHz, CDCl3) δ 8.07 (dd, 2H, J ) 7.0, 1.5 Hz),
7.55 (tt, 1H, J ) 7.3, 1.5 Hz), 7.44 (dt, 2H, J ) 7.3, 7.0 Hz), 5.75
(dt, 1H, J ) 15.4, 6.6 Hz), 5.50 (ddt, 1H, J ) 15.4, 7.5, 1.2 Hz),
5.26 (dd, 1H, J ) 7.2, 7.0 Hz), 3.42 (m, 1H), 2.08 (m, 2H,),
1.38-1.86 (m, 10H), 1.23 (d, 3H, J ) 6.6 Hz), 1.04-1.27 (m,
5H); 13C NMR (75 MHz, CDCl3) δ 165.8, 134.3, 132.7, 130.8,
129.5, 128.3, 127.4, 79.4, 57.7, 41.9, 35.5, 31.9, 28.8, 28.6, 26.4,
25.9, 25.8, 25.3, 19.4; IR (film, cm-1) 2929, 2854, 1717, 1270,
1111; MS (FAB) m/z 378 (M + Na+). HRMS calcd for
C21H29N3O2Na (M + Na+): 378.2157; Found: m/z 378.2164.
252 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 2- and 2,6-Substituted Piperidines
Preparation of 24a and 24b. Triphenylphosphine (885 mg, 3.37
mmol) and H2O (0.45 mL) were added to a stirred solution of 23a
(300 mg, 0.84 mmol) in THF (22 mL), and the reaction was stirred
for 30 h at room temperature. Solvent was removed and the residue
was dried under high vaccum. The residue was then dissolved in
CH2Cl2 (10 mL), and methyl chloroformate (0.13 mL, 1.68 mmol)
and Et3N (0.45 mL, 3.37 mmol) were added at 0 °C. After the addition,
it was allowed to warm to room temperature and was stirred for an
additional 1 h. Evaporation of the solvent and purification of the residue
by column chromatography on silica gel eluted with 5% EtOAc in
hexane gave 24a (244 mg; 80%): colorless oil; [R]2D4 -8.78 (c 1.07,
1H NMR (300 MHz, CDCl3) δ 5.70 (dt, 1H, J ) 15.4, 6.2 Hz),
5.46 (dd, 1H, J ) 15.4, 7.1 Hz), 4.45(br, 1H), 3.75 (t, 1H, J ) 6.8
Hz), 3.67 (br, 1H), 3.64 (br s, 3H), 2.05 (m, 2H,), 1.63-1.85 (m,
7H), 1.34-1.46 (m, 5H), 1.16-1.32 (m, 4H), 1.12 (d, 3H, J ) 6.6
Hz),; 13C NMR (75 MHz, CDCl3) δ 156.4, 132.2, 132.1, 77.5, 51.8,
46.7, 43.6, 36.4, 31.8, 28.8, 28.7, 26.5, 26.1, 26.0, 25.3, 21.1; IR
(film, cm-1) 3325, 2924, 1698, 1537, 1256, 1085; MS (FAB) m/z
306 (M + Na+). HRMS calcd for C16H29NO3Na (M + Na+):
306.2045; Found: m/z 306.2041.
Compound 25b. was obtained from 24b in 91% yield; colorless
oil [R]2D6 +8.2 (c 1.26, CHCl3); Rf ) 0.16 (25% EtOAc in hexane);
1H NMR (300 MHz, CDCl3) δ 5.70 (dt, 1H, J ) 15.2, 6.2 Hz),
5.46 (dd, 1H, J ) 15.2, 7.0 Hz), 4.48 (br, 1H), 3.75 (t, 1H, J ) 6.8
Hz), 3.68 (br, 1H), 3.64 (br s, 3H), 2.04 (m, 2H,), 1.54-1.86 (m,
6H), 1.12 (d, 3H, J ) 6.6 Hz), 1.12-1.40 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 156.4, 132.2, 132.0, 77.5, 51.8, 46.9, 43.6, 36.6,
32.0, 28.8, 28.6, 26.5, 26.1, 26.0, 25.4, 21.2; IR (film, cm-1) 3324,
2924, 1698, 1537, 1256, 1085; MS (FAB) m/z 306(M + Na+).
HRMS calcd for C16H29NO3Na (M + Na+): 306.2045; Found: m/z
306.2054.
Compound 27. was obtained from 26 in 98% yield; colorless
oil [R]2D3 -3.78 (c 0.95, CHCl3); Rf ) 0.18 (25% EtOAc in hexane);
1H NMR (300 MHz, CDCl3) δ 5.55 (dt, 1H, J ) 15.2, 6.2 Hz),
5.44 (dd, 1H, J ) 15.2, 7.1 Hz), 4.33 (br, 1H), 3.73 (t, 1H, J ) 6.8
Hz), 3.62 (br, 1H), 2.02 (m, 2H,), 1.62-1.85 (m, 6H), 1.41 (s, 9H),
1.29-1.47 (m, 6H), 1.07 (d, 3H, J ) 6.6 Hz), 0.87-1.22 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 155.3, 132.3, 132.0, 78.9, 77.5, 46.0,
43.6, 36.6, 31.9, 28.7, 28.7, 28.3, 26.5, 26.1, 26.0, 25.4, 21.1; IR
(film, cm-1) 3343, 2926, 1693, 1527, 1248, 1078; MS (FAB) m/z
326 (M + H+). HRMS calcd for C19H36NO3 (M + H+): 326.2695;
Found: m/z 326.2702.
Pd(II)-Catalyzed Cyclization. A mixture of 25 (20 mg, 0.064
mmol) and PdCl2(CH3CN)2 (5.6 mg, 0.021 mmol) was stirred in
THF (1.6 mL) at room temperature for 6.5 h. After removal of the
solvent, the residue was purified by column chromatography on
silica gel eluted with 5% EtOAc in hexane to give 28. Compound
28a was obtained from 25a in 81% yield: colorless oil; [R]2D5 -31.11
(c 1.26, CHCl3); Rf ) 0.77 (20% EtOAc in hexane); 1H NMR (300
MHz, CDCl3) δ 5.42 (m, 2H), 4.41(m, 1H), 4.03 (m, 1H), 3.67 (s,
3H), 1.87-1.97(m, 2H), 1.40-1.80 (m, 10H), 1.23 (d, 3H, J )
6.8 Hz), 0.99-1.32 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 156.5,
135.8, 128.8, 52.6, 52.0, 47.5, 40.3, 32.9, 32.8, 29.7, 26.5, 26.2,
26.0, 25.7, 20.6, 13.8.; IR (film, cm-1) 2924, 2852, 1698, 1445,
1360; MS (EI+) m/z 265(M+). HRMS calcd for C16H27NO2 (M+):
265.2042; Found: m/z 265.2037. Compound 28b was obtained from
25b in 85% yield: colorless oil; [R]2D4 +17.4 (c 0.78, CHCl3); Rf )
0.77 (20% EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 5.47
(m, 2H), 4.70(m, 1H), 4.35 (m, 1H), 3.69 (s, 3H), 1.49-1.76 (m,
9H), 1.14 (d, 3H, J ) 6.9 Hz), 0.99-1.35 (m, 8H); 13C NMR (75
MHz, CDCl3) δ 156.5, 136.4, 128.9, 52.3, 50.9, 46.4, 40.5, 32.8,
32.7, 30.2, 29.7, 28.2, 26.2, 26.0, 20.5, 14.2; IR (film, cm-1) 2924,
2852, 1698, 1443, 1360; MS (FAB) m/z 266 (M+H+). HRMS calcd
for C16H28NO2 (M+H+): 266.2120; Found: m/z 266.2113.
1
CHCl3); Rf ) 0.37 (25% EtOAc in hexane); H NMR (300 MHz,
CDCl3) δ 8.05 (d, 2H, J ) 7.0 Hz), 7.53 (t, 1H, J ) 7.3 Hz), 7.42 (t,
2H, J ) 7.7 Hz), 5.72 (dt, 1H, J ) 15.4, 6.6 Hz), 5.48 (dd, 1H, J )
15.4, 7.7 Hz), 5.24 (dd, 1H, J ) 7.2, 7.0 Hz), 4.45 (br, 1H), 3.64 (br,
1H), 3.62 (br s, 3H), 2.03 (m, 2H,), 1.64-1.84 (m, 6H), 1.40 (m, 4H),
1.16-1.25 (m, 5H), 1.10 (d, 3H, J ) 6.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 165.9, 156.4, 134.5, 132.7, 130.9, 129.5, 128.3, 127.3, 79.5,
51.8, 46.9, 41.9, 36.5, 32.0, 28.8, 28.6, 26.4, 26.0, 25.9, 25.3, 21.3; IR
(film, cm-1) 3339, 2929, 2854, 1714, 1530, 1271, 1111; MS (FAB)
m/z 388 (M + H+). HRMS calcd for C23H34NO4 (M + H+): 388.2488;
Found: m/z 388.2483. Diastereisomer 24b was obtained from 23b in
74% yield: colorless oil; [R]2D3 +18.5 (c 0.53, CHCl3); Rf ) 0.37 (25%
EtOAc in hexane); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, 2H, J )
7.0 Hz), 7.54 (t, 1H, J ) 7.5 Hz), 7.43 (t, 2H, J ) 7.7 Hz), 5.72 (dt,
1H, J ) 15.4, 6.6 Hz), 5.48 (dd, 1H, J ) 15.4, 7.7 Hz), 5.23 (dd, 1H,
J ) 7.2, 7.0 Hz), 4.48 (br, 1H), 3.66 (br, 1H), 3.64 (br s, 3H), 2.05
(m, 2H,), 1.64-1.85 (m, 6H), 1.16-1.39 (m, 8H), 1.09 (d, 3H, J )
6.6 Hz) 1.03-1.11 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 165.8,
156.4, 134.7, 132.7, 130.8, 129.5, 128.2, 127.2, 79.5, 51.8, 46.8, 41.8,
36.4, 32.0, 28.7, 28.6, 26.4, 25.9, 25.8, 25.2, 21.3; IR (film, cm-1
)
3341, 2928, 2854, 1714, 1530, 1271, 1111; MS (FAB) m/z 388 (M +
H+). HRMS calcd for C23H34NO4 (M + H+): 388.2488; Found: m/z
388.2479.
Preparation of 26. Triphenylphosphine (295 mg, 1.12 mmol) and
H2O (0.15 mL) were added to a stirred solution of 23a (100 mg, 0.28
mmol) in THF (7.5 mL), and the reaction was stirred for 30 h at room
temperature. Solvents were evaporated and the residue was dried under
high vaccum. The residue was then dissolved in CH2Cl2 (4.5 mL),
and Boc anhydride (119 mg, 0.54 mmol) and Et3N (0.15 mL, 1.1
mmol) were added at room temperature, and the mixture was stirred
for 3 h. Evaporation of the solvent and purification of the residue by
column chromatography on silica gel eluted with 5% EtOAc in hexane
gave 26 (103 mg; 85%): colorless oil; [R]2D4 -10.37 (c 1.32, CHCl3);
1
Rf ) 0.45 (20% EtOAc in hexane); H NMR (300 MHz, CDCl3) δ
8.04 (d, 2H, J ) 7.1 Hz), 7.53 (t, 1H, J ) 7.3 Hz), 7.42 (t, 2H, J )
7.1 Hz), 5.73 (dt, 1H, J ) 15.4, 6.7 Hz), 5.47 (dd, 1H, J ) 15.4, 7.7
Hz), 5.25 (dd, 1H, J ) 7.1, 7.0 Hz), 4.27 (br, 1H), 3.61 (br, 1H), 2.03
(m, 2H,), 1.62-1.85 (m, 6H), 1.42 (s, 9H), 1.15-1.50 (m, 9H), 1.07
(d, 3H, J ) 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 165.7, 155.3,
134.7, 132.6, 130.8, 129.5, 128.2, 127.1, 79.4, 46.2, 41.8, 36.7, 32.0,
28.7, 28.6, 28.3, 27.3, 26.3, 25.9, 25.8, 25.3, 21.3; IR (film, cm-1
)
3371, 2929, 2854, 1714, 1517, 1271, 1113; MS (FAB) m/z 430 (M +
H+). HRMS calcd for C26H40NO4 (M + H+): 430.2957; Found: m/z
430.2952.
Acknowledgment. This work was supported by Grant-in-
Aid for Scientific Research on Priority Areas 17035084 and in
part by the 21st COE Program from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
Hydrolysis of Benzoates 24a, 24b, and 26. A solution of
benzoate (0.4 mmol) in methanol (15 mL) and aq NaOH (3.2 M
solution, 1.5 mL, 4.8 mmol) was stirred for 24 h at room
temperature. Solvent was removed under vaccum, water was added
to the residue, and the mixture was extracted with EtOAc. The
organic extract was dried on MgSO4. Evaporation of the solvent
and purification of the residue by column chromatography on silica
gel eluted with 40% EtOAc in hexane gave the corresponding
alcohol 25a, 25b, and 27.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for all new compounds and synthetic
procedures and physical and characterization data for 13a-f,
14a-f, 15a-b, and 15d-e. This material is available free of
charge via the Internet at http://pubs.acs.org.
Compound 25a. was obtained from 24a in 96% yield; colorless
oil [R]2D5 -2.19 (c 1.05, CHCl3); Rf ) 0.16 (25% EtOAc in hexane);
JO801926G
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