Organometallic enantiomeric scaffolding: A strategy for the enantiocontrolled construction of regio-and stereodivergent trisubstituted piperidines from a common precursor

Article abstract of DOI:10.1021/ja201012p

Reported herein is a general and efficient method to construct 2,3,6-trisubstituted piperidines in a substituent-independent fashion. From the high enantiopurity organometallic scaffold (-)-Tp(CO)₂[(η-2,3,4)- (1S,2S)-1-benzyloxycarbonyl-5-oxo-5,6-dihydro-2H-pyridin-2-yl)molybdenum (Tp = hydridotrispyrazolylborato), a variety of TpMo(CO)₂-based 2,3,6-trifunctionalized complexes of the (η-3,4,5-dihydropyridinyl) ligand were easily obtained in 5 steps through a sequence of highly regio-and stereospecific metal-influenced transformations (15 examples). From the 2,3,6-trifunctionalized molybdenum complexes, either 2,6-cis-3-trans or 2,3,6-cis systems were selectively obtained through the choice of an appropriate stereodivergent demetalation protocol. The potential of this strategy in synthetic chemistry was demonstrated by the short total synthesis of four natural and one non-natural alkaloids: indolizidines (±)-209I and (±)-8-epi-219F in the racemic series, and enantiocontrolled syntheses of (-)-indolizidine 251N, (-)-quinolizidine 251AA, and (-)-dehydroindolizidine 233E.

Full text of DOI:10.1021/ja201012p

ARTICLE
pubs.acs.org/JACS
Organometallic Enantiomeric Scaffolding: A Strategy for the
Enantiocontrolled Construction of Regio- and Stereodivergent
Trisubstituted Piperidines from a Common Precursor
Heilam Wong,† Ethel C. Garnier-Amblard, and Lanny S. Liebeskind*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S Supporting Information
b
ABSTRACT: Reported herein is a general and efficient method to construct 2,3,6-
trisubstituted piperidines in a substituent-independent fashion. From the high
enantiopurity organometallic scaffold (ꢀ)-Tp(CO)2[(η-2,3,4)-(1S,2S)-1-benzyl-
oxycarbonyl-5-oxo-5,6-dihydro-2H-pyridin-2-yl)molybdenum (Tp = hydrido-
trispyrazolylborato), a variety of TpMo(CO)2-based 2,3,6-trifunctionalized com-
plexes of the (η-3,4,5-dihydropyridinyl) ligand were easily obtained in 5 steps
through a sequence of highly regio- and stereospecific metal-influenced transformations (15 examples). From the 2,3,6-
trifunctionalized molybdenum complexes, either 2,6-cis-3-trans or 2,3,6-cis systems were selectively obtained through the choice
of an appropriate stereodivergent demetalation protocol. The potential of this strategy in synthetic chemistry was demonstrated by
the short total synthesis of four natural and one non-natural alkaloids: indolizidines (()-209I and (()-8-epi-219F in the racemic
series, and enantiocontrolled syntheses of (ꢀ)-indolizidine 251N, (ꢀ)-quinolizidine 251AA, and (ꢀ)-dehydroindolizidine 233E.
’ INTRODUCTION
“Molecular scaffolding” provides a means to rapidly probe
biological function through the systematic variation of structure.
The scaffold is typically a small organic molecule whose periph-
ery can be easily adorned with molecular fragments of diverse
shapes, electronegativities, polarizabilities, and hydrogen-bond-
ing capabilities, thus allowing chemical space around the scaffold
to be investigated and varied for maximum biological effect. In
decorating a scaffold to take an early screening hit to an actual
lead drug candidate, or in a more basic research environment to
probe biological function, a variety of well-developed and
dependable synthetic methods are now routinely used to pre-
Figure 1. 3-Dimensional scaffolding: systematic exploration of 3D
chemical space.
dictably probe two-dimensional space around the border of
aromatic and heteroaromatic scaffolds (i.e., cross coupling,1
tools used to elaborate 2D space, would play an important role in
taking an early screening hit to an actual lead drug candidate or in
using chemical synthesis to probe biological function.
CꢀH functionalization,2 electrophilic aromatic substitution,3
and directed metalation4). Since the practice of drug discovery
is influenced by ease of use and dependability of available
synthetic organic tools, it is not a surprise that much of the
activity in small molecule hit-to-lead drug development of the
past 1/2 century has been significantly focused within the “flat
world” found around the periphery of (hetero)aromatic
scaffolds.
It is surprising, however, that there exists no family of
correspondingly general synthetic tools that allow the site-
specific and enantiospecific probing of three-dimensional space
fully about the periphery of biomedically important nonplanar
scaffolds in a systematic fashion (Figure 1), even though drugable
platforms such as piperidines and 2H-tetrahydropyrans are
commonly found in a vast array of important pharmacophores
that possess broad-ranging biological activities.5 Such general 3D
scaffolding tools, if as easy to use and as broadly applicable as the
Much effort has been focused on the development of synthetic
approaches to various specific substitution families of piperi-
dines.6 The Comins6k,7 and Amat/Bosch6i laboratories have
come closest to achieving the goal of systematic scaffolding
around the piperidine ring. Additional piperidine functionaliza-
tion tools that fall under the rubric of “scaffolding” have also been
described by other laboratories, most notably those of Marazano,6l,8
Husson/Royer,6m and Charette6n (Figure 2). These scaffolding
methods are sometimes restricted to a single scaffold antipode
and are applicable only to systems bearing a piperidine core.
Furthermore, since these strategies rely on a preexisting sp3-
stereocenter to induce control over subsequently generated
Received: February 10, 2011
Published: April 22, 2011
r
2011 American Chemical Society
7517
dx.doi.org/10.1021/ja201012p J. Am. Chem. Soc. 2011, 133, 7517–7527
|

Journal of the American Chemical Society
ARTICLE
Figure 2. Enantiomeric scaffolding for substituted piperidine synthesis.
Figure 4. Key organometallic enantiomeric scaffolds.
These π-complexes of unsaturated O- and N-heterocyclic ligands
function as organometallic enantiomeric scaffolds.10,12 Ana-
logous CpMo(CO)2-based variants have also been investiga-
ted.13 Because the reactivity and selectivity traits of the organo-
metallic enantiomeric scaffolds are (mostly) independent of the
nature of the heterocycle ring, those common traits allow a single
synthetic strategy to be equally applied to the regio- and
stereocontrolled elaboration of both piperidine and tetrahydro-
pyran heterocycle families.14
Figure 3. Organometallic enantiomeric scaffolding: elements of regio-
and stereocontrol.
stereocenters, high stereocontrol in the final target is pre-
dicated upon the realization of efficient substrate- or reagent-
based stereocontrol tactics. Not surprisingly, stereoselectiv-
ities vary and depend on the identity of previously established
stereocenters.
Complementing the scaffolding efforts mentioned above,
organometallic enantiomeric scaffolds offer strategic advantage
for the systematic variation of structure in three dimensions
about the periphery of not just N- but also O-based six-
membered ring heterocycles. Here, conceptually simple, readily
available, single enantiomers of air- and moisture-stable organo-
metallic π-complexes of unsaturated heterocyclic ligands
function as enantiomeric scaffolds for the regio-, stereo-, and
enantiocontrolled construction of substituted heterocycle deri-
vatives (Figure 3). Functionalization of the organometallic
scaffold periphery uses some elements of reaction control that
are standard in synthetic organic chemistry, but owing to the
organometallic nature of the system, strategically novel ap-
proaches to bond formation and regio- and stereocontrol not
achievable using traditional organic systems are also feasible. The
scaffolds provide a single source of planar chirality that controls,
in a predictable and systematic fashion, the regio- and stereo-
controlled introduction of multiple substituents about nonplanar
heterocycles over multiple steps. Also, in contrast to traditional
metal catalysis where one metal atom influences one step of
many turnovers, in organometallic enantiomeric scaffolding
efficiency is achieved with one metal atom influencing multiple,
different steps, each of one turnover, for the controlled introduc-
tion of many substituents and many stereocenters. Not insignif-
icantly, the organometallic auxiliary can provide a dominant yet
highly tunable form of “substrate control” over both regio- and
stereochemistry, overriding perturbations by existing substitu-
ents on stereo- and regiochemistry.
Organometallic enantiomeric scaffolds should be particularly
well-suited for the construction of focused libraries employed
toward the exploration of structureꢀactivity relationships in 3D
chemical space. To exemplify this concept, we demonstrate
herein the use of 5-oxo-dihydropyridinyl scaffold 2 for (1) the
easy variation of critical substituents at different piperidine ring
positions throughout a synthetic sequence, (2) substituent
independent reactivity, diastereoselectivity, and enantioselec-
tivity, and (3) the stereodivergent introduction of substituents
at the 3-position of the piperidine ring. The potential of this
strategy for the synthesis of variously substituted piperidines is
specifically demonstrated by the stereodivergent construction
of 2,3,6-cis and 2,6-cis-3-trans piperidines from the same
high enantiopurity organometallic scaffold (ꢀ)-Tp(CO)2-
[(η-2,3,4)-(2S)-1-benzyloxycarbonyl-5-oxo-5,6-dihydro-
2H-pyridin-2-yl)molybdenum 2 in a substituent-independent
fashion (Scheme 1). These studies include the total syntheses
of 5 alkaloids: (()-indolizidine 209I,15 (()-8-epi-indolizidine
219F,16 and enantiocontrolled syntheses of indolizidine (ꢀ)-
251N,17 (ꢀ)-quinolizidine 251AA,18 and (ꢀ)-dehydroindolizidine
233E.19 The Harman group has recently described a novel and
elegant stereocontrolled approach to substituted piperidines
using a tungsten-mediated dearomatization of the pyridine
ring.20
’ RESULTS AND DISCUSSION
In an earlier disclosure from this laboratory,12j a highly
regioselective abstraction (>84:1) of methoxide carried out on
3-methyl 2,6-dimethoxy-(η-3,4,5)-dihydropiperidinyl molybde-
num complex 6 derived from the η3-pyridinylmolybdenum
complex 5 was described (Scheme 2). From scaffold 6, various
nucleophiles were sequentially introduced, first at the 2- and then
Our laboratory has studied the easily prepared, highly en-
antiopure, air- and moisture-stable complexes TpMo(CO)2-
(5-oxo-η3-dihydropyranyl/η3-dihydropyridinyl), 1ꢀ2,9 and
TpMo(CO)2(2-oxo-η3-dihydropyranyl/η3-dihydropyridinyl),
3ꢀ4,10 where Tp = hydridotrispyrazolylborato11 (Figure 4).
7518
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
at the 6-position. This methodology, coupled with effective
demetalation procedures, proved useful for the enantiocon-
trolled construction of substituted piperidines and the natural
product (ꢀ)-indolizidine 209B (Scheme 2).21 However, the first
generation preparation of organometallic dihydropyridinyl scaf-
folds such as 5 had clear tactical deficiencies: it was limited by a
substrate-specific enzymatic resolution to achieve high enantio-
purity material and involved a lengthy synthetic sequence
(8 steps from N-benzyl glycine).12j
This initial scaffolding strategy for constructing substituted
piperidines has now been rendered efficient, general, and sub-
stituent-independent. Rather than beginning with a substituent-
specific scaffold, the new strategy relies on the N-protected
5-oxo-η3-dihydropyridinyl scaffold 2, a general enantiomeric
platform (Scheme 3) that is easily prepared using an aza-
Achmatowicz tactic.9
Thus, Scheme 3 provides an overview of how 2,3,6-trisubsti-
tuted piperidine-based alkaloids are obtained from scaffold 2
beginning with the generalized 1,2-introduction of a carbanionic
substituent at the 5-position, providing the adducts 7ꢀ12 (refer
to Table 1 for specific structures). Dehydration provides the
stable η3-pyridinyl complexes 13ꢀ18 that undergo a novel and
high-yielding 2,6-oxidation of the scaffold with bromine in
methanol, generating intermediates I. Highly regio- and stereo-
selective synthetic protocols are then used to transform the
dimethoxy intermediates into the trisubstituted dihydropyridi-
nylmolybdenum complexes 30ꢀ41 (see Table 2 and Table 3 for
structures). Finally, two different stereodivergent demetalation
procedures can provide either 2,6-cis-3-trans or 2,3,6-cis trisub-
stituted dehydropiperidines in a fully stereocontrolled fashion
(see Table 4 for specific structures).
Preparation of the Organometallic Scaffolds. Using a
rapid-throughput aza-Achmatowicz-based sequence, simple
and scalable procedures were recently disclosed for the prepara-
tion of racemic (()-2a, as well as the related diastereomers (ꢀ)-
2b and (þ)-2b0, which represent the functional equivalents of
the separate antipodes of 2a (Figure 5).9
Scheme 1. Organometallic Enantiomeric Scaffolding: Con-
cise Stereodivergent Syntheses of Indolizidine, Dehydroin-
dolizidine, and Quinolizidine Alkaloids from a Common
Precursor
That synthetic procedure comprises treatment of N-protected
furfurylamines with m-CPBA followed by metalation of the crude
22
reaction mixture with Mo(DMF)3(CO)3 and finally ligand
exchange with KTp.23 Although isolated yields are modest, this
sequence can be conducted on a large scale without rigorous
purification of the intermediates and reproducibly provides
45% isolated yields of the 5-oxopyridinyl molybdenum scaffold
(()-2a. Applying the same sequence to furfurylamine (S)-
CO2CH(n-Pr)Ph urethane9 provided 36ꢀ39% isolated yields
of a 1:1 diastereomeric mixture of the N-protected oxopyridinyl
scaffolds (ꢀ)-2b and (þ)-2b0. These diastereoisomers were
Scheme 2. First Generation Organometallic Enantiomeric Scaffolding
Scheme 3. Overview: Substituent Independent Trifunctionalization Sequence Starting from Scaffold 2
7519
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
Figure 5. Oxopyridinylmolybdenum scaffolds.
Table 1. First Functionalization of the Scaffold; 5-Substituted
η3-Pyridinyl Complexes
(THF, ꢀ78 °C) consistently gave the corresponding alcohol in
low isolated yields (<35%) along with recovery of the starting
material. Using less polar reaction solvents, such as dichlorome-
thane25 or toluene, with commercially available solutions of
Grignard reagents in diethyl ether produced the corresponding
alcohols in 45ꢀ55% yield, with the remainder of the mass
balance representing recovery of the starting material 2a. Since
competitive deprotonation alpha to the ketone was likely re-
sponsible for the recovered starting material (after a protic
workup), the benefit of less basic organocerium reagents was
explored.26 Using a cerium-modified reagent derived from alkyl
Grignard reagents, alcohols 7ꢀ11 were obtained in 66ꢀ75%
yields (Table 1, entries 1ꢀ10). However, the cerium-modified
protocol did not improve the reaction with PhMgBr, which still
gave product in the 25ꢀ35% yield range using THF as solvent. In
this case, conversion to the alcohol 12a using PhMgBr was
improved to near 50% yield (Table 1, entry 11) when dichloro-
methane was the reaction solvent.
The outcome of the carbanion addition was independent of
the nature of the N-protecting group (Table 1, compare entries
1ꢀ3 and 4ꢀ6), and no epimerization27 of 7b, 8b, or 10b was
observed when the functionalization reaction was performed
using the chiral, nonracemic starting material 2b (Table 1, entries
2, 5, and 9). Finally, dehydration of alcohols 7ꢀ12 to the crucial
η3-pyridinylmolybdenum complexes 13ꢀ18 was easily achieved
upon their exposure to TFAA/Et3N. When using the chiral,
nonracemic system, excellent yields were obtained and full
retention of stereochemistry was observed27 for 13b, 14b, and
16b (Table 1). Therefore, in contrast to the previously reported
substituent-specific scaffold,12j the 5-oxopyridinyl scaffold 2
allows access to a broad range of 5-substituted η3-pyridinyl
complexes (13ꢀ18 in Table 1) that are suitable for further
functionalization.
Second Functionalization of the Scaffold. With a general
route to 5-substituted η3-pyridinylmolybdenum complexes in
hand, the next challenge was to develop a versatile, regio- and
stereodefined procedure for the introduction of additional
substituents about the heterocycle ring. We had previously
established that η3-pyranyl-12l and η3-pyridinylmolybdenum12j
complexes dissolved in CH2Cl2 reacted with bromine at ꢀ78 °C
followed by the addition of sodium methoxide to provide 2,6-
dimethoxy-functionalized molybdenum complexes in excellent
yields, a transformation analogous to the bromine-induced
oxidative dimethoxylation of furan.28 Unfortunately, this same
procedure when applied to the η3-pyridinylmolybdenum com-
plexes 13ꢀ17 led predominantly to decomposition of the
molybdenum complexes. However, by carrying out the bromina-
tion in neutral methanol as solvent, the 3-substituted-2,6-di-
methoxy-η3-dihydropyridinyl complexes, I, depicted in Table 2
were obtained with high efficiency. The bromine-mediated
2,6-dimethoxylation was compatible with alkyl, phenyl
(shown in Scheme 4), and alkene-bearing substituents as R1.
yield
no. (%)a
yield
(%)a
entry
#
R1
dr
#
dr
1
2
2a Me
2b Me
2c Me
2a Et
2b Et
2c Et
7a
7b
7c
8a
8b
8c
9a
9c
69
69 >99.5:0.5b 13b
13a12j 99
99 99.5:0.5
3
71
13c
99
4
68
14a
91
5
68 >99.5:0.5b 14b
91 99.5:0.5
6
75
67
71
14c
99
7
2a n-Pr
2c n-Pr
2b n-Bu
2a but-3-
enyl
15a
15c
91
8
99
9
10b 67
99.5:0.5 16b
17a
84 99.5:0.5
99
10
11a
66
11c
2a Ph
12a
49
18a
99
a Isolated yield. b As a surrogate for possible π-face racemization,
epimerization of the products derived from the high purity (>99.5:0.5
dr) diastereomer 2b was monitored by chromatography (HPLC col-
umn, Zorbax Eclipse C8). c The reaction was conducted without cerium
using PhMgBr with dichloromethane as the reaction solvent.
easily separated and obtained in excellent stereochemical purity
(>99.7:0.3 dr) on large scale by a simple chromatographic
separation on silica gel eluting with 15:1 toluene/EtOAc.24 Since
the oxopyridinyl scaffolds bearing either the N-Cbz or the N-(S)-
CO2CH(n-Pr)Ph urethane protecting groups display identical
reaction profiles in all synthetic manipulations explored to date,
the chiral, nonracemic urethane can be retained and used as a
Cbz equivalent. The availability of both of the π-facial antipodes
(ꢀ)-2b and (þ)-2b0 ensures accessibility to both enantiomers of
piperidine-based alkaloids.
For the current study, in order to obtain somewhat simpler 1H
NMR spectra to allow more rapid screening of reaction condi-
tions and reaction product analysis, racemic scaffold (()-2c
bearing a simple -CO2Me protecting group was also prepared
and used in a number of reaction sequences described within.
First Functionalization of the Scaffold. Installation of a
substituent at the 5-position was conducted on scaffolds 2
bearing three different N-protecting groups: (()-2a, PG =
Cbz; (ꢀ)-(1S, 2S)-2b, PG = (S)-CO2(n-Pr)CHPh; and (()-
2c, PG = CO2Me. The addition of Grignard reagents to the
ketonic functionality of 2a under standard reaction conditions
7520
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
Table 2. 6-Substituted 5-Alkylidene-η-2,3,4-Dihydropyridinylmolybdenum Complexes
a Isolated yield.
The η3-dihydropyridinyl complexes possessing ionizable methoxy
groups anti to the molybdenum, such as I, are typically somewhat
sensitive, so that their careful purification is of limited general
value. Therefore, with the exception of intermediate I, R1 = Et,
rather than purify, the crude materials were not analyzed but were
carried on without purification through the next functionali-
zation steps.
the molybdenum scaffolds.29 The resulting 6-substituted 5-alky-
lidene-η3-dihydropyridinylmolybdenum complexes were stable,
and the majority of the complexes (21ꢀ28) were characterized
by 1H NMR spectroscopy (urethane rotamers and double bond
stereoisomers rendered full spectroscopic characterization at this
stage difficult; full compound characterization took place at the
next reaction step). The very high regio- and stereocontrol
shown by the examples listed in Table 2 follows earlier
precedent12j and is fully supported by the synthesis of the various
natural products described below.
Consistent with previously described results,12j the ꢀ78 °C
addition of 1 equiv of triphenylcarbenium hexafluorophosphate
to the oxidative dimethoxylation adducts I of compounds 13ꢀ17
induced a highly regioselective abstraction of the methoxide
group adjacent to the R1 substituent. Subsequent addition of a
Grignard reagent produced the sensitive monosubstitution deri-
vatives II depicted in the graphic of Table 2. The instability of
these Grignard adducts under the reaction conditions, and to
subsequent chromatography, precluded their purification and full
characterization. As a practical alternative, rather than quenching
the reaction mixture 10 min after addition of the Grignard
reagent, the reaction mixture was allowed to warm to ꢀ40 °C
for 1 h in the presence of the Lewis acidic magnesium salts
generated under the reaction conditions. This process stimulated
loss of methanol from intermediates II and caused the formation
of stable exocyclic olefins 19ꢀ29 in very good yields (Table 2).
This one-pot reaction sequence was used for the introduction of
alkyl, functionalized alkyl, and alkenyl chains at the 2-position of
The exocyclic olefins 19ꢀ29 were isolated as mixtures of E
and Z isomers,30 the E-isomer predominating in all cases.
Assignment of stereochemistry to the exocyclic double bond
isomers was accomplished through a NOE experiment per-
formed on compound (E)-28: the proton Hb can clearly be
1
assigned by H NMR and, when irradiated, did not show any
correlation with Hc, whereas strong interactions were observed
between Hb and the terminal allylic proton Ha (Figure 6; refer to
the Supporting Information for the NOE experiment). Although
the exocyclic olefin isomers were found to equilibrate during slow
silica gel column chromatography and upon SiO2 thin-layer
chromatography (but not during flash chromatography31),
no isomerization was observed during the 1HNMRNOEexperiment.
Third Functionalization of the Scaffold. As a model reac-
tion to probe additional functionalizations about the scaffold
7521
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
Table 3. Introduction of Functional Groups at the Scaffold 6-Position Using Copper-Modified Grignard Reagents
a Isolated yield. b As a surrogate for possible π-face racemization, epimerization of the products derived from the high enantiopurity (>99.5:0.5 dr)
diastereomers 19, 23, and 28 was monitored by chromatography (HPLC column, Zorbax Eclipse C8).
periphery, protonation of the exocyclic double bond of molyb-
denum complex 20 with tetrafluoroboric acid proceeded smoothly32
to generate the corresponding cationic η4-diene intermediate III
(Table 3).33 Subsequent nucleophilic functionalization of the
cationic complex using n-propylMgCl took place adjacent to the
ring nitrogen and anti to the TpMo(CO)2 moiety. Unfortu-
nately, with a Grignard reagent as the nucleophile, the desired
product 31 was always accompanied by recovery of some starting
material. These observations are consistent with a competition
between nucleophilic addition at C2 of the cation diene complex
III and its deprotonation by the basic Grignard reagent to
regenerate the material 20 (Table 3). The undesired deprotona-
tion, a side reaction observed in related systems,34 was minimized by a
switch to in situ generated, copper-modified Grignard reagents
Table 3 a wide variety of 2,3,6-trisubstituted dihydropiperidinylmo-
lybdenum complexes can be constructed using this chemistry.
A number of copper-modified Grignard reagents add at the
6-position of the scaffold in very good yields (Table 3). Of
importance, those reactions carried out with chiral, nonracemic
starting materials 19, 23, and 28 did not show any epimerization
of the final products (Table 3, entries 1, 7, and 12).27 The total
synthesis of the various natural products described later in this
manuscript provided full confirmation of the reactivity pattern
shown in Table 3. Thus, after four steps from scaffold 2 a large
number of trisubstituted piperidine precursors can be obtained,
where R1, R2, and R3 are introduced independently from each
other and in a fully regio- and stereocontrolled fashion.
Stereodivergent Demetalations of the Scaffold. One virtue
of organometallic enantiomeric scaffolding is the ability to use
organometallic reaction fundamentals to affect a divergent
stereochemical outcome of a reaction from the same starting
(RMgX and CuBr DMS). Using this reagent system the expected
3
products 30ꢀ41 were obtained from the 5-alkylidene dihydropyr-
idinyl complexes 19ꢀ29 in good to excellent yields. As depicted in
7522
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
Table 4. Regiospecific and Stereodivergent Demetalations
a Isolated yield.
Scheme 4. Sequential Functionalization of (()-Tp(CO)2(η3)-Pyridinylmolybdenum 18
material. For example, it was previously demonstrated that
3-substituted η3-3,4,5-pyranyl12l and -pyridinylmolybdenum
complexes12j could be demetalated in a stereodivergent fashion
relative to the 3-substituent. Demetalation using a CO/NOþ
ligand exchange followed by nucleophilic attack of hydride on the
resulting cationic intermediate at the more substituted terminus
of the π-complex and anti to the TpMo(CO)(NO)þ moiety35
(Method A) delivered one stereoisomer, while protodemetala-
tion under acidic conditions12k,13a (Method B) placed hydrogen,
also at the more substituted end of the η3-allylmolybdenum, but
syn to the TpMo unit. Using these same stereodivergent deme-
talation procedures the η3-allylmolybdenum complexes 30,
32ꢀ40 were easily converted to either 2,6-cis-3-trans or 2,3,
6-cis trisubstituted dehydropiperidines. Reductive demetalation
of 2,3,6-trisubstituted molybdenum complexes (30, 32ꢀ35, 39,
40) in DME as the solvent gave 2,6-cis-3-trans 43ꢀ48 in
52ꢀ61% isolated yield, with complete regio-, stereo- and
enantiocontrol (Table 4, entries 1ꢀ7). Alternatively, acidic
protodemetalation of complexes 32 and 40 with HCl in CH3CN
afforded the unsaturated 2,3,6-cis-dehydropiperidines 49 and 50
in 42ꢀ66% isolated yields. The use of acetonitrile as the solvent
moderates the acidity of the system and helps to minimize the
formation of the more substituted olefin regioisomer.12j
The scope of the reductive demetalation protocol is fairly
broad (Table 4, entries 1ꢀ7), although an acid-sensitive acetal
was not well-tolerated during the acidic protodemetalation
process; an ethylene glycol protected aldehyde (not shown)
was hydrolyzed producing a moderate yield of the corresponding
aldehyde. However, by substituting 2,2-dimethyl-1,3-diol for
ethylene glycol for protection of the aldehyde, a more robust
ketal was produced. In this case the expected protodemetalation
product 49 was isolated in 66% yield from the acidic
7523
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
Scheme 6. Demonstration of Stereodivergence: Synthesis of
Indolizidine (()-8-epi-219F
Figure 6. NOE experiment on compound (E)-28.
Scheme 5. Total Synthesis of Indolizidine (()-209I
and is limited to construction of the indolizidine skeleton. Ma
took advantage of a formal [4 þ 2] cycloaddition of a chiral,
nonracemic 3-chloro-1-substituted-amine with a substituted
propiolic acid ester to form a substituted piperidine core.
Charette approached (ꢀ)-209I via a novel Grob fragmentation
of an aza-bicyclo[2.2.2]octene. Michael described a formal synthesis
of (ꢀ)-209I in over 20 steps commencing with tert-butyl
hexenoate.37a An asymmetric synthesis of (ꢀ)-219F was de-
scribed by Toyooka and co-workers16a,b where the common
precursor 2,6-disubstituted tetrahydropyridine was derived from
amino adipic acid through 8 transformations. Toyooka also
described total syntheses of (ꢀ)-251AA18 and (ꢀ)-251N17
using the same synthetic approach. No synthesis of indolizidine
233E has yet been reported based on a Scifinder search per-
formed on November 29, 2010.
Using the organometallic scaffolding strategy, a total synthesis
of indolizidine (()-209I15,37 was undertaken first. Compound
47, described above (Table 4, entry 6), underwent a one-pot
hydrogenation/hydrogenolysis that saturated the double bond
and cleaved the benzylic protecting group from the primary
alcohol. Compound 53, obtained in near quantitative yield,
possessed the same NMR signatures as the same compound
obtained by Charette in his synthesis of (ꢀ)-209I.40 Without
further purification a classical Mitsunobu reaction was carried
out,41 providing the desired indolizidine (()-209I in 75% yield.
In contrast to the generation of the 2,6-cis-3-trans dehydropi-
peridine substitution pattern used in the first scaffold-based
synthesis, the second scaffolding sequence highlights the use
of the stereodivergent demetalation tactic to construct the
unnatural 2,3,6-cis dehydropiperidine from which indolizidine
(()-8-epi-219F16b was derived (Scheme 6). Compound 49,
which can be synthesized from scaffold 2a in 6 steps, was
catalytically hydrogenated to afford the trisubstituted piperidine
54 that was directly carried forward to aldehyde 55. For removal
of the robust 5,5-dimethyl-1,2-dioxane acetal, standard acid-
catalyzed hydrolysis conditions were ineffective. Rather, cleavage
of this acetal group was achieved by treatment with a buffered
solution of formic acid. The formic acid serves as both a proton
source for the catalysis as well as a trap for the 1,3-diol produced
upon hydrolysis.42 Application of these conditions to substrate
54 led quantitatively to aldehyde 55.
demetalation conditions (Table 4, entry 8). Using both protocols
(reductive or protodemetalation), a series of 2,6-cis-3-trans and
2,3,6-cis dehydropiperidines was obtained in reasonable isolated
yields (52ꢀ66%). Together, these two demetalation methods
allow the sequential functionalizations depicted above to serve as
a versatile strategy for the generation of a variety of trisubstituted
4,5-dehydropiperidines from the common scaffold 2.
The trifunctionalization of the η3-pyridinylmolybdenum scaf-
folds is not restricted to substituents attached at the 5-position of
the scaffold through an sp3-carbon. For example, bromine-
induced oxidative dimethoxylation of the (()-TpMo(CO)2(5-
phenyl-η3-pyridinyl) complex 18 generates the intermediate IV
shown in Scheme 4. Two subsequent methoxide ionization/
carbanion addition sequences (TrPF6 then MeMgBr; HBF4 then
CuBr DMS/i-PrMgBr) provides the trifunctionalized dihydro-
3
pyridinyl complex 51 in 53% overall yield. Activation of 51 with
NOPF6 followed by treatment with NaCNBH3 stereospecifically
delivers the 2,3,6-trisubstituted-4,5-dehydropiperidine 52 in
61% yield.
Total Synthesis of Indolizidine and Quinolizidine Alka-
loids. The piperidine ring is embedded within the pharmacolog-
ically active indolizidine and quinolizidine families of alkaloid
natural products, of which many hundreds of structurally diverse
examples have been detected and identified from amphibian
skin.19b,36 To showcase the concept of organometallic scaffolding,
syntheses of the indolizidine alkaloids (()-209I,15,37 (()-8-epi-
219F,16b and (ꢀ)-251N,17 the quinolizidine alkaloid (ꢀ)-251AA,18
and 6,7-dehydroindolizidine (ꢀ)-233E19 were undertaken,
all from the common scaffold 2 (Schemes 5ꢀ8). Two of the
syntheses were carried out in the racemic series, and three used
the high enantiopurity scaffold.
Alkaloids (ꢀ)-209I, (ꢀ)-219F, (ꢀ)-251N, (ꢀ)-251AA, and
(ꢀ)-233E were first reported by Daly.16c,19,36b,38 A total synthe-
sis of (()-209I was described by Rassat and co-workers where
the 9-azabicyclo[3.3.1]nonane skeleton was derived from a
symmetrical 1,5-octanediepoxide.15 This racemic series approach
allowed the formation of both indolizidine and quinolizidine
families through a flexible installation of functional side chains.
Asymmetric syntheses of (ꢀ)-209I were accomplished by
Enders,37b Ma,39 and Charette.40 Enders approached the indo-
lizidine skeleton from a chiral nonracemic pyrrolidine hydrazone,
in which the 8-substituent was preinstalled. The Enders’ strategy
required preinstallation of a substituent in the starting material
Prior to generation of the indolizidine aldehyde 55 was
converted into the corresponding terminal alkyne 57 in 73%
yield using dimethyl (1-diazo-2-oxopropyl)phosphonate 56.43
After some exploration of debenzylation conditions,44 the free
alcohol intermediate 58 was obtained from 57 using boron
trichloride. A Mitsunobu reaction transformed this intermediate
to the intended indolizidine (()-8-epi-219F in 70% yield.
7524
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
Scheme 7. Synthesis of Quinolizidine (ꢀ)-251AA HCl and Indolizidine (ꢀ)-251N HCl
3
3
Scheme 8. Synthesis of (ꢀ)-6,7-Dehydroindolizidine 233E
Sequences involving the chiral, nonracemic scaffolds for the
synthesis of indolizidines and quinolizidines of high enantiopur-
ity are shown in Scheme 7. The synthesis of indolizidine (ꢀ)-
251AA18 was achieved in 8 steps from scaffold 2b. A one-pot
hydrogenation/hydrogenolysis of compound 46 led to the
isolation of compound (ꢀ)-59 in 89% yield. A subsequent
Mitsunobu reaction provided the expected quinolizidine (ꢀ)-
251AA in 67% yield. The same sequence was used for a total
synthesis of indolizidine (ꢀ)-251N,17 starting from compound
48 (obtained in 6 steps from chiral, nonracemic complex 2b) and
proceeding through intermediate 60 (Scheme 7).
The diastereomeric excess of precursors (ꢀ)-46 and (ꢀ)-48
was determined by HPLC (>99.5:0.5 dr).27 Since the molybde-
num scaffolds described in this study showed no evidence of
π-face racemization,27 the quinolizidine (ꢀ)-251AA and indoli-
zidine (ꢀ)-251N, produced by the hydrogenation/hydrogeno-
lysis/Mitsunobu reaction sequence, are assumed to have an
enantiomeric ratio of >99.5:0.5.
Finally, a total synthesis of 6,7-dehydroindolizidine (ꢀ)-
233E19 was carried out (Scheme 8). From the trisubstituted
dehydropiperidine (ꢀ)-42, deprotection of the benzyl alcohol
and the urethane in the presence of the two double bonds was
achieved using BCl3. A subsequent Mitsunobu reaction delivered
6,7-dehydroindolizidine (ꢀ)-233E in 54% isolated yield over the
two steps. The diastereomeric ratio of the precursor (ꢀ)-42 was
>95.5:0.5 as assayed by HPLC. Therefore, just as described for
quinolizidine (ꢀ)-251AA and indolizidine (ꢀ)-251N above,
since no evidence of π-face racemization is found in the trans-
formations described within,27 6,7-dehydroindolizidine (ꢀ)-233E,
produced by the deprotection/Mitsunobu reaction sequence, is
assumed to have an enantiomeric ratio of >99.5:0.5.
chiral, nonracemic relatives, (ꢀ)-2b and (þ)-2b0, allows the
TpMo(CO)2(5-oxo-η3-pyridinyl) system to be used as a plat-
form for a variety of versatile and efficient peripheral functiona-
lizations. The nucleophilic addition of organocerium reagents to
the ketone, followed by a highly regioselective ionization/nu-
cleophilic addition/ionization sequence, led to the controlled
functionalization of the 2- and 3-positions. A third functionaliza-
tion at C-6 (treatment with HBF4 followed by nucleophilic
addition) leads to 2,6-cis-3-substituted piperidine precursors,
which after stereodivergent demetalation gives access to either
2,6-cis-3-trans or 2,3,6-cis trisubstituted piperidines of high
enantiopurity. This sequential functionalization of scaffold 2
was highlighted by the total synthesis of four naturally occurring
alkaloids and one non-natural alkaloid.
The TpMo(CO)2 unit shields one face of the π-ligand.
Therefore, nucleophiles approach the organometallic scaffolds
from the π-face opposite the TpMo(CO)2 moiety leading to the
dominant introduction of substituents around the scaffold per-
iphery with cis relative stereochemistry. Thus, the 2- and 6-posi-
tions of the piperidine ring are easily adorned with a variety of
substituents placed with cis relative stereochemistry.12g,j,l,m Two
different stereodivergent demetalation protocols enabled the
3-substituent to be oriented either cis or trans to the cis-2,6-
substitutent pair leading to cis-2,3,6-trisubstituted and 2,6-cis-3-
trans-trisubstituted dehydropiperidines.45 Finally, the use of
organometallic enantiomeric scaffolds is currently under con-
sideration for the generation of focused libraries in order to probe
chemical space not easily addressed using traditional synthetic
organic methods.
’ ASSOCIATED CONTENT
’ CONCLUSIONS
S
Supporting Information. Full experimental details and
b
The efficient and scalable synthesis of the racemic TpMo-
(CO)2(5-oxo-η3-pyridinyl) scaffolds, ( ( )-2a, (()-2c, and their
characterization data for all compounds and copies of proton
and carbon NMR spectra of all new compounds prepared.
7525
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
This material is available free of charge via the Internet at http://
pubs.acs.org.
(12) (a) Coombs, T. C.;Zhang, Y.;Garnier-Amblard, E. C.;Liebeskind,
L. S. J. Am. Chem. Soc. 2009, 131, 876–877. (b) Cheng, B.; Liebeskind, L. S.
Org. Lett. 2009, 11, 3682–3685. (c) Chen, W.; Liebeskind, L. S. J. Am. Chem.
Soc. 2009, 131, 12546–12547. (d) Arrayꢀas, R. G.; Yin, J.; Liebeskind, L. S.
J. Am. Chem. Soc. 2007, 129, 1816–1825. (e) Zhang, Y.; Liebeskind, L. S.
J. Am. Chem. Soc. 2006, 128, 465–472. (f) Zhang, Y.; Liebeskind, L. S. J. Am.
Chem. Soc. 2005, 127, 11258–11259. (g) Shu, C.; Liebeskind, L. S. J. Am.
Chem. Soc. 2003, 125, 2878–2879. (h) Arrayꢀas, R. G.;Liebeskind, L. S.J. Am.
Chem. Soc. 2003, 125, 9026–9027. (i) Alcudia, A.; Arrayꢀas, R. G.; Liebes-
kind, L. S. J. Org. Chem. 2002, 67, 5773–5778. (j) Shu, C.; Alcudia, A.; Yin, J.;
Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123, 12477–12487. (k) Arrayꢀas,
R. G.; Liebeskind, L. S. J. Am. Chem. Soc. 2001, 123, 6185–6186. (l) Yin, J.;
Llorente, I.; Villanueva, L. A.; Liebeskind, L. S. J. Am. Chem. Soc. 2000,
122, 10458–10459. (m) Moretto, A. F.; Liebeskind, L. S. J. Org. Chem. 2000,
65, 7445–7455. (n) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000,
2, 4083–4086. (o) Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000,
2, 3909–3911. (p) Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc. 1999,
121, 5811–5812.
’ AUTHOR INFORMATION
Corresponding Author
lanny.liebeskind@emory.edu
Present Addresses
†Lonza AG, 68 N. Huangge Ave, Guangzhou 511455, P. R. China.
’ ACKNOWLEDGMENT
This work was supported by Grant GM043107, awarded by
the National Institute of General Medical Sciences, DHHS.
(13) (a) Rubio, A.; Liebeskind, L. S. J. Am. Chem. Soc. 1993,
115, 891–901. (b) Hansson, S.; Miller, J. F.; Liebeskind, L. S. J. Am.
Chem. Soc. 1990, 112, 9660–9661.
’ REFERENCES
(1) Cross-Coupling Reactions: A Practical Guide; Miyaura, N., Ed.;
Springer-Verlag: Berlin, Heidelberg, New York, 2006.
(2) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077–1101.
(3) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Wein-
heim, 2002.
(14) While substituent introduction anti to the large TpMo(CO)2
moiety is the norm, substituents can be introduced syn to the metalꢀ
ligand unit through appropriate tactics. See: Rubio, A.; Liebeskind, L. S.
J. Am. Chem. Soc. 1993, 115, 891–901. Also see Supporting
Information to Ward, Y. D.; Villanueva, L. A.; Allred, G. D.; Liebeskind,
L. S. J. Am. Chem. Soc. 1996, 118, 897–898. Additional, general
approaches to functionalization syn to the TpMo(CO)2 moiety have
been uncovered and will be disclosed in due course.
(4) Hartung, C. C.; Snieckus, V. In Modern Arene Chemistry; Astruc,
D., Ed.; Wiley-VCH: Weinheim, 2002; p 330.
(5) (a) Over 12,000 piperidine entities have been mentioned in
clinical or preclinical studies. See: Watson, P. S.; Jiang, B.; Scott, B. Org.
Lett. 2000, 2, 3679–3681. (b) Murphy, P. V.; Dunne, J. L. Curr. Org.
Synth. 2006, 3, 403–437. (c) Daly, J. W. Cell. Mol. Neurobiol. 2005,
25, 513–552. (d) Gao, Z.; Hartung, R.; Stefany, D. Pct Int. Appl. WO
2010065798 A1, 2010. (e) Spoors, P. G.; Kallander, L. S.; Claremon,
D. A. Pct Int. Appl. WO2009038719 A1, 2009. (f) Kharkar, P. S.; Reith,
M. E. A.; Dutta, A. K. J. Comput. -Aided Mol. Des. 2008, 22, 1–17.
(g) Cerma, A. K.; Malhotra, S. R.; Abhijit, K.; Shirumalla, R. Patent
EP1834953 A1, 2007. (h) Yang, W.-Q.; Ishigami, K.; Kitahara, T. Proc.
Jpn. Acad., Ser. B 2001, 77B, 157–160. (i) Shi, G.; Alfonso, D.; Fatope,
M. O.; Zeng, L.; Gu, Z.-M.; Zhao, G.-X.; He, K.; MacDougal, J. M.;
McLaughlin, J. L. J. Am. Chem. Soc. 1995, 117, 10409–10410.
(6) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680. (b) Laschat, S.; Dickner,
T. Synthesis 2000, 1781–1813. (c) Dhavale, D. D.; Desai, V. N.; Saha,
N. N.; Tilekar, J. N. ARKIVOC 2002, 91–105. (d) Weintraub, P.
Tetrahedron 2003, 59, 2953–2989. (e) Buffat, M. G. P. Tetrahedron
2004, 60, 1701–1729. (f) Cossy, J. Chem. Rec. 2005, 5, 70–80.
(g) Dhavale, D. D.; Matin, M. M. ARKIVOC 2005, iii, 110–132. (h)
Pearson, M. S. M.; Mathꢀe-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur.
J. Org. Chem. 2005, 2005, 2159–2191. (i) Escolano, C.; Amat, M.; Bosch, J.
Chem.—Eur. J. 2006, 12, 8198–8207. (j) Ravindran, G.; Muthusubrama-
nian, S.; Perumal, S. ARKIVOC 2008, xiii, 57–64. (k) Joseph, S.; Comins,
D. L. Curr. Opin. Drug Discovery Dev. 2002, 5, 870–880. (l) Guilloteau-
Bertin, B.; Compꢁere, D.; Gil, L.; Marazano, C.; Das, B. C. Eur. J. Org. Chem.
2000, 1391–1399. (m) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999,
28, 383–394. (n) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7, 2747–
2750.(o) Toyooka, N.; Nemoto, H. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2003; Vol. 29,
pp 419ꢀ448.
(15) Michel, P.; Rassat, A.; Daly, J. W.; Spande, T. F. J. Org. Chem.
2000, 65, 8908–8918.
(16) (a) Toyooka, N.; Zhou, D.; Nemoto, H.; Garraffo, H. M.;
Spande, T. F.; Daly, J. W. Beilstein J. Org. Chem. 2007, 3, 29. (b)
Toyooka, N.; Dejun, Z.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.;
Daly, J. W. Tetrahedron Lett. 2006, 47, 581–582. (c) Garraffo, H. M.;
Caceres, J.; Daly, J. W.; Spande, T. F.; Andriamaharavo, N. R.; An-
driantsiferana, M. J. Nat. Prod. 1993, 56, 1016–1038.
(17) Toyooka, N.; Dejun, Z.; Nemoto, H.; Garraffo, H. M.; Spande,
T. F.; Daly, J. W. Heterocycles 2006, 70, 541–548.
(18) Toyooka, N.; Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.;
Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H. M.; Spande, T. F. Bioorg.
Med. Chem. Lett. 2007, 17, 5872–5875.
(19) (a) Saporito, R. A.; Donnelly, M. A.; Madden, A. A.; Garraffo,
H. M.; Spande, T. F. J. Nat. Prod. 2010, 73, 317–321. (b) Daly, J. W.;
Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556–1575.
(20) Harrison, D. P.; Sabat, M.; Myers, W. H.; Harman, W. D. J. Am.
Chem. Soc. 2011, 132, 17282–17295.
(21) (a) Wu, H.; Yu, M.; Zhang, Y.; Zhao, G. Chin. J. Chem. 2009,
27, 183–188. (b) Michael, J. P.; Accone, C.; de Koning, C. B.; van der
Westhuyzen, C. W. Beilstein J. Org. Chem. 2008, 4, 5. (c) Kobayashi,
S.; Toyooka, N.; Zhou, D.; Tsuneki, H.; Wada, T.; Sasaoka, T.; Sakai,
H.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Beilstein
J. Org. Chem. 2007, 3, 30. (d) Toyooka, N.; Dejun, Z.; Nemoto, H.;
Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006,
47, 577–580.
(22) Pasquali, M.; Leoni, P.; Sabatino, P.; Braga, D. Gazz. Chim. Ital.
1992, 122, 275–277.
(23) Trofimenko, S. J. Am. Chem. Soc. 1967, 89, 3170–3171.
(24) The solubilities of (ꢀ)-2b and (þ)-2b0 were sufficiently
different in various ethereal solvents that their large-scale separation is
potentially feasible upon an eventual engineering of the crystallization
process.
(25) The use of CH2Cl2 as solvent for Grignard addition has been
reported: Wakefield, B. J. In Organomagnesium Methods in Organic
Synthesis, Academic Press, London, 1995, while dilution of a THF
solution of commercial Grignard reagent by Et2O has been reported
for a vinyl addition to β-formyl amide: Schleich, S.; Helmchen, G. Eur. J.
Org. Chem. 1999, 2515ꢀ2521.
(7) Comins, D. L. J. Heterocycl. Chem. 1999, 36, 1491–1500.
(8) Compꢁere, D.; Marazano, C.; Das, B. C. J. Org. Chem. 1999,
64, 4528–4532.
(9) Coombs, T. C.; Lee, M. D., IV; Wong, H.; Armstrong, M.;
Cheng, B.; Chen, W.; Moretto, A. F.; Liebeskind, L. S. J. Org. Chem.
2008, 73, 882–888.
(10) Garnier, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2008,
130, 7449–7458.
(11) Trofimenko, S. Chem. Rev. 1972, 72, 497–509.
7526
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527

Journal of the American Chemical Society
ARTICLE
(26) Organocerium reagents dramatically suppress enolization dur-
ing nucleophilic addition to hindered and highly enolizable carbonyl
compounds. For representative references, see: (a) Krasovskiy, A.;
Kopp, F.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 497–500. (b)
Imamoto, T. Pure Appl. Chem. 1990, 62, 747–752. (c) Imamoto, T.;
Takiyama, No.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am. Chem. Soc.
1989, 111, 4392–4398. (d) Denmark, S. E.; Weber, T.; Piotrowski,
D. W. J. Am. Chem. Soc. 1987, 109, 2224–2225. (e) Imamoto, T.;
Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.; Hatanaka, Y.;
Yokoyama, M. J. Org. Chem. 1984, 49, 3904–3912.
(44) Debenzylation in the presence of an unprotected terminal
alkyne was reported. See: (a) Kurosawa, W.; Kobayashi, H.; Kan, T.;
Fukuyama, T. Tetrahedron 2004, 60, 9615–9628. (b) Caldwell, J. J.;
Colmon, R.; Kerr, W.; Magennis., E. J. Synlett 2001, 1428–1430. (c)
Ohrui, H.; Kohgo, S.; Kitano, K.; Sakata, S.; Kodama, E.; Yoshimura, K.;
Matsuoka, M; Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000,
43, 4516–4525. (d) Schmitz, W. D.; Messerschmidt, N. B.; Romo, D.
J. Org. Chem. 1998, 63, 2058–2059. (e) Foff, D. A.; Harris, R. N., III;
Bottaro, J. C.; Bedford, C. D. J. Org. Chem. 1986, 51, 4711–4714.
(f) Qureshi, S.; Shaw, G. J. Chem. Soc., Perkin Trans. 1 1985, 875–882.
(45) The ability to elaborate the periphery of both hydropyrans and
piperidines was expanded recently, a significant aspect being the
placement of substituents syn to the TpMo(CO)2 unit: (a) Lee,
M. D., IV Ph.D. Thesis, Emory University, 2008. (b) Cheng, B. Ph.D.
Thesis, Emory University, 2008. (c) Coombs, T. C. Ph.D. Thesis, Emory
University, 2008.
(27) The diastereomers (ꢀ)-2b and (þ)-2b0 represent the func-
tional equivalents of the separate antipodes of 2a. In transformations of
the diastereomers (ꢀ)-2b and (þ)-2b0 and of their downstream
reaction derivatives, diastereomer epimerization is used as a surrogate
for possible π-face racemization. In all cases explored to date, high
diastereopurity (>99.5:0.5 dr, monitored by high pressure liquid chro-
matography using a Zorbax Eclipse C8 column) is observed for reaction
products derived from (ꢀ)-2b and (þ)-2b0.
(28) Clauson-Kass, L. Acta Chem. Scand. 1947, 619–622.
(29) It is likely that aromatic and heteroaromatic carbon nucleo-
philes will also be effective (for example, see reference 12j), but they
were not systematically explored in this project. 3-Furanyllithium/CuBr
was briefly investigated as a carbon nucleophile, but the single experi-
ment was rendered problematic by isomerization of the 3-furanyl lithiate
to the 2-furanyl lithiate under the reaction conditions.
(30) The E and Z stereoisomers equilibrate during silica gel chro-
matography. An analytical sample of pure E-28 was eventually obtained
by careful column chromatography on SiO2 eluting with toluene. For all
other isomers, no separation was performed and the mixtures were used
directly in the next step.
(31) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923–2925.
(32) Pearson, A. J.; Ghidu, V. P. Org. Lett. 2002, 4, 4069–4071.
(33) Protonation of the exocyclic olefins was slow. IR spectroscopy
was used to monitor the protonation process and determine when the
protonation was complete. A gradual disappearance of two starting
material bands (one in the 1800s and the other in the 1900s cmꢀ1) and a
buildup of two new bands, one in the 1900s and one in the low
2000s cmꢀ1, was observed.
(34) (a) Pearson, A. J. Aust. J. Chem. 1976, 29, 1101–1103. (b)
Pearson, A. J. Aust. J. Chem. 1977, 30, 345–350. (c) Potter, G. A.;
McCague, R. J. Chem. Soc., Chem. Commun. 1992, 635–637.
(35) (a) Faller, J. W.; Rosan, A. M. J. Am. Chem. Soc. 1976,
98, 3388–3389. (b) Faller, J. W.; Rosan, A. M. J. Am. Chem. Soc. 1977,
99, 4858–4859. (c) Villanueva, L. A.; Ward, Y. D.; Lachicotte, R.;
Liebeskind, L. S. Organometallics 1996, 15, 4190–4200.
(36) (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626. (b) Daly,
J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon Press: Amsterdam, 1999;
Vol. 13, pp 1ꢀ161.
(37) (a) de Koning, C.; Michael, C. J.; Rile, D. Heterocycles 2009,
79, 935–953. (b) Enders, D.; Thiebes, C. Synlett 2000, 1745–1748.
(38) Daly, J. W.; Garraffo, H. M.; Spande, T. F.; Giddings, L.-A.;
Saporito, R. A.; Vieites, D. R.; Vences, M. J. Chem. Ecol. 2008,
34, 252–279.
(39) Yu, S.; Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 7364–7370.
(40) Lemonnier, G.; Charette, A. B. J. Org. Chem. 2010, 75, 7465–
7467.
(41) The intramolecular Mitsunobu reaction was superior to the
conventional ring-closure procedure (PPh3/CBr4/Et3N), providing the
cyclization product in a shorter reaction time and a better yield. For a
leading reference, see: Bernotas, R. C.; Cube, R. V. Tetrahedron Lett.
1991, 32, 161–164.
(42) Kanda, Y.; Kawanishi, Y.; Oda, K.; Sakata, T.; Mihara, S.-i.;
Asakura, K.; Kanemasa, T.; Ninomiya, M.; Fujimotoa, M.; Konoike, T.
Bioorg. Med. Chem. 2001, 9, 897–907.
(43) Roth, G. J.; Liepold, B.; M€uller, S. G.; Bestmann, H. J. Synthesis
2004, 59–62.
7527
dx.doi.org/10.1021/ja201012p |J. Am. Chem. Soc. 2011, 133, 7517–7527