Enantiocontrolled synthesis of 2,6-disubstituted piperidines by desymmetrization of meso-η-(3,4,5)-dihydropyridinylmolybdenum complexes. Application to the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine

Article abstract of DOI:10.1021/ja029537y

A conceptually new approach to the enantiocontrolled synthesis of 2,6-disubstituted piperidines was achieved by desymmetrization of meso-2,6-dimethoxy-η-(3,4,5)-dihydropyridinylmolybdenum complexes. After protection of the piperidine nitrogen as a urethan

Full text of DOI:10.1021/ja029537y

Published on Web 02/12/2003
Enantiocontrolled Synthesis of 2,6-Disubstituted Piperidines by
Desymmetrization of meso-η-(3,4,5)-Dihydropyridinylmolybdenum Complexes.
Application to the Total Synthesis of (-)-Dihydropinidine and
(-)-Andrachcinidine
Chutian Shu and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Pierce DriVe, Atlanta, Georgia 30322
Received December 1, 2002 ; E-mail: chemLL1@emory.edu
Scheme 1. Enantiocontrolled Synthesis of Disubstituted
Piperidines by Chiral Auxiliary-Induced Pseudo-Desymmetrization
Enantiomerically pure iron and molybdenum π-complexes are
powerful scaffolds for the enantiocontrolled construction of sub-
stituted carbo- and heterocycles.1 Traditionally, the complexes are
prepared either by resolution of racemic complexes or by face-
selective π-complexation from enantiopure precursors.2 Desym-
metrization, despite being a powerful tool for the preparation of
enantiomerically pure “organic” molecules,3 has been explored only
recently for organometallic π-complexes using hydride abstraction.4
Scheme 2. Preparation of Pseudo-Symmetrical Dimethoxy
Complex 1a
While interesting, the practicality of the reported enantioselectiVe
hydride abstraction approaches was limited by moderate enantio-
selectivities and the lengthy steps required to prepare the stoichio-
metric chiral, nonracemic hydride abstraction reagents. Herein we
report a conceptually different approach that uses a pseudo-
desymmetrization involving a highly diastereoselective methoxide
abstraction from (+)- or (-)-15 (Scheme 1), where R* ) (+)- or
(-)-trans-2-(R-cumyl)cyclohexyl (TCC).6 Through a sequential,
one-pot methoxide abstraction/nucleophilic addition/methoxide
abstraction/nucleophilic addition, and then protodemetalation/N-
deprotection, a simple and enantiocontrolled synthetic entry to a
variety of 2,6-disubstituted piperidines is achieved. 2,6-Disubstituted
piperidines have attracted much attention due to their interesting
structures and potent biological activities.7
a R* ) (+)- or (-)-trans-2-(R-cumyl)cyclohexyl, TCC. (a) Mo(CO)3-
(DMF)3 then KTp, 84%. (b) TMSI, 94%. (c) (+)- or (-)-TCC chlorofor-
mate, Et3N, DMAP, 91%. (d) Ph3CPF6 then Et3N, 88%. (e) Br2 then
NaOMe, 96%.
Scheme 3. Sequential Functionalization of (-)-1; Total Synthesis
of (-)-Dihydropinidinea
Chiral carbamate protected complexes 1 were prepared from the
known (()-ethyl 3-acetoxy-4,5-dehydro-1-piperidinecarboxylate 28
in five simple steps (Scheme 2). Treatment of 2 with Mo(CO)3-
(DMF)39 followed by KTp10 (Tp ) hydridotrispyrazolylborate) gave
meso-η3-allylmolybdenum complex 3 in 84% yield. N-Deprotection
of 3 with 4 equiv of TMSI at reflux in CH2Cl2 afforded the free
amine in 94% yield. Reprotection with the chloroformate derived
from either (+)- or (-)-TCC6 in the presence of Et3N and catalytic
DMAP provided the urethane complexes (+)- or (-)-4 in 91%
yield. Conversion of 4 to the pseudo-meso complex 1 was trivially
accomplished by a two-stage process: hydride abstraction with
Ph3CPF6 followed by deprotonation of the formed η4-diene cation
with Et3N to generate an η3-pyridinyl complex (88%) and then
conversion into (+)- or (-)-1 in 96% yield following a previously
described one-pot protocol (treatment with Br2 then NaOMe at -78
°C).11
The sequential functionalization of (-)-1 was carried out in the
same manner as that of the analogous 2,6-dimethoxy-3-substituted
dihydropyranyl11 and -dihydropyridinyl complexes,12 whose meth-
oxide abstraction selectivity is imparted from the unsymmetrically
substituted nature of the dihydropyranyl and dihydropyridinyl rings.
In contrast, the methoxide abstraction selectivity for pseudo-
symmetrical complexes 1 relies solely on the “desymmetrization”
imparted by the chiral, nonracemic N-protecting group. In the event,
methoxide abstraction from (-)-1 with 1.0 equiv of Ph3CPF6,
addition of MeMgBr, ionization of the remaining methoxide with
a R* ) (-)-TCC. (a) Ph3CPF6 then R1M; HBF4 then R2M. (b) HCl in
EtOAc. (c) H2, Pd/C, 79%. (d) KOH/EtOH, seal tube (150 °C), 83%.
HBF4, and addition of PhMgBr (all steps without intermediate
purification, 53% overall yield) provided the 2,6-disubstituted
dihydropyridinylmolybdenum complex (-)-5a (Scheme 3). To
measure the selectivity for the first methoxide abstraction from 1,
the diastereomeric molybdenum complex (+)-5b was prepared by
reversing the order of nucleophiles added (PhMgBr then MeMgBr).
With both diastereomers in hand, the selectivity of the first
1
methoxide abstraction was estimated by H NMR analysis of the
crude products (-)-5a and (+)-5b to be at least 40/1.13
Support for the structure assignments of (-)-5a and (+)-5b was
obtained by a total synthesis of (-)-dihydropinidine from (-)-1.14
Complex (-)-5c, prepared in 75% overall yield from (-)-1 in the
same manner as that of 5a/b, was subjected to protodemetalation
(HCl) and hydrogenation (H2, Pd/C) to afford the protected
dihydropinidine 6 in 79% yield. Deprotection of 6 with KOH/EtOH
in a sealed tube (150 °C) for 24 h provided (-)-dihydropinidine in
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J. AM. CHEM. SOC. 2003, 125, 2878-2879
10.1021/ja029537y CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Stereocontrolled Functionalization of (+)-1; Total
Synthesis of (-)-Andrachcinidinea
crystallographic studies. However, the diastereoselective methoxide
abstraction described herein is distinctively different as the selectiv-
ity arises solely from the chiral auxiliary. Unfortunately, the
structural origin of the highly selective methoxide abstraction from
(+)- or (-)-1 remains obscure. All attempts to obtain crystals of
(+)- or (-)-1, or any alkoxide congeners suitable for X-ray
crystallography, met with failure.
In summary, a novel and enantiocontrolled synthesis of 2,6-
disubstituted piperidines using a diastereoselective methoxide
abstraction of dimethoxy complexes with chiral protecting groups
has been disclosed. While the method described should allow the
enantiocontrolled synthesis of diverse 2,6-disubstituted piperidines,
the synthetic potential was specifically demonstrated by the efficient
synthesis of (-)-dihydropinidine and (-)-andrachcinidine.
a R* ) (+)-TCC. (a) Ph3CPF6 then allylMgCl; HBF4 then CH2dC(OLi)-
C3H7, 58%. (b) K-Selectride, 64%. (c) Ac2O, Et3N, DMAP, 93%. (d) NOPF6
then NaCNBH3, 64%. (e) PdCl2, CuCl, O2, DMF/H2O, 66%. (f) KOH/
EtOH, seal tube (140 °C), then CbzCl, NaOH, 62%. (g) p-NO2PhCO2H,
Ph3P, DEAD, 76%. (h) KOH/MeOH then H2, Pd/C, MeOH/EtOAc, 90%.
Acknowledgment. This work was supported by grant #GM43107,
awarded by the National Institute of General Medical Sciences,
DHHS. We thank Dr. Anna Ericsson for her contributions to the
early stages of this project and our colleagues, Drs. Kenneth
Hardcastle and Karl Hagen, for their skilled and efficient assistance
with X-ray crystallography.
83% yield (Scheme 3). The optical rotation of its hydrochloride
salt was consistent with that reported in the literature ([R]D -10.5,
c ) 0.2 EtOH, lit.15 [R]D -11.6, c ) 1.03 EtOH).
The synthetic power of this novel pseudo-desymmetrization
method was demonstrated by a total synthesis of (-)-andrachcini-
dine,16 an alkaloid isolated from Andrachne aspera. Sequential
functionalization of (+)-1 (Ph3CPF6 then allylMgCl; HBF4 then
CH2dC(OLi)C3H7) afforded (+)-5d in 58% yield (Scheme 4). The
selective reduction of (+)-5d with K-Selectride gave a single
diastereomer of an alcohol (64%) that was acetylated (Ac2O, Et3N,
and DMAP) to provide acetate 7 in 93% yield. The reductive
demetalation of 7 with NOPF6 at -40 °C followed by NaCNBH3
at room temperature proceeded smoothly to give a mixture of two
cyclohexene olefinic regioisomers (64%) that was subjected to a
selective Wacker oxidation17 of the allyl side chain to give ketone
8 and its olefin isomer in 66% yield. Unfortunately, an X-ray
crystallographic analysis of crystalline 8 demonstrated that the
selective reduction of (+)-5d with K-Selectride had produced the
undesired alcohol stereochemistry.
The alcohol stereochemistry was adjusted, and the synthesis of
andrachcinidine was completed using a modified reaction sequence
(Scheme 4). As before, complex 7 was reductively demetalated to
give a mixture of olefin regioisomers. Prior to the Wacker oxidation,
the (+)-TCC auxiliary and the acetate were cleaved with KOH/
EtOH in a seal tube (140 °C), and the amine was reprotected with
CbzCl to give 9 (62% overall yield). The undesired alcohol
stereochemistry was then inverted by a modified Mitsunobu reaction
(76%),18 and a subsequent Wacker oxidation proceeded exclusively
at the allyl side chain and delivered the keto-olefin isomer mixture
10 in 66% yield. Finally, basic hydrolysis followed by hydrogena-
tion led to cleavage of the N- and O-protecting groups and reduction
of the olefinic double bond and afforded (-)-andrachcinidine in
90% yield from 10 (18% overall from molybdenum complex 7).
The spectroscopic data (1H and 13C NMR) of the synthetic product
are in excellent agreement with those reported in the literature ([R]D
-20, c ) 0.18 CHCl3, lit. [R]D -20, c ) 1.6 CHCl3).16 This
synthesis, together with the X-ray structure of 8, confirmed the
proposed structure of (-)-andrachcinidine.
Supporting Information Available: A complete description of the
synthesis and characterization data of all compounds prepared in this
study and X-ray crystallography data of (-)-8 (PDF and CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
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1
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In the related 2,6-dimethoxy-3-substituted dihydropyranyl and
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the 3-substituent and the TpMo(CO)2, with support from X-ray
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