Synthesis of enantioenriched 2- and 2,6-substituted piperidin-3-ols from α-dibenzylamino aldehydes

Article abstract of DOI:10.1002/ejoc.200601009

Homochiral α-dibenzylamino aldehydes react with 4-butenylmagnesium bromide in diethyl ether at 0°C to yield anti-β-amino alcohols in excellent yield and dr. These anti diastereoisomers were transformed into enantioenriched 2- and 2,6-substituted 3-piperid

Full text of DOI:10.1002/ejoc.200601009

FULL PAPER
DOI: 10.1002/ejoc.200601009
Synthesis of Enantioenriched 2- and 2,6-Substituted Piperidin-3-ols from
α-Dibenzylamino Aldehydes
José M. Andrés,[a] Rafael Pedrosa,*[a] and Alfonso Pérez-Encabo[a]
Dedicated to Professor Joan Bosch on occasion of his 60th birthday
Keywords: Asymmetric synthesis / Amino aldehydes / Deoxocassine / Deoxoprosophylline / 3-Piperidinols
Homochiral α-dibenzylamino aldehydes react with 4-buten-
ylmagnesium bromide in diethyl ether at 0 °C to yield anti-
β-amino alcohols in excellent yield and dr. These anti dia-
stereoisomers were transformed into enantioenriched 2- and
2,6-substituted 3-piperidinols in good yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
3-Hydroxylated piperidines are abundant in nature and
some of them display potent physiological effects.[1] In this
context, several synthetic methods have been developed for
the synthesis of polysubstituted piperidine alkaloids.[2] Dif-
ferent methods that allow the formation of a piperidine
ring[3] in racemic[4] or in enantioenriched forms have been
described. Some of these strategies employed an asymmet-
ric synthesis methodology,[5] but in most approaches an
enantiopure substance was used as the starting material:
amines,[6] amino acids,[7] and sugar derivatives[8] have been
the most commonly used starting materials.
As a part of our investigations[9] exploring the chemistry
of chiral α-dibenzylamino aldehydes derived from natural
α-amino acids, we herein wish to disclose an efficient syn-
thesis of enantiopure 2- and 2,6-substituted 3-hydroxy-
piperidines starting from this class of compound.
As summarized in the retrosynthetic analysis shown in
Scheme 1, the 2-mono- (R2 = H) or 2,6-substituted (R2 =
alkyl) 3-piperidinols can be traced back to δ-amino-γ-hy-
droxy carbonyl compound A through a stereoselective in-
tramolecular reductive amination reaction. Compound A
may be prepared by elaboration of olefin B, which in turn
can be easily obtained by nucleophilic addition of 4-buten-
ylmagnesium bromide to homochiral α-dibenzylamino al-
dehyde C derived from natural α-amino acids.
Scheme 1.
Results and Discussion
The 2- and 2,6-substituted 3-hydroxypiperidines were
synthesized starting from α-dibenzylamino aldehydes 1a–c
readily prepared[10] from commercially available α-amino
acids. These aldehydes reacted with 4-butenylmagnesium
bromide in diethyl ether at 0 °C to afford the Felkin–Anh
anti-2a–c amino alcohols in good yields and with excellent
diastereoselectivities (Scheme 2 and Table 1).
Diastereoisomeric amino alcohols anti- and syn-2a–c
were separated by flash chromatography and their stereo-
chemistry determined by conversion into the corresponding
oxazolidinones, as described previously for related com-
pounds.[9c]
As summarized in Scheme 3, the synthesis of enantio-
enriched 2-substituted 3-hydroxypiperidines 5a–c starts from
amino alcohols anti-2a,[11] 2b, or anti-2c previously pro-
tected as acetates anti-3a, b, and anti-3c, respectively. γ-Ace-
toxy-δ-dibenzylamino aldehydes anti-4a, b, and anti-4c were
obtained in 70–75% yields by oxidative cleavage of the
double bond with N-methylmorpholine N-oxide (NMO)
[a] Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid,
Doctor Mergelina s/n, 47011 Valladolid, Spain
Fax: +34-983-423013
E-mail: pedrosa@qo.uva.es
Eur. J. Org. Chem. 2007, 1803–1810
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
synthesized from anti-3c as outlined in Scheme 4. This
amino alcohol derivative was transformed into γ-acetoxy-
δ-dibenzylamino ketone (6) by Wacker oxidation[15] of the
double bond in the presence of palladium chloride in 64%
yield. Debenzylation of 6 by hydrogenolysis with palladium
hydroxide in methanol, with concomitant intramolecular
reductive amination, yielded 7 in 78% yield as a single dia-
stereoisomer. The stereochemistry of 7 was established on
the basis of COSY and NOESY experiments. The NOESY
cross peak between proton signals arising from C-2 and C-6
revealed a cis relationship between the substituents at these
positions.
Scheme 2.
Table 1. Stereoselective addition of 4-butenylmagnesium bromide
to N,N-dibenzylamino aldehydes 1a–c.
R
Aldehyde % Yield[a]
Products (% dr)[b]
CH3
1a
70
75
85
anti-2a (97) syn-2a (3)
anti-2b (97) syn-2b (3)
anti-2c (86) syn-2c (14)
CH2OTBDMS 1b
Ph ent-1c
[a] Combined yield of diastereomers after purification by flash
chromatography. [b] Determined by 1H NMR analysis of the crude
reaction mixture.
and a catalytic amount of osmium tetraoxide followed by
treatment with sodium periodate on silica gel.[12] The alde-
hydes were subjected to hydrogenolysis on Pearlman’s cata-
lyst in methanol to give 2-substituted O-acetyl-3-piperidin-
ols. The crude acetates were treated with lithium aluminium
hydride at 0 °C to yield the final 2-substituted 3-hydroxy-
piperidines 5a, 5b,[13] and 5c[14] in 51–55% yields over two
steps.
Scheme 4.
The anti-amino-alcohol derivative 4b was used as the
starting material for the synthesis of (–)-deoxoprosophyl-
line. To this end, anti-4b was treated with dodecylmagne-
sium bromide at –78 °C in THF to give a mixture of dia-
stereoisomeric alcohols at C-6, which, by oxidation[16] with
SO3·Py complex, led to ketone 8 in 69% yield (two steps).
Deprotection of 8 by treatment with TBAF in THF gave
the monoacetate of the dibenzylamino hydroxy ketone 9,
with the acetyl group having migrated from the secondary
to the primary hydroxy group.[17] Compound 9 was pro-
tected as diacetate 10 by reaction with acetic anhydride and
compound 10 was subjected to hydrogenolysis/cyclization
by stirring under hydrogen in the presence of palladium hy-
droxide on carbon in methanol (Scheme 5). This treatment
led to diacetate 11 in 80% yield as a single diastereoisomer,
which was transformed into (–)-deoxoprosophylline by re-
duction with lithium aluminium hydride in 91% yield. The
identity of the alkaloid was established by comparison of
its spectral and physical characteristics with those described
in the literature.[18]
Finally, the synthesis of (+)-deoxocassine is summarized
in Scheme 6. The all-cis stereochemistry of this compound
requires syn-2a as the starting amino alcohol, which, how-
ever, was obtained as the minor diastereoisomer from the
reaction of 1a with 4-butenylmagnesium bromide. Instead,
syn-2a was prepared by isomerization of anti-2a in two
steps. Swern oxidation of this amino alcohol yielded diben-
zylamino ketone 12 in 89% yield, which was reduced with
sodium borohydride in methanol[19] to a diastereomeric
mixture of amino alcohols (dr 93:7) in which syn-2a was the
Scheme 3.
A different approach was used for the synthesis of 2,6- major diastereoisomer. Enantiopure syn-2a was obtained by
substituted piperidin-3-ol derivatives. In this way, flash chromatography (silica gel, hexanes/EtOAc) of the re-
(2R,3S,6S)-3-acetoxy-2-phenyl-6-methylpiperidine (7) was action mixture and transformed into the acetate syn-3a in
1804
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Eur. J. Org. Chem. 2007, 1803–1810

Enantioenriched Piperidinols from α-Dibenzylamino Aldehydes
FULL PAPER
Experimental Section
General: Reactions were carried out in oven-dried glassware under
argon and by using anhydrous solvents. Starting α-(dibenzylamino)
aldehydes 1a–c were prepared as described previously.[10] The 1H
(300 MHz) and 13C NMR (75 MHz) spectra were recorded on a
Bruker AC 300 or AMX 300 spectrometer using TMS as the in-
ternal standard. IR spectra were recorded on a Perkin–Elmer Spec-
trum BX spectrometer as a film or KBr dispersion. Optical rota-
tions were measured on a Perkin–Elmer 241 Polarimeter in a 1-dm
cell.
Reaction of Amino Aldehydes 1 with 4-Butenylmagnesium Bromide.
General Method: A 1  solution of 4-butenylmagnesium bromide
in diethyl ether (2 mL, 2 mmol) was added to a solution of amino
aldehydes 1 (1 mmol) in anhydrous diethyl ether (5 mL) at 0 °C
under argon. The mixture was stirred at this temperature until the
reaction was complete (TLC) and then quenched with a saturated
solution of aqueous ammonium chloride (10 mL). The organic
layer was separated and the aqueous phase extracted with diethyl
ether (2ϫ20 mL). The combined organic layers were washed with
brine and dried with anhydrous Na2SO4. The solvent was removed
under vacuum and the residue purified by flash chromatography
(silica gel, hexane/ethyl acetate).
Scheme 5.
89% yield by reaction with acetic anhydride. Oxidation with
NMO and catalytic osmium tetraoxide, followed by reac-
tion of the intermediate diol with sodium periodate trans-
formed the acetate into syn-4a in 72% yield for the two
steps.
(2S,3R)-2-(Dibenzylamino)-6-hepten-3-ol (anti-2a): Yield 210 mg,
68%. Colorless oil. [α]2D0 = +17.7 (c = 1.1, CHCl3) [ref.[11] [α]2D0
=
+18.9 (c = 2.01, CHCl )]. IR (film): ν = 3367, 1640, 1603 cm–1. 1H
˜
3
NMR (CDCl3): δ = 1.10 (d, J = 9.4 Hz, 3 H), 1.30–1.44 (m, 1 H),
1.76–1.90 (m, 2 H), 1.95–2.21 (m, 2 H), 2.66–2.78 (q, J = 7.9 Hz,
1 H), 3.45 (d, J = 14.0 Hz, 2 H), 3.51–3.68 (m, 1 H), 3.75 (d, J =
14.0 Hz, 2 H), 4.92 (d, J = 10.8 Hz, 1 H), 4.98 (d, J = 17.8 Hz, 1 H),
5.70–5.90 (m, 1 H), 7.19–7.35 (m, 10 H) ppm. 13C NMR (CDCl3): δ
= 8.6 (CH3), 30.2 (CH2), 33.3 (CH2), 54.7 (CH2), 57.2 (CH), 73.1
(CH), 114.7 (CH2), 126.9 (2 CH arom.), 128.2 (4 CH arom.), 128.8
(4 CH arom.), 138.7 (CH), 140.0 (2 C arom.) ppm.
(2S,3R)-1-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-6-hepten-
3-ol (anti-2b): Yield 289 mg, 73%. Colorless oil. [α]2D0 = +36.5 (c =
2.4, CDCl ). IR (film): ν = 3452, 2929, 1641, 1072, 838 cm–1. 1H
˜
3
NMR (CHCl3): δ = 0.09 (s, 3 H), 0.11 (s, 3 H), 0.91 (s, 9 H), 1.32–
1.49 (m, 1 H), 1.82–1.93 (m, 1 H), 1.98–2.20 (m, 2 H), 2,68 (dt, J1
= 1.78, J2 = 7.29 Hz, 1 H), 3.02 (br. s, 1 H), 3.62 (d, J = 13.72 Hz,
2 H), 3.88 (d, J = 13.72 Hz, 2 H), 3.90 (m, 1 H), 4.02 (dd, J1
=
1.78, J2 = 5.10 Hz, 2 H), 4.95 (dq, J1 = 1.65, J2 = 10.1 Hz, 1 H),
5.10 (dq, J1 = 1.65, J2 = 16.7 Hz, 1 H), 5.82 (m, 1 H), 7.19–7.38
(m, 10 H) ppm. 13C NMR (CDCl3): δ = –5.6 (2 CH3), 18.0 (C),
25.8 (3CH3), 29.7 (CH2), 34.0 (CH2), 55.2 (2 CH2), 61.1 (CH2),
61.2 (CH), 71.5 (CH), 114.4 (CH2), 126.9 (2 CH arom.), 128.2 (4
CH arom.), 128.8 (4 CH arom.), 138.9 (2 C arom.), 139.8
(CH) ppm.
Scheme 6.
(1R,2S)-1-(Dibenzylamino)-1-phenyl-5-hexen-2-ol (anti-2c): Yield
271 mg, 73%. Colorless solid with m.p. 82–85 °C (from EtOAc/
Reaction of aldehyde syn-4a with an excess of dodecyl-
magnesium bromide at –78 °C led to an equimolar mixture
of epimeric alcohols, which, without isolation, was trans-
formed into ketone 13 in 62% yield. Debenzylation fol-
lowed by intramolecular reductive amination of 13 as de-
scribed above furnished trisubstituted piperidine 14 in 59%
yield as a single diastereoisomer. (+)-Deoxocassine[20] was
obtained in 87% yield by removal of the acetyl group in 13
by reduction with lithium aluminium hydride.
In summary, an efficient synthesis of enantiopure 2- and
2,6-substituted 3-piperidinols was successfully carried out
from α-dibenzylamino aldehydes that are readily accessible
from commercially available α-amino acids.
hexane). [α]2D0 = –92.0 (c = 1.1, CHCl ). IR (film): ν = 3520, 1630,
˜
3
1595, 750, 700 cm–1. 1H NMR (CDCl3): δ = 1.38 (s, 1 H), 1.46–
1.56 (m, 1 H), 2.16–2.28 (m, 3 H), 3.12 (d, J = 13.8 Hz, 2 H), 3.60
(d, J = 8.6 Hz, 1 H), 3.88 (d, J = 13.8 Hz, 2 H), 4.34 (t, J = 8.6 Hz,
1 H), 5.0 (d, J = 10.0 Hz, 1 H), 5.1 (d, J = 17.1 Hz, 1 H), 5.87–
5.93 (m, 1 H), 7.25–7.49 (m, 15 H) ppm. 13C NMR (CDCl3): δ =
29.7 (CH2), 33.0 (CH2), 54.6 (2 CH2), 68.0 (CH), 69.8 (CH), 114.8
(CH2), 126.9 (2 CH arom.), 127.7 (CH arom.), 128.3 (6 CH arom.),
128.8 (4 CH arom.), 129.9 (2 CH arom.), 135.3 (C arom.), 138.8
(CH), 139.5 (C arom.) ppm.
(1S,2R)-1-(Dibenzylamino)-1-phenyl-5-hexen-2-ol (syn-2c): Yield
44 mg, 12%. Colorless solid with m.p. 92–93 °C. [α]2D0 = –115.8 (c
Eur. J. Org. Chem. 2007, 1803–1810
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
1
= 1.4, CHCl ). IR (film): ν = 3360, 1640, 1600, 695 cm–1. 1H NMR (film): ν = 1736, 1454, 1244, 749, 700 cm–1. H NMR (CDCl ): δ
˜
˜
3
3
(CDCl3): δ = 1.20–1.42 (m, 2 H), 2.14–2.36 (m, 2 H), 3.11 (d, J = = 1.04 (d, J = 6.7 Hz, 3 H), 1.48–1.57 (m, 1 H), 1.79–1.97 (m, 3
13.3 Hz, 2 H), 3.60 (d, J = 10.3 Hz, 1 H), 4.05 (d, J = 13.3 Hz, 2
H), 4.30–4.36 (m, 1 H), 4.59 (br. s, 1 H), 4.92–5.04 (m, 2 H), 5.70–
H), 2.02 (s, 3 H), 2.78 (dq, J1 = 6.9, J2 = 7.2 Hz, 1 H), 3.42 (d, J
= 13.7 Hz, 2 H), 3.74 (d, J = 13.7 Hz, 2 H), 4.90–4.97 (m, 2 H),
5.84 (m, 1 H), 7.27–7.54 (m, 15 H) ppm. 13C NMR (CDCl3): δ = 5.09 (td, J1 = 3.13, J2 = 7.90 Hz, 1 H), 5.69–5.80 (m, 1 H), 7.19–
30.1 (CH2), 33.3 (CH2), 53.6 (2 CH2), 67.2 (CH), 67.4 (CH), 114.6
(CH2), 127.4 (2 CH arom.), 128.0 (CH arom.), 128.4 (2 CH arom.),
7.39 (m, 10 H) ppm. 13C NMR (CDCl3): δ = 8.5 (CH3), 21.1 (CH3),
29.0 (CH2), 31.1 (CH2), 54.1 (2 CH2), 54.8 (CH), 74.6 (CH), 114.6
128.6 (4 CH arom.), 129.1 (4 CH arom.), 130.0 (2 CH arom.), 134.0 (CH2), 126.8 (2 CH arom.), 128.1 (4 CH arom.), 128.7 (4 CH
(C arom.), 138.6 (CH), 138.7 (2 C arom.) ppm.
arom.), 138.0 (2 C arom.), 139.8 (CH), 170.7 (CO2) ppm.
23H29NO2 (351.48): calcd. C 78.59, H 8.32, N 3.99; found C
C
Preparation of Amino Alcohol syn-2a from Amino Alcohol anti-2a:
DMSO (3.3 mL, 46.5 mmol) was added to a stirred solution of oxal-
yl chloride (1.95 mL, 22.35 mmol) in CH2Cl2 (50 mL) cooled to
–78 °C under argon. After stirring the mixture for 15 min, a solu-
tion of the amino alcohol anti-2a (5.1 g, 16.5 mmol) in CH2Cl2
(50 mL) was added and the mixture was stirred for 30 min at
–78 °C before addition of triethylamine (6.6 mL, 47.4 mmol). Then
the reaction was warmed to room temp. whilst stirring for 45 min
and the mixture was quenched with water (50 mL). The aqueous
phase was extracted with CH2Cl2 (50 mL) and the combined or-
ganic layers washed with saturated aqueous NaHCO3 and brine.
The organic phase was dried (MgSO4) and then concentrated to
yield an oil which was purified by flash chromatography (silica gel,
hexane/ethyl acetate, 20:1).
78.71, H 8.23, N 3.87.
(2S,3R)-1-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-6-hepten-
3-yl Acetate (anti-3b): Yield 351 mg, 87%. Colorless oil. [α]2D0
=
+8.45 (c = 1.3, CHCl ). IR (film): ν = 1741, 1241, 1028, 839, 748,
˜
3
699 cm–1. H NMR (CDCl3): δ = 0.08 (s, 3 H), 0.1 (s, 3 H), 0.95
1
(s, 9 H), 1.51–1.67 (m, 1 H), 1.68–1.93 (m, 3 H), 1.96 (s, 3 H), 2.83–
2.90 (m, 1 H), 3.68 (d, J = 13.72 Hz, 2 H), 3.87 (d, J = 13.72 Hz,
2 H), 3.83–3.94 (m, 1 H), 4.87–4.96 (m, 2 H), 5.2 (dt, J1 = 3.6, J2
= 7.3 Hz, 1 H), 5.64–5.79 (m, 1 H), 7.15–7.34 (m, 10 H) ppm. 13C
NMR (CDCl3): δ = –5.8 (2 CH3), 18.1 (C), 21.2 (CH3), 25.9 (3
CH3), 28.7 (CH2), 30.9 (CH2), 55.1 (2 CH2), 59.4 (CH), 59.5 (CH2),
72.0 (CH), 114.4 (CH2), 126.8 (2 CH arom.), 128.1 (4 CH arom.),
128.9 (4 CH arom.), 138.1 (CH), 140.0 (2 C arom.), 170.1
(CO2) ppm. C29H43NO2Si (465.74): calcd. C 74.79, H 9.31, N 3.01;
found C 74.92, H 9.23, N 2.89.
(S)-2-(Dibenzylamino)-6-hepten-3-one (12): Yield 5.4 g, 89%. Col-
orless oil. [α]2D0 = –40.2 (c = 1.0, CHCl ). IR (film): ν = 1712, 1451,
˜
3
749, 698 cm–1. H NMR (CDCl3): δ = 1.18 (d, J = 6.7 Hz, 3 H),
1
(1R,2S)-1-(Dibenzylamino)-1-phenyl-5-hexen-3-yl Acetate (anti-3c):
2.20–2.31 (m, 2 H), 2.62 (dt, J1 = 7.4, J2 = 17.1 Hz, 1 H), 2.84 (dt,
J1 = 7.4, J2 = 17.1 Hz, 1 H), 3.39 (q, J = 6.7 Hz, 1 H), 3.48 (d, J
= 13.7 Hz, 2 H), 3.71 (d, J = 13.7 Hz, 2 H), 4.92–5.0 (m, 2 H),
5.70–5.83 (m, 1 H), 7.25–7.42 (m, 10 H) ppm. 13C NMR (CDCl3):
δ = 6.9 (CH3), 27.8 (CH2), 38.8 (CH2), 54.5 (2 CH2), 62.0 (CH),
114.9 (CH2), 127.1 (2 CH arom.), 128.4 (4 CH arom.), 128.7 (4 CH
arom.), 137.4 (CH), 139.2 (C arom.), 212.0 (C=O) ppm.
Yield 346 mg, 91%. Colorless oil. [α]2D0 = –90.75 (c = 1.3, CHCl3).
IR (film): ν = 1736, 1460, 1224, 749, 698 cm–1. H NMR (CHCl ):
1
˜
3
δ = 1.68 (s, 3 H), 1.73–1.85 (m, 1 H), 2.04–2.11 (m, 2 H), 2.37–2.45
(m, 1 H), 3.13 (d, J = 13.6 Hz, 2 H), 3.85 (d, J = 10.1 Hz, 1 H),
3.95 (d, J = 13.6 Hz, 2 H), 5.04–5.15 (m, 2 H), 5.80–5.99 (m, 2 H),
7.27–7.47 (m, 15 H) ppm. 13C NMR (CDCl3): δ = 20.7 (CH3), 29.0
(CH2), 31.6 (CH2), 54.3 (2 CH2), 64.8 (CH), 71.9 (CH), 114.9
(CH2), 127.0 (2 CH arom.), 127.4 (CH arom.), 127.8 (2 CH arom.),
128.4 (4 CH arom.), 128.9 (4 CH arom.), 129.7 (2 CH arom.), 134.5
(C arom.), 138.1 (CH), 139.4 (2 CH arom.), 170.3 (CO2) ppm.
Sodium borohydride (1.04 g. 27.5 mmol, 1.5 equiv.) was added to
a stirred solution of ketone 12 (2.25 g, 6.1 mmol) in MeOH/THF
(9:2, 44 mL) cooled to –20 °C. After stirring for 2 h, the mixture
was quenched with H2O and extracted several times with diethyl
ether. The ethereal layer was washed with NaCl solution and dried
with MgSO4, the solvents were removed, and the residue 2a puri-
fied by flash chromatography (silica gel, hexane/ethyl acetate, 15:1).
C
28H31NO2 (413.55): calcd. C 81.32, H 7.56, N 3.39; found C
81.46, H 7.44, N 3.27.
(2S,3S)-2-(Dibenzylamino)-6-hepten-3-yl Acetate (syn-3a): Yield
287 mg, 89%. Colorless oil. [α]2D0 = –13.11 (c = 0.4, AcOEt). IR
(film): ν = 1735, 1494, 1452, 1370, 749, 700 cm–1 1H NMR
.
(2S,3S)-2-(Dibenzylamino)-6-hepten-3-ol (syn-2a): Yield 1.76 g,
˜
78%. Colorless oil. [α]2D0 = +24.1 (c = 1.0, EtOAc). IR (film): ν =
˜
(CDCl3): δ = 1.02 (d, J = 7.2 Hz, 3 H), 1.61–1.72 (m, 2 H), 1.80–
1.92 (m, 2 H), 2.08 (s, 3 H), 2.82 (dq, J1 = 6.9, J2 = 7.2 Hz, 1 H),
3.35 (d, J = 13.6 Hz, 2 H), 3.88 (d, J = 13.6 Hz, 2 H), 4.87–4.96
(m, 2 H), 5.02 (q, J = 6.3 Hz, 1 H), 5.65–5.81 (m, 1 H), 7.18–7.38
(m, 10 H) ppm. 13C NMR (CDCl3): δ = 9.2 (CH3), 21.3 (CH3),
29.5 (CH2), 31.1 (CH2), 54.3 (2 CH2), 54.8 (CH), 75.8 (CH), 114.6
(CH2), 126.7 (2 CH arom.), 128.1 (4 CH arom.), 128.8 (4 CH
arom.), 138.0 (CH), 140.2 (2 C arom.), 170.6 (CO2) ppm.
C23H29NO2 (351.48): calcd. C 78.59, H 8.32, N 3.99; found C
78.43, H 8.43, N 4.12.
3410, 1639 cm–1. 1H NMR (CDCl3): δ = 1.03 (d, J = 6.6 Hz, 3 H),
1.18–1.31 (m, 1 H), 1.50–1.62 (m, 1 H), 1.95–2.20 (m, 1 H), 2.20–
2.35 (m, 1 H), 2.59 (dq, J1 = 6.55, J2 = 9.60 Hz, 1 H), 3.32 (d, J =
13.3 Hz, 2 H), 3.51 (dt, J1 = 3.10, J2 = 9.33 Hz, 1 H), 3.84 (d,
13.3 Hz, 2 H), 4.49 (br. s, 1 H), 4.93 (d, J = 10.35 Hz, 1 H), 5.10
(dq, J1 = 2.65, J2 = 17.40 Hz, 1 H), 5.80–5.89 (m, 1 H), 7.22–7.35
(m, 10 H) ppm. 13C NMR (CDCl3): δ = 8.0 (CH3), 30.1 (CH2),
33.2 (CH2), 53.2 (2 CH2), 58.3 (CH), 70.1 (CH), 114.4 (CH2), 127.2
(2 CH arom.), 128.5 (4 CH arom.), 128.9 (4 CH arom.), 138.7 (2
C arom.), 138.8 (CH) ppm.
Oxidative Cleavage of the Olefin 3a–c to Aldehydes 4a–c: A catalytic
amount of OsO4 in toluene (5% solution, 5 mol-%) was added to
a stirred solution of olefin 3 (4.08 mmol) and NMO (2.38 g,
20.35 mmol) in acetone (10 mL) and water (2 mL) at room tem-
perature. After stirring for 8 h, a saturated aqueous solution of
Na2SO3 (5 mL) was added to the mixture and extracted with ethyl
acetate (3 ϫ 50 mL). The combined extracts were dried with
Na2SO4 and the solvent removed under vacuum to afford a crude
dihydroxylated compound which was used without purification in
the next step. The crude dihydroxylated product was dissolved in
CH2Cl2 (20 mL) and added in one portion to a vigorously stirred
Acetylation of Amino Alcohols 2. General Method: Ac2O (0.15 mL,
1.52 mmol) and DMAP (28.0 mg, 0.23 mmol) was added to a solu-
tion of 2 (0.92 mmol) in CH2Cl2 (5 mL). The solution was stirred
for 1.5 h and quenched with water (5 mL). After separation, the
organic layer was washed with a saturated NaHCO3 solution
(2 ϫ 5 mL) and brine (5 mL) and then dried with anhydrous
MgSO4. The solvent was distilled and the residue purified by flash
chromatography.
(2S,3R)-2-(Dibenzylamino)-6-hepten-3-yl Acetate (anti-3a): Yield
290 mg, 90%. Colorless oil. [α]2D0 = +13.8 (c = 1.2, CHCl3). IR
1806
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1803–1810

Enantioenriched Piperidinols from α-Dibenzylamino Aldehydes
FULL PAPER
suspension of NaIO4 supported on silica gel (8 g, 20% NaIO4) in
CH2Cl2 (20 mL) at 0 °C. After stirring at the same temperature for
1 h, the solid was removed by filtration and washed with CH2Cl2
(3ϫ30 mL). The filtrate was concentrated under vacuum and the
residue purified by column chromatography (silica gel, hexane/
EtOAc).
tion in the next step. The residue (0.92 mmol) was dissolved in an-
hydrous diethyl ether (4 mL) and added to a suspension of LiAlH4
(35.0 mg, 0.92 mmol) in Et2O (4 mL) at 0 °C. The mixture was
stirred for 1 h at this temperature and then quenched by addition
of a 15% NaOH aqueous solution. The mixture was filtered off
and the solids washed with Et2O. The solvent was eliminated under
vacuum and the residue purified by flash chromatography (silica
gel, CH2Cl2/MeOH).
(2S,3R)-2-(Dibenzylamino)-6-oxo-3-hexyl Acetate (anti-4a): Yield
1.02 g, 71%. Colorless oil. IR (film): ν = 1728, 1246, 749, 698 cm–1.
˜
1H NMR (CDCl3): δ = 1.06 (d, J = 9.1 Hz, 3 H), 1.72–1.89 (m, 1
H), 1.97 (s, 3 H), 1.97–2.06 (m, 1 H), 2.11–2.27 (m, 2 H), 2.78 (dq,
J1 = 6.2, J2 = 6.5 Hz, 1 H), 3.35 (d, J = 13.76 Hz, 2 H), 3.76 (d, J
= 13.76 Hz, 2 H), 5.04–5.14 (m, 1 H), 7.19–7.37 (m, 10), 9.58 (s, 1
(2S,3R)-2-Methyl-3-piperidinol (5a): Yield 90 mg, 51%. Colorless
solid with m.p. 130–131 °C (from CH2Cl2/hexane). [α]2D0 = –11.5 (c
= 0.6, CHCl3) [ref.[21]: m.p. 130 °C, [α]2D0 = +16.2 (c = 0.92, CHCl3)
for the (2R,3S) enantiomer]. IR (KBr): ν = 3402, 3275, 1050 cm–1.
˜
H) ppm. 13C NMR (CDCl3): δ = 8.3 (CH3), 20.9 (CH3), 23.7 1H NMR (CDCl3): δ = 1.18 (d, J = 6.3 Hz, 3 H), 1.21–1.38 (m, 1
(CH2), 38.8 (CH2), 54.0 (2 CH2), 54.1 (CH), 73.9 (CH), 126.9 (2
CH arom.), 128.2(4 CH arom.), 128.9 (CH arom.), 139.5 (2 C
H), 1.43–1.60 (m, 1 H), 1.68–1.77 (m, 1 H), 1.96–2-06 (m, 1 H),
2.34 (br. s, 2 H), 2.37–2.49 (m, 1 H), 2.56 (dt, J1 = 2.9, J2 = 12.2 Hz,
arom.), 170.6 (CO2), 201.6 (C=O) ppm. C22H27NO3 (353.45): 1 H), 2.91–2.98 (m, 1 H), 3.14 (ddd, J1 = 4.3, J2 = 8.2, J3 = 12.9 Hz,
calcd. C 74.76, H 7.70, N 3.96; found C 74.69, H 7.53, N 3.81.
1 H) ppm. 13C NMR (CDCl3): δ = 18.5 (CH3), 25.4 (CH2), 33.6
(CH2), 45.6 (CH2), 58.4 (CH), 73.3 (CH) ppm. C6H13NO (115.17):
calcd. C 62.57, H 11.38, N 12.16; found C 62.71, H 11.26, N 12.08.
(2S,3S)-2-(Dibenzylamino)-6-oxo-3-hexyl Acetate (syn-4a): Yield
1.04 g, 72%. Colorless oil. [α]2D0 = –18.1 (c = 0.4, CHCl3). IR (film):
ν = 1729, 1243, 749, 699 cm–1. 1H NMR (CDCl ): δ = 1.08 (d, J =
(2S,3R)-2-(Hydroxymethyl)-3-piperidinol (5b): Yield 104 mg, 53%.
Colorless solid with m.p. 120–121 °C (MeOH/Et2O). [α]2D0 = –44.5
˜
3
6.9 Hz, 3 H), 1.78–2.21 (m, 4 H), 2.1 (s, 3 H), 2.81–2.92 (m, 1 H),
3.32 (d, J = 13.6 Hz, 2 H), 3.92 (d, J = 13.6 Hz, 2 H), 4.90–5.0 (m, (c = 0.4, MeOH) [ref.[13]: [α]2D1 = +58.3 (c = 1.06, MeOH) for the
1 H), 7.20–7.40 (m, 10 H), 9.52 (s, 1 H) ppm. 13C NMR (CDCl3): (2R,3S) enantiomer]. IR (KBr): ν = 3420, 1050 cm–1. 1H NMR
˜
δ = 9.1 (CH3), 21.1 (CH3), 24.1 (CH2), 39.8 (CH2), 54.3 (2 CH2),
54.4 (CH), 75.5 (CH), 126.9 (2 CH arom.), 128.1 (4 CH arom.),
(CD3OD): δ = 1.25–1.41 (m, 1 H), 1.43–1.58 (m, 1 H), 1.68–1.77
(m, 1 H), 1.98–2.06 (m, 1 H), 2.38 (td, J1 = 3.1, J2 = 9.8 Hz, 1 H),
128.9 (CH arom.), 140.0 (2 C arom.), 170.7 (CO2), 201.4 2.52 (td, J = 2.5, 12.1 Hz, 1 H), 2.93–3.02 (m, 1 H), 3.23–3.34 (m,
(C=O) ppm. C22H27NO3 (353.45): calcd. C 74.76, H 7.70, N 3.96;
found C 74.88, H 7.58, N 4.09.
1 H), 3.55 (dd, J1 = 7.2, J2 = 10.7 Hz, 1 H), 3.88 (dd, J1 = 3.1, J2
= 10.7 Hz, 1 H) ppm. 13C NMR (CDCl3): δ = 26.1 (CH2), 34.9
(CH2), 46.5 (CH2), 63.7 (CH2), 65.0 (CH), 69.6 (CH) ppm.
C6H13NO2 (131.17): calcd. C 54.94, H 9.99, N 10.86; found C
55.06, H 10.10, N 10.74.
(2S,3R)-1-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-6-oxo-3-
hexyl Acetate (anti-4b): Yield 1.26 g, 70%. Colorless oil. [α]2D0
=
+12.6 (c = 0.6, CHCl ). IR (film): ν = 1729, 1243, 749, 699 cm–1.
˜
3
1H NMR (CDCl3): δ = 0.09 (s, 3 H), 0.13 (s, 3 H), 0.95 (s, 9 H),
(2R,3S)-2-Phenyl-3-piperidinol (5c): Yield 146 mg, 55%. Colorless
1.82–1.98 (m, 2 H), 1.97 (s, 3 H), 2.01–2.28 (m, 2 H), 2.85 (ddd, J1 solid with m.p. 144–146 °C (MeOH/Et2O). [α]2D0 = –32.4 (c = 1.0,
= 3.0, J2 = 6.1, J3 = 9.4 Hz, 1 H), 3.65 (d, J = 13.6 Hz, 2 H), 3.83
(dd, J1 = 6.1, J2 = 10.7 Hz, 1 H), 3.91 (d, J = 13.6 Hz, 2 H), 3.97
CHCl3) [ref.[14]: m.p. 143–144 °C, [α]2D2 = –23.0 (c = 1.5, MeOH)].
1
IR (KBr): ν = 3250, 750, 700 cm–1. H NMR (CDCl ): δ = 1.32–
˜
3
(dd, J1 = 3.0, J2 = 10.7 Hz, 1 H), 5.22 (dt, J1 = 5.7, J2 = 9.4 Hz, 1 1.48 (m, 1 H), 1.55–1.79 (m, 2 H), 1.90 (br. s, 2 H), 2.08–2.15 (m,
H), 7.22–7.41 (m, 10 H), 9.5 (s, 1 H) ppm. 13C NMR (CDCl3): δ = 1 H), 2.62 (td, J1 = 3.0, J2 = 11.6 Hz, 1 H), 2.91–2.99 (m, 1 H),
–5.6 (2 CH3), 18.1 (C), 21.1 (CH3), 23.4 (CH2), 25.8 (3 CH3), 38.5
(CH2), 55.1 (2 CH2), 58.6 (CH), 59.0 (CH2), 70.7 (CH), 126.9 (2
CH arom.), 128.3 (4 CH arom.), 129.1 (4 CH arom.), 139.8 (C
3.24 (d, J = 8.8 Hz, 1 H), 3.48 (ddd, J1 = 4.4, J2 = 8.8, J3 = 10.7 Hz,
1 H), 7.15–7.37 (m, 5 H) ppm. 13C NMR (CDCl3): δ = 25.2 (CH2),
33.2 (CH2), 46.7 (CH2), 69.3 (CH), 72.5 (CH), 127.8 (CH arom.),
arom.), 170.2 (CO2), 201.8 (C=O) ppm. C28H41NO4Si (483.71): 128.1 (2 CH arom.), 128.5 (2 CH arom.), 141.4 (C arom.) ppm.
calcd. C 69.52, H 8.54, N 2.90; found C 69.66, H 8.67, N 2.81.
C11H15NO (177.24): calcd. C 75.54, H 8.53, N 7.90; found C 75.62,
H 8.66, N 7.79.
(1R,2S)-1-(Dibenzylamino)-5-oxo-1-phenyl-2-pentyl Acetate (anti-
4c): Yield 1.27 g, 75 %. Colorless oil. IR (film): ν = 1726, 750,
Synthesis of 2,6-Substituted 3-Piperidinol Derivative 7
˜
697 cm–1. 1H NMR (CDCl3): δ = 1.63 (s, 3 H), 1.90–2.07 (m, 1 H),
2.16–2.31 (m, 1 H), 2.34–2.49 (m, 1 H), 2.58–2.69 (m, 1 H), 3.08
(d, J = 13.3 Hz, 2 H), 3.80 (d, J = 10.3 Hz, 1 H), 3.91 (d, J =
13.3 Hz, 2 H), 5.75–5.87 (m, 1 H), 7.15–7.52 (m, 15 H), 9.70 (s, 1
H) ppm. 13C NMR (CDCl3): δ = 21.5 (CH3), 28.3 (CH2), 35.6
(CH2), 54.8 (2 CH2), 65.8 (CH), 72.9 (CH), 126.9 (2 CH arom.),
127.1 (CH arom.), 127.8 (2 CH arom.), 128.1 (4 CH arom.), 128.6
(4 CH arom.), 129.4 (2 CH arom.), 134.5 (C arom.), 139.4 (2 CH
arom.), 170.8 (CO2), 201.5 (C=O) ppm. C27H29NO3 (415.52):
calcd. C 78.04, H 7.03, N 3.37; found C 78.17, H 7.11, N 3.26.
(1R,2S)-1-(Dibenzylamino)-5-oxo-1-phenyl-2-hexyl Acetate (6):
Oxygen was bubbled through a solution of ent,anti-3c (372 mg,
0.92 mmol), palladium chloride bis(acetonitrile) complex (34 mg,
0.13 mmol, 0.14 equiv.), and cupric chloride (176 mg, 1.3 mmol,
1.4 equiv.) in methanol (7 mL) at room temperature. After stirring
for 25 h, the reaction mixture was filtered and the solvent evapo-
rated under reduced pressure. The residue was treated with ethyl
acetate (15 mL), water (15 mL), and an aqueous ammonia solution
(3 mL). The organic layer was separated, dried with anhydrous
Na2SO4, evaporated under reduced pressure, and purified by col-
umn chromatography on silica gel (hexane/ethyl acetate, 8:1) to give
Synthesis of 2-Substituted 3-Piperidinols 5a–c: 20 % Pd(OH)2/C
(100 mg) was added in one portion to a solution of the appropriate
dibenzylamino aldehyde 4 (1.5 mmol) in methanol (20 mL). The
mixture was stirred under 1 atm of hydrogen and the reaction mon-
itored by TLC. After completion of the reaction, the catalyst was
removed by filtration through Celite. The Celite was washed with
methanol (20 mL) and the solvent evaporated under reduced pres-
sure to afford a yellowish residue which was used without purifica-
6 (308 mg, 78%) as a colorless oil. [α]2D0 = +97.7 (c = 1.0, CHCl3).
1
IR (film): ν = 1736, 1718, 1241, 735, 701 cm–1. H NMR (CDCl ):
˜
3
δ = 1.61 (s, 3 H), 1.82–1.95 (m, 1 H), 2.11 (s, 3 H), 2.20–2.32 (m,
1 H), 2.38–2.50 (m, 1 H), 2.59–2.68 (m, 1 H), 3.06 (d, J = 13.5 Hz,
2 H), 3.79 (d, J = 10.5 Hz, 1 H), 3.95 (d, J = 13.5 Hz, 2 H), 5.75
(ddd, J1 = 3.0, J2 = 7.9, J3 = 10.5 Hz, 1 H), 7.22–7.44 (m, 15
H) ppm. 13C NMR (CDCl3): δ = 20.5 (CH3), 25.6 (CH2), 29.9
Eur. J. Org. Chem. 2007, 1803–1810
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1807

J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
(CH3), 38.3 (CH2), 54.1 (2 CH2), 64.4 (CH), 71.4 (CH), 127.0 (2
CH arom.), 127.4 (CH arom.), 127.8 (2 CH arom.), 128.3 (4 CH
(2S,3S)-2-(Dibenzylamino)-6-oxo-3-octadecyl Acetate (13): Yield
763 mg, 62%. Colorless oil. [α]2D0 = –16.8 (c = 0.3, EtOAc). IR
1
arom.), 129.0 (4 CH arom.), 129.5 (2 CH arom.), 134.3 (C arom.), (film): ν = 1736, 1715, 1241, 747, 698 cm–1. H NMR (CDCl ): δ
˜
3
139.3 (2 C arom.), 170.4 (CO2), 207.8 (C=O) ppm. C28H31NO3
(429.55): calcd. C 78.29, H 7.27, N 3.26; found C 78.16, H 7.38, N
3.21.
= 0.89 (t, J = 6.4 Hz, 3 H), 1.08 (d, J = 6.7 Hz, 3 H), 1.15–1.40
(m, 18 H), 1.45–1.58 (m, 2 H), 1.70–1.82 (m, 1 H), 1.88–2.02 (m,
1 H), 2.10 (s, 3 H), 2.03–2.21 (m, 2 H), 2.27 (t, J = 7.4 Hz, 2 H),
2.82 (dq, J1 = 6.7, J2 = 6.9 Hz,1 H), 3.34 (d, J = 13.5 Hz, 2 H),
3.87 (d, J = 13.5 Hz, 2 H), 4.91–4.97 (m, 1 H), 7.20–7.36 (m, 10
H) ppm. 13C NMR (CDCl3): δ = 9.2 (CH3), 14.1 (CH3), 21.2
(CH3), 22.7 (CH2), 23.7 (CH2), 25.6 (CH2), 29.2 (CH2), 29.3 (CH2),
29.4 (CH2), 29.5 (CH2), 29.6 (2 CH2), 31.9 (CH2), 38.3 (CH2), 42.7
(CH2), 53.4 (CH2), 54.3 (2 CH2), 54.7 (CH), 75.6 (CH), 126.8 (2
CH arom.), 128.1 (4 CH arom.), 128.9 (4 CH arom.), 140.1 (2 C
arom.), 170.7 (CO2.), 210.2 (C=O) ppm. C34H51NO3 (521.77):
calcd. C 78.26, H 9.85, N 2.68; found C 78.39, H 9.75, N 2.61.
(2R,3S,6S)-6-Methyl-2-phenyl-3-piperidinyl Acetate (7): 20 %
Pd(OH)2/C (55 mg) was added in one portion to a solution of the
dibenzylamino ketone 6 (180 mg, 0.42 mmol) in methanol (10 mL).
The mixture was stirred under 1 atm of hydrogen and the reaction
monitored by TLC. After completion of the reaction, the catalyst
was removed by filtration through Celite and washed with meth-
anol (20 mL). The solvent was evaporated under reduced pressure
to afford piperidine 7 (76 mg, 78%) as a colorless solid, m.p. 52–
54 °C (diethyl ether). [α]2D0 = –6.9 (c = 0.3, CHCl ). IR (film): ν =
˜
3
3446, 1736, 1247, 1039 cm–1. H NMR (CDCl3): δ = 1.11 (d, J =
1
Synthesis of (–)-Deoxoprosophylline
6.4 Hz, 3 H), 1.30–1.60 (m, 2 H), 1.62 (br. s, 1 H), 1.70–1.75 (m, 1
H), 1.78 (s, 3 H), 2.10–2.21 (m, 1 H), 2.78–2.91 (m, 1 H), 3.65 (d,
J = 10.2 Hz, 1 H), 4.81 (ddd, J = 4.2, 8.8, 10.2 Hz, 1 H), 7.17–7.40
(m, 5 H) ppm. 13C NMR (CDCl3): δ = 20.9 (CH3), 22.1 (CH3),
30.8 (CH2), 32.9 (CH2), 52.3 (CH), 65.9 (CH), 74.2 (CH), 127.6
(CH arom.), 127.7 (2 CH arom.), 128.1 (2 CH arom.), 141.0 (C
arom.), 169.9 (CO2) ppm. C14H19NO2 (233.31): calcd. C 72.07, H
8.21, N 6.00; found C 72.19, H 8.30, N 6.11.
(2S,3R)-2-(Dibenzylamino)-3-hydroxy-6-oxooctadecyl Acetate (9):
nBu4NF (1.30 g, 4.41 mmol, 3 equiv.) was added to a solution of 8
(0.89 g, 1.47 mmol) in THF (30 mL) at room temp. The solution
was stirred for 1 h and then an aqueous NH4Cl solution (40 mL)
was added. The mixture was extracted with chloroform
(2ϫ50 mL). The organic layer was washed with brine, dried with
anhydrous MgSO4, and the solvent removed under reduced pres-
sure. The residue was purified by chromatography on silica gel
using hexane/EtOAc (8:1) as eluent to afford 9 (584 mg, 74%) as a
Synthesis of Compounds 8 and 13: Dodecylmagnesium bromide
(2.8 mL, 1  in Et2O, 2.0 equiv.) was added at –78 °C to a solution
of the corresponding amino aldehydes anti-4b or syn-4a (1.4 mmol)
in anhydrous diethyl ether (40 mL). The mixture was stirred at that
temperature until the reaction was complete (TLC) and then
quenched with a solution of aqueous saturated ammonium chlo-
ride (50 mL). The organic layer was separated and the aqueous
phase extracted with diethyl ether (2ϫ40 mL). The combined or-
ganic layers were washed with brine and dried with anhydrous
Na2SO4. The solvent was removed under vacuum and the residue
used in the next reaction. A solution of sulfur trioxide–pyridine
complex (1.13 g, 7.1 mmol) in DMSO/CH2Cl2 (10 mL/10 mL) was
added to a stirred solution of the amino alcohol (2.36 mmol) and
triethylamine (0.99 mL, 7.1 mmol) in DMSO/CH2Cl2 (5 mL/5 mL)
over 20 min. The reaction vessel was maintained at 20 °C by im-
mersion in a water bath and the reaction was monitored by TLC
analysis. After completion of the reaction the mixture was poured
into saturated NaCl (50 mL) at 0 °C and the mixture extracted with
Et2O (3ϫ50 mL). The combined organic layers were washed with
1% HCl, H2O, saturated NaHCO3, and saturated NaCl and then
dried with MgSO4, filtered, and concentrated to afford a clear oil
that was purified by flash chromatography.
colorless oil. [α]2D0 = +14.6 (c = 0.8, CHCl ). IR (film): ν = 3447,
˜
3
1739, 1712, 1245, 748, 699 cm–1. H NMR (CDCl3): δ = 0.89 (t, J
1
= 6.3 Hz, 3 H), 1.18–1.43 (m, 18), 1.44–1.87 (m, 4 H), 2.13 (s, 3
H), 2.33 (t, J = 7.6 Hz, 2 H), 2.32–2.55 (m, 1 H), 2.72–2.86 (m, 2
H), 3.64 (d, J = 13.5 Hz, 2 H), 3.66–3.81 (m, 1 H), 3.84 (d, J =
13.5 Hz, 2 H), 4.35–4.48 (m, 1 H), 4.52 (d, J = 4.8 Hz, 2 H), 7.24–
7.40 (m, 10 H) ppm. 13C NMR (CDCl3): δ = 14.1 (CH3), 21.1
(CH3), 22.6 (CH2), 23.8 (CH2), 27.9 (CH2), 29.1 (CH2), 29.2 (CH2),
29.3 (CH2), 29.4 (CH2), 29.6 (3 CH2), 31.8 (CH2), 38.5 (CH2), 42.8
(CH2), 55.0 (2 CH2), 60.0 (CH), 61.4 (CH2), 69.6 (CH), 127.0 (2
CH arom.), 128.3 (4 CH arom.), 128.9 (4 CH arom.), 139.4 (2 C
arom.), 171.2 (CO2), 212.5 (C=O) ppm.
(2S,3R)-3-Acetoxy-2-(dibenzylamino)-6-oxooctadecyl Acetate (10):
Ac2O (0.35 mL, 3.54 mmol) and a crystal of DMAP were added to
a solution of 9 (118 mg, 0.22 mmol) in CH2Cl2 (5 mL). The solu-
tion was stirred for 1.5 h and quenched with water (5 mL). After
separation, the organic layer was washed with a saturated NaHCO3
solution (2ϫ5 mL) and brine (5 mL), and then dried with anhy-
drous MgSO4. The solvent was distilled and the residue purified by
chromatography (silica gel, hexane/EtOAc: 10:1) to afford 10
(99 mg, 78%) as a colorless oil. [α]2D0 = +13.02 (c = 0.8, CHCl3).
1
IR (film): ν = 1741, 1242, 749, 699 cm–1. H NMR (CDCl ): δ =
˜
3
(2S,3S)-1-(tert-Butyldimethylsilyloxy)-2-(dibenzylamino)-6-oxo-3-
0.88 (t, J = 6.6 Hz, 3 H), 1.20–1.38 (m, 18 H), 1.45–1.61 (m, 2 H),
1.68–1.85 (m, 1 H), 1.97 (s, 3 H), 1.98–2.22 (m, 3 H), 2.09 (s, 3 H),
2.25 (t, J = 7.1 Hz, 2 H), 2.93–2.99 (m, 1 H), 3.57 (d, J = 13.5 Hz,
2 H), 3.81 (d, J = 13.5 Hz, 2 H), 4.31 (dd, J1 = 3.4, J2 = 11.9 Hz,
1 H), 4.41 (dd, J1 = 6.2, J2 = 11.9 Hz, 1 H), 5.24 (m, 1 H), 7.21–
7.40 (m, 10 H) ppm. 13C NMR (CDCl3): δ = 14.0 (CH3), 20.9 (2
CH3), 22.6 (CH2), 23.6 (CH2), 25.5 (CH2), 29.1 (CH2), 29.2 (CH2),
29.3 (CH2), 29.4 (CH2), 29.5 (3 CH2), 31.8 (CH2), 37.2 (CH2), 42.7
(CH2), 54.5 (2 CH2), 57.4 (CH), 60.3 (CH2), 70.8 (CH), 127.1 (2
CH arom.), 128.2 (4 CH arom.), 128.9 (4 CH arom.), 139.1 (2 C
arom.), 170.3 (CO2), 170.7 (CO2), 209.8 (C=O) ppm.
octadecyl Acetate (8): Yield 993 mg, 69%. Colorless oil. [α]2D0
=
–28.5 (c = 1.0, CHCl ). IR (film): ν = 1739, 1710, 1241, 747,
˜
3
699 cm–1. H NMR (CDCl3): δ = 0.09 (s, 3 H), 0.13 (s, 3 H), 0.89
1
(t, J = 6.8 Hz, 3 H), 0.96 (s, 9 H), 1.10–1.35 (m, 18 H), 1.42–1.56
(m, 2 H), 1.71–1.92 (m, 2 H), 1.96 (s, 3 H), 2.06–2.21 (m, 2 H),
2.23 (t, J = 7.4 Hz, 2 H), 2.82 (ddd, J1 = 3.1, J2 = 6.8, J3 = 9.7 Hz,
1 H), 3.68 (d, J = 13.6 Hz, 2 H), 3.83 (dd, J1 = 6.8, J2 = 10.8 Hz,
1 H), 3.90 (d, J = 13.6 Hz, 2 H), 3.96 (dd, J1 = 3.1, J2 = 10.8 Hz,
1 H), 5.18–5.27 (m, 1 H), 7.21–7.40 (m, 10 H) ppm. 13C NMR
(CDCl3): δ = –5.7 (2 CH3), 14.1 (CH3), 18.1 (C), 21.1 (CH3), 22.6
(CH2), 23.7 (CH2), 25.1 (CH2), 25.8 (3 CH3), 29.2 (CH2), 29.3
(CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (2 CH2), 31.9 (CH2), 37.3 (2S,3R,6R)-2-(Acetoxymethyl)-6-dodecyl-3-piperidinyl Acetate (11):
(CH2), 42.7 (CH2), 53.3 (CH2), 55.1 (2 CH2), 59.0 (CH), 59.2 20% Pd(OH)2/C (63 mg) was added in one portion to a solution
(CH2), 71.4 (CH), 126.9 (2 CH arom.), 128.2 (4 CH arom.), 129.1 of amino ketone 10 (237 mg, 0.410 mmol) in dry methanol
(4 CH arom.), 139.9 (2 CH arom.), 170.2 (CO2), 210.3 (C=O) ppm.
(10 mL). The mixture was stirred under 1 atm of hydrogen and the
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Enantioenriched Piperidinols from α-Dibenzylamino Aldehydes
FULL PAPER
1
reaction monitored by TLC. After completion of the reaction
(45 h) the catalyst was removed by filtration through Celite and
washed with methanol (20 mL). The solvent was evaporated under
reduced pressure to afford 11 (126 mg, 80 %) as a colorless oil.
= 3126, 1466, 1018, 867 cm–1. H NMR (CDCl3): δ = 0.88 (t, J =
6.6 Hz, 3 H), 1.10 (d, J = 6.5 Hz, 3 H), 1.18–1.45 (m, 22 H), 1.45–
1.65 (m, 4 H), 1.85–1.95 (m, 1 H), 2.43–2.68 (m, 2 H), 2.75 (q, J
= 6.5 Hz, 1 H), 3.5 (br. s, 1 H) ppm. 13C NMR (CDCl3): δ = 14.1
(CH3), 18.7 (CH3), 22.6 (CH2), 25.8 (CH2), 26.1 (CH2), 29.3 (CH2),
29.6 (5 CH2), 29.7 (CH2), 31.8 (CH2), 32.0 (CH2), 37.0 (CH2), 55.7
[α]2D0 = –31.0 (c = 0.3, CHCl ). IR (film): ν = 1740, 1231, 1037,
˜
3
785 cm–1. H NMR (CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H), 1.05–
1
1.50 (m, 22 H), 1.71–1.82 (m, 2 H), 1.84–2.21 (m, 3 H), 2.02 (s, 3 (CH), 57.1 (CH), 67.9 (CH) ppm.
H), 2.07 (s, 3 H), 2.48–2.57 (m, 1 H), 2.89 (ddd, J1 = 2.7, J2 = 6.9,
J3 = 9.7 Hz, 1 H), 4.02 (dd, J = 6.9, 11.1 Hz, 1 H), 4.19 (dd, J1 =
Acknowledgments
2.7, J2 = 11.1 Hz, 1 H), 4.53 (td, J1 = 4.6, J2 = 9.7 Hz, 1 H) ppm.
13C NMR (CDCl3): δ = 14.1 (CH3), 20.8 (CH3), 21.1 (CH3), 22.6
(CH2), 26.1 (CH2), 29.3 (2 CH2), 29.6 (4 CH2), 30.2 (CH2), 31.0
(CH2), 31.8 (CH2), 36.5 (CH2), 55.8 (CH), 58.5 (CH), 65.2 (CH2),
71.1 (CH), 170.2 (CO2), 170.8 (CO2), 211.9 (C=O) ppm.
C22H41NO4 (383.57): calcd. C 68.89, H 10.77, N 3.65; found C
69.00, H 10.84, N 3.53.
The authors thank the Spanish Ministerio de Educación y Ciencia
(DGI, Project CTQ2005-01191/BQU) and the Consejería de Uni-
versidades e Investigación (JCyL, Project VA025A06) for financial
support.
(–)-Deoxoprosophylline: A solution of 11 (138 mg, 0.36 mmol) in
anhydrous THF (1 mL) was added dropwise to a suspension of
LiAlH4 (14.0 mg, 0.36 mmol) in THF (2 mL) at 0 °C. The mixture
was stirred for 1 h at that temperature and then quenched by ad-
dition of a 15% aqueous solution of NaOH. The mixture was fil-
tered off and the solids washed with THF. The solvent was elimin-
ated under vacuum to afford the titled compound (98 mg, 91%) as
a colorless solid. M.p. 89–91 °C (from EtOAc). [α]2D0 = –10.3 (c =
0.1, CHCl3) [ref.[7a] m.p. 91.0–91.5 °C, [α]2D0 = –11.4 (c = 0.24,
[1] a) M. J. Schneider in Alkaloids: Chemical and Biological Per-
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CHCl )]. IR (film): ν = 3267, 1465, 1060, 800 cm–1 1H NMR
.
˜
3
(CDCl3): δ = 0.87 (t, J = 6.3 Hz, 3 H), 1.02–1.51 (m, 22 H), 1.52–
1.85 (m, 2 H), 1.95–2.10 (m, 2 H), 2.50–2.61 (m, 2 H), 3.20 (br. s,
3 H), 3.41 (dt, J1 = 5.3, J2 = 9.6 Hz, 1 H), 3.70 (dd, J1 = 5.3, J2 =
10.9 Hz, 1 H), 3.84 (dd, J1 = 5.0, J2 = 10.9 Hz, 1 H) ppm. 13C
NMR (CDCl3): δ = 14.1 (CH3), 22.9 (2 CH2), 26.5 (CH2), 29.3 (2
CH2), 29.6 (4 CH2), 31.9 (2 CH2), 33.8 (CH2), 36.2 (CH2), 56.1
(CH), 63.4 (CH), 63.9 (CH2), 69.7 (CH) ppm.
Synthesis of (+)-Deoxocassine
(2S,3S,6R)-6-Dodecyl-2-methyl-3-piperidinyl Acetate (14): 20%
Pd(OH)2/C (80 mg) was added in one portion to a solution of the
dibenzylamino ketone 13 (1.0 mmol) in methanol (20 mL). The
mixture was stirred under 1 atm of hydrogen and the reaction mon-
itored by TLC. After completion of the reaction, the catalyst was
removed by filtration through Celite and washed with methanol
(20 mL). The solvent was evaporated under reduced pressure to
afford piperidine 14 as an oil which was purified by flash
chromatography. Yield 191 mg, 59%. Colorless oil. [α]2D0 = +19.9 (c
= 0.4, EtOAc). IR (film): ν = 1736, 1243, 1019, 752 cm–1. 1H NMR
˜
(CDCl3): δ = 0.87 (t, J = 6.5 Hz, 3 H), 1.05 (d, J = 6.5 Hz, 3 H),
1.15–1.40 (m, 22 H), 1.40–1.70 (m, 4 H), 1.95–2.10 (m, 1 H), 2.11
(s, 3 H), 2.52–2.61 (m, 1 H), 2.87 (q, J = 6.5 Hz, 1 H), 4.81 (br. s,
1 H) ppm. 13C NMR (CDCl3): δ = 14.1 (CH3), 18.6 (CH3), 21.3
(CH3), 22.7 (CH2), 25.9 (CH2), 26.8 (CH2), 29.3 (3 CH2), 29.6 (4
CH2), 29.7 (CH2), 31.9 (CH2), 37.0 (CH2), 53.9 (CH), 56.6 (CH),
70.6 (CH), 171.1 (CO2) ppm. C20H39NO2 (325.53): calcd. C 73.79,
H 12.08, N 4.30; found C 73.66, H 11.99, N 4.41.
(+)-Deoxocassine: A solution of 14 (299 mg, 0.92 mmol) in anhy-
drous THF (4 mL) was added dropwise to a suspension of LiAlH4
(35.0 mg, 0.92 mmol) in THF (4 mL) at 0 °C. The mixture was
stirred for 1 h at that temperature and then quenched by addition
of 15% aqueous solution of NaOH. The mixture was filtered off
and the solids washed with THF. The solvent was eliminated under
vacuum and the residue purified by flash chromatography. Yield
227 mg, 87%. Colorless solid. M.p. 48–50 °C (from MeOH/Et2O).
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[α]2D0
= +11.8 (c =
1.0, CHCl3) [ref.[20] m.p. 47.5–48.5 °C,
[α]2D0 = –12.3 (c = 0.19, CHCl ) for (–)-deoxocassine]. IR (film): ν
˜
3
Eur. J. Org. Chem. 2007, 1803–1810
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1809

J. M. Andrés, R. Pedrosa, A. Pérez-Encabo
FULL PAPER
[14] M. Haddad, M. Larchevêque, Tetrahedron Lett. 2001, 42,
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Received: November 22, 2006
Published Online: February 21, 2007
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1803–1810