The direct and highly diastereoselective synthesis of 3,4-epoxy-2-piperidones. Application to the total synthesis and absolute configurational assignment of 3α,4α-epoxy-5β-pipermethystine

Article abstract of DOI:10.1039/c7ob02700a

The substrate-controlled asymmetric total synthesis and absolute configurational assignment of biologically active 3α,4α-epoxy-5β-pipermethystine, a minor component in the aerial parts of kava, has been achieved by featuring, as a key step, the environmentally friendly and direct synthesis of 2,3-epoxyamides from allyl amines. By using the chiron approach, first a carbohydrate-derived dehydropiperidine was prepared and subjected to a stereoselective tandem C-H/CC oxidation reaction. In this attempt, the required α,α-trans-epoxy-2-piperidone skeleton of the kava metabolite precursor was not achieved, although the tandem oxidation was highly stereoselective. However, starting from non-carbohydrate 3-hydroxy-4,5-dehydropiperidine, and using the same tandem oxidation, the target intermediate was obtained in high yield and complete unprecedented anti-stereoselectivity. Since the proposed mechanistic course of this tandem oxidation implies the transient formation of an α,β-unsaturated amide followed by the subsequent epoxidation reaction, this second approach supports the previously established biotransformation proposal of (-)-pipermethystine to (-)-3α,4α-epoxy-5β-pipermethystine.

Full text of DOI:10.1039/c7ob02700a

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Direct and Highly Diastereoselective Synthesis of 3,4-
Epoxy-2-Piperidones. Application to the Total Synthesis
and Absolute Configurational Assignment of 3α,4α-
Epoxy-5β-Pipermethystine
a†
a†
b
a
Urbano Osorio-Nieto, Laura Y. Vázquez-Amaya, Herbert Höpfl, Leticia Quintero, and Fernando
Sartillo-Piscil.a*
aCentro de Investigación de la Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de
Puebla (BUAP). 14 Sur Esq. San Claudio, Col. San Manuel. 72570, Puebla, México.
bCentro de Investigaciones Químicas, Instituto de Investigación en Ciencias Básicas y Aplicadas,
Universidad Autónoma del Estado de Morelos. Avenida Universidad 1001, Col. Chamilpa. 62209,
Cuernavaca, México.
†
U. O.-N. and L. Y. V.-A., contributed equally to this work
*
2
To whom correspondence should be addressed (fernando.sartillo@correo.buap.mx). Telephone:+52
22 2955500 ext. 7391. Fax number: + 52 222 2454972
1
13
¥
Electronic supplementary information (ESI) available: H and C NMR spectra of new and relevant
products. X-ray crystallographic data for 13, (1´S,3R,4R,5S)-20 and (1´S,3S,4S,5R)-20
1

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ABSTRACT. The substrate-controlled asymmetric total synthesis and absolute configurational
assignment of biologically active 3,4-epoxy-5-pipermethystine, a minor component in the aerial
parts of kava, has been achieved by featuring, as a key step, the environmentally friendly and direct
synthesis of 2,3-epoxyamides from allyl amines. By using the chiron approach, first a carbohydrate-
derived dehydropiperidine was prepared and exposed to a stereoselective tandem C−H/C═C oxidation
reactions. In this attempt, the required,-trans-epoxy-2-piperidone skeleton of the kava metabolite
precursor was not achieved, albeit the tandem oxidation was highly stereoselective. However, starting
from non-carbohydrate 3-hydroxy-4,5-dehydropiperidine, and using the same tandem oxidation, the
target intermediate was obtained in high yield and complete unprecedent anti-stereoselectivity. Since the
proposed mechanistic course of this tandem oxidation implies the transient formation of an ,-
unsaturated amide followed by the subsequent epoxidation reaction, this second approach supports the
previously established biotransformation proposal of (-)-pipermethystine to (-)-3,4-epoxy-5-
pipermethystine.
2

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INTRODUCTION
With approximately 3,000 species reported so far, the family of Piperaceae constitutes a major group
1
of the flowering plants. The Piperacea family is divided into more than ten genera such as Arthanthe,
2
Ottonia, Macropiper, Zippelia, Peperomia, Manekia, Piperanthera, Piper and others. The genus of
Piper, and in particular, Piper methysticum, has been used for centuries in religious ceremonies and
3
social drink in the South Pacific and more recently in Europe and North America. It is also recognized
4
5
6
as widespread source of biologically active natural compounds such as lactones, terpenes, lignans,
7
8
9
10
hydroquinones, steroids, (dihydro)chalcones, amides and alkaloids. While some of these compounds
have antioxidant,7a,11 anticonceptive,12 anti-inflamatory,13 antimicrobial,14 antidiabetic,15 and other16
pharmacological benefits, others such as awaine (1),17 pipermethystine (2),18 and ,4-epoxy-5-
1
7
3a
pipermethystine (3), are associated to health problems, e.g. nauseas and hepatotoxicity. The true is
that, pharmacological studies of these alkaloids 1-3 are unclear (Figure 1).
Figure 1. Piperidine alkaloids extracted from Piper: 1-3 from Piper methysticum, (-)-4 from Piper
crassinervium, (+)-5 from Piper capense, and (+)-6 from Piper tuberculatum
Due to the low concentration of 3 in nature and the difficulty of plant recollection in significant
quantities, extensive biological tests have not been conducted so far. Unfortunately, addressing this
3

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problem by synthesis is not easy, especially the preparation in enantiopure form. General methodologies
1
9
for preparing 5-oxygenated -5,5-dihydro-2(1H)-pyridones or 5-oxygenated -3,4-epoxy-2-piperidones
2
0
are not available. There is a single report from the group of Liebeskind revealing an enantiodivergent
approach to 5-hydroxy-5,6-dihydro-2(1H)-pyridones, and the subsequent application to the total
synthesis of the enantiomers of pipermethysthine 2 in high optical purity and good overall yield (ee >
9
9%, 32%). However, subsequent efforts to transform pipermethystine (-)-2 into (-)-3,4-5-epoxy-
pipermethystine [(-)-3] via double-bond epoxidation have not been disclosed. This is probably due to the
2
1
difficulty in achieving the epoxidation of ,-unsaturated amides or lactams. Structurally less complex
2
2
biologically active alkaloid such as (-)-tedanalactam (4) required synthesis routes of 7 or more than 10
2
3
24
steps. Others, such as (+)-kausine (5), which could be prepared by acylation of tedanalactam, have
not been synthesized in the laboratory, yet. Recently, by means of a direct chemical method to obtain
2
5
2
,3-epoxyamides (glycidic amides) from allyl amines, the syntheses of (-)-4 and (+)-piplaroxide (6)
have been achieved, not only in few steps, but also using an economical and eco-friendly approach.26
Although this methodology represents a convenient synthetic alternative for the epoxidation of
2
7
unsaturated amides, the poor stereoselectivity associated with this protocol is an issue that needs to be
addressed. To this end, the present work approaches this problem by replacing the chiral auxiliary
strategy employed previously by a substrate-controlled strategy, in order to develop a protocol for the
streoselective synthesis of optically pure 5-oxygenated -3,4-epoxy-2-piperidones. In addition, this
method was applied to achieve the first total synthesis and configurational assignment of (+)-,4-
epoxy-5-pipermethystine [(-)-3].
RESULTS AND DISCUSSION
Previously, the chemical structure and relative configuration of (-)-,4-epoxy-5-pipermethystine
[
(+)-3], was established by Tang and co-workers based exclusively on NMR data analysis, revealing that
the acetyloxy group at the C-5 position is anti-oriented to the epoxide ring.17 Accordingly, the
carbohydrate derived dehydropiperidine 7 might be a suitable precursor for the synthesis of either (-) or
4

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(+)-3. For this purpose, the chiron approach strategy was suggested because of two reasons. First, the
configurational integrity of the stereogenic center at C-4 can be preserved, which would provide
certainty about the absolute configuration. Second, due to steric restrictions originated from the fused
trans-dehydro piperidine/furanose moiety and the substituent at the C-4 position, an anti -facial
epoxidation reaction of 7 to 8 mediated by NaClO 25
or (-)-3 would be accomplished by
was anticipated. Finally, the synthesis of either (+)
2
a
sequential hydrolysis/oxidative C−C bond
cleavage/decarboxylation protocol and acylation reactions (Scheme1).
Scheme 1. Chiron approach strategy to ,4-epoxy-5-pipermethystine [(+) or (-)-3]
To test the proposed synthetic strategy, starting from diacetone-D-glucose (DAG), chiron 7 was
prepared in five-steps (Scheme 2). DAG was quantitatively oxidized to ketone 9 using aqueous NaOCl,
2
8
TEMPO and Bu
4
NHSO
4
, and without further purification, ketone 9 was then subjected to reductive
amination (benzylamine and TiCl
4
, followed by NaBH ) to give the secondary amine 10 in 76% overall
4
yield. Applying the sequential SHOWO protocol29 (hydrolysis/oxidation/Wittig olefination), the
respective allylamine 11 was obtained in moderate yield. Allylation of 11 with allyl bromide and
Na
Hoveyda-Grubbs 1 generation catalyst, afforded the desired carbohydrate-derived dehydropiperidine
(Scheme 2). Having prepared precursor 7, the direct tandem oxidation of the allyl amine function to
2
CO to yield diallyl amine 12, followed by the ring-closing metathesis reaction of 12•HCl with the
3
st
30
7
the corresponding epoxyamide amide was explored.25
Scheme 2. Synthesis of the carbohydrate-derived dehydropiperidine 7 starting from DAG
5

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However, the stereoisomer obtained was not the expected product, but the reaction afforded the contrary
stereoisomer in good chemical yield (75%) and absolute stereoselectivity. It seems, therefore, that the
1
,2-O-isopropylidene moiety along with the axial-oriented H-4, and not the C-4 substituent, are
determinant for the stereochemical outcome of the reaction. Thus, intermediate A, which is presumably
-
formed during the tandem reaction with NaClO
2
, showcases the preferential attack by ClO on the exo-
face for the epoxidation step to provide exclusively 13 (Scheme 3).
Scheme 3. Substrate-controlled direct stereoselective synthesis of glycidic amide 13 from
dehydropiperidine 7
Although the oxidation of 7 mediated by NaClO gave the undesired stereoisomer precursor for the
2
total synthesis of ,4-epoxy-5-pipermethystine, the high stereoselectivity with which 13 was
achieved indicates that the substrate-controlled strategy is effective for the stereoselective synthesis of
the 3,4-epoxy-2-piperidones. Consequently, having in mind the total synthesis and absolute
configuration determination of either (3R,4S,5S)-3 or (3S,4R,5R)-3, two further chiral dehydropiperidine
6

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precursors were prepared, i.e., (1´S,5R)-14 and (1´S,5S)-14). In this new approach, an anti-
stereoselective epoxidation reaction (-face) is expected due to the presence of the bulky
tributyldimethylsilanoxy (OTBS) group in the allylic position. To enable the determination of the
absolute configuration of the target natural product, (S)-4-methoxy--methylbenzylamine31 was
employed as a chiral auxiliary (Scheme 4).
Scheme 4. Second approach to the direct synthesis of ,4-epoxy-5-pipermethystines [(3R,4R,5S)-
3
and (3S,4S,5R)-3] starting from 3-O-silyloxy-4,5-dehydropiperidines (1´S, 5R)-14 and (1´S,5S)-14
The synthetic pathway to the 3-O-silyloxy-4,5-dehydropiperidines (1´S,5R)-14 and (1´S,5S)-14 is
depicted in Scheme 5. Trans-cinnamaldehyde 16 was transformed into racemic -silylnitrile (+/-)-17
upon treatment with TBSCl, KCN and ZnCl .32 Conversion of (+/-)-17 to (1´S,5R)-14 and (1´S,5S)-14
2
was accomplished by following Brussee’s synthetic route, which involves the transformation of
unsaturated cyanohydrins into chiral unsaturated azaheterocycles via ring-closing metathesis.33 In
accordance, compound (+/-)-17 was first converted in good yield into the diastereomeric mixture of
homoallyl amines (1´S)-18 via a sequential protocol: a) partial reduction of CN with DiBAL, b)
transimination with (S)-4-methoxy--methylbenzylamine [(S)-B] and NH
4
Br, and c) imine reduction
7

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with NaBH
4
. Then, the diastereomeric mixture of homoallylic amines was subjected to a standard
allylation reaction (allyl iodine, Na
2
CO ) to obtain the corresponding diastereomeric mixture of the
3
tertiary unsaturated amines (1´S)-19, which were finally transformed into the desired 3-O-silyloxy-4,5-
dehydropiperidines (1´S,5R)-14 and (1´S,5S)-14 by ring-closing metathesis using the Hoveyda-Grubbs
2nd generation catalyst (Scheme 5). At this stage, diastereoisomeric dehydropiperidines (1´S,5R)-14 and
(1´S,5S)-14 were separated by chromatography.
Scheme 5. Synthesis of 3-O-silyloxy-4,5-dehydropiperidines (1´S,5R)-14 and (1´S,5S)-14 starting
from trans-cinnamaldehyde 16
To further explore the oxidation reactions to the corresponding epoxyamides, allyl amines (1´S,5R)-14
and (1´S,5S)-14 were subjected to the above-described tandem oxidation reaction with NaClO , to yield
2
the respective 3,4-epoxy-5-silyloxy-2-piperidones (1´S,3R,4S,5S)-15 and (1´S,3S,4R,5R)-15 in good
yields and with the desired anti-stereoselectivity. Removal of the TBS group with tetrabutylammonium
fluoride (TBAF) afforded the respective alcohols (1´S,3R,4R,5S)-20 and (1´S,3S,4S,5R)-20 as crystalline
materials. Based on the chiral amine substituent of known configuration, single-crystal X-ray diffraction
analysis enabled the assignment of the absolute configuration of the remaining stereogenic centers
8

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within the piperidine ring as depicted in Scheme 6. Interestingly, the 3,4-epoxy-5-hydroxypiperidine-2-
ones (1´S,3R,4R,5S)-20 and (1´S,3S,4S,5R)-20 can be obtained also in similar yields by tandem
oxidation with NaClO starting from (1´S,5R)-21 and (1´S,5S)-21, which are obtained by removal of the
2
TBS group from (1´S,5R)-14 and (1´S,5S)-14 (Scheme 6).
Scheme 6. Highly diastereoselective tandem oxidation of both protected and unprotected 4,5-
dehydropiperidines to the corresponding 3,4-epoxy-2-piperidones
Epoxidation reactions of allyl alcohols generally occur in a syn-stereoselective way with the hydroxyl
group being responsible for the stereoinduction by means of hydrogen bonding with the oxidation
3
4
reagent. As far as we know, the oxidation of (1´S,5R)-21 and (1´S,5S)-21 constitute the first example
for an epoxidation reaction of a six-membered cyclic allyl alcohol occurring in an anti-stereoselective
3
5
manner. The lack of a hydrogen bonding interaction during the epoxidation step for (1´S,5R)-21 and
(1´S,5S)-21 suggests that the half-chair conformers C and D, formed after the C−H oxidation step of 14
and 21, respectively, have the lowest energy when the OR substituent is oriented in pseudo-equatorial
position leaving thus the pseudo-axial position prone to be epoxidated. In this conformation, the
9

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presence of an intramolecular C−H•••O hydrogen-bonding interaction between the C−H benzylic
hydrogen atom and the oxygen atom from the dehydropiperidone carbonyl group might exert a further
3
6
stabilization effect on the key intermediates C and D. This hypothesis is supported somewhat by the
observation of short CHO intramolecular contacts in the molecular structures extracted from the
SXRD analyses of (1´S,3R,4R,5S)-20 and (1´S,3S,4S,5R)-20. As seen also in Scheme 7, the
corresponding OH distances are 2.32 and 2.27 Å, being significantly shorter than the sum of the van
der Waals radii of hydrogen and oxygen (2.72 Å).
Scheme 7. Diastereoselective epoxidation pathway of 14 and 21 to 15 and 20 via the half-chair low
energy conformers C and D. And The molecular structures of (1´S,3R,4R,5S)-20 (left) and
(1´S,3S,4S,5R)-20 (right) obtained by SXRD analysis exhibit short intramolecular CHO contacts
1
0

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Scheme 8. Completion of the total synthesis of (-) and (+)-3,4-epoxy-5-pipermethystine, enabling
the determination of the absolute configuration of (-)-3
Starting from (1´S,3R,4R,5S)-20 and (1´S,3S,4S,5R)-20, the synthesis of 3,4-epoxy-5-
pipermethystine 3 was achieved in three steps. First, acetylation with acetic anhydride (AcO ) in basic
2
media provided (1´S,3R,4R,5S)-22 and (1´S,3S,4S,5R)-22, which by oxidative debenzylation with ceric
ammonium nitrate (CAN) gave (3R,4R,5S)-23 and (3S,4S,5R)-23, respectively. A second acylation with
hydrocinnamoyl chloride (24) in the presence of n-BuLi yielded (-) and (+)-3,4-epoxy-5-
pipermethystine with ~34% overall yield for this three-step sequences (Scheme 8). In addition, the
stereoselective synthesis enabled to establish by means of polarimetry that the naturally occurring
alkaloid (-)-3 possesses the absolute configuration 3R,4R,5S. The NMR data of the enantiomers
synthetized herein are in full agreement with the data and structure reported by the Tang group.17
Because of the close chemical structural relationship between (-)-pipermethystine 2 and (-)-3,4-
epoxy-5-pipermethystine 3, it has been suggested that the latter is biosynthesized from the former via
1
7
enzymatic epoxidation. However, due to the intrinsic complications to achieve the epoxidation of ,-
1
1

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2
1
unsaturated lactams by synthetic methods, this hypothesis has not been chemically proved yet. The
finding that naturally occurring 3,4-epoxy-5-pipermethystine 3 preserves the configurational
integrity at C-5 of pipermethystine 2 provides the missing experimental proof for the hypothetical
biosynthesis of (-)-3 from (-)-2 (Scheme 9).
Scheme 9. Proposal for the biosynthetic pathway to (-)-3 from alkaloid (-)-2
CONCLUSIONS
A direct and stereoselective protocol for the synthesis of 5-oxygenated -3,4-epoxy-piperidin-2-ones
from chiral dehydropiperidines was achieved. Another remarkable feature of this stereoselective reaction
mediated by NaClO is that a-facial anti-stereoselective epoxidation occurs, even though a free
2
hydroxyl group at the allylic position is present. Based on the elementary synthetic tandem oxidation
protocol established herein, the first total synthesis of (-)-,4-epoxy-5-pipermethystine was
accomplished. In addition, the absolute configuration of this biologically active natural product was
established, which allowed to support the previously proposed biosynthetic enzyme-mediated oxidation
of (-)-pipermethystine into (-)-3,4-epoxy-5-pipermethystine.
EXPERIMENTAL SECTION
Commercially available reagents were used without further purification. Column chromatography
(CC) was performed using silica gel (200-300 mesh) with solvents indicated in the text. Melting points
were determined on an open capillary tube and are uncorrected. Optical rotations were measured in a
digital polarimeter using the sodium D line (589 nm) and are reported as degrees at 20 °C.
1
2

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1
13
Concentrations are given as g/100 mL. Unless otherwise stated, H NMR and C NMR spectra were
obtained on a 500 MHz equipment. All samples were analyzed in CDCl with TMS as internal reference
3
using a relative scale in parts per million (ppm) for the chemical shift () and Hz for the coupling
constants (J). Splitting patterns are designated as follow: s, singlet; d, doublet; t, triplet; q, quartet; qu,
quintet; m, multiplet; and br, broad. High resolution mass spectra (HRMS) were acquired in the
electron-impact (EI) mode using a TOF mass analyzer or in fast-atom-bombardment (FAB) mode using
a QMS mass analyzer.
(3R)-N-Benzyl-(3-deoxy-1,2:5,6-di-O-isopropylidene--D-glucofuranose)-3-yl amine (10)
To a solution of DAG (5.00 g, 19.2 mmol), TEMPO (0.60 g, 3.84 mmol) and
TBAHS (1.30 g, 3.84 mmol) in 50 mL of CH
2
Cl at 0 °C was added dropwise a
2
solution of NaOCl (23.8 mL, 38.4 mmol) at 12 % in water. The solution was
stirred for 1 hour, whereafter four portions of a solution of NaOCl (11.9 mL,
1
9.2 mmol) were added within an interval of 2 hrs. The reaction was quenched after 24 hours by adding
dropwise a solution of NaOH (5 mL, 1N). After extraction with methylene chloride (4 x 10 mL), the
combined organic phases were dried over Na SO and concentered at reduced pressure. The
2
4
intermediate ketone 9 (6.00 g, 19.2 mmol) was obtained as reddish crystalline material and subjected to
the subsequent reaction step without further purification. To a balloon bottom flask containing a solution
of ketone 9 in dry THF (50 mL) at 0 °C was slowly added TiCl
4
(1.92 mL, 1.92 mmol, 1M solution in
toluene). Then, BnNH (2.51 mL, 23.04 mmol) was added dropwise and the mixture was allowed to stir
2
at room temperature for 24 h. After evaporating the solvent at reduced pressure, the solid was washed
with AcOEt until a white color was observed. The corresponding imine (7.2 g) was obtained as reddish
crystalline solid and was reduced without further purification. For the reduction, to a solution of the
imine in MeOH (50 mL) at 0 °C was added a solution of NaBH
4
(1.79 g, 48 mmol) in MeOH (10 mL) in
three portions. After stirring at room temperature for 12 h, the reaction was quenched by adding a
1
3

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saturated aqueous solution of NH
was washed with AcOEt (4 x 10 mL), whereupon the combined organic portions were dried over
Na SO and concentrated at reduced pressure. The crude was purified by column chromatography using
a mixture of hexane: AcOEt (5:1, v/v). The secondary amine 10 was obtained as colorless crystalline
4
Cl (5 mL) followed by AcOEt (30 mL) and water (5mL). The solid
2
4
solid (5.09 g, 76%). Rf. = 0.53 (2:1 hexane/AcOEt). Mp. = 75-77 °C. [] 20
1H NMR (500 MHz, CDCl
= +113.8 (c =1.0, CHCl ).
D
3
3
) δ (ppm): 7.38 – 7.31 (m, 5H), 5.78 (d, J = 4.0 Hz, 1H), 4.59 (t, J = 4.5 Hz,
1
6
1
H), 4.36 (td, J = 7.0, 3.0 Hz, 1H), 4.19 (t, J = 8.0 Hz, 1H), 3.97 (d, J =13.0 Hz, 1H), (3.93 (dd, J = 8.0,
.5 Hz, 1H), 3.84 (dd, J = 9.5, 3.5 Hz, 1H), 3.76 (d, J = 13.0 Hz, 1H), 3.07 (dd, J = 9.5, 4.5 Hz, 1H),
1
3
.56 (s, 1H), 1.53 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H). C-NMR (125 MHz, CDCl
C-], 109.5 [(CH C-],
-), 26.7 (-CH ), 26.5 (-
, 349.1889).
3
) δ
(ppm): 140.0 (ipso), 128.4 (ortho), 128.1 (meta), 127.1 (para), 112.0 [(CH
3
)
2
)
3 2
1
04.4 (C1), 78.9 (C4), 77.8 (C2), 75.6 (C5), 65.0 (C6), 61.0 (C3), 52.2 (PhCH
2
3
CH
3
), 26.2 (-CH ), 25.4 (-CH ). HRMS-EI m/z 349.1880 (calcd. for C19
3
3
H
27NO
5
(3aR,5R,6R,6aR)-N-Benzyl-2,2-dimethyl-5-vinyltetrahydrofuro[2,3-d][1,3]dioxol-6-amine (11)
To a solution of 10 (0.75 g, 2.14 mmol) in dry AcOEt (15 mL) at 0 °C was added
H
5
IO
then for an additional 90 minutes at room temperature. The reaction was
quenched by adding a saturated aqueous solution of NaHCO (1.5 mL),
whereupon the organic phase was extracted with AcOEt (4 x 5 mL). After drying the combined organic
phases over Na SO and concentration at reduced pressure, the residue was dissolved in dry THF and
6
(0.97 g, 4.28 mmol). The mixture was stirred at 0 °C for ten minutes and
3
2
4
added dropwise to a solution of the corresponding Wittig reagent, which was prepared from
methyltriphenylphosphonium iodide (1.32 g, 3.1 mmol) and n-BuLi (2.58 mL, 3.1 mmol, 1.2 M solution
in hexane). The reaction mixture was allowed to react for 10 hrs. before adding 3 mL of a saturated
aqueous solution of NaHCO
3
. The organic phase was separated, and the aqueous phase extracted with
SO and concentrated at reduced
AcOEt (4 x 10 mL). The combined organic phases were dried over Na
2
4
1
4

Page 15 of 33
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DOI: 10.1039/C7OB02700A
pressure. Purification by column chromatography (SiO
2
, hexane/AcOEt, 10:1, v/v) yielded 0.253 g
43%) of 11 as a viscous yellow oil. Rf = 0.47 (3:1 hexane/AcOEt). [] 20
= +76.51, (c =1.0, CHCl ).
) δ (ppm): 7.37–7.30 (m, 4H), 7.27–7.23 (m, 1H), 5.86 (ddd, J = 17.0, 10.5,
(
D
3
1H NMR (500 MHz, CDCl
3
6
1
.5 Hz, 1H), 5.78 (d, J = 4.0 Hz, 1H), 5.45 (dt, J = 17.0, 1.5 Hz, 1H), 5.26 (ddd, J = 10.5, 1.5, 1.0 Hz,
H), 4.56 (t, J = 4.0 Hz, 1H), 4.12 (dd, J = 9.5, 6.5 Hz, 1H), 3.95 (d, J = 13.0 Hz, 1H), 3.82 (d, J = 13.5
1
3
Hz, 1H), 2.80 (dd, J = 9.5, 4.5 Hz, 1H), 1.89 (br, 1H), 1.54 (s, 3H), 1.35 (s, 3H). C NMR (125 MHz,
CDCl ) δ (ppm): 139.9 (ipso), 135.3 (C5), 128.3 (ortho), 128.0 (meta), 127.0 (para), 118.2 (C6), 111.8
(CH C-], 104.2 (C1), 80.7 (C4), 77.7 (C2), 65.1 (C3), 51.9 (PhCH -), 26.6 (-CH ), 26.4 (-CH ).
HRMS-EI m/z 276.1596 (calcd. for C16 , 276.1599).
3
[
3
)
2
2
3
3
H22NO
3
(
3aR,5R,6R,6aR)-N-Allyl-N-benzyl-2,2-dimethyl-5-vinyltetrahydrofuro-[2,3-d]-[1,3]dioxol-6-amine
12)
(
To a mixture of 11 (0.18 g, 0.66 mmol) and Na
2
CO (0.33 g, 1.98 mmol) in dry
3
MeCN (10 mL) was added dropwise a solution of allyl iodide (0.121 mL, 1.98
mmol) in MeCN (1 mL). The reaction mixture was stirred overnight at room
temperature followed by reflux for two additional hours. Ater removal of the
solvent by distillation at reduced pressure, the resulting solid was washed with AcOEt (5 x 5 mL). The
combined organic phases were filtered through Na SO , concentrated and purified by column
chromatography (SiO , hexane/AcOEt, 17:1, v/v) to obtain 0.183 g 12 (88%) as a viscous yellow liquid.
Rf. = 0.55 (8:1 hexane/AcOEt). []
.35–7.20 (m, 5H), 5.87–5.78 (m, 2H), 5.69 (d, J = 4.0 Hz, 1H), 5.42 (dt, J = 17.0, 1.5 Hz, 1H), 5.30 (dt,
2
4
2
2
0
1
D
= +66.4 (c =1.0, CHCl
3
). H NMR (500 MHz, CDCl ) δ (ppm):
3
7
J = 10.5, 1.0 Hz, 1H), 5.19 (ddd, J = 17.0, 3.5, 1.5 Hz, 1H), 5.10 (ddd, J =10.5, 3.5, 2.0 Hz, 1H), 4.67(t,
J = 4.0 Hz 1H), 4.64 (dd, J = 10.0, 7.0 Hz, 1H), 4.04 (d, J = 14.5 Hz, 1H), 3.83 (d, J = 14.5 Hz, 1H),
3
1
.42 (dd, J = 14.5, 5.5 Hz, 1H), 3.34 (dd, J = 14.5, 7.0, 1H), 2.93 (dd, J = 10.0, 4.0, 1H), 1.58 (s, 3H),
1
3
.34 (s, 3H). C NMR (125 MHz, CDCl ) δ (ppm): 140.2 (ipso), 136.8 (C8), 135.9 (C5), 128.3 (ortho),
3
1
5

Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02700A
1
6
28.1 (meta), 126.7 (para), 118.7 (C6), 116.9 (C9), 112.1 [(CH
6.7 (C3), 55.2 (PhCH -), 54.8 (C7), 26.6 (-CH ), 26.2 (-CH
, 315.1834).
3
)
2
C-], 103.8 (C1), 79.1 (C2), 76.5 (C4),
2
3
3
). HRMS-EI m/z 315.1825 (calcd. for
C
19
H25NO
3
(3aR,4aR,8aR,8bR)-8-Benzyl-2,2-dimethyl-3a,4a,7,8,8a,8b-hexahydro-[1,3]dioxolo[4',5':4,5]furo[3,2-
b]pyridine (7)
A mixture of 12 (0.21 g, 0.68 mmol) and Hoveyda-Grubbs 1st generation
catalyst (0.017 mg, 0.027 mmol) in dry CH Cl (10 mL) was refluxed for 2 h,
whereupon the solvent was removed by reduced pressure. The residue was
purified by column chromatography (SiO , hexane/AcOEt, 15:1, v/v) to obtain
.168 g of 7 (86%) as colorless crystalline solid. Rf. = 0.55 (4:1 hexane/AcOEt). Mp. = 143-146 °C.
2
2
2
0
] 20
= +46.3 (c =1.0, CHCl
). H NMR (500 MHz, CDCl ) δ (ppm): 7.38–7.25 (m, 5H), 6.02 (ddd, J =
1
[
D
3
3
1
1
3
0.5, 3.5, 1.5 Hz, 1H), 5.91 (d, J = 3.5 Hz, 1H), 5.59 (ddt, J = 10.0, 4.0, 2.5 Hz, 1H), 4.80 (td, J = 4.0,
.0 Hz, 1H), 4.62–4.58 (m, 1H), 4.27 (d, J = 12.5 Hz, 1H), 3.36 (d, J = 12.5 Hz, 1H), 3.28 (ddt, J = 17.5,
.5, 2.5 Hz, 1H), 2.79 (ddt, J = 17.5, 4.0, 2.5 Hz, 1H), 2.30 (dd, J = 9.0, 4.0 Hz, 1H), 1.60 (s, 3H), 1.37
1
3
(
s, 3H). C NMR (125 MHz, CDCl ) δ (ppm): 137.2 (ipso), 129.4 (ortho), 128.2 (meta), 127.5 (C6),
3
1
5
2
27.3 (para), 125.4 (C5), 112.6 [(CH
3
)
2
C-], 106.1 (C1), 77.2 (C2), 74.0 (C4), 68.6 (C3), 59.1 (PhCH -),
2
+
4.1 (C7), 26.2 (-CH
3
), 26.0 (-CH
3
). HRMS-FAB m/z [M + H] : 288.1608 (calcd. for C17
H22NO
3
,
88.1600).
1
6

Page 17 of 33
Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02700A
(1aS,3aR,3bR,6aR,7aS,7bS)-3-Benzyl-5,5-dimethylhexahydro-[1,3]dioxolo[4',5':4,5]furo[3,2-
b]oxireno[2,3-d]pyridin-2(1aH)-one (13)
To a solution of 7 (0.05 g, 0.17 mmol) and NaH
in a mixture of THF/t-BuOH/H O (3 mL/1.29 mL/1.29 mL) was added NaClO
0.12 g, 1.03 mmol) dissolved in H O (1 mL). The mixture was stirred for 20
2
PO (0.24 g, 1.29 mmol) at 0 °C
4
2
2
(
2
minutes before adding dropwise a saturated solution of NaOH (1 mL). After
washing with brine (2 x 5 mL) and extracting the aqueous layer with AcOEt (4 x 10 mL), the combined
organic phases were dried over Na
2
SO and concentrated at vacuum. The crude was purified by column
4
chromatography (SiO
2
, hexane/AcOEt, 5:1, v/v) to obtain 0.040 g of 13 (75 %) as a white solid. Rf. =
.51 (1:1 hexane/AcOEt). Mp. = 148-150 °C. [] 20
= +4.86 (c =1.0, CHCl
). H NMR (500 MHz,
1
0
D
3
CDCl ) δ (ppm): 7.38–7.23 (m, 5H), 5.77 (d, J = 3.5 Hz, 1H), 5.53 (dd, J = 15.5, 1.0 Hz, 1H), 4.44 (d, J
3
=
9.5 Hz, 1H), 4.40 (td, J = 3.5, 1.0 Hz, 1H), 4.05 (d, J = 15.5 Hz, 1H), 3.86 (dt, J = 4.5, 0.5 Hz, 1H),
1
3
3
.70 (d, J = 4.5 Hz, 1H), 3.40 (dd, J = 9.5, 3.5 Hz, 1H), 1.57 (s, 3H), 1.34 (s, 3H). C NMR (125 MHz,
CDCl ) δ (ppm): 166.9 (C7), 136.2 (ipso), 128.9 (meta), 127.6 (para), 127.3 (ortho), 113.4 [(CH C-],
06.1 (C1), 76.4 (C4), 75.8 (C2), 55.4 (C3), 51.6 (C5), 51.0 (C6), 46.7 (PhCH -), 26.1 (-CH ), 26.1 (-
3
)
3 2
1
2
3
+
CH
3
). HRMS-FAB m/z [M + H] : 318.1329 (calcd. for C17
H
20NO , 318.1341).
5
2
-(( tert-Butyldimethylsilyl)oxy)-4-phenylbut-3-en-nitrile [(+/-)-17]
To a mixture of KCN (1.95 g, 30 mmol), ZnI
2.26 g, 15 mmol) in dry MeCN (6 mL) at room temperature was added trans-
cinnamaldehyde (1.05 mL, 10 mmol). The reaction mixture was refluxed for 10
2
(0.03 g, 0.10 mmol) and TBSCl
(
h and then stirred for 38 hours at room temperature. After removing the solvent at reduced pressure, the
residue was washed with AcOEt (3 x 15). The organic layer was concentrated at reduced pressure and
purified by column chromatography (SiO
, hexane/AcOEt, 98:2, v/v) to obtain 3.15 g of (+/-)-1737
2
1
7

Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02700A
1
(
77%) as a yellow greenish oil. Rf. = 0.60 (9:1 hexane/AcOEt). H NMR (500 MHz, CDCl
3
) δ (ppm):
7
.42–7.29 (m, 5H), 6.81 (dd, J = 15.5, 1.5 Hz, 1H), 6.18 (dd, J = 16.0, 6.0 Hz, 1H), 5.13 (dd, J = 6.0, 1.5
1
3
Hz, 1H), 0.94 (s, 9H), 0.22 (s, 3H), 0.19 (s, 3H). C NMR (125 MHz, CDCl
33.6 (C3), 128.7 (Ph), 126.9 (Ph), 123.6 (C4), 118.4 (-CN), 62.6 (C2), 25.5 [(H
(H C) C-], -4.9 (-CH ), -5.0 (-CH ).
3
) δ (ppm): 135.0 (ipso),
1
3
C) C-], 18.1
3
[
3
3
3
3
N-((S)-1-(4-Methoxyphenyl)ethyl)-4-phenyl-2-((tert-butyl dimethylsilyl)oxy)but-3-en-1-amines [(1´S)-
8]
1
To a solution of 17 (0.10 g, 0.36 mmol) in dry THF at -70 °C was added
dropwise diisobutylaluminum hydride (1.82 mL, 1.82 mmol, 1M solution in
hexane). The reaction mixture was stirred for 3 h before adding NH
.92 mmol) and dry MeOH (1.5 mL). The reaction mixture was stirred for 1
hour, whereafter (S)-(-)-4-methoxy--methylbenzylamine (0.14 g, 0.91 mmol) dissolved in dry MeOH
1 mL) was added. After keeping the mixture stirring for 1 h at room temperature, NaBH (0.034 g,
.915 mmol) was added at 0 °C. The reaction was allowed to react overnight and quenched by addition
4
Cl (0.05 g,
0
(
4
0
of a 1:4 (v/v) solution of THF/HCl (1N, 3 mL). The combined phases were separated and the aqueous
phase extracted with EtOAc (4 x 10 mL). A saturated solution of NaOH (3 mL) was added to the
aqueous phase and extracted with AcOEt (4 x 10 mL). The combined organic portions were
concentrated at reduced pressure and the product purified by column chromatography (SiO ,
2
hexane/AcOEt, as gradient mixture from 97:3 to 90:10, v/v) to obtain 0.10 g of the diastereomeric
1
mixture of (1’S)-18. Reported as a diastereomeric mixture: Rf. = 0.60 (2:1 hexane/AcOEt). H NMR
(500 MHz, CDCl
3
) δ (ppm): 7.36–7.21 (m, 16H), 6.88–6.85 (m, 4H), 6.52 (d, J = 16.0 Hz, 1H), 6.49 (d,
J = 16.0 Hz, 1H), 6.13 (dd, J = 16.0, 6.5 Hz, 1H), 6.13 (dd, J = 16.0, 6.5 Hz, 1H), 4.44–4.37 (m, 2H),
3
1
.81 (s, 3H), 3.80 (s, 3H), 3.79–3.73 (m, 2H), 2.62–2.49 (m, 4H), 1.79 (br, 2H), 1.34 (d, J = 6.5 Hz, 3H),
.33 (d, J = 6.5 Hz, 3H), 0.92 (s, 9H), 0.92 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H).
1
8

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DOI: 10.1039/C7OB02700A
13C NMR (125 MHz, CDCl
) δ (ppm): 158.4 (para Ar), 137.6 (ipso Ph), 136.8 (ipso Ar), 131.4 (C3),
31.3 (C3), 130.2 (C4), 130.2 (C4), 128.5 (meta Ph), 127.6 (para Ph), 127.5 (ortho Ar), 127.4 (para
Ph), 126.3 (ortho Ph), 113.7 (meta Ar), 113.6 (meta Ar), 73.3 (C2), 72.8 (C2), 57.5 (C1’), 57.0 (C1’),
3
1
5
1
4
6.2 (-OCH
8.2 [(H C)
12.2654 (calcd. for C25
3
), 54.2 (C1), 54.0 (C1), 25.9 [(CH
C-], -4.0 (-CH ), -4.0 (-CH ), -4.7 (-CH
Si, 412.2672).
3
)
3
C-], 25.8 [(CH
3
)
3
C-], 24.5 (C2’), 18.2 [(H
3
C) C-],
3
), -4.8 (-CH
3
). HRMS-FAB m/z [M + H]+:
3
3
3
3
3
H
38NO
2
N-Allyl-2-((tert-butyldimethylsilyl)oxy)-N-((S)-1-(4-methoxyphenyl)ethyl)-4-phenylbut-3-en-1-amines
(1’S)-19]
[
To a mixture of diastereomeric (1’S)-18 (0.49 g, 1.19 mmol) and Na
2
CO
3
(0.15 g, 1.42 mmol) in dry MeCN (10 mL) at room temperature was added
dropwise a solution of allyl iodide (0.13 mL, 1.42 mmol) in dry MeCN (1
mL). The reaction was stirred overnight and then refluxed for 3 hrs. The
solvent was removed under reduced pressure, whereupon the solid was
washed with AcOEt (4 x 5 mL). After evaporation of the organic phase under reduced pressure, the
residue was purified by column chromatography (SiO , hexane/AcOEt, 98:2, v/v) to obtain 0.44 g of
2
diastereomeric (1’S)-19 (82%) as a yellow oil. Reported as a diastereomeric mixture: Rf. = 0.66 (10:1
1
hexane/AcOEt). H NMR (500 MHz, CDCl
3
) δ (ppm): 7.37–7.21 (m, 16H), 6.82–6.76 (m, 4H), 6.49 (d,
J = 15.5 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 6.27 (dd, J = 16.0, 6.5 Hz, 1H), 6.12 (dd, J = 16.0, 6.0 Hz,
1
6
1
3
1
1
H), 5.89–5.82 (m, 2H), 5.18–5.06 (m, 4H), 4.24 (qu, J = 6.0 Hz, 2H), 3.91 (q, J = 6.5, 1H), 3.89 (q, J =
.0, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.21–3.09 (m, 4H), 2.63–2.54 (m, 3H), 2.47 (dd, J = 13.0, 7.5 Hz,
H), 1.31 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 7.0 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s,
1
3
H), 0.02 (s, 3H), 0.01(s, 3H). C NMR (125 MHz, CDCl ) δ (ppm): 158.2 (para Ar), 158.1 (para Ar),
3
37.4 (ipso Ph), 137.3 (ipso Ph), 137.3 (C6), 137.3 (C6), 135.9 (ipso Ar), 135.8 (ipso Ar), 132.8 (C3),
32.7 (C3), 128.9 (C4), 128.9 (ortho Ar), 128.8 (C4), 128.8 (ortho Ar), 128.4 (meta Ph), 128.4 (meta
1
9

Organic & Biomolecular Chemistry
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Ph), 127.0 (para Ph), 126.3 (ortho Ph), 126.3 (ortho Ph), 116.4 (C7), 116.3 (C7), 113.2 (meta Ar), 113.2
(
meta Ar), 73.0 (C2), 72.6 (C2), 58.7 (C1’), 57.9 (C1’), 57.2 (C1), 56.7 (C1), 55.1 (-OCH ), 55.1 (-
3
OCH
3
), 54.8 (C5), 54.7 (C5), 25.9 [(CH
), -4.4 (-CH ), -4.6 (-CH ), -4.6 (-CH
Si, 450.2828).
3
)
3
C-], 18.3 [(H
3
C)
3
C-], 18.2 [(H
3
C)
3
C-], 16.3 (C2’), 15.0 (C2’),
+
-4.4 (-CH
3
3
3
3
). HRMS-FAB m/z [M + H] : 450.2816 (calcd. for
C
28
H40NO
2
(
S)-3-((tert-Butyldimethylsilyl)oxy)-1-((S)-1-(4-methoxyphenyl)ethyl)-3,4-dehydropiperidine
(1’S,5R)-14] and (R)-3-((tert-Butyldimethylsilyl)oxy)-1-((S)-1-(4-methoxyphenyl)ethyl)-3,4-
[
dehydropiperidine [(1’S,5S)-14]
A mixture of (1’S)-19 (0.4 g, 0.90 mmol) and Hoveyda-Grubbs 2nd generation catalyst (0.028 g, 0.04
mmol) in dry CH
2
Cl (20 mL) was refluxed for 7 h. After removal of the solvent under reduced pressure,
2
a black viscous liquid was obtained, which was purified by column chromatography (SiO
2
,
hexane/AcOEt, 98:2, v/v) to obtain 0.26 g of a mixture of (1’S,5R)-14 and (1’S,5S)-14 as a yellow
brownish oil (82% combined yield).
1’S,5R)-14. Rf. = 0.54 (6:1 hexane/AcOEt). [] 20
NMR (500 MHz, CDCl
= -38.9 (c =1.0, CHCl
). H
1
(
D
3
3
) δ (ppm): 7.25–7.22 (m, 2H), 6.87–6.84 (m, 2H), 5.77–
.73 (m, 1H), 5.68–5.65 (m, 1H), 4.33–4.30 (m, 1H), 3.80 (s, 3H), 3.48 (q, J =
.5 Hz, 1H), 3.21–3.17 (m, 1H), 2.88 (dd, J =11.0, 5.5 Hz, 1H), 2.81 (ddd, J =
5
6
1
0
6.5, 5.5, 2.5 Hz, 1H), 2.01 (dd, J = 10.5, 8.5 Hz), 1.36 (d, J = 6.5 Hz, 3H), 0.84 (s, 9H), 0.006 (s, 3H), -
.01 (s, 3H). 13C NMR (125 MHz, CDCl
3
) δ (ppm): 158.4 (para), 135.7 (ipso), 130.1 (C4), 128.4
(
ortho), 126.9 (C5), 113.5 (meta), 66.8 (C3), 63.2 (C1’), 55.2 (-OCH
(CH C-], 19.4 (C2’), 18.2 [(CH C-], -4.6 (-CH ), -4.7 (-CH ). HRMS-EI m/z 347.2299 (calcd. for
Si, 347.2281).
3
), 54.7 (C2), 49.8 (C6), 25.8
[
3
)
3
3
)
3
3
3
C
20
H
33NO
2
2
0

Page 21 of 33
Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02700A
(
1’S,5S)-14. Rf. = 0.50 (6:1 hexane/AcOEt). [] 20
1H NMR (500 MHz, CDCl
D
= +28.4 (c = 0.83, CHCl ).
3
3
) δ (ppm): 7.22–7.19 (m, 2H), 6.81–6.79 (m, 2H),
5
4
.70 (dtd, J = 10.5, 3.0, 1.5 Hz, 1H), 5.63 (ddd, J = 10.0, 5.0, 1.5 Hz, 1H), 4.26–
.23 (m, 1H), 3.75 (s, 3H), 3.41, (q, J = 7.0 Hz, 1H), 2.95 (ddd, J = 16.5, 5.5, 2.5
Hz, 1H), 2.81–2.77 (m, 1H), 2.69 (dd, J = 11.0, 5.0 Hz, 1H), 2.78 (dd, J =11.5,
1
3
6
.5 Hz, 1H), 1.34 (d, J = 6.5 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 3H), -0.001 (s, 3H). C NMR (125 MHz,
CDCl ) δ (ppm): 158.4 (para), 135.4 (ipso), 128.9 (C4), 128.6 (ortho), 127.5 (C5), 113.5 (meta), 66.5
C3), 63.2 (C1’), 55.2 (-OCH ), 54.9 (C2), 49.8 (C6), 25.9 [(CH C-], 19.5 (C2’), 18.3 [(CH C-], -4.6
-CH ), -4.7 (-CH ). HRMS-EI m/z 347.2274 (calcd. for C20 Si, 347.2281).
3
(
(
3
3
)
3
)
3 3
3
3
H
33NO
2
(R)-3-Hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-3,4-dehydropiperidine [(1’S,5R)-21]
To a solution of (1’S,5R)-14 (0.23 g, 0.66 mmol) in dry THF (7 mL) at 0 °C was
added dropwise TBAF (0.66 mL, 0.66 mmol, 1M solution in THF). After 8 h, the
reaction was quenched by adding a saturated aqueous solution of NaHCO
mL). The phases were separated and the aqueous phase extracted with AcOEt (3
x 10 mL) and CH Cl (3 x 10 mL). After drying the organic phases over Na SO
and concentration under reduced pressure, the residue was purified by column chromatography (SiO
3
(1.0
2
2
2
4
2
,
2
0
hexane/AcOEt, 1:5, v/v) to give 0.14 g (90%) of (1’S,5R)-21 as a yellow oil. Rf. = 0.30 (AcOEt). []
D
1
=
-85.18 (c =1.0, CHCl
3
). H NMR (500 MHz, CDCl
3
) δ (ppm): 7.26–7.20 (m, 2H), 6.87–6.84 (m, 2H),
5
.87–5.83 (m, 1H), 5.79–5.75 (m, 1H), 4.06–4.04 (m, 1H), 3.79 (s, 3H), 3.51(q, J = 6.5 Hz, 1H), 2.99 (d,
1
3
J = 17.0 Hz, 1H), 2.83–2.76 (m, 2H), 2.49 (dd, J = 11.0, 3.0 Hz, 1H), 1.38 (d, J = 6.5 Hz, 3H). C NMR
(
(
(
125 MHz, CDCl
meta), 64.7 (C3), 63.0 (C1’), 55.2 (-OCH
calcd. For C14 , 233.1416).
3
) δ (ppm): 158.6 (para), 135.3 (ipso), 129.1 (C5), 128.5 (ortho), 127.8 (C4), 113.5
3
), 54.4 (C2), 50.4 (C6), 18.9 (C2’). HRMS-EI m/z 233.1421
H
19NO
2
2
1

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DOI: 10.1039/C7OB02700A
(S)-3-Hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-3,4-dehydropiperidine [(1’S,5S)-21]
Following the same deprotection procedure as for (1’S,5R)-21, 0.06 g (91%) of
(1’S,5S)-21 were obtained as white crystalline solid. Rf. = 0.34 (AcOEt). Mp. =
2
0
1
8
7
5
4-86 °C []
D
= +50.13 (c =1.0, CHCl
3
). H NMR (300 MHz, CDCl ) δ (ppm):
3
.21 (dt, J = 10.0 3.5 Hz, 2H), 6.86 (dt, J = 9.0, 3.0 Hz, 2H), 5.90-5.86 (m, 1H),
.85–5.82 (m, 1H), 3.97–3.94 (m, 1H), 3.80 (s, 3H), 3.50(q, J = 7.0 Hz, 1H), 3.27
(
dd, J = 18.5, 4.0 Hz, 1H), 2.80-2.74 (m, 2H), 2.27 (dd, J = 11.5, 2.5 Hz, 1H), 1.39 (d, J = 7.0 Hz, 3H).
) δ (ppm): 158.6 (para), 135.2 (ipso), 129.3 (C5), 128.6 (ortho), 127.6 (C4),
13.6 (meta), 64.5 (C3), 63.2 (C1’), 55.2 (-OCH ), 54.4 (C2), 50.1 (C6), 19.3 (C2’). HRMS-EI m/z
33.1419 (calcd. for C14 , 233.1416).
13C NMR (75 MHz, CDCl
3
1
2
3
H
19NO
2
(3R,4S,5S)-5-((tert-Butyldimethylsilyl)oxy)-3,4-epoxy-1-((S)-1-(4- methoxyphenyl)ethyl)piperidine-2-
one [(1’S,3R,4S,5S)-15]
To a solution of (1’S,5R)-14 (0.17 g, 0.49 mmol), 2-methyl-2-butene (0.52 mL,
.9 mmol) and NaH PO (0.68 g, 5.0 mmol) in THF/t-BuOH/H O (11.5 mL/5
mL/5 mL) at 0 °C was added NaClO (0.36 g, 3.9 mmol) dissolved in H O (1
4
2
4
2
2
2
mL). The solution was stirred for 20 minutes at 0 °C, whereupon a saturated
solution of NaOH (1.5 mL) was added and the organic layer was extracted with
AcOEt (4 x 10 mL). After drying the combined organic phases over Na
reduced pressure, the residue was purified by column chromatography (SiO
to obtain 0.17 g of (1S’,3R,4S,5S)-15 (92%) as white crystalline material. Rf. = 0.28 (6:1
2
SO
4
and concentration under
2
, hexane/AcOEt, 12:1, v/v)
2
0
1
hexane/AcOEt). Mp. = 91-93 °C. []
D
= -77.7 (c =1.0, CHCl
3
). H NMR (500 MHz, CDCl ) δ (ppm):
3
7
3
.24–7.21 (m, 2H), 6.84–6.81 (m, 2H), 5.94 (q, J = 7.0 Hz, 1H), 4.31 (dt, J = 2.5, 2.0 Hz, 1H), 3.78 (s,
H), 3.59 (dd, J = 4.0, 0.5 Hz, 1H), 3.38 (ddd, J = 4.0, 2.5, 1.0 Hz, 1H), 3.22 (dd, J = 13.0, 2.5 Hz, 1H),
2
2

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DOI: 10.1039/C7OB02700A
1
3
2
.80 (dt, J = 13.0, 1.5 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H), 0.75 (s, 9H), -0.05 ( s, 3H), -0.19 (s, 3H). C
NMR (125 MHz, CDCl ) δ (ppm): 165.4 (C2), 158.8 (para), 131.3 (ipso), 128.9 (ortho), 113.7 (meta),
), 54.3 (C4), 51.0 (C3), 49.7 (C1’), 42.6 (C6), 25.7 [(CH C-], 18.0 [(CH C-],
), -5.1 (-CH ). HRMS-EI m/z 377.2029 (calcd. for C20 Si, 377.2022).
3
6
1
4.6 (C5), 55.2 (-OCH
3
3
)
3
)
3 3
5.9 (C2’), -4.9 (-CH
3
3
H
31NO
4
(3S,4R,5R)-5-((tert-Butyldimethylsilyl)oxy)-3,4-epoxy-1-((S)-1-(4-methoxyphenyl)ethyl)piperidin-2-
one [(1’S,3S,4R,5R)-15]
Following the same procedure as for (1S’,3R,4S,5S)-15, 0.17 g of (1’S,3S,4R,5R)-
2
0
1
5 (84%) were obtained as a yellow oil. Rf. = 0.28 (6:1 hexane/AcOEt). []
D
=
1
-28.0 (c =1.0, CHCl
3
). H NMR (500 MHz, CDCl
3
) δ (ppm): 7.18–7.15 (m, 2H),
6
.87–6.84 (m, 2H), 5.87 (q, J = 7.0 Hz, 1H), 4.30 (q, J = 1.0 Hz, 1H), 3.79 (s,
3
1
H), 3.59 (dd, J = 4.0, 1.0 Hz, 1H), 3.41–3.39 (m, 1H), 2.86 (dd, J = 13.5, 2.5 Hz, 1H), 2.70 (dt, J =
1
3
4.0, 1.5 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H). C NMR (125 MHz,
) δ (ppm): 165.3 (C2), 158.8 (para), 131.4 (ipso), 128.5 (ortho), 113.8 (meta), 64.8 (C5), 55.2 (-
CDCl
OCH
3
3
), 54.5 (C4), 51.3 (C3), 49.9 (C1’), 44.3 (C6), 25.6 [(CH
3
)
3
C-], 18.0 [(CH
3
3
) C-], 15.2 (C2’), -4.6
(
CH
3
), -4.7 (CH ). HRMS-EI m/z 377.2035 (calcd. for C20
3
H31NO
4
Si, 377.2022).
(3R,4R,5S)-5-Hydroxy-3,4-epoxy-1-((S)-1-(4-methoxyphenyl)ethyl)piperidin-2-one [(1’S,3R,4R,5S)-
2
0]
To a solution of (1’S,3R,4S,5S)-15 (0.16 g, 0.46 mmol) in dry THF (15 mL) at 0
C was added dropwise TBAF (0.5 mL, 0.4 mmol, 1M solution in THF). After 2
h, the reaction was quenched by adding a saturated aqueous solution of NaHCO
°
3
(0.5 mL). The phases were separated and the aqueous phase extracted with AcOEt
(3 x 10 mL) and CH
2
Cl (3 x 10 mL). After drying the combined organic phases over Na SO and
2
2
4
2
3

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concentration under reduced pressure, the crude was purified by column chromatography (SiO
2
,
hexane/AcOEt, 1:1, v/v) to yield (1’S,3R,4R,5S)-20 (0.11 g, 90%) as white crystalline solid. Rf. = 0.57
2
0
1
(AcOEt). Mp. = 181-183 °C. []
D
= -86.3 (c = 1.0, CHCl
3
). H NMR (500 MHz, CDCl ) δ (ppm):
3
7
.25–7.22 (m, 2H), 6.87 (dt, J = 9.0, 3.0 Hz, 2H), 5.97 (q, J = 7.0 Hz, 1H), 4.29 (ddd, J = 7.5, 5.5, 2.5
Hz, 1H), 3.79 (s, 3H), 3.61 (dd, J = 4.0, 0.5 Hz, 1H), 3.52 (ddd, J = 4.5, 3.0, 1.5 Hz,1H), 3.30 (dd, J =
1
1
3.5, 3.0 Hz, 1H), 2.84 (ddd, J = 13.5, 2.0, 1.5 Hz, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 7.5 Hz,
1
3
H). C-NMR (125 MHz, CDCl
3
) δ (ppm): 165.2 (C2), 159.1 (para), 131.4 (ipso), 128.5 (ortho), 114.0
(
meta), 64.1 (C5), 55.2 (-OCH
3
), 53.6 (C4), 51.1 (C3), 49.6 (C1’), 42.0 (C6), 15.6 (C2’).
(3S,4S,5R)-5-Hydroxy-3,4-epoxy-1-((S)-1-(4-methoxyphenyl)ethyl)piperidin-2-one [(1’S,3S,4S,5R)-
2
0]
Following the same procedure as for (1’S,3R,4R,5S)-20, 0.102 g of
(1’S,3S,4S,5R)-20 (85%) were obtained as white crystalline solid. Rf. = 0.57
AcOEt). Mp. = 130-133 °C. [] 20
= -106.8 (c = 1.0, CHCl
). H NMR (500
1
(
D
3
MHz, CDCl
3
) δ: 7.19–7.16 (m, 2H), 6.86 (dt, J = 8.5, 3.5 Hz, 2H), 5.89 (q, J =
7
.0 Hz, 1H), 4.36 (ddd, J = 8.0, 5.0, 2.5 Hz, 1H), 3.79 (s, 3H), 3.61 (dd, J = 4.0, 1.0 Hz, 1H), 3.57 (dd, J
1
3
=
4.5, 3.5 Hz, 1H), 2.90 (d, J = 2.5 Hz, 2H), 1.98 (d, J = 8.5 Hz, 1H), 1.46 (d, J = 7.0 Hz, 3H). C NMR
) δ (ppm): 165.2 (C2), 158.9 (para), 131.0 (ipso), 128.5 (ortho), 113.9 (meta), 64.5
), 54.1 (C4), 51.1 (C3), 49.9 (C2’), 43.6 (C6), 15.3 (C1’).
(
125 MHz, CDCl
C5), 55.2 (-OCH
3
(
3
(3R,4R,5S)-5-Acetyloxy-3,4-epoxy-1-((S)-1-(4-methoxyphenyl)ethyl)piperidin-2-one [(1’S,3R,4R,5S)-
2
2]
2
4

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To a solution of (1’S,3R,4R,5S)-20 (0.06 g, 0.23 mmol) and DMAP (0.008 g,
0
.07 mmol) in dry MeCN (10 mL) was added dropwise a solution of
triethylamine (0.05 mL, 0.35 mmol) in dry MeCN (1 mL). After addition of a
solution of acetic anhydride (0.033 mL, 0.35 mmol) in dry MeCN (1 mL), the
solution was stirred for 1.5 hours at room temperature, whereafter NaHCO
neutral pH. The liquid phase was filtered, dried over Na SO , concentrated at reduced pressure and
purified by column chromatography (SiO , hexane/AcOEt, 5:1, v/v) to give 0.07 g of (1’S,3R,4R,5S)-22
3
was added until reaching a
2
4
2
(
95%) as white crystalline solid. Rf. = 0.40 (1:1 hexane/AcOEt). Mp. = 116-118 °C. [] 20
D
= -61.38 (c =
1
1
5
.0, CHCl
3
). H NMR (500 MHz, CDCl
3
) δ (ppm): 7.23–7.20 (m, 2H), 6.84 (dt, J = 9.5, 3.0 Hz, 2H),
.96 (q, J = 7.0 Hz, 1H), 5.29 (dd, J = 5.5, 3.0 Hz, 1H), 3.78 (s, 3H), 3.64 (dd, J = 4.0, 0.5 Hz, 1H), 3.54
(ddd, J = 4.5, 3.0, 1.5 Hz, 1H), 3.30 (dd, J = 14.0, 2.5 Hz, 1H), 2.99 (ddd, J = 14.0, 2.0, 1.5 Hz, 1H),
1
3
1
.74 (s, 3H), 1.43 (d, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl
3
) δ (ppm): 169.6 (MeCO
), 51.5 (C4), 51.0
-), 15.5 (C2’). HRMS-EI m/z 305.1266 (calcd. for
2
), 164.8
(
C2), 158.9 (para), 131.1 (ipso), 128.8 (ortho), 113.5 (meta), 65.8 (C5), 55.2 (-OCH
C3), 49.6 (C1’), 39.1 (C6), 20.5 (H CCO
, 305.1263).
3
(
3
2
C
16
H19NO
5
(3S,4S,5R)-5-Acetyloxy-3,4-epoxy-1-((S)-1-(4-methoxyphenyl)ethyl)piperidin-2-one [(1’S,3S,4S,5R)-
2
2]
Following the same procedure as for (1’S,3R,4R,5S)-22, 0.06 g of (1’S,3S,4S,5R)-
2
2 were obtained (98%) as a greenish viscous liquid. Rf. = 0.40 (1:1
hexane/AcOEt). [] 20
= -20.91 (c = 1.0, CHCl
). H NMR (500 MHz, CDCl
1
) δ
D
3
3
(ppm): 7.17–7.13 (m, 2H), 6.85 (dt, J = 9.5, 3.0 Hz, 2H), 5.87 (q, J = 7.0 Hz, 1H),
5
.34 (dd, J = 4.5, 2.0 Hz, 1H), 3.79 (s, 3H), 3.64 (dd, J = 3.5, 1.0 Hz, 1H), 3.62 (ddd, J = 4.0, 3.0, 1.0
1
3
Hz, 1H), 2.99–2.92 (m, 2H), 2.10 (s, 3H), 1.38 (d, J = 7.0 Hz, 3H). C NMR (125 MHz, CDCl
3
) δ
(
ppm): 170.0 (MeCO ), 164.9 (C2), 158.9 (para), 130.7 (ipso), 128.5 (ortho), 113.9 (meta), 66.5 (C5),
2
2
5

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5
3
5.2 (-OCH
3
), 51.9 (C4), 51.2 (C3), 50.0 (C1’), 40.76 (C6), 20.8 (H
3
CCO
2
-), 14.9 (C2’). HRMS-EI m/z
05.1257 (calcd. for C16
H
19NO , 305.1263).
5
(3R,4R,5S)-5-Acetyloxy-3,4-epoxypiperidin-2-one [(3R,4R,5S)-23]
To a solution of (1’S,3R,4R,5S)-22 (0.06 g, 0.186 mmol) in MeCN (7 mL) at 0 °C
was added a solution of ceric ammonium nitrate (0.31 g, 0.56 mmol) in water (1.5
mL). The mixture was stirred for 6 h before adding 1 mL of H
the product with AcOEt (4 x 5 mL), the combined organic phases were dried over Na
solvent removed under reduced pressure. The crude was purified by column chromatography (SiO
hexane/AcOEt, 2:1, v/v) to obtain 0.02 g (64%) of (3R,4R,5S)-23 as white crystalline solid. Rf. = 0.51
2
O. After extracting
2
SO and the
4
2
,
2
0
1
(AcOEt). Mp. = 101-104 °C. []
D
= +46.3, (c = 1.0, CHCl
3
). H NMR (500 MHz, CDCl ) δ (ppm):
3
5
3
.72 (br, 1H), 5.45–5.44 (m, 1H), 3.67 (ddd, J = 4.0, 3.0, 1.5 Hz, 1H), 3.56 (dd, J = 14.0, 2.5 Hz, 1H),
1
3
.51 (dd, J = 3.0, 2.5 Hz, 1H), 3.26 (ddt, J = 14.0, 6.0, 1.5 Hz, 1H), 2.12 (s, 3H). C NMR (125 MHz,
CDCl
3
) δ (ppm): 170.2 (MeCO
2
), 167.4 (C2), 65.8 (C5), 52.2 (C4), 50.5 (C3), 41.0 (C6), 20.8
+
(H
3
CCO
2
-). HRMS-FAB m/z [M + H] : 172.0617 (calcd. for C
7
H
10NO , 170.0610).
4
(3S,4S,5R)-5-Acetyloxy-3,4-epoxypiperidin-2-one [(3S,4S,5R)-23]
Following the same procedure as for (3R,4R,5S)-23, 0.02 g of (3S,4S,5R)-23 were
obtained (61%) as white crystalline solid. Rf. = 0.51 (AcOEt), Mp. = 101-104 °C.
2
0
+
[
]
D
= -46.36, (c = 1.0, CHCl ). HRMS-FAB m/z [M + H] : 172.0621 (calcd. for
3
C
7
H10NO
4
, 172.0610).
(3R,4R,5S)-5-Acetyloxy-3,4-epoxy-(1-hydrocinnamoyl)piperidin-2-one [(-)-(3R,4R,5S)-3]
2
6

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A mixture of cinnamic acid (0.74 g, 5.00 mmol) and Pd(OH) /C 5% wt. (0.034
2
mg) in AcOEt under H (100 psi) was stirred for 22 h at room temperature. Then,
2
the solution was passed through a pad of silica gel using AcOEt as mobile phase.
The resulting hydrocinnamic acid was isolated as colorless crystalline solid in
quantitative yield. To a solution of the hydrocinnamic acid (0.12 g, 0.79 mmol) in dry CH
2
Cl at 0 °C
2
was added a solution of DMF (0.06 mL, 0.79 mmol) in dry CH Cl (0.3 mL) followed by small portions
2
2
of oxalyl chloride (0.07 mL, 0.79 mmol). After stirring for 1 hour at room temperature, the solvent was
removed to yield the corresponding acyl halide. For the final step, to a solution of (3R,4R,5S)-23 (0.045
g, 0.26 mmol) in dry THF (8.0 mL) at -78 °C was added dropwise n-BuLi (0.21 mL, 0.34 mmol, 1 M
solution in hexane). After stirring for 20 minutes, the previous freshly prepared hydrocynnamic acid
chloride was dissolved in dry THF (2.0 mL) and added by cannula. The reaction mixture was allowed to
react for 2 h before adding H
After drying the combined organic phases over Na
product was purified by column chromatography (SiO
of the natural occurring alkaloid (-)-(3R,4R,5S)-3 as a yellow oil. Rf. = 0.34 (hexane/AcOEt). []
2
O (1.0 mL). The aqueous phase was extracted with AcOEt (4 x10 mL).
SO and concentration under reduced pressure, the
, hexane/AcOEt, 9:1, v/v) to obtain 0.42 g (53%)
2
4
2
2
0
D
= -
CO] δ (ppm):
.29–7.24 (m, 4H), 7.19–7.16 (m, 1H), 5.64 (ddd, J = 3.0, 2.5, 0.5 Hz, 1H), 4.46 (ddd, J = 15.0, 2.5, 1.5
1
7
20
1
7
7
6.8 (c = 1.0, Me
2
CO), lit. []
D
= -98.8, (c = 0.5, Me
2
CO). H NMR [500 MHz, (CD
3 2
)
Hz, 1H), 3.89 (ddd, J = 4.0, 3.0, 1.5 Hz, 1H), 3.67 (dd, J = 4.0, 1.0 Hz, 1H), 3.34 (dd, J = 14.5, 2.5 Hz,
1
H), 3.25 (ddd, J = 17.5, 9.0, 6.5 Hz, 1H), 3.18 (ddd, J = 17.5, 8.5, 6.5 Hz, 1H), 2.96–2.86 (m, 2H), 2.02
(
(
(
s, 3H). 13C-NMR [125 MHz, (CD
3
)
2
CO] δ (ppm): 175.0 (C7), 170.3 (MeCO ), 169.2 (C2), 142.1
2
ipso), 129.2 (Ph), 129.1 (Ph), 126.8 (Ph), 66.8 (C5), 53.4 (C4), 52.5 (C3), 41.8 (C6), 41.6 (C8), 31.4
C9), 20.6 (H CCO -).
3
2
(3S,4S,5R)-5-Acetyloxy-3,4-epoxy-(1-hydrocinnamoyl)piperidin-2-one [(+)-(3S,4S,5R)-3]
2
7

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Following the same procedure as for (-)-(3R,4R,5S)-3, 0.04 g of (+)-(3S,4S,5R)-
2
0
3
(52%) were obtained as a yellow oil. Rf. = 0.34 (hexane/AcOEt). []
75.3, (c = 1.3, Me CO).
D
=
+
2
CONFLICTS OF INTEREST
There are no conflicts to declare
ACKNOWLEDGMENTS
Financial support was provided by CONACyT (project number: 255891) and the Marcos Moshinsky
Foundation. U.O.N acknowledges CONACyT for graduate scholarship (grant number: 383339) and
LYVA BUAP-VIEP for an undergraduate scholarship. Access to the X-ray facilities of the Chemical
Research Center at Morelos State University (LANEM) is gratefully acknowledged.
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