An intramolecular Michael reaction strategy for the synthesis of 2,6-disubstituted-3-piperidinols

Article abstract of DOI:10.1016/S0040-4020(02)00680-4

A new synthetic strategy for 2,6-disubstituted-3-hydroxypiperidines via intramolecular Michael reaction of an α-amino-β-hydroxy-δ-acrylate is described. The latter was derived from L-alanine in a few steps via the key intermediacy of an enantiopure γ-amino-β-keto sulfone.

Full text of DOI:10.1016/S0040-4020(02)00680-4

Tetrahedron 58 (2002) 7983–7986
An intramolecular Michael reaction strategy for the synthesis of
2,6-disubstituted-3-piperidinols
*
Saumitra Sengupta and Somnath Mondal
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
Dedicated in memory of Dr Darshan Ranganathan
Received 13 February 2002; revised 22 May 2002; accepted 20 June 2002
Abstract—A new synthetic strategy for 2,6-disubstituted-3-hydroxypiperidines via intramolecular Michael reaction of an a-amino-b-
hydroxy-d-acrylate is described. The latter was derived from L-alanine in a few steps via the key intermediacy of an enantiopure g-amino-b-
keto sulfone. q 2002 Published by Elsevier Science Ltd.
The Cassia and Prosopis species produce a number of 2,6-
disubstituted-3-piperidinol alkaloids 1 (e.g. cassine, azimic
acid, spectaline, julifloridine, prosopinine, etc.) which show
a broad spectrum of biological properties including
anaesthetic, analgesic, antitumor and antibiotic activi-
ties.1–3 The 2-substituents (R) in 1 can be a methyl or a
hydroxymethyl group whereas the 6-substituents (R0) are
usually long-chain saturated or unsaturated appendages. All
four pairs of diastereomeric racemates that are possible for a
2,3,6-trisubstituted piperidine ring have been found in these
alkaloids. In view of such structural diversity and their
significant biological properties, in recent years, much
attention has been paid towards stereo- and enantioselective
syntheses of these alkaloids.4 We now present a new
strategy by which 2,6-disubstituted-3-piperidinol rings can
be readily constructed via intramolecular Michael reaction
of a chiral-pool derived a-amino-b-hydroxy-d-acrylates
viz. 2 (Scheme 1). Recently, intramolecular Michael
additions in d-unsaturated amines and amides5 have been
shown to provide an attractive synthetic route to piperidine
rings,6 albeit for simpler targets, which formed the basis of
our present strategy.
which, without purification, was reacted with NaSO2Tol
(DMF, rt) to give the enantiopure g-amino-b-keto sulfone 6
(70%) in a good overall yield.7,8 a-Alkylation of 6 with
ethyl g-bromocrotonate using K2CO3 in DMF at room
temperature7,8 produced the a-alkylated b-keto sulfone 7a
as a 50:50 diastereomeric mixture. In this reaction, care
must be taken not to use more than one equivalent of the
bromocrotonate electrophile as formation of the a,a-
dialkylated product can easily occur. Subsequent desulfona-
tion of 7a with Al(Hg) in 10% aqueous THF gave the trans-
g-unsaturated a-amino ketone 7b in 86% overall yield. The
keto-group in 7b was reduced under chelation controlled
conditions (NaBH4, MeOH, 2508C)9 to produce the anti-
amino alcohol (78% de) and its hydroxy group protected as
the acetate (Ac2O, Et3N, CH2Cl2, rt) to give the key
a-amino-b-acetoxy-d-acrylate 8 in 83% yield from 7.
Intramolecular Michael addition in 8 was first attempted
using KOBu-t in THF according to the Hirama-protocol.5b
However, repeated attempts at this reaction under a variety
of conditions failed to induce any cyclization, returning the
starting material on each occasion. In order to increase the
nucleophilicity of the amine group, the Boc-protecting
group in 8 was removed (TFA, CH2Cl2, rt) and the liberated
amine salt 9, without isolation, was treated with excess Et3N
to induce the intramolecular Michael reaction. This indeed
led to a smooth cyclization reaction producing the
diastereomeric piperidines 10a and b in an 82% combined
yield. Although the diastereoselectivity of this cyclization
step is poor, perhaps due to lack of any stereochemical bias
With a goal of the synthesis of spectaline, azimic acid and
julifloridine,1 all having a C2-methyl substituent (R¼Me in
1), L-alanine was chosen as the chiral-pool precursor
(Scheme 2). Thus, Boc-L-alanine (4) was first converted to
the corresponding a-diazoketone 5 (65%) via the mixed
carbonate method (ClCO2Et, Et3N, THF, 08C then excess
CH2N2). The latter upon treatment with 47% aqueous HBr
in ether at 08C produced the corresponding a-bromo ketone
Keywords: intramolecular Michael reaction; diastereomeric piperidines;
unsaturated amines.
*
Corresponding author. Fax: þ91-33-4734266;
e-mail: jusaumitra@yahoo.co.uk
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00680-4

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S. Sengupta, S. Mondal / Tetrahedron 58 (2002) 7983–7986
Scheme 2. (i) EtO2CCl, Et3N, THF, 08C then excess CH2N2, ether; (ii) 47% HBr, ether, 08C; (iii) NaSO2Tol, DMF, rt; (iv) ethyl g-bromocrotonate, K2CO3,
DMF, rt; (v) Al(Hg), THF–H2O, reflux; (vi) NaBH4, MeOH, 2508C; (vii) Ac2O, Et3N, CH2Cl2, rt; (viii) TFA, CH2Cl2, rt; (ix) Et3N (excess), CH2Cl2, rt.
between the two transition states (e.g. absence of any allylic
chiral center which could have provided p-face differen-
tiation during the cyclization reaction5b–d) and/or the
reversible nature of the reaction, the two diastereomers
could be easily separated by column chromatography over
silica gel (10a (38%): Rf 0.5; 10b (44%): Rf 0.3 in 40%
EtOAc in light petroleum).
hydrogens of the C6–CH2CO2Et substituent) and the one-
proton multiplet at d 2.96–3.00. The latter resonance was
thus assigned to the H-6 proton of the piperidine ring.
Chemical shift values for the hydrogens in the other
diastereomer 10b were similarly determined and are listed
together with those of 10a in Table 1. Pertinent 13C NMR
resonances (C-2, C-3, C-6 and C2-Me carbons) of the two
diastereomers are also listed in Table 1. The chemical shift
values for the C-2 and C-6 carbons could not be assigned
with certainty and may be interchanged. As evident from
Table 1, the proton chemical shifts of the H-2, H-3, H-6 and
the C2-Me hydrogens in 10a are consistently upfield relative
to the corresponding protons in 10b. On the other hand, the
carbon chemical shifts of the C-2, C-3, C-6 and the C2-Me in
10a are all deshielded relative to the corresponding carbons
in 10b. Literature reports on 2,3,6-trisubstituted piperidine
ring systems revealed that the H-2, H-3 and H-6 protons of
the 2,6-cis isomers appear at a more upfield region than the
corresponding protons of the 2,6-trans isomers
(Dd<0.4 ppm),10 based on which we assigned 10a as the
2,6-cis and 10b as the 2,6-trans isomer. The trend in the 13C
NMR chemical shift differences, as observed in our case,
was also corroborated by the literature data on similar
systems.10c
Stereochemical assignments to 10a and b were made on the
basis of their 1H and 13C NMR spectra. Unfortunately,
neither 10a or 10b gave any nOe enhancement between
their H-2 and H-6 protons, which could have identified the
2,6-cis diastereomer of this pair. Hence, the 2,6-relative
stereochemistries in 10a and b were assigned on the basis of
1
the chemical shift differences of their H and 13C NMR
spectra and comparing them with literature reports on
similar systems.4,10 Two-dimensional NMR techniques
(1H–1H COSY) were used to determine the chemical shifts
of the H-2, H-3 and H-6 protons in 10a and b. Thus, for 10a,
cross-peaks were obtained between the three-proton doublet
at d 1.07 (C2-Me ) and a one-proton double quartet at d 2.74.
The latter was thus assigned as the H-2 ring proton.
Similarly, cross-peaks between two one-proton signals at d
2.74 (dq) and 4.35 (ddd) led us to assign the latter as the ring
H-3 proton. Additional cross-peaks were found between the
two-proton multiplet at d 2.30–2.44 (due to the methylene
In conclusion, we have described a new synthetic route to
2,6-disubstituted-3-piperidinols via an intramolecular
Michael reaction strategy. The ester functionality in the
C6-side chain of 10 can be suitably exploited to construct the
C6-appendages of the target alkaloids.
Table 1. Diagnostic 1H and 13C NMR data of 10a and 10b
1. Experimental
1.1. General
1H NMR (d)
13C NMR (d)
1H NMR (d)
13C NMR (d)
All melting points are uncorrected. IR spectra were recorded
on a Perkin–Elmer-297 spectrophotometer. 1H NMR
spectra were recorded in CDCl3 on a Brucker DPX-200
(200 MHz) or a Brucker AVANCE 300 (300 MHz)
instrument and are reported in parts per million (ppm)
downfield from tetramethylsilane as internal standard. 13C
H-2 2.74
H-3 4.35
C-2 55.4/60.4a H-2 3.08
C-3 75.4
C-2 50.1/60.4a
H-3 4.35–4.58 C-3 73.0
H-6 2.96–3.00 C-6 60.4/55.4a H-6 3.30–3.40 C-6 60.4/50.1a
CH3 1.07
CH3 18.8
CH3 1.15
CH3 17.6
a
These values are interchangeable.

S. Sengupta, S. Mondal / Tetrahedron 58 (2002) 7983–7986
7985
NMR spectra were recorded in CDCl3 on a BRUCKER
AVANCE 300 (75 MHz) instrument. Optical rotations were
measured on a JASCO DIP-360 polarimeter. Elemental
analyses were performed at the Indian Association for the
Cultivation of Science. All reactions were carried out under
a nitrogen atmosphere. Reactions were monitored by thin
layer chromatography (TLC) on glass plates precoated with
silica gel G (Tara Chemicals). Compounds were visualized
by staining with iodine or warming on a hot plate after
spraying with aqueous H2SO4. Column chromatography
was performed on silica gel (60–120 mesh, Tara Chemi-
cals). Light petroleum refers to the fraction boiling at 60–
808C range. The a-amino diazoketone 5 was prepared from
L-alanine (4) according to the method of Ye and
McKervey.11
petroleum) to give 7b (0.23 g, 86%) as a colorless oil;
[Found: C, 60.12; H, 8.32; N, 4.75%; C15H25NO5 requires:
C, 60.18; H, 8.42 and N, 4.68%]; [a]2D0¼22.0 (c 1.0,
CHCl3); nmax (neat) 3350, 2920, 1710, 1650, 1500, 1440,
1360, 1250, 1145 cm21; dH (300 MHz, CDCl3) 1.28 (t, 3H,
J¼7.5 Hz, CH3CH2O–), 1.32 (d, 3H, J¼7.3 Hz, Me ), 1.44
(s, 9H, C(CH3)3), 2.40–2.80 (m, 4H, CO–CH2CH2–
CHv), 4.18 (q, 2H, J¼7.1 Hz, CH3CH2O–), 4.21–4.33
(m, 1H, NCHMe), 5.10 (br s, 1H, NH), 5.84 (d, 1H,
J¼15.6 Hz, CHvCH–CO2Et), 6.91 (dt, 1H, J¼6.6,
15.6 Hz, CH2–CHvCH); dC (75 MHz, CDCl3) 14.2, 17.6,
25.7, 28.3, 37.1, 55.0, 60.2, 79.8, 122.3, 146.6, 155.4, 166.3,
208.0.
1.1.3. (6R,7S )-Ethyl 6-acetoxy-7-(t-butyloxycarbonyl-
amino)oct-2-enoate (8). NaBH4 (0.02 g, 0.6 mmol) was
added to a solution of 7b (0.15 g, 0.5 mmol) in MeOH
(5 ml) at 2508C. After 15 min, the reaction was quenched
with brine and the whole extracted with CH2Cl2. The
organic layer was dried (Na2SO4) and the solvent removed
under reduced pressure to give the hydroxy ester. The latter
was dissolved in CH2Cl2 (3 ml) and was treated with Ac2O
(0.06 g, 0.06 ml, 0.06 mmol), Et3N (0.06 g, 0.6 mmol) and a
catalytic amount of DMAP at room temperature. After
completion of the reaction (ca. 3 h), more CH2Cl2 (10 ml)
was added and the whole washed with water. The organic
layer was dried (Na2SO4) and the solvent removed under
reduced pressure. The residue was purified by column
chromatography over silica gel (30% EtOAc in light
petroleum) to give 8 (0.15 g, 83%) as a colorless oil;
[Found: C, 59.42; H, 8.55; N, 4.14%; C17H29NO6 requires:
C, 59.46; H, 8.51 and N, 4.08%]; [a]2D0¼24.2 (c 1.0,
CHCl3); nmax (neat) 3340, 2970, 1700 (br), 1500, 1450,
1360, 1240 cm21; dH (300 MHz, CDCl3) 1.10 (d, 3H,
J¼6.9 Hz, Me ), 1.28 (t, 3H, J¼7.2 Hz, CH3CH2O–), 1.44
(s, 9H, C(CH3)3), 1.65–1.77 (m, 2H, CH2–CH2–CHv),
2.07 (s, 3H, COCH3), 2.17–2.31 (m, 2H, CH2–CH2–
CHv), 3.86 (m, 1H, NCHMe), 4.18 (q, 2H, J¼7.2 Hz,
CH3CH2O–), 4.58 (br s, 1H, NH), 4.84–4.89 (m, 1H, CH–
OCO), 5.82 (d, 1H, J¼15.6 Hz, CHvCH–CO2Et), 6.92 (dt,
1H, J¼6.9, 15.6 Hz, CH2–CHvCH); dC (75 MHz, CDCl3)
14.2, 15.6, 18.5, 21.0, 28.3, 48.3, 60.2, 75.7, 80.2, 121.9,
147.5, 155.1, 166.4, 170.3.
1.1.1. (S )-3-(t-Butyloxycarbonylamino)-1-( p-toluenesul-
fonyl)butan-2-one (6). 47% HBr (0.3 ml, 6.0 mmol) was
added dropwise to a solution of the a-amino diazoketone 511
(0.60 g, 2.8 mmol) in ether (15 ml) at 08C. After 30 min, the
reaction was neutralized with satd NaHCO3 solution and the
ether layer was separated. It was washed with water, dried
(Na2SO4) and the solvent removed in vacuo to give the
corresponding a-bromo ketone. The latter was dissolved in
DMF (5 ml) and NaSO2Tol (0.55 g, 3.1 mmol) was added to
it at room temperature. After 30 min, the reaction was
diluted with CH2Cl2 (10 ml) and washed with water. The
organic layer was dried (Na2SO4) and evaporated in vacuo.
The residue was purified by column chromatography over
silica gel (30% EtOAc in light petroleum) to give 6 (0.67 g,
70%) as a white crystalline solid; mp 121–1228C (ether–
light petroleum); [Found: C, 56.24; H, 6.80; N, 4.05%;
C16H23NO5S requires: C, 56.28; H, 6.80 and N, 4.10%];
[a]2D0¼21.8 (c 1.8, CHCl3); nmax (CHCl3) 3420, 2980,
1700, 1590, 1490, 1445, 1360, 1320, 1220, 1150 cm21; dH
(300 MHz, CDCl3) 1.24 (d, 3H, J¼8.0 Hz, Me ), 1.44 (s, 9H,
C(CH3)3), 2.45 (s, 3H, Ph-Me ), 4.21 (d, 1H, J¼13.8 Hz,
NCH–CH–SO2), 4.29–4.36 (m, 1H, NCHMe–), 4.42 (d,
1H, J¼13.8 Hz, NCH–CH–SO2), 5.18 (br s, 1H, NH ), 7.36
(d, 2H, J¼8.0 Hz, Ph), 7.77 (d, 2H, J¼8.1 Hz, Ph); dC
(75 MHz, CDCl3) 16.3, 21.6, 28.2, 56.0, 63.3, 80.4, 128.4,
129.9, 135.9, 145.4, 155.2, 198.4.
1.1.2. (S )-Ethyl 7-(t-butyloxycarbonylamino)-6-oxooct-
2-enoate (7b). Ethyl g-bromocrotonate (0.17 g, 0.87 mmol)
was added to a mixture of the g-amino-b-keto sulfone 6
(0.30 g, 0.87 mmol) and K2CO3 (0.13 g, 0.96 mmol) in
DMF (3 ml) at room temperature and the mixture stirred for
5 h. It was then acidified with dil. HCl and diluted with
CH2Cl2 (15 ml). The aqueous layer was separated and the
organic layer was washed with water and dried (Na2SO4).
Removal of solvent under reduced pressure followed by
column chromatography over silica gel (20% EtOAc in light
petrioleum) gave the a-alkylated g-amino-b-keto sulfone
(7a) as a 50:50 diastereomeric mixture (by NMR). Freshly
prepared Al(Hg) (from aluminum foil (0.3 g) and 2%
aqueous HgCl2 solution] was added to a solution of 7a in
THF–H2O (9:1, 7 ml) and the mixture heated under reflux
for 6 h. The reaction mixture was filtered, washed with THF
and the filtrate diluted with CH2Cl2 (10 ml). It was washed
with water, dried (Na2SO4) and the solvent removed under
reduced pressure. The residue was purified by column
chromatography over silica gel (20% EtOAc in light
1.1.4. 3-Acetoxy-6-ethoxycarbonylmethyl-2-methyl-
piperidine (10a,b). Trifluoroacetic acid (0.40 g, 0.25 ml,
3.48 mmol) was added to a solution of 8 (0.10 g,
0.29 mmol) in CH2Cl2 (2 ml) at 08C and the solution stirred
at room temperature for 1 h. All volatiles were then
removed under reduced pressure and the residue was
redissolved in CH2Cl2 (3 ml). Excess Et3N (0.15 g, 0.2 ml,
1.45 mmol) was added to it and the mixture stirred
overnight at room temperature. The reaction was then
diluted with CH2Cl2 (10 ml) and washed with water. The
organic layer was dried (Na2SO4) and the solvent removed
under reduced pressure. The residue was purified by column
chromatography over silica gel (30–50% EtOAc in light
petroleum) to give the cyclized products 10a and b.
10a (0.024 g, 34%); mp 52–538C (EtOAc–light
petroleum); [Found: C, 59.40, H, 8.59, N, 5.82%;
C12H21NO4 requires: C, 59.24, H, 8.70 and N, 5.76%];
[a ]2D0¼26.9 (c 0.5, CHCl3); nmax (CHCl3) 3320, 2940,

7986
S. Sengupta, S. Mondal / Tetrahedron 58 (2002) 7983–7986
1725, 1575, 1430, 1365, 1280 cm21; dH (300 MHz, CDCl3)
1.07 (d, 3H, J¼6.1 Hz, Me ), 1.25 (t, 3H, J¼7.1 Hz,
CH3CH2O–), 1.25–1.39 (m, 3H), 1.67–1.71 (m, 1H),
2.04 (s, 3H, OCOCH3), 2.04–2.11 (m, 1H), 2.30–2.44 (m,
2H, EtO2CCH2–CH), 2.74 (dq, 1H, J¼6.0, 9.0 Hz, Me–
CH–N), 2.96–3.00 (m, 1H, EtO2CCH2–CH–N), 4.14 (q,
2H, J¼7.1 Hz, CH3CH2O–), 4.35 (ddd, 1H, J¼4.6, 5.5,
9.8 Hz, AcOCH–CHN); dC (75 MHz, CDCl3) 14.1, 18.8,
21.1, 30.1, 31.2, 40.6, 52.5, 55.4, 60.4, 75.4, 170.4, 172.2.
Xu, Y.-M.; Liao, L.-X.; Zhou, W.-S. Tetrahedron Lett. 1998,
39, 9227. (d) Agami, C.; Couty, F.; Lam, H.; Mathieu, H.
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15589. (f) Takahara, H.; Takahashi, S.; Kouno, S.; Momose, T.
J. Org. Chem. 1998, 63, 2224. (g) Ojima, I.; Vidal, E. S. J. Org.
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10b (0.034 g, 48%); colorless oil; [Found: C, 59.33, H, 8.51,
N, 5.89%; C12H21NO4 requires: C, 59.24, H, 8.70 and N,
5.76%]; [a ]D20¼þ4.2 (c 0.3, CHCl3); nmax (CHCl3) 3320,
2940, 1725, 1580, 1430, 1365, 1230 cm21; dH (300 MHz,
CDCl3) 1.15 (d, 3H, J¼6.6 Hz, Me ), 1.26 (t, 3H, J¼7.1 Hz,
CH3CH2O–), 1.40–1.60 (m, 1H), 1.62–1.70 (m, 2H),
1.80–1.94 (m, 2H), 2.07 (s, 3H, OCOCH3), 2.39 (dd, 1H,
J¼5.4, 15.6 Hz, EtO2CCH2–CH), 2.57 (dd, 1H, J¼8.2,
15.5 Hz, EtO2CCH2–CH), 3.08 (dq, 1H, J¼6.0, 6.8 Hz,
Me–CH–N), 3.30–3.40 (m, 1H, EtO2CCH2–CH–N), 4.15
(q, 2H, J¼7.0 Hz, CH3CH2O–), 4.35–4.58 (m, 1H,
AcOCH–CHN); dC (75 MHz, CDCl3) 14.2, 17.6, 21.3,
24.5, 27.6, 38.9, 46.8, 50.1, 60.4, 73.0, 170.4, 172.1.
ˆ
5. (a) Hirama, M.; Iwakuma, T.; Ito, S. J. Chem. Soc., Chem.
Commun. 1987, 1523. (b) Oishi, T.; Iwakuma, T.; Hirama, M.;
ˆ
Ito, S. Synlett 1995, 404. (c) Akiyama, E.; Hirama, M. Synlett
1996, 100. (d) Carretero, J. C.; Arrayas, R. G.; Storch de
Gracia, I. Tetrahedron Lett. 1996, 37, 3379. (e) McAlonan, H.;
Stevenson, P. J.; Thompson, N.; Treacy, A. B. Synlett 1997,
1359.
6. For recent reviews on piperidine ring syntheses, see (a) Bailey,
P. D.; Millwood, P. A.; Smith, P. O. J. Chem. Soc., Chem.
Commun. 1998, 633. (b) Laschat, S.; Dickner, T. Synthesis
2000, 1781.
7. (a) Lygo, B. Synlett 1992, 793. (b) Lygo, B.; Rudd, C. N.
Tetrahedron Lett. 1995, 36, 3577. (c) Charrier, C.; Ettouati, L.;
Paris, J. Tetrahedron Lett. 1999, 40, 5705.
Acknowledgments
Financial support of this project from DST, New Delhi
(SP/S1/G-14/97) is warmly acknowledged. One of us (S. M.)
thanks UGC, New Delhi for a senior research fellowship.
8. (a) Sengupta, S.; Sen Sarma, D.; Mondal, S. Synth. Commun.
1998, 28, 4409. (b) Sengupta, S.; Sen Sarma, D.; Mondal, S.
Tetrahedron 1998, 54, 9791. (c) Sengupta, S.; Das, D.;
Mondal, S. Synlett 2001, 1464.
9. (a) Albeck, A.; Perskey, R. Tetrahedron 1994, 50, 6333.
(b) Rotella, D. P. Tetrahedron Lett. 1995, 36, 5453. (c) Albeck,
A.; Estreicher, G. I. Tetrahedron 1997, 53, 5325. (d) Sengupta,
S.; Sen Sarma, D. Tetrahedron Lett. 2001, 42, 485.
(e) Hoffman, R. V.; Weiner, W. S.; Maslouh, N. J. Org.
Chem. 2001, 5790. and references therein.
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