Forming tertiary organolithiums and organocuprates from nitrile precursors and their bimolecular reactions with carbon electrophiles to form quaternary carbon stereocenters

Article abstract of DOI:10.1002/anie.201205001

Unstabilized tertiary organolithium intermediates are conveniently generated by reductive decyanation of nitriles, and these reagents and their derived cuprates couple in useful yields with carbon- centered electrophiles (see example). Chiral tertiary org

Full text of DOI:10.1002/anie.201205001

Angewandte
Chemie
DOI: 10.1002/anie.201205001
Synthetic Methods
Forming Tertiary Organolithiums and Organocuprates from Nitrile
Precursors and their Bimolecular Reactions with Carbon Electrophiles
to Form Quaternary Carbon Stereocenters**
Martin J. Schnermann, Nicholas L. Untiedt, Gonzalo Jimꢀnez-Osꢀs, Kendall N. Houk,* and
Larry E. Overman*
The stereoselective formation of quaternary carbons is one of
the most demanding challenges in organic synthesis.[1] An
especially direct way to construct such stereocenters would be
to combine a prochiral tertiary organometallic and a carbon-
centered electrophile (Scheme 1A). However, this strategy is
not mentioned in the numerous reviews of stereoselective
synthesis of chiral quaternary carbons,[1] and to our knowl-
edge has never been employed in target-directed organic
synthesis. This omission undoubtedly derives from the
challenge in generating tertiary organometallic intermediates,
particularly those containing three alkyl substituents.[2–4] We
were recently drawn to explore this undeveloped approach
for forming quaternary carbon stereocenters in the context of
fashioning the demanding C8–C14 bond and the C8 quater-
nary stereocenter of rearranged spongian diterpenes such as
aplyviolene (4) and dendrillolide A (5) by the reaction of
tertiary organocuprate 1 and cyclopentenone 2. This coupling
was anticipated to take place from the convex face of
Scheme 1. A) Forming quaternary carbon stereocenters by the reaction
of prochiral tertiary organometallics and a carbon-centered electrophile
[*] Dr. M. J. Schnermann, N. L. Untiedt, Prof. L. E. Overman
Department of Chemistry, University of California, Irvine
and B) the potential use of this strategy to synthesize rearranged
1102 Natural Sciences II, Irvine, CA 92697-2025 (USA)
spongian diterpenes such as aplyviolene and dendrillolide A.
E-mail: leoverma@uci.edu
Homepage: http://faculty.sites.uci.edu/overman/
Dr. G. Jimꢀnez-Osꢀs, Prof. K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095-1569 (USA)
E-mail: houk@chem.ucla.edu
nucleophile 1 and from the face of 2 opposite the branched
side chain (Scheme 1B).[5]
We report herein that a) unstabilized tertiary organo-
lithium intermediates can be conveniently generated by
reductive decyanation of nitrile precursors and that these
reagents and their derived cuprates couple in useful yields
with carbon-centered electrophiles, b) chiral tertiary organo-
lithium and organocuprate intermediates in the cis-per-
hydroazulene and cis-perhydropentalene series react with
electrophiles with high diastereoselectivity from the osten-
sibly more-hindered concave face, and c) computational
studies that suggest the origin of this unexpected diastereo-
selectivity.
Homepage: http://www.chem.ucla.edu/houk/
[**] We thank Dr. Joe Ziller, University of California, Irvine, for the single-
crystal X-ray analyses and Dr. John Greaves, University of California,
Irvine, for mass spectrometric analyses. This research was sup-
ported by the NIH Neurological Disorders & Stroke Institute (Grant
R01-NS12389), the NIH National Institutes of General Medical
Sciences (Grant R01-GM098601), and NIH and MECD postdoctoral
fellowships for M.J.S. (CA138084) and G.J.O (EX2010-1063). NMR
spectra, mass spectra, and the X-ray analyses were obtained at UC
Irvine using instrumentation acquired with the assistance of NSF
and NIH Shared Instrumentation grants. Computations were
performed on the National Science Foundation Terascale Comput-
ing System at the National Center for Supercomputing Applications
(NCSA), San Diego Supercomputing Center (SDSC), the California
NanoSystems Institute clusters, and the UCLA Hofman2 cluster at
IDRE. We thank Dr. Nathan E. Genung for experimental assistance.
Unrestricted funds from Amgen and Merck are also gratefully
acknowledged.
ꢀ
Reductive lithiation of C X bonds is widely practiced to
generate organolithium intermediates,[6] with reductive lith-
iation using lithium 4,4’-di-tert-butylbiphenylide (LiDBB)
having been employed to produce achiral tertiary organo-
lithium intermediates from chloride, bromide and sulfide
precursors.[7–9] We conjectured that chiral tertiary nitriles,
which are more readily synthesized than tertiary halides or
sulfides, might constitute useful progenitors of chiral tertiary
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205001.
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organolithium reagents. Many a-heterosubstituted lithium
reagents—including fully substituted ones—have been
formed from nitrile precursors and trapped with carbon-
centered electrophiles to yield valuable products;[10] more-
over, the generation of an assortment of tertiary-benzylic
lithium intermediates from benzylic nitrile precursors and
their bimolecular trapping has also been reported.[11] None-
theless, whether less-stable trialkyl tertiary organolithium
intermediates could be generated from nitrile precursors and
subsequently trapped was unknown, and had been suggested
might not be feasible.[11] Encouraged by Rychnovskyꢀs
reductive formation of one such intermediate and its intra-
molecular trapping,[12] we chose to examine whether unstabi-
lized tertiary lithium reagents and their derived cuprates[13]
could be generated from nitrile precursors and trapped in
bimolecular reactions with carbon-centered electrophiles.
Initially we investigated the formation of simple tertiary
organolithium intermediates from six tertiary nitrile precur-
sors. After considerable optimization, the following proce-
dure was found to be effective: the tertiary nitrile (1.5 equiv)
was added rapidly to 3 equiv of freshly prepared LiDBB[14] in
THF at ꢀ788C, followed 1 min later by the addition of
1.0 equiv of an aldehyde. A variety of neopentylic alcohols
could be prepared in this way in useful yields, with the
presence of alkene, alkyl ether, triisopropylsilyl ether (but not
tert-butyldimethylsilyl ether), and electron-rich aromatic
rings being tolerated (Table 1).
methyl substituent.[15] In the optimized procedure, a THF
solution of Me3SiCH2CuCNLi (generated from trimethyl-
silylmethyllithium and copper cyanide) was added rapidly to
the freshly prepared tertiary organolithium intermediate at
ꢀ788C, and, after 5 min, a THF solution of an enone and
a trialkylsilyl chloride was added.[16] In this way, eight diverse
3-substituted cyclohexanones 6 were formed in yields of 56–
75% (Table 2). In addition, three trans-cyclopentenoxysilane
adducts 7 were prepared in good yields (51–81%) and > 20:1
diastereoselectivities by the reaction of tertiary organocup-
rate intermediates with cyclopentenone 2.
Table 2: 1,4-Addition of tertiary organocuprates derived from tertiary
nitriles to cyclohex-2-en-1-one or enone 2.
Entry
1
R
Yield 6 [%]
Yield 7 [%]
tBu
71
78[e]
2
3
4
63
56
75
The conversion of reductively generated tertiary organo-
lithium intermediates to tertiary organocuprates, and the use
of the latter in conjugate reactions, was investigated next.
After exploring the formation and reactivity of various
lithium and dilithium organocuprates, we settled on dilithium
cyanocuprates containing a “non-transferable” trimethylsilyl-
51[e]
5
6
7
8
70[d]
72
Table 1: Trapping of tertiary organolithium intermediates derived from
nitriles with p-anisaldehyde.[a]
60
81[f]
Entry
1
R
Yield [%]
71
67
tBu
[a] Conditions: 2.0 equiv nitrile, 4.0 equiv LiDBB, ꢀ788C, 30 s; 3.1 equiv
TMSCH2CuCNLi, 5 min. [b] Conditions: 1.0 equiv 2-cyclohexenone,
5.0 equiv TMSCl, ꢀ788C, 1 h; 1n HCl, RT. [c] Conditions: 1.0 equiv 2,
2.0 equiv TBSCl, ꢀ788C, 1 h. [d] Isolated as the silyl enol ether.
[e] 2.5 equiv of TMSCH2CuCNLi used in [a]. [f] 2.0 equiv of
TMSCH2CuCNLi used in [a] and 5.0 equiv of TBSCl in [c]. TMS=Tri-
methylsilyl; TBS=tert-butyldimethylsilyl.
2
3
73
66
4
5
6
71
61
59
To explore whether this chemistry could be used to form
quaternary stereocenters, we examined its utility in the
pivotal fragment coupling step of the projected total synthe-
ses of aplyviolene (4) and dendrillolide A (5) depicted in
Scheme 1B. Salient results of our investigation of the
reactivity of tertiary organolithium and organocuprate
reagents generated from cis-perhydroazulene nitriles 8 and
9 are summarized in Scheme 2.[17] We were delighted to find
7
70
[a] Conditions: 1.5 equiv nitrile, 3.0 equiv LiDBB, ꢀ788C, 1 min; 1 equiv
aldehyde. LiDBB=lithium di-tert-butylbiphenylide. TIPS=triisopropyl-
silyl.
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lene series (Scheme 3). Reductive lithiation of cis-perhydro-
pentalene nitrile 15 and quenching with methanol or carbon
dioxide gave hydrocarbon 16 (d.r. = 2.6:1) or carboxylic acid
17 (d.r. = 4.1:1), with the major isomer in each case arising
from preferential reaction from the concave face of the cis-
perhydropentalene nucleophile.[21,22] In addition, nitrile 15
was converted to an organocuprate and coupled with methyl
vinyl ketone to give 18, again with reaction occurring
preferentially from the concave face.[23,24]
The results summarized in Scheme 2 and 3 show that the
tertiary lithium and cuprate reagents in these cis-bicyclic ring
systems react with electrophiles preferentially from the
concave face in an apparently electrophile-independent
fashion. As organolithium intermediates typically undergo
protonation by SE2ret pathways,[3,25] the observation that the
lithium reagents formed from nitriles 8, 9, and 15 protonate
from the concave face indicates that lithium preferentially
resides on the concave face of these cis-bicyclic ring systems.
Computational studies were undertaken to gain further
insight into the origin of this preference.
To this aim, the thermodynamic stability of different
intermediates occurring after the proposed decyanation and
reduction of the radical species with LiDBB, were evaluated
at the B3LYP/6-31 + G(d,p) level.[26] Both naked carbanionic
(8-an, 15-an) and organolithium (8-Li, 15-Li) species derived
from cis-perhydroazulene and cis-perhydropentalene precur-
sors 8 and 15, respectively, were considered. In accordance
with the experimental conditions and related computa-
tional[27] and X-ray[28] data, only monomeric species were
considered and lithium was solvated with three discrete
dimethyl ether molecules. Both epimers at the reacting center
(labeled as a,b) and all possible ring conformations were
considered, in order to obtain theoretical diastereomeric
ratios based on Boltzmann distributions at 298 K estimated
from relative enthalpies (DH) of these intermediates.[29]
Activation enthalpies (DH°) for the pyramidal inversion of
naked carbanions (8-inv, 15-inv), were also calculated. For
comparison, the relative enthalpies of epimeric carboxylated
Scheme 2. Reductive lithiation/electrophilic trapping of chiral cis-per-
hydroazulene nitriles 8, 9, and 13: [a] 8 (2.0 equiv), THF, ꢀ788C;
LiDBB (4.0 equiv), 30 s; TMSCH2CuCNLi (2.0 equiv), 5 min; 1.0 equiv
2, TBSCl (5.0 equiv), in THF, 1 h. [b] 8, THF, ꢀ788C; LiDBB
(2.2 equiv), 30 s; MeOH; O3, CH2Cl2: MeOH, 788C; dimethyl sulfide.
[c] 8 or 9, THF, ꢀ788C; LiDBB (2.2 equiv), 30 s; CO2; 1n HCl. [d] as
[c] but with 13.
that the organocuprate intermediate derived from nitrile 8
reacted with cyclopentenone 2 to give a single coupled
product 10 in 70% yield. To our surprise, the relative
configuration of this product showed that electrophilic
addition had taken place with high stereoselectivity from
the concave face of the cis-perhydroazulene nucleophile.[18]
To gain insight into the possible origin of this unexpected
diastereoselection, the lithium reagent generated from nitrile
8 was quenched with methanol to give largely one
hydrocarbon product; 1H NMR nOe analysis of the
derived ketone 11 established that protonation of the
tertiary organolithium intermediate also took place
with high stereoselectivity from the concave face.[19] In
a similar fashion, carboxylation of the lithium reagent
generated from nitrile 8, or from epimeric nitrile 9,
took place from the concave face to give carboxylic
acid 12 in > 20:1 diastereoselectivity. The selective
formation of carboxylic acid 14 from saturated nitrile
precursor 13 shows that the exomethylene group plays
at most a minor role in the facial selectivity of the
reaction of chiral tertiary lithium reagents in this
ꢀ
(12-CO2ꢀ, 17-CO2 ) and protonated products, expressed as
diastereomeric ratios, were also calculated.[30]
In good agreement with experimental observations, these
calculations revealed a greater stability of those species
Scheme 3. Reductive lithiation and reactivity of cis-perhydropentalene nitrile 15:
[a] 15, THF, ꢀ788C; LiDBB (2.2 equiv), 30 s; MeOH. [b] 15, THF, ꢀ788C;
LiDBB (2.2 equiv), 30 s; CO2; 1n HCl. [c] 15 (4.0 equiv), THF, ꢀ788C; LiDBB
(8.0 equiv), 30 s; CuCN-(LiCl)2 (2.0 equiv), 5 min; TMSCl (5.0 equiv); methyl
series.[20]
Reductive decyanation was also used to generate
analogous unstabilized tertiary organolithium and
organocuprate intermediates in the cis-perhydropenta- vinyl ketone in THF, 1 h; 1n HCl.
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bearing either the lone-electron pair or the lithium
atom on the concave faces (> 1.7 and > 0.5 kcalmolꢀ1
for perhydroazulene and perhydropentalene deriva-
tives, respectively, Table S1, Supporting Information).
The neutralization of the negative charge with bulky
solvated Li cations provides diastereomeric ratios
closer to the experimental data, proving to be a more
realistic model. Conversely, values derived from
naked anions look slightly overestimated, in partic-
ular for perhydropentalene 15-an. In addition, the
calculated lowest barriers for the epimerization of the
carbanionic species were perfectly feasible under the
reaction conditions (4.0 and 9.1 kcalmolꢀ1 for 8-inv,
15-inv, respectively). As the formation of contact ion
pairs (i.e. organolithium) are likely nearly barrierless
processes, it is conceivable that the rapid equilibration
of such metalated species can also occur through the
aforementioned inversion transition structures.
These studies support the notion that observed
selectivity is independent of the ground-state energy
of the diastereomeric products. Whereas the epimeric
protonated products showed similar calculated ener-
ꢀ
gies, the bulkier CO2 moieties are preferentially
positioned on the less-hindered convex face by 2.3 and
0.7 kcalmolꢀ1 for the cis-perhydroazulene and cis-
perhydropentalene carboxylate products, respectively
(Table S1). Although the [Li(OMe2)3]+ units are
ꢀ,
indeed bulkier than CO2 they are placed at a much
ꢀ
larger distance ( ꢁ 2.1 ꢁ) than the covalent C C bond
formed in the product ( ꢁ 1.6 ꢁ), minimizing steric
Figure 1. Optimized structures of solvated organolithium intermediates derived
from perhydroazulene nitrile 8 after reductive lithiation. The Newman projec-
tions of interest (shown as insets) are viewed from the C1!C2 and C3!C4
directions. Relative enthalpies calculated at the B3LYP/6-31+G(d,p) level are
displayed.
interactions.
The observed stereoselectivities can be easily
rationalized by torsional strain considerations
(Figure 1). As seen in the minimum-energy structures
of cis-perhydroazulene organolithium epimers 8-Li-
a and 8-Li-b depicted in Figure 1, in each epimer the
methyl substituent at the reacting center resides in an
equatorial position in order to avoid syn-pentane repulsions
with the fused ring. In addition, the seven-membered and
five-membered rings adopt nearly optimal conformations in
both epimeric intermediates. However, there are significant
differences in the dihedral angles around the bridgehead
carbons in the two epimers. Inspection of Newman projec-
and organocuprates and employed these intermediates in the
stereocontrolled construction of quaternary carbon stereo-
centers. Tertiary cis-perhydroazulene and cis-perhydropenta-
lene lithium and cuprate intermediates react with carbon
electrophiles with high diastereoselectivity from the sterically
more-hindered concave face. Theoretical studies suggest that
the thermodynamic preference for the residence of both
a naked carbanion or lithium species on the concave faces of
such systems dictate the observed stereoselectivity. Differ-
ential torsional strain occurring at the bridgehead atoms
towards the five-membered ring is at the origin of this stability
pattern. The application of prochiral tertiary organometallic
and related radical intermediates[22] for fragment coupling in
the stereocontrolled synthesis of natural products containing
quaternary carbon stereocenters is under current investiga-
tion.
ꢀ
ꢀ
tions along the C1 C2 and C3 C4 bonds of the lithiated five-
membered ring (labeled with blue and red dots in Figure 1
insets, respectively) indicates that b epimers are more
eclipsed then the a ones, reflected by smaller dihedral
angles.[31] Such effects have been reported previously to
govern the stereoselectivities in a wide variety of situations.[32]
Eclipsing and staggering around the bonds attached to the
ꢀ
two bridgehead carbons of 8-Li are correlated. Thus, C3 C4 is
ꢀ
eclipsed and C1 C2 is staggered in less stable 8-Li-b, while
ꢀ
ꢀ
C3 C4 is staggered and C1 C2 is eclipsed in more stable 8-Li-
a. As the C2 Li bond is quite long in these intermediates, it is
unlikely that the eclipsing involving these atoms contributes
significantly to instability. Instead, the conformation around
ꢀ
Received: June 26, 2012
Published online: && &&, &&&&
ꢀ
the C3 C4 bond appears to be more important.
In summary, we have developed a general procedure for
the synthesis of tertiary trialkyl-substituted organolithiums
Keywords: diastereoselectivity · fragment-coupling ·
fused-ring systems · lithiation · terpenoids
.
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precursors. For several more complex examples, see: a) A.
[1] For recent reviews, see: a) J. P. Das, I. Marek, Chem. Commun.
2011, 47, 4593; b) C. Hawner, A. Alexakis, Chem. Commun.
2010, 46, 7295; c) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J.
Org. Chem. 2007, 5969; d) Quaternary Stereocenters-Challenges
and Solutions for Organic Synthesis (Eds.: J. Christoffers, A.
Baro), Wiley-VCH, Weinheim, 2005; e) C. J. Douglas, L. E.
Overman, Proc. Natl. Acad. Sci. USA 2004, 101, 5363; f) D. J.
Ramon, M. Yus, Curr. Org. Chem. 2004, 8, 149.
[2] The generation, configurational stability and steroselectivity of
the reaction of chiral lithium reagents that contain at least one
stabilizing substituent (heteroatom or aryl) has received consid-
erable study.[3] To our knowledge, there are no such reports for
tertiary lithium reagents containing three different alkyl sub-
stituents with the exception of cyclopropyl and cyclobutyl
examples.[4]
Guijarro, D. M. Rosenberg, R. R. Rieke, J. Am. Chem. Soc.
1999, 121, 4155; b) R. D. Rieke, M. V. Hanson, Tetrahedron
1997, 53, 1925; c) B. H. Lipshutz, S. Sengupta, Org. React. 1992,
41, 135; d) Reference [7d].
[14] B. Mudryk, T. Cohen, Org. Synth. 1995, 72, 173.
[15] S. H. Bertz, M. Eriksson, G. B. Miao, J. P. Snyder, J. Am. Chem.
Soc. 1996, 118, 10906.
[16] The use of a silyl chloride was required in order to achieve
synthetically useful yields of the 1,4 adduct. For a discussion on
the current understanding of the role of silyl chlorides in cuprate
reactions and leading references, see: N. Yoshikai, E. Nakamura,
Chem. Rev. 2012, 112, 2339.
[17] For details of the synthesis of these nitriles, see the Supporting
Information.
[18] The relative configuration of 10 was determined unambiguously
by conversion to crystalline 19, the relative configuration of
which was secured by crystallographic analysis. CCDC 885481
[3] For reviews and leading references, see: a) R. E. Gawley, Top.
Stereochem. 2010, 26, 93; b) J. Clayden, Organolithiums: Selec-
tivity for Synthesis Pergamon, Oxford, 2002, pp. 169 – 335; c) A.
Basu, S. Thayumanavan, Angew. Chem. 2002, 114, 740; Angew.
Chem. Int. Ed. 2002, 41, 716.
[4] The reaction of a few tertiary cyclopropyl and cyclobutyl lithium
and magnesium intermediates with carbon electrophiles to form
new quaternary carbon stereocenters has been reported, see:
a) Y. Gaoni, Tetrahedron 1989, 45, 2819; b) K. Mandelt, I.
Meyer-Wilmes, L. Fitjer, Tetrahedron 2004, 60, 11587; c) D. M.
Hodgson, Y. K. Chung, I. Nuzzo, G. Freixas, K. K. Kulikiewicz,
E. Cleator, J. M. Paris, J. Am. Chem. Soc. 2007, 129, 4456.
[5] The tetrasubstituted lithium enolate analogue of 1 is known to
react with cyclopentenones analogous to 2 exclusively from the
convex face, see: a) A. D. Lebsack, L. E. Overman, R. J.
Valentekovich, J. Am. Chem. Soc. 2001, 123, 4851; b) M. J.
Schnermann, L. E. Overman, J. Am. Chem. Soc. 2011, 133,
16425.
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[19] Identical results were realized with epimeric nitrile 9; see
Supporting Information for details.
[20] See Supporting Information for the preparation of nitrile 13.
[21] The synthesis of nitrile 15 and the methyl epimer of product 18 is
reported in the accompanying paper.[22]
[22] M. J. Schnermann, L. E. Overman, Angew. Chem. 2012, DOI:
10.1002/ange.201204977; Angew. Chem. Int. Ed. 2012, DOI:
10.1002/anie.201204977.
[23] In this instance, the trimethylsilylmethyl ligand underwent
competitive addition to methyl vinyl ketone and a homocuprate
was employed.
[24] The impact of additives (TMEDA, HMPA, MgBr2, ZnCl2) and
reaction temperature was examined in the protonation of the
organolithium intermediates derived from nitriles 9 and 15.
Diastereoselection was not significantly modified in any of these
efforts, although the scope of these studies was limited by the
highly reactive nature of the tertiary organolithium intermedi-
ates and the requirement that THF be used as the solvent for the
arene-radical anion-mediated lithiation.[14]
[25] a) To our knowledge, no information is currently available on
the configurational stability of tertiary organolithiums having
only alkyl substituents; b) the stereochemistry of protonation
and methylation of 4-tert-butyl-1-phenylcyclohexyllithium has
been investigated, see: B. A. Keys, E. L. Eliel, E. Juristi, Isr. J.
Chem. 1989, 29, 171.
[6] For a general review of reductive lithiation, see: J. Clayden,
Organolithiums: Selectivity for Synthesis Pergamon, Oxford,
2002, pp. 149 – 165.
[7] From tertiary chlorides and bromides: a) P. K. Freeman, L. L.
Hutchinson, Tetrahedron Lett. 1976, 17, 1849; b) P. K. Freeman,
L. L. Hutchinson, J. Org. Chem. 1980, 45, 1924; c) D. J. Rawson,
A. I. Meyers, Tetrahedron Lett. 1991, 32, 2095; d) S. Hong, E. J.
Corey, J. Am. Chem. Soc. 2006, 128, 1346; aryl sulfides: e) J. P.
Cherkauskas, T. Cohen, J. Org. Chem. 1992, 57, 6; f) B. Mudryk,
T. Cohen, J. Am. Chem. Soc. 1993, 115, 7932; g) R. Ivanov, I.
Marek, T. Cohen, Tetrahedron Lett. 2010, 51, 174; aryl selenides:
h) A. Krief, A. Nazih, M. Hobe, Tetrahedron Lett. 1995, 36, 8111.
[8] Remarkable progress has been recorded in recent years by
Knochel and co-workers in generating and trapping polyfunc-
tional aromatic and primary and secondary organomagnesium
and organozinc reagents by exchange reactions.[9] However, such
reactions would be problematic with tertiary halide precursors.
[9] a) P. Knochel, A. Krasovskiy, I. Sapountzis in Handbook of
Functionalized Organometallics, Vol. 1 (Ed.: P. Knochel), Wiley-
VCH, Weinheim, 2005, pp. 109 – 172; b) P. Knochel, H. Leuser,
L.-Z. Gong, S. Perrone, F. F. Kneisel in Handbook of Function-
alized Organometallics, Vol. 1 (Ed.: P. Knochel), Wiley-VCH,
Weinheim, 2005, pp. 251 – 346.
[10] a) E. Zeller, D. S. Grierson, Heterocycles 1988, 27, 1575; b) D.
Guijarro, M. Yus, Tetrahedron 1994, 50, 3447; c) S. D. Rychnov-
sky, T. Hata, A. I. Kim, A. J. Buckmelter, Org. Lett. 2001, 3, 807;
d) M. A. Perry, M. D. Morrin, B. W. Slafer, S. D. Rychnovsky, J.
Org. Chem. 2012, 77, 3390.
[11] J. P. Tsao, T. Y. Tsai, I. C. Chen, H. J. Liu, J. L. Zhu, S. W. Tsao,
Synthesis 2010, 4242.
[12] T. E. La Cruz, S. D. Rychnovsky, Chem. Commun. 2004, 168.
[13] A number of achiral tertiary organocuprates (generally tert-
butyl) have been generated from lithium, zinc and magnesium
[26] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. 1988, 37, 785.
[27] a) M. Capꢂ, J. M. Saꢃ, J. Am. Chem. Soc. 2004, 126, 16738; b) H.
Lange, R. Huenerbein, R. Frçhlich, S. Grimme, D. Hoppe,
Chem. Asian J. 2008, 3, 78.
[28] a) I. Hoppe, M. Marsch, K. Harms, G. Boche, D. Hoppe, Angew.
Chem. 1995, 107, 2328; Angew. Chem. Int. Ed. Engl. 1995, 34,
2158; b) W. Zarges, M. Marsch, K. Harms, W. Koch, G. Frenking,
G. Boche, Chem. Ber. 1991, 124, 543; c) H. V. Ly, J. Konu, M.
Parvez, R. Roesler, Dalton Trans. 2008, 3454.
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Angewandte
Communications
[29] The structures of each of the two epimers of the same complex
are very similar; thus, it was assumed that temperature and
entropy effects are negligibly small and thus DDG ꢁ DDH.
[30] See Supporting Information for further computational details
and full descriptions of the calculated structures.
[31] Structures and Newman projections of perhydropentalene
lithiums 15-Li-a and 15-Li-b can be found in the Supporting
Information.
P. Caramella, J. Mareda, P. H. Mueller, K. N. Houk, J. Am.
Chem. Soc. 1982, 104, 4974; d) M. N. Paddon-Row, N. G.
Rondan, K. N. Houk, J. Am. Chem. Soc. 1982, 104, 7162;
e) M. J. Lucero, K. N. Houk, J. Org. Chem. 1998, 63, 6973;
f) P. H. Cheong, H. Yun, S. J. Danishefsky, K. N. Houk, Org. Lett.
2006, 8, 1513; g) M. J. Martinelli, B. C. Peterson, V. V. Khau,
D. R. Hutchinson, M. R. Leanna, J. E. Audia, J. J. Droste, Y.-D.
Wu, K. N. Houk, J. Org. Chem. 1994, 59, 2204; h) K. N. Houk,
M. N. Paddon-Row, N. G. Rondan, Y.-D. Wu, F. K. Brown, D. C.
Spellmeyer, J. T. Metz, Y. Li, R. J. Loncharich, Science 1986, 231,
1108.
[32] a) H. Wang, P. Kohler, L. E. Overman, K. N. Houk, submitted;
b) P. Caramella, N. G. Rondan, M. N. Paddon, K. N. Houk, J.
Am. Chem. Soc. 1981, 103, 2438; c) N. G. Rondan, M. N. Paddon,
6
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Angewandte
Chemie
Communications
Synthetic Methods
M. J. Schnermann, N. L. Untiedt,
G. Jimꢁnez-Osꢁs, K. N. Houk,*
L. E. Overman*
&&&& — &&&&
Forming Tertiary Organolithiums and
Organocuprates from Nitrile Precursors
and their Bimolecular Reactions with
Carbon Electrophiles to Form Quaternary
Carbon Stereocenters
Unstabilized tertiary organolithium inter-
mediates are conveniently generated by
reductive decyanation of nitriles, and
these reagents and their derived cuprates
couple in useful yields with carbon-cen-
tered electrophiles (see example). Chiral
tertiary organolithium and organocuprate
derivatives of substituted cis-perhydro-
azulenes and cis-perhydropentalenes
react with electrophiles with high
diastereoselectivity from the more-hin-
dered concave face.
Angew. Chem. Int. Ed. 2012, 51, 1 – 7
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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