A route to "all-cis" 2-methyl-6-substituted piperidin-3-ol alkaloids from syn-(2R,1′S)-2-(1-dibenzylaminomethyl)epoxide: Rapid total synthesis of (+)-deoxocassine

Article abstract of DOI:10.1002/ejoc.201101333

A general strategy leading to the synthesis of two cis-2-methyl-6- substituted piperidin-3-ols is described. syn-(2R,1′S)-2-(1- Dibenzylaminomethyl) epoxide (13) was used as common building block. The key step involved oxirane ring opening of 13 by the nucleophilic lithium aza-enolate of hydrazones 12a and 12b. Subsequent hydrazone hydrolysis and intramolecular reductive amination afforded the alkaloid (+)-deoxocassine and a new C-6 ethyl analogue of this substance in good yields.

Full text of DOI:10.1002/ejoc.201101333

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101333
A Route to “all-cis” 2-Methyl-6-Substituted Piperidin-3-ol Alkaloids from
syn-(2R,1ЈS)-2-(1-Dibenzylaminomethyl)epoxide: Rapid Total Synthesis of
(+)-Deoxocassine
Pierre-Yves Géant,[a] Jean Martínez,[a] and Xavier J. Salom-Roig*[a]
Keywords: Alkaloids / Epoxides / Hydrazones / Amination / Total synthesis
A general strategy leading to the synthesis of two cis-2-
methyl-6-substituted piperidin-3-ols is described. syn-
(2R,1ЈS)-2-(1-Dibenzylaminomethyl) epoxide (13) was used
as common building block. The key step involved oxirane
ring opening of 13 by the nucleophilic lithium aza-enolate of
hydrazones 12a and 12b. Subsequent hydrazone hydrolysis
and intramolecular reductive amination afforded the alkaloid
(+)-deoxocassine and a new C-6 ethyl analogue of this sub-
stance in good yields.
(+)-carpamic acid (6).[3] Besides their interesting structural
features, these compounds display a wide range of bio-
logical activities due to their ability to mimic carbohydrates
in a variety of enzymatic processes.[4] In light of this, con-
siderable effort has been invested into the development of
syntheses of “all-cis” 2-methyl-6-substituted piperidin-3-ols.
Although several syntheses based on a chiral pool ap-
proach[5] or the use of asymmetric synthesis[6] have been
reported, they often do not allow for adequate diversity and
substitution. The importance of this 2,3,6-trisubstituted pi-
peridine scaffold makes short, efficient, and versatile access
to C-6 analogues of “all-cis” 2-methyl-6-substituted piper-
idin-3-ols still attractive.
Introduction
cis-2-Methyl-6-substituted piperidin-3-ol alkaloids have
been isolated from leaves and twigs of the plant genera Cas-
sia and Prosopis.[1] Most of them have an “all-cis” relative
configuration as a stereochemical feature. Structural diver-
sity is due to a long side chain at C-6. Typical representa-
tives of this class of compound include (+)-deoxocassine
(1), (+)-cassine (2), (+)-prosafrinine (3), (+)-spectaline (4),
(+)-spicigerine (7) azimine (8), and carpaine (9, Figure 1).[2]
The last two compounds are symmetrical macrocyclic dilac-
tones, which can be hydrolyzed to (+)-azimic acid (5) and
Herein, we describe a concise asymmetric general route
to “all-cis” 2-methyl-6-substituted piperidin-3-ol alkaloids
from syn-(2R,1ЈS)-2-(1-dibenzylaminomethyl) epoxide (13)
as a common key building block.[7] This approach should
be adaptable to the production of other structurally related
alkaloids such as 2–7. To demonstrate the synthetic interest
of this methodology, we have realized the total synthesis of
(+)-deoxocassine (1) and its C-6 ethyl-substituted analogue
10.
Results and Discussion
As depicted in Scheme 1, retrosynthetic analysis led us
to dibenzylamino ketone 11, which after debenzylation and
concomitant intramolecular reductive amination, should
lead to target piperidines 1 and 10. In the key step of the
synthesis, dibenzylamino ketone 11 was planned to be pre-
pared in a one-pot procedure by ring opening of epoxide
13, obtained from α-bromo-αЈ-(R)-sulfinylketone 14, with
the lithiated anion of hydrazones 12a and 12b and subse-
quent hydrazone hydrolysis.
Figure 1. Structures of naturally occurring cis-2-methyl-6-substi-
tuted piperidin-3-ol alkaloids.
[a] Institut de Biomolécules Max Mousseron (IBMM), UMR
5247,
Université de Montpellier I et II, CNRS,
Place Eugène Bataillon, 34095 Montpellier, France
Fax: +33-4-67144866
E-mail: salom-roig@univ-montp2.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101333.
62
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Eur. J. Org. Chem. 2012, 62–65

Total Synthesis of (+)-Deoxocassine
subject of major importance in organic chemistry,[12] in par-
ticular in C–C bond formation. N,N-Dialkylhydrazones of-
fer many advantages such as high nucleophilicity of their
metalated species (particularly organolithium derivatives),
regioselectivity, and controlled α-monoalkylation. Aza-
enolates, usually formed by deprotonation with LDA, can
react with quite a number of electrophiles. In particular,
oxiranes have rarely been employed.[13] In this context, ini-
tial attention focused upon the preparation of the required
dimethylhydrazones. 2-Butanone (Scheme 3) was then con-
verted into its dimethylhydrazone 12a in 82% yield by reac-
tion with dimethyl hydrazine in refluxing CH2Cl2. Ana-
logue 12b was obtained by a two-step sequence starting
from commercially available alcohol 20. This derivative was
oxidized by using PCC to the corresponding ketone 21 in
95% yield. Dimethylhydrazone 12b was obtained in quanti-
tative yield by using a procedure similar to that used for
12a.
Scheme 1. Retrosynthetic pathway to piperidine derivatives 1 and
10.
The synthesis of epoxide 13 was performed according to
the path shown in Scheme 2 by using the methodology re-
ported in an earlier study.[8] To the lithiated anion of (+)-
(R)-methyl p-tolyl sulfoxide (15), obtained by using LDA as
base at –78 °C, was added (Ϯ)-methyl 2-bromopropionate
(16), which produced an epimeric mixture of α-bromo-αЈ-
(R)-sulfinylketone 14 in 95% yield. The latter furnished
ketone 17 through a combined in situ substitution–epi-
merization process, a so-called dynamic kinetic resolution.
To reduce stereoselectively the carbonyl group, the resulting
crude residue of derivative 17 was treated successively with
ZnI2, which chelated between the carbonyl group and the
basic oxygen of the sulfoxide group, and then with DIBAL
at –78 °C. Desired syn-amino alcohol 18 was obtained in
two steps in 94% yield in multigram amounts and with ex-
cellent stereoselectivity (Ͼ95:5).[9] Thereafter, compound 18
was heated at reflux in CHCl3 in the presence of an excess
amount of tert-butyl bromide to afford the corresponding
sulfide 19.[10] The crude reaction mixture was then treated
with Meerwein’s salt (Me3OBF4), and the resulting sulfo-
nium salt was treated with K2CO3 to afford, after purifica-
tion by column chromatography on silica gel, key interme-
diate 13 in 78% yield along with methyl p-tolyl sulfide.[11]
Scheme 3. Synthesis of N,N-dimethylhydrazones 12a and 12b. Rea-
gents and conditions: (a) NH2NMe2, CH2Cl2, reflux, 82%;
(b) PCC, CH2Cl2, 95%; (c) NH2NMe2, CH2Cl2, reflux, 100%.
Oxirane ring opening of 13 was achieved by addition to
the aza-enolate of dimethylhydrazones 12a or 12b at room
temperature (Scheme 4). A large excess of aza-enolate
(11 equiv. for 12a and 5.3 equiv. for 12b), generated from
the corresponding hydrazones and butyllithium at 0 °C, was
required to reach a complete opening of oxirane 13. The
use of an excess amount of anhydrous LiCl as additive, ac-
cording to a known literature procedure for enolate oxirane
ring opening,[13d,14] did not improve the results. Exposure
of the mixture of crude hydrazone 22 and the excess
Scheme 2. Synthesis of compound 13. Reagents and conditions:
(a) LDA, THF, –78 °C, then 16, 95%; (b) Bn2NH, THF, r.t.;
(c) ZnI2, r.t., 30 min, then DIBAL-H, THF, –78 °C, 94% (two
steps); (d) tBuBr, CHCl3, reflux; (e) Me3OBF4, CH2Cl2, r.t., 5 h,
then K2CO3, 78% (two steps).
With the necessary key building block in hand, we fo-
cused on the synthesis of the piperidine ring by coupling
hydrazones 12a and 12b with oxirane 13. The wide applica-
Scheme 4. Synthesis of “all-cis” piperidine derivatives 1 and 10.
Reagents and conditions: (a) BuLi, THF, 0 °C to r.t. then 13;
bility of N,N-dimethylhydrazones in synthesis has been a (b) SiO2, THF/H2O; (c) H2 (balloon), Pd(OH)2/C, EtOH.
Eur. J. Org. Chem. 2012, 62–65
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63

P.-Y. Géant, J. Martínez, X. J. Salom-Roig
SHORT COMMUNICATION
amount of hydrazones 12a or 12b to SiO2, in a 1:1 mixture
of water/THF, provided desired ketones 11a and 11b in 63
and 79% yield, respectively, in a one-pot procedure, after
purification by column chromatography on silica gel.
Experimental Section
Typical Procedure for the Synthesis of 11b: nBuLi (2.5 m in hexane,
0.4 mL, 1 mmol) was slowly added to a solution of hydrazone 12b
(255 mg, 1.00 mmol) in THF (2 mL) at 0 °C. The mixture was
stirred at 0 °C for 1.5 h. The system was then warmed to room
temperature and stirred for 10 min. A solution of epoxide 13
(48 mg, 0.179 mmol) in THF (5 mL) was added. The mixture was
stirred for 6.5 h at room temperature and then quenched with satu-
rated aqueous NH4Cl (5 mL). The phases were separated, and the
aqueous layer was extracted with EtOAc (3ϫ5 mL). The combined
organic layers were dried with MgSO4 and concentrated under re-
duced pressure. The residue was dissolved in THF (3 mL) and H2O
(3 mL) and SiO2 (1 g) were added. The mixture was stirred over-
night, filtered, and the phases were separated. The aqueous layer
was extracted with EtOAc (3ϫ5 mL). The combined organic layers
were dried with MgSO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on sil-
ica gel (cyclohexane/EtOAc, 99:1 to 95:5) to give 11b as a white
Completion of the synthesis was achieved by in situ
amine debenzylation and reductive cyclization of the re-
sulting aminoketones. Thus, dibenzylaminoketones 11a and
11b were subjected to catalytic hydrogenation in the pres-
ence of 20% Pd(OH)2/C. (+)-Deoxocassine (1)[15] and its C-
6 ethyl analogue 10 were specifically obtained in 75 and
61% yield, respectively, after purification by chromatog-
raphy on silica gel in a two-step sequence. A high degree of
stereocontrol was observed, as Δ1-piperidine intermediate
23 was hydrogenated from the less-hindered α-face of the
molecule,[5e] resulting in the “all-cis” configuration. Not
even a trace amount of the C-6 epimer could be detected in
1
either case by H NMR spectroscopic analysis of the crude
solid (72 mg, 79%). Rf = 0.29 (cyclohexane/EtOAc, 4:1). [α]D
=
reaction mixture. The optical rotation of synthetic 1 {[α]D
= +11.6 (c = 0.95, CHCl3)} was consistent with that re-
ported for natural 1 {[α]D = +11.8 (c = 1.0, CHCl3)}.[5h]
The 1H NMR, 13C NMR, and mass spectra and the melting
point of synthetic 1 were also in good agreement with the
reported values.[5h] Deoxocassine C-6 ethyl analogue 10,
which to the best of our knowledge has never been de-
scribed, exhibited an optical rotation of [α]D = +8.8 (c =
1.1, CHCl3). It is interesting to note that the “all-cis” rela-
tionship between the substituents in 1 and 10 was con-
firmed by the small J2,3 value (1.3 Hz), typical for the axial–
equatorial H-2 and H-3 protons[5b,16] (Figure 2). Moreover,
the cis relationship between the substituents at the 2,6-posi-
tions for compound 10 was confirmed by NOESY experi-
ments (see the Supporting Information).
+21.2 (c = 0.85, CHCl3). M.p. 39 °C. 1H NMR (400 MHz, CDCl3):
δ = 7.33–7.22 (m, 10 H, CHarom), 4.49 (br. s, 1 H, OH), 3.80 (d, J
= 13.3 Hz, 2 H, NCHaHbPh), 3.43 (td, J = 2.5, 9.2 Hz, 1 H,
CHOH), 3.30 (d, J = 13.3 Hz, 2 H, NCHaHbPh), 2.61–2.42 (m, 3
H, CHN, CH2C=O), 2.39–2.26 (m, 2 H, CH2C=O), 1.88–1.78 (m,
1 H, CHaHbCHOH), 1.53–1.50 (m, 2 H, CH2CH2C=O), 1.31–1.24
[m, 19 H, CHaHbCHOH, (CH2)9], 1.04 (d, J = 6.7 Hz, 3 H, 3 H,
CH3CHN), 0.88 (t, J = 6.9 Hz, 3 H, CH3CH2) ppm. 13C NMR
(100 MHz, CDCl3):
δ = 211.5 (C=O), 138.9 (Carom), 129.1
(CHarom), 128.5 (CHarom), 127.3 (CHarom), 69.9 (CH), 58.3 (CH),
53.3 (CH2), 43.0 (CH2), 38.6 (CH2), 31.9 (CH2), 29.7 (CH2), 29.6
(CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.3 (CH2), 27.4 (CH2),
23.9 (CH2), 22.7 (CH2), 14.2 (CH3), 8.0 (CH3) ppm. MS (ESI): m/z
= 480.5 [M + H]+. HRMS: calcd. for C32H50NO2+ 480.3842; found
480.3840.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data of the
new prepared compounds, and copies of the 1H and 13C NMR
spectra.
Figure 2. Major conformer of cis-2-methyl-6-substituted piperidin-
3-ols.
Acknowledgments
Thanks are expressed to Mr. Pierre Sánchez for his help in mass
spectrometry analysis and to Aurélien Lebrun for recording some
NMR spectra. We thank the Ministère de lЈEnseignement Supéri-
eur et de la Recherche for providing a research grant for the PhD
thesis project of P.Y.G.
Conclusions
In conclusion, we have achieved a flexible total synthesis
of (+)-deoxocassine (1) and its C-6 ethyl analogue 10 by
using a new, general, and efficient protocol. The approach
involves the coupling of the aza-enolates of hydrazones 12a
and 12b with oxirane 13 as a key reaction step. On the basis
of previous reported syntheses, it is interesting to note that
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Total Synthesis of (+)-Deoxocassine
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Received: September 12, 2011
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Published Online: November 17, 2011
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