Enantioselective construction of highly substituted vinylidenecylopentanes by palladium-catalyzed asymmetric [3+2] cycloaddition reaction

Article abstract of DOI:10.1002/anie.201300275

A new cycloadduct: The title reaction of methylene-trimethylenemethane (TMM) with α,β-unsaturated N-acyl pyrroles is an efficient method for the construction of vinylidenecyclopentanes. An asymmetric protocol using this unique donor forms cycloadducts in

Full text of DOI:10.1002/anie.201300275

Angewandte
Chemie
DOI: 10.1002/anie.201300275
Asymmetric Catalysis
Enantioselective Construction of Highly Substituted
Vinylidenecylopentanes by Palladium-Catalyzed Asymmetric
[3+2] Cycloaddition Reaction**
Barry M. Trost* and Autumn Maruniak
The transition-metal catalyzed [3+2] trimethylenemethane
(TMM) cycloaddition reaction is a versatile method for the
construction of highly substituted five-membered rings with
high chemo-, regio-, and diastereoselectivity.[1] Since 2006, the
first asymmetric TMM reactions utilizing a series of chiral
phosphoramidite ligands to form substituted carbocycles[2]
and heterocycles[3] with high enantioselectivity have been
reported.
The search for novel TMM donors bearing diverse
functionalities represents an important dimension to enhance
the power of this methodology. Recently, asymmetric meth-
odologies for cyano-[4] and vinyl-substituted[5] donors to
generate tetrasubstituted cyclopentanes with three contigu-
ous stereocenters were reported. Methylene-substituted
donor 1 constitutes a structurally and electronically distinct
donor of a nature quite different than any examined. Previous
work by our group established that allene acetates could
participate in asymmetric allylic alkylation reactions.[6] We
envisioned this methylene-TMM donor could give rise to two
interesting and useful products through the generation of the
unsymmetrical Pd-TMM complex 2, which features electroni-
cally distinct sp2- and sp-hybridized electrophilic carbons
(Scheme 1).
Attack at position a of the zwitterionic intermediate 3
would lead to the vinylidenecyclopentane 4a, while attack at
position b would yield diene 4b. Initial efforts to effect this
cycloaddition with achiral phosphite or phosphorus triamine
ligands typically used for TMM cycloadditions failed to
generate any desired cycloadducts. Herein, we describe our
efforts to develop this methodology, which led to excellent
yields of the cycloaddition products with concomitant enan-
tioselectivity. We also demonstrate a unique synthetic appli-
cation of the cycloadducts evolving from their selective
behavior in further catalytic transformations.
The methylene-TMM donor is synthesized readily in three
steps by SN2’ addition of an organocopper reagent to a 1,4-
butynediol derivative [Eq. (1); DMAP = 4-dimethylamino-
pyridine, Ms = mesyl, HMPA = hexamethylphosphoric tri-
amide]. The tert-butyl carbonate was required for ionization
of the donor.
The reactivity and synthetic utility of a,b-unsaturated
N-acyl pyrroles[7] prompted us to examine acceptor 7a,
derived from cinnamic acid. In the initial ligand screen
(Table 1), we were surprised to observe limited reactivity
under typical TMM reaction conditions. While no reactivity
was observed with triisopropylphosphite (L1) as a ligand, the
reaction using hexamethylphosphorus triamide (L2) as ligand
was very messy with complete consumption of the starting
donor but only trace amounts of vinylidene cycloadduct.
Furthermore, no reaction was observed with chiral bis(2-
naphthyl) ligand L3, which was developed as a preferred
ligand for the asymmetric TMM reaction with other donors.[8]
These data indicated that reactivity of methylene-TMM
intermediate was sensitive to the electronic environment of
the ligand—while more electron-deficient phosphite and
phosphoramidite ligands were not reactive enough, phospho-
rus triamide ligands were too reactive. This led to the
investigation of diamidophosphite systems, which contain
two nitrogen atoms and an oxygen atom around the
phosphorus center. Inspired by monodentate diamidophos-
Scheme 1. Palladium-catalyzed TMM cycloaddition reaction with meth-
ylene-TMM donor. EWG=electron-withdrawing group,
Boc=tert-butoxycarbonyl, TMS=trimethylsilyl.
[*] Prof. B. M. Trost, A. Maruniak
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost
[**] We thank the NSF for their generous support of our programs and
Johnson Matthey for generous gifts of palladium salts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300275.
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Table 1: Initial ligand screen.[a]
Table 2: Palladium-catalyzed [3+2] reactions with methylene-TMM
donor.[a]
[a] Reactions were conducted for 12 h at 608C in 0.2m toluene with
1.5 equiv of 1, 5% [Pd(dba)2], and 10% (for L1–L5) or 6% (for L6 and L7)
ligand. Yields are isolated values; ee values were determined by chiral
HPLC with a chiral stationary phase column. [b] Reaction conducted with
5% Pd(OAc)2.
[a] Reactions were conducted for 12 h at 608C in 0.2m toluene with 5%
[Pd(dba)2], 6% L7, and 1.5 equiv 1. Yields are combined isolated values;
ee values were determined by HPLC with a chiral stationary phase
column and represent absolute values. [b] Reaction conducted at 408C,
2.0 equiv 1. [c] 80% yield based on recovered starting material.
phosphites like Quiphos and its derivatives[9] we began our
studies with L4 as a ligand. While we did observe reactivity
using this ligand [Eq. (2); dba = dibenzylideneacetone], addi-
Using our optimized conditions, we examined the scope of
the cycloaddition reaction with respect to N-acyl pyrrole
acceptor (Table 2). Excellent yields and enantioselectivities
were obtained with a broad range of substrates. The
regioselectivity of the cycloaddition that led to adduct 8l is
particularly noteworthy, showing the strong activation of the
acyl pyrrole subunit.
Aromatic substituents were well tolerated and ee was
insensitive to substitution pattern of the aromatic ring or
electronic nature of the substituent, including aryl chlorides
and aryl bromides (7b–7e). Heterocycles were also well
tolerated (7 f and 7g). Acceptors bearing aliphatic substitu-
ents at the b-position did not undergo addition to the donor;
however, a range of acceptors bearing non-aromatic sub-
stituents performed well, including alkynes (7h–7j) and
dimethyl acetal (7k). Only 1,4-addition was observed with
7l. Lowering the temperature of the reaction to 408C when
non-aromatic acceptors were used improved the ee of the
cycloadducts while increasing the equivalents of TMM donor
maintained the yield.[10]
Allenes are stable functional groups that possess versatile
reactivity and selectivity in organic reactions.[11] The exocyclic
allene of 8 serves as a useful handle for further transforma-
tions to a diverse range of highly substituted cyclopentane
products. One particularly useful reaction is the carbopalla-
dation of allenes,[12] which leads to a p-allyl intermediate that
is subject to nucleophilic attack [Eq. (3)]. Both terminal
carbons of the allene are electrophilic, which may lead to
a mix of products.
tion of the donor was limited to highly activated acceptors
such as benzylidene Meldrumꢀs acid 5 and there was no
enantioinduction. No reaction was observed with N-acyl
pyrrole 7a. However, encouraged by the this limited reac-
tivity, we investigated ligands derived from trans-1,2-cyclo-
hexanediamine.[5] In the presence of monodentate ligand L5,
the cycloadduct 8a was obtained in 38% yield and 65% ee.
While the yield remained modest, employing ligand L6 led to
an increase in enantioselectivity from 65% to 73% ee.
Further structural and electronic modifications to this class
of ligand did not improve yield or enantioselectivity. Chang-
ing the chiral scaffold to the sterically more demanding trans-
1,2-stilbenediamine backbone of L7 dramatically improved
reactivity and enantioselectivity. Under all reaction condi-
tions, only the allene cycloadduct was formed, which is
consistent with the initially formed trimethylenemethane
intermediate reacting with the acceptor to give 4a faster than
it can equilibrate to its regioisomer, which would have given
4b.
Tethering of the nucleophile to the allene to control
selectivity is well documented[13] and we envisioned that
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scope of this reaction, including the use of other acceptors and
new applications of this methodology are underway.
Received: January 11, 2013
Revised: March 28, 2013
Published online: && &&, &&&&
elaboration of the acyl pyrrole moiety would allow directed
nucleophilic addition to the allene to generate a third
stereocenter (Scheme 2). Heating the cycloadduct with ben-
zylamine at reflux furnished the corresponding amide, which
Keywords: [3+2] cycloaddition · allenes · asymmetric catalysis ·
.
palladium · trimethylenemethane
[1] a) B. M. Trost, Angew. Chem. 1986, 98, 1; Angew. Chem. Int. Ed.
Engl. 1986, 25, 1; b) B. M. Trost, Pure Appl. Chem. 1988, 60,
1615; c) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96, 49;
d) S. Yamago, E. Nakamura, Org. React. 2002, 61, 1.
[2] a) B. M. Trost, J. P. Stambuli, S. M. Silverman, U. Schwçrer, J.
Am. Chem. Soc. 2006, 128, 13328; b) B. M. Trost, D. A. Bringley,
P. S. Seng, Org. Lett. 2012, 14, 234.
[3] a) B. M. Trost, D. A. Bringley, S. M. Silverman, J. Am. Chem.
Soc. 2011, 133, 7664; b) B. M. Trost, S. M. Silverman, J. P.
Stambuli, J. Am. Chem. Soc. 2007, 129, 12398; c) B. M. Trost,
S. M. Silverman, J. Am. Chem. Soc. 2010, 132, 8238; d) B. M.
Trost, S. M. Silverman, J. Am. Chem. Soc. 2012, 134, 4941.
[4] a) B. M. Trost, N. Cramer, S. M. Silverman, J. Am. Chem. Soc.
2007, 129, 12396; b) B. M. Trost, S. M. Silverman, J. P. Stambuli,
J. Am. Chem. Soc. 2011, 133, 19483.
Scheme 2. Functionalization of allene in TMM cycloadduct 8a.
Bn=benzyl, THF=tetrahydrofuran, DMF=dimethylformamide.
[5] B. M. Trost, T. M. Lam, J. Am. Chem. Soc. 2012, 134, 11319.
[6] B. M. Trost, D. R. Fandrick, D. C. Dinh, J. Am. Chem. Soc. 2005,
127, 14186.
[7] a) D. A. Evans, G. Borg, K. A. Scheidt, Angew. Chem. 2002, 114,
3320; Angew. Chem. Int. Ed. 2002, 41, 3188; b) T. Kinoshita, S.
Okada, S. Park, S. Matsunaga, M. Shibasaki, Angew. Chem. 2003,
115, 4828; Angew. Chem. Int. Ed. 2003, 42, 4680; c) S. Matsu-
naga, T. Kinoshita, S. Okada, S. Harada, M. Shibasaki, J. Am.
Chem. Soc. 2004, 126, 7559.
was then reduced to protected amine 9. This amine was well
positioned to participate in palladium-catalyzed carboamina-
tion of the allene to form the bridged piperidine bearing
a tertiary amine stereocenter and vinyl phenyl substituent
producing the novel azabicyclo[2.2.1]heptane 10. Similarly,
tertiary alcohols such as 13 could be formed through the
carbolactonization of 11 and subsequent methanolysis of the
lactone 12 with sodium methoxide.
In summary, we have demonstrated a palladium-catalyzed
asymmetric addition of a unique donor to a,b-unsaturated
N-acyl pyrroles in the [3+2] TMM cycloaddition, providing
substituted vinylidenecyclopentanes in excellent yield and
enantioexcess. This transformation forms a new and unusual
class of TMM cycloadducts and uses a new type of diamido-
phosphite ligand being developed by our group for substi-
tuted asymmetric TMM reactions. The uniqueness of the
efficacy of L7 is remarkable and a topic for future efforts.
Both the allene and acyl pyrrole moieties can be functional-
ized to yield complex products. Investigations into the full
[8] Ref. [3b].
[9] a) G. Delapierre, M. Achard, G. Buono, Tetrahedron Lett. 2002,
43, 4025; b) V. N. Tsarev, S. E. Lyubimov, A. A. Shiryaev, S. V.
Zheglov, O. G. Bondarev, V. A. Davankov, A. A. Kabro, S. K.
Moiseev, V. N. Kalinin, K. N. Gavrilov, Eur. J. Org. Chem. 2004,
2214.
[10] At 608C, ee for compounds 8h, 8i, and 8j were 80%, 67%, and
79%, respectively.
[11] a) S. Patai in The Chemistry of Ketenes, Allenes, and Related
Compounds, Wiley, New York, 1980; b) H. F. Schuster, G. M.
Coppola in Allenes in Organic Synthesis, Wiley, New York, 1984;
c) S. R. Landor in The Chemistry of Allenes, Vols. 1 – 3, Aca-
demic Press, New York, 1982; d) N. Krause, A. S. K. Hashmi in
Modern Allene Chemistry, Vols. 1 – 2, Wiley-VCH, Weinheim,
2004.
[12] S. Ma, Carbopalladation of Allenes in Handbook of Organo-
palladium Chemistry for Organic Synthesis (Eds: E. Negishi, A.
de Meijere), Wiley-Interscience, New York, 2002.
[13] R. C. Larock, Y. He, W. W. Leong, X. Han, M. D. Refvik, J. M.
Zenner, J. Org. Chem. 1998, 63, 2154.
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Communications
Asymmetric Catalysis
B. M. Trost,* A. Maruniak
&&&& — &&&&
Enantioselective Construction of Highly
Substituted Vinylidenecylopentanes by
Palladium-Catalyzed Asymmetric [3+2]
Cycloaddition Reaction
A new cycloadduct: The title reaction of
methylene-trimethylenemethane (TMM)
with a,b-unsaturated N-acyl pyrroles is an
efficient method for the construction of
vinylidenecyclopentanes. A asymmetric
protocol using this unique donor forms
cycloadducts in excellent yield and enan-
tioselectivity, making use of a bisdiami-
dophosphite ligand derived from trans-
1,2-stilbenediamine.
4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 4
These are not the final page numbers!