Synthesis and reactivity of pelletierine-derived building blocks and pelletierine analogs

Article abstract of DOI:10.1016/j.tet.2012.05.051

Lycopodium alkaloids are unique (and often impressive in terms of structures) polycyclic alkaloids that attract great interest from a biological point of view and that also provide ideal targets for total synthesis. Propylpiperidine units closely related to pelletierine are involved in the biosynthesis of these alkaloids. Therefore, stable pelletierine-like compounds, especially a (R)-phenylglycinol-based oxazolopiperidine analog, were prepared and their reactivity investigated. The compounds described in this work expand the tool-box of small building blocks in the piperidine series and pelletierine analogs and could be suitable for the synthesis of Lycopodium alkaloids following biosynthetically inspired strategies.

Full text of DOI:10.1016/j.tet.2012.05.051

Tetrahedron 68 (2012) 6276e6283
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and reactivity of pelletierine-derived building blocks and pelletierine
analogs
a
a
b
a
a,
*
ꢀ
ꢀ
Lok-Hang Yan , Flore Dagorn , Edmond Gravel , Blandine Seon-Meniel , Erwan Poupon
a
ꢀ
ꢀ
ꢀ
ꢀ
Laboratoire de Pharmacognosie associe au CNRS (UMR 8076 BioCIS), LabEx LERMIT, Universite Paris-Sud, Faculte de Pharmacie, 5, rue Jean-Baptiste Clement,
ˇ
92 296 Chatenay-Malabry, France
b CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, LabEx LERMIT, 91191 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Lycopodium alkaloids are unique (and often impressive in terms of structures) polycyclic alkaloids that
attract great interest from a biological point of view and that also provide ideal targets for total synthesis.
Propylpiperidine units closely related to pelletierine are involved in the biosynthesis of these alkaloids.
Therefore, stable pelletierine-like compounds, especially a (R)-phenylglycinol-based oxazolopiperidine
analog, were prepared and their reactivity investigated. The compounds described in this work expand
the tool-box of small building blocks in the piperidine series and pelletierine analogs and could be
suitable for the synthesis of Lycopodium alkaloids following biosynthetically inspired strategies.
Ó 2012 Published by Elsevier Ltd.
Received 7 February 2012
Received in revised form 7 May 2012
Accepted 15 May 2012
Available online 23 May 2012
Keywords:
Alkaloids
Iminium
Piperidine
Pelletierine
Phenylglycinol
1. Introduction
but also, in some cases, because their highly intricate structures
designate them as beautiful targets for total synthesis featuring
Pelletierine, named in honor of Joseph Pelletier, is probably one
of the most renowned alkaloid and one the most simple in terms of
chemical structure. Isolated by Charles Tanret in 1878 from the bark
of pomegranate tree (Punica granatum L., Lythraceae), which was
traditionally used as an anti-helminthic drug, pelletierine has
a long history of chemical controversies.1 From the initial aldehydic
(3-(2-piperidinyl)propionaldehyde) structure proposed by Hess
and Eichel in 1917 (Fig. 1) to the final conclusions with the work of
Gilman and Marion, several critical points, especially regarding
terminology, have been debated. It is now accepted that (ꢀ)-pel-
letierine refers to (ꢀ)-1-(2-piperidinyl)propan-2-one and iso-
pelletierine to (ꢁ)-pelletierine. Finally, the absolute configuration,
as well as the biogenetic origin, was revealed in the 1960s.1e
The implication of pelletierine (1), or at least analogous C5NeC3
units, in the biosynthesis of complex alkaloids of the genus Lyco-
podium (Lycopodiaceae) is a matter of particular significance.2 In-
deed, with more than 250 known structures and a permanently
enriched list,3 Lycopodium alkaloids have attracted a great deal of
interest thanks to promising biological activities (huperzine A is
a potent inhibitor of acetylcholinesterase, nankakurine A4 shows
neurotrophic properties to cite two examples among many others)
state-of-the-art methodology.5
In terms of biosynthesis, Lycopodium alkaloids were shown to
derive from C5NeC3 units as beautifully demonstrated some years
ago by Spenser with the revealing of lycopodine (2) biosynthesis by
feeding experiments.6 The studies clearly demonstrated the in-
corporation of lysine in combination with a polyketide derivative
(3) as the precursor of the three side-chain carbons (Scheme 1).7
Whether pelletierine (1) sensu stricto is incorporated cannot be
Lythraceae]
* Corresponding author. Tel.: þ33 1 46 83 55 86; fax: þ33 1 46 83 53 99; e-mail
address: erwan.poupon@u-psud.fr (E. Poupon).
Fig. 1. Structures related to pelletierine.
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2012.05.051

L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
6277
Scheme 1. Lycopodium alkaloids: diversity and biosynthesis.
ascertained, but synthons with the same latent polarities may be, at
least, commonly traced in Lycopodium alkaloids as depicted in
Scheme 1 with the example of nankakurine A (4). Thus the Lyco-
podium class of alkaloids may be divided in several groups
according to the number of pelletierine-like molecules in-
corporated in the final structure.8 Indeed, from two up to four
C5NeC3 units can be found in these alkaloids as exemplified on
Scheme 1 with lyconadin A (5), above mentioned huperzine A (6),
lycoperine A (7), himeradine A (8) and complanadine D (9).9
Puzzled by Nature’s diversification of skeletons within Lycopo-
dium alkaloids starting from C5NeC3 units analogous to pelletierine
(1), we were interested in the synthesis of pelletierine-derived
building blocks. Such compounds may display different latent or
masked reactivities in different oxidation states enabling further
functionalization through biomimetic strategies. The present work
describes the first results toward this aim with the synthesis of
several stable pelletierine analogs (in fact (ꢀ)-pelletierine (1) is
known to be prone to both racemization and degradation along
with displaying an inconvenient volatility),10 from which at least
two may be considered as building blocks sensu stricto.
chain could retrosynthetically come from Michael acceptor 12
bearing a free aldehyde function (Scheme 2).
Scheme 2. Retrosynthesis and potential reactivities of phenyloxazolopelletierine (10).
Glutaraldehyde (13) and 1-(triphenylphosphoranylidene)-2-
propanone (14) were engaged to afford Michael acceptor 12 by
a Wittig reaction in 71% yield. Several experiments were then
conducted in order to investigate the best conditions for the con-
densation of 12 with (R)-(ꢀ)-phenylglycinol (11) (See Scheme 3). A
satisfactory yield of 50% is observed when reacting 12 and 11 in
dichloromethane at room temperature (the yield drops to 11% when
the reaction was conducted in methanol). The so-called ‘phenyl-
oxazolopelletierine’ (10) appears by NMR as a mixture of two di-
astereoisomers that are not separable by chromatography column.13
Careful analysis of NMR spectra permitted to establish the rel-
ative stereochemistry of both stereomers (see selected NMR data
on Scheme 3).
2. Results and discussion
2.1. Conception, synthesis of ‘phenyloxazolopelletierine’ (10):
(R)-(L)-phenylglycinol as the nitrogen source
We thought of designing a stable analog of pelletierine, such as
compound 10, which can be seen as a stable equivalent of dehy-
dropelletierine. It features a protected nitrogen atom with a phe-
nylethanol moiety provided by (ꢀ)-phenylglycinol (11) (used as the
nitrogen source and chirality inducer).11 The primary alcohol also
permits the stabilization of a potential iminium by forming an
oxazolidine ring.12 The piperidine ring and the propanone side

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L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
Scheme 3. Synthesis of phenyloxazolopelletierine (10).
2.2. Reactivity of ‘phenyloxazolopelletierine’ (10)
Scheme 4. Reactivity of phenyloxazolopelletierine (10).
Reactivity studies were conducted on compound 10 in order to
evaluate the dual iminium/enamine reactivity, (which could permit
access to substituted piperidines at the C-2 or C-3 positions) as well
as the reactivity of the side chain.14 Moreover, it was anticipated
that diastereoselective transformations might be expected with the
presence of the chiral appendage.
2.2.1. Protection of the carbonyl group. Various conditions were
evaluated so as to protect the carbonyl of the propanone side chain
as a cyclic diketal but were all unsuccessful. Conversely, the pro-
tection as a dithioketal 15 (2:1 mixture of diastereomers)15 was
easy using a large excess of 1,2-ethanedithiol and BF3$Et2O in
dichloromethane at room temperature. Unfortunately, depro-
tection under the few conditions tested (diacetoxyiodobenzene
(PIDA) and [bis(trifluoroacetoxy)]iodobenzene (PIFA)) did not per-
mit to regenerate 10 as depicted on Scheme 4.
2.2.2. Oxidative conditions. Oxidation under classical mercuric ac-
etate and EDTA conditions led to the formation of lactam 16 in good
yields (9:1 mixture of diastereomers resulting from partial epi-
merization at C-6)16 without further purification.17,18
An interesting reaction was observed when 10 was treated with
iodine. Whereas a lactam, such as 16 could be expected, the imi-
nium form 17 was obtained in useful yields and appeared to be
stable. Such an iminium is believed to be an intermediate toward
lactams in the phenyloxazolopiperidine series. In fact, when treated
with an aqueous solution of H2SO4, 17 cleanly gave lactam 16 in
high yield. A complex rearrangement was then observed when
treating 17 with manganese dioxide resulting in the formation of
bicyclic lactam 18 (in 60% yield, obtained as a single diastereomer)
Scheme 5. Particular reactivity of phenyloxazolopelletierine (10) under oxidizing
conditions.
result was observed in the morphinane series in the late 1960s by
the Kitano group.19
featuring a novel CeO bond at the b-position of the piperidine ring
(Scheme 5). This outcome was surprisingly welcome as it provided
another interesting pelletierine-like building block. Such a reaction
probably takes place through radical intermediates and is, to the
best of our knowledge, seldom described in the literature. A similar
2.2.3. Reaction with nucleophiles and electrophiles. The enamine
reactivity was tested with methylvinylketone (MVK) as a simple
Michael acceptor (Scheme 4). Although a monoalkylation of

L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
6279
compound 10 was possible albeit in moderate yield, the diaster-
eoselectivity of this reaction was difficult to evaluate because of an
additional instability in NMR tube that rapidly resulted in an epi-
merization leading to a complex mixture of diastereomers. A rapid
NMR analysis of chromatography fractions accounts for the for-
mation of tentative structure 19 as the major diastereomer (w66%,
indicative yield) as depicted on Scheme 4, along with hardly sep-
arable small amounts of its disubstituted counterpart confirmed by
the observation of a m/z [MþNa]þ 422 peak on the mass spectrum
when 4 equiv were employed.
When protected analog 15 was treated with an excess of MVK,
double adduct 20 was obtained in 25% yield (8:2 mixture of
diastereomers).
The oxazolidine ring opening and the following trapping of the
iminium by a cyanide ion leading to a-aminonitrile 21 was possible
by treatment of 15 with trimethylsilyl cyanide in dichloromethane
at room temperature. All subsequent reagents investigated (AgBF4,
LiBF4, TBAF, SiO2.) systematically gave back 15.
2.3. Use of (S)-1-phenylethylamine and benzylamine as
nitrogen sources
The use of chirality inductors devoid of any iminium stabiliza-
tion ability was then investigated. Such an approach should permit
a biosynthetically inspired dimerization as witnessed in the course
of the biosynthesis of Lycopodium alkaloids, such as complanadine
D (9). Reaction of Michael acceptor 12 with (S)-phenylethylamine
(22) in dichloromethane at room temperature led to a mixture of
compounds, in which no dimerization compound 24 could be iso-
lated by column chromatography. The only compound that could be
characterized was 26, logically resulting from an intramolecular
Mannich reaction to give a pseudopelletierine analog (Scheme 6).20
When targeting a,a
0-disubstituted compounds of type 28 (See
Scheme 7) to mimick the assembly of alkaloids, such as lycoperine
A (7), an unexpected result was observed and further studied. Bis-
Michael acceptor 29 was prepared by a double Wittig reaction on
glutaraldehyde (13).
Scheme 7. Particular reactivity with a double Michael acceptor.
The loss of one side chain could be explained by a plausible retro-
Mannich reaction mechanism providing reactive iminium in-
termediates 31 and 32 as depicted on Scheme 7.21 Only the recourse
to benzylamine (33) permitted the isolation of a,a
0-disubstituted
piperidine 34 as an 85:15 mixture of diastereoisomers with pre-
dominant trans configuration (Scheme 8).22
85:15
Scheme 8. Reactivity with a double Michael acceptor and benzylamine.
Scheme 6. Reaction with (S)-1-phenylethylamine (22).
3. Conclusion
Condensation of bis-Michael acceptor 29 was studied first with
(S)-1-phenylethylamine (22) and surprisingly only the pseudo-
pelletierine analog 26 could be isolated in low yield. Even more
striking was the isolation of phenyloxazolopelletierine 10 in 45%
yield when (R)-(ꢀ)-phenylglycinol (11) was employed. In both
The described chemistry provides an entry to new and stable
equivalents of pelletierine that are currently being studied. At least
two of them can be considered as building blocks and are currently
being studied for the biomimetic assembly of Lycopodium alkaloid
skeletons. The main results of the present work include the
cases, expected
a,a
0-disubstituted piperidines were not isolated.

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L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
synthesis of phenyloxazolopelletierine (10), the reactivity of which
was investigated especially in oxidative conditions (where an
original rearrangement leading to 18 was observed). The access to
HRMS (ESI) calcd for C16H22NO2 260.1651 [MþH]þ found 260.1639.
Rf¼0.56 (cyclohexane/EtOAc 1:1).
a
,a
0-disubstituted piperidines was also studied and permitted the
4.2.3. Dithioketal 15. To a solution of phenyloxazolopelletierine 10
(200 mg, 0.77 mmol) in CH2Cl2 (8 mL) were successively added 1,2-
ethanedithiol (1.29 mL, 15.4 mmol) and boron trifluoride (1.27 mL,
10.0 mmol). The reaction mixture was stirred overnight at room
temperature and then washed with a 2 M aqueous solution of
NaOH (5ꢂ25 mL), dried over MgSO4 and concentrated under re-
duced pressure to give compound 15 (216 mg, 84%) as a yellow
observation of unusual retro-Mannich reactions.
4. Experimental section
4.1. General methods
General: Reactions were monitored by thin-layer chromatog-
viscous oil. 1H NMR (400 MHz, CDCl3):
d
¼7.22e7.43 (m, 5H, Ph),
raphy carried out on silica gel plates (Merck TLC Silicagel 60
)
4.76 (dd, 3JH,H¼7.2, 4.4 Hz, 1H, CHePh), 4.55 (t, 3JH,H¼2.8, 2.0 Hz, 1H,
F254
2
3
using UV light as visualizing agent and sulfuric vanillin/heat and
Draggendorff reagent/heat as developing agents. Merck Silicagel
NeCHeO), 4.39 (dd, JH,H¼7.6 Hz, JH,H¼7.2 Hz, 1H, CH2eO), 3.81
2 3
(dd, JH,H¼7.6 Hz, JH,H¼4.4 Hz, 1H, CH2eO), 3.27e3.33 (m, 4H, 2
GeduranÒ Si 60 (particle size 40e63
mm) was used for flash chro-
CH2eS), 2.76 (td, JH,H¼7.6, 2.4 Hz, 1H, NeCH), 2.31 (d,
3
2
matography. NMR spectra were recorded in deuterated chloroform
on AM-300 (300 MHz) or AM-400 (400 MHz) Bruker spectrometers
and calibrated using undeuterated chloroform as an internal ref-
erence. The following abbreviations are used to explain the multi-
plicities: s¼singlet; d¼doublet, t¼triplet; q¼quartet; qu¼quintet;
m¼multiplet; br¼broad. IR spectra were recorded on Vector 22
Bruker spectrometer and values are reported in cmꢀ1 units. Mass
2JH,H¼15.2 Hz, 1H, CH2), 2.18 (m, 1H, CH2), 2.07 (dd, JH,H¼15.2 Hz,
3JH,H¼7.6 Hz, 1H, CH2), 1.99 (m, 1H, CH2), 1.73 (s, 3H, CH3), 1.52e1.66
(m, 2H, CH2), 1.36 (m, 1H, CH2). 13C NMR (100 MHz, CDCl3):
d¼142.7
(CIV Ph), 128.4 (2 CH Ph), 127.7 (2 CH Ph), 126.9 (CH Ph), 89.0
(NeCHeO), 69.3 (CH2eO), 65.7 (C), 64.9 (CHePh), 55.7 (NeCH),
50.5 (CH2), 39.8 (CH2), 39.6 (CH2), 33.9 (CH3), 32.6 (CH2), 26.8 (CH2),
18.4 (CH2). HRMS (ESI) calcd for C18H26NOS2 336.1456 [MþH]þ
found 336.1460. Rf¼0.73 (cyclohexane/Et2O 1:1).
ꢀ
spectra were recorded at the ‘Service d’Analyse des Medicaments et
ꢀ
ꢀ
des Metabolites’ (Universite Paris-Sud). Optical rotation measure-
ments were conducted using an Optical Activity polAAR 32
polarimeter.
4.2.4. Lactam 16. To a solution of phenyloxazolopelletierine 10
(50 mg, 0.193 mmol) in a minimum of EtOH was added a solution of
mercury acetate (65 mg, 0.203 mmol) and sodium salt of ethyl-
enediaminetetraacetic acid (68 mg, 0.203 mmol) in a mixture wa-
ter/EtOH (6 mL, 2:1). The reaction mixture was stirred at 80 ꢃC for
4 h, cooled to room temperature and filtered through a pad of
CeliteÒ. CH2Cl2 (5 mL) was added to the filtrate followed by satu-
rated solution of ammonium chloride (5 mL). After separation of
the two layers, the aqueous layer was extracted with CH2Cl2
(2ꢂ5 mL). The combined organic phases were dried over MgSO4
and concentrated under reduced pressure to afford compound 16
4.2. Procedures for the synthesis of compounds
4.2.1. Michael acceptor 12. A mixture of glutaraldehyde (17.2 mL of
a 50% aqueous solution, 94.3 mmol) and 1-(triphenylphosphor-
anylidene)-2-propanone (5 g, 15.7 mmol) in THF (75 mL) was stir-
red at room temperature for 23 h, after which water (75 mL) was
added. The mixture was then extracted by Et2O (3ꢂ70 mL). The
combined organic phases were dried over MgSO4 and concentrated
under reduced pressure. The oily residue was then purified by flash
chromatography on silica gel with a gradient solvent system: cy-
clohexane/EtOAc (8:2 to 5:5) to afford compound 12 (1.57 g, 71%) as
(42 mg, 79%) as orange oil. 1H NMR (300 MHz, CDCl3):
d
¼7.21e7.32
(m, 5H, Ph), 5.18 (t, 3JH,H¼6.6 Hz, 1H, CHePh), 4.09 (d, 3JH,H¼6.6 Hz,
3
2H, CH2eOH), 3.99 (m, 1H, NeCH), 2.80 (dd, JH,H¼3.9 Hz,
a yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.76 (s, 1H, CHO), 6.75
2JH,H¼18.0 Hz, 1H, CH2), 2.68 (dd, JH,H¼8.4 Hz, JH,H¼18.0 Hz, 1H,
3
2
3
3
(dt, JH,H¼16 Hz, 7.0 Hz, 1H,¼CHeCH2), 6.07 (d, JH,H¼16 Hz,
CH2), 2.52 (m, 2H, CH2eCO), 1.95 (s, 3H, CH3), 1.73e1.85 (m, 2H,
3
1H,¼CHeCO), 2.48 (t, JH,H¼7.0 Hz, 2H, CH2eCHO), 2.25 (q,
CH2), 1.61e1.70 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3):
d¼205.8
3JH,H¼7.0 Hz, 2H, CH2eCH¼), 2.22 (s, 3H, CH3), 1.80 (qu,
(CO), 172.5 (NeCO), 137.2 (CIV Ph), 128.6 (2 CH Ph), 127.6 (2 CH Ph),
126.1 (CH Ph), 63.6 (CHePh), 63.3 (CH2eOH), 51.7 (CeCH), 47.4
(CH2), 31.6 (CH2), 30.3 (CH3), 27.7 (CH2), 16.4 (CH2). IR nmax: 3290,
1711, 1615 cmꢀ1. HRMS (ESI) calcd for C16H21NNaO3 298.1414
3JH,H¼7.0 Hz, 2H, CH2). 13C NMR (75 MHz, CDCl3):
¼201.5 (CHO),
d
198.5 (CO), 147.0 (CH), 131.9 (CH), 43.0 (CH2), 31.7 (CH2), 27.0 (CH3),
20.3 (CH2). IR nmax: 1707, 1670, 1625 cmꢀ1. HRMS (ESI) calcd for
C8H12NaO2 163.0732 [MþNa]þ found 163.0730. Rf¼0.33 (cyclo-
hexane/EtOAc 1:1).
[MþNa]þ found 298.1412. Rf¼0.54 (CH2Cl2/MeOH 9:1).
27ꢃC
546
a
½ ꢄ
¼ꢀ7.38 (c¼0.4, CHCl3).
4.2.2. Phenyloxazolopelletierine 10. A mixture of compound 12
(500 mg, 3.57 mmol) and (R)-phenylglycinol (587 mg, 4.28 mmol)
in CH2Cl2 (10 mL) was stirred for 4 days at room temperature. The
reaction mixture was concentrated under reduced pressure and
then purified by flash chromatography on silica gel with cyclo-
4.2.5. Iminium 17. A mixture of phenyloxazolopelletierine 10
(500 mg, 1.93 mmol) and iodine (490 mg, 1.93 mmol) in CH2Cl2
(11 mL) was stirred at room temperature for 4 days, after which the
solvent was removed under vacuum. The residue was then purified
by flash chromatography on silica gel with a gradient solvent sys-
tem: CH2Cl2/MeOH (100:09 to 90:10) to afford compound 17
hexane/Et2O (8:2) as eluent.
A mixture of inseparable di-
astereoisomers 10 (463 mg, 50%) was obtained in a 7:3 ratio in favor
(563 mg, 76%) as a yellow oil. 1H NMR (300 and 400 MHz, CDCl3):
of 10a as a yellow oil: 1H NMR (400 MHz, CDCl3):
d
¼7.37e7.21 (m,
d
¼7.43e7.56 (m, 5H, Ph), 5.82 (dd, JH,H¼10, 8.8 Hz, 1H, CHePh),
3
5H, Ph), 4.13 (t, 2JH,H¼3JH,H¼7.2 Hz, 1H, CH2), 3.83 (dd, 3JH,H¼9.6 Hz,
3JH,H¼2.4 Hz, 1H, NeCHeO), 3.73 (t, 3JH,H¼7.2 Hz, 1H, CHePh), 3.55
(t, 2JH,H¼3JH,H¼7.2 Hz, 1H, CH2), 3.04 (m, 1H, NeCHeCH2), 2.41 (dd,
5.59 (ddd, JH,H¼10.8 Hz, JH,H¼10 Hz, JH,H¼3.0 Hz, OeCH2), 4.77
2
3
5
2 3 5
(ddd, JH,H¼10.8 Hz, JH,H¼8.8 Hz, JH,H¼3.0 Hz, OeCH2), 4.59 (m,
3
1H, NeCH), 3.26 (dt, JH,H¼10.8, 5.4 Hz, 1H, CH2), 3.02 (dt,
3
2
2
3
2JH,H¼18 Hz, JH,H¼7.2 Hz, 1H, CH2), 2.03 (dd, JH,H¼13.6 Hz,
3JH,H¼2.4 Hz, 1H, CH2), 1.97 (dd, 2JH,H¼18 Hz, 3JH,H¼7.2 Hz, 1H, CH2),
1.83 (m, 1H, CH2), 1.52e1.66 (m, 2H, CH2), 1.48 (s, 3H, CH3), 1.45 (m,
1H, CH2), 1.25e1.35 (m, 1H, CH2). 13C NMR (75 MHz, CDCl3):
3JH,H¼13.8, 5.4 Hz, 1H, CH2), 2.55 (dd, JH,H¼19.2 Hz, JH,H¼6.8 Hz,
2
3
1H, CH2), 2.39 (m, 1H, CH2), 2.32 (dd, JH,H¼19.2 Hz, JH,H¼3.6 Hz,
1H, CH2), 2.15e2.17 (m, 2H, CH2), 1.89e1.92 (m, 1H, CH2), 1.58 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3):
d
¼204.0 (CO), 178.2 (C), 133.7 (CIV
d
¼206.7 (CO), 143.1 (CIV Ph), 128.5 (2 CH Ph), 127.8 (2 CH Ph), 127.3
(CH Ph), 95.5 (CH), 74.5 (CH2), 65.0 (CHePh), 55.3 (CH), 49.2 (CH2),
32.9 (CH2), 30.1 (CH2), 29.8 (CH3), 22.3 (CH2). IR nmax: 1714 cmꢀ1
Ph), 130.5 (2 CH Ph), 129.8 (2 CH Ph), 128.9 (CH Ph), 78.5 (OeCH2),
67.4 (CHePh), 53.5 (NeCH), 45.2 (CH2), 29.6 (CH3), 27.2 (CH2),
25.3 (CH2), 15.6 (CH2). IR nmax: 1714, 1644 cmꢀ1. HRMS (ESI) calcd
.

L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
6281
for C16H20NO2 258.1489 [M]þ found 258.1489. Rf¼0.35 (CH2Cl2/
(ESI) calcd for C26H38NO3S2 476.2288 [MþH]þ found 476.2273.
Rf¼0.19 (cyclohexane/Et2O 1:1).
MeOH 9:1).
4.2.6. Bicyclic lactam 18. A mixture of iminium 17 (176 mg,
0.457 mmol) and manganese dioxide (238 mg, 2.74 mmol) in CHCl3
(4 mL) was stirred at room temperature for 6 h. The reaction
mixture was then filtered through a pad of silica gel and rinsed with
dichloromethane. The filtrate was concentrated and the residue
was purified by flash chromatography on silica gel with CH2Cl2 as
the eluent to afford 18 (75 mg, 60%).1H NMR (300 MHz, C6D6):
4.2.9.
0.16 mmol) in dry CH2Cl2 (5 mL) was added trimethylsilyl cyanide
(33 L, 0.25 mmol) under nitrogen atmosphere. The reaction mix-
ture was stirred at room temperature for two days, after which tri-
methylsilyl cyanide (33 L, 0.25 mmol) and dry CH2Cl2 (5 mL) were
added again. After 24 h of stirring, the mixture was washed with
water, dried over MgSO4 and concentrated under reduced pressure
to give compound 21 (65.9 mg, 94%) as an orange viscous oil.1H NMR
a-Aminonitrile 21. To a solution of compound 15 (54 mg,
m
m
d
¼7.08e7.19 (m, 5H, Ph), 3.72 (m, 3H, CHeOeCH2), 3.62 (t,
3JH,H¼7.6 Hz, 1H, CHePh), 3.17 (m, 1H, NeCH), 2.48 (m, 1H,
OeCHeCH2), 2.01 (dd, 2JH,H¼16.8, 3JH,H¼4.8 Hz, 1H, OeCHeCH2 and
NeCHeCH2), 1.85e1.92 (m, 2H, 2 CH2), 1.76e1.84 (m, 1H, CH2eCO),
1.28 (s, 3H, CH3), 1.19e1.23 (m, 1H, NeCHeCH2). 13C NMR (75 MHz,
(300 MHz, CDCl3):
d
¼7.29e7.39 (m, 5H, Ph), 4.03 (dd, 2JH,H¼10.0 Hz,
3JH,H¼4.2 Hz, 1H, CH2eOTMS), 3.96 (dd, JH,H¼5.4, 4.2 Hz, 1H,
CHePh), 3.86 (dd, 2JH,H¼10.0 Hz, 3JH,H¼5.4 Hz,1H, CH2eOTMS), 3.60
(dd, 3JH,H¼5.1, 2.1 Hz, 1H, NCeCHeN), 3.31e3.39 (m, 4H, 2 CH2eS),
3
3
C6D6):
d
¼204.8 (CO), 171.9 (CO), 139.6 (CIV Ph), 128.8 (2 CH Ph),
2.73 (dd, JH,H¼15, 10.8 Hz, 1H, NeCH), 2.51 (br d, 2JH,H¼14 Hz, 1H,
128.0 (2 CH Ph), 127.7 (CH Ph), 70.6 (CH2eO), 63.2 (CHePh), 62.1
(NeCH), 59.1 (OeCH), 49.0 (CH2), 30.5 (CH2), 29.7 (CH3), 25.4 (CH2).
IR nmax: 1748, 1708, 1150 cmꢀ1. HRMS (ESI) calcd for C16H19NNaO3
CH2), 2.22 (br d, 2JH,H¼14 Hz,1H, CH2),1.82 (s, 3H, CH3),1.66e1.75 (m,
4H, 2 CH2), 0.86 (m, 2H, CH2), ꢀ0.04 (s, 9H, OSi(CH3)3). 13C NMR
(75 MHz, CDCl3):
d
¼140.5 (CIV Ph), 128.5 (2 CH Ph), 127.6 (2 CH Ph),
296.1257 [MþNa]þ found 296.1252. Rf¼0.8 (CH2Cl2/MeOH 9:1).
126.9 (CH Ph),121.2 (CN), 66.1 (CHePh), 65.6 (OeCH2), 64.3 (C), 52.5
(NeCH), 46.0 (NCeCHeN), 40.2 (CH2), 39.8 (CH2), 38.6 (CH2), 34.4
27ꢃC
589
½
a
ꢄ
¼þ10.3 (c¼0.14, CHCl3).
(CH3), 29.2 (CH2), 28.4 (CH2), 15.8 (CH2), ꢀ0.6 (OSi(CH3)3). IR nmax
:
4.2.7. MVK-adduct 19. A mixture of phenyloxazolopelletierine 10
(100 mg, 0.39 mmol) and methylvinylketone (0.032 mL, 0.39 mmol)
in MeOH (3 mL) was stirred at reflux for 6 h and at room temper-
ature overnight. Methylvinylketone (0.094 mL, 1.16 mmol) was
added again and the reaction mixture was stirred at reflux for 6 h.
The solvent was removed under vacuum. The oily residue was then
purified by flash chromatography on silica gel with a gradient
solvent system: cyclohexane/Et2O (85:15 to 8:2) to afford com-
pound 19 (84 mg, 66%, indicative yield, unstable compound con-
taminated with traces of disubstituted adduct) as a brown oil. 1H
2141, 1250, 1107, 840 cmꢀ1. HRMS (ESI) calcd for C21H34NOS2Si
408.1851 [MꢀCN]þ found 408.1853. Rf¼0.65 (cyclohexane/Et2O 7:3).
4.2.10. Pseudopelletierine analog 26. A mixture of compound 12
(200 mg, 1.43 mmol) and (S)-phenylethylamine (0.22 mL,
1.71 mmol) in CH2Cl2 (5 mL) was stirred for 6 days at room tem-
perature, after which the reaction mixture was concentrated under
reduced pressure. The oily residue was then purified by flash
chromatography on silica gel with a gradient solvent system: hex-
ane/EtOAc (95:5) to CH2Cl2/MeOH (98:2 to 97:3) to afford com-
pound 26 (51 mg, 15%) as a yellow oil. 1H NMR (400 MHz, CDCl3):
NMR (300 MHz, CDCl3):
d
¼7.15e7.28 (m, 5H, Ph), 4.03 (t,
2JH,H¼3JH,H¼8 Hz, 1H, OeCH2), 3.63 (t, 3JH,H¼8 Hz, 1H, CHePh), 3.62
d
¼7.35e7.19 (m, 5H, Ph), 3.93 (q, 3JH,H¼6.4 Hz, 1H, CHePh), 3.52 (br
3
2
2
(d, JH,H¼10 Hz, OeCHeN), 3.45 (t, JH,H¼3JH,H¼8 Hz, 1H, OeCH2),
2.99e3.01 (m, 1H, NeCH), 2.49e2.56 (m, 1H, CH), 2.28e2.40 (m, 1H,
CH2), 2.07 (s, 3H, CH3), 1.91e1.96 (m, 1H, CH2), 1.50e1.88 (m, 4H, 2
CH2), 1.35 (s, 3H, CH3), 0.80e1.30 (m, 4H, 2 CH2). 13C NMR (75 MHz,
m, 1H, NeCH), 3.28 (br m, 1H, NeCH), 2.64 (dd, JH,H¼16.4 Hz,
4JH,H¼6.8 Hz,1H, CH2eCO), 2.55 (dd, 2JH,H¼16.4 Hz, 4JH,H¼6.8 Hz,1H,
CH2eCO), 2.16 (d, 2JH,H¼16.4 Hz,1H, CH2eCO), 2.10 (d, 2JH,H¼16.4 Hz,
1H, CH2eCO), 1.91 (m, 1H, CH2), 1.72 (m, 1H, CH2), 1.46e1.51 (m, 2H,
CH2), 1.39 (m, 1H, CH2), 1.35 (m, 1H, CH2), 1.29 (d, 3JH,H¼6.4 Hz, 1H,
CDCl3):
d
¼209.2 (CO), 207.0 (CO), 143.2 (CIV Ph), 128.5 (CH Ph), 127.3
(CH Ph), 126.3 (CH Ph), 99.8 (OeCHeN), 74.3 (OeCH2), 64.8
(CHePh), 54.9 (NeCH), 49.0 (CH2), 41.4 (CH2), 34.1 (CH2), 30.0
(CH2), 29.7 (2 CH3), 29.0 (CH), 26.4 (CH2). IR nmax: 1714 cmꢀ1. HRMS
(ESI) calcd for C20H27NNaO3 352.1882 [MþNa]þ found 352.1870.
Rf¼0.45 (cyclohexane/EtOAc 1:1).
CH3). 13C NMR (100 MHz, CDCl3):
d
¼212.1 (CO), 146.1 (CIV Ph), 128.6
(2 CH Ph),127.1 (2 CH Ph),126.9 (CH Ph), 58.3 (CHePh), 51.1 (NeCH),
50.3 (NeCH), 42.7 (CH2), 42.5 (CH2), 29.6 (2 CH2), 22.6 (CH3), 16.7
(CH2). IR nmax: 1716 cmꢀ1. HRMS (ESI) calcd for C16H22NO 244.1696
[MþH]þ found 244.1697. Rf¼0.63 (cyclohexane/EtOAc 1:1).
4.2.8. Double MVK-adduct 20. To a solution of compound 15
(38.2 mg, 0.114 mmol) in a mixture CH2Cl2/MeOH (2 mL, 1:1) was
added methylvinylketone (92 mL, 1.14 mmol). The reaction mixture
was stirred at room temperature for 4 h then heated at reflux for
24 h, cooled to room temperature and concentrated under vacuum.
The oily residue was then purified by flash chromatography on
silica gel with a gradient solvent system: cyclohexane/Et2O (5:5 to
4:6) to afford compound 20 (13.5 mg, 25%). 1H NMR (400 MHz,
4.2.11. Double Michael acceptor 29. A mixture of glutaraldehyde
(0.9 mL of a 50% aqueous solution, 5 mmol) and 1-(triphenyl-
phosphoranylidene)-2-propanone (3.18 g, 10 mmol) in toluene
(10 mL) was stirred at reflux for 3 h. The reaction mixture was
cooled with an ice bath, filtered to remove triphenylphosphine
oxide and the filtrate was concentrated. The oily residue was then
purified by flash chromatography on silica gel with cyclohexane/
EtOAc (6:4) as eluent to afford compound 29 (521 mg, 58%) as
3
CDCl3):
d
¼7.22e7.38 (m, 5H, Ph), 4.08 (dd, 2JH,H¼8 Hz, 3JH,H¼8.8 Hz,
a yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼6.77 (dt, JH,H¼16.0,
3
3
1H, OeCH2), 3.95 (dd, JH,H¼8.8, 5.6 Hz, 1H, CHePh), 3.64 (s, 1H,
7.0 Hz, 2H, 2 CH2eCH¼), 6.09 (d, JH,H¼16.0 Hz, 2H, 2 COeCH¼),
2
3
3
OeCHeN), 3.56 (dd, JH,H¼8 Hz, JH,H¼5.6 Hz, OeCH2), 3.18e3.34
(m, 4H, 2 CH2eS), 3.01 (m, 1H, CH2), 2.69e2.78 (m, 2H, CH2),
2.64e2.66 (m, 1H, NeCH), 2.41e2.57 (m, 2H, CH2), 2.31e2.39 (m,
2H, 2 CH2), 2.19 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.04e2.10 (m, 2H, 2
CH2), 1.83e1.87 (m, 2H, CH2), 1.66e1.70 (m, 2H, CH2), 1.55 (s, 3H,
2.27 (q, JH,H¼7.0 Hz, 4H, 2 CH2), 2.24 (s, 6H, 2 CH3), 1.67 (qu,
3JH,H¼7.0 Hz, 2H, CH2). 13C NMR (100 MHz, CDCl3):
¼198.4 (2 CO),
d
146.9 (2 CH), 131.7 (2 CH), 31.7 (2 CH2), 27.0 (2 CH3), 26.4 (CH2). IR
nmax: 1672, 1626 cmꢀ1. HRMS (ESI) calcd for C11H16NaO2 203.1044
[MþNa]þ found 203.1042. Rf¼0.34 (cyclohexane/ethyl acetate 1:1).
CH3), 1.45e1.53 (m, 1H, CH2). 13C NMR (100 MHz, CDCl3):
d
¼209.6
(CO), 209.1 (CO), 145.2 (CIV Ph), 128.6 (2 CH Ph), 127.1 (2 CH Ph),
126.2 (CH Ph), 102.3 (OeCHeN), 74.3 (OeCH2), 65.6 (C), 64.2
(CHePh), 61.3 (NeCH), 46.9 (CH2), 39.8 (CH2eS), 39.2 (CH2eS), 38.3
(CH2), 37.6 (CH2), 34.0 (CH3), 33.0 (CH2), 31.2 (CH2), 30.5 (CH2), 30.2
(CH3), 30.1 (CH3), 26.9 (CH2), 21.8 (CH2). IR nmax: 1715 cmꢀ1. HRMS
4.2.12. a,a
0-disubstituted piperidine 34. A mixture of compound 29
(100 mg, 0.556 mmol) and benzylamine (0.091 mL, 0.833 mmol) in
CH2Cl2 (2 mL) was stirred for 21 h at room temperature. The re-
action mixture was concentrated under reduced pressure and the
oily residue was then purified by flash chromatography on silica gel

6282
L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
6. Conroy anticipated a propylpiperidine (C5NeC3) as a common pattern as early
as 1960 but proposed a totally polyketide origin for it, see Conroy, H. Tetrahe-
dron Lett. 1960, 1, 34e37.
7. (a) Hemscheidt, T.; Spenser, I. D. J. Am. Chem. Soc. 1996, 118, 1799e1800 See
also for previous work: (b) Castillo, M.; Gupta, R. N.; MacLean, D. B.; Spenser,
I. D. Can. J. Chem. 1970, 48, 1893e1903; (c) Braekman, J.-C.; Gupta, R. N.;
MacLean, D. B.; Spenser, I. D. Can. J. Chem. 1972, 50, 2591e2602; (d) Castillo,
M.; Gupta, R. N.; Ho, Y. K.; MacLean, D. B.; Spenser, I. D. J. Am. Chem. Soc. 1970,
92, 1074e1075.
8. Historical classification of Lycopodium alkaloids based on the number of carbon
and nitrogen atoms present in the structural framework (C16N, C16N2, C27N3)
was proposed by MacLean: (a) MacLean, D. B. In; Brossi, A., Ed. The Alkaloids:
Chemistry and Pharmacology; Academic: 1983; vol. 26, pp 241e297; Another
classification was then proposed by Ayer: (b) Ayer, W. A.; Trifonov, L. S. In;
Cordell, G. A., Brossi, A., Eds. The Alkaloids: Chemistry and Pharmacology; Aca-
demic: San Diego, 1994; vol. 45, pp 233e266.
9. Isolation of: (a) Huperzine A: Liu, J.-S.; Zhu, Y.-L.; Yu, C.-M.; Zhou, Y.-Z.; Han, Y.-Y.;
Wu, F.-W.; Qi, B.-F. Can. J. Chem. 1986, 64, 837e839; (b) Lyconadin A: Kobayashi,
J.; Hirasawa, Y.; Yoshida, N.; Morita, H. J. Org. Chem. 2001, 66, 5901e5904; (c)
Himeradine A: Morita, H.; Hirasawa, Y.; Kobayashi, J. J. Org. Chem. 2003, 68,
4563e4566; (d) Lycoperine A: Hirasawa, Y.; Kobayashi, J.; Morita, H. Org. Lett.
2006, 8, 123e126; (e) Complanadine D: Ishiuchi, K.; Kubota, T.; Mikami, Y.;
Obara, Y.; Nakahata, N.; Kobayashi, J. Bioorg. Med. Chem. 2007, 15, 413e417.
10. As a free base, (ꢀ)-pelletierine is known to racemize probably via a ring
opening:
with a gradient solvent system: CH2Cl2/MeOH (100:0 to 98:2). A
mixture of inseparable diastereoisomers 34 (77 mg, 48%) was
obtained in an 85:15 ratio in favor of the trans isomer 34a (de-
termined by integration of signals in the 1H NMR spectrum) as
a viscous orange oil: 1H NMR (400 MHz, CDCl3):
d
¼7.20e7.32 (m,
5H, Ph), 3.70 (d, 2JH,H¼14.4 Hz, 1H, CH2), 3.59 (d, 2JH,H¼14.4 Hz, 1H,
CH2), 3.37e3.42 (m, 1H, NeCH), 3.27e3.34 (m, 1H, NeCH), 2.73 (dd,
2JH,H¼15.4 Hz, JH,H¼6.8 Hz, 1H, CH2), 2.59 (dd, JH,H¼16.4 Hz,
3
2
2
3
3JH,H¼4.8 Hz, 1H, CH2), 2.46 (dd, JH,H¼15.4 Hz, JH,H¼7.2 Hz, 1H,
CH2), 2.27 (dd, 2JH,H¼16.4 Hz, 3JH,H¼8 Hz, 1H, CH2), 1.98 (s, 3H, CH3),
1.93 (s, 3H, CH3), 1.67 (br m, 4H, 3 CH2), 1.31e1.36 (m, 2H, 2 CH2). 13
C
NMR (100 MHz, CDCl3):
Ph), 128.3 (2 CH Ph), 128.2 (CH Ph), 57.9 (CH), 51.6 (CH), 51.3 (CH2),
d
¼207.9 (2 CO), 140.2 (CIV Ph), 128.5 (2 CH
48.8 (CH2), 46.6 (CH2), 29.9 (2 CH3), 25.4 (2 CH2), 20.0 (CH2). IR nmax
:
1707 cmꢀ1. HRMS (ESI) calcd for C18H26NO2 288.1958 [MþH]þ
found 288.1954. Rf¼0.20 (cyclohexane/EtOAc 1:1).
Acknowledgements
Jean-Christophe Jullian for NMR assistance, Pr Delphine Joseph
and Zacharias Amara for fruitful discussion and advice.
Supplementary data
racemization
NMR spectra (1H, 13C) of compounds 10,12,15e21, 26, 29 and 34.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.051.
11. For selected recent applications (2010, 2011, and early 2012) of (ꢀ)-phenyl-
glycinol in nitrogen-containing heterocyclic chemistry, see: (a) Amat, M.; Subrizi,
F.; Elias, V.; Llor, N.; Molins, E.; Bosch, J. Eur. J. Org. Chem. 2012, 1835e1842; (b)
ꢀ
Amat, M.; Arroniz, C.; Molins, E.; Escolano, C.; Bosch, J. Org. Biomol. Chem. 2011, 9,
2175e2184; (c) Arena, G.; Zill, N.; Salvadori, J.; Girard, N.; Mann, A.; Taddei, M.
Org. Lett. 2011,13, 2294e2297; (d) Amat, M.; Perez, M.; Proto, S.; Gatti, T.; Bosch, J.
References and notes
ꢀ
Chem.dEur. J. 2010, 16, 9438e9441; (e) Amat, M.; Elias, V.; Llor, N.; Subrizi, F.;
Molins, E.; Bosch, J. Eur. J. Org. Chem. 2010, 4017e4026; (f) Jida, M.; Deprez-
Poulain, R.; Malaquin, S.; Roussel, P.; Agbossou-Niedercorn, F.; Deprez, B.; La-
conde, G. Green. Chem. 2010, 12, 961e964; (g) Salvadori, J.; Airiau, E.; Girard, N.;
Mann, A.; Taddei, M. Tetrahedron 2010, 66, 3749e3753.
1. Isolation of pelletierine: (a) Tanret, C. C. R. Acad. Sci. 1878, 86, 1270e1272; For an
historical perspective on pelletierine, see: (b) Drillien, G.; Viel, C. Bull. Soc. Chim.
Fr. 1963, 2393e2400; (c) Gilman, R. E.; Marion, L. Bull. Soc. Chim. Fr. 1961,
1993e1995 For the absolute configuration: (d) Beyerman, H. C.; Maat, L.; Van
Veen, A.; Zweistra, A. Recl. Trav. Chim. Pays-Bas 1965, 84, 1367e1379 Bio-
synthesis: (e) Gupta, R. N.; Spenser, I. D. Can. J. Chem. 1969, 47, 445e447; For
a recent asymetric organocatalytic synthesis of (þ)-pelletierine, see: (f) Mon-
aco, M. R.; Renzi, P.; Scarpino Schietroma, D. M.; Bella, M. Org. Lett. 2011, 13,
4546e4549; For a recent synthesis from chiral non-racemic 2-allyl-(N-tert-
12. For the particular use of (ꢀ)-phenylglycinol involved in: (a) N-Cyanomethy-
loxazolidine systems, see Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28,
ꢀ
383e394; (b) Oxazolopiperidone lactams: Amat, M.; Perez, M.; Bosch, J. Synlett
ꢀ
2011, 143e160; (c) Amat, M.; Perez, M.; Bosch, J. Chem.dEur. J. 2011, 17,
7724e7732; (e) Escolano, C.; Amat, M.; Bosch, J. Chem.dEur. J. 2006, 12,
8198e8207.
ꢀ
ꢀ
butylsulfinyl)piperidine, see: (g) Bosque, I.; Gonzalez-Gomez, J. C.; Foubelo, F.;
Yus, M. J. Org. Chem. 2012, 77, 780e784.
13. In order to favour thermodynamically stable cis-oxazolidine, the use of Lewis
acids is common especially with related cyano-phenyloxazolopiperidine (see
structure A below), see: (a) Guz, N. R.; Pfeiffer, M.; Dickman, D. Org. Process
Res. Dev. 2010, 14, 1476e1478 and references cited therein). In our case,
treatment of 10 with a catalytic amount (10 mol %) of zinc bromide in di-
chloromethane did not permit the conversion of trans-10 into cis-10, therefore
rising questions concerning the occurrence of such a phenomenon with 10. As
the oxazolidine is the masked form of the corresponding iminium or enamine,
this phenomenon of epimerization has usually no consequences on reactivity.
The diastereocontrol of the oxazolidine ring formation of phenyl-
oxazolopiperidine (see structure B below) is admirally studied in a recent
paper; see: (b) Zill, N.; Schoenfelder, A.; Girard, N.; Taddei, M.; Mann, A. J. Org.
Chem. 2012, 77, 2246e2253; For the first synthesis of building block A, see: (c)
Guerrier, L.; Royer, J.; Grierson, D.; Husson, H.-P. J. Am. Chem. Soc. 1983, 105,
7754e7755 .
2. Recent review articles dealing with Lycopodium alkaloids: (a) Ma, X.; Gang, D. R.
Nat. Prod. Rep. 2004, 21, 752e772; (b) Kobayashi, J.; Morita, H. In; Cordell, G. A., Ed.
The Alkaloids: Chemistry and Biology; Elsevier: San Diego, 2005; vol. 61, pp 1e57;
(c) Hirasawa, Y.; Kobayashi, J.; Morita, H. Heterocycles 2009, 77, 679e729.
3. For recently isolated new Lycopodium alkaloids, see: Lyconadins C, D, E, and F: (a)
Ishiuchi, K.; Kubota, T.; Ishiyama, H.; Hayashi, S.; Shibata, T.; Mori, K.; Obara, Y.;
Nakahata, N.; Kobayashi, J. Bioorg. Med. Chem. 2011, 19, 749e753; (b) Ishiuchi, K.;
Kubota, T.; Ishiyama, H.; Hayashi, S.; Shibata, T.; Kobayashi, J. Tetrahedron Lett.
2011, 52, 289e292; Lycotetrastine, A.; Hirasawa, Y.; Astulla, A.; Shiro, M.; Morita,
H. Tetrahedron Lett. 2011, 52, 4126e4128; Lycopoclavamines and related faw-
cettimine structures Katakawa, K.; Mito, H.; Kogure, N.; Kitajima, M.; Wong-
seripipatana, S.; Arisawa, M.; Takayama, H. Tetrahedron 2011, 67, 6561e6567.
4. (a) First structure disclosed: Hirasawa, Y.; Morita, H.; Kobayashi, J. Org. Lett.
2004, 6, 3389e3391; (b) Revised structure: Hirasawa, Y.; Kobayashi, J.; Obara,
Y.; Nakahata, N.; Kawahara, N.; Goda, Y.; Morita, H. Heterocycles 2006, 68,
2357e2364.
5. Selected total syntheses of Lycopodium alkaloids disclosed in 2010, 2011, and
2012: (a) Li, H.; Wang, X.; Lei, X. Angew. Chem., Int. Ed. 2012, 51, 491e495; (b)
Nakayama, A.; Kogure, N.; Kitajima, M.; Takayama, H. Angew. Chem., Int. Ed.
2011, 50, 8025e8028; (c) Tsukano, C.; Zhao, L.; Takemoto, Y.; Hirama, M. Eur. J.
Org. Chem. 2010, 4198e4200; (d) Yang, Y.-R.; Shen, L.; Huang, J.-Z.; Xu, T.; Wei,
K. J. Org. Chem. 2011, 76, 3684e3690; (e) Hiroya, K.; Suwa, Y.; Ichihashi, Y.;
Inamoto, K.; Doi, T. J. Org. Chem. 2011, 76, 4522e4532; (f) Laemmerhold, K. M.;
Breit, B. Angew. Chem., Int. Ed. 2010, 49, 2367e2370; (g) Canham, S. M.; France,
D. J.; Overman, L. E. J. Am. Chem. Soc. 2010, 132, 7876e7877; (h) Yang, Y.-R.; Lai,
Z.-W.; Shen, L.; Huang, J.-Z.; Wu, X.-D.; Yin, J.-L.; Wei, K. Org. Lett. 2010, 12,
3430e3433; (i) Bisai, V.; Sarpong, R. Org. Lett. 2010, 12, 2551e2553; (j) Naka-
mura, Y.; Burke, A. M.; Kotani, S.; Ziller, J. W.; Rychnovski, S. D. Org. Lett. 2010,
12, 72e75; (k) Ramharter, J.; Weinstabl, H.; Mulzer, J. J. Am. Chem. Soc. 2010, 132,
14338e14339; (l) Liau, B. B.; Shair, M. D. J. Am. Chem. Soc. 2010, 132,
9594e9595; (m) Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Am. Chem. Soc.
2010, 132, 5924e5925; (n) Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132,
5926e5927; (o) Cheng, X.; Waters, S. P. Org. Lett. 2010, 12, 205e207; (p) Altman,
R. A.; Nilsson, B. L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J. M.; Taupin, V. J.
Org. Chem. 2010, 75, 7519e7534.
14. Enamine reactivity of (ꢀ)-phenyloxazolopiperidine, see: (a) Poupon, E.;
Franc¸ ois, D.; Kunesch, N.; Husson, H.-P. J. Org. Chem. 2004, 69, 3836e3841; (b)
Franc¸ ois, D.; Poupon, E.; Lallemand, M.-C.; Kunesch, N.; Husson, H.-P. J. Org.
Chem. 2000, 65, 3209e3212.
15. Such an epimerization of the oxazolidine probably occurs through ring open-
ing/ring closure and has already been observed in similar series (see Ref. 13a
and Ref. 13c for examples).
16. A partial epimerization at C-6 is observed and might be explained by a similar
mechanism as the one depicted in Ref. 10.
17. For mercuric acetate oxidation of tertiary amines, see: (a) Leonard, N. J.; Mor-
row, D. F. J. Am. Chem. Soc. 1958, 80, 371e375; (b) Leonard, N. J.; Musker, W. K. J.
Am. Chem. Soc. 1960, 82, 5148e5155 and for tertiary amine conversion into
€
lactams, see: (c) Mohrle, H. Arch. Pharmacol. 1964, 297, 474e487.

L.-H. Yan et al. / Tetrahedron 68 (2012) 6276e6283
6283
18. For conversions of oxazolopiperidines into lactams: (a) With potassium
permanganate Franc¸ ois, D.; Poupon, E.; Kunesch, N.; Husson, H.-P. Eur. J.
Org. Chem. 2004, 4823e4829; (b) With bromine under alkaline condi-
21. Selected examples of retro-Mannich reactions: (a) Winkler, J. D.; Muller, C. L.;
Scott, R. D. J. Am. Chem. Soc. 1988, 110, 4831e4832; (b) Ragains, J. R.; Winkler, J.
D. Org. Lett. 2006, 8, 4437e4440; (c) Winkler, J. D.; Fitzgerald, M. E. Synlett 2009,
562e564; (d) Cramer, N.; Juretschke, J.; Laschat, S.; Baro, A.; Frey, W. Eur. J. Org.
Chem. 2004, 1397e1400.
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tions Lienard, P.; Varea, T.; Quirion, J.-C.; Husson, H.-P. Synlett 1994,
143e144.
19. Ibuka, T.; Kitano, M. Chem. Pharm. Bull. 1967, 15, 1809e1810.
20. We also believe that this phenomenon mostly occurs during purification by
chromatography in contact with silica gel. Expected dimeric compound 24 may
in fact be present in crude mixture (m/z 509 [MþNa]þ).
22. The stereochemical outcome is consistent with literature. See for example, in
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the Lobeline series: (a) Compere, D.; Marazano, C.; Das, B. C. J. Org. Chem.1999, 64,
4528e4532 and also: (b) Felpin, F.-X.; Lebreton, J. J. Org. Chem. 2002, 67,
9192e9199.