Enantioselective carbolithiation initiated cascade reactions

Article abstract of DOI:10.1021/ja060076g

Enantioselective cascade reactions are very powerful synthetic protocols for the assembly of complex architectures. Our current approach is to exploit a (-)-sparteine-controlled enantioselective carbolithiation of 2-propenylarylamines to provide chiral in

Full text of DOI:10.1021/ja060076g

Published on Web 07/25/2006
Enantioselective Carbolithiation Initiated Cascade Reactions
Anne-Marie L. Hogan and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, UniVersity College Dublin,
Belfield, Dublin 4, Ireland
Received January 5, 2006; E-mail: donal.f.oshea@ucd.ie
Scheme 1. Retrosynthetic Analysis of Indole 3
The synthetic power of the intermolecular alkene carbolithiation
transformation lies in its ability to construct a carbon-carbon bond
and generate a new organolithium species in a single step. This
has been accomplished for the unactivated carbon-carbon double
bonds of ethene and styrene, following which the newly formed
organolithium species could be further reacted with electrophiles.1
We have previously expanded the synthetic utility of this trans-
formation for ortho-amino-substituted styrenes.2 Our methodology
involved a cascade reaction sequence of alkyllithium addition to
the styrene double bond, subsequent trapping of the intermediate
organolithium with a suitable electrophile, followed by an in situ
ring closure and dehydration to generate the substituted indole ring
(eq 1).
of 1a with phenyllithium10 followed by carbolithiation with n-BuLi
in the presence of (-)-sparteine for 4 h under varying reaction
conditions. We observed that for a ratio of PhLi:n-BuLi:(-)-
sparteine of 1:2:3 the optimal temperature for combined isolated
yield and enantiomeric ratio (er) was -15 °C, with a lower
temperature reducing isolated yield and a higher temperature
reducing er (Table 1, entries 1-3). The use of 2 equiv of BuLi
was adopted as it was found to result in improved isolated yields
when compared to a lower stoichiometric ratio (entry 4). A study
of the quantity of (-)-sparteine additive employed revealed its
crucial role in gaining selectivity. The best results were obtained
when an equal ratio of organolithium (PhLi + n-BuLi) to (-)-
sparteine was used (entry 2). A slight reduction in er was observed
when (-)-sparteine was reduced to 2 equiv (entry 5).
Further reduction in levels of (-)-sparteine resulted in a
significant loss of enantioselectivity (entries 6 and 7). We also
recorded a lowering of isolated yield for each reduction in (-)-
sparteine used. When no (-)-sparteine is added, the reaction does
not proceed and starting material is isolated upon reaction workup
(entry 8). All er’s were determined using chiral HPLC and compared
Our current goal is to advance this methodology for 2-prope-
nylarylamines 1, which could establish a new asymmetric route to
the indole scaffold 3 (Scheme 1).3 As the chiral center of 3 is
generated at the beginning of the reaction sequence by formation
of the exocyclic carbon-carbon bond via the carbolithiation
(disconnection 1, blue) and is not involved in subsequent steps
(disconnection 2 and 3, blue), any asymmetric influence exerted
on this C-C bond formation should be carried through to the final
cascade products (Scheme 1).4 If successful, this approach could
facilitate the stereoselective generation of a structurally diverse
product set from the common intermediate 2, by changing the
electrophile chosen to react with this intermediate. This retrosyn-
thetic analysis contrasts with the more orthodox approach, which
indicates a Friedel-Crafts alkylation of a presynthesized indole
ring with an activated carbon-carbon double bond (disconnection
1, brown). Recent examples of this approach have successfully
employed imidazolidinone5 in conjunction with R,â-unsaturated
aldehydes, Sc(OTf)3-pybox6 controlled reaction with acyl phos-
Table 1. Optimization of Carbolithiation Conditionsa
7
phonates, and bis(oxazoline)-Cu(OTf)2 with R′-hydroxy enones.
The starting substrates, (E)-benzyl-(2-propenylaryl)amines 1a,b
were prepared by a high-yielding Suzuki-Miyaura cross-coupling
of benzyl-(2-bromoaryl)amines with (E)-propenyl boronic acid
(Supporting Information). Our objective was to exploit the inex-
pensive commercially available natural product (-)-sparteine as
the selectivity mediator for our cascade reactions.8 The carbolithia-
tion of â-methylstyrene with n-butyllithium has been accomplished
with high enantioselectivity using (-)-sparteine to induce asym-
metry in the reaction.9
Carbolithiation reaction conditions were optimized in cumene
as solvent for the formation of benzyl-[2-(2-methylhexyl)phenyl]-
amine 4a obtained by protonation of intermediate 2a with methanol
(Table 1). The reaction sequence involves initial NH deprotonation
temp
C)
n-BuLi
(equiv)
(
−
)-sparteine
yield
(%)
entry
(
°
(equiv)
erb
1
2
3
4
5
6
7
8
-25
-15
0
-15
-15
-15
-15
-15
2
2
2
1.2
2
2
2
2
3
3
3
1.2
2
1
0.1
0
70
89
74
56
75
44
20
0
93:7
92:8
90:10
85:15
91:9
82:18
71:29
a Conditions: (i) PhLi, rt, 15 min; (ii) n-BuLi, (-)-sparteine, 4 h; (iii)
MeOH. b Determined using chiral HPLC.
9
10360
J. AM. CHEM. SOC. 2006, 128, 10360-10361
10.1021/ja060076g CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Carbolithiationa
Table 3. Scope of Indole Synthesisa
yield
(%)
yield
entry
substrate
product
R1
R2
erb
entry
3
R1
R2
R3
(%)
erb
1
2
3
1a
1a
1b
4b
4c
4d
H
H
Etc
n-Hex
n-Bu
52
76
60
93:7
92:8
ndd
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Etd
n-Hex
n-Bu
n-Bu
H
60
30
38
51
45
40
58
43
31
92:8
93:7c
93:7
92:8
92:8
nde
92:8
93:7
92:8
CH3
Ph
COCH3
OCH3
a Conditions: (i) PhLi, rt, 15 min, cumene; (ii) R2Li, (-)-sparteine, -15
°C, 4 h; (iii) MeOH. b Determined by chiral HPLC. c Reaction with 5 equiv
of EtLi and (-)-sparteine. d Chiral HPLC separation was not achieved.
(CH2)3OH
H
H
H
OCH3
OCH3
to a racemic mixture generated using tetramethylethylenediamine
(TMEDA) as additive (Supporting Information). The absolute
configuration was assigned based upon the generation of (S)-3-
methyl heptanoic acid from 4a.9b,c
We next applied the reaction of 1a with ethyl- and n-hexyllithium
and found both generated the desired products 4b,c in good yields
with er’s of 93:7 and 92:8 (Table 2, entries 1 and 2). In addition,
we tested benzyl-(4-methoxy-2-propenylphenyl)amine 1b as a
starting substrate and found that it underwent efficient carbolithia-
tion with n-BuLi to provide 4d.
(CH2)3OH
a Conditions: (i) PhLi, rt, 15 min, cumene; (ii) R2Li, (-)-sparteine, -15
°C, 4 h; (iii) electrophile; (iv) 2 M HCl. b Determined using chiral HPLC.
c An increased er of 99:1 was obtained after one recrystallization from
pentane. d Reaction with 5 equiv of EtLi and (-)-sparteine. e Chiral HPLC
separation was not achieved.
high synthetic potential, which can then be converted into a range
of products simply by changing the electrophile. As organolithium
chemistry is ubiquitous in synthetic chemistry the applications of
this approach could be far-reaching.
To demonstrate the potential generality of this reaction, the
carbolithiation conditions were applied to a series of cascade
reactions utilizing different electrophiles (Scheme 2). The reaction
of 2a with DMF, Weinreb base N-methoxy-N-methyl acetamide,
benzonitrile, 2,2-diethoxypropionitrile,11 or γ-butyrolactone fol-
lowed by acidification gave rise to the 1,3- and 1,2,3-substituted
indoles 3a-e in acceptable yields, all with an er of 92:8 ((1%)
(Table 3, entries 1-5). The tolerance of the reaction sequence to
incorporation of functional groups by varying the electrophile is
exceptional with alkyl, aryl, keto, and alcohol groups being
successfully introduced at the C-2 position of the indole products.
We were pleased to discover that the indole cascade reaction
sequence was also successful with a variety of electrophiles for
ethyl- and n-hexylithium (entries 6 and 7) and the starting substrate
1b (entries 8 and 9).
Acknowledgment. This work was supported by Science Foun-
dation Ireland. A.-M.L.H. thanks IRCSET for funding.
Supporting Information Available: All experimental procedures,
compound characterization data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc. 1969,
91, 6362. (b) Wei, X.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun.
1996, 187. (c) Wei, X.; Johnson, P.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 2000, 1109. (d) Clayden, J. Organolithiums: SelectiVity for
Synthesis; Pergamon Press: Oxford, U.K., 2002; pp 273-335.
(2) (a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054.
(b) Kessler, A.; Coleman, C. M.; Charoenying, P.; O’Shea, D. F. J. Org.
Chem. 2004, 69, 7836.
(3) Several natural products and medicinal applications of this structural class
are known: (a) Rawson, D. J.; Dack, K. N.; Dickinson, R. P.; James, K.
Bioorg. Med. Chem. Lett. 2002, 12, 125. (b) Chang-Fong, J.; Rangisetty,
J. B.; Dukat, M.; Setola, V.; Raffay, T.; Roth, B.; Glennon, R. Bioorg.
Med. Chem. Lett. 2004, 14, 1961. (c) Christian, O. E.; Compton, J.;
Christian, K. R.; Mooberry, S. L.; Valeriote, F. A.; Crews, P. J. Nat. Prod.
2005, 68, 1592.
In summary, our results exemplify the power of reversing the
order of bond formation, so that selectivity control is achieved in
the first step of the reaction to generate a chiral intermediate of
(4) Intramolecular asymmetric carbolithiation routes to indolines have been
described: (a) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122,
6787. (b) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000, 122, 6789.
(5) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172.
(6) (a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J.
Am. Chem. Soc. 2003, 125, 10780. (b) Evans, D. A.; Fandrick, K. R.;
Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942.
Scheme 2. Synthetic Potential of Lithiated Intermediate 2
(7) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J.
Am. Chem. Soc. 2005, 127, 4154.
(8) For reviews of (-)-sparteine in organolithium chemistry, see: (a) Beak,
P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res. 1996, 29, 2283. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282.
(9) (a) Klein, S.; Marek, I.; Poisson, J. F.; Normant, J. F. J. Am. Chem. Soc.
1995, 117, 8853. (b) Norsikian, S.; Marek, I.; Normant, J. F. Tetrahedron
Lett. 1997, 38, 7523. (c) Norsikian, S.; Marek, I.; Klein, S.; Poisson, J.
F.; Normant, J. F. Chem.sEur. J. 1999, 5, 2055.
(10) Phenyllithium ensured complete deprotonation prior to carbolithiation.
Cottineau, B.; O’Shea, D. F. Tetrahedron Lett. 2005, 46, 1935.
(11) Acetal protecting group was also removed during acidification step.
JA060076G
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