Diastereoselective construction of syn-α-oxyamines via three-component α-oxyaldehyde-dibenzylamine-alkyne coupling reaction: Application in the synthesis of (+)-β-conhydrine and its analogues

Article abstract of DOI:10.1039/c2ob26007g

A Cu(i)-catalyzed α-oxyaldehyde-dibenzylamine-alkyne coupling reaction was delineated for the construction of α-oxyamines with excellent yields and diastereoselectivity. Crystal structure analysis and theoretical calculations were also supportive of the formation of syn-α-oxyamines as the major products. Application of the methodology addresses the synthesis of (+)-β-conhydrine along with analogs having two different diversity features. A ring size variation allows construction of piperidine and pyrrolidine rings while a variation of side arm functionality is achieved by complete regioselective opening of epoxide by different organocopper ylides (Gilman reagents). A lactam-Cu(i) complexation motif is proposed which allows an intramolecular attack of ylides at the terminal epoxy carbon via the six-membered cyclic transition state. The present work features the synthesis of (+)-β-conhydrine over eight steps in 26% yield and its seven analogs in 21-28% yields.

Full text of DOI:10.1039/c2ob26007g

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PAPER
Diastereoselective construction of syn-α-oxyamines via three-component
α-oxyaldehyde–dibenzylamine–alkyne coupling reaction: application in the
synthesis of (+)-β-conhydrine and its analogues†
Sharad Chandrakant Deshmukh, Arundhati Roy and Pinaki Talukdar*
Received 23rd May 2012, Accepted 17th July 2012
DOI: 10.1039/c2ob26007g
A Cu(I)-catalyzed α-oxyaldehyde–dibenzylamine–alkyne coupling reaction was delineated for the
construction of α-oxyamines with excellent yields and diastereoselectivity. Crystal structure analysis and
theoretical calculations were also supportive of the formation of syn-α-oxyamines as the major products.
Application of the methodology addresses the synthesis of (+)-β-conhydrine along with analogs having
two different diversity features. A ring size variation allows construction of piperidine and pyrrolidine
rings while a variation of side arm functionality is achieved by complete regioselective opening of
epoxide by different organocopper ylides (Gilman reagents). A lactam–Cu(I) complexation motif is
proposed which allows an intramolecular attack of ylides at the terminal epoxy carbon via the six-
membered cyclic transition state. The present work features the synthesis of (+)-β-conhydrine over eight
steps in 26% yield and its seven analogs in 21–28% yields.
Introduction
In recent years, the scaffolds of natural products have inspired
the synthesis of focused compound libraries in drug discovery
research.1 Due to their diverse biological activities, substituted
piperidines and pyrrolidines have been the target of considerable
synthetic efforts.2 Critical analyses of large number of piperidine
and pyrrolidine based natural product structures have led to the
identification of a few privileged skeletal fragments.3 Among
these, 2-(hydroxyalkyl)-piperidine and 2-(hydroxyalkyl)-pyrroli-
dine (Fig. 1) are two privileged subunits, which have aroused
widespread synthetic interest because of their frequent appear-
ance in many biologically active alkaloids3b and interesting
Fig. 1 Structures of natural products having 2-(hydroxyalkyl)-piperi-
dine and 2-(hydroxyalkyl)-pyrrolidine skeletal fragments.
stereochemical feature present around the α-oxyamine moiety.
Nojirimycin 14 and (+)-α-conhydrine 25 are examples of natural
products with a 2-(hydroxyalkyl)-piperidine moiety present in
piperidine and 2-(hydroxyalkyl)-pyrrolidine can be identified.
These natural products have glycosidase inhibitory activities and
their structures. On the other hand, a 2-(hydroxyalkyl)-pyrroli-
dine nucleus can be found in 1,4-dideoxy-1,4-imino hexitol 3,6
uniflorine A,7 casuarine,8 australine, etc. (−)-Swainsonine 49 and
thus have potential utility as antiviral, anticancer, antidiabetic,
and antiobesity drugs.11 As a result, these natural products and
(−)-erycibelline 510 are indolizidine and nortropane alkaloids
their analogs have been attractive and important synthetic
targets.
respectively, in which fused scaffolds of 2-(hydroxyalkyl)-
In the scientific literature, synthesis of natural product analogs
is commonly focused towards either enantiomers or diastereo-
mers. An alternate approach is also frequently executed by intro-
Department of Chemistry, Dmitri Mendeleev Block, Indian Institute of
Science Education and Research, Pune, India.
E-mail: ptalukdar@iiserpune.ac.in; Fax: +91 20 2589 9790;
Tel: +91 20 2590 8098
†Electronic supplementary information (ESI) available: Additional
experimental procedures, crystal structures, theoretical calculations and
1H-, 13C-NMR spectra. CCDC 856727. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2ob26007g
ducing various functional groups on an important synthetic
intermediate to create a diverse molecular library.12 However, the
manipulation of the ring size, which is frequently executed in
medicinal chemistry research13 for the generation of analogs, is
less reflected in the synthesis of natural product analogs.14
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metal catalyzed α-oxyaldehyde–amine–alkyne (three-com-
ponent) coupling reaction reported by Huang et al. for the dia-
stereoselective construction of syn-α-oxyamine18 which can be
applied in the synthesis of (+)-β-conhydrine. Starting from the
optically pure acetonide protected glyceraldehyde 12, piperidine
and phenylacetylene an AuI catalyzed (5 mol%) three-com-
ponent reaction in water at room temperature was successful in
constructing the corresponding syn-α-oxyamine product in 65%
yield and with a syn to anti ratio up to 82 : 18. We realized that
simple alteration of the alkyne and the amine components would
be necessary for further construction of piperidine and pyrroli-
dine rings. On the other hand, the acetonide protected 1,2-diol
moiety would also be helpful for accessing analogs of con-
hydrine having varied side arm functionality. We realized that
the three-component coupling (A3-coupling) reaction would also
be significant providing a shorter synthetic route. However, a
further improvement of diastereoselectivity during the three-
component coupling (A3-coupling) reaction described by Huang
et al.18 was necessary to establish the novelty of our strategy.
Therefore, we decided to introduce a di-substituted amine with
bulkier substituents which can also be removed easily whenever
necessary. A terminal alkyne, substituted with a protecting
group, orthogonal to that of amine was thought to be ideal for
chain elongation for further construction of either piperidine or
pyrrolidine ring. Our judgment led to the selection of the di-
benzylamine 13 anticipating the role of benzyl group for driving the
diastereoselectivity. Additionally, the hydrogenolysis conditions
for removing this protecting group are also suitable for complete
reduction of the alkyne CuC bond. We also decided to replace
AuI with CuBr due to the established importance of the Cu(I)
salt in the three-component aldehyde–amine–alkyne coupling
reaction.19 Also, the ready availability, low toxicity, insensitivity
to air, and cheaper price led us to explore the methodology with
a Cu(I)halide.
Scheme 1 Synthetic approaches to diastereoselective construction of
α-oxyamines for the synthesis of conhydrine and its analogs. (A) Syn-
thesis of (+)-β-conhydrine and its analogs 8a–8d via diastereoselective
addition of allylmagnesium bromide to N-benzylimine 6 followed by
epoxide opening with different R–, (B) Palladium-catalyzed diastereo-
selective aza-Claisen rearrangement of allylic trichloroacetimidate 9 fol-
lowed by RCM cyclization for the synthesis of (+)-α-conhydrine 2 and
its pyrrolidine analog 11.
Considering (+)-α-conhydrine 2 as an example, various synthetic
methods are reported for the natural product, its enantiomer and
diastereomers.15 Each of these strategies feature new synthesis
aimed at the 2-(hydroxymethyl)-piperidine moiety with stereo-
selective construction of the α-oxyamine moiety. One of these
design principles is associated with the diastereoselective con-
struction of a α-oxyamine followed by the formation of the
piperidine ring. Following this strategy, Gálvez and co-workers
have reported a diastereoselective Grignard reaction (syn–anti =
98 : 2) on the imine 6 to obtain the syn-α-oxyamine stereo-
chemistry followed by
a ring-closure metathesis (RCM)
approach to build the piperidine ring (Scheme 1A).16 Sub-
sequently, the acetonide protected dihydroxy moiety was con-
verted to an epoxide ring forming the intermediate 7. They
further extended the methodology for the synthesis of
(+)-β-conhydrine 8a (over 7-steps in 21% overall yield) and its
analogues 8b–8d having various side arms by the opening of the
epoxide ring of 7 by different carbon nucleophiles. In 2007,
Sutherland and co-workers adapted a Pd(II)-catalyzed [3,3]-sig-
matropic (Overman reaction) approach to construct anti-α-oxy-
amine with high diastereoselectivity (syn–anti = 1 : 16).17
Subsequent attachment of linkers of different lengths provided
intermediates 10a and 10b, respectively. Further, a RCM strategy
was applied to synthesize (+)-α-conhydrine 2 (over 13-steps in
4% overall yield) and 11 as the first ring-contracted pyrrolidine
analog of 2.
Applicability of the methodology in the diastereoselective
construction of the amino group was evaluated by the reaction of
aldehyde 12 and di-benzylamine 13 with various terminal
alkynes in the presence of CuBr as catalyst in toluene as solvent
(Fig. 2A).19a The substitution pattern of the terminal alkynes
was varied from 14a to 14g (Fig. 2B). The three-component
reaction of 12, di-benzylamine 13 and phenyl acetylene 14a
(R = –Ph) resulted in the formation of the major syn-diastereo-
mer 15a in 68% yield and with syn–anti = 78 : 22 (Fig. 2C).
When cyclohexenyl acetylene 14b, was introduced, a significant
enhancement in diastereoselectivity, syn–anti = 91 : 9 was
achieved for the syn-α-oxyamine 15b with 65% yield. Introduc-
tion of terminal alkyne 14c with aliphatic side chain R = –tBu
resulted in formation of 15c in 73% yield and an excellent syn to
anti ratio of >99% was observed. Similarly, the reactions of the
alkyne 14d (R = –CH2OCH3) under comparable conditions pro-
vided aminoalkyne 15d as a single diastereomer with 88% yield.
The complete diastereoselectivities were also maintained when
alkynes 14e–14g (R = –CH2OTBDPS, –CH2NHBoc, and
–TMS) were subjected to the copper(I) catalyzed three com-
ponent reaction. In these cases, the yields of the reactions were
calculated to be 70%, 76% and 84%, respectively.
Results and discussion
We set the challenge to develop a new strategy to synthesize con-
hydrine and its analogs by simultaneously addressing the vari-
ation (i) in ring size and (ii) side arm functionality. We decided
to rely on the principle of diastereoselective construction of the
α-oxyamine followed by the formation of either a piperidine or a
pyrrolidine ring. In this regard, we realized the importance of the
The syn-stereochemistry of the three-component reaction
product was convincingly confirmed by the crystal structure of
the α-oxyamine 15c (Fig. 3A). The relative stereochemistry of
This journal is © The Royal Society of Chemistry 2012
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the acetonide protected secondary hydroxyl group and the di-
benzyl protected amino group in 15c matched the stereo-
chemistry present in the unnatural (+)-β-conhydrine. Excellent
diastereoselectivity observed in each of these multi-component
reactions was further rationalized by the geometry optimization
study of the intermediate iminium cation 16 (Fig. 3B). Interest-
ingly, the computational gas-phase modelling at 0 K by the
DFT-B3LYP/6-311G(d,p) method20 using Gaussian 0321
confirmed the presence of a sterically crowded si face (Fig. 3C
and 3D) allowing attack of the alkynide anion preferentially
from the more accessible re face. We believe that π-stacking
interactions between the phenyl groups of the iminium cation 16
and phenyl acetylene 14a allow the approach of the alkyne from
the si-face although steric crowding governs the formation of the
syn-product 15a (Fig. 2). As a result, the anti-addition product
was also formed as the minor isomer reducing the diastereoselec-
tivity during the aldehyde–amine–alkyne coupling reaction.
After confirming the stereochemistry of the three-component
reaction product, the TMS-protected aminoalkyne 15g was
engaged for the next stages to construct the pyrrolidine and
piperidine cores for generating analogues of (+)-β-conhydrine.
Deprotection of the trimethylsilyl group of 15g under TBAF
conditions afforded the terminal alkyne 17 in 93% yield
(Scheme 2). The terminal alkyne 17 was then treated with ethyl
chloroformate in the presence of BuLi following the methodo-
logy described by Knochel and co-worker to introduce the ester
moiety of 18a with 85% yield.19a The ester 18a then reacted
with 10% Pd(OH)2/C (10 mol%) under 100 psi hydrogen atmos-
phere, complete hydrogenolysis of benzyl groups and the
reduction of CuC bond occurred. The crude reaction mixture
was then subjected to cyclization using NaOEt to provide the
γ-lactam 19a in 82% yield over two steps. Further deprotection
of ketal group of 19a was carried out by ethanolic HCl to afford
the diol 20a in 95% yield. The diol 20a was then converted to
the epoxy-γ-lactam intermediate 21a in 84% yield by reacting
with DIAD in presence of PPh3 (Mitsunobu conditions).22
Fig. 2 Cu(I) catalyzed three component reaction of acetonide protected
D-glyceraldehyde 12 and di-benzylamine 13 with various terminal
alkynes 14a–14g.
A similar strategy was also employed to construct the piperi-
dine core required to synthesize (+)-β-conhydrine analogues
(Scheme 2). The terminal alkyne 17 when treated with ethyl di-
Fig. 3 X-ray crystal structure of 15c (A); representation of the of the
iminium cation 16 (B); side view of the DFT-B3LYP/6-311G(d,p) geo-
metry optimized structure of 16 (C) and the space filling model of opti-
mized structure of 16 from the more hindered si face (D).
azoacetate under
5 mol% CuI conditions following the
Scheme 2 Synthesis of the epoxy-γ- and epoxy-δ-lactam 21a and 21b, respectively.
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methodology described by Fu and Suarez,23 the 3-alkynoate
compound 18b was formed in 94% yield. However, the
3-alkynoate 18b was isolated as an inseparable mixture with the
corresponding allene isomer in 87 : 13 ratio which was deter-
Therefore, the treatment of Me2CuLi with the epoxide 21a in
Et2O–THF provided the desired hydroxy-γ-lactam 23a as a
single regioisomer in 77% yield (Table 1, entry 1, step I).
Finally, the γ-lactam 23a was reduced by LiAlH4 in THF under
refluxing conditions to furnish 24a as the pyrrolidine analogue
of (+)-β-conhydrine in 81% yield (Table 1, entry 1, step II). The
epoxy group of 21a was also opened with other Gilman reagents
(R = Bu, tBu and Ph) to obtain hydroxy-γ-lactams 23b–23d with
76%, 72% and 68% yields, respectively. Formation of the single
regioisomeric products 23a–23d during each of the epoxide
opening reactions supported our hypothesis of the intramolecular
attack by R− as a result of lactam–Cu+ complexation. Syn-
thesized hydroxy-γ-lactams 23b–23d were then converted to
corresponding pyrrolidine analogues 24b–24d with 86%, 84%
and 72% yields, respectively (Table 1, entries 2–4).
1
mined from the H-NMR data. This observation was not surpri-
sing considering the literature report by Fu and co-worker.
No further purification was attempted as complete hydrogenation
of these unsaturated moieties would lead to a single product.
When the alkyne 18b along with its allene isomer was treated
with 10% Pd(OH)2/C (10 mol%) under hydrogen atmosphere
(100 psi), complete hydrogenolysis of benzyl groups along with
complete reduction of alkyne and allene occurred. The crude
amino ester was then converted to the δ-lactam 19b using
NaOEt with 81% yield over two steps. In the next step, the
deprotection of the ketal moiety of 19b was carried out by etha-
nolic HCl to afford the diol 20b in 94% yield. The diol 20b was
then converted to the epoxide.
With the crucial epoxy-γ- and epoxy-δ-lactam intermediates
21a and 21b in hand, we next investigated the scope of the stra-
tegy to synthesize (+)-β-conhydrine and its analogues. Following
the methodology described by Fray et al.,24 treatment of the
epoxide 21a with methylmagnesium iodide in presence of
20 mol% CuI resulted in the exclusive formation of an un-
expected iodohydrin 22a in 53% yield (Scheme 3). The change
of the Grignard reagent to methylmagnesium bromide also
resulted in the corresponding bromo derivative 22b in 53%
yield. A similar iodide mediated epoxide opening product 22c
was also formed in 56% yield during the reaction of 21b with
methylmagnesium iodide in presence of 20 mol% CuI. The
structure of the undesired 22a was confirmed by X-ray crystallo-
graphy (Scheme 3).
Scheme 4 Proposed regioselective pathways for intramolecular
epoxide ring-opening by X− (route a) and R− (route b).
Exclusive formation of halohydrins 22a–22c indicate that the
halide (X− = I− and Br−) from the Grignard reagent is acting as
the better nucleophile compared to the alkyl anion (R−). These
observations can be explained by the Schlenk equilibrium of the
Grignard reagent that resulted in the formation of MgX2 and X−
acted as the better nucleophile compared to Me−.25 A chelation
motif of MgX2 with the lactam further supported the regioselec-
tive attack of X− to the terminal epoxy-carbon via the 6-mem-
bered cyclic transition state (Scheme 3, route a).26 We believed
that the lactam–Mg2+ complexation-motif if it exists, can be
turned into advantage by altering the nucleophile. Therefore, we
decided to employ organocopper based ylides (i.e. Gilman
reagent) for achieving regioselective intramolecular attack of R−
taking advantage of the better nucleophilicity of R− in the
Gilman reagent and a lactam–Cu+ complexation (Scheme 4,
route b).27
Table 1 Synthesis of β-(+)-conhydrine 8a and its analogues 24a–24d,
26b–26d
Step I
Step II
Entry Epoxide
R
Producta % Yield Product % Yield
1
2
3
4
5
6
7
8
21a
21a
21a
21a
21b
21b
21b
21b
23a
23b
23c
23d
25a
25b
25c
25d
77
76
72
68
73
73
75
77
24a
24b
24c
24d
8a
81
86
84
72
78
73
77
78
26b
26c
26d
a Confirmed by H NMR analysis of products isolated in each reaction.
No regioisomer corresponding to primary hydroxyl group was detected.
1
Scheme 3 Formation of halohydrins 22a–22c from epoxylactams in
the presence of Grignard conditions. X-ray crystal structure of 22a.
This journal is © The Royal Society of Chemistry 2012
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further variation in the ring size and with a broader prospect of
employing a wide range of side arm functionality. The syn-
thesized (+)-β-conhydrine analogues deserve to be evaluated for
their biological activity and elaborated to other structurally
diverse analogues for structure activity relation (SAR) studies.
Efforts along these lines are in progress.
Fig. 4 X-ray crystal structures of hydroxy-γ-lactam 23d (A) and
hydroxy-δ-lactam 25b (B).
Experimental section
In order to synthesize the (+)-β-conhydrine, the epoxy-
δ-lactam intermediate 21b was treated with Me2CuLi to furnish
the single regioisomeric hydroxy-δ-lactam 25a in 73% yield.
The LAH reduction of 25a provided (+)-β-conhydrine 8a with
78% yield. Starting from acetonide protected D-glyceraldehyde
12, synthesis of the natural product was achieved in 8-steps in
26% overall yield. The structure of the LiAlH4 reduction product
was confirmed by comparing the recorded NMR (1H- and 13C-)
spectral and specific rotation data (observed: +7.1 in EtOH,
reported +7.9 in EtOH) with the data available in the literature.28
We also synthesized (+)-β-conhydrine analogues 26b, 26c and
8c (R = Bu, tBu and Ph) following the epoxide opening followed
by lactam reduction strategy (Table 1, entries 6–8) in 21–28%
yields.
The crystal structure of the hydroxy-γ-lactam 23d (Fig. 4A)
and that of hydroxy-δ-lactam 25b (Fig. 4B) also corroborated
with the desired stereochemistry present in (+)-β-conhydrine.
Examination of the crystal structures of 23d and 25b reveal sig-
nificant similarity in their solid state packing. From the crystal
structures of 23d and 25b, it is evident that each molecule forms
an intermolecular H-bond through –OH, and –NH with the free
CvO oxygen atom of the next one, resulting in the formation of
1D hydrogen bonded extended sheet type assembly (Fig. S6.A
and S6.B†). Each of these hydrogen bonded 1D networks are
further linked via hydrophobic interactions to provide the 3D
packing in the solid state.
General methods
The acetonide protected D-glyceraldehyde was prepared from
D-mannitol according to the published methods.29 Other sub-
strates and reagents were purchased from common commercial
sources and used without additional purification. THF and
diethyl ether were pre-dried over Na wire. Then the solvent was
refluxed over Na (1%, w/v) and benzophenone (0.2%, w/v)
under an inert atmosphere until the blue color of the benzo-
phenone ketyl radical anion persists. All reactions were con-
ducted under a nitrogen atmosphere. Solvents: petroleum ether
and ethyl acetate (EtOAc) were distilled prior to thin layer and
column chromatography. Reactions were controlled using TLC
on silica. Column chromatography was performed on silica gel
(100–200 mesh).
General copper(I) catalyzed aldehyde–amine–alkyne reaction
procedure
Method A. To a solution of (R)-2,2-dimethyl-1,3-dioxolane-
4-carbaldehyde 12 (1.0 mmol) in dry toluene (2.0 mL) were
added dibenzylamine 13 (1.0 mmol), 4 Å molecular sieves
(500 mg), CuBr (0.05 mmol), and alkyne 14a–14g (1.0 mmol).
The reaction mixture was stirred at room temperature for 48 h.
After completion, the reaction mixture was filtered through celite
bed and washed with Et2O (2 × 10 mL). The combined filtrate
was concentrated under reduced pressure to obtain a liquid
which was further purified by column chromatography over
silica gel (Eluent: 0–5% EtOAc in petroleum ether) to furnish
the corresponding multi-component reaction product 15a–15g.
Conclusions
In conclusion, a Cu(I) catalyzed three-component coupling reac-
tion strategy was efficiently employed for the diastereoselective
construction of syn-α-oxyamines which was confirmed by a
single-crystal X-ray diffraction study and theoretical calculation.
The methodology was further applied in the synthesis of
(+)-β-conhydrine and its analogs having various ring size and
side arm functionality. Ring size variation was addressed by the
construction of piperidine and pyrrolidine rings. On the other
hand, side arm variation was implemented by regioselective
opening of epoxides by Gilman reagents. A lactam–Cu(I) com-
plexation motif was proposed indicating an intramolecular attack
of the R− on the terminal epoxide carbon via a six-membered
transition state. Single-crystal X-ray diffraction studies allowed
the confirmation of the stereochemistry of the epoxide opened
products which were finally converted to (+)-β-conhydrine
and its analogs. The present work reports the synthesis of
(+)-β-conhydrine over eight-steps in 26% overall yield along with
its seven analogs over same number of steps in 21–28% yields.
Although, the present work covered the synthesis of piperidine
and pyrrolidine analogues, the methodology is also amenable for
Synthesis of (R)-N,N-dibenzyl-1-((S)-2,2-dimethyl-1,3-dioxo-
lan-4-yl)-3-phenylprop-2-yn-1-amine 15a (C28H29NO2). Follow-
ing Method A, reaction of 12 (300 mg, 2.30 mmol) with 13
(456 g, 2.31 mmol) and alkyne 14a (0.250 g, 2.44 mmol) in dry
toluene (5 mL) in the presence of CuBr (18 mg, 0.13 mmol),
4 Å molecular sieves (1.50 g) was carried out. The crude
product was subjected to column chromatography over silica gel
(Eluent: 1% EtOAc in petroleum ether) to furnish 15a (644 mg,
68%) as colorless oil. IR (KBr) ν (cm−1): 2987, 2808, 1592,
1495, 1370, 1256, 1210, 1149, 1067; [α]2D5 = −70.30 (c = 0.5,
1
CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 7.49–7.45 (m,
6H), 7.35–7.32 (m, 3H), 7.30 (t, J = 7.3 Hz, 4H), 7.22 (t, J =
7.3 Hz, 2H), 4.36 (q, J = 6.4 Hz, 1H), 4.06 (dd, J = 8.4, 6.4 Hz,
1H), 3.97–3.90 (m, 3H), 3.80 (d, J = 7.4 Hz, 1H), 3.55 (d, J =
13.9 Hz, 2H), 1.34 (s, 3H), 1.28 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 139.5 (2C), 132.0 (2C), 129.1 (4C), 128.5 (2C),
128.3, 128.4 (4C), 127.1 (2C), 123.0, 109.8, 86.9, 84.4, 76.5,
67.5, 56.2, 55.6 (2C), 26.7, 25.7; HRMS (ESI) Calcd for
C28H30NO2 [M + H]+ 412.2277, found 412.2281.
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2986, 2220, 1713, 1495, 1454, 1370, 1243, 1148, 1074; [α]D25
=
Synthesis of (R)-N,N-dibenzyl-1-((S)-2,2-dimethyl-1,3-doxolan-
4-yl)-3-(trimethylsilyl)prop-2-yn-1-amine 15g (C25H33NO2Si).
Following Method A, reaction of 12 (5.00 g, 38.4 mmol) with
13 (6.91 g, 34.9 mmol) and alkyne 14g (3.46 g, 34.9 mmol) in
dry toluene (75 mL) in the presence of CuBr (275 mg,
1.92 mmol), 4 Å molecular sieves (190.10 g) was carried out.
The crude product was subjected to column chromatography
over silica gel (Eluent: 2% EtOAc in petroleum ether) to furnish
15g (11.95 g, 84%) as colorless oil. IR (KBr) ν (cm−1): 2986,
2161, 1647, 1495, 1370, 1250, 1074, 1001; [α]2D0 = −113.5 (c =
1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.43 (d, J =
7.2 Hz, 4H), 7.30 (t, J = 7.4 Hz, 4H), 7.21 (t, J = 7.3 Hz, 2H),
4.25 (q, J = 6.4 Hz, 1H), 4.01 (dd, J = 8.2, 6.4 Hz, 1H), 3.88
(dd, J = 8.2, 6.4 Hz, 1H), 3.83 (d, J = 14.2 Hz, 2H), 3.61 (d, J =
7.4 Hz, 1H), 3.43 (d, J = 14.2 Hz, 2H), 1.22 (s, 3H), 1.34 (m,
3H), 0.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ (ppm): 139.5
(2C), 129.1 (4C), 128.3 (4C), 127.1 (2C), 109.7, 100.7, 91.7,
76.2, 67.5, 56.5 (2C), 55.5, 26.7, 25.8, 0.4 (3C); HRMS (ESI)
Calcd for C25H34NO2Si 408.2359 [M + H]+, found 408.2355.
−123.9 (c = 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ (ppm):
7.43 (d, J = 7.3 Hz, 4H), 7.31 (t, J = 7.3 Hz, 4H), 7.28–7.20 (t,
J = 7.3 Hz, 2H), 4.32 (q, J = 6.5 Hz, 1H), 4.28 (q, J = 7.2 Hz,
2H), 4.03 (dd, J = 8.5, 6.6 Hz, 1H), 3.93 (d, J = 14.3 Hz, 2H),
3.90 (dd, J = 8.5, 5.9 Hz, 1H), 3.70 (d, J = 7.1 Hz, 1H), 3.48 (d,
J = 13.8 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.32 (s, 3H), 1.26 (s,
3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 153.5, 138.8 (2C),
129.0 (4C), 128.4 (4C), 127.3 (2C), 110.1, 83.1,78.7, 75.8, 67.1,
62.3, 55.7 (2C), 55.2, 26.5, 25.4, 14.2; HRMS (ESI) Calcd for
C25H30NO4 408.2175 [M + H]+, found 408.2184.
Synthesis of (R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)pyrrolidin-
2-one 19a (C9H15NO3)
To a solution of 18a (10.00 g, 24.54 mmol) in EtOH (100 mL)
was added 10% Pd(OH)2/C (2.45 g, 2.45 mmol) and the reaction
mixture was stirred at room temperature under 100 psi pressure
of hydrogen for 24 h. The reaction mixture was filtered through
celite and the celite bed was washed with EtOH (2 × 20 mL). To
the combined solution was added NaOEt (1.67 g, 24.54 mmol)
and refluxed for 2 h. The reaction mixture was concentrated
under reduced pressure to obtain a liquid which was purified by
column chromatography over silica gel (Eluent: 60% EtOAc in
petroleum ether) to furnish the pure 19a (3.73 g, 82% over 2
steps) as colourless oil. IR (KBr) ν (cm−1): 3261, 2987, 2894,
1631, 1456, 1381, 1328, 1292, 1217, 1074; [α]2D5 = −47.2 (c =
Synthesis of (R)-N,N-dibenzyl-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-
prop-2-yn-1-amine 17 (C22H25NO2)
To a solution of TMS-alkyne 15g (7 g, 17.2 mmol) in dry THF
(40 mL) placed at 0 °C, TBAF (2.25 g, 8.6 mmol, 1 M in THF)
was added drop wise and the mixture was stirred at this tempera-
ture for 1 h. The reaction mixture was diluted by adding H2O
(50 mL) followed by the extraction of the product in Et2O
(2 × 50 mL). The combined organic layer was dried over
Na2SO4 and concentrated in vacuo. The crude product was
purified by column chromatography over silica gel (Eluent: 2%
EtOAc in petroleum ether) to afford 7 (5.37 g, 93%) as colorless
oil. IR (KBr) ν (cm−1): 3289, 3027, 2986, 2805, 1715, 1602,
1370, 1257, 1150, 1074, 1027; [α]2D5 = −99.1 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ (ppm): 7.44 (d, J = 7.3 Hz, 4H),
7.31 (t, J = 7.6 Hz, 4H), 7.23 (t, J = 7.3 Hz, 2H), 4.29 (q, J =
6.2 Hz, 1H), 4.01 (dd, J = 8.4, 6.6 Hz, 1H), 3.91 (dd, J = 8.2,
6.6 Hz, 1H), 3.89 (d, J = 14.2 Hz, 2H), 3.57 (d, J = 7.3 Hz, 1H),
3.46 (d, J = 13.7 Hz, 2H), 2.37 (s, 1H), 1.33 (s, 3H), 1.28
(s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 139.4 (2C),
129.0 (4C), 128.4 (4C), 127.2 (2C), 109.8, 78.7, 76.4, 74.5,
67.2, 55.5 (2C), 55.1, 26.6, 25.5; HRMS (ESI) Calcd for
C22H26NO2 336.1966 [M + H]+, found 336.1965.
1
0.5, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 6.14 (br s,
1H), 4.04 (dd, J = 8.4, 6.4 Hz, 1H), 3.96 (dd, J = 7.2, 5.4 Hz,
1H), 3.66 (dd, J = 8.5, 5.4 Hz, 1H), 3.61 (q, J = 6.8 Hz, 1H),
2.36–2.31 (m, 2H), 2.20–2.11 (m, 1H), 1.73–1.66 (m, 1H), 1.33
(s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm):
178.0, 110.1, 79.3, 66.2, 67.1, 29.8, 26.8, 25.3, 23.1; HRMS (ESI)
Calcd for C9H15NO3Na 208.0949 [M + Na]+, found 208.0949.
Synthesis of (R)-5-((S)-1,2-dihydroxyethyl)pyrrolidin-2-one 20a
(C6H11NO3)
To a solution of 19a (2.12 g, 11.5 mmol) in EtOH (20 mL) was
added 2 M HCl (6 mL) and the mixture was stirred at room temp-
erature for 2 h. After completion of the reaction, the solution was
neutralized with solid K2CO3 and reaction mixture was concen-
trated under reduced pressure. The crude product was subjected to
column chromatography over silica gel (Eluent: 20% MeOH in
CHCl3) to furnish the pure 20a (1.58 g, 95%) as white solid.
Mp. 94–96 °C; IR (KBr) ν (cm−1): 3229, 2927, 1651, 1416,
1393, 1269, 1106, 1085, 1039, 1008; [α]2D5 = −11.6 (c = 0.5,
Synthesis of (R)-ethyl 4-(dibenzylamino)-4-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)but-2-ynoate 18a (C25H29NO4)
1
MeOH); H NMR (400 MHz, DMSO-d6) δ (ppm): 7.40 (br s,
To a solution of 17 (4.00 g, 11.90 mmol) in dry Et2O (40 mL)
cooled at −78 °C was added dropwise n-BuLi (8.2 mL,
13.10 mmol, 1.6 M in hexane). The reaction mixture was stirred
at the same temperature for 30 min followed by addition of ethyl
chloroformate (2.58 g, 23.80 mmol). The reaction mixture was
allowed to come to room temperature and stirred for 2 h. The
reaction mixture was quenched with water (20 mL) and the
product was extracted with Et2O (2 × 30 mL), dried over
Na2SO4. The crude product was subjected to column chromato-
graphy over silica gel (Eluent: 3% EtOAc in petroleum ether) to
furnish 18a (4.12 g, 85%) as colorless oil. IR (KBr) ν (cm−1):
1H), 4.76 (d, J = 4.6 Hz, 1H), 4.53 (t, J = 5.0 Hz, 1H), 3.56–3.52
(m, 1H), 3.35–3.32 (m, 2H), 3.31–3.25 (m, 1H), 2.16–1.96 (m,
3H), 1.84–1.75 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ
(ppm): 177.2, 74.2, 62.9, 55.3, 30.1, 23.3; HRMS (ESI) Calcd for
C6H11NO3Na 168.0637 [M + Na]+, found 168.0634.
Synthesis of (R)-5-((S)-oxiran-2-yl)pyrrolidin-2-one 21a
(C6H9NO2)
To a solution of 20a (1.20 g, 8.27 mmol) in anhydrous CHCl3
(80 mL) were added PPh3 (3.26 g, 12.41 mmol) and DIAD
This journal is © The Royal Society of Chemistry 2012
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(2.51 g, 12.41 mmol). The reaction mixture was refluxed for
36 h and then allowed to come to room temperature. The reac-
tion mixture was concentrated under reduced pressure to obtain a
liquid which was purified by column chromatography over silica
gel (Eluent: 4% MeOH in CHCl3) to furnish the pure 21a
(884 mg, 84%) as colorless oil. IR (KBr) ν (cm−1): 2948, 1682,
1462, 1437, 1279, 1255, 1108, 877; [α]2D5 = −55.3 (c = 1.0,
(td, J = 9.2, 4.6 Hz, 1H), 2.45–2.38 (m, 1H), 2.30–2.27 (m, 1H),
1.94–1.91 (m, 1H), 1.76–1.68 (m, 1H), 1.40 (s, 3H), 1.33 (s,
3H), 1.33–1.22 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (ppm):
171.7, 109.9, 79.2, 66.3, 56.3, 31.4, 26.9, 25.4, 24.9, 19.8;
HRMS (ESI) Calcd for C10H17NO3Na 222.1106 [M + Na]+,
found 222.1106.
1
CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 6.60 (br s, 1H),
Synthesis of (R)-6-((S)-1,2-dihydroxyethyl)piperidin-2-one 20b
(C7H13NO3)
3.46 (q, J = 6.3 Hz, 1H), 2.96 (ddd, J = 6.2, 3.7, 2.5 Hz, 1H),
2.82 (t, J = 4.6 Hz, 1H), 2.63 (dd, J = 4.6, 2.7 Hz, 1H),
2.48–2.25 (m, 3H), 2.10–1.99 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 178.6, 56.0, 54.7, 44.9, 29.7, 23.8; HRMS
(MALDI): Calcd for C6H11KNO3 184.0371 [M + H2O + K]+,
found 184.0469.
To a solution of 19b (2.10 g, 199.08 mmol) in EtOH (20 mL)
was added 2 M HCl (5 mL) and the mixture was stirred for 2 h
at room temperature. After the completion of the reaction, the
solution was neutralized with solid K2CO3 and concentrated
in vacuo. The crude product was purified by column chromato-
graphy over silica gel (Eluent: 20% MeOH in CHCl3) to afford
20b (1.58 g, 94%) as colorless oil. IR (KBr) ν (cm−1): 3291,
Synthesis of (R)-ethyl 5-(dibenzylamino)-5-((S)-2,2-dimethyl-1,3-
dioxolan-4-yl)pent-3-ynoate 18b (C26H31NO4)
3205, 2911, 1646, 1473, 1404, 1309, 1167, 1028, 955; [α]D25
=
+4.40 (c = 0.4, MeOH); 1H NMR (500 MHz, DMSO-d6)
δ (ppm): 6.62 (br s, 1H), 4.88 (d, J = 5.3 Hz, 1H), 4.56 (t, J =
5.5 Hz, 1H), 3.44–3.40 (m, 1H), 3.36–3.31 (m, 1H), 3.24–3.19
(m, 2H), 2.09–2.00 (m, 2H), 1.72 (t, J = 5.4 Hz, 1H), 1.55–1.44
(m, 1H), 1.35–1.28 (m, 1H); 13C NMR (100 MHz, DMSO-d6)
δ (ppm): 171.1, 74.4, 63.4, 55.0, 31.7, 25.1, 20.2; HRMS (ESI)
Calcd for C7H13NO3Na 182.0793 [M + Na]+, found 182.0797.
To a solution of 17 (4 g, 11.9 mmol) in CH3CN (40 mL) were
added ethyl diazoacetate (1.62 g, 14.2 mmol) and CuI (112 mg,
0.59 mmol, 5 mol%). The reaction mixture was stirred for 12 h
at room temperature. Then the crude reaction mixture was con-
centrated in vacuo and subsequently filtered through a short pad
of silica by eluting with Et2O. The filtrate was further concen-
trated in vacuo. The crude product was subjected to column
chromatography over silica gel (Eluent: 4% EtOAc in petroleum
ether) to furnish 18b (4.72 g, 94%) as pale yellow oil. IR (KBr)
ν (cm−1): 2984, 17.44, 1560, 1495, 1370, 1258, 1072, 1028;
[α]2D5 = −70.50 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.43 (d, J = 7.3 Hz, 4H), 7.28 (t, J = 7.6 Hz, 4H), 7.20
(t, J = 8.0 Hz, 2H), 4.28–4.19 (m, 3H), 4.00 (dd, J = 8.2,
6.4 Hz, 1H), 3.89–3.84 (m, 3H), 3.58 (dt, J = 7.3, 2.3 Hz, 1H),
3.47 (d, J = 13.7 Hz, 2H), 3.35 (d, J = 2.3 Hz, 2H), 1.34–1.21
(m, 6H), 1.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm):
168.4, 139.6 (2C), 128.9 (4C), 128.3 (4C), 127.0 (2C), 109.8,
78.4, 78.3, 76.4, 67.4, 61.7, 55.5 (3C), 26.6, 26.3, 25.6, 14.3;
HRMS (ESI) Calcd for C26H31NO4Na, 444.2151 [M + Na]+,
found 444.2150.
Synthesis of (R)-6-((S)-oxiran-2-yl)piperidin-2-one 21b
(C7H11NO2)
To a solution of 20b (830 mg, 5.22 mmol) in anhydrous CHCl3
(20 mL) were added PPh3 (1.51 g, 5.74 mmol) and DIAD (diiso-
propyl azodicarboxylate) (1.16 g, 5.74 mmol). The reaction
mixture was refluxed for 24 h. The reaction mixture was allowed
to come to the room temperature and solvent was removed under
reduced pressure. The crude product was purified by column
chromatography over silica gel (Eluent: 4% MeOH in CHCl3) to
afford 21b (604 mg, 82%) as colorless oil. IR (KBr) ν (cm−1):
2950, 1645, 1473, 1395, 1302, 1175, 919; [α]2D5 = −30.80 (c =
1
1.0, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 6.50 (br s,
1H), 3.08–3.03 (m, 1H), 2.94–2.91 (m, 1H), 2.82 (t, J = 4.6 Hz,
1H), 2.62 (dd, J = 4.6, 2.3 Hz, 1H), 2.43–2.27 (m, 2H),
1.98–1.88 (m, 2H), 1.76–1.56 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 172.1, 55.8, 55.1, 45.2, 31.4, 25.1, 19.5;
HRMS (ESI) Calcd for C7H11NO2Na 164.0687 [M + Na]+,
found 164.0685.
Synthesis of (R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)piperidin-
2-one 19b (C10H17NO3)
To a solution of 18b (6.30 g, 14.9 mmol) in ethanol (60 mL)
placed in a Parr apparatus was added 10% Pd(OH)2/C (2.09 g,
1.49 mmol) and subsequently stirred under 100 psi H2 pressure
at room temperature for 24 h. The reaction mixture was filtered
through a small celite pad. To the resulting filtrate was added
NaOEt (1.01 g, 14.9 mmol) and refluxed for 2 h. The reaction
mixture was dried under reduced pressure and re-dissolved in
EtOAc (30 mL). The organic layer was washed with H2O (2 ×
10 mL), dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography over
silica gel (Eluent: 60% EtOAc in petroleum ether) to afford 19b
(2.36 g, 81% over 2 steps) as yellow oil. IR (KBr) ν (cm−1):
3322, 2994, 2858, 1659, 1463, 1378, 1292, 1221, 1160, 1085,
1031; [α]2D5 = −14.4 (c = 0.5, CHCl3); 1H NMR (500 MHz,
CDCl3) δ (ppm): 6.20 (br s, 1H), 4.04 (dd, J = 8.6, 6.4 Hz, 1H),
3.85–3.89 (m, 1H), 3.66 (dd, J = 8.6, 5.5 Hz, 1H), 3.32–3.29
General procedure for opening of epoxide Gilman reagent
Method B. To a suspension of CuI (5.00 mmol) in dry Et2O
(20 mL) placed at −35 °C, was added dropwise BuLi
(10.00 mmol, 1.6 M in hexane). To the suspension was added
dropwise a solution of either of the epoxides 21a and 21b
(1.00 mmol) in dry THF (4.5 mL) and the mixture was stirred
for an additional 2 h at the same temperature. The reaction
mixture was carefully quenched at −35 °C with saturated NH4Cl
(15 mL). The reaction mixture was allowed to come to room
temperature with vigorous stirring. The organic layer was separated
and the aqueous layer was extracted with CHCl3 (3 × 25 mL).
7542 | Org. Biomol. Chem., 2012, 10, 7536–7544
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The combined organic layers were dried over anhydrous NaSO4,
filtered and concentrated in vacuo. The dried mass was subjected
to column chromatography over silica gel to furnish the pure
lactam 23a–23d, 25a–25d.
Notes and references
1 (a) L. A. Marcaurelle and C. W. Johannes, Prog. Drug Res., 2008, 66,
189; (b) J. W. H. Li and J. C. Vederas, Science, 2009, 325, 161;
(c) T. F. Molinski, D. S. Dalisay, S. L. Lievens and J. P. Saludes, Nat.
Rev. Drug Discovery, 2009, 8, 69.
2 D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435.
(R)-6-((R)-1-Hydroxypropyl)piperidin-2-one 25a (C8H15NO2).
Following Method B, the Gilman reagent was prepared by
adding MeLi (1.6 M) in pentane (11 mL, 17.7 mmol) to a sus-
pension of CuI (1.68 g, 8.85 mmol) in dry Et2O (40 mL) at
−35 °C. Opening of the epoxide was carried out by adding a sol-
ution of 21b (250 mg, 1.77 mmol) in dry THF (7 mL) to the
freshly prepared Gilman reagent and stirring for 2 h at the same
temperature. The crude product was subjected to column chrom-
atography over silica gel (Eluent: 4% MeOH in CHCl3) to
furnish 25a (203 mg, 73%) as colorless oil. IR (KBr) ν (cm−1):
3384, 2958, 1645, 1487, 1416, 1323, 1166, 1090; [α]2D5 = +3.8
(c = 0.4, CHCl3); 1H NMR (500 MHz, DMSO-d6) δ (ppm):
6.76 (s, 1H), 4.88 (d, J = 5.5 Hz, 1H), 3.18–3.09 (m, 2H),
2.16–2.03 (m, 2H), 1.82–1.76 (m, 2H), 1.59–1.45 (m, 2H),
1.28–1.20 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6) δ (ppm): 170.9, 74.9, 57.4, 31.7, 25.5,
24.6, 20.1,10.4; HRMS (ESI) Calcd for [C8H15NO2Na]+
180.1000 [M + Na]+, found 180.1004.
3 (a) M. E. Welsch, S. A. Snyder and B. R. Stockwell, Curr. Opin. Chem.
Biol., 2010, 14, 347; (b) M. A. Wijdeven, J. Willemsen and F. P. J. T. Rutjes,
Eur. J. Org. Chem., 2010, 2831.
4 S. Inouye, T. Tsuruoka and T. Niida, J. Antibiot. Ser. A, 1966, 19, 288.
5 (a) T. Wertheim, Justus Liebigs Ann. Chem., 1856, 100, 328; (b) J. Vetter,
Food Chem. Toxicol., 2004, 42, 1373; (c) E. Späth and E. Adler,
Monatsh. Chem., 1933, 63, 127.
6 A. T. Carmona, J. Fuentes, I. Robina, R. Garcia Eliazar, R. Demange,
P. Vogel and L. Winters Ana, J. Org. Chem., 2003, 68, 3874.
7 T. Matsumura, M. Kasai, T. Hayashi, M. Arisawa, Y. Momose, I. Arai,
S. Amagaya and Y. Komatsu, Pharm. Biol., 2000, 38, 302.
8 R. J. Nash, P. I. Thomas, R. D. Waigh, G. W. J. Fleet,
M. R. Wormald, P. M. d. Q. Lilley and D. J. Watkin, Tetrahedron
Lett., 1994, 35, 7849.
9 (a) M. J. Schneider, F. S. Ungemach, H. P. Broquist and T. M. Harris,
Tetrahedron, 1983, 39, 29; (b) P. R. Dorling, C. R. Huxtable and
S. M. Colegate, Biochem. J., 1980, 191, 649.
10 Y. Lu, T. Yao and Z. Chen, Yaoxue Xuebao, 1986, 21, 829.
11 N. Asano, in Modern Alkaloids: Structure, Isolation, Synthesis and
Biology, ed. E. Fattorusso and O. Tagialatela-Scafati, Wiley-VCH Verlag,
Weinheim, Germany, 2008, pp. 111–138.
12 Y.-F. Chang, C.-W. Guo, T.-H. Chan, Y.-W. Pan, E.-L. Tsou and
W.-C. Cheng, Mol. Diversity, 2011, 15, 203.
13 L. Guandalini, E. Martini, L. Di Cesare Mannelli, S. Dei, D. Manetti,
S. Scapecchi, E. Teodori, C. Ghelardini and M. N. Romanelli, Bioorg.
Med. Chem. Lett., 2012, 22, 1936.
14 E. M. Driggers, S. P. Hale, J. Lee and N. K. Terrett, Nat. Rev. Drug Dis-
covery, 2008, 7, 608.
General procedure for reduction of lactam by LiAlH4
15 (a) F. Galiovsky and H. Mulley, Monatsh. Chem., 1948, 79, 426;
(b) V. Ratovelomanana, J. Royer and H. P. Husson, Tetrahedron Lett.,
1985, 26, 3803; (c) P. Guerreiro, V. Ratovelomanana-Vidal and
J.-P. Genet, Chirality, 2000, 12, 408; (d) D. L. Comins and
A. L. Williams, Tetrahedron Lett., 2000, 41, 2839; (e) C. Agami,
F. Couty and N. Rabasso, Tetrahedron Lett., 2000, 41, 4113;
(f) C. Agami, F. Couty and N. Rabasso, Tetrahedron, 2001, 57, 5393;
(g) S. K. Pandey and P. Kumar, Tetrahedron Lett., 2005, 46, 4091;
(h) D. Enders, B. Nolte, G. Raabe and J. Runsink, Tetrahedron: Asymme-
try, 2002, 13, 285; (i) S. R. V. Kandula and P. Kumar, Tetrahedron: Asym-
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Chem., 2007, 72, 5358.
Method C. To a suspension of LiAlH4 (3.00 mmol) in dry
THF (10 mL) placed at 0 °C was added a solution of one of the
lactams 23a–23d, 25a–25d (1.00 mmol) in THF (5 mL) and the
resulting mixture was stirred at reflux for 8 h. After cooling to
0 °C, the reaction mixture was quenched by the addition of satu-
rated aqueous NH4Cl (8 mL). The crude product was extracted
with CHCl3 (3 × 15 mL). The combined organic layers were
dried over Na2SO4 and concentrated under vacuum. The dried
mass was subjected to column chromatography over silica gel to
furnish the pure lactam 24a–24d, 8a, 26b–26d.
16 J. A. Gálvez, M. D. Diaz de Villegas, R. Badorrey and P. López-Ram-de-
Víu, Org. Biomol. Chem., 2011, 9, 8155.
Synthesis of (+)-β-conhydrine (8a). Following Method C,
reaction of 25a (150 mg, 0.95 mmol) with LiAlH4 (108 mg,
2.86 mmol) followed by purification by column chromatography
over silica gel (Eluent: 30% MeOH in CHCl3) provided
(+)-β-conhydrine 8a (107 mg, 78%) as colorless oil. IR (KBr)
ν (cm−1): 3447, 3326, 2965, 2855, 1467, 1392, 1128, 1030;
[α]2D5 = +7.1 (c = 0.6, EtOH); 1H NMR (400 MHz, CDCl3)
δ (ppm): 3.24–3.20 (m, 1H), 3.11–3.07 (m, 2H), 2.57 (t, J =
10.3 Hz, 1H), 2.36 (t, J = 7.5 Hz, 1H), 1.78–1.76 (m, 1H),
1.65–1.52 (m, 3H), 1.39–1.29 (m, 3H), 1.78–1.09 (m, 1H), 0.96
(t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm): 72.6,
62.9, 45.4, 26.5, 25.4, 22.6, 22.3, 9.8; HRMS (ESI) Calcd for
C8H18NO 144.1388 [M + H]+, found 144.1380.
17 A. G. Jamieson and A. Sutherland, Org. Lett., 2007, 9, 1609.
18 B. Huang, X. Yao and C.-J. Li, Adv. Synth. Catal., 2006, 348, 1528.
19 (a) N. Gommermann and P. Knochel, Tetrahedron, 2005, 61, 11418;
(b) N. Gommermann and P. Knochel, Chem. Commun., 2005, 4175;
(c) N. Gommermann, C. Koradin, K. Polborn and P. Knochel, Angew.
Chem., Int. Ed., 2003, 42, 5763.
20 (a) P. Hohenberg and W. Kohn, Phys. Rev., 1964, 136, B864;
(b) W. Kohn and L. Sham, Phys. Rev., 1965, 140, A1133;
(c) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (d) C. Lee, W. Yang
and R. G. Parr, Phys. Rev. B, 1988, 37, 785.
21 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery, T. Vreven, K. N. Kudin,
J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone,
B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson,
H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
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Acknowledgements
We thank Director, IISER Pune, and DST (Grant No. INT/
RFBR/P-96) for financial support. S.C.D. thanks CSIR and A.R.
thanks UGC for research fellowships.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 7536–7544 | 7543

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