Cyclization via carbolithiation of α-amino alkyllithium reagents

Article abstract of DOI:10.1021/ol801523r

(Chemical Equation Presented) We report a new route to tertiary α-amino stereocenters by sequential alkylation of α-amino nitriles followed by reductive lithiation of the nitrile and cycllzation onto an alkene. Reductive lithiation of α-amino nitriles usi

Full text of DOI:10.1021/ol801523r

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4017-4020
Cyclization via Carbolithiation of
r-Amino Alkyllithium Reagents
Robert J. Bahde and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
California 92697-2025
srychnoV@uci.edu
Received July 5, 2008
ABSTRACT
We report a new route to tertiary r-amino stereocenters by sequential alkylation of r-amino nitriles followed by reductive lithiation of the
nitrile and cyclization onto an alkene. Reductive lithiation of r-amino nitriles using lithium 4,4′-di-tert-butylbiphenylide (LiDBB) and subsequent
intramolecular carbolithiation proceeded with modest to high diastereoselectivity to deliver cyclic or spirocyclic ring systems. The stereoselectivity
of these intramolecular carbolithiations was examined using density function calculations to evaluate plausible transition state models.
Tertiary R-amino stereogenic centers are found in many classes
of alkaloids, including the cylindricines,1 fasicularin,2 and
pinnaic acid,3 and these stereogenic centers are often incorpo-
rated into rings. Previously, we reported the reductive lithiation
and cyclization of cyanohydrins to form spirocyclic ethers, often
with high stereoselectivity.4 A similar strategy might allow
complex alkaloid skeletons to be rapidly assembled from
R-amino nitriles. Nitriles may be deprotonated in the alpha
position, and these anions are excellent nucleophiles for
alkylation.5 Thus, the R-amino nitrile substrates might be
assembled using the facile alkylation adjacent to the nitrile, and
subsequent reductive lithiation would trigger an intramolecular
carbolithiation reaction. Herein, we describe several model
studies that delineate the scope of this reductive cyclization
strategy.
effectively in the synthesis of alkaloids.6 Both Husson7 and
Grierson8 have reported isolated examples of R-amino nitrile
reduction and intramolecular alkylation, but they have not
reported cyclization onto alkenes. Intramolecular cyclization of
alkyllithium reagents onto unactivated alkenes has been exten-
sively studied by Bailey9 and by a number of other groups.10
Wiberg and Bailey used computational methods to predict a
four-centered transition state for insertion of an alkene into the
organolithium bond.11 The classic intramolecular carbolithiation
of an R-amino alkyllithium reagent was reported by Coldham
using an optically pure secondary R-amino stannane to generate
the alkyllithium intermediate.12 Transmetalation of stannanes
is not an effective method for the preparation of tertiary alkyl-
lithium reagents, however, and neither is the deprotonation
(5) For a recent review, see: Fleming, F. F.; Zhang, Z. Tetrahedron 2005,
61, 747–789.
Husson has studied the stereoselective reductive decyanation
of R-amino nitriles extensively and applied this method very
(6) (a) Husson, H.-P.; Royer, J. Chem. Soc. ReV. 1999, 28, 383–394.
(b) Bonin, M.; Romero, J. R.; Grierson, D. S.; Husson, H.-P. Tetrahedron
Lett. 1982, 23, 3369–3372.
(1) (a) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.;
White, A. H. Tetrahedron 1993, 49, 8645–8656. (b) Li, C.; Blackman, A. J.
Aust. J. Chem. 1994, 47, 1355–1361. (c) Li, C.; Blackman, A. J. Aust.
J. Chem. 1995, 48, 955–965. Review of synthetic work. (d) Liu, J.; Hsung,
R. P. Chemtracts 2005, 18, 321–330.
(7) (a) Ribeiro, C. M. R.; Sebastiao, J. M.; Bonin, M.; Quirion, J.;
Husson, H.-P. Tetrahedron Lett. 1994, 35, 7227–7230. (b) Roulland, E.;
Cecchin, F.; Husson, H. P. J. Org. Chem. 2005, 70, 4474–4477.
(8) (a) Zeller, E.; Grierson, D. S. Heterocycles 1988, 27, 1575–1578.
(b) Zeller, E.; Sajus, H.; Grierson, D. S. Synlett 1991, 44–46. (c) Zeller, E.;
Grierson, D. S. Synlett 1991, 878–880.
(2) (a) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Carte, B.; Killmer,
L. B.; Faucette, L.; Johnson, R. K. Tetrahedron Lett. 1997, 38, 363–364.
Review of synthetic work: (b) Weinreb, S. M. Chem. ReV. 2006, 106, 2531–
2549. (c) Schar, P.; Cren, S.; Renaud, P. Chimia 2006, 60, 131–141.
(3) (a) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871–3874. (b) Arimoto, H.;
Hayakawa, I.; Kuramoto, M.; Uemura, D. Tetrahedron Lett. 1998, 39, 861–
862.
(9) (a) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002, 646,
59–67. (b) Bailey, W. F.; Jiang, X. Tetrahedron 2005, 61, 3183–3194.
(10) For leading references, see: (a) Chamberlin, A. R.; Bloom, S. H.;
Cervini, L. A.; Fotsch, C. H. J. Am. Chem. Soc. 1988, 110, 4788–4796. (b)
Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem. 1988, 53, 1336–1338. (c)
Mudryk, B.; Cohen, T. J. Am. Chem. Soc. 1993, 115, 3855–3865. (d) Deng,
K.; Bensari, A.; Cohen, T. J. Am. Chem. Soc. 2002, 124, 12106–12107. (e)
Bailey, W. F.; Jiang, X. L. Tetrahedron 2005, 61, 3183–3194.
(4) Rychnovsky, S. D.; Takaoka, L. R. Angew. Chem., Int. Ed. 2003,
42, 818–820.
10.1021/ol801523r CCC: $40.75
Published on Web 08/14/2008
2008 American Chemical Society

method commonly used for carbamate-activated R-amino alkyl-
lithium reagent generation.13 The poor accessibility of these re-
agents means that intramolecular carbolithiation reactions using
tertiary R-amino alkyllithium reagents are essentially unknown.
Reduction of thiophenols and of nitriles with the power-
ful reducing agent lithium 4,4′-di-tert-butylbiphenylide
(LiDBB)14 in THF has proven to be a general route to many
unusual and complex alkyllithium reagents.15 We recently
reported that the reductive lithiation of R-amino nitriles provides
a facile, and in some cases stereoselective, route to tertiary
R-amino alkyllithium reagents.16 These nitrile reductive lithia-
tion reactions provide an ideal entry into highly substituted
carbolithiation precursors of interest in this study.
Table 1. Alkylation of N-Benzyl-2-cyanopiperidine 1
The piperidine substrates were assembled as outlined in Table
1. The starting material, N-benzyl-2-cyanopiperidine (1), was
prepared in two steps from piperidine.16a,17 Cyanopiperidine
1 was deprotonated with LDA and alkylated with a series
of primary alkyl bromides and iodides (2-8) to give the
substituted cyanopiperidines 9-15. It is important to mention
that the fully substituted nitriles demonstrated a propensity
to undergo retro-Strecker reactions when exposed to mild
acidic media, so care was taken during purification and
characterization to minimize this side reaction.18 Halides 2,
3, and 6-8 were generated from commercially available
alcohol precursors. Methoxy ethers 4 and 5 were readily
prepared in high yield utilizing Grubbs’ cross metathesis as
a key step.19 The alkene metathesis afforded E-alkenes in
greater than a 20:1 ratio.20
spiropiperidine diastereomer 16 with two new stereogenic
centers with 20:1 selectivity (Table 2, entry 1). The configu-
ration of 16 has the methyl group cis to the nitrogen atom and
was assigned by NOE experiments.20 Carbolithiation did not
occur when cyanopiperidine 10 was subjected to the same
conditions or upon warming. Reductive decyanation generated
the tertiary organolithium species as shown by deuteration
studies; however, the lithiated intermediate did not undergo
cyclization. This result is consistent with Coldham’s observation
that temperature plays a key role in intramolecular carbolithia-
tion reactions.21 To overcome the entropic requirements to form
a six-membered ring, prohibitively high temperatures were
Reductive decyanation of N-benzyl 2-cyanopiperidine 9
generated a tertiary R-amino organolithium species that under-
went intramolecular carbolithiation to produce, after protonation,
(11) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaksa, T. V.;
Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113, 5720–
5727.
(12) Coldham, I.; Hufton, R.; Snowden, D. J. J. Am. Chem. Soc. 1996,
118, 5322–5323.
(13) (a) Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. Top.
Organomet. Chem. 2003, 5, 139–176. (b) Beak, P.; Zajdel, W. J.; Reitz,
D. B. Chem. ReV. 1984, 84, 471–523.
Table 2. Spiroannulation of N-Benzyl-2-cyanopiperidines
(14) Freeman’s reagent: Freeman, P. K.; Hutchinson, L. L. Tetrahedron
Lett. 1976, 17, 1849–1852.
(15) Reviews: (a) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22,
152–161. (b) Yus, M. Chem. Soc. ReV. 1996, 25, 155–161. Leading
references: (c) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978, 43,
1064–1071. (d) Boeckman, R. K.; Enholm, E. J.; Demko, D. M.; Charette,
A. B. J. Org. Chem. 1986, 51, 4743–4745. (e) Guijarro, D.; Yus, M.
Tetrahedron 1994, 50, 3447–3452. (f) Foubelo, F.; Gutierrez, A.; Yus, M.
Synthesis 1999, 503–514.
(16) (a) Wolckenhauer, S. A.; Rychnovsky, S. D. Org. Lett. 2004, 6,
2745–2748. (b) Wolckenhauer, S. A.; Rychnovsky, S. D. Tetrahedron 2005,
61, 3371–3381.
(17) (a) De Kimpe, N.; Stevens, C. J. J. Org. Chem. 1993, 58, 2904–
2906. (b) Davis, B. G.; Maughan, M. A. T.; Chapman, T. M.; Villard, R.;
Courtney, S. Org. Lett. 2002, 4, 103–106.
(18) Only fully substituted R-aminonitrile compounds displayed a
propensity to undergo a retro-Strecker reaction. To avoid decomposition,
compounds were purified using basic aluminia flash chromatography and
characterized in d6-benzene.
(19) (a) Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153–3155.
(b) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360–11370.
(20) Details are provided in the Supporting Information section.
(21) (a) Oestreich, M.; Roland, F.; Hoppe, D. Tetrahedron Lett. 1998,
39, 1745–1748. (b) Ashweek, N. J.; Coldham, I.; Snowden, D. J.; Vennall,
G. P. Chem.-Eur. J. 2002, 8, 195–207.
(22) Alkyllithium intermediates deprotonating THF over extended
periods of time. (a) Deng, K.; Bensari-Bouguerra, A.; Whetstone, J.; Cohen,
T. J. Org. Chem. 2006, 71, 2360–2372. (b) Stanetty, P.; Minovilovic, M. D.
J. Org. Chem. 1997, 62, 1514–1515.
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Org. Lett., Vol. 10, No. 18, 2008

required that led to decomposition and protonation of the
alkyllithium intermediate.22
Scheme 2. Carbolithiation of Pyrrolidine 26
Much like carbolithiation, spiroannulation onto allylic meth-
oxy ethers occurred to form five-membered rings but not six-
membered rings. Methyl ether 11 gave spirocycle 18 with a
diastereomeric ratio of 2:1 (Table 2, entry 2).20 The SN′
cyclization led to modest selectivity in contrast to the carbo-
lithiation with substrates 9. Surprisingly, cyclization of methyl
ether 12 did not lead to the six-membered spirocycle,4 but
instead gave only the reduced product.
The alkyllithium cyclizations were also effective with
alkynyl piperidine 15 (Table 2, entry 3). Selective cis-
carbolithiation onto the TBS-alkyne at -78 °C produced the
E-alkene 20 as the only isomer in modest yield. The
configuration of the alkene was assigned by NOE analysis.20
Cyclizations with primary chlorides were explored as an
alternative to previously reported spiroannulations with phos-
phate leaving groups.4,7,8 Subtle differences in N-alkyl-2-
cyanopiperidines can lead to different outcomes through
competitive reduction between the primary chloride and the
nitrile moiety.7,8 We anticipated that the reductive decya-
nation of chloro nitriles 13 and 14 might produce a tertiary
R-amino organolithium more rapidly than the potentially
competitive halide reduction.15 In the event, halide reduction
occurred before reductive decyanation, and the intermediate
alkyllithium reagent cyclized onto the nitrile to produce a
spirocyclic ketone after hydrolysis of the intermediate imine.
Both the spirocyclic cyclohexanone 21 and the cyclohep-
tanone 22 were formed in moderate yield under these
conditions (Table 2, entry 4). Side products lacking both the
nitrile and chloride were observed in both cases. Preferential
reduction of the alkyl chloride contrasts sharply with the
cyanohydrin results, where decyanation is the dominant
pathway.4
Pyrrolidines were also effective substrates in the spiroan-
nulation reaction (Scheme 2). Synthesis of 25 was achieved
by an intramolecular Strecker reaction.23 Alkylation condi-
tions from Table 1 were replicated and afforded cyclization
precursor 26 in quantitative yield. Reductive lithiation with
LiDBB in THF generated the cyclized spiropyrrolidine 27
in a 4:1 diastereomeric ratio in excellent yield. The methyl
group of the major isomer 27 is cis to the nitrogen atom
with respect to the newly formed cyclopentane ring.20 The
2-cyano pyrrolidines are excellent substrates for reductive
cyclization reactions.
The diastereoselectivity observed during the carbolithiation
of nitriles 9 and 26 was rationalized by invoking coordination
between the equatorial lone pair of the nitrogen atom and
the lithium atom in the transition state (see below). A similar
explanation for the selectivity in tetrahydropyranyl reductive
cyclizations has been proposed.4 Acyclic nitrile 30 was
selected to probe this coordination effect. The synthesis of
nitrile 30 began with cyanomethylation of dibenzylamine to
produce the tertiary amine 28 as outlined in Scheme 3.
N-Boc amino nitriles also generate tertiary R-amino alkyl-
lithium reagents on reduction with LiDBB, and the intramo-
lecular carbolithiation of a model compound was investigated.16
The N-Boc piperidine was prepared by a route analogous to
the synthesis of compound 9, and it includes an efficient
alkylation of the R-amino nitrile anion with bromide 2.20
Attempted cyclization of 23, however, was not effective
(Scheme 1). Reductive decyanation produced the expected
alkyllithium reagent, but no cyclized product was detected after
12 h at -78 °C. Attempted carbolithiation reactions at higher
temperature (-45 °C) were also unsuccessful and only led to
the protonated product 24. One explanation for the lack of
cyclization product is that the alkyllithium reagent produced
from 23 is strongly coordinated with the N-Boc oxygen, and it
may not be electrophilic enough to engage the alkene.
Scheme 3
.
Sequential Cyanomethylation and Alkylation to
Prepare Carbolithiation Precursor 30
Scheme 1
.
Reductive Lithation of Boc Aminonitrile 23 Does
Not Lead to Cyclization
Alkylation with primary bromide 2 produced the tertiary
R-amino nitrile 30 in modest yield. As noted previously,
some of these R-amino nitriles are prone to retro-Strecker
reactions,18 and that accounts for the modest yield of
compound 30 in the alkylation reaction.
Org. Lett., Vol. 10, No. 18, 2008
4019

an approach is limited by the sometimes-unfavorable equilib-
rium found with ketone substrates in that process.
Scheme 4. Spiroannulation of Amino Nitrile 33
Reductive lithiation of amino nitrile 33 with LiDBB under
standard conditions, followed by protonation of the alkyl-
lithium product, led to the spirocyclic pyrrolidine 34 in
moderate yield. In this case, there is only one isomer possible.
Several of these spirocyclization reactions proceeded with
high diastereoselectivity. One possible explanation for the
selectivity is that coordination between the lithium and
nitrogen atoms during carbolithiation of piperidine 9 (and
pyrrolidine 26) would favor the observed product. Hetero-
atom coordination of alkyllithium reagents has been invoked
to explain the selectivity of intramolecular carbolithiation
reactions, but the outcome is not always straightforward.10c-e
This proposal was explored using DFT calculations.26 The
two lowest-energy transition states are depicted in Figure 1.
The atom distances present in these models closely match
the transition states determined by Bailey and Wiberg for
the intramolecular carbolithiation of 5-hexen-1-yllithium.11
The favored transition state resembles a four-membered
C-C-C-Li ring with the alkene inserting into the orga-
nolithium bond. The more stable transition state includes
coordination between the nitrogen and lithium atoms (Li-N
distance ) 1.925 Å) and leads to the observed “cis” product.
The geometry of the other transition state precludes
lithium-nitrogen coordination (Li-N distance ) 3.29 Å),
and it is much higher in energy.27
Finally, reductive lithiation conditions of nitrile 30 induced
an intramolecular carbolithiation reaction, but only in low
yield. The cyclization led to a 1:1 mixture of diastereomers.
The stereochemical outcome of this cyclization reaction is
quite different from the examples with piperidine (9) and
pyrrolidine (26) rings.
The spiroannulation reaction may also be applied to form
pyrrolidine rings. An example of this strategy is presented in
Scheme 4. The cyclization substrate 33 was assembled by
sequential nitrogen and carbon alkylation reactions. Benzyl-
amine was cleanly monoalkylated with chloroacetonitrile. The
nitrile group reduces the nucleophilicity of the nitrogen atom,
disfavoring overalkylation.24 The alkene side chain was intro-
duced by alkylation with 4-bromobutene under more vigorous
conditions. Deprotonation of the amino nitrile 32 and double
alkylation with 1,5-diiodopentane gave the highly substituted
amino nitrile 33.25 In theory, the same product could be prepared
by a Strecker reaction with cyclohexanone, but in practice, such
We demonstrate that tert-R-amino alkyllithium reagents
can be prepared by reductive lithiation of R-amino nitriles
and that in many cases these alkyllithium reagents will
undergo intramolecular carbolithiation. These intramolecular
carbolithiation reactions can be highly stereoselective and
lead to [4.4] and [4.5] spirocyclic structures. This new
annulation reaction should be a useful tool in the synthesis
of alkaloid structures.
Acknowledgment. This work was supported in part by
the National Institutes of General Medicine (GM-65388).
Supporting Information Available: Preparation and
characterization of the described compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL801523R
(23) Bonnett, R.; Clark, V.M.; Giddey, A.; Todd, A. J. Chem Soc. 1959,
2087–2093.
(24) Tokuyama, H.; Kuboyama, T.; Amano, A.; Yamashita, T.; Fuku-
yama, T. Synthesis 2000, 1299–1304.
(25) Guillaume, D.; Brum-Bousquet, M.; Aitken, D. J.; Husson, H.-P.
Bull. Chim. Soc. Fr. 1994, 131, 391–396.
(26) Geometry optimizations were performed with B3LYP/6-31G* as
implemented in Gaussian 03. Minima were characterized by their vibrational
frequencies. The transition states were characterized by vibrational frequency
calculations as well as internal reaction coordinate calculations. The energies
reported are enthalpies without zero-point corrections. Transition state
geometries and the full Gaussian 03 reference is included in the Supporting
Information section.
(27) The relative energy between the two transition states in Figure 1 is
unreasonably large, but the actual values are unlikely to be very accurate
because of the complete neglect of solvation in these calculations.
Figure 1. B3LYP/6-31G(d) transition states for the carbolithiation-
cyclization of an N-methyl 2-lithiopiperidine.
4020
Org. Lett., Vol. 10, No. 18, 2008