Henry-Nef reaction: A practical and versatile chiral pool route to 2-substituted pyrrolidine and piperidine alkaloids

Article abstract of DOI:10.1016/j.tet.2013.05.055

The paper describes the synergistic protocol developed by combinatorial Henry and Nef reaction for the synthesis of 2-substituted pyrrolidine and piperidine alkaloids containing 1,3-aminoketone and 1,3-amino alcohol units. The utility of the protocol is demonstrated by asymmetric synthesis of 12 natural products of which asymmetric synthesis of (-)-N-methylpelletierine is presented for the first time. The one-carbon homologation described also provides an alternate route for the synthesis of key intermediates homoprolinol and homopipecolinol used as synthetic precursors for several alkaloids and construction of β-amino acids from α-amino acids.

Full text of DOI:10.1016/j.tet.2013.05.055

Tetrahedron xxx (2013) 1e15
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
HenryeNef reaction: a practical and versatile chiral pool route
to 2-substituted pyrrolidine and piperidine alkaloids
*
Chinmay Bhat, Santosh G. Tilve
Department of Chemistry, Goa University, Taleigao-Plateau, Goa 403 206, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The paper describes the synergistic protocol developed by combinatorial Henry and Nef reaction for the
synthesis of 2-substituted pyrrolidine and piperidine alkaloids containing 1,3-aminoketone and 1,3-
amino alcohol units. The utility of the protocol is demonstrated by asymmetric synthesis of 12 natural
products of which asymmetric synthesis of (ꢀ)-N-methylpelletierine is presented for the first time. The
one-carbon homologation described also provides an alternate route for the synthesis of key in-
termediates homoprolinol and homopipecolinol used as synthetic precursors for several alkaloids and
Received 15 March 2013
Received in revised form 13 May 2013
Accepted 15 May 2013
Available online xxx
Keywords:
Pyrrolidine
Piperidine
Henry
construction of b-amino acids from a-amino acids.
Ó 2013 Published by Elsevier Ltd.
Nef
Chiral pool
2-Substituted
Alkaloids
1. Introduction
develop for practical applications from industrial point of view. On
the other hand, ‘chiral pool’ strategies, wherein the starting mate-
rial can easily be carved from the naturally available sources like
amino acids, though requires large number of synthetic manoeu-
vring, but still is the best bet for chiral integrity and accordingly for
industrial application.10 Keeping this in mind, we thought of de-
veloping a practical and versatile chiral pool strategy for the syn-
2-Substituted pyrrolidines and piperidine alkaloids containing
a stereogenic nitrogen centre are ubiquitously found in nature and
as active components in the various drug candidates.1 Some of the
alkaloids containing 1,3-aminoketone and 1,3-amino alcohol units
are depicted in Fig. 1. These alkaloids are isolated from 60 species of
the genus Sedum and are usually referred as Sedum2 alkaloids,
which are of immense interest due to their memory-enhancing
properties and application as anti-Alzheimer agents.3 Owing to
their vast pharmaceutical applications, the access to these motifs is
gaining major importance from industrial prospective.4 These
motifs are also potent key building blocks in organic synthesis.5 As
a consequence, the asymmetric synthesis of 2-substituted pyrroli-
dine and piperidine alkaloids is of current interest and formidable
challenge in synthetic organic chemistry. The protocols designed in
the earlier days mainly involve racemic synthesis by polar addi-
tions, photocyclizations, cycloadditions and radical cyclizations.6
The modern asymmetric methods encompass chiral pool strate-
gies,7 chiral auxiliary mediated synthesis using chiral organo me-
tallic reagents8 and organocatalysis.9 All these methods have their
advantages and limitations. For example, recent development in
organocatalysis nevertheless has tremendous potential is yet to
thesis of 2-substituted pyrrolidine and piperidine alkaloids from
L-
proline and -pipecolinic acid. The molecules of our interest are
L
those containing 1,3-aminoketone and 1,3-amino alcohol units,
principal units present in various natural products.11 Another at-
traction was the potential of 1,3-amino alcohol units to act as
chiral ligands and chiral auxiliaries.12 A vast variety of methods
are available in the literature for the synthesis of these amino al-
cohols, however, only few asymmetric methods are reported,13
mainly involving proline catalyzed
a
-aminoxylation,13a rhodium
catalyzed asymmetric transformations13b and asymmetric Mannich
reaction.13c
2. Results and discussion
2.1. Henry-Nef reaction on protected prolinols and
pipecolinols
In a preliminary communication we had described the de-
velopment of HenryeNef protocol for the synthesis of some of the
* Corresponding author. Tel.: þ91 (0)832 6519317; fax: þ91 832 2452886; e-mail
addresses: santoshtilve@yahoo.co.in, stilve@unigoa.ac.in (S.G. Tilve).
0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2013.05.055
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2
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
O
O
O
O
H
H
N
N
H
N
H
N
norhygrine 2
pelletierine 3
N-methylpelletierine 4
hygrine 1
HO
OH
H
HO
OH
H
N
H
N
N
N
H
allosedridine 8
pseudohygroline 5
hygroline 6
sedridine 7
OH
H
OH
H
OH
H
OH
H
N
H
N
N
N
H
epi-ethylnorlobelol 12
ethylnorlobelol 11
N-methylsedridine 9 N-methylallosedridine 10
OH
OH
OH OH
OH
H
H
H
N
H
N
Ph
N
H
Ph
N
H
andrachamine 16
allosedamine 14
halosaline 15
sedamine 13
Fig. 1. 2-Substituted pyrrolidine and piperidine alkaloids with 1,3-aminoketone and alcohol units.
pyrrolidine alkaloids.14 This paper illustrates the full account of
application of this protocol for the synthesis of pyrrolidine and
piperidine alkaloids and key homologated prolinol and pipecolinol
intermediates, known precursors for the synthesis of large pool of
alkaloids.
HenryeNef protocol is in combination involves two major syn-
thetic steps; the formation of the nitro functionality from carbonyls
and successive transformation to next carbonyl unit mainly by
oxidative or reductive methods. Even though this method is well
documented in the literature,15 surprisingly, not well explored for
synthetic applications, turned our synthetic attention in this area.
We envisioned the intermediates 17e19 can serve as ideal pre-
cursors for the synthesis of our targeted alkaloids (Scheme 1).
These units could be derived by performing Nef reaction on the
corresponding nitroalkenes 20e22. Based on this we formulated
a retrosynthetic sequence as outlined in Scheme 2.
At the outset of our study, we undertook several investigative
methods to arrive with the nitrofunctional intermediates 20e22.
Despite there are numerous reports available on Henry reaction as
a tool for natural products, the application for 2-substutited
O
OH
n=1, 2
N
N
n=1; (-)-norhygrine 2
H
H
12
(-)-2'-epi-ethylnorlobelol
n=2; (+)-pelletierine 3
HO
n=1, 2
OH
N
N
n=1; (-)-pseudohygroline 5
H
O
n=2; (-)-N-methyl allosedridine 10
n=1, 2
(+)-sedridine 7
R
N
PG
n=1; R= Me, 17
n=2; R=Me, 18
19
R=Et,
HO
OH
n=1, 2
N
N
H
n=1; (-)-hygroline 6
(-)-allosedridine 8
n=2; (+)-N-methyl sedridine 9
O
OH
n=1, 2
N
N
H
n=1; (-)-hygrine 1
n=2; (-)-N-methylpelletierine 4
11
(+)-ethylnorlobelol
Scheme 1. Synthetic strategy through common intermediates.
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C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
3
O
n=1, 2
n=1, 2
NO2
1-12
akaloids
N
PG
N
PG
20-22
17-19
n=1, 2
n=1, 2
+
R
NO2
R=Me, Et
CHO
COOH
N
PG
N
H
n=1; 23
24
n=2;
Scheme 2. Retrosynthetic approach.
pyrrolidine and piperidine alkaloids is not yet explored.16 The in-
tegrity of the chirality was of major concern for us since the al-
dehyde 23 (24) having a stereogenic centre existing between
carbonyl and nitrogen with a lone pair of electrons was readily
racemizable under any drastic condition. Henry reaction of 23 was
thus carried out initially with nitroethane using weak bases like
piperidine, K2CO3, pyridine and Et3N, but resulted either in the low
yield with the starting material remaining unreacted or total de-
composition. The change of solvent and reaction conditions did not
affect much to improve the fate of the reaction. Recent elegant
work carried out by Fioravanti et al. for the diastereoselective
synthesis of E and Z nitroalkenes,17 prompted us to employ the
same method on our substrates. The initial reaction carried out on
Cbz-prolinal 23a with nitroethane gave us the nitroalkenes E and Z
using piperidine base in CH2Cl2 over molecular sieves and only one
E-isomer in toluene at reflux. But unfortunately, in our hand, failed
to produce good yield when applied for the large-scale synthesis of
it. Then we thought of carrying out the Henry reaction with excess
of nitroethane in the presence of catalytic amount of KOH
(0.1e0.2 mol %) in methanol. The reaction smoothly took place
giving us different possible isomers (four diastereomers) of the
nitro alcohol 25 within 1 h. Since the requisite nitro olefin was
desired irrespective of E and Z isomeric forms, the alcoholic mix-
ture 25 was as such subjected to mesylation and subsequent
elimination of the mesylate formed in the reaction mixture to
furnish 20a as a single isomer without any epimerization (Scheme
3). On obtaining the requisite nitro olefin 20a, our next job was to
introduce the carbonyl functionality to arrive at the key in-
termediate 17a through Nef reaction.
stoichiometric ratio of NaBH4 and slight excess resulted in poly-
merization.18 We then directly applied some of the mild Nef
methods on the nitro olefin 20a. Initially we subjected the nitro-
alkene 20a for the treatment with activated Al powder in the
presence of NiCl2,19 which resulted in immediate total de-
composition of the substrate showing very high exothermic
change. The reaction of nitro olefin 20a with SnCl220 also resulted in
decomposition. The application of McMurray Nef reaction21 using
TiCl3, which even though produced the product 17a, the poor yield
disfavoured us for adapting it. The substrate 20a was then subjected
to react with NaBH4 in methanol, after 2 h H2O2 and K2CO3 were
added and left overnight.22 It gave a clean keto product 17a after
column chromatographic purification in 65% yield (Scheme 4).
O
NaBH4/MeOH
H
H
NO2
20a
N
N
H2O2/K2CO3/18h, 65%
17a
Cbz
Cbz
H2O2
NaBH4/MeOH
H
O
K2CO3
N
O
H
N
NO2
Cbz
N
Cbz
Scheme 4. Successful Nef reaction with plausible mechanism.
CH3CH2NO2 (11.0 eq)
H
O2N
H
MeSO2Cl (1.0 eq)
H
1-2 mL 3N KOH in MeOH
1-2 drops of conc. H2SO4
O
NO2
N
N
N
Et3N / DCM
90% for two steps
Cbz
Cbz
H
23a
Cbz
OH
25
20a
Scheme 3. Successful Henry reaction.
The application of general conventional Nef method using
strong acidebase treatment for the generation of carbonyl group
from nitro was strictly ruled out in order to avoid the consequences
of racemization and deprotection of the carbamate protecting
group. The alternate methods were probed for the suitable Nef
conditions. Initially we thought of converting nitroalkene 20a to
nitroalkane by reduction using NaBH4 and then transforming
to carbonyl. But it was observed reduction gave poor yield with
Once a platform was set-up for the optimized Nef reaction
conditions, we prepared a series of nitro olefinic compounds
20e22(aec) starting from proline and pipecolinic acid with dif-
ferent carbamate protecting groups and successfully converted
them to carbonyl intermediates 17e19(aec) with yield ranging
from 55 to 75% using the same method (Scheme 5, Table 1).
However, Henry reaction of phenylnitromethane with any of the
aldehyde 23 could not be accomplished.
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4
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
O
R
n=1, 2
n=1, 2
n=1, 2
d
e
n=1, 2
a, b, c
R
NO2
CHO
N
N
PG
COOH
N
PG
N
H
PG
17, 18, 19
20, 21, 22
23, 24
40% average overall yield
n=1, R=Me; 23, 20, 17
24, 21, 18
n=2, R=Me;
n=2, R=Et; 22, 19
17-23; a, PG=Cbz
b, PG=Boc
c, PG=COOEt
Scheme 5. General synthetic route from L-proline and L-pipecolinic acid. Reagents and conditions: (a) LAH, THF, reflux, 8 h, 90%; (b) For PG¼eCbz: CbzeCl, K2CO3, CH3CN, 0 ꢂC, 6 h,
85e90%; For PG¼eBoc: (Boc)2O, Et3N, CH2Cl2, 0 ꢂC, 80e90%; For PG¼eCOOEt: ClCOOEt, K2CO3, CH3CN, 0 ꢂC, 80e90%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, e78 ꢂC, 95%; (d) (i)
CH3CH2NO2 (n-PrNO2), 0.1e0.2 mol % of 3 N KOH, two drops of concd H2SO4; (ii) MeSO2Cl, Et3N, CH2Cl2 (80e90%, two steps); (e) NaBH4, MeOH, K2CO3, H2O2, rt, 18 h (56e75%).
2.2. Synthesis of 2-substituted pyrrolidine and piperidine
alkaloids
The synthetic utility of the key keto intermediates 17e19 ach-
ieved through Nef reaction was realized by transforming them to
various natural products 1e12.
Table 1
Preparation of requisite Nef products for the synthesis of natural products
Nitro compounds
Nef product
Yield (%)
The target alkaloids 5e12 differ with respect to their hydroxyl
configuration at the second carbon atom of the aliphatic chain. For
achieving this, we explored the diastereoselective reduction of the
carbonyls using different reducing agents as shown (Scheme 6).
From this study it is clear that the bulky reducing agent tri-tert-
butoxyaluminium hydride [LiAl(OtBu)3H] is an effective reducing
reagent in getting the cis (SR) diastereoselectivity. It gave stereo-
selectively cis (SR)-isomer in all the cases and maximum selectivity
was obtained when tert-butoxycarbonyl was the protecting group.
The other two reducing agents Zn(BH4)2 and NaBH4 also favoured cis
(SR)-isomer but with less selectivity. Least selectivity of cis (SR) over
trans (SS) was observed when NaBH4 was used as a reducing agent
and when benzyloxycarbonyl was the protecting group. It is in-
teresting to note that trans (SS) selectivity over cis (SR) was observed
when Zn(BH4)2 was used as a reducing agent for the tert-butoxy
protecting group in the case of five-membered ring, but the same not
shown by six-membered piperidine carbonyls with any of the pro-
tecting groups used. The reason for the high diastereoselectivity
observed during the reduction of carbonyl using LiAl(OtBu)3H is el-
egantly explained by Davies et al.23 by invoking a transition state 32
for the six-membered piperidine nucleus (Fig. 2).
O
H
H
65
NO2
N
N
Cbz
20a
20b
20c
Cbz
17a
17b
17c
18a
18b
18c
O
O
H
H
H
56
56
65
60
60
75
NO2
NO2
N
N
Boc
Boc
H
N
N
COOEt
COOEt
O
N
N
NO2
NO2
NO2
NO2
NO2
NO2
Cbz
Cbz
21a
21b
21c
22a
22b
22c
O
O
The reduced alcohols 26e31 were then separated for complet-
ing the total synthesis of targeted natural products.
N
N
Boc
Boc
(ꢀ)-Pelletierine, ent-3, was first isolated by Tanret in 1878 from
Prunica granatum L.,24 though its structure remained unresolved
partly due to inability of the chemists to synthesize it.25 The
structure was assigned through NMR studies by Gilman and Marion
after 83 years26 and further confirmed by first total synthesis by
Beyerman and Maat in 1963.27a Many syntheses of it and its ana-
logues thereafter have been elaborated in the literature.27,9b
For the synthesis of (þ)-pelletierine 3, the carbobenzyloxy
group of 18a was chemo selectively deprotected using hydroge-
nation over Pd/C without affecting the carbonyl group (Scheme 7).
The physical and spectral properties of thus synthesized 3 as its HCl
salt matched very well with the literature values.
N
N
COOEt
COOEt
O
N
N
Cbz
Cbz
19a
O
O
70
65
Synthesis of compound 3 also constitutes the formal synthesis
of natural products like (ꢁ)-vertine, 5-epi-(þ)-cermizine C and
(ꢀ)-lasubine (Scheme 8).27j,p,q,28
N
N
Boc
Boc
19b
19c
(ꢀ)-Hygrine 1 and (ꢀ)-norhygrine 2 were isolated together from
plant extracts2,29 and numerous racemic and asymmetric syntheses
have been reported.30 The synthesis of (ꢀ)-norhygrine 2 was ac-
complished from 17a similar to pelletierine 3 (Scheme 7).
N
N
COOEt
COOEt
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C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
5
HO
HO
O
n=1, 2
n=1, 2
n=1, 2
Reduction
+
R
R
R
N
N
N
PG
trans
PG
(S, R)
cis
PG
(S, S)
17 18 19
,
,
29
n=1, R=Me;
n=2, R=Me;
26
27
n=1, R=Me;
n=2, R=Me;
30
n=2; R=Et; 31
n=2; R=Et; 28
a
b
c
17-31; , PG=Cbz; , PG=Boc; ,PG=COOEt
Carbonyl
compound
Reducing agents
Diastereomeric ratio with different protecting
groups
PG=Boc
79:21
PG=Cbz
50:50
92:8
PG=COOEt
58:42
n=1; R=Me
n=2; R=Me
n=2; R=Et
NaBH4
LiAl(OtBu)3H
Zn(BH4)2
NaBH4
81:19
99:1
15:85
72:28
45:55
56: 44
94: 6
54:46
62: 38
75: 25
60: 40
62: 38
75: 25
60: 40
LiAl(OtBu)3H
Zn(BH4)2
NaBH4
LiAl(OtBu)3H
Zn(BH4)2
99.7: 0.3
63: 37
71: 29
99.7: 0.3
64: 36
58: 42
55: 45
95: 5
58: 42
Scheme 6. Diastereoselective reduction of carbonyls ([26/29]/[27/30]/[28/31]) (diastereomeric ratio was determined by HPLC using Kromasil column, flow rate 1 mL/min, eluent
10% IPAþn-hexane).
(ꢀ)-N-Methylpelletierine 4 was isolated24c along with (ꢀ) and
OtBu
OH
R
O
N
(ꢁ)-pelletierine 3 from the same source and few racemic syntheses
of it are reported.27qet To the best of our knowledge no asymmetric
synthesis of 4 till date is reported. The LAH reduction of compound
18c gave the mixture of diastereomers 37, which as such were ox-
idized with DesseMartin periodinane (DMP) to give (ꢀ)-N-meth-
ylpelletierine 4, the spectral data were well consistent with the
reported data (Scheme 8). Incidentally this is a first asymmetric
synthesis of (ꢀ)-N-methylpelletierine 4. Similarly the synthesis of
(ꢀ)-hygrine 1 was achieved starting from 17c (Scheme 9).
Al
H
32
Fig. 2. Transition state for reduction with LiAl(OtBu)3H.
O
O
n=1, 2
H2, Pd/C
n=1, 2
(þ)-Sedridine 7 was isolated from Sedum acre,27c,31 (ꢀ)-allose-
dridine 8 was isolated from Sedum nedum32 while N-methylse-
dridine 9 and N-methylallosedridine 10 were first isolated from
Sedum polytrichoides33 and Sedum sarmentosum,2,34 respectively,
and different syntheses of these alkaloids have been detai-
led.23,27k,35 (ꢀ)-Pseudohygroline 5 and (ꢀ)-hygroline 6 are the five-
membered Sedum alkaloids mainly isolated from Schizanthus
N
H
N
EtOH, rt, 95%
Cbz
n=1; (-)-norhygrine 2
n=1; 17a
n=2; 18a
n=2; (+)-pelletierine 3
Scheme 7. Synthesis of (ꢀ)-norhygrine and (þ)-pelletierine.
O
N
H
(+)-pelletierine 3
ref. 27j, 27q
H
ref.27p, 27q
ref. 28
O
HO
H
N
O
N
HO
N
O
(-)-lasubine II
O
O
O
5- epi -(+)-cermizine C 34
35
33
racemic vertine
Scheme 8. Synthetic approaches from (þ)-pelletierine.
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6
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
O
HO
O
n=1, 2
DMP, DCM
n=1, 2
LAH, THF
Reflux
n=1, 2
N
N
rt
N
COOEt
n=1; (-)-hygrine 1
n=1; 17c
n=1; 36
n=2; 37
n=2; (-)-N-methylpelletierine 4
n=2; 18c
Scheme 9. Synthesis of (ꢀ)-hygrine and (ꢀ)-N-methylpelletierine.
hookeri, Carallia brachiata and Erythroxylon coca36 and several
asymmetric synthesis of them are described in the liter-
ature.23,35m,37 A straightforward deprotection of benzyloxycarbonyl
group of compounds 30a, 27a, 31a and 28a resulted in accom-
plishing the synthesis of (þ)-sedridine 7, (ꢀ)-allosedridine 8,
(þ)-ethylnorlobelol 11 and (ꢀ)-epi-ethylnorlobelol 12 (Scheme 10).
The synthesis of (ꢀ)-N-methylsedridine 9 and (ꢀ)-N-methyl-
allosedridine 10 was achieved by LAH reduction of compounds
30c and 27c by reducing the ethoxycarbamate to methyl group
(Scheme 11). The similar treatment of compounds 29c and 26c
produced (ꢀ)-hygroline 6 and (ꢀ)-pseudohygroline 5, respectively.
terminal nitro olefin to aldehyde, which was further reduced in situ
using NaBH4 to furnish the alcohol 38 in an average 45% overall
yield starting from proline and pipecolinic acid (Scheme 13).
The homologated prolinol and pipecolinol found application in
the synthesis of numerous natural and unnatural products as
depicted in Scheme 14.35j,40,41 The synthesis of histamine H1 an-
tagonist, clamastine 47, was achieved by Clayden et al. by synthe-
sizing homologated prolinol via ArndsteEistert method followed
by chlorination and subsequent nucleophilic substitution by bi-
phenyl alcoholic compound.41a,b A simplest 2-sustituted piperidine
alkaloid coniine 48 and some of the Sedum alkaloids have been
OH
OH
OH
OH
H2, Pd/C
EtOH,rt
H , Pd/C
2
R
R
EtOH, rt
N
R
R
N
H
N
N
H
Cbz
Cbz
R=Me, 30a
R=Et, 31a
R=Me, (+)-sedridine 7
R=Me, 27a
R=Et, 28a
R=Me, (-)-allosedridine 8
R= Et, (+)-ethylnorlobelol11
R=Et, (-)-2'-epi-ethylnorlobelol 12
Scheme 10. Synthesis of sedridine and norlobelol.
HO
HO
HO
HO
n=1, 2
n=1, 2
n=1, 2
LAH, THF
Reflux
n=1, 2
LAH, THF
Reflux
N
N
N
N
COOEt
COOEt
n=1; 26c
n=1; (-)-pseudohygroline 5
n=2; (-)-N-methylallosedridine
n=1; 29c
n=1; (-)-hygroline 6
n=2; (-)-N-methylsedridine
27c
n=2;
10
30c
n=2;
9
Scheme 11. Synthesis of (ꢀ)-N-methylsedridine and (ꢀ)-N-methylallosedridine.
2.3. Homologation of proline and pipecolinic acid via
reductive Nef reaction
synthesized by Paserella et al. using enzymatic reagent based dif-
ferentiation of protected pipecolinols.35j,41e,g Davies and Mackervey
have synthesized coniceine 50 involving the synthesis of homolo-
gated prolinol as a major step.41c Compound 38 has been trans-
formed to alkene 51 whose synthetic utility is well explored and
smoothly described recently by Cheng et al. by synthesizing it using
Betti base as a chiral auxiliary.27j Recent work by Foubelo et al. have
demonstrated the applicability of alkene 51 by synthesizing various
natural products.27p The synthesis of tylophora alkaloid (ꢀ)-anto-
Homologated proline and pipecolinic acids are also important as
they constitute important intermediates for the straightforward
synthesis of natural products. The very few methods reported in
the literature for such homologation are depicted in Scheme 12. The
old and frequently used method for homologation of acids is
ArndsteEistert reaction.38 Cardillo et al. successfully homologated
proline through tosylation, cyanation and subsequent reduction
during the synthetic evolution of endomorphin-1 analogues39
€
fine 52 was accomplished by Furstner and Kennedy using homol-
ogated prolinol.40 Some of the active drugs like SB-269970 53
€
whereas Kennedy and Furstner could achieve this through hydro-
have also been obtained through one-carbon homologation of
boration reaction for the synthesis of tylophora alkaloids.40 The
homologation was also done through the Wittig olefination strat-
egy for the synthesis of (þ) hygrine.30i
prolinol.41d Very recently Gomez et al. fabulously described the
ꢀ
chemoenzymatic synthesis of polyhydroxy indolizidines and qui-
nolizidines starting from racemic 38b.41f
We thought of evaluating our HenryeNef protocol by preparing
nitro olefin 44 and subsequent transformations. However our ear-
lier Nef method using NaBH4, H2O2 and K2CO3 failed in effecting the
conversion of nitro olefin 44 to corresponding aldehyde. After
several experimentations, McMurray's21 Nef protocol using TiCl3
and NH4OAc proved to be effective for the transformation of the
It is noteworthy to mention that conversion of proline/pipeco-
linic acid to one-carbon homologated proline/pipecolinic acid
through our HenryeNef protocol opens a new route for the syn-
thesis of
-amino acids remains challenge for synthetic chemists as they are
of paramount importance to pharmaceutical applications.43
b-amino acid 46 from a
-amino acids.42 The synthesis of
b
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C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
7
n=1, 2
OH
N
38
PG
n=1, 2
45%
N
GP
Our method
OH
N
PG
n=1, 2
44
38
OH
N2
N
PG
O2N
43
38
O
d
o
N
N
h
t
GP
e
PG
m
t
OMe
39
K
r
e
47%
e
t
n
n
s
i
e
E
–
d
y
t
'
s
d
n
m
r
e
A
t
h
o
44%
d
n=1,2
OH
N
H
O
OTs
40
N
C
ol
CN
N
m
PG
d
o
e
h
t
na
r
PG
42
e
41
e
m
s
s
'
's
N
o
l
m
l
i
PG
et
d
27%
r
h
a
od
C
n=1, 2
n=1, 2
OH
OH
38
N
PG
N
PG
38
Scheme 12. Methods for one-carbon homologation of proline and pipecolinic acid.
(i) Swern oxidation
(i) LAH, THF
reflux
n=1, 2 OH
n=1, 2
n=1, 2 OH
NO2
(ii) CH3NO2, 3N KOH
N
H
N
N
(ii) CbzCl, K2CO3
O
Cbz
45
Cbz
in MeOH, 1h, 2-3 drops of
CH3CN, 0 oC,
44
conc.H2SO4
90% for 2 steps
90% for 2 steps
38, 44, 45, 46; a, n=1; b, n=2
(Ref 9b)Carter and co-workers
(i) TiCl3, NH4OAc
MeOH, 6h
n=1, 2
n=1, 2
2008
J. Org. Chem.
, 73, 5155
COOH
OH
N
N
H
then NaBH4, MeOH Cbz
55%
38
β
46
-amino acid
45% oerall yield
Scheme 13. Reductive Nef method for homologation of proline and pipecolinic acid.
3. Conclusion
The synthesis of homoprolinol and homopipecolinol constitutes the
formal synthesis of plethora of alkaloids and also opens an alternate
In summary, we have developed a practical HenryeNef reaction
protocol for the synthesis of 2-substituted pyrrolidine and piperi-
dine alkaloids containing 1,3-amino alcohol and 1,3-aminoketone
units. For Henry reaction catalytic amount of KOH was found to be
most appropriate base while for Nef reaction NaBH4/H2O2 found to
be useful for 1,3-amino secondary alcohols and TiCl3 for 1,3-amino
primary alcohols. The versatility of this protocol was demonstrated
by synthesizing 12 naturally occurring alkaloids, which include
the first asymmetric synthesis of (ꢀ)-N-methylpelletierine.
route for the synthesis of
b-amino acids from a-amino acids.
4. Experimental
4.1. General remarks
Chemicals and solvents were purchased from commercial sup-
pliers and purified by standard techniques whenever necessary.
Column chromatography was performed on silica gel (60e120
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8
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
N
H
OH
(-)-coniine
48
N
H
R
Ref 35j, 41e
R=H, sedridine 7
R=Et, ethylnorlobelol 11
R=n-Pr, halosaline 49
R=Ph, sedamine 13
O
Ref 35j, 9a
N
Cl
b
,
a
(S, S)-clemastine 47
1
4
f
c
1
4
n=1, 2
e
f
e
R
R
OH
N
N
PG
38
R
e
f
coniceine
50
4
1
O
j
d
7
2
f
N
Davies and Mckervey
e
S
R
O
N
Ref 40
n=1, 2
OH
N
R
OMe
51
SB-269970 53
MeO
5-HT7 receptorant agonist
H
N
(-)-antofine
52
MeO
Scheme 14. Synthetic application of homologated prolinol and pipecolinol.
mesh). 1H (400 MHz) and 13C (100 MHz) NMR spectra were
recorded on a Bruker AVANCE 400 instrument. Chemical shifts are
chromatography (SiO2, hexane/EtOAc, 9:1).
Note: for the synthesis of nitro olefins 22(aec) and 44(a, b),
the intermediate nitro aldol products obtained were purified
by column chromatography (SiO2, hexane/EtOAc, 7:3) giving
mixture of diastereomers. The diastereomeric mixture was
then treated with of MeSO2Cl (1.0 mmol) and Et3N (2.0 mmol)
and same procedure was carried out further as earlier.
expressed in
d relative to tetramethylsilane (TMS). The spectra were
recorded in CDCl3 as solvent (
d
¼7.28 ppm for 1H,
¼77.0 ppm for
d
13C). The multiplicities of carbon signals were obtained from DEPT
135 experiment. Optical rotations (concentration in grams/100 mL
solvent) were measured using sodium D line on ADP 220 polar-
imeter. Infrared (IR) spectra were recorded in a Shimadzu FTIR in-
strument. High-resolution mass spectra (HRMS) were recorded on
a Micro Mass ES-QTOF Mass spectrometer.
II General procedure of Nef reaction
To
a pre cooled solution of nitroalkene 20e22(aec)
(1.0 mmol) in MeOH (10 mL) was added NaBH4 (2.0 mmol) in
portion. After 2 h stirring at rt, the reaction mixture was cooled
to 0 ꢂC. To this cold mixture, 30% H2O2 (2.6 mL) and K2CO3
(7.9 mmol) were added and the reaction mixture was further
stirred for 18 h at rt. The reaction mixture was then acidified
with 2 N HCl (5 mL), extracted with CH2Cl2 (3ꢃ20 mL). The
combined organic layer was washed with brine (2ꢃ20 mL),
dried over anhyd Na2SO4 and concentrated under reduced
pressure. The crude product obtained was purified by column
chromatography (SiO2, hexane/EtOAc, 8.5:1.5).
4.2. General procedures
I
General procedure of Henry reaction
To a stirred solution of nitroethane (11.0 mmol) in metha-
nol (5 mL) was added 3 N KOH (1e2 mL). After 10 min, was
added prolinal/pipecolinal 23/24(aec) (1.0 mmol) in metha-
nol (5 mL). The reaction mixture was stirred at rt for 1 h. It
was then acidified with concd H2SO4, diluted with water
(20 mL) and extracted with EtOAc (3ꢃ25 mL). The combined
organic layer was washed with brine (2ꢃ25 mL) and dried
over anhyd Na2SO4. To the crude residue obtained after
concentrating the solvent, was added CH2Cl2 (20 mL) fol-
lowed by drop wise addition of CH3SO2Cl (2.0 mmol) at 0 ꢂC.
The reaction mixture was stirred for 20 min, Et3N (3.0 mmol)
was added and stirring continued further for 20 min. After the
reaction mixture had attained the rt, 2 N HCl (15 mL) was
added. The CH2Cl2 layer was separated and the aqueous layer
was extracted with CH2Cl2 (2ꢃ25 mL). The combined organic
extract was washed with brine (2ꢃ25 mL), dried over anhyd
Na2SO4 and concentrated under reduced pressure. The
crude product obtained was further purified by column
III General procedures for diastereoselective reduction of keto to
hydroxyl group using different reducing agents
(a) Reduction with LiAl(OtBu)3H
To a cooled solution of LiAl(OtBu)3H (3.0 mmol) inTHF (5 mL),
the ketone17e19(aec) (1.0 mmol) inTHF (5mL) was added drop
wise under nitrogen atmosphere. The reaction mixture was
stirred further for 8 h at 0 ꢂC and then quenched with ice-cold
water (5 mL), acidified with 1 N HCl (2 mL). It was then extrac-
ted in ethyl acetate (3ꢃ15 mL). The combined organic layer was
dried over anhyd Na2SO4 and concentrated under reduced
pressure. The residue was column chromatographed (SiO2,
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C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
9
eluent hexane/EtOAc,1:1) to give a diastereomeric mixture ([26/
29]/[27/30]/[28/31]) [yield 90e95%]. The diastereomeric mix-
ture (26e31) was subjected to HPLC using Kromasil column (n-
hexane/IPA, 9:1) to find the ratio of [26/29]/[27/30]/[28/31] [cis
(SR)/trans (SS)] as shown in the table of Scheme 6.
The separation of diastereomeric mixtures was done using
flash chromatography for the characterization purpose (n-hex-
ane/EtOAc, 9:1).
(0.83 mL, 11.0 mmol) gave the product 20b (0.23 g, 90% for two
steps) as a pale yellow thick liquid; Rf¼0.40 (hexane/EtOAc, 8:2);
28
[a
]
ꢀ12.0 (c 0.1, CHCl3); IR (neat) 3100, 2970, 2936, 2880, 1690,
D
1536 cmꢀ1 1H NMR (CDCl3, 400 MHz): 1.44 (s, 9H, tBuH),
; d
1.64e1.71 (m, 2H, H-3), 1.8e2.2 (m, 2H, H-4), 2.2 (s, 3H, H-30),
3.41e3.54 (m, 2H, H-5), 4.40e4.51 (m, 1H, H-2), 6.96 (d, J¼7.6 Hz,
1H, H-10); 13C NMR (CDCl3, 100 MHz): 12.7 (C-30), 24.3 (C-3), 28.8
d
(OC(CH3)3), 32.5 (C-4), 48.0 (C-5), 54.8 (C-2), 89.1 (OCMe3), 137.1 (C-
10), 147.5 (C-20), 154.3 (NCO); HRMS: m/z calcd for C12H20N2O4Na
[MþNa]þ: 279.1321; found: 279.1320.
(b) Reduction with NaBH4
To a cooled solution of NaBH4 (3.0 mmol) in CH3OH (5 mL),
the ketone 17e19(aec) (1.0 mmol) in CH3OH (5 mL) was
added drop wise under nitrogen atmosphere. The reaction
mixture was stirred further for 8 h at 0 ꢂC and then quenched
with ice-cold water (5 mL) and acidified with 1 N HCl (2 mL). It
was then extracted in ethyl acetate (3ꢃ15 mL). The combined
organic layer was dried over anhyd Na2SO4 and concentrated
under reduced pressure. The residue was column chromato-
graphed (hexane/EtOAc, 1:1) to give a diastereomeric mixture
([26/29]/[27/30]/[28/31]) [yield 90e95%]. The diastereomeric
mixture (26e31) was subjected to HPLC using Kromasil
column (n-hexane/IPA, 9:1) to find the ratio of [26/29]/[27/
30]/[28/31] [cis (SR)/trans (SS)] as shown in the table of
Scheme 6.
4.3.3. Ethyl (2S)-2-[(10E)-20-nitroprop-10-en-10-yl]pyrrolidine-1-
carboxylate (20c). Following the general procedure I, Henry-
olefination of compound 23c (0.17 g, 1.0 mmol) with nitroethane
(0.83 mL, 11.0 mmol) gave the title compound 20c (0.2 g, 90%) as
28
a pale yellow dense liquid; Rf¼0.50 (hexane/EtOAc, 8:2); [
a]
þ12.0 (c 0.1, CHCl3); IR (neat) 3008, 2979, 2934, 1690, 1385 cmꢀD1
;
1H NMR (CDCl3, 400 MHz):
d
1.19e2.29 (m, 9H, H-4, H-3, H-30,
OCH2CH3), 3.26e3.56 (m, 2H, H-5), 4.10e4.12 (m, 2H, OCH2CH3),
4.47e4.54 (m, 1H, H-2), 6.91 (d, J¼8 Hz, 1H, H-10); 13C NMR (CDCl3,
100 MHz) :
d
12.7 (CH2CH3), 14.7 (C-30), 24.4 (C-3), 32.4 (C-4), 46.7
(C-5), 54.9 (C-2), 61.3 (OCH2), 135.4 (C-10), 155.0 (NCO); HRMS: m/z
calcd for C10H16N2O4Na [MþNa]þ: 251.1008; found: 251.1006.
The separation of diastereomeric mixture was done using
flash chromatography for the characterization purpose
(n-hexane/EtOAc, 9:1).
4.3.4. Benzyl (2S)-2-(20-oxopropyl)pyrrolidine-1-carboxylate
(17a). Following the general procedure II, Nef reaction on 20a
(c) Reduction with Zn(BH4)2
(0.29 g, 1.0 mmol) gave 17a (0.17 g, 65%) as a thick liquid; Rf¼0.30
28
A solution of the ketone 17e19(aec) (1.0 mmol) in THF
(5 mL) was stirred at 0 ꢂC, Zn(BH4)2 solution (0.3 mL) [Pre-
pared in the laboratory using ZnCl2 (2.0 g) and NaBH4 (1.3 g) in
28 mL THF according to the reported procedure44] was added
under nitrogen atmosphere. The reaction mixture was stirred
further for 8 h. It was then quenched with ice-cold water and
acidified with 1 N HCl (5 mL). It was then extracted with ethyl
acetate (3ꢃ15 mL). The combined organic layer was dried over
anhyd Na2SO4 and concentrated under reduced pressure. The
residue was column chromatographed (hexane/EtOAc, 1:1) to
give a diastereomeric mixture ([26/29]/[27/30]/[28/31]) [yield
90e95%]. The diastereomeric mixture (26e31) was subjected
to HPLC using Kromasil column (n-hexane/IPA, 9:1) to find the
ratio of ([26/29]/[27/30]/[28/31]) [cis (SR)/trans (SS)] as shown
in the table of Scheme 6.
(hexane/EtOAc, 8:2); [
a
]
ꢀ38.0 (c 0.5, CHCl3); IR (neat) 1711,
D
1693 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 1.66e2.15 (m, 7H, H-3, H-
4, H-30), 2.42e2.45 (m, 1H, H-10A), 2.82e3.15 (m, 1H, H-10B),
3.41e3.42 (m, 2H, H-5), 4.20e4.23 (m, 1H, H-2), 5.08e5.17 (m, 2H,
CH2Ph), 7.29e7.36 (m, 5H, PhH); 13C NMR (CDCl3, 100 MHz):
d 23.6
(C-3), 30.3 (C-30), 30.9 (C-4), 46.6 (C-10), 47.6 (C-5), 54.0 (C-2), 66.6
(CH2Ph), 127.3 (PhCH), 127.6 (PhCH), 128.2 (PhCH), 137.0 (PhC),
153.6 (NCO), 206.8 (C-20); HRMS: m/z calcd for C15H19NO3Na
[MþNa]þ: 284.1263; found: 284.1266.
4.3.5. tert-Butyl (2S)-2-(20-oxopropyl)pyrrolidine-1-carboxylate
(17b). Following the general procedure II, compound 20b (0.25 g,
1.0 mmol) on Nef reaction gave 17b (0.13 g, 56%) as a thick liquid;
28
Rf¼0.45 (hexane/EtOAc, 8:2); [
a
]
D
ꢀ43.3 (c 0.1, CHCl3); IR (neat)
2974, 1713, 1690 cmꢀ1 1H NMR (CDCl3, 400 MHz):
; d 1.50 (s, 9H,
tBuH), 1.62e2.15 (m, 4H, H-4, H-3), 2.40e2.42 (m, 1H, H-10A),
2.90e3.11 (m, 1H, H-10B), 3.14e3.36 (m, 2H, H-5), 4.10e4.16 (m, 1H,
The separation of diastereomeric mixture was done using
flash chromatography for the characterization purpose (n-
hexane/EtOAc 9:1).
H-2); 13C NMR (CDCl3, 100 MHz):
d 23.4 (C-3), 28.5 (OC(CH3)3), 30.6
(C-30), 30.7 (C-4), 46.4 (C-5), 48.6 (C-10), 53.4 (C-2), 79.5 (OeCMe3),
154.3 (NCO), 206.9 (C-20); HRMS: m/z calcd for C12H21NO3Na
[MþNa]þ: 250.1419; found: 250.1418.
4.3. Experimental procedures and characterization
4.3.1. Benzyl (2S)-2-[(10E)-20-nitroprop-10-en-10-yl]pyrrolidine-1-
carboxylate (20a). Following the general procedure I, Henry-
olefination of compound 23a (0.23 g, 1.0 mmol) with nitroethane
(0.83 mL, 11.0 mmol) gave 20a (0.26 g, 90% for two steps) as pale
4.3.6. Ethyl (2S)-2-(20-oxopropyl)pyrrolidine-1-carboxylate
(17c). Following the general procedure II, compound 20c (0.23 g,
1.0 mmol) on Nef reaction gave 17c (0.11 g, 56%) as a viscous liquid;
28
yellow thick liquid; Rf¼0.25 (hexane/EtOAc, 8:2); [
a
]
28 þ13.0 (c 0.1,
Rf¼0.20 (hexane/EtOAc, 9:1); [
a
]
D
ꢀ39.3 (c 0.1, CHCl3); IR (neat)
D
CHCl3); IR (neat) 3108, 2979, 2934, 2882, 1698, 1526 and
2974, 1713, 1693 cmꢀ1 1H NMR (CDCl3, 400 MHz):
; d 1.2 (t, 3H,
1356 cmꢀ1
;
1H NMR (CDCl3, 400 MHz):
d
1.64e1.71 (m, 2H, H-3),
OCH2CH3), 1.65e1.83 (m, 1H, H-3A), 1.85e1.87 (m, 2H, H-4),
2.01e2.05 (m, 1H, H-3B), 2.12 (s, 3H, H-30), 2.42e2.45 (m, 1H, H-
10A), 2.89e3.23 (m, 1H, H-10B), 3.36e3.40 (m, 2H, H-5), 4.11e4.21
1.80e1.87 (m, 2H, H-4), 1.8 (s, 3H, H-30), 3.51e3.59 (m, 2H, H-5),
4.43e4.57 (m, 1H, H-2), 4.97e5.16 (m, 2H, CH2Ph), 7.24e7.26 (m,
1H, H-10), 7.31e7.36 (m, 5H, PhH); 13C NMR (CDCl3,100 MHz):
d
12.7
(m, 3H, H-2, eOCH2CH3); 13C NMR (CDCl3, 100 MHz):
d 14.7
(C-30), 24.4 (C-3), 31.5 (C-4), 46.9 (C-5), 55.0 (C-2), 67.6 (CH2ePh),
127.8 (PhCH), 128.5 (PhCH), 128.5 (PhCH), 135.1 (C-10), 136.4 (PhC),
148.2 (C-20), 154.8 (NCO); HRMS: m/z calcd for C15H18N2O4Na
[MþNa]þ: 313.1164; found: 313.1169.
(eCH2CH3), 23.6 (C-3), 30.2 (C-4), 31.7 (C-30), 46.4 (C-5), 48.5 (C-10),
53.4 (C-2), 60.8 (OCH2CH3), 154.9 (NCO), 206.0 (C-20); HRMS: m/z
calcd for C10H17NO3Na [MþNa]þ: 222.1106; found: 222.1102.
4.3.7. tert-Butyl (2S)-2-[(20R)-20-hydroxypropyl]pyrrolidine-1-
carboxylate (26b). Following the general procedures IIIaec, re-
duction of 17b (0.23 g, 1.0 mmol) gave 26b (0.12 g, 98%) as a thick
liquid (yield after separation of the diastereomers as mentioned in
4.3.2. tert-Butyl (2S)-2-[(10E)-20-nitroprop-10-en-10-yl]pyrrolidine-1-
carboxylate (20b). Following the general procedure I, Henry-
olefination of compound 23b (0.19 g, 1.0 mmol) with nitroethane
Please cite this article in press as: Bhat, C.; Tilve, S. G., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.055

10
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
28
the general procedures IIIaec); Rf¼0.25 (hexane/EtOAc, 7:3); [
a
]
refluxed for 8 h. It was quenched with drop wise addition of ice-
cold water (1 mL) and further treated with 2 N NaOH (1 mL) so-
lution. The organic compound was extracted with EtOAc (3ꢃ10 mL).
The combined organic layer was then dried over anhyd Na2SO4. The
organic layer was filtered and concentrated in vacuo to get the pure
D
ꢀ11.2 (c 0.2, CHCl3) {lit.23
[
a]
28 þ10.9 (c 0.7, CHCl3) for (RS)-isomer};
D
IR (neat) 3426, 2971, 1694, 1673 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
t
d
1.18 (d, 3H, H-30), 1.46e2.02 (m, 15H, BuH, H-3, H-4, H-10),
3.31e3.34 (m, 2H, H-5), 3.80e3.87 (buried m, 1H, H-20), 3.90e3.98
(buried m, 1H, H-2); 13C NMR (CDCl3, 100 MHz):
d
23.8 (C-3), 23.9
product 5 (0.07 g, 95%) as a very thick liquid; [
a
]
28 ꢀ90 (c 0.2, EtOH)
D
29
29
(C-30), 28.5 (OC(CH3)3), 32.5 (C-4), 45.8 (C-10), 46.4 (C-5), 55.7 (C-2),
{lit.37f
[
a
]
þ70.7 (c 2.0, EtOH); lit.37a
[
a
]
þ97.0 (c 3.4, EtOH) for
D
D
66.5 (C-20), 79.7 (OCMe3), 155.6 (NCO); HRMS: m/z calcd for
(RR)-isomer}; ee 92%; IR (neat) 3362, 2964, 1418 cmꢀ1 1HMR
;
C
12H23NO3Na [MþNa]þ: 252.1576; found: 252.1581.
(CDCl3, 400 MHz):
d
1.15 (d, J¼6.4 Hz, 2H, H-30), 1.32e1.49 (m, 3H,
H-10A, H-3A), 1.72e1.78 (m, 2H, H-4), 1.97e2.03 (1H, m, H-3B),
2.31e2.36 (m, 4H, NCH3, H-5A), 2.67e2.69 (m, 1H, H-2), 3.02e3.06
(m, 1H, H-5B), 3.88e3.92 (m, 1H, H-20); 13C NMR (CDCl3, 100 MHz):
4.3.8. tert-Butyl (2S)-2-[(20S)-20-hydroxypropyl]pyrrolidine-1-
carboxylate (29b). Following the general procedures IIIaec, re-
duction of 17b (0.23 g, 1.0 mmol) gave 29b (0.12 g, 98%) as a thick
d
22.6 (C-4), 24.2 (C-30), 30.4 (C-3), 42.7 (NCH3), 42.8 (C-10), 55.4 (C-
liquid (yield after separation of the diastereomers as mentioned in
5), 65.5 (C-2), 67.3 (C-20); HRMS: m/z calcd for C8H17NONa
[MþNa]þ: 144.1388; found: 144.1397.
28
the general procedures IIIaec); Rf¼0.25 (hexane/EtOAc, 7:3); [
a]
D
ꢀ80.2 (c 0.1, CHCl3) {lit.23
[
a
]
D
23 þ78.5 (c 0.7, CHCl3) for (RR)-isomer};
IR (neat) 3426, 2971, 1694, 1673 cmꢀ1; 1H NMR (400 MHz, CDCl3):
4.3.12. (2S)-1-[(2S)-1-Methylpyrrolidin-2-yl]propan-2-ol
(6). Following the similar procedure described for compound 5,
compound 29c (0.1 g, 0.5 mmol) on LAH (0.076 g, 2.0 mmol) re-
duction gave the pure product 6 (0.065 g, 95%) as a very thick
d
1.17e2.01 (d, 3H, H-30), 1.32e2.01 (m, 6H, H-10, H-3, H-4), 1.46 (s,
9H, tBuH), 3.26e3.37 (m, 2H, H-5), 3.65e3.70 (m, 1H, H-2),
3.71e4.18 (m, 1H, H-20), 4.97 (br s, OH); 13C NMR (CDCl3, 100 MHz):
23
22
d
22.5 (C-3), 23.6 (C-30), 28.4 (OC(CH3)3), 31.1 (C-4), 45.6 (C-10), 46.5
colourless liquid; [
a
]
ꢀ50 (c 0.2, EtOH) {lit.37a
[
a
]
ꢀ49.0 (c 0.4,
D
D
(C-5), 53.7 (C-2), 63.6 (C-20), 79.2 (OCMe3), 156.6 (NCO); HRMS: m/z
calcd for C12H23NO3Na [MþNa]þ: 252.1576; found: 252.1573.
EtOH) for (RR)-isomer}; ee 99%; IR (neat) 3362, 2964 cmꢀ1; H NMR
(CDCl3, 400 MHz):
d
1.04e1.08 (m, 3H, H-30), 1.32e1.49 (m, 3H, H-
10A, H-3A), 1.72e1.78 (m, 2H, H-4), 2.01e2.09 (m, 1H, H-3B), 2.20 (s,
3H, NCH3), 2.30e2.32 (m, 1H, H-5A), 2.8e2.90 (m, 1H, H-5B),
3.70e3.60 (m, 1H, H-20), 3.80 (s br, 1H, eOH); 13C NMR(CDCl3,
4.3.9. 1-[(2S)-Pyrrolidin-2-yl]acetone (2). Acetonyl carbamate 17a
(0.18 g, 6.8 mmol) in EtOH (15 mL) was stirred with 10% Pd/C
(20 mg) under H2 atmosphere (2 kg/cm2) for 8 h in Parr hydro-
genator at rt. The mixture was then filtered, washed with EtOH and
100 MHz):
d
23.3 (C-4), 23.7 (C-30), 28.3 (C-3), 37.1 (C-10), 40.6
(NCH3), 57.1 (C-5), 62.7 (C-2), 64.8 (C-20); HRMS: m/z calcd for
C8H17NONa [MþNa]þ: 144.1388; found: 144.1384.
then concentrated to give (ꢀ)-norhygrine 2 (0.07 g, 81%) as a pale
33
yellow thick liquid; [
a
]
D
30ꢀ30.2 (c 0.2, CHCl3) {lit.14
[
a
]
ꢀ29.6 (c
D
0.14, CHCl3); ee 99%; IR (neat) 3310, 1712 cmꢀ1
;
1H NMR (CDCl3,
4.3.13. Benzyl (2S)-2-[(1E)-2-nitroprop-1-en-1-yl]piperidine-1-
carboxylate (21a). Following the general procedure I, Henry-
olefination of compound 24a (0.25 g, 1.0 mmol) with nitroethane
(0.83 mL, 11.0 mmol) gave the title compound 21a (0.26 g, 85% for
400 MHz):
d
1.62e2.25 (m, 4H, H-4, H-3), 2.22 (s, 3H, H-30), 2.96
(dd, J¼6.0, 18.6 Hz, 2H, H-10), 3.33e3.42 (m, 2H, H-5), 3.89e3.94 (m,
1H, H-2), 9.43 (br s, 1H, NH); 13C NMR (CDCl3, 100 MHz):
d 23.6
(C-3), 30.3 (C-4), 30.1 (C-30), 44.9 (C-10), 45.2 (C-5), 55.1 (C-2), 205.8
(C-20).
two steps) as pale yellow thick liquid; Rf¼0.45 (hexane/EtOAc, 8:2);
28
[a
]
ꢀ33.0 (c 0.1, CHCl3); IR (neat) 3108, 2979, 2934, 2882,1698,
D
1526 and 1356 cmꢀ1 1H NMR (CDCl3, 400 MHz):
; d 1.50e1.53 (m,
4.3.10. 1-[(2S)-1-Methylpyrrolidin-2-yl]acetone$HCl
(1$HCl). To
2H, H-4), 1.56e1.84 (m, 4H, H-3 and H-5), 2.17 (s, 3H, H-30),
2.97e3.03 (t, J¼12 Hz, 1H, H-6), 4.11e4.15 (m, 1H, H-2), 5.08e5.18
(m, 3H, PhCH2 and H-10), 7.28e7.36 (m, 5H, PhH); 13C NMR (CDCl3,
a cooled suspension of LAH (0.114 g, 3.0 mmol) in THF (15 mL) was
added compound 17c (0.20 g, 1.0 mmol) in THF (5 mL) drop wise
under nitrogen atmosphere and refluxed further for 6 h. It was
quenched with drop wise addition of ice-cold water (1 mL) and
further treated with 2 N NaOH (1 mL) solutions. The reaction mass
was filtered and directly dried over anhyd Na2SO4 to give 36 (0.18 g,
90%). The crude mass was as such dissolved in CH2Cl2 (20 mL) and
cooled to 0 ꢂC under nitrogen atmosphere, added NaHCO3 (0.1 g,
1.2 mmol) and DMP (0.5 g, 1.2 mmol), brought to rt in 30 min. The
reaction mass was filtered and concentrated under reduced pres-
sure. The crude mass was then treated with 5 N HCl (2 mL) in 10 mL
CH2Cl2 for 2 h, concentrated and further purified by column chro-
matography (SiO2, CHCl3/MeOH, 8.5:1.5) to afford compound 1$HCl
(0.17 g, 95%) as pale yellow thick liquid; Rf¼0.20 (CHCl3/MeOH,
100 MHz): d
12.7 (C-30), 19.5 (C-4), 24.9 (C-5), 29.4 (C-3), 40.4 (C-6),
48.8 (C-2), 67.5 (PhCH2), 128.0 (PhCH), 128.2 (PhCH), 128.5 (PhCH),
128.6 (PhCH), 131.7 (PhCH), 133.5 (C-10), 136.3 (PhC), 148.8 (C-20),
155.4 (NCO); HRMS: m/z calcd for
327.1322; found: 327.1321.
C
16H20N2O4Na [MþNa]þ:
4.3.14. tert-Butyl (2S)-2-[(1E)-2-nitroprop-1-en-1-yl]piperidine-1-
carboxylate (21b). Following the general procedure I, Henry-
olefination of compound 24b (0.213 g, 1.0 mmol) with nitro-
ethane (0.83 mL, 11.0 mmol) gave the product 21b (0.23 g, 85% for
two steps) as a pale yellow crystalline solid; Rf¼0.55 (hexane/
28
EtOAc, 8:2); [
a
]
ꢀ48.4 (c 0.1, CHCl3); mp¼80 ꢂC; IR (neat) 3108,
D
30
30
9:1); [
a
]
ꢀ33.2 (c 0.2, H2O) {lit.30h
[
a
]
þ34.5 (c 0.5, H2O) for R-
2979, 2934, 2882, 1694, 1526 cmꢀ1
1.42 (s, 9H, BuH), 1.47e1.78 (m, 6H, H-4, H-5, H-3), 2.22 (s, 3H),
;
1H NMR (CDCl3, 400 MHz):
D
D
isomer]; ee 96%; IR (neat) 3390, 2900, 1721 cmꢀ1; 1H NMR (CDCl3,
d
t
400 MHz):
d
1.87e2.41 (m, 4H, H-3, H-4), 2.27 (s, 3H, H-30), 2.81 (d,
2.88 (t, J¼12.4 Hz, 1H, H-6), 3.99e4.02 (m, 1H, H-6), 4.90e5.10
J¼6.0 Hz, NCH3), 2.80e2.82 (m, 1H, H-5A), 3.11 (dd, J¼6.6, 18.6 Hz,
1H, H-10A), 3.45 (dd, J¼6.6,18.6 Hz,1H, H-10B), 3.59e3.75 (m, 1H, H-
5B), 3.76e3.83 (m, 1H, H-2), 11.67 (s, 1H, NH); 13C NMR (CDCl3,
(buried m, 1H, H-2), 7.27e2.29 (d, J¼8.8 Hz, 1H, H-10); 13C NMR
(CDCl3, 100 MHz):
d
12.7 (C-30), 19.6 (C-4), 24.9 (C-5), 28.3
(OC(CH3)3), 29.5 (C-3), 40.1 (C-6), 48.5 (C-2), 80.1 (OCMe3),132.5 (C-
10), 148.4 (C-20), 154.6 (NCO); HRMS: m/z calcd for C13H22N2O4Na
[MþNa]þ: 293.1477; found: 293.1479.
100 MHz): d
22.0 (C-3), 30.3 (C-30), 30.5 (C-4), 40.3 (NCH3), 44.2 (C-
10), 56.2 (C-5), 64.2 (C-2), 204.9 (C-20); GCeMS: m/z calcd for
C8H15NO [M]þ: 141; found: 141.
4.3.15. Ethyl (2S)-2-[(1E)-2-nitroprop-1-en-1-yl]piperidine-1-
carboxylate (21c). Following the general procedure I, Henry-
olefination of compound 24c (0.18 g, 1.0 mmol) with nitroethane
4.3.11. (2R)-1-[(2S)-1-Methylpyrrolidin-2-yl]propan-2-ol
(5). To
a suspension of LAH (0.076 g, 2.0 mmol) in THF (10 mL) cooled at
0 ꢂC was added compound 26c (0.1 g, 0.5 mmol) in THF (5 mL) drop
wise under nitrogen atmosphere. The reaction mixture was then
(0.83 mL, 11.0 mmol) gave 21c (0.20 g, 85%) as a pale yellow dense
28
liquid; Rf¼0.40 (hexane/EtOAc, 8:2); [
a
]
ꢀ32.3 (c 0.1, CHCl3); IR
D
Please cite this article in press as: Bhat, C.; Tilve, S. G., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.055

C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
11
(neat) 3108, 2979, 2934, 2882, 1692, 1380 cmꢀ1
;
1H NMR (CDCl3,
reduction of 18a (0.29 g, 1.0 mmol) gave 27a (0.27 g, 95%) as a thick
400 MHz):
d
1.26e1.30 (buried m, 3H, CH2CH3), 1.47e1.90 (m, 6H,
liquid (yield after separation of the diastereomers as mentioned in
25
H-4, H-5, H-3), 2.26 (s, 3H, H-30), 2.92e2.98 (m, 1H, H-6A),
4.06e4.13 (m, 3H, H-6B, CH2CH3), 5.01e5.07 (buried m, 1H, H-2),
the general procedures IIIaec); [
a
]
28 ꢀ50.6 (c 0.1, CHCl3) {lit.35l
[a]
D
ꢀ52.37 (c 1.275, CHCl3)}; IR (neat) 3430, 2990, 1680, 1670 cmꢀ1; 1DH
7.28e7.32 (d, J¼9.2 Hz, 1H, H-2); 13C NMR (CDCl3, 100 MHz):
d
12.7
NMR (CDCl3, 400 MHz): d
1.20e1.84 (m, 11H, H-4, H-30, H-5, H-3, H-
(CH2CH3), 14.5 (C-30), 19.4 (C-4), 24.9 (C-5), 29.4 (C-3), 40.2 (C-6),
48.6 (C-2), 61.6 (OCH2CH3), 131.8 (C-10), 148.7 (C-20), 155.5 (NCO);
HRMS: m/z calcd for C11H18N2O4Na [MþNa]þ: 265.1164; found:
265.1162.
10A, OH), 2.21e2.40 (buried m, 1H, H-10B), 2.88e2.94 (m, 1H, H-6A),
3.70e3.90 (buried m, 1H, H-6B), 4.05e4.07 (m, 1H, H-2), 4.40e4.43
(m, 1H, H-2), 5.14 (s, 2H, CH2Ph), 7.34e7.37 (m, 5H, PhH); 13C NMR
(CDCl3, 100 MHz):
d
18.9 (C-4), 23.6 (C-30), 25.4 (C-5), 25.5 (C-3),
28.9 (C-10), 39.3 (C-6), 48.7 (C-2), 65.8 (C-20), 67.1 (PhCH2), 127.8
(PhCH), 127.9 (PhCH), 128.4 (PhCH), 136.7 (PhCH), 136.7 (PhC), 155.7
(NCO).
4.3.16. Benzyl (2S)-2-(2-oxopropyl)piperidine-1-carboxylate
(18a). Following the general procedure II, Nef reaction on 21a
28
(0.29 g, 1.0 mmol) gave 18a (0.18 g, 65%) as a thick liquid; [a]
D
ꢀ10.0 (c 0.5, CHCl3) {lit.27f
[a
]
26 þ10.2 (c 2.5, CHCl3) for R-isomer};
4.3.21. tert-Butyl (2S)-2-[(2R)-2-hydroxypropyl]piperidine-1-
carboxylate (27b). Following the general procedures IIIaec, re-
duction of 18b (0.25 g, 1.0 mmol) gave 27b (0.24 g, 94%) as a thick
D
IR (neat) 2990, 1693, 1711 cmꢀ1 1H NMR (CDCl3, 400 MHz):
;
d
1.41e1.66 (m, 6H, H-4, H-5, H-3), 2.01e2.29 (m, 4H, H-30),
2.69e2.86 (m, 2H, H-10), 4.01e4.07 (buried m, 1H, H-6A),
4.70e4.72 (buried m, 1H, H-6B), 4.80e4.82 (buried m, 1H, H-2),
5.09e5.19 (m, 2H, CH2Ph), 7.28e7.37 (m, 5H, PhH); 13C NMR (CDCl3,
liquid (yield after separation of the diastereomers as mentioned in
28
the general procedures IIIaec); [
a
]
D
ꢀ63.4 (c 0.05, CHCl3) {lit.35j
33
[a
]
þ56.0 (c 1.15, CHCl3) for (RS)-isomer, 85% ee}; IR (neat)
D
100 MHz):
d
18.8 (C-4), 25.2 (C-5), 28.3 (C-3), 30.1 (C-30), 39.8 (C-
3426, 2971, 1694, 1673 cmꢀ1 1H NMR (CDCl3, 400 MHz):
;
10), 44.3 (C-6), 47.5 (C-2), 65.3 (OCH2Ph), 126.9 (PhCH), 127.6
(PhCH), 127.9 (PhCH), 128.5 (PhCH), 128.5 (PhCH), 136.7 (PhC),
155.3 (NCO), 206.9 (C-20).
d
1.20e1.82 (m, 11H, H-4, H-5, H-3, H-30, H-10A, OH), 1.45 (s, 9H,
tBuH), 2.67e2.85 (m, 2H, H-10B, H-6A), 3.80e3.83 (buried m, 1H, H-
6B), 3.90e3.94 (buried m, 1H, H-2), 4.30e4.33 (buried m, 1H, H-20);
13C NMR (CDCl3,100 MHz): 19.0 (C-4), 23.5 (C-30), 25.5 (C-3 and C-
d
4.3.17. tert-Butyl (2S)-2-(2-oxopropyl)piperidine-1-carboxylate
(18b). Following the general procedure II, compound 21b (0.25 g,
1.0 mmol) on Nef reaction gave 18b (0.15 g, 60%) as a thick yellow
5), 29.0 (OeC(CH3)3), 29.6 (C-10), 39.9 (C-6), 40.5 (C-2), 66.5 (C-20),
79.7 (OCMe3), 156.5 (NCO).
liquid; [
a
]
28 ꢀ14.0 (c 0.1, CHCl3) {lit.27j
[a]
33 ꢀ12.7 (c 0.22, CHCl3)}; IR
4.3.22. Ethyl (2S)-2-[(2S)-2-hydroxypropyl]piperidine-1-carboxylate
(30c). Following the general procedures IIIaec, reduction of 18c
(0.23 g, 1.0 mmol) gave 30c (0.23 g, 95%) as a thick liquid (yield
D
D
(neat) 2974, 1720, 1680 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 1.43 (s,
t
9H, BuH), 1.22e1.60 (m, 6H, H-4, H-5, H-3), 2.16 (s, 3H, H-30),
2.61e2.63 (m, 2H, C-10), 2.72e2.78 (m, 1H, H-6A), 3.94 (br s, 1H, H-
6B), 4.60e4.70 (buried m, 1H, H-2); 13C NMR (CDCl3, 100 MHz):
after separation of the diastereomers as mentioned in the general
28
procedures IIIaec); [
a
]
ꢀ16.0 (c 0.04, CHCl3); IR (neat) 3450,
D
d
18.8 (C-4), 25.2 (C-5), 28.3 (OeC(CH3)3), 28.4 (C-3), 30.0 (C-30), 39.3
2900, 1680 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d 1.22e1.90 (m, 12H,
(C-10), 44.2 (C-6), 47.2 (C-2), 79.6 (OCMe3), 154.7 (NCO), 207.1 (C-20).
H-4, H-5, H-3, OCH2CH3, H-30), 1.90e1.97 (m, 1H, H-10A), 2.62e2.69
(m, 1H, H-10B), 3.10e3.20 (buried m, 1H, H-6), 3.40e3.60 (buried
m, 1H, H-6B), 3.92e3.95 (m, 1H, H-2), 4.05e4.10 (q, J¼6.8 Hz, 2H,
OCH2CH3), 4.40e4.42 (buried m, 1H, H-20); 13C NMR (CDCl3,
4.3.18. Ethyl (2S)-2-(2-oxopropyl)piperidine-1-carboxylate
(18c). Following the general procedure II, compound 21c (0.24 g,
1.0 mmol) on Nef reaction gave 18c (0.13 g, 60%) as a pale yellow
100 MHz):
d
13.6 (C-30), 18.1 (C-4), 21.4 (OCH2CH3), 24.4 (C-5), 28.3
viscous liquid;Rf¼0.35 (hexane/EtOAc, 8:2); [
a]
D
28 ꢀ10.6 (c0.1, CHCl3);
(C-3), 38.1 (C-10), 38.3 (C-6), 46.1 (C-2), 60.7 (OCH2CH3), 62.3 (C-20)
IR (neat) 2970,1710,1690 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
1.21 (t,
156.1 (NCO).
J¼4 Hz, 3H, CH2CH3),1.35e1.60 (m, 6H, H-4, H-5, H-3), 2.15 (s, 3H, H-
30), 2.60e2.65 (m, 2H, H-10), 2.76e2.82 (m, 1H, H-6A), 3.90e4.00
(buried m,1H, H-6B), 4.07e4.08(m, 2H, OCH2CH3), 4.70e4.80 (buried
4.3.23. Ethyl (2S)-2-[(2R)-2-hydroxypropyl]piperidine-1-carboxylate
(27c). Following the general procedures IIIaec, reduction of 18c
(0.23 g, 1.0 mmol) gave 27c (0.23 g, 95%) as a thick liquid (yield after
m,1H, H-2); 13C NMR (CDCl3, 100 MHz):
d 13.6 (OCH2CH3),17.8 (C-4),
24.2 (C-5), 27.3 (C-3), 29.0 (C-30), 38.5 (C-20), 43.2 (C-6), 46.3 (C-2),
separation of the diastereomers as mentioned in the general pro-
28
60.2 (OCH2CH3), 154.5 (NCO), 205.9 (C-20); HRMS: m/z calcd for
cedure IIIaec); [
a
]
ꢀ56.8 (c 0.2, CHCl3); IR (neat) 3510, 2994,
D
C
11H19NO3Na [MþNa]þ: 236.1263; found: 236.1261.
1680, 1670 cmꢀ1 1H NMR (CDCl3, 400 MHz):
; d 1.22e1.67 (m, 12H,
H-30, H-4, H-5, H-3, OCH2CH3), 1.84e1.87 (m, 1H, eOH), 2.15e2.35
(m, 2H, H-10), 2.84e2.91 (m, 1H, H-6A), 3.81e3.86 (m, 1H, H-6B),
4.00e4.03 (m, 1H, H-2), 4.13 (m, 2H, OCH2CH3), 4.38e4.39 (m, 1H,
4.3.19. Benzyl (2S)-2-[(2S)-2-hydroxypropyl]piperidine-1-
carboxylate (30a). Following the general procedures IIIaec, re-
duction of 18a (0.29 g, 1.0 mmol) gave 30a (0.27 g, 95%) as a thick
H-20); 13C NMR (CDCl3, 100 MHz):
d
13.6 (C-30), 17.9 (C-6), 25.4
liquid (yield after separation of the diastereomers as mentioned in
(OCH2CH3), 25.4 (C-5), 29.0 (C-3) 39.2 (C-10), 39.5 (C-6), 49.5 (C-2),
61.3 (OCH2CH3), 65.1 (C-20), 155.0 (NCO).
28
the general procedures IIIaec); [
a]
ꢀ25.82 (c 0.1, CHCl3) {lit.35l
D
25
[
a]
ꢀ28.52 (c 2.920, CHCl3)}; IR (neat) 3420, 2970, 1690,
D
1675 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
1.19e1.76 (m, 10H, H-4, H-
4.3.24. 1-[(2S)-Piperidin-2-yl]acetone (3). Compound 18a (0.28 g,
1.0 mmol) was dissolved in EtOH and hydrogenated over Pd/C
(1 atm) at rt for 6 h. The reaction mixture was then filtered and
concentrated under reduced pressure to give 3 as a colourless thick
liquid. It was then treated with 5 N HCl (2 mL) in chloroform
(10 mL) for 2 h at rt and dried under reduced pressure. The crude
mass was subjected to column chromatography (SiO2, chloroform/
methanol, 9:1) to give 3$HCl (0.13 g, 70%) as a pale yellow thick
5, H-3, H-30, OH), 2.00 (t, J¼13.2 Hz, 1H, H-10A), 2.77 (t, J¼12.8 Hz,
1H, H-10B), 3.20e3.33 (buried m, 1H, H-20), 3.50e3.55 (buried m,
1H, H-6A), 4.05e4.08 (m, 1H, H-6B), 4.40e4.60 (buried m, 1H, H-2),
5.16e5.19 (m, 2H, PhCH2), 7.30e7.37 (m, 5H, PhCH); 13C NMR
(CDCl3, 100 MHz):
d
19.1 (C-4), 22.5 (C-30), 25.4 (C-5), 29.3 (C-3),
39.3 (C-10), 39.3 (C-6), 47.4 (C-2), 65.2 (C-20), 67.5 (PhCH2), 126.9
(PhCH), 127.9 (PhCH), 128.1 (PhCH), 128.3 (PhCH), 128.5 (PhCH),
136.5 (PhC), 156.8 (NCO).
liquid; IR (neat) 3310, 1710 cmꢀ1; [
a
]
28 ꢀ16.2 (c 0.05, EtOH) {lit.27k
D
23
[a
]
ꢀ9.2 (c 1.2, EtOH)}; ee 99%; 1H NMR (CDCl3, 400 MHz):
D
4.3.20. Benzyl (2S)-2-[(2R)-2-hydroxypropyl]piperidine-1-
carboxylate (27a). Following the general procedures IIIaec,
d
1.41e1.90 (m, 6H, H-5, H-5, H-3), 2.15 (s, 3H, H-30), 2.70e2.90 (m,
2H, H-10), 3.21e3.27 (m, 1H, H-6A), 3.35e3.45 (m, 2H, H-6B, H-5);
Please cite this article in press as: Bhat, C.; Tilve, S. G., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.055

12
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
13C NMR (CDCl3, 100 MHz):
d
24.3 (C-4), 25.4 (C-5), 30.6 (C-30), 31.9
(0.83 mL, 11.0 mmol) gave the product 22a (0.24 g, 80% for two
steps) as a pale yellow thick liquid; Rf¼0.40 (hexane/EtOAc, 8:2);
(C-3), 46.4 (C-10), 49.9 (C-6), 52.37 (C-2), 208.4 (CO).
26
[a
]
ꢀ39.1 (c 0.14, CHCl3); IR (neat) 3100, 2989, 2934, 2800,1690,
D
4.3.25. 1-[(2S)-1-Methylpiperidin-2-yl]acetone (4). Following the
similar procedure as described for compound 1, compound 18c
(0.22 g, 1.0 mmol) gave compound 4$HCl (0.09 g, 60%) as a pale
1520 and 1348 cmꢀ1 1H NMR (CDCl3, 400 MHz):
; d 0.90e1.81 (m,
9H, H-4, H-5, H-3, H-40), 2.48e2.62 (m, 2H, H-30), 2.89e2.96 (m, 1H,
H-6A), 4.03e4.06 (m, 1H, H-6B), 5.00e5.08 (m, 3H, H-2, CH2Ph),
28
yellow thick liquid (SiO2, CHCl3/MeOH, 9:1); [
a
]
ꢀ25.0 (c 0.2,
7.18e7.31 (m, 6H, H-10, PhH); 13C NMR (CDCl3, 100 MHz):
d 12.6 (C-
D
H2O); IR (neat) 3390, 2920, 1716 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
1.20e1.70 (m, 6H), 1.94 (s, 3H, H-30), 2.32 (s, 3H, NCH3), 2.32e2.51
(m, 2H, H-10), 2.80e2.95 (buried m, 1H, H-6A), 3.03e3.08 (m, 2H, H-
40), 19.4 (C-4), 20.2 (C-5), 24.9 (C-3), 29.9 (C-30), 40.3 (C-6), 48.5 (C-
2), 67.6 (CH2Ph), 127.9 (PhCH), 128.1 (PhCH), 128.2 (PhCH), 128.6
(PhCH), 128.7 (PhCH), 130.9 (C-10), 136.3 (PhC), 155.7 (C-20), 155.8
(NCO); HRMS: m/z calcd for C17H22N2O4Na [MþNa]þ: 341.1477;
found: 341.1478.
d
6B and H-2); 13C NMR (CDCl3, 100 MHz):
d 23.1 (C-4), 24.2 (C-5),
29.6 (C-3), 29.8 (C-30), 42.0 (C-2), 44.5 (C-10), 55.0 (C-6), 59.0
(NCH3), 205.5 (CO).
4.3.31. tert-Butyl (2R)-2-[(1Z)-2-nitrobut-1-en-1-yl]piperidine-1-
carboxylate (22b). Following the general procedure I, Henry-
olefination of compound 24b (0.22 g, 1.0 mmol) with nitroethane
(0.83 mL, 11.0 mmol) gave the product 22b (0.24 g, 85% for two
4.3.26. (2S)-1-[(2S)-Piperidin-2-yl]propan-2-ol (7). Compound 30a
(0.25 g, 0.9 mmol) was dissolved in EtOH and directly hydrogenated
(1 atm) over Pd/C (0.025 g) for 6 h at rt. The reaction mixture was
then filtered and dried under reduced pressure to give the product
7 (0.12 g, 95%) as colourless crystalline compound turning viscous
steps) as a pale yellow thick liquid; Rf¼0.45 (hexane/EtOAc, 8:2);
26
[
a
]
ꢀ46.8 (c 0.05, CHCl3); IR (neat) 2964, 2900, 1690, 1520 and
D
28
25
on exposure to atmosphere; [
a
]
þ27.5 (c 0.07, EtOH) {lit.35l
[
;
a
]
1340 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
1.06 (t, J¼7.2 Hz, 3H, H-40),
D
þ28.4 (c 1.13, EtOH)}; ee 99%; IR (neat) 3375, 2960, 1418 cmꢀ1
1DH
1.38 (s, 9H, BuH), 1.41e1.80 (m, 6H, H-4, H-5, H-3), 2.58e2.68 (m,
2H, C-30), 2.80e2.87 (m, 1H, H-6A), 3.94e3.97 (m, 1H, H-6B),
4.90e4.98 (buried m, 1H, H-2), 7.20 (d, J¼3.2 Hz, 1H, H-10); 13C NMR
t
NMR (CDCl3, 400 MHz):
d
1.11 (d, J¼7.2 Hz, 3H, H-30), 1.28e1.78 (m,
8H, H-4, H-5, H-3, H-10), 1.50e1.60 (m, 3H), 2.50e2.57 (m, 1H, H-
6A), 2.85e2.89 (m, 1H, H-6B), 3.03e3.05 (m,1H, H-2), 3.50 (br s, 2H,
OH and NH), 4.02e4.10 (m, 1H, H-20); 13C NMR (CDCl3, 100 MHz):
(CDCl3, 100 MHz):
d
12.7 (C-40), 19.6 (C-4), 20.2 (C-5), 25.1 (C-3),
28.4 (OC(CH3)3), 30.0 (C-30), 40.1 (C-6), 48.1 (C-2), 80.3 (OC(CH3)3),
131.7 (C-10), 154.4 (C-20), 154.5 (NCO); HRMS: m/z calcd for
d
23.6 (C-30), 24.4 (C-4), 25.4 (C-5), 30.9 (C-3), 43.3 (C-10), 46.6 (C-6),
54.8 (C-2), 64.8 (C-20).
C
14H24N2O4Na [MþNa]þ: 307.1634; found: 307.1637.
4.3.27. (2R)-1-[(2S)-Piperidin-2-yl]propan-2-ol (8). Following the
same procedure as for (SS)-isomer compound 27a (0.25 g,
0.9 mmol) on hydrogenation gave 8 (0.12 g, 95%) as a pale yellow
crystalline solid becoming viscous on exposure to atmosphere;
4.3.32. Ethyl (2R)-2-[(1Z)-2-nitrobut-1-en-1-yl]piperidine-1-
carboxylate (22c). Following the general procedure I, Henry-
olefination of compound 24c (0.18 g, 1.0 mmol) with nitroethane
(0.83 mL, 11.0 mmol) gave the product 22c (0.20 g, 80% for two
[
a
]
28 ꢀ15.6 (c 0.05, EtOH) {lit.35l
[
a
]
23 ꢀ16.2 (c 1.5, MeOH)}; ee 99%;
steps) as a colourless thick liquid; Rf¼0.35 (hexane/EtOAc, 8:2);
D
D
26
IR (neat) 3350, 2924 cmꢀ1
;
1H NMR (CDCl3, 400 MHz):
d
1.06 (d,
[a
]
ꢀ50.9 (c 0.04, CHCl3); IR (neat) 2960, 1690, 1550 and
D
J¼6 Hz, 3H, H-30), 1.18e1.78 (m, 8H, H-4, H-5, H-3, H-10), 2.49e2.69
(m, 1H, H-6A), 2.96e3.01 (m, 1H, H-6B), 3.30 (br s, 2H, NH and OH),
1360 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
1.07 (t, J¼6 Hz, 3H, H-40),
1.89 (t, J¼7.2 Hz, 3H, CH2CH3), 1.37e1.82 (m, 6H, H-4, H-5, H-3),
2.57e2.72 (m, 2H, H-30), 2.86e2.93 (m, 1H, H-6A), 4.00e4.09 (m,
2H, H-6B, OCH2CH3), 4.95e5.01 (buried m, 1H, H-2), 7.19 (d,
3.91e3.95 (m, 1H, H-20); 13C NMR (CDCl3, 100 MHz):
d
23.9 (C-30),
24.4 (C-4), 27.0 (C-5), 34.1 (C-3), 44.1 (C-10), 45.9 (C-6), 58.3 (C-2),
69.1 (C-20).
J¼2.4 Hz, 1H, H-10); 13C NMR (CDCl3, 100 MHz):
d
12.7 (C-40), 14.6
(OCH2CH3), 19.5 (C-4), 20.2 (C-5), 24.9 (C-3), 29.9 (C-30), 40.1 (C-6),
48.3 (C-2), 61.2 (OCH2CH3), 131.1 (C-10), 154.2 (C-20), 155.5 (NCO);
HRMS: m/z calcd for C12H20N2O4Na [MþNa]þ: 279.1321; found:
279.1321.
4.3.28. (2S)-1-[(2S)-1-Methylpiperidin-2-yl]propan-2-ol
(9). Following the similar procedure as for compound 5, compound
30c (0.1 g, 0.5 mmol) gave 9 (0.06 g, 90%) as a pale yellow thick
liquid; [
a
]
28 ꢀ35.0 (c 0.06, EtOH) {lit.35j
[
a
]
D þ34.5 (c 0.85, EtOH) for
D
(RR)-isomer}; ee 99%; IR (neat) 3380, 2967, 1420 cmꢀ1
;
1H NMR
4.3.33. Benzyl (2R)-2-(2-oxobutyl)piperidine-1-carboxylate
(19a). Following the general procedure II, Nef reaction on 22a
(CDCl3, 400 MHz):
d
1.10 (d, J¼6 Hz, 3H, H-30), 1.20e1.82 (m, 8H, H-
26
4, H-5, H-3, H-10), 2.35 (s, 3H, NCH3), 2.39e2.42 (m, 1H, H-6A),
2.57e2.60 (m,1H, H-6B), 2.90e2.95 (m,1H, H-2), 3.60 (br s,1H, OH),
(0.32 g, 1.0 mmol) gave 19a (0.22 g, 75%) as a thick liquid; [a]
D
ꢀ10.1 (c 0.32, CHCl3); IR (neat) 2974, 1710, 1680 cmꢀ1
;
1H NMR
3.75e3.91 (m, 1H, H-20); 13C NMR (CDCl3, 100 MHz):
d
20.9, 22.6,
(CDCl3, 400 MHz):
d
0.92 (t, J¼7.2 Hz, 3H, H-40),1.35e1.61 (m, 6H, H-
24.1, 26.2, 30.0, 39.1, 39.3, 50.2, 60.8, 62.5, 68.0.35j
4, H-5, H-3), 2.34e2.42 (m, 2H, H-30), 2.53e2.65 (m, 2H, H-10),
2.76e2.82 (m, 1H, H-6A), 3.96e3.99 (m, 1H, H-6B), 4.71e4.72 (m,
1H, H-2), 5.04 (s, 2H, PhCH2), 7.21e7.30 (m, 5H); 13C NMR (CDCl3,
4.3.29. (2R)-1-[(2S)-1-Methylpiperidin-2-yl]propan-2-ol
(10). Similar procedure followed as for compound 5, compound
27c (0.1 g, 0.5 mmol) furnished the product 10 (0.06 g, 90%) as
100 MHz): d
7.6 (C-40), 18.8 (C-4), 25.2 (C-5), 28.3 (C-3), 39.8 (C-30),
42.9 (C-10), 47.6 (C-2), 67.1 (PhCH2), 126.9 (PhCH), 127.8 (PhCH),
127.9 (PhCH), 128.4 (PhCH), 128.5 (PhCH), 136.8 (PhC), 155.3 (NCO),
209.5 (C-20).
a thick colourless liquid; [
a
]
28 ꢀ70.0 (c 0.05, EtOH) {lit.35j
[
a
]
D þ67.5
D
(c 0.65, EtOH) for (SR)-isomer}; ee 99%; IR (neat) 3362, 2964,
1418 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
1.10 (d, J¼6.4 Hz, 3H, H-30),
1.14e1.82 (m, 8H, H-4, H-5, H-3, H-10), 2.35 (s, 3H, NCH3), 2.38e2.44
(m, 1H, H-6A), 2.55e2.58 (m, 1H, H-6B), 2.90e2.95 (m, 1H, H-2),
4.3.34. tert-Butyl (2R)-2-(2-oxobutyl)piperidine-1-carboxylate
(19b). Following the general procedure II, Nef reaction on 22b
3.85e3.93 (m, 1H, H-20); 13C NMR (CDCl3, 100 MHz):
d
20.8 (C-4),
(0.28 g, 1.0 mmol) gave 19b (0.18 g, 70%) as a thick liquid; Rf¼0.25
26
22.6 (C-5), 24.1 (C-30), 26.1 (C-3), 39.2 (C-10), 39.2 (C-2), 51.8 (C-6),
(hexane/EtOAc, 8:2); [
a
]
D
ꢀ10.5 (c 0.18, CHCl3); IR (neat) 2994,
60.8 (C-20), 68.1 (NCH3).
1711, 1680 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
0.96 (t, J¼7.2 Hz, 3H,
H-40), 1.37 (s, 9H, tBuH), 1.30e1.55 (m, 6H, H-4, H-5, H-3), 2.33e2.57
(m, 4H, H-10, H-30), 2.69e2.75 (m, 1H, H-6A), 3.89e3.99 (buried m,
1H, H-6B), 4.60e4.64 (buried m, 1H, H-2); 13C NMR (CDCl3,
4.3.30. Benzyl (2R)-2-[(1Z)-2-nitrobut-1-en-1-yl]piperidine-1-
carboxylate (22a). Following the general procedure I, Henry-
olefination of compound 24a (0.25 g, 1.0 mmol) with nitroethane
100 MHz): d
7.6 (C-40), 18.9 (C-4), 25.3 (C-5), 28.38 (OC(CH3)3), 28.5
Please cite this article in press as: Bhat, C.; Tilve, S. G., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.055

C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
13
(C-3), 36.1 (C-30), 39.3 (C-10), 42.9 (C-6), 47.4 (C-2), 79.6 (OC(CH3)3),
154.7 (NCO), 209.7 (CO); HRMS: m/z calcd for C14H25NO3Na
[MþNa]þ: 278.1732; found: 278.1735.
(C-5), 31.0 (C-3), 32.4 (C-30), 40.9 (C-10), 45.4 (C-6), 58.2 (C-2),
73.7 (C-20).
4.3.40. Benzyl (2S)-2-[(E)-2-nitrovinyl]pyrrolidine-1-carboxylate
(44a). Following the general procedure I, Henry-olefination of
compound 23a (0.23 g, 1.0 mmol) with nitromethane (0.66 mL,
11.0 mmol) gave 44a (0.24 g, 90% for two steps) as a pale yellow
4.3.35. Ethyl (2R)-2-(2-oxobutyl)piperidine-1-carboxylate
(19c). Following the general procedure II, Nef reaction on 22c
(0.32 g, 1.0 mmol) gave 19c (0.15 g, 60%) as a thick liquid; Rf¼0.20
26
(hexane/EtOAc, 8:2); [
a
]
D
ꢀ10.1 (c 0.05, CHCl3); IR (neat) 2990,
thick liquid; Rf¼0.55 (hexane/EtOAc, 8:2); IR (neat) 2989, 2934,
26
1718, 1685 cmꢀ1; 1H NMR (CDCl3, 400 MHz):
d
0.96 (t, J¼7.2 Hz, 3H,
2800,1690, 1520 and 1350 cmꢀ1; [
a
]
ꢀ76.1 (c 0.13, CHCl3); 1H
D
H-40), 1.17 (t, J¼6.8 Hz, 3H, OCH2CH3), 1.31e1.62 (m, 6H, H-4, H-5, H-
3), 2.34e2.49 (m, 2H, H-30), 2.53e2.65 (m, 2H, H-10), 2.73e2.79 (m,
1H, H-6A), 3.93e3.95 (m, 1H, H-6B), 4.03 (q, J¼7.2 Hz, 2H,
NMR (CDCl3, 400 MHz): d 1.76e2.11 (m, 4H, H-4, H-3), 3.39e3.45
(m, 2H, H-5), 4.46e4.54 (m, 1H, H-2), 4.49e5.09 (m, 2H, OCH2Ph),
6.76e6.95 (m, 1H, H-20), 7.00e7.04 (m, 1H, H-10), 7.21e7.28 (m, 5H,
OCH2CH3), 4.67e4.68 (m, 1H, H-2); 13C NMR (CDCl3, 100 MHz):
d
7.7
PhH); 13C NMR (CDCl3, 100 MHz):
d 23.4 (C-4), 31.2 (C-3), 46.7 (C-5),
(C-40), 14.6 (OCH2CH3), 18.8 (C-4), 25.2 (C-5), 28.3 (C-3), 36.1 (C-30),
39.5 (C-10), 42.9 (C-6), 47.4 (C-2), 61.3 (OCH2CH3), 115.5 (NCO),
209.6 (C-20); HRMS: m/z calcd for C12H21NO3Na [MþNa]þ:
250.1419; found: 250.1418.
55.2 (C-2), 67.3 (PhCH2), 127.9 (PhCH), 128.2 (PhCH), 128.3 (PhCH),
128.6 (PhCH), 136.0 (PhC), 140.0 (C-10), 141.4 (C-20), 154.6 (NCO);
HRMS: m/z calcd for C14H16N2O4Na [MþNa]þ: 299.1008; found:
299.1004.
4.3.36. Benzyl (2S)-2-[(2S)-2-hydroxybutyl]piperidine-1-carboxylate
(31a). Following the general procedures IIIaec, compound 19a
(0.29 g, 1.0 mmol) gave 31a (0.27 g, 95%) as a colourless thick liquid;
4.3.41. Benzyl (2S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate
(38a). To a solution of ammonium acetate (4.0 g, 52 mmol) in
MeOH/H2O (4:3, 16 mL) was added 15% aq TiCl3 (3.6 mL, 3.5 mmol)
followed by a solution of 44a (0.28 g, 1.0 mmol) in MeOH (5 mL) at
0 ꢂC. After stirring for 3 h at rt, the mixture was extracted with ether
(20 mLꢃ3). The ether layer was washed with saturated aq NaHCO3
(15 mLꢃ4) and saturated aq NaCl (20 mLꢃ2), dried over anhyd
Na2SO4 and concentrated under reduced pressure. The crude
product was immediately treated with NaBH4 (0.37 g, 1.0 mmol) in
10 mL MeOH. After 1 h stirred at rt, the reaction mixture was
concentrated and diluted with ethyl acetate (30 mL), washed with
dil HCl (10 mLꢃ3). The crude mixture was column chromato-
[
a
]
26 ꢀ27.9 (c 0.08, CHCl3); IR (neat) 3430, 2990, 1680, 1660 cmꢀ1
;
D
1H NMR (CDCl3, 400 MHz):
d
0.70e0.90 (3H, m, H-40), 1.10e1.97 (m,
10H, H-4, H-5, H-3, H-10, H-30), 2.59e2.71 (m, 2H, H-6A, OH),
3.10e3.20 (buried m, 1H, H-6B), 3.96e3.99 (m, 1H, H-20), 4.42e4.47
(m, 1H, H-20), 5.02e5.13 (m, 2H, PhCH2), 7.25e7.30 (m, 5H, PhH);
13C NMR (CDCl3, 100 MHz): 10.5 (C-40), 19.2 (C-4), 25.5 (C-5), 29.2
d
(C-3), 29.4 (C-30), 37.1 (C-10), 39.3 (C-6), 47.3 (C-2), 67.5 (OCH2Ph),
68.6 (C-20), 127.9 (PhCH), 128.1 (PhCH), 128.4 (PhCH), 128.5 (PhCH),
136.6 (PhC), 156.8 (NCO).
graphed (SiO2, hexane/EtOAc/7:3) to give the title compound 38a
26
4.3.37. Benzyl (2S)-2-[(2R)-2-hydroxybutyl]piperidine-1-carboxylate
(28a). Following the general procedures IIIaec, compound 19a
(0.29 g, 1.0 mmol) gave 28a (0.27 g, 95%) as a colourless thick
(0.14 g, 55%) as a colourless thick liquid; [
a
]
D
ꢀ7.0 (c 0.04, CHCl3)
{lit.41a
[
a
]
D ꢀ7.6 (c 1.1, CHCl3)}; IR (neat) 3400, 2900, 1690 cmꢀ1; 1H
NMR (CDCl3, 400 MHz): d
1.52e2.05 (m, 6H, H-4, H-3, H-10),
26
liquid; [
a
]
ꢀ46.8 (c 0.13, CHCl3); IR (neat) 3400, 2995, 1680,
3.41e3.45 (m, 2H, H-20), 3.55e3.61 (m, 2H, H-5), 4.18e4.26 (m, 1H,
H-2), 5.15e5.16 (m, 2H, PhCH2), 7.33e7.38 (m, 5H, PhCH); 13C NMR
1670 cmꢀ1D
; d 0.70e0.84 (buried m,
1H NMR (CDCl3, 400 MHz):
3H, H-40), 1.32e1.70 (m, 10H, H-4, H-5, H-3, H-30, H-10), 2.79e2.85
(m, 1H, H-6A), 3.40e3.45 (buried m, 1H, H-6B), 3.95e3.97 (m, 1H,
H-2), 4.36e4.37 (m, 1H, H-20), 5.01e5.08 (m, 2H, CH2Ph),
(CDCl3, 100 MHz): d
23.6 (C-4), 31.1 (C-3), 38.2 (C-10), 46.3 (C-5),
54.3 (C-2), 59.0 (C-20), 67.1 (PhCH2), 126.8 (PhCH), 127.0 (PhCH),
127.5 (PhCH), 135.6 (PhC), 155.7 (NCO).
7.20e7.28 (m, 5H, PhH); 13C NMR (CDCl3, 100 MHz):
d
10.0 (C-40),
18.9 (C-4), 25.5 (C-5), 29.2 (C-3), 30.3 (C-30), 37.6 (C-10), 39.6 (C-6),
48.9 (C-2), 67.1 (CH2Ph), 71.4 (C-20), 127.9 (PhCH), 128.0 (PhCH),
128.1 (PhCH), 128.2 (PhCH), 128.3 (PhCH), 136.8 (PhC), 155.9
(NCO).
4.3.42. Benzyl (2S)-2-[(E)-2-nitrovinyl]piperidine-1-carboxylate
(44b). Following the general procedure I, Henry-olefination of
compound 24a (0.25 g, 1.0 mmol) with nitromethane (0.66 mL,
11.0 mmol) gave the product 44b (0.26 g, 90% for two steps) as
26
a pale yellow thick liquid; Rf¼0.65 (hexane/EtOAc, 8:2); [
a]
4.3.38. (2S)-1-[(2S)-Piperidin-2-yl]butan-2-ol (11). Following the
similar procedure as for compound 2, compound 31a (0.29 g,
ꢀ64.0 (c 0.05, CHCl3); IR (neat) 2900, 2800,1690, 1520, 1340 cmꢀD1
;
1H NMR (CDCl3, 400 MHz):
d 1.34e1.67 (m, 4H, H-4, H-5),
26
1.0 mmol) gave 11 (0.15 g, 95%) as a colourless thick liquid; [
a
]
1.76e1.77 (m, 2H, H-3), 2.78e2.84 (m, 1H, H-6A), 4.00e4.06 (m,
1H, H-6B), 5.04e5.11 (m, 3H, H-2, PhCH2), 6.86 (d, J¼13.2 Hz, 1H,
H-20), 7.14e7.19 (dd, J¼8.8 and 4.8 Hz, 1H, H-10), 7.26e7.32 (m, 5H,
D
þ18.6 (c 0.05, EtOH) {lit.35j
[
a
]
D þ17.5 (c, 0.80, EtOH)}; ee 99%; IR
(neat) 3370, 2970 cmꢀ1
;
1H NMR (CDCl3, 400 MHz):
d
0.90 (t,
J¼7.2 Hz, 3H, H-40), 1.17e1.93 (m, 10H, H-4, H-5, H-3, H-30, H-10),
2.80e2.83 (m, 1H, H-6A), 3.23e3.24 (m, 1H, H-6B), 3.40e3.43
(m, 1H, H-2), 3.56e3.67 (m, 1H, H-20 and NH), 3.87 (br s, 1H,
PhH); 13C NMR (CDCl3, 100 MHz):
d 19.7 (C-4), 24.9 (C-5), 28.8 (C-
3), 40.6 (C-6), 49.6 (C-2), 67.7 (PhCH2), 128.0 (PhCH), 128.3 (PhCH),
128.6 (PhCH), 136.2 (PhC), 140.6 (C-10), 140.9 (C-20), 155.3 (NCO);
HRMS: m/z calcd for C14H16N2O4Na [MþNa]þ: 313.1164; found:
313.1163.
OH); 13C NMR (CDCl3, 100 MHz):
d
10.1 (C-40), 22.1 (C-4), 22.6 (C-
5), 28.8 (C-3), 30.2 (C-30), 39.3 (C-10), 45.1 (C-6), 54.7 (C-2), 67.9
(C-20).
4.3.43. Benzyl
(2S)-2-(2-hydroxyethyl)piperidine-1-carboxylate
4.3.39. (2R)-1-[(2S)-Piperidin-2-yl]butan-2-ol (12). Similar pro-
cedure was followed as for compound 2, compound 28a (0.29 g,
(38b). Following the similar procedure as for compound 38a,
compound 44b (0.29 g, 1.0 mmol) gave 38b (0.15 g, 55%) as a pale
1.0 mmol) gave 12 (0.15 g, 95%) as a colourless thick liquid; [
a
]
yellow thick liquid; [
a
]
26 ꢀ20.2 (c 0.06, CHCl3) {lit.41d
[
a
]
25 ꢀ18.5 (c
26
D
D
D
ꢀ7.6 (c 0.06, EtOH) {lit.35j
[
a
]
;
ꢀ6.6 (c 0.80, EtOH)}; ee 99%; IR
1.0, CHCl3)}; IR (neat) 3400, 2900, 1690 cmꢀ1
;
1H NMR (CDCl3,
D
(neat) 3370, 2980, 1410 cmꢀ1
1H NMR (CDCl3, 400 MHz):
d
0.85
400 MHz): d
1.35e1.92 (m, 8H, H-4, H-5, H-3, H-10), 2.65e2.71 (m,
(t, J¼7.2 Hz, 3H, H-40), 1.31e1.79 (10H, H-4, H-5, H-3, H-30, H-10),
2.62e2.68 (m, 1H, H-6A), 2.82e2.87 (m, 1H, H-6B), 3.12e3.15 (m,
1H, H-2), 3.68e3.74 (m, 1H, H-20), 4.60 (br s, 2H, OH and
2H, H-20), 3.20e3.30 (m, 1H, H-6A), 3.51e3.54 (m, 1H, H-6B),
3.97e4.00 (m, 1H, H-2), 4.40e4.41 (m, 1H, OH), 5.03e5.06 (m, 2H,
PhCH2), 7.23e7.28 (m, 5H, PhH); 13C NMR (CDCl3, 100 MHz):
d
19.1
NH); 13C NMR (CDCl3, 100 MHz):
d
9.9 (C-40), 23.6 (C-4), 25.0
(C-4), 25.2 (C-5), 29.2 (C-3), 32.3 (C-10), 39.3 (C-6), 46.9 (C-2), 58.5
Please cite this article in press as: Bhat, C.; Tilve, S. G., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.055

14
C. Bhat, S.G. Tilve / Tetrahedron xxx (2013) 1e15
(C-20), 67.4 (PhCH2), 127.8 (PhCH), 127.9 (PhCH), 128.0 (PhCH), 128.1
10. Hollingsworth, R. I.; Wang, G. Chem. Rev. 2000, 100, 42267.
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for some recent examples of asymmetric conjugate addition reactions
(PhCH), 128.5 (PhCH), 136.5 (PhC), 156.7 (NCO).
Acknowledgements
We acknowledge IISc, Bangalore, for 1H NMR and HRMS facili-
ties and DST, New Delhi, for financial assistance. We also thank NIO,
Goa for optical activity measurements. One of authors (C.B.) is
thankful to CSIR, New Delhi, for awarding Senior Research
Fellowship.
Supplementary data
with nitrogen nucleophiles to furnish b-amino ketones see: (j) Myers, J. K.;
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.055.
Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959; (k) Guerin, D. J.; Miller, S. J.
J. Am. Chem. Soc. 2002, 124, 2134; (l) Sibi, M. P.; Prabagaran, N.; Ghorpade,
S. G.; Jasperse, C. P. J. Am. Chem. Soc. 2003, 125, 11796; (m) Yamigawa, N.;
Qin, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419; (n)
Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
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Please cite this article in press as: Bhat, C.; Tilve, S. G., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.05.055