A divergent approach to 3-piperidinols: A concise syntheses of (+)-swainsonine and access to the 1-substituted quinolizidine skeleton

Article abstract of DOI:10.1021/jo3011914

Nucleophilic addition of Grignard reagents and organolithium species to a 3-silyloxy-3,4,5,6-tetrahydropyridine Noxide provides trans-2,3-disubstituted N-hydroxypiperidines exclusively. The application of this methodology to the preparation of a diversity of useful trans-2-substituted-3-hydroxypiperidines, a concise synthesis of (+)-swainsonine, and an enantiopure 1- substituted quinolizidine of utility in target-directed synthesis is reported.

Full text of DOI:10.1021/jo3011914

Article
pubs.acs.org/joc
A Divergent Approach to 3‑Piperidinols: A Concise Syntheses of
(+)-Swainsonine and Access to the 1‑Substituted Quinolizidine
Skeleton
Glenn Archibald,∥ Chih-Pei Lin,§ Peter Boyd, David Barker,* and Vittorio Caprio*,‡
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
S
* Supporting Information
ABSTRACT: Nucleophilic addition of Grignard reagents and organolithium species to a 3-silyloxy-3,4,5,6-tetrahydropyridine N-
oxide provides trans-2,3-disubstituted N-hydroxypiperidines exclusively. The application of this methodology to the preparation
of a diversity of useful trans-2-substituted-3-hydroxypiperidines, a concise synthesis of (+)-swainsonine, and an enantiopure 1-
substituted quinolizidine of utility in target-directed synthesis is reported.
additions of electrophiles,8 access to a single, suitably
substituted cyclic nitrone such as 5, which maps onto the 2-
hydroxy-3-substituted piperidine substructure, would enable the
parallel, enantioselective synthesis of the core structures of all
INTRODUCTION
Flexible and stereoselective syntheses of diversely function-
alized piperidines are of much value in synthetic and medicinal
■
chemistry. Methods for the construction of trans-2-substituted-
3-hydroxypiperidines are of particular importance,1 as this
substructure is found in a range of bioactive alkaloids (Figure
1). These include the antimalarial (+)-febrifugine 1,2 a range of
targets 1−4 and associated compound libraries. The use of
nitrones to access the 2-substituted 3-hydroxy piperidine motif
has received scant attention however. There are few examples
of diastereoselective nucleophilic additions to either simple or
highly substituted six-membered ring nitrones.9 There are a
number of reports covering the substrate-controlled stereo-
selective 1,3-dipolar cycloadditions of functionalized tetrahy-
dropyridine N-oxides,10 but these are mainly focused on the
conversion of 6-substituted derivatives to trans-2,6-disubsti-
tuted piperidines. The only two reports of nitrones related to 5
are restricted to describing the in situ generation and trapping
of these species in the presence of allyl alcohol.10l,m In contrast,
O-protected derivatives of pyrroline N-oxide 6 have been
studied in some detail. These species undergo highly
stereoselective dipolar cycloadditions to alkenes and nucleo-
philic additions with Grignard reagents and have shown much
utility in the synthesis of 2,3-disubstituted pyrrolidine alkaloids
(Figure 2).11
Recently, we have shown that nitrone (S)-5a may be
efficiently accessed from L-glutamic acid and is sufficiently
stable for purification and storage. However, our studies
revealed that the stereoselectivity of 1,3-dipolar cycloadditions
onto 5a, while in favor of the trans-adducts did not match the
levels obtained with nitrone 6.12 We also briefly studied the
addition of Grignard reagents to nitrone 5a. In this instance,
stereoselectivity was highly in favor of the trans-2,3-
Figure 1. Naturally occurring trans-2-substituted-3-hydroxypiperidines.
iminocyclitols, including the α-glucosidase inhibitor deoxynojir-
imycin 2,3 and Prosopis alkaloids, including prosophylline 3,
which displays antibiotic and anesthetic properties.4 This motif
is also embedded within the bicyclic structure of hydroxylated
indolizidines such as the α-mannosidase inhibitor (−)-swainso-
nine (−)-4.5 The widespread occurrence of the 3-hydrox-
ypiperidine substructure has led to the recent designation of
this fragment as a privileged scaffold in drug discovery.1d
We reasoned that as the nitrone functional group is known to
undergo cycloaddition with a wide range of alkenes and
alkynes,6 nucleophilic addition with an array of organometallic
species,7 and, most recently, samarium iodide-mediated
Received: June 14, 2012
Published: August 14, 2012
© 2012 American Chemical Society
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manganese dioxide18 proved to be a reliable, repeatable method
and provided a separable, regioisomeric mixture of nitrones 5b
and 10, in a combined 80% yield, in a moderate 2.2:1 ratio in
favor of the desired regioisomer 5b.
The regioselectivity of the oxidation is lower than the 6:1
ratio observed during the conversion of the 3-benzyloxy-
substituted N-hydroxypiperidine to nitrone 5a.12 It has been
established, by Cicchi and co-workers, that high regioselectivity
observed in the oxidation of N-hydroxypyrrolidines to nitrones
6 arises from selective activation and subsequent loss of the C2
proton antiperiplanar to the adjacent C−O bond in a
nitrosonium intermediate.19 Although no such relationship
exists in the predicted major conformer of nitrosonium 11a a
similar explanation for regiocontrol can apply in our case if we
apply the Curtin−Hammett principle20 and consider that the
most rapid proton loss is that of H-2 axial of the relatively
inaccessible conformer 11b (Scheme 2).
Figure 2. Structures of tetrahydropyridine N-oxides 5a/b and
pyrroline N-oxide 6.
disubstituted isomer and equivalent to results observed with
nitrone 6. Unfortunately, isolated yields of products were
consistently low. We attributed product loss to complications
arising from competing deprotonation at the benzylic position
by the organometallic nucleophile and/or loss of the potentially
hydrophilic hydroxypiperidine products to aqueous media
during the workup procedure. We envisaged that both
problems could be alleviated by the use of the more lipophilic
and robust TBDPS moiety as O-protecting group, and we now
report a method for the efficient and highly stereoselective
synthesis of a diversity of trans-2-substituted-3-hydroxypiper-
idines based on the addition of Grignard and organolithium
reagents to O-silyl-protected nitrone 5b.
Scheme 2
RESULTS AND DISCUSSION
■
Preparation of Nitrone 5b. Our strategy toward nitrone
5b is a slight modification of a route previously developed
toward O-benzyl nitrone 5a12 and centers on regioselective
oxidation of the corresponding N-hydroxypiperidine, prepared
by cyclization of a suitably protected triol (Scheme 1). The
The lower levels of regiocontrol observed in the synthesis of
5b compared to 5a may then be attributed to the much
diminished populations of 11b, and/or perhaps to higher levels
of steric hindrance to proton removal, in moving from a 3-
benzyloxy to a more bulky O-TBDPS moiety. Nitrone 5b is
stable to purification and storage at 0 °C for up to 4 days. We
attribute this stability to the presence of the protected hydroxyl
group sterically blocking the dimerization observed with more
simple nitrones such as 2,3,4,5-tetrahydropyridine N-oxide.21
Addition of Organometallic Reagents to Nitrone 5b.
We next examined the reactivity of 5b with a range of Grignard
and organolithium reagents and reduction of the resulting
adducts. The results of this study are summarized in Table 1.
Optimum conditions for the addition of Grignard species
involved adding a solution of the nucleophile to nitrone in THF
at 0 °C while the organolithium reagents were added at −78
°C. Addition of a range of primary and secondary alkyl, allyl,
vinyl, alkynyl, aryl, and heteroaryl organometallic species
proceeded in good to excellent yield. Even tert-butyllithium
also undergoes addition, albeit in lower yield (Table 1, entry
12). The lower yields arising from addition of alkyllithiums
(Table 1, entries 10−12) in comparison to the Grignard
counterparts (Table 1, entries 1−3) may be partly attributed to
the greater basicity of the former, leading to the competing
formation of hydroxyenamines. The only addition that proved
problematic was that of a 3-pyridyl moiety (entry 9). The
addition of lithiothiophene and lithiofuran (entries 15 and 16)
proceeded smoothly; however, addition of 3-lithiopyridine,
prepared in diethyl ether, or toluene following the method of
Cai et al.,22 provided none of the desired product. The best
results were obtained by addition of a THF solution of (3-
pyridyl)magnesium chloride, prepared from isopropylmagne-
sium chloride and 3-bromopyridine, using conditions devel-
oped by Trecourt et al.23 While the addition with
allylmagnesium bromide (entry 5, Table 1) proceeds with
86:14 trans:cis ratio, in all other cases the trans-isomer is the
only product isolated. Reduction of the N-hydroxy group of 12,
using zinc in the presence of catalytic indium,24 proceeded
Scheme 1. Synthesis of Nitrone 5b
sequence commences with O-protection of the secondary
alcohol in L-glutamate-derived hydroxy diester 7 followed by
reduction to triol 8. Reduction of 7 using lithium aluminum
hydride resulted in silyl deprotection while the use of lithium
borohydride/MeOH13 and calcium borohydride14 led to
extensive migration of the silyl group. The desired reduction
product 8 was obtained using DIBAL-H in THF at −78 °C
provided that the workup procedure was maintained at −20 °C
to avoid silyl deprotection. Finally, we found that reduction
could be achieved most conveniently, in near quantitative yield,
using in situ-prepared zinc borohydride under the conditions
developed by Yamakawa et al.15 The position of the O-TBDPS
group in 8 was unambiguously determined by single crystal X-
ray analysis. Compound 8 was then converted to N-
hydroxypiperidine 9 using the strategy previously developed
en route to the O-benzyl-protected derivative.12 Oxidation of 9
was initially attempted using HgO16 and TPAP/NMO,17 but
these reagents gave low yields. However, freshly prepared
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Table 1. Addition of Nucleophiles to Nitrone 5b and Reduction of the Resulting Hydroxylamines 12a−o
a
Addition carried out at 0 °C in THF (M = MgBr/MgCl) or at −78 °C using 1.5 equiv of RM (M = Li); see Experimental Section for details.
b
c
Isolated, chromatographically pure products. Relative stereochemistry determined by 2D-NOESY studies performed on piperidines 13a−o. The
d
trans-product was obtained exclusively in all cases except entry 5 (dr = 86:14). All reductions preformed using 5 equiv of Zn/10 mol % In, EtOH/
NH4Cl except entry 13 (1.2 equiv of In, EtOH/1% HCl)
smoothly to afford the corresponding piperidine in all cases
except entry 13 where rapid, clean conversion only occurred
using stoichiometric quantities of In and 1% aqueous HCl in
place of ammonium chloride. The stereochemistry of addition
was determined by analysis of the 2D-NOESY spectra obtained
for reduction products 13a−o (Figure 3). Strong correlations
performed owing to the considerable line broadening observed
in the H NMR spectra of these N-hydroxylamines.
1
Recently, Reissig and co-workers have reported the highly
diastereoselective addition of lithiated methoxyallene 14 to
chiral five-membered cyclic nitrones of type 6.25 The resulting
adducts rearrange to 1,2-oxazines which have shown utility in
the synthesis of furan and pyran derivatives,26 amino
alcohols,25,27 and pyrrolidines.27 We were also able to effect
the stereoselective addition of 14 to nitrone 5b. The resulting
allenyl adduct 15 was isolable but unstable, undergoing
rearrangement to oxazine 16 on prolonged stirring (Scheme 3).
We postulate that the trans-stereoselectivity observed in the
above additions can be rationalized by application of the model
depicted in Figure 4.28 In this model reaction occurs,
preferentially, with a nitrone conformer bearing an axially
Figure 3. Selected NOE observed in adducts 13a−o.
Scheme 3. Synthesis of trans-Oxazine 16
were observed between the axial protons on either face of the
piperidine ring: H2/H4/H6 and H3/H5 indicating a trans-
diaxial substitution pattern across C2/C3. Unfortunately,
stereochemical analysis of adducts 12a−o, and hence
determination of accurate levels of diastereoselectivity of
addition by analysis of crude mixtures 12, could not be
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Scheme 5. Synthesis of (+)-Swainsonine
Figure 4. Proposed origin of stereocontrol in addition of organo-
metallic reagents to 5b.
disposed C−O bond, for maximum π*(nitrone)−σ*(C−O)
overlap. Nucleophilic addition to the least hindered face gives
rise to the selectivity observed.
The significance of a number of members of the small library
of trans-2,3-disubstituted piperidines detailed above further
underlines the potential of our methodology. For instance,
differentially N/O-protected derivatives of piperidines 13a, 13e,
13f, and 13g have been used as key intermediates en route to
Prosopis alkaloids,29 febrifugine 1,30 swainsonine 4,31 and a
range of Substance P antagonists,29 respectively.
Total Synthesis of (+)-Swainsonine. With the scope of
nitrone 5b established, we became interested in the use of this
compound in the targeted synthesis of more complex
molecules. This was initially illustrated by the development of
a novel, concise, enantioselective route to (+)-swainsonine
(+)-4.32 While naturally occurring (−)-swainsonine is a potent
inhibitor of α-mannosidase,5 the (+)-enantiomer has been
shown to inhibit the action of rhamnosidase32b and thus has
potential as an anti-tuberculosis agent. Our synthetic route
centers on the construction of hexahydroindolizines such as 17,
which have been previously shown to undergo highly
diastereoselective dihydroxylation to give the core of
swainsonine (Scheme 4).33,31b Inspired by our successful
the resulting cis-alkene. This may be partially attributable to
adherence of the unprotected amine moiety to the catalysts.34
Unfortunately, this problem was only partially alleviated by the
use of catalyst poisons including ethylenediamine, quinoline,
and 3,6-dithiaoctane-1,8-diol. We reasoned that reversal of
reduction steps would alleviate this problem owing to reduced
catalyst binding of the hydroxylamine moiety.35 Indeed, Lindlar
hydrogenation of alkyne 20 followed by N−O bond reduction,
with accompanying deprotection, proceeded smoothly to afford
the cis-alkene 19 in good overall yield. The structure and
stereochemistry of 19 was further established by single crystal
X-ray analysis. Key bicycle 17 was then accessed by cyclization
of 19 under Mitsunobu conditions using DCAD (dicyclohex-
ylcarbodiimide). Dihydroxylation of 17, using AD-mix-α,
followed by acetylation of the resulting mixture of diols gave
a separable 9:1 diastereomeric mixture of diacetates in favor of
22.33d Finally, global deprotection of 22 yielded (+)-swainso-
nine [mp 143−144 °C, [α]D +79.9 (c 0.37, MeOH); lit.32a mp
143−145 °C, [α]D +83.3 (c 0.5, MeOH)].
Synthesis of Quinolizidines. We next became interested
in modifying the general strategy described in Scheme 4 to
prepare enantiopure quinolizidine skeleta. In particular, we
focused on the synthesis of quinolizidine 23. O-Deprotected 23
provides access, via short synthetic sequences to the 1-
substituted quinolizidine alkaloids epiquinamide,36,37 (−)-lupi-
nine,38,39 and (−)-lusitanine.40 We envisioned that compound
23 could be accessed via addition of the homologue of 18,
lithium acetylide 24, to nitrone 5b. In practice, the addition of
24 to 5b furnished the trans-adduct 25 as sole product in 85%
yield (Scheme 6).
Scheme 4. Retrosynthesis of (+)-Swainsonine
addition of trimethylsilylacetylide to 5b (Table 1, entry 13),
we based our strategy toward 17 on the reaction of 5b with the
lithium acetylide 18 followed by Lindlar reduction to cis-alkene
19 and cyclization.
Our approach to (+)-swainsonine proceeded largely as
planned (Scheme 5). Thus, addition of the lithium acetylide 18
onto nitrone 5b gave trans-diastereoisomer 20 as the sole
product in high yield. The stereochemistry of addition was
determined by analysis of the 2D-NOESY spectrum of 20
which exhibited key correlations identical to those depicted in
Figure 3. In a fashion similar to the reduction of 12l, reductive
cleavage of the N−O bond of 20 proceeded sluggishly using
catalytic In/Zn in the presence of aqueous NH4Cl and resulted
in partial deprotection of the O-TBS group. However, rapid,
clean reduction, with concomitant total cleavage of the primary
silyl ether, occurred using stoichiometric In in 1% HCl/EtOH
to furnish propargylpiperidine 21. All attempts at partial
reduction of the alkyne moiety of 21 by Lindlar catalysis
resulted in significant overreduction and/or isomerization of
Hydrogenation of 25 to the alkane, followed by N−O bond
cleavage, with simultaneous removal of the TBS moiety using
indium in 1% HCl/EtOH gave (2-hydroxybutyl)piperidine 26.
In contrast to compound 19, piperidine 26 failed to cyclize
under Mitsunobu conditions using either DEAD or DCAD.
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pressure. Purification of the residue by flash column chromatography,
eluting with EtOAc/hexanes (gradient 1:49 to 1:1), gave the silyloxy
diester (15.6 g, 95%) as a colorless oil. [α]D20 −29.0 (c 1.09, CHCl3);
νmax(neat)/cm−1 2952, 2932, 2858, 1737, 1427, 1256, 1110; δH (400
MHz; CDCl3) 1.09 (9H, s, SitBu), 1.98−2.13 (2H, m, H-3), 2.33−2.44
(1H, m, CHa,Hb-4), 2.44−2.56 (1H, m, CHa,Hb-4), 3.45 (3H, s, 1-
OMe), 3.64 (3H, s, 5-OMe), 4.29 (1H, t, J = 5.4 Hz, H-2), 7.33−7.46
(6H, m, H-Ar), 7.60−7.68 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.3
(C, SitBu), 26.8 (CH3, SitBu), 28.9 (CH2, C-4), 29.9 (CH2, C-3), 51.4
(CH3, 1-OMe), 51.5 (CH3, 5-OMe), 71.4 (CH, C-2), 127.5 (CH, C-
Ar), 127.6 (CH, C-Ar), 129.7 (CH, C-Ar), 129.8 (CH, C-Ar), 132.9
(C, C-Ar), 133.0 (C, C-Ar), 135.7 (CH, C-Ar), 135.9 (CH, C-Ar),
172.8 (CO, C-1), 173.3 (CO, C-5); HRMS (CI, NH3)
Scheme 6. Synthesis of Quinolizidine 23
+
C23H34NO5Si [MNH4 ] calcd 432.2206, obsd 432.2202.
A solution of the silyloxy diester prepared above (11.2 g, 27.0
mmol) in THF (60 mL) was added slowly to a stirred suspension of
ZnCl2 (8.10 g, 59.4 mmol) and NaBH4 (4.50 g, 119 mmol) in THF
(40 mL) at 0 °C. Et3N (8.24 mL, 59.4 mmol) was added and the
mixture stirred at 0 °C for 10 min. The reaction mixture was warmed
to 80 °C, stirred for a further 4 h, and then cooled to 0 °C. CHCl3
(100 mL) was added to the suspension, the mixture was stirred for 10
min, and then saturated aqueous NH4Cl (100 mL) was added
dropwise. The aqueous phase was extracted with CHCl3 (4 × 250
mL), and the combined organic extracts were washed with brine (100
mL), dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash column chromatography, using EtOAc/
hexanes (gradient 1:3 to 1:1), to give the title compound (9.46 g,
98%) as a white solid. Recrystallization from Et2O/hexanes (1:1)
However use of Appel conditions provided rapid conversion to
quinolizidine 23 in 70% yield.
CONCLUSION
■
We have shown that 3-hydroxytetrahydropyridine N-oxide 5b
undergoes highly diastereoselective nucleophilic addition with a
wide range of Grignard reagents and organolithium species.
Furthermore, we have demonstrated that this methodology
enables the efficient generation of libraries of trans-2-
substituted-3-hydroxypiperidines of synthetic/therapeutic
value. Additionally, the utility of synthon 5b in the
enantioselective synthesis of specific targets, with multiple
stereocenters, has been established by the development of a
concise synthetic route to (+)-swainsonine 4 and O-protected
hydroxyquinolizidine 23.
20
afforded colorless needles. mp 75−77 °C; [α]D +19.3 (c 1.18,
CHCl3); νmax(neat)/cm−1 3289, 2957, 2927, 2876, 2876, 1584, 1428,
1108, 1080, 1018, 991; δH (300 MHz; CDCl3) 1.07 (9H, s, SitBu),
1.35−1.67 (4H, m, H-3, H-4), 2.54 (2H, br s, 2 × OH), 3.32−3.55
(4H, m, H-5, H-1), 3.74−3.84 (1H, m, H-2), 7.31−7.46 (6H, m, H-
Ar), 7.63−7.73 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.2 (C, SitBu),
27.0 (CH3, SitBu), 27.7 (CH2, C-4), 29.6 (CH2, C-3), 62.4 (CH2, C-
5), 65.4 (CH2, C-1), 73.4 (CH, C-2), 127.6 (CH, C-Ar), 127.6 (CH,
C-Ar), 129.7 (CH, C-Ar), 133.7 (C, C-Ar), 133.9 (C, C-Ar), 135.6
(CH, C-Ar), 135.7 (CH, C-Ar); HRMS (CI, NH3) C21H31O3Si
[MH+] calcd 359.2042, obsd 359.2038.
EXPERIMENTAL SECTION
■
(3S)-3-(tert-Butyldiphenylsilyloxy)-N-hydroxypiperidine (9).
p-Toluenesulfonyl chloride (5.49 g, 28.8 mmol) was added
portionwise to a solution of diol 8 (3.44 g, 9.60 mmol) in CH2Cl2
(80 mL) at 0 °C and the mixture stirred for 30 min. A solution of Et3N
(4.0 mL, 29.0 mmol) and DMAP (0.24 g, 1.92 mmol) in CH2Cl2 (20
mL) was added dropwise and the mixture warmed to rt and stirred
overnight. Brine (80 mL) was added and the aqueous phase extracted
with CH2Cl2 (3 × 100 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with EtOAc/hexanes
(gradient 1:19 to 3:17), to give the ditosylate (6.20 g, 97%) as a
colorless oil. [α]D20 −8.5 (c 2.0, CHCl3); νmax(neat)/cm−1 2931, 2857,
1598, 1427, 1358, 1174; δH (400 MHz; CDCl3) 0.98 (9H, s, SitBu),
1.37−1.47 (2H, m, H-3), 1.47−1.57 (2H, m, H-4), 2.44 (6H, s, Ar-
Me), 3.72−3.86 (5H, m, H-1, H-2, H-5), 7.24−7.36 (8H, m, H-Ar),
7.38−7.45 (2H, m, H-Ar), 7.49−7.56 (4H, m, H-Ar), 7.59−7.64 (2H,
m, H-Ar), 7.70−7.74 (2H, m, H-Ar); δC (75 MHz; CDCl3) 19.2 (C,
SitBu), 21.6 (CH3, Ar-Me), 23.8 (CH2, C-4), 26.8 (CH3, SitBu), 29.5
(CH2, C-3), 69.7 (CH, C-2), 70.1, 71.4 (CH2, C-3, C-5), 127.6 (CH,
C-Ar), 127.7 (CH, C-Ar), 127.7 (CH, C-Ar), 127.8 (CH, C-Ar), 127.8
(CH, C-Ar), 129.8 (CH, C-Ar), 129.8 (CH, C-Ar), 129.8 (CH, C-Ar),
129.9 (CH, C-Ar), 132.6 (CH, C-Ar), 133.0 (CH, C-Ar), 133.0 (C, C-
Ar), 133.0 (C, C-Ar), 135.7 (CH, C-Ar), 135.7 (CH, C-Ar), 144.7 (C,
C-Ar), 144.8 (C, C-Ar); HRMS (FAB+) C35H43O7S2Si [MH+] calcd
667.2220, obsd 667.2222.
All reactions sensitive to air or moisture were performed under a
nitrogen atmosphere using oven-dried glassware in dry, freshly distilled
solvents, unless otherwise noted. Flash column chromatography was
performed using normal phase or reverse phase (C18) silica gel. Thin
layer chromatography was performed on silica gel plates. Melting
points are uncorrected. IR spectra were recorded using an FT-IR ATR
spectrometer. NMR spectra were recorded using a 300 or 400 MHz
spectrometer. Chemical shifts are reported in parts per million (ppm)
relative to TMS (1H δ 0.00), CDCl3 (1H δ 7.26, 13C δ 77.00), CD3OD
(1H δ 3.31, 13C δ 49.00) or DMSO-d6 (1H δ 2.50, 13C δ 39.52). H
1
NMR values are reported as chemical shifts δ, relative integral,
multiplicity (s, singlet; d, doublet; dd, doublet of doublets; ddd,
doublet of doublet of doublets; dddd, doublet of doublet of doublet of
doublets; dt, doublet of triplets; t, triplet; td, triplet of doublets; m,
multiplet; br, broad peak), coupling constant (J) and assignment.
Coupling constants were taken directly from the spectra. Assignments
were made with the aid of DEPT, COSY, HSQC, HMBC, and
NOESY experiments. High-resolution mass spectroscopy (HRMS)
was carried out by either electron impact (EI+), chemical ionization
(CI), electrospray ionization (ESI), or fast atom bombardment (FAB)
on a MicroTOF-Q mass spectrometer. Optical rotations were
1
measured using a polarimeter at the sodium-D line (589 nm). H
and 13C NMR spectra for all new compounds are reported in
Supporting Information.
(2S)-2-(tert-Butyldiphenylsilyloxy)pentane-1,5-diol (8). tert-
Butyldiphenylsilyl chloride (11.4 mL, 41.6 mmol) was added to a
solution of diester 7 (6.98 g, 39.6 mmol) and imidazole (4.0 g, 59.4
mmol) in CH2Cl2 (70 mL) at 0 °C. The mixture was warmed to rt and
stirred for 3 h. Saturated aqueous NH4Cl (50 mL) was added and the
aqueous phase extracted with CH2Cl2 (3 × 40 mL). The combined
organic extracts were dried (MgSO4) and concentrated under reduced
NH2OH·HCl (5.44 g, 78.3 mmol) was added to a solution of the
ditosylate prepared above (11.6 g, 17.4 mmol) in Et3N (100 mL) at
room temperature. The reaction mixture was stirred under reflux for 4
h and then cooled to room temperature. Et2O (100 mL) was added
and the suspension stirred for 1 h and filtered through Celite. The
filtrate was dried (MgSO4) and concentrated under reduced pressure.
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The residue was purified by flash column chromatography, eluting
4.5 mL). The suspension was stirred under reflux for 4 h, cooled to rt,
and filtered through a pad of Celite. The filtrate was concentrated, and
saturated aqueous Na2CO3 (15 mL) was added. The aqueous phase
was extracted with EtOAc (3 × 20 mL), and the combined organic
extracts were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with MeOH/CH2Cl2 (gradient 1:99 to 9:91), to give the trans-
2,3-disubstituted-piperidine.
with MeOH/CH2Cl2 (gradient 1:99 to 1:19), to give the title
20
compound (4.46 g, 73%) as a colorless oil. [α]D −24.2 (c 2.34,
CHCl3); νmax(neat)/cm−1 3177, 3070, 2930, 2855, 1427, 1103; δH
(300 MHz; DMSO-d6, 393 K) 1.07 (9H, s, SitBu), 1.18−1.48 (2H, m,
CHa,Hb-4, CHa,Hb-5), 1.59−1.77 (2H, m, CHa,Hb-4, CHa,Hb-5),
2.35−2.50 (2H, m, CHa,Hb-2, CHa,Hb-6), 2.80−2.91 (1H, m, CHa,Hb-
6), 3.02−3.14 (1H, m, CHa,Hb-2), 3.87−4.00 (1H, m, 3-H), 7.36−7.59
(6H, m, H−Ar), 7.60−7.71 (4H, m, H-Ar); δC (75 MHz; DMSO-d6,
393 K) 18.0 (C, SitBu), 20.0 (CH2, C-4), 26.1 (CH3, SitBu), 31.9
(CH2, C-5), 56.9 (CH2, C-6), 64.8 (CH2, C-2), 67.9 (CH, C-3), 126.8
(CH, C-Ar), 128.8 (CH, C-Ar), 133.6 (C, C-Ar), 134.4 (CH, C-Ar);
HRMS (CI, NH3) C21H30NO2Si [MH+] calcd 356.2046, obsd
356.2049.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-methylpiperidine
(13a). Following general procedure A, reaction of methylmagnesium
bromide (3.0 M in Et2O, 0.17 mL, 0.50 mmol) and nitrone 5b (0.12 g,
0.33 mmol) followed by purification of the residue by column
chromatography, using EtOAc/hexanes (1:4), gave the 2-methylpiper-
idin-1-ol 12a (0.10 g, 81%) as a yellow oil. Following general
procedure C, reduction of 2-methylpiperidin-1-ol 12a (0.20 g, 0.53
(3S)-3-tert-Butyldiphenylsilyloxy-3,4,5,6-tetrahydropyridine
N-Oxide (5b) and (5S)-5-tert-Butyldiphenylsilyloxy-3,4,5,6-
tetrahydropyridine N-Oxide (10). Activated MnO2 (1.43 g, 16.5
mmol) was added portionwise to a solution of hydroxylamine 9 (2.34
g, 6.58 mmol) in CH2Cl2 (50 mL) at 0 °C and the reaction mixture
stirred for 2 h. The resulting suspension was filtered through a pad of
MgSO4/Celite and the filtrate concentrated under reduced pressure, at
a water bath temperature below 20 °C. The residue was purified by
flash column chromatography, eluting with MeOH/CH2Cl2 (gradient
0:100 to 1:19), to give the title compounds 5b (1.29 g, 55%) and 10
(0.59 g, 25%) as colorless oils. Data for 5b: Rf (5% MeOH/CH2Cl2)
20
mmol) gave the title compound (0.15 g, 81%) as a yellow oil. [α]D
+26.0 (c 2.16, CHCl3); νmax(neat)/cm−1 3071, 3048, 2930, 2856,
1427, 1105, 1085; δH (300 MHz; CDCl3) 1.05 (9H, s, SitBu), 1.13
(3H, d, J = 6.3 Hz, H-1′), 1.16−1.42 (2H, m, CHa,Hb-4, CHa,Hb-5),
1.47−1.57 (1H, m, CHa,Hb-5), 1.70−1.81 (1H, m, CHa,Hb-4), 1.97
(1H, br s, NH), 2.52 (1H, td, J = 11.6, 3.1 Hz, CHa,Hb-6), 2.59 (1H,
dq, J = 8.4, 6.3 Hz, H-2), 2.78−2.89 (1H, m, CHa,Hb-6), 3.25 (1H,
ddd, J = 9.9, 8.4, 4.1 Hz, H-3), 7.29−7.45 (6H, m, H-Ar), 7.64−7.74
(4H, m, H-Ar); δC (75 MHz; CDCl3) 19.3 (C, SitBu), 19.4 (CH2, C-
1′), 25.7 (CH2, C-5), 27.0 (CH3, SitBu), 34.1 (CH2, C-4), 45.7 (CH2,
C-6), 58.6 (CH, C-2), 75.7 (CH, C-3), 127.3 (CH, C-Ar), 127.5 (CH,
C-Ar), 129.3 (CH, C-Ar), 129.5 (CH, C-Ar), 133.9 (C, C-Ar), 134.8
(C, C-Ar), 135.8 (CH, C-Ar), 135.9 (CH, C-Ar); HRMS (EI+)
C22H31NOSi [M+] calcd 353.2175, obsd 353.2171.
20
0.10; [α]D −113.8 (c 2.53, CHCl3); νmax(neat)/cm−1 3071, 2931,
2858, 1590, 1427, 1105, 1081; δH (400 MHz; CDCl3) 1.07 (9H, s,
SitBu), 1.69−1.85 (3H, m, H-4, CHa,Hb-5), 2.11−2.23 (1H, m,
CHa,Hb-5), 3.59−3.71 (1H, m, CHa,Hb-6), 3.72−3.85 (1H, m,
CHa,Hb-6), 4.34−4.42 (1H, m, H-3), 6.93−6.97 (1H, m, H-2),
7.35−7.49 (6H, m, H-Ar), 7.61−7.69 (4H, m, H-Ar); δC (100 MHz;
CDCl3) 18.9 (CH2, C-5), 19.0 (C, SitBu), 26.7 (CH3, SitBu), 27.6
(CH2, C-4), 58.4 (CH2, C-6), 65.4 (CH, C-3), 127.8 (CH, C-Ar),
127.9 (CH, C-Ar), 130.0 (CH, C-Ar), 130.1 (CH, C-Ar), 132.8 (C, C-
Ar), 133.0 (C, C-Ar), 135.5 (CH, C-Ar), 135.6 (CH, C-Ar), 137.4
(CH, C-2); HRMS (ESI) C21H28NO2Si [MH+] calcd 354.1884, obsd
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-ethylpiperidine
(13b). Following general procedure A, reaction of ethylmagnesium
bromide (3.0 M in Et2O, 0.29 mL, 0.87 mmol) and nitrone 5b (0.21 g,
0.58 mmol) followed by purification of the residue by column
chromatography, using EtOAc/hexanes (1:4), gave the 2-ethyl-
piperidin-1-ol 12b (0.18 g, 81%) as a yellow oil. Following general
procedure C, reduction of 2-ethylpiperidin-1-ol 12b (0.15 g, 0.39
20
20
mmol) gave the title compound (0.12 g, 84%) as a yellow oil. [α]D
354.1884. Data for 10: Rf (5% MeOH/CH2Cl2) 0.17; [α]D −9.8 (c
+30.4 (c 2.40, CHCl3); νmax(neat)/cm−1 3070, 2932, 2857, 1427,
1105, 1075; δH (400 MHz; CDCl3) 0.86 (3H, t, J = 7.5 Hz, H-1′), 1.05
(9H, s, SitBu), 1.14−1.41 (3H, m, CHa,Hb-2′, CHa,Hb-4, CHa,Hb-5),
1.47−1.57 (1H, m, CHa,Hb-5), 1.69−1.79 (1H, m, CHa,Hb-4), 1.88−
2.04 (2H, m, NH, CHa,Hb-2′), 2.41 (1H, td, J = 8.3, 3.3 Hz, H-2), 2.51
(1H, td, J = 11.2, 3.0 Hz, CHa,Hb-6), 2.83−2.92 (1H, m, CHa,Hb-6),
3.34 (1H, ddd, J = 9.6, 8.3, 4.1 Hz, H-3), 7.31−7.44 (6H, m, H-Ar),
7.64−7.72 (4H, m, H-Ar); δC (100 MHz; CDCl3) 10.0 (CH3, C-1′),
19.4 (C, SitBu), 24.7 (CH2, C-2′), 25.4 (CH2, C-5), 27.0 (CH3, SitBu),
34.0 (CH2, C-4), 45.7 (CH2, C-6), 64.2 (CH, C-2), 73.6 (CH, C-3),
127.3 (CH, C-Ar), 127.5 (CH, C-Ar), 129.4 (CH, C-Ar), 129.5 (CH,
C-Ar), 133.9 (C, C-Ar), 134.9 (C, C-Ar), 135.8 (CH, C-Ar), 135.9
(CH, C-Ar); HRMS (ESI) C23H34NOSi [MH+] calcd 368.2404, obsd
368.2411.
2.43, CHCl3); νmax(neat)/cm−1 3071, 2931, 2857, 1623, 1427, 1104;
δH (400 MHz; CDCl3) 1.07 (9H, s, SitBu), 1.56−1.67 (1H, m,
CHa,Hb-4), 1.67−1.78 (1H, m, CHa,Hb-4), 2.25−2.37 (1H, m,
CHa,Hb-3), 2.63−2.77 (1H, m, CHa,Hb-3), 3.66−3.80 (2H, m, H-6),
4.18−4.25 (1H, m, H-5), 7.16−7.22 (1H, m, H-2), 7.33−7.49 (6H, m,
H-Ar), 7.60−7.68 (4H, m, H-Ar); δC (100 MHz; CDCl3) 19.1 (C,
SitBu), 21.6 (CH2, C-3), 25.0 (CH2, C-4), 26.8 (CH3, SitBu), 64.0
(CH2, C-6), 65.5 (CH, C-5), 127.8 (CH, C-Ar), 127.9 (CH, C-Ar),
130.0 (CH, C-Ar), 130.1 (CH, C-Ar), 132.8 (C, C-Ar), 133.1 (C, C-
Ar), 135.6 (CH, C-Ar), 135.9 (CH, C-2); HRMS (ESI) C21H28NO2Si
[MH+] calcd 354.1884, obsd 354.1883.
General Procedure A: Synthesis of 2-Substituted-3-silyloxy-
1-hydroxypiperidines Using Grignard Reagents. The Grignard
reagent was added dropwise to a solution of nitrone 5b in THF (10
mL) at 0 °C and the mixture stirred at this temperature for 1 h.
Saturated aqueous NH4Cl (10 mL) was added and the aqueous phase
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were dried (MgSO4) and concentrated under reduced pressure. The
residue was purified by flash column chromatography, eluting with the
specified solvent to give the trans-2,3-disubstituted-piperidin-1-ol.
General Procedure B: Synthesis of 2-Substituted-3-silyloxy-
1-hydroxypiperidines Using Organolithium Reagents. A
solution of nitrone 5b in THF (3 mL) was added dropwise to a
solution of the organolithium in THF (7 mL) at −78 °C and the
mixture stirred at this temperature for 1 h. Saturated aqueous NH4Cl
(10 mL) was added and the aqueous phase extracted with EtOAc (3 ×
20 mL). The combined organic extracts were dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with the specified solvent to
give the trans-2,3-disubstituted-piperidin-1-ol.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-isopropylpiperidine
(13c). Following general procedure A, reaction of isopropylmagne-
sium chloride (2.0 M in THF, 0.44 mL, 0.87 mmol) and nitrone 5b
(0.21 g, 0.58 mmol) followed by purification of the residue by column
chromatography, using MeOH/CH2Cl2 (0.5:99.5), gave the 2-
isopropylpiperidin-1-ol 12c (0.17 g, 73%) as a colorless oil. Following
general procedure C, reduction of 2-isopropylpiperidin-1-ol 12c
(0.097 g, 0.24 mmol) gave the title compound (0.076 g, 82%) as a
yellow oil. [α]D20 +24.9 (c 1.36, CHCl3); νmax(neat)/cm−1 3071, 2932,
2857, 1472, 1428, 1105, 1079; δH (300 MHz; CDCl3) 0.67 (3H, d, J =
i
i
6.8 Hz, Pr), 0.94 (3H, d, J = 6.8 Hz, Pr), 1.04 (9H, s, SitBu), 1.09−
1.28 (1H, m, CHa,Hb-5), 1.37 (1H, tdd, J = 12.2, 9.8, 4.0 Hz, CHa,Hb-
4), 1.45−1.57 (1H, m, CHa,Hb-5), 1.71−1.83 (1H, m, CHa,Hb-4),
2.29−2.43 (2H, m, H-2, H-1′), 2.48 (1H, td, J = 11.6, 3.0 Hz, CHa,Hb-
6), 2.84−2.94 (1H, m, CHa,Hb-6), 3.44 (1H, ddd, J = 9.7, 8.3, 4.2 Hz,
H-3), 7.31−7.46 (6H, m, H-Ar), 7.64−7.74 (4H, m, H-Ar); δC (75
i
i
General Procedure C: Reduction of N-Hydroxypiperidines.
Zinc powder (5 equiv) and indium powder (10 mol %) were added to
a solution of hydroxylamine in EtOH/saturated aqueous NH4Cl (2:1,
MHz; CDCl3) 15.3 (CH3, Pr), 19.3 (C, SitBu), 20.5 (CH3, Pr), 25.5
(CH2, C-5), 26.0 (CH, C-1′), 27.0 (CH3, SitBu), 34.3 (CH2, C-4),
45.9 (CH2, C-6), 67.9 (CH, C-2), 71.3 (CH, C-3), 127.3 (CH, C-Ar),
7973
dx.doi.org/10.1021/jo3011914 | J. Org. Chem. 2012, 77, 7968−7980

The Journal of Organic Chemistry
Article
127.6 (CH, C-Ar), 129.4 (CH, C-Ar), 129.6 (CH, C-Ar), 133.8 (C, C-
Ar), 135.1 (C, C-Ar), 135.9 (CH, C-Ar), 135.9 (CH, C-Ar); HRMS
(ESI) C24H36NOSi [MH+] calcd 382.2572, obsd 382.2561.
0.62 mmol) followed by purification of the residue by column
chromatography, using EtOAc/hexanes (1:9), gave the 2-vinyl-
piperidin-1-ol 12f (0.20 g, 85%) as a colorless oil. Following general
procedure C, reduction of 2-vinylpiperidin-1-ol 12f (0.11 g, 0.30
mmol) gave the title compound (0.085 g, 79%) as a colorless oil.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-benzylpiperidine
(13d). Following general procedure A, reaction of benzylmagnesium
chloride (2.0 M in THF, 0.45 mL, 0.89 mmol) and nitrone 5b (0.21 g,
0.59 mmol) followed by purification of the residue column
chromatography using MeOH/CH2Cl2 (0.5:99.5), gave the 2-
benzylpiperidin-1-ol 12d (0.24 g, 92%) as a colorless oil. Following
general procedure C, reduction of 2-benzylpiperidin-1-ol 12d (0.13 g,
0.31 mmol) gave the title compound (0.13 g, 99%) as a colorless oil.
[α]D20 +6.8 (c 1.34, CHCl3); νmax(neat)/cm−1 3070, 3027, 2932, 2857,
1453, 1427, 1104, 1084; δH (300 MHz; CDCl3) 1.09 (9H, s, SitBu),
1.19−1.41 (2H, m, CHa,Hb-4, CHa,Hb-5), 1.44−1.54 (1H, m, CHa,Hb-
5), 1.61 (1H, br s, NH), 1.79−1.89 (1H, m, CHa,Hb-4), 2.18 (1H, dd, J
= 10.5, 13.3 Hz, CHa,HbPh), 2.34 (1H, td, J = 11.5, 2.8 Hz, CHa,Hb-6),
2.66 (1H, ddd, J = 2.6, 8.5 10.5 Hz, H-2), 2.70−2.79 (1H, m, CHa,Hb-
6), 3.45 (1H, ddd, J = 9.9, 8.5, 4.3 Hz, H-3), 3.51 (1H, dd, J = 13.4, 2.6
Hz, CHa,HbPh), 7.16−7.33 (5H, m, CH2Ph), 7.33−7.46 (6H, m, H-
Ar), 7.68−7.78 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.4 (C, SitBu),
25.1 (CH2, C-5), 27.1 (CH3, SitBu), 34.6 (CH2, C-4), 39.2 (CH2,
CH2Ph), 46.0 (CH2, C-6), 64.9 (CH, C-2), 74.4 (CH, C-3), 126.2
(CH, C-Ph), 127.4 (CH, C-Ar), 127.6 (CH, C-Ar), 128.5 (CH, C-Ph),
129.3 (CH, C-Ph), 129.5 (CH, C-Ar), 129.6 (CH, C-Ar), 133.9 (C, C-
Ar), 134.8 (C, C-Ar), 135.9 (CH, C-Ar), 136.0 (CH, C-Ar), 139.6 (C,
C-Ph); HRMS (ESI) C28H36NOSi [MH+] calcd 430.2561, obsd
430.2571.
20
[α]D +12.5 (c 1.10, CHCl3); νmax(neat)/cm−1 3072, 2932, 2857,
1427, 1104; δH (300 MHz; CDCl3) 1.03 (9H, m, SitBu), 1.16−1.45
(2H, m, CHa,Hb-4, CHa,Hb-5), 1.47−1.59 (1H, m, CHa,Hb-5), 1.70−
1.85 (2H, m, CHa,Hb-4, NH), 2.55 (1H, td, J = 11.5, 2.9 Hz, CHa,Hb-
6), 2.83−2.93 (1H, m, CHa,Hb-6), 2.99−3.08 (1H, m, H-2), 3.44 (1H,
ddd, J = 9.7, 8.4, 4.1 Hz, H-3), 5.05−5.25 (2H, m, H-1′), 5.82−5.96
(1H, m, H-2′), 7.29−7.45 (6H, m, H-Ar), 7.63−7.72 (4H, m, H-Ar);
δC (75 MHz; CDCl3) 19.4 (C, SitBu), 25.1 (CH2, C-5), 27.0 (CH3,
SitBu), 34.1 (CH2, C-4), 45.4 (CH2, C-6), 66.0 (CH, C-2), 73.7 (CH,
C-3), 116.2 (CH2, C-1′), 127.3 (CH, C-Ar), 127.4 (CH, C-Ar), 129.4
(CH, C-Ar), 129.5 (CH, C-Ar), 133.9 (C, C-Ar), 134.9 (C, C-Ar),
135.9 (CH, C-Ar), 136.0 (CH, C-Ar), 139.4 (CH, C-2′); HRMS (ESI)
C23H32NOSi [MH+] calcd 366.2248, obsd 366.2255.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-phenylpiperidine
(13g). Following general procedure A, reaction of phenylmagnesium
chloride (2.0 M in THF, 0.42 mL, 0.86 mmol) and nitrone 5b (0.10 g,
0.28 mmol) followed by purification of the residue by column
chromatography, using MeOH/CH2Cl2 (0.5:99.5), gave the 2-
phenylpiperidin-1-ol 12g (0.098 g, 80%) as a colorless oil. Following
general procedure C, reduction of 2-phenylpiperidin-1-ol 12g (0.11 g
0.26 mmol) gave the title compound (0.080 g, 76%) as a colorless oil.
20
[α]D −15.2 (c 1.60, CHCl3); νmax(neat)/cm−1 3070, 2931, 2855,
1427, 1103; δH (400 MHz; CDCl3) 0.75 (9H, s, SitBu), 1.28−1.48
(2H, m, CHa,Hb-4, CHa,Hb-5), 1.48−1.57 (1H, m, CHa,Hb-5), 1.68−
1.79 (1H, m, CHa,Hb-4), 1.80 (1H, br s, NH), 2.59−2.69 (1H, m,
CHa,Hb-6), 2.90−2.98 (1H, m, CHa,Hb-6), 3.49 (1H, d, J = 8.7 Hz, H-
2), 3.62−3.70 (1H, m, H-3), 7.18−7.42 (13H, m, H-Ar), 7.55−7.61
(2H, m, H-Ar); δC (100 MHz; CDCl3) 19.0 (C, SitBu), 25.3 (CH2, C-
5), 26.6 (CH3, SitBu), 35.1 (CH2, C-4), 46.8 (CH2, C-6), 69.6 (CH,
C-2), 74.5 (CH, C-3), 127.2 (CH, C-Ar), 127.4 (CH, C-Ar), 128.1
(CH, C-Ar), 128.6 (CH, C-Ar), 129.3 (CH, C-Ar), 129.3 (CH, C-Ar),
133.5 (C, C-Ar), 135.2 (C, C-Ar), 135.9 (CH, C-Ar), 142.6 (C, C-Ar);
HRMS (EI+) C27H33NOSi [M+] calcd 415.2331, obsd 415.2324.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(3′,4′-dimethoxy-
phenyl)piperidine (13h). Following general procedure A, reaction of
3,4-dimethoxyphenylmagnesium bromide (0.5 M in THF, 1.9 mL,
0.96 mmol) and nitrone 5b (0.11 g, 0.32 mmol) followed by
purification of the residue by column chromatography, using EtOAc/
hexanes (5:95), gave the 2-(3,4-dimethoxyphenyl)piperidin-1-ol 12h
(0.12 g, 73%) as a colorless oil. Following general procedure C,
reduction of 2-(3′,4′-dimethoxyphenyl)piperidin-1-ol 12h (0.11 g,
0.23 mmol) gave the title compound (0.10 g, 97%) as a colorless oil.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-allylpiperidine
(trans-13e) and (2S,3S)-3-(tert-Butyldiphenylsilyloxy)-2-allylpi-
peridine (cis-13e). Following general procedure A, reaction of
allylmagnesium chloride (1.0 M in Et2O, 1.13 mL, 1.13 mmol) and
nitrone 5b (0.27 g, 0.75 mmol) followed by purification of the residue
by column chromatography, using MeOH/CH2Cl2 (0.5:99.5), gave
the trans-2-allylpiperidin-1-ol trans-12e (0.21 g, 70%) and cis-2-
allylpiperidin-1-ol cis-12e (0.032 g, 11%) as a colorless oils. Following
general procedure C, reduction of the first eluted compound, trans-2-
allylpiperidin-1-ol trans-12e (0.11 g, 0.28 mmol) gave trans-13e (0.095
g, 91%) as a yellow oil. [α]D20 +11.1 (c 1.88, CHCl3); νmax(neat)/cm−1
3072, 2932, 2857, 1428, 1105, 1083; δH (400 MHz; CDCl3) 1.05 (9H,
s, SitBu), 1.15−1.41 (2H, m, CHa,Hb-4, CHa,Hb-5), 1.45−1.54 (1H, m,
CHa,Hb-5), 1.66−1.82 (2H, m, NH, CHa,Hb-4), 1.82−1.93 (1H, m,
CHa,Hb-3′), 2.42−2.53 (2H, m, H-2, CHa,Hb-6), 2.77−2.89 (2H, m,
CHa,Hb-6, CHa,Hb-3′), 3.34 (1H, ddd, J = 9.9, 8.6, 4.2 Hz, H-3), 5.02−
5.12 (2H, m, H-1′), 5.71 (1H, dddd, J = 16.9, 10.2, 8.8, 5.7 Hz, H-2′),
7.32−7.44 (6H, m, H-Ar), 7.65−7.73 (4H, m, H-Ar); δC (100 MHz;
CDCl3) 19.4 (C, SitBu), 25.4 (CH2, C-5), 27.0 (CH3, SitBu), 34.5
(CH2, C-4), 37.1 (CH2, C-3′), 45.9 (CH2, C-6), 62.1 (CH, C-2), 73.9
(CH, C-3), 117.7 (CH2, C-1′), 127.3 (CH, C-Ar), 127.5 (CH, C-Ar),
129.4 (CH, C-Ar), 129.6 (CH, C-Ar), 133.8 (C, C-Ar), 134.8 (C, C-
Ar), 135.8 (CH, C-2′), 135.8 (CH, C-Ar), 135.9 (CH, C-Ar); HRMS
(EI+) C24H33NOSi [M+] calcd 379.2331, obsd 379.2323.
Following general procedure C, reduction of the second eluted
compound, cis-2-allylpiperidin-1-ol cis-12e (0.027 g, 0.068 mmol) gave
cis-13e (0.021 g, 81%) as an opaque oil. [α]D20 −13.1 (c 0.20, CHCl3);
νmax(neat)/cm−1 3072, 2931, 2856, 1427, 1104; δH (300 MHz;
CDCl3) 1.11 (9H, s, SitBu), 1.27−1.46 (2H, m, CHa,Hb-4, CHa,Hb-5),
1.65−1.78 (1H, m, CHa,Hb-4), 1.79−1.97 (1H, m, CHa,Hb-5), 2.14−
2.40 (2H, m, H-3′), 2.56−2.70 (2H, m, H-2, CHa,Hb-6), 2.86 (1H, br
s, NH), 3.05−3.18 (1H, m, CHa,Hb-6), 3.79−3.86 (1H, m, H-3),
4.89−5.01 (2H, m, H-1′), 5.55−5.71 (1H, m, H-2′), 7.32−7.48 (6H,
m, H-Ar), 7.65−7.74 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.5 (C,
SitBu), 21.1 (CH2, C-5), 27.2 (CH3, SitBu), 31.0 (CH2, C-4), 35.3
(CH2, C-3′), 44.9 (CH2, C-6), 60.1 (CH, C-2), 68.7 (CH, C-3), 117.0
(CH2, C-1′), 127.5 (CH, C-Ar), 127.6 (CH, C-Ar), 129.7 (CH, C-Ar),
129.7 (CH, C-Ar), 133.7 (C, C-Ar), 134.2 (C, C-Ar), 135.5 (CH, C-
2′), 136.0 (CH, C-Ar), 136.1 (CH, C-Ar); HRMS (ESI) C24H34NOSi
[MH+] calcd 380.2404, obsd 380.2395.
20
[α]D −17.4 (c 2.08, CHCl3); νmax(neat)/cm−1 3017, 2933, 2856,
1591, 1516, 1463, 1262, 1104; δH (300 MHz; CDCl3) 0.80 (9H, s,
SitBu), 1.30−1.48 (2H, m, CHa,Hb-4, CHa,Hb-5), 1.48−1.57 (1H, m,
CHa,Hb-5), 1.74−1.84 (1H, m, CHa,Hb-4), 1.91 (1H, br s, NH), 2.64
(1H, td, J = 11.4, 2.6 Hz, CHa,Hb-6), 2.89−2.99 (1H, m, CHa,Hb-6),
3.43 (1H, d, J = 8.7 Hz, H-2), 3.56−3.67 (1H, m, H-3), 3.78 (3H, s,
3′-OMe), 3.87 (3H, s, 4′-OMe), 6.76 (1H, d, J = 8.2 Hz, H-5′), 6.84
(1H, d, J = 1.9 Hz, H-2′), 6.86 (1H, dd, J = 8.2, 1.9 Hz, H-6′), 7.17−
7.27 (4H, m, H-Ar), 7.27−7.42 (4H, m, H-Ar), 7.53−7.69 (2H, m, H-
Ar); δC (75 MHz; CDCl3) 18.9 (C, SitBu), 25.1 (CH2, C-5), 26.6
(CH3, SitBu), 35.1 (CH2, C-4), 46.7 (CH2, C-6), 55.7 (CH3, C-3′),
55.9 (CH3, C-4′), 69.3 (CH, C-2), 74.5 (CH, C-3), 110.8 (CH, C-5′),
111.1 (CH, C-2′), 121.0 (CH, C-6′), 127.1 (CH, C-Ar), 127.1 (CH,
C-Ar), 129.2 (CH, C-Ar), 133.4 (C, C-Ar), 135.0 (C, C-Ar), 135.3 (C,
C-1′), 135.8 (CH, C-Ar), 135.8 (CH, C-Ar), 148.3 (C, C-4′), 148.8
(C, C-3′); HRMS (ESI) C29H38NO3Si [MH+] calcd 476.2615, obsd
476.2604.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(3′-pyridyl)-
piperidine (13i). Following general procedure A, reaction of (3-
pyridyl)magnesium chloride, prepared by reaction of 3-bromopyridine
(0.11 mL, 0.67 mmol) and isopropylmagnesium chloride (2.0 M in
THF, 0.31 mL, 0.62 mmol), with nitrone 5b (0.15 g, 0.42 mmol)
followed by purification of the residue by column chromatography
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-vinylpiperidine
(13f). Following general procedure A, reaction of vinylmagnesium
bromide (1.0 M in THF, 0.93 mL, 0.93 mmol) and nitrone 5b (0.22 g,
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using MeOH/CH2Cl2 (1:99), gave the 2-(3′-pyridyl)piperidin-1-ol 12i
(0.11 g, 62%) as a colorless oil. Following general procedure C,
reduction of 2-(3′-pyridyl)piperidin-1-ol 12i (0.11 g, 0.58 mmol) gave
prepared by reaction of n-BuLi (1.6 M in hexanes, 0.48 mL, 0.77
mmol) and ethynyltrimethylsilane (0.091 g, 0.93 mmol), followed by
purification of the residue by column chromatography, using EtOAc/
hexanes (gradient 1:39 to 1:4), gave the 2-(trimethylsilylethynyl)-
piperidin-1-ol 12l (0.22 g, 80%) as a colorless oil. Indium powder
20
the title compound (0.077 g, 71%) as a colorless oil. [α]D −16.5 (c
1.54, CHCl3); νmax(neat)/cm−1 3071, 2932, 2857, 1590, 1577, 1426,
1103; δH (300 MHz; CDCl3) 0.76 (9H, s, SitBu), 1.24−1.61 (3H, m,
CHa,Hb-4, H-5), 1.70−2.00 (2H, m, CHa,Hb-4, NH), 2.65 (1H, td J =
11.5, 2.6 Hz, CHa,Hb-6), 2.90−3.00 (1H, m, CHa,Hb-6), 3.53 (1H, d, J
= 8.7 Hz, H-2), 3.57−3.68 (1H, m, H-3), 7.16 (1H, dd, J = 4.7, 7.7 Hz,
H-5′), 7.20−7.30 (4H, m, H-Ar), 7.30−7.45 (4H, m, H-Ar), 7.52−
7.63 (3H, m, H-Ar, H-4′), 8.50 (1H, dd, J = 1.4, 4.7 Hz, H-6′), 8.60
(1H, d, J = 1.6 Hz, H-2′); δC (75 MHz; CDCl3) 18.9 (C, SitBu), 25.1
(CH2, C-5), 26.5 (CH3, SitBu), 34.9 (CH2, C-4), 46.6 (CH2, C-6),
67.0 (CH, C-2), 74.4 (CH, C-3), 123.2 (CH, C-5′), 127.2 (CH, C-
Ar), 127.4 (CH, C-Ar), 129.4 (CH, C-Ar), 129.4 (CH, C-Ar), 133.0
(C, C-Ar), 134.7 (C, C-Ar), 135.5 (CH, C-4′), 135.7 (CH, C-Ar),
135.8 (CH, C-Ar), 138.0 (C, C-3′), 148.8 (CH, C-6′), 150.3 (CH, C-
2′); HRMS (ESI) C26H33N2OSi [MH+] calcd 417.2357, obsd
417.2366.
(0.070 g, 0.61 mmol) was added to
a solution of 2-
(trimethylsilylethynyl)piperidin-1-ol 12l (0.18 g, 0.31 mmol) in
EtOH (3 mL) and the suspension heated to 80 °C. Aqueous HCl
(2 M, 0.045 mL) was added and the suspension heated to 100 °C and
stirred for 2 h. The reaction was concentrated under reduced pressure
and the residue dissolved in EtOAc (20 mL). The pH was adjusted to
10 by the dropwise addition of an aqueous solution of 2 M NaOH.
The mixture was filtered through Celite and the filtrate concentrated
under reduced pressure. The residue was dissolved in EtOAc (20 mL)
and washed with brine (20 mL), and the aqueous phase was extracted
with EtOAc (3 × 20 mL). The combined organic extracts were dried
(Na2SO4) and concentrated under reduced pressure. The residue was
purified by flash column chromatography, eluting with EtOAc/hexanes
(3:17), to give the title compound (0.093 g, 70%) as a colorless oil.
20
[α]D −5.3 (c 1.66, CHCl3); νmax(neat)/cm−1 3071, 3051, 2932,
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-butylpiperidin-1-ol
(12a). Following general procedure B, reaction of nitrone 5b (0.30 g,
0.83 mmol) and MeLi (1.6 M in Et2O, 0.78 mL, 1.25 mmol) followed
by purification of the residue by column chromatography using
EtOAc/hexanes (1:4) as eluent gave the 2-methylpiperidin-1-ol 12a
(0.20 g, 64%) as a colorless oil.
2857, 2175, 1590, 1428, 1249, 1105, 840; δH (400 MHz; CDCl3) 0.12
(9H, s, SiMe3), 1.09 (9H, s, SitBu), 1.18−1.38 (2H, m, CHa,Hb-4,
CHa,Hb-5), 1.53−1.63 (1H, m, CHa,Hb-5), 1.71−1.81 (1H, m,
CHa,Hb-4), 1.81 (1H, br s, NH), 2.55 (1H, ddd, J = 12.3, 9.1, 3.2
Hz, CHa,Hb-6), 2.86−2.95 (1H, m, CHa,Hb-6), 3.45 (1H, d, J = 7.0 Hz,
H-2), 3.71 (1H, ddd, J = 8.0, 7.2, 3.5 Hz, H-3), 7.32−7.45 (6H, m, H-
Ar), 7.68−7.78 (4H, m, H-Ar); δC (100 MHz; CDCl3) −0.1 (CH3,
SiMe3), 19.4 (C, SitBu), 24.0 (CH2, C-5), 27.0 (CH3, SitBu), 32.4
(CH2, C-4), 44.3 (CH2, C-6), 55.4 (CH, C-2), 72.1 (CH, C-3), 88.1
(C, C-2′), 106.1 (C, C-1′), 127.4 (CH, C-Ar), 127.5 (CH, C-Ar),
129.4 (CH, C-Ar), 129.5 (CH, C-Ar), 133.6 (C, C-Ar), 134.6 (C, C-
Ar), 135.8 (CH, C-Ar), 135.9 (CH, C-Ar); HRMS (ESI)
C26H38NOSi2 [MH+] calcd 436.2486, obsd 436.2491.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-butylpiperidine
(13j). Following general procedure B, reaction of nitrone 5b (0.10 g,
0.28 mmol) and n-BuLi (1.6 M in hexanes, 0.27 mL, 0.42 mmol)
followed by purification of the residue by column chromatography,
using EtOAc/hexanes (1:9), gave the 2-butylpiperidin-1-ol 12j (0.070
g, 50%) as a colorless oil. Following general procedure C, reduction of
2-butylpiperidin-1-ol 12j (0.068 g, 0.17 mmol) gave the title
20
compound (0.048 g, 73%) as a colorless oil. [α]D +22.5 (c 0.84,
CHCl3); νmax(neat)/cm−1 3071, 2931, 2857, 1428, 1105, 1082; δH
(300 MHz; CDCl3) 0.86 (3H, t, J = 6.9 Hz, 1′-H), 1.05 (9H, s, SitBu),
1.13−1.44 (7H, m, CHa,Hb-4, CHa,Hb-5, 2′-H, 3′-H, CHa,Hb-4′),
1.49−1.60 (1H, m, CHa,Hb-5), 1.70−1.81 (1H, m, CHa,Hb-4), 1.83−
1.98 (1H, m, CHa,Hb-4′), 2.32 (1H, m, NH), 2.42−2.58 (2H, m, H-2,
CHa,Hb-6), 2.82−2.93 (1H, m, CHa,Hb-6), 3.34 (1H, ddd, J = 9.6, 8.2,
4.1 Hz, H-3), 7.30−7.45 (6H, m, H-Ar), 7.63−7.73 (4H, m, H-Ar); δC
(75 MHz; CDCl3) 14.0 (CH3, C-1′), 19.4 (C, SitBu), 22.8 (CH2, C-
2′), 25.2 (CH2, C-5), 27.1 (CH3, SitBu), 27.8 (CH2, C-3′), 31.6 (CH2,
C-4′), 33.9 (CH2, C-4), 45.5 (CH2, C-6), 62.8 (CH, C-2), 73.7 (CH,
C-3), 127.3 (CH, C-Ar), 127.5 (CH, C-Ar), 129.4 (CH, C-Ar), 129.5
(CH, C-Ar), 133.9 (C, C-Ar), 134.9 (C, C-Ar), 135.9 (CH, C-Ar),
135.9 (CH, C-Ar); HRMS (ESI) C25H38NOSi [MH+] calcd 396.2717,
obsd 396.2719.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(4′-methoxyphenyl)-
piperidine (13m). Following general procedure B, reaction of nitrone
5b (0.26 g 0.74 mmol) and (4 methoxyphenyl)lithium, prepared from
n-BuLi (1.6 M in hexanes, 0.69 mL, 1.11 mmol) and 4-bromoanisole
(0.23 g, 1.26 mmol), followed by purification of the residue by column
chromatography, using MeOH/CH2Cl2 (0.5:99.5), gave the 2-(4′-
methoxyphenyl)piperidin-1-ol 12m (0.22 g, 69%) as a colorless oil.
Following general procedure C, reduction of 2-(4′-methoxyphenyl)-
piperidin-1-ol 12m (0.13 g, 0.27 mmol) gave the title compound (0.11
20
g, 92%) as a colorless oil. [α]D −37.0 (c 1.76, CHCl3); νmax(neat)/
cm−1 3071, 2932, 2856, 1612, 1512, 1427, 1249, 1239, 1104; δH (400
MHz; CDCl3) 0.79 (9H, s, SitBu), 1.27−1.47 (2H, m, CHa,Hb-4,
CHa,Hb-5), 1.48−1.56 (1H, m, CHa,Hb-5), 1.70−1.84 (2H, m,
CHa,Hb-4, NH), 2.57−2.67 (1H, m, CHa,Hb-6), 2.89−2.96 (1H, m,
CHa,Hb-6), 3.44 (1H, d, J = 8.7 Hz, H-2), 3.57−3.65 (1H, m, H-3),
3.80 (3H, s, OMe), 6.79−6.85 (2H, m, H-3′, H-5′), 7.17−7.26 (6H,
m, H-Ar, H-2′, H-6′), 7.28−7.41 (4H, m, H-Ar), 7.54−7.61 (2H, m,
H-Ar); δC (100 MHz; CDCl3) 18.9 (C, SitBu), 25.3 (CH2, C-5), 26.7
(CH3, SitBu), 35.1 (CH2, C-4), 46.8 (CH2, C-6), 55.3 (CH3, OMe),
68.9 (CH, C-2), 74.6 (CH, C-3), 113.5 (CH, C-3′, C-5′), 127.2 (CH,
C-Ar), 127.2 (CH, C-Ar), 129.2 (CH, C-Ar), 129.3 (CH, C-Ar), 129.4
(CH, C-2′, C-6′), 133.5 (C, C-Ar), 135.0 (C, C-1′), 135.2 (C, C-Ar),
135.9 (CH, C-Ar), 135.9 (CH, C-Ar), 159.0 (C, C-4′); HRMS (ESI)
C28H36NO2Si [MH+] calcd 446.2510, obsd 446.2522.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-tert-butylpiperidine
(13k). Following general procedure B, reaction of nitrone 5b (0.26 g,
0.74 mmol) and tert-BuLi (1.7 M in pentane, 0.65 mL, 1.10 mmol)
followed by purification of the residue by column chromatography,
using EtOAc/hexanes (1:9), gave the tert-butylpiperidin-1-ol 12k
(0.099 g, 31%) as a colorless oil. Following general procedure C,
reduction of tert-butylpiperidin-1-ol 12k (0.082 g, 0.20 mmol) gave the
title compound (0.073 g, 93%) as a colorless oil. [α]D20 +46.0 (c 1.18,
CHCl3); νmax(neat)/cm−1 3071, 2933, 2858, 1474, 1428, 1105, 1075;
δH (300 MHz; CDCl3) 0.96−1.18 (19H, m, CHa,Hb-5, SitBu, CtBu),
1.24−1.45 (2H, m, CHa,Hb-4, CHa,Hb-5), 1.57−1.70 (1H, m, CHa,Hb-
4), 1.87 (1H, br s, NH), 2.33 (1H, d, J = 7.8 Hz, H-2), 2.47 (1H, td, J
= 11.6, 3.0 Hz, CHa,Hb-6), 2.82−2.93 (1H, m, CHa,Hb-6), 3.67 (1H,
ddd, J = 9.4, 7.7, 3.7 Hz, H-3), 7.31−7.46 (6H, m, H-Ar), 7.70−7.82
(4H, m, H-Ar); δC (75 MHz; CDCl3); 19.3 (C, SitBu), 24.9 (CH2, C-
(2S,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(2′-furanyl)-
piperidine (13n). Following general procedure B, reaction of nitrone
5b (0.20 g, 0.56 mmol) and 2-lithiofuran, prepared by reaction of n-
BuLi (1.6 M in hexanes, 0.53 mL, 0.84 mmol) and furan (0.065 g, 0.96
mmol), followed by purification of the residue by column
chromatography, using EtOAc/hexanes (1:9), gave the 2-(2′-furanyl)-
piperidin-1-ol 12n (0.17 g, 72%) as a yellow oil. Following general
procedure C, reduction of 2-(2′-furanyl)piperidin-1-ol 12n (0.10 g,
0.24 mmol) gave the title compound (0.091 g, 94%) as a yellow oil.
[α]D20 +4.5 (c 1.82, CHCl3); νmax(neat)/cm−1 3071, 2930, 2856, 1590,
1427, 1104; δH (300 MHz; CDCl3) 0.88 (9H, m, SitBu), 1.22−1.49
(2H, m, CHa,Hb-4, CHa,Hb-5), 1.49−1.60 (1H, m, CHa,Hb-5), 1.70−
1.83 (2H, m, CHa,Hb-4, NH), 2.59 (1H, td, J = 11.5, 2.9 Hz, CHa,Hb-
t
t
5), 27.0 (CH3, SitBu), 28.1 (CH3, Bu), 33.8 (C, Bu), 35.0 (CH2, C-
4), 46.3 (CH2, C-6), 70.7 (CH, C-2), 74.0 (CH, C-3), 127.2 (CH, C-
Ar), 127.6 (CH, C-Ar), 129.2 (CH, C-Ar), 129.6 (CH, C-Ar), 133.7
(C, C-Ar), 135.5 (C, C-Ar), 135.7 (CH, C-Ar), 135.9 (CH, C-Ar);
HRMS (ESI) C25H38NOSi [MH+] calcd 396.2717, obsd 396.2717.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(trimethylsilyl-
ethynyl)piperidine (13l). Following general procedure B, reaction of
nitrone 5b (0.22 g, 0.62 mmol) with (trimethylsilylethynyl)lithium,
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6), 2.87−2.96 (1H, m, CHa,Hb-6), 3.67 (1H, d, J = 8.6 Hz, H-2), 3.85
(1H, ddd, J = 9.7, 8.6, 4.2 Hz, H-3), 6.19 (1H, dd, J = 3.2, 0.8 Hz, H-
3′), 6.28 (1H, dd, J = 3.2, 1.9 Hz, H-4′), 7.24−7.48 (9H, m, H-Ar, H-
5′), 7.59−7.66 (2H, m, H-Ar); δC (75 MHz; CDCl3) 19.0 (C, SitBu),
25.1 (CH2, C-5), 26.7 (CH3, SitBu), 34.5 (CH2, C-4), 46.0 (CH2, C-
6), 61.8 (CH, C-2), 72.4 (CH, C-3), 107.3 (CH, C-3′), 110.0 (CH, C-
4′), 127.2 (CH, C-Ar), 127.3 (CH, C-Ar), 129.3 (CH, C-Ar), 129.3
(CH, C-Ar), 133.5 (C, C-Ar), 134.9 (C, C-Ar), 135.8 (CH, C-Ar),
135.8 (CH, C-Ar), 141.2 (CH, C-5′), 155.1 (C, C-2′); HRMS (ESI)
C25H32NO2Si [MH+] calcd 406.2197, obsd 406.2192.
(2S,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(2′-thienyl)-
piperidine (13o). Following general procedure B, reaction of nitrone
5b (0.22 g, 0.62 mmol) with 2-lithiothiophene, prepared by reaction of
n-BuLi (1.6 M in hexanes, 0.58 mL, 0.93 mmol) and thiophene (0.089
g, 1.06 mmol), followed by purification of the residue by column
chromatography, using EtOAc/hexanes (1:9), gave 2-(2′-thienyl)-
piperidin-1-ol 12o (0.23 g, 85%) as a colorless oil. Following general
procedure C, reduction of 2-(2′-thienyl)piperidin-1-ol 12o (0.12 g,
0.26 mmol) gave the title compound (0.090 g, 81%) as a yellow oil.
[α]D20 +2.7 (c 1.32, CHCl3); νmax(neat)/cm−1 3338, 3072, 3048, 2934,
2856, 1590, 1428, 1106; δH (300 MHz; CDCl3) 0.85 (9H, s, SitBu),
1.24−1.43 (2H, m, CHa,Hb-4, CHa,Hb-5), 1.43−1.55 (1H, m, CHa,Hb-
5), 1.65−1.75 (1H, m, CHa,Hb-4), 1.87 (1H, br s, NH), 2.56−2.68
(1H, m, CHa,Hb-6), 2.87−2.97 (1H, m, CHa,Hb-6), 3.57−3.67 (1H, m,
H-3), 3.84 (1H, d, J = 8.3 Hz, H-2), 6.93 (1H, dd, J = 5.0, 3.4 Hz, H-
4′), 7.00−7.04 (1H, m, H-3′), 7.16−7.20 (1H, m, H-5′), 7.20−7.28
(2H, m, H-Ar), 7.28−7.43 (6H, m, H-Ar), 7.58−7.67 (2H, m, H-Ar);
δC (75 MHz; CDCl3) 19.0 (C, SitBu), 24.8 (CH2, C-5), 26.7 (CH3,
SitBu), 34.6 (CH2, C-4), 46.4 (CH2, C-5), 64.3 (CH, C-2), 75.4 (CH,
C-3), 123.9 (CH, C-5′), 125.5 (CH, C-3′), 126.1 (CH, C-4′), 127.3
(CH, C-Ar), 127.3 (CH, C-Ar), 129.3 (CH, C-Ar), 129.3 (CH, C-Ar),
133.4 (C, C-Ar), 135.0 (C, C-Ar), 135.7 (CH, C-Ar), 135.8 (CH, C-
Ar), 146.3 (C, C-2′); HRMS (ESI) C25H32NOSSi [MH+] calcd
422.1968, obsd 422.1977.
organic extracts were dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with EtOAc/hexanes (1:19), to give the title compound (1.12
20
g, 90%) as a colorless oil. [α]D −23.0 (c 2.04, CHCl3); νmax(neat)/
cm−1 3222, 3073, 2930, 2857, 1471, 1253, 1427, 1104; δH (300 MHz;
DMSO-d6, 373 K) 0.07 (6H, s, SiMe2), 0.88 (9H, s, SitBu), 1.07 (9H,
s, SitBu), 1.24−1.46 (2H, m, CHa,Hb-5, CHa,Hb-4), 1.56−1.82 (2H, m,
CHa,Hb-5, CHa,Hb-4), 2.57−2.69 (1H, m, CHa,Hb-6), 2.85−2.99 (1H,
m, CHa,Hb-6), 3.53−3.62 (1H, m, H-2), 3.91−4.01 (1H, m, H-3),
4.20−4.27 (2H, m, H-3′), 7.35−7.49 (6H, m, H-Ar), 7.49−7.59 (1H,
m, NOH), 7.61−7.76 (4H, m, H-Ar); δC (75 MHz; DMSO-d6, 373 K)
−5.9 (CH3, SiMe2), 17.2 (C, SitBu), 18.3 (C, SitBu), 19.5 (CH2, C-5),
25.1 (CH3, SitBu), 26.3 (CH3, SitBu), 29.2 (CH2, C-4), 50.8 (CH2, C-
3′), 54.2 (CH2, C-6), 63.9 (CH, C-2), 71.7 (CH, C-3), 82.3 (C, C-2′),
83.2 (C, C-1′), 126.9 (CH, C-Ar), 126.9 (CH, C-Ar), 128.9 (CH, C-
Ar), 129.0 (CH, C-Ar), 133.2 (C, C-Ar), 133.4 (C, C-Ar), 134.7 (CH,
C-Ar), 134.7 (CH, C-Ar); HRMS (ESI) C30H46NO3Si2 [MH+] calcd
524.3011, obsd 524.3012.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(3-hydroxyprop-1-
ynyl)piperidine (21). Indium powder (0.44 g, 3.80 mmol) was added
to a solution of hydroxylamine 20 (0.99 g, 1.90 mmol) in EtOH (22
mL) and the suspension heated to 80 °C. Aqueous HCl (1 M, 3.4 mL)
was added and the suspension heated to 100 °C and stirred for 2 h.
The reaction mixture was cooled to rt and the pH adjusted to 10 by
the dropwise addition of an aqueous solution of 2 M NaOH. The
mixture was filtered through Celite and the filtrate concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and
washed with a solution of saturated brine (20 mL), and the aqueous
phase was extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with MeOH/CH2Cl2 (gradient 5:95 to 9:91), to give the title
compound (0.64 g, 85%) as a yellow oil. [α]D20 −0.4 (c 1.08, CHCl3);
νmax(neat)/cm−1 3285, 3071, 2932, 2856, 1428, 1105; δH (300 MHz;
CDCl3) 1.08 (9H, s, SitBu), 1.18−1.34 (1H, m, CHa,Hb-5), 1.34−1.49
(1H, m, CHa,Hb-4), 1.58−1.74 (1H, m, CHa,Hb-5), 1.78−1.91 (1H, m,
CHa,Hb-4), 2.52−2.64 (1H, m, CHa,Hb-6), 2.84−3.00 (3H, m,
CHa,Hb-6, NH, OH), 3.45−3.52 (1H, m, H-2), 3.61−3.70 (1H, m,
H-3), 4.04 (2H, d, J = 1.5 Hz, H-1), 7.31−7.41 (6H, m, H-Ar), 7.63−
7.73 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.3 (C, SitBu), 23.4 (CH2,
C-5′), 26.9 (CH3, SitBu), 31.4 (CH2, C-4′), 43.6 (CH2, C-6′), 50.4
(CH2, C-1), 54.1 (CH, C-2′), 71.5 (CH, C-3′), 83.6, (C, C-2), 84.2
(C, C-3), 127.4 (CH, C-Ar), 127.5 (CH, C-Ar), 129.6 (CH, C-Ar),
129.6 (CH, C-Ar), 133.8 (C, C-Ar), 133.9 (C, C-Ar), 135.8 (CH, C-
Ar), 135.9 (CH, C-Ar); HRMS (EI) C24H31NO2Si [M+] calcd
393.2124, obsd 393.2119.
(4aS,5S)-5-(tert-Butyldiphenylsilyloxy)-4-methoxy-
2,4a,5,6,7,8-hexahydropyrido[1,2-b][1,2]oxazine (16). Following
general procedure B, reaction of nitrone 5b (0.055 g, 0.17 mmol) with
lithiated methoxyallene, prepared by reaction of n-BuLi (1.6 M in
hexanes, 0.15 mL, 0.23 mmol) and methoxyallene (0.018 g, 0.26
mmol), followed by purification of the residue by column
chromatography, using EtOAc/hexanes (1:4), gave the 2-(1′-
methoxypropa-1,2-dien-1-yl)piperidin-1-ol 15 (0.036 g, 50%) as a
colorless oil. A solution of 2-(1′-methoxypropa-1,2-dien-1-yl)-
piperidin-1-ol 15 (0.033 g, 0.078 mmol) in CH2Cl2 (1.5 mL) was
stirred at rt for 5 d. The solvent was removed under reduced pressure
and the residue purified by flash column chromatography, eluting with
EtOAc/hexanes (1:9), to give the title compound (0.031 g, 95%) as a
20
colorless oil. [α]D +36.1 (c 0.62, CHCl3); νmax(neat)/cm−1 3072,
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-((Z)-3-hydroxyprop-
1-enyl)piperidine (19). Lindlar catalyst (0.095 g) was added
portionwise to a solution of hydroxylamine 20 (0.38 g, 0.75 mmol)
in EtOAc (10 mL). The mixture was stirred under a hydrogen
atmosphere for 1.25 h, filtered through Celite, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography, eluting with EtOAc/hexanes (gradient 1:19 to
2931, 2866, 1669, 1428, 1105; δH (400 MHz; CDCl3) 0.99−1.11 (9H,
m, SitBu), 1.23−1.40 (2H, m, CHa,Hb-6, CHa,Hb-7), 1.57−1.80 (2H,
m, CHa,Hb-6, CHa,Hb-7), 2.69−2.88 (1H, m, CHa,Hb-8), 3.07−3.21
(1H, m, H-4a), 3.22−3.49 (4H, m, OMe, CHa,Hb-8), 4.13−4.58 (3H,
m, H-2, H-5), 4.53 (1H, t, J = 2.5 Hz, H-3), 7.29−7.44 (6H, m, H-Ar),
7.65−7.73 (4H, m, H-Ar); δC (100 MHz; CDCl3) 19.3 (C, SitBu),
20.0 (CH2, C-7), 26.8 (CH3, SitBu), 33.7 (CH2, C-6), 53.1 (CH2, C-
8), 54.0 (CH3, OMe), 65.9 (CH, C-4a), 66.7 (CH2, C-2), 70.7 (CH,
C-5), 91.0 (CH, C-3), 127.3 (CH, C-Ar), 127.3 (CH, C-Ar), 129.3
(CH, C-Ar), 129.3 (CH, C-Ar), 134.3 (C, C-Ar), 135.2 (C, C-Ar),
135.9 (CH, C-Ar), 156.2 (C, C-4); HRMS (ESI) C25H34NO3Si
[MH+] calcd 424.2302, obsd 424.2315.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(3-(tert-butyl-
dimethylsilyloxy)prop-1-ynyl)piperidin-1-ol (20). A solution of
n-BuLi (1.5 M in hexanes, 1.98 mL, 2.97 mmol) was added dropwise
to a solution of 3-(tert-butyldimethylsilyloxy)prop-1-yne (0.61 g, 3.56
mmol) in THF (8 mL) at −78 °C. The solution was stirred for 15 min
and then warmed to 0 °C and stirred for an additional 30 min. A
solution of nitrone 5b (0.84 g, 2.38 mmol) in THF (18 mL) was
added at −78 °C and the mixture warmed to 0 °C and stirred for a
further 1 h. Saturated aqueous NH4Cl (10 mL) was added and the
aqueous phase extracted with EtOAc (3 × 50 mL). The combined
20
3:17), to give the alkene (0.34 g, 90%) as a colorless oil. [α]D
−38.8 (c 0.60, CHCl3); νmax(neat)/cm−1 3228, 2928, 2856, 1427,
1090; δH (300 MHz; DMSO-d6, 373 K) 0.06 (6H, s, SiMe2), 0.91 (9H,
s, SitBu), 1.03 (9H, s, SitBu), 1.15−1.36 (2H, m, CHa,Hb-4, CHa,Hb-5),
1.39−1.64 (2H, m, CHa,Hb-5, CHa,Hb-4), 2.36−2.49 (1H, m, CHa,Hb-
6), 2.95−3.06 (1H, m, CHa,Hb-6), 3.08−3.19 (1H, m, H-2), 3.55−3.68
(1H, m, H-3), 4.23−4.44 (2H, m, H-3′), 5.25−5.37 (1H, m, H-1′),
5.53−5.65 (1H, m, H-2′), 7.10−7.20 (1H, m, NOH), 7.34−7.49 (6H,
m, H-Ar), 7.60−7.71 (4H, m, H-Ar); δC (75 MHz; DMSO-d6, 373 K)
−5.9 (CH3, SiMe2), −5.8 (CH3, SiMe2), 17.2 (C, SitBu), 18.2 (C,
SitBu), 19.8 (CH2, C-5), 25.2 (CH3, SitBu), 26.3 (CH3, SitBu), 32.1
(CH2, C-4), 56.3 (CH2, C-6), 59.5 (CH2, C-3′), 70.1 (CH, C-2), 72.1
(CH, C-3), 126.7 (CH, C-Ar), 126.8 (CH, C-Ar), 128.8 (CH, C-Ar),
128.9 (CH, C-Ar), 129.1 (CH, C-1′), 132.7 (CH, C-2′), 133.2 (C, C-
Ar), 134.0 (C, C-Ar), 134.7 (CH, C-Ar), 134.8 (CH, C-Ar); HRMS
(ESI) C30H48NO3Si2 [MH+] calcd 526.3167, obsd 526.3163.
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Article
Indium powder (0.43 g, 3.70 mmol) was added to a solution of the
alkene prepared above (0.97 g, 1.85 mmol) in EtOH (22 mL) and the
suspension heated to 80 °C. Aqueous HCl (1 M, 3.4 mL) was added
and the suspension heated to 100 °C and stirred for 2 h. The reaction
mixture was cooled to rt and the pH adjusted to 10 by the dropwise
addition of an aqueous solution of 2 M NaOH. The mixture was
filtered through Celite and the filtrate concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed
with brine (20 mL), and the aqueous phase was extracted with CH2Cl2
(3 × 30 mL). The combined organic extracts were dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with MeOH/CH2Cl2 (gradient
3:97 to 9:91), to give the title compound (0.63 g, 86%) as a white
solid. Recrystallization from Et2O/hexanes (1:1) gave white needles.
washed with a 10% CuSO4(aq) (15 mL). The aqueous layer was
extracted with EtOAc (3 × 30 mL), and the combined organic extracts
were concentrated under reduced pressure. The residue was purified
by flash column chromatography, eluting with EtOAc/hexanes
(gradient 1:9 to 3:7), to give the title compound 22 (0.23 g, 68%)
and the (1S,2R,8S,8aR)-isomer (0.025 g, 7.6%) as colorless oils. Data
for 22: Rf (25% EtOAc/hexanes) 0.14; [α]D20 +63.4 (c 0.50, CHCl3);
νmax(neat)/cm−1 2933, 2856, 1743, 1428, 1371, 1243, 1223, 1079; δH
(300 MHz; CDCl3) 1.01 (9H, s, SitBu), 1.14−1.55 (3H, m, 6-H,
CHa,Hb-7), 1.70−1.90 (5H, m, CHa,Hb-5, CHa,Hb-7, OAc), 1.98 (3H,
s, OAc), 2.15 (1H, dd, J = 8.8, 4.1 Hz, 8a-H), 2.56 (1H, dd, J = 11.2,
7.7 Hz, CHa,Hb-3), 2.86−2.96 (1H, m, CHa,Hb-5), 2.98 (1H, dd, J =
11.2, 1.9 Hz, CHa,Hb-3), 3.96 (1H, ddd, J = 10.5, 8.8, 4.6 Hz, 8-H),
5.33−5.42 (1H, m, 2-H), 5.51 (1H, dd, J = 6.4, 4.1 Hz, 1-H), 7.30−
7.46 (6H, m, H-Ar), 7.57−7.68 (4H, m, H-Ar); δC (75 MHz; CDCl3)
19.0 (C, SitBu), 20.5 (CH3, OAc), 20.7 (CH3, OAc), 23.3 (CH2, C-6),
26.8 (CH3, SitBu), 33.9 (CH2, C-7), 52.1 (CH2, C-5), 60.1 (CH2, C-
2), 68.5 (CH, C-8), 69.4 (CH, C-2), 71.7 (CH, C-1), 71.9 (CH, C-
8a), 127.4 (CH, C-Ar), 127.7 (CH, C-Ar), 129.6 (CH, C-Ar), 129.7
(CH, C-Ar), 133.7 (C, C-Ar), 134.6 (C, C-Ar), 135.7 (CH, C-Ar),
135.8 (CH, C-Ar), 170.0 (CO, 2-OAc), 170.3 (CO, 1-OAc);
HRMS (ESI) C28H38NO5Si [MH+] calcd 496.2514, obsd 496.2512.
Data for (1S,2R,8S,8aR)-isomer: Rf (25% EtOAc/hexanes) 0.34;
20
mp 123.1−124.5 °C; [α]D −19.7 (c 1.33, CHCl3); νmax(neat)/cm−1
3261, 3072, 3048, 2946, 2930, 2905, 2873, 1590, 1427, 1106, 1092; δH
(300 MHz; CDCl3) 1.04 (9H, s, SitBu), 1.14−1.31 (1H, m, CHa,Hb-
5), 1.36−1.51 (1H, m, CHa,Hb-4), 1.57−1.70 (1H, m, CHa,Hb-5),
1.70−1.82 (1H, m, CHa,Hb-4), 2.59 (1H, ddd, J = 12.8, 9.8, 3.2 Hz,
CHa,Hb-6), 2.83 (1H, dt, J = 12.8, 4.3 Hz, CHa,Hb-6), 3.40−3.57 (2H,
m, H-2, H-3), 3.74 (2H, br s, NH, OH), 4.08 (1H, ddt, J = 14.6, 5.1,
1.2 Hz, CHa,Hb-1′), 4.23 (1H, ddd, J = 14.6, 5.9, 1.2 Hz, CHa,Hb-1′),
5.46 (1H, ddt, J = 11.5, 6.3, 1.2 Hz, H-3′), 5.74−5.85 (1H, m, H-2′),
7.31−7.46 (6H, m, H-Ar), 7.63−7.72 (4H, m, H-Ar); δC (75 MHz;
CDCl3) 19.3 (C, SitBu), 24.5 (CH2, C-5), 27.0 (CH3, SitBu), 32.3
(CH2, C-4), 43.8 (CH2, C-6), 59.1 (CH, C-2), 59.6 (CH2, C-1′), 72.9
(CH, C-3), 127.4 (CH, C-Ar), 127.6 (CH, C-Ar), 129.6 (CH, C-Ar),
129.7 (CH, C-Ar), 131.4 (CH, C-3′), 133.5 (CH, C-2′), 133.6 (C, C-
Ar), 134.4 (C, C-Ar), 135.8 (CH, C-Ar), 135.8 (CH, C-Ar); HRMS
(EI+) C24H33NO2Si [M+] calcd 395.2281, obsd 395.2288.
20
[α]D −54.8 (c 1.46, CHCl3); νmax(neat)/cm−1 2934, 2858, 1743,
1427, 1371, 1243, 1223, 1104; δH (300 MHz; CDCl3) 1.02 (9H, s,
SitBu), 1.17−1.37 (2H, m, CHa,Hb-6, CHa,Hb-7), 1.41−1.52 (1H, m,
CHa,Hb-6), 1.63−1.74 (1H, m, CHa,Hb-7), 1.95−2.08 (7H, m,
CHa,Hb-5, 2 × OAc), 2.22 (1H, dd, J = 9.3, 6.9 Hz, CHa,Hb-3),
2.34−2.43 (1H, m, 8a-H), 2.74−2.84 (1H, m, CHa,Hb-5), 3.45 (1H,
dd, J = 9.4, 6.9 Hz, CHa,Hb-3), 3.57−3.68 (1H, m, 8-H), 4.92 (1H, t, J
= 7.4 Hz, 1-H), 5.17 (1H, dt, J = 7.4, 6.9 Hz, 2-H), 7.32−7.46 (6H, m,
H-Ar), 7.64−7.72 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.2 (C,
SitBu), 20.6 (CH3, OAc), 20.7 (CH3, OAc), 23.7 (CH2, C-6), 26.8
(CH3, SitBu), 34.3 (CH2, C-7), 51.2 (CH2, C-5), 58.3 (CH2, C-3),
68.0 (CH, C-2), 71.2 (CH, C-8a), 73.6 (CH, C-8), 74.7 (CH, C-1),
127.4 (CH, C-Ar), 127.7 (CH, C-Ar), 129.5 (CH, C-Ar), 129.7 (CH,
C-Ar), 133.4 (C, C-Ar), 134.7 (C, C-Ar), 135.7 (CH, C-Ar), 135.8
(CH, C-Ar), 169.6 (CO, OAc), 170.0 (CO, OAc); HRMS (ESI)
C28H38NO5Si [MH+] calcd 496.2514, obsd 496.2521.
(8S,8aR)-8-(tert-Butyldiphenylsilyloxy)-3,5,6,7,8,8a-hexahy-
droindolizine (17). A solution of di-p-chlorobenzyl azodicarboxylate
(DCAD) (0.34 g, 0.93 mmol) in CH2Cl2 (5 mL) was added to a
stirred solution of amino alcohol 19 (0.30 g, 0.75 mmol) and PPh3
(0.24 g, 0.93 mmol) in CH2Cl2 (20 mL) over a period of 10 min at 0
°C. The solution was stirred for 1 h at 0 °C and then filtered through a
short pad of Celite and concentrated under reduced pressure. The
residue was purified by column chromatography on basic alumina,
eluting with EtOAc/hexanes (gradient 0:100 to 3:97), to give the title
20
(1R,2S,8S,8aS)-Octahydroindolizine-1,2,8-triol. (+)-Swainso-
nine (+)-(4). A solution of indolizidine 22 (0.40 g, 0.81 mmol),
Et3N (1.57 mL, 11.3 mmol), and triethylamine trihydrofluoride (1.32
mL, 8.07 mmol) in MeCN (25 mL) was stirred at 80 °C for 5 d. The
reaction was cooled to rt and saturated aqueous NaHCO3 (50 mL)
added. The aqueous phase was extracted with EtOAc (3 × 80 mL),
and the combined organic extracts were dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with MeOH/CH2Cl2 (gradient
1:99 to 3:97), to give the diacetate (0.182 g, 88%) as a tan solid.
Recrystallization from Et2O/hexanes (1:1) yielded colorless needles.
compound (0.25 g, 89%) as an opaque oil. [α]D +72.7 (c 0.48,
CHCl3); νmax(neat)/cm−1 3071, 2932, 2856, 1427, 1110, 1082; δH
(300 MHz; CDCl3) 1.06 (9H, s, SitBu), 1.20−1.57 (3H, m, CHa,Hb-7,
H-6), 1.72−1.83 (1H, m, CHa,Hb-7), 2.36 (1H, td, J = 11.2, 3.2 Hz,
CHa,Hb-5), 2.79−2.89 (1H, m, CHa,Hb-5), 2.97−3.07 (1H, m, H-8a),
3.14−3.25 (1H, m, CHa,Hb-3), 3.50−3.66 (2H, m, CHa,Hb-3, H-8),
5.76−5.84 (1H, m, H-1), 6.02−6.10 (1H, m, H-2), 7.29−7.44 (6H, m,
H-Ar), 7.64−7.72 (4H, m, H-Ar); δC (75 MHz; CDCl3) 19.3 (C,
SitBu), 24.3 (CH2, C-6), 27.0 (CH3, SitBu), 34.2 (CH2, C-7), 48.8
(CH2, C-5), 57.8 (CH2, C-3), 72.9 (CH, C-8), 74.0 (CH, C-8a), 127.4
(CH, C-Ar), 127.5 (CH, C-Ar), 128.4 (CH, C-1), 129.4 (CH, C-Ar),
129.5 (CH, C-Ar), 131.6 (CH, C-2), 134.1 (C, C-Ar), 134.6 (C, C-
Ar), 135.8 (CH, C-Ar), 135.8 (CH, C-Ar); HRMS (EI+) C24H31NOSi
[M+] calcd 377.2175, obsd 377.2175.
20
mp 126−128 °C; [α]D −58.8 (c 1.04, CHCl3); νmax(neat)/cm−1
3338, 2961, 2809, 1727, 1417, 1371, 1217, 1032; δH (300 MHz;
CDCl3) 1.23 (1H, tdd, J = 12.5, 11.0, 5.3 Hz, CHa,Hb-7), 1.54−1.77
(2H, m, C-6), 1.84−1.98 (2H, m, H-8a, CHa,Hb-5), 2.02−2.14 (4H,
m, 2-OAc, CHa,Hb-7), 2.17 (3H, s, 1-OAc), 2.60 (1H, dd, J = 11.0, 8.2
Hz, CHa,Hb-3), 2.97−3.07 (1H, m, CHa,Hb-5), 3.09 (1H, br s, OH),
3.20 (1H, dd, J = 11.0, 2.3 Hz, CHa,Hb-3), 3.49 (1H, ddd, J = 10.8, 8.9,
4.7 Hz, H-8), 5.16 (1H, ddd, J = 8.2, 6.3, 2.3 Hz, H-2), 5.47 (1H, dd, J
= 6.3, 3.6 Hz, H-1); δC (75 MHz; CDCl3) 20.5 (CH3, 2-OAc), 20.6
(CH3, 1-OAc), 23.2 (CH2, C-6), 31.5 (CH2, C-7), 51.8 (CH2, C-5),
58.5 (CH2, C-3), 65.9 (CH, C-8), 70.6 (CH, C-2), 71.8 (CH, C-1),
72.7 (CH, C-8a), 170.3 (CO, 2-OAc), 171.9 (CO, 1-OAc);
HRMS (ESI) C12H20NO5 [MH+] calcd 258.1336, obsd 258.1333.
A solution of NaOMe (1 M, 0.14 mL, 0.14 mmol) was added
dropwise to a solution of the diacetate prepared above (0.073 g, 0.28
mmol) in MeOH (10 mL) at rt and the mixture stirred for 1 h. The
solution was concentrated under reduced pressure and the residue
purified by reverse phase chromatography (C-18), eluting with milli-Q
water to give the title compound (0.039 g, 80%) as a white solid. mp
(1R,2S,8S,8aR)-8-(tert-Butyldiphenylsilyloxy)octahydro-
indolizine-1,2-diyl Diacetate (22) and (1S,2R,8S,8aR)-8-(tert-
Butyldiphenylsilyloxy)octahydroindolizine-1,2-diyl Diacetate.
A solution of alkene 17 (0.25 g, 0.67 mmol) in t-BuOH (2.5 mL)
was added to a solution of AD-mix-α (1.75 g) and MeSO2NH2 (0.076
g, 0.80 mmol) in t-BuOH/H2O (1:2, 7.5 mL) at 0 °C. The suspension
was stirred vigorously at 1−4 °C for 4 d. Saturated aqueous Na2SO3
(15 mL) was added and the mixture stirred for a further 2 h. The
reaction mixture was extracted with EtOAc (3 × 50 mL), and the
combined organic extracts were dried (Na2SO4) and concentrated
under reduced pressure. The residue was passed through a short pad
of silica gel eluting with MeOH/CHCl3 (9:91), to give a crude mixture
of diols. DMAP (8 mg, 0.066 mmol), pyridine (0.32 mL, 3.98 mmol),
and Ac2O (0.25 mL, 2.65 mmol) were added to a solution of the crude
diols in CH2Cl2 (16 mL) at rt and the mixture stirred overnight.
MeOH (5 mL) was added and the mixture concentrated under
reduced pressure. The residue was dissolved in EtOAc (30 mL) and
143−144 °C (lit.32a 143−145 °C); [α]D +79.9 (c 0.37, MeOH);
20
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Article
[lit.32a [α]D +83.3 (c 0.50, MeOH)]; νmax(neat)/cm−1 3364, 2941,
127.5 (CH, C-Ar), 129.4 (CH, C-Ar), 129.5 (CH, C-Ar), 133.6 (C, C-
Ar), 134.5 (C, C-Ar), 135.8 (CH, C-Ar), 135.8 (CH, C-Ar); HRMS
(ESI) C25H38NO2Si [MH+] calcd 412.2666, obsd 412.2663.
24
2800, 1316, 1072, 1023; δH (400 MHz; CD3OD) 1.20 (1H, tdd, J =
12.7, 11.2, 4.9 Hz, CHa,Hb-7), 1.52−1.73 (2H, m, H-6), 1.70 (1H, dd,
J = 9.2, 3.3 Hz, H-8a), 1.87 (1H, td, J = 11.6, 3.1 Hz, CHa,Hb-5), 1.98−
2.06 (1H, m, CHa,Hb-7), 2.41 (1H, dd, J = 10.4, 6.8 Hz, CHa,Hb-3),
2.88−2.95 (2H, m, CHa,Hb-3, CHa,Hb-5), 3.79 (1H, ddd, J = 11.0, 9.2,
4.7 Hz, H-8), 4.18−4.25 (2H, m, H-1, H-2); δC (100 MHz; CD3OD)
24.5 (CH2, C-6), 34.1 (CH2, C-7), 53.1 (CH2, C-5), 63.1 (CH2, C-3),
67.0 (CH, C-8), 69.8 (CH, C-2), 70.7 (CH, C-1), 75.2 (CH, C-8a);
HRMS (ESI) C8H16NO3 [MH+] calcd 174.1125, obsd 174.1120.
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(4-(tert-butyl-
dimethylsilyloxy)but-1-ynyl)piperidin-1-ol (25). A solution of n-
BuLi (1.6 M in hexanes, 0.39 mL, 0.63 mmol) was added dropwise to
a solution of 4-(tert-butyldimethylsilyloxy)but-1-yne (0.14 g, 0.76
mmol) in THF (7 mL) at −78 °C. The solution was stirred for 15 min
and then warmed to 0 °C and stirred for an additional 30 min. A
solution of nitrone 5b (0.18 g, 0.50 mmol) in THF (3 mL) was added
at −78 °C and the mixture warmed to 0 °C and stirred for a further 1
h. Saturated aqueous NH4Cl (10 mL) was added and the aqueous
phase extracted with EtOAc (3 × 10 mL). The combined organic
extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with EtOAc/hexanes (gradient 1:19 to 1:9), to give the title
(1S,9aS)-1-(tert-Butyldiphenylsilyloxy)octahydro-1H-quinoli-
zine (23). CBr4 (0.092 g, 0.29 mmol) and PPh3 (0.080 g, 0.37 mmol)
were added portionwise to a solution of amino alcohol 26 (0.10 g, 0.25
mmol) in CH2Cl2 (4 mL) at 0 °C and the mixture stirred for 30 min.
Et3N (0.10 mL, 0.74 mmol) was added and the mixture stirred for 1 h
at 0 °C and then a further 6 h at rt. Water (5 mL) was added and the
aqueous phase extracted with CH2Cl2 (3 × 15 mL). The combined
organic extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash column chromatography,
eluting with EtOAc/hexanes (gradient 1:9 to 1:1), to give the title
20
compound (0.068 g, 70%) as a yellow oil. [α]D +25.4 (c 1.40,
CHCl3); νmax(neat)/cm−1 2931, 2856, 1427, 1110, 1084; δH (400
MHz; CDCl3) 0.93−1.09 (10H, m, CHa,Hb-9, SitBu), 1.17−1.33 (2H,
m, CHa,Hb-2, CHa,Hb-8), 1.33−1.49 (2H, m, H-3), 1.49−1.63 (2H, m,
H-7), 1.66−1.73 (1H, m, CHa,Hb-2), 1.73−1.82 (2H, m, H-9a,
CHa,Hb-8), 1.95 (1H, td, J = 11.6, 3.2 Hz, CHa,Hb-4), 2.02 (1H, td, J =
11.8, 3.3 Hz, CHa,Hb-6), 2.28−2.37 (1H, m, CHa,Hb-9), 2.58−2.66
(1H, m, CHa,Hb-4), 2.75−2.84 (1H, m, CHa,Hb-6), 3.38−3.47 (1H, m,
H-1), 7.30−7.43 (6H, m, H-Ar), 7.65−7.72 (4H, m, H-Ar); δC (100
MHz; CDCl3) 19.4 (C, SitBu), 23.1 (CH2, C-3), 24.2 (CH2, C-8), 25.6
(CH2, C-7), 27.0 (CH3, SitBu), 29.1 (CH2, C-9), 34.3 (CH2, C-2),
55.8 (CH2, C-4), 56.2 (CH2, C-6), 68.9 (CH, C-9a), 74.6 (CH, C-1),
127.3 (CH, C-Ar), 127.5 (CH, C-Ar), 129.3 (CH, C-Ar), 129.5 (CH,
C-Ar), 133.7 (C, C-Ar), 134.9 (C, C-Ar), 135.8 (CH, C-Ar), 135.9
(CH, C-Ar); HRMS (ESI) C25H36NOSi [MH+] calcd 394.2561, obsd
394.2564.
20
compound (0.23 g, 85%) as a colorless oil. [α]D −21.0 (c 1.06,
CHCl3); νmax(neat)/cm−1 3205, 3072, 2952, 2929, 2856, 1471, 1427,
1102; δH (400 MHz; DMSO-d6, 393 K) 0.03 (6H, s, SiMe2), 0.86 (9H,
s, SitBu), 1.06 (9H, s, SitBu), 1.22−1.42 (2H, m, CHa,Hb-4, CHa,Hb-5),
1.59−1.77 (2H, m, CHa,Hb-4, CHa,Hb-5), 2.28 (2H, td, J = 7.1, 1.9 Hz,
H-2′), 2.52−2.63 (1H, m, CHa,Hb-6), 2.89−2.97 (1H, m, CHa,Hb-6),
3.47 (1H, br s, H-2), 3.60 (2H, t, J = 7.1 Hz, H-1′), 3.87−3.96 (1H, m,
H-3), 7.37−7.48 (6H, m, H-Ar), 7.54 (1H, br s, NOH), 7.63−7.74
(4H, m, H-Ar); δC (100 MHz; DMSO-d6, 393 K) −5.9 (CH3, SiMe2),
17.3 (C, SitBu), 18.4 (C, SitBu), 19.6 (CH2, C-5), 22.3 (CH2, C-2′),
25.2 (CH3, SitBu), 26.3 (CH3, SitBu), 29.5 (CH2, C-4), 54.3 (CH2, C-
6), 61.1 (CH2, C-1′), 64.4 (CH, C-2), 71.9 (CH, C-3), 78.8 (C, C-2′),
81.5 (C, C-3′), 127.0 (CH, C-Ar), 127.0 (CH, C-Ar), 129.0 (CH, C-
Ar), 129.1 (CH, C-Ar), 133.3 (C, C-Ar), 133.5 (C, C-Ar), 134.8 (CH,
C-Ar), 134.8 (CH, C-Ar); HRMS (ESI) C31H48NO3Si2 [MH+] calcd
538.3167, obsd 538.3160.
ASSOCIATED CONTENT
■
S
* Supporting Information
CIF and ORTEP diagrams of compounds 8 and 19; 1H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: v.caprio@mmu.ac.uk; d.barker@auckland.ac.nz
■
(2R,3S)-3-(tert-Butyldiphenylsilyloxy)-2-(4-hydroxybutyl)-
piperidine (26). Pd/C (96 mg) was added portionwise to a solution
of alkyne 25 (0.64 g, 1.19 mmol) in MeOH (15 mL) and the mixture
stirred under an atmosphere of hydrogen for 12 h. The reaction
mixture was filtered through Celite and the filtrate concentrated under
reduced pressure to give a yellow oil. The residue was purified by flash
column chromatography, eluting with EtOAc/hexanes (gradient 1:19
to 1:9), giving the alkane (0.58 g, 90%) as a colorless oil. Indium
powder (0.22 g, 1.93 mmol) was added to a solution of the above
prepared alkane (0.53 g, 0.97 mmol) in EtOH (22 mL) and the
suspension heated to 80 °C. Aqueous HCl (2 M, 3 mL) was added
and the suspension heated to 100 °C and stirred for 2 h. The reaction
mixture was cooled to rt and the pH adjusted to 10 by the dropwise
addition of an aqueous solution of 2 M NaOH. The mixture was
filtered through Celite and the filtrate concentrated under reduced
pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed
with brine (20 mL), and the aqueous phase was extracted with CH2Cl2
(3 × 30 mL). The combined organic extracts were dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified by
flash column chromatography, eluting with MeOH/CH2Cl2 (gradient
1:19 to 1:17), to give the title compound (0.36 g, 91%) as a yellow oil.
Present Addresses
∥Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-
̈
Platz 1, D-45470, Mullheim-an-der-Ruhr, Germany.
̈
§School of Chemistry, Centre for Green Chemistry, Monash
University, PO Box 23, Clayton, Victoria 3800, Australia.
‡School of Science and the Environment, Manchester
Metropolitan University, All Saints Campus, Oxford Road,
Manchester, M15 6BH, UK.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to The University of Auckland Staff
Research Fund and Doctoral Scholarship Scheme for funding of
this work.
REFERENCES
20
[α]D +21.2 (c 0.92, CHCl3); νmax(neat)/cm−1 3252, 3071 2930,
■
2857, 1427, 1104, 1074; δH (400 MHz; CDCl3) 1.05 (9H, s, SitBu),
1.12−1.61 (8H, m, H-3′, H-5, H-2′, CHa,Hb-4′, CHa,Hb-4), 1.72−1.82
(1H, m, CHa,Hb-4), 1.84−1.96 (1H, m, CHa,Hb-4′), 2.44−2.55 (2H,
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(CH2, C-1′), 32.4 (CH2, C-3′), 33.6 (CH2, C-4), 45.1 (CH2, C-6),
61.9 (CH2, C-4′), 62.2 (CH, C-2), 73.5 (CH, C-3), 127.3 (CH, C-Ar),
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