Catalyzed Olefin Isomerization Leading to Highly Stereoselective Claisen Rearrangements of Aliphatic Allyl Vinyl Ethers

Article abstract of DOI:10.1021/ja037655v

Iridium(I)-catalyzed olefin isomerization in bis(allyl) ethers is integrated into a generally applicable strategy for affecting highly stereoselective Claisen rearrangements. Catalyzed alkene isomerization affords allyl vinyl ethers from easily prepared d

Full text of DOI:10.1021/ja037655v

Published on Web 10/01/2003
Catalyzed Olefin Isomerization Leading to Highly Stereoselective Claisen
Rearrangements of Aliphatic Allyl Vinyl Ethers
Scott G. Nelson,* Christopher J. Bungard, and Kan Wang
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received July 30, 2003; E-mail: sgnelson@pitt.edu
Claisen and related [3,3] sigmatropic rearrangements share the
defining characteristic of rapidly introducing molecular complexity
from simple, easily obtained starting materials.1 Activated variants
of the Claisen rearrangement have greatly extended the synthetic
utility of the parent allyl vinyl ether rearrangement by allowing
reactions to be performed under conditions that afford excellent
stereocontrol and substrate compatibility while facilitating substrate
preparation.2 The parent Claisen rearrangements offer useful
complements to the more extensively utilized enolate Claisen
Figure 1. Isomerization-Claisen rearrangement (ICR) reactions.
variants by affording direct access to aldehyde functionalities
amenable to immediate elaboration using the wealth of transforma-
tions available for these functional groups.3 With the goal of broadly
exploiting Claisen-derived R-chiral aldehydes in synthesis activities,
we have developed highly stereoselective Claisen rearrangements
from easily prepared di(allyl) ethers 1 (Figure 1). The Claisen
rearrangements involve catalyzed olefin isomerization to generate
the vinyl ether moiety followed by thermal [3,3] sigmatropic
rearrangement to afford syn-2,3-dialkyl-4-pentenal derivatives 2
with high diastereoselectivity.
The strategic nature of Claisen rearrangements in synthesis
activities has generated considerable interest in addressing the
operational limitations associated with aliphatic allyl vinyl ether
Ir(I)-bis(phosphine) or Ir(I)-tris(phosphine) complexes 4 and 5,
respectively (eq 1).9 Catalysts incorporating σ-basic phosphines
having large cone angles provided very efficient alkene isomer-
ization catalysts. Thus, the di- and triphosphine complexes obtained
using PCy3 mediated highly E-selective isomerization exclusively
at the less substituted allyl ether in 1a to afford the corresponding
vinyl ether 6 (eq 2). Iridium complexes derived from aryl (less
basic) phosphines provide catalysts exhibiting attenuated reactivity
toward allyl ether isomerization. More importantly, attempted
isomerization of bis(allyl) ether 1a using the aryl phosphine-derived
catalysts 4b/c or 5b/c was complicated by competing allyl ether
migration, affording variable amounts of Claisen adduct 7 derived
from the isomeric bis(allyl) ether 8.
rearrangements.4,5 Among the strategies for simplifying vinyl ether
introduction, several groups have recognized metal-catalyzed allyl
ether isomerization as a convenient route to the enol ether com-
ponent of Claisen substrates. Bis(allyl) or allyl homoallylic ethers
are subject to metal-catalyzed isomerization to the corresponding
vinyl ether Claisen substrates.6 Unfortunately, these olefin isomer-
ization catalyst systems have not been integrated into generally
applicable, highly diastereoselective Claisen rearrangements.
Considering the ready availability of bis(allyl) ethers 1 from
nucleophilic addition to R,â-unsaturated aldehydes followed by
O-allylation, we sought alkene isomerization catalysts that would
render these substrates effective precursors to highly stereoselective
Claisen rearrangements. These catalysts would necessarily achieve
both chemo- and stereoselective isomerization of only one allyl
residue and would not interfere with the ensuing thermal Claisen
rearrangement nor accelerate epimerization of the emergent alde-
hyde reaction product. Successfully developing catalysts satisfying
these criteria would allow thermolysis of bis(allyl) ethers in the
presence of the catalyst complex to afford direct access to
diastereomerically enriched 2,3-dialkyl 4-pentenal derivatives 2.
Considering the success of iridium-based complexes as alkene
isomerization catalysts, we initially examined Ir(I)-based catalyst
systems for effecting chemo- and stereoselective allyl ether isomer-
ization in bis(allyl) ether substrates.7 Preliminary investigations
revealed efficiency of both alkene isomerization and the ensuing
Claisen rearrangement to be critically dependent on catalyst
composition. Typical Ir(I)-phosphine precatalysts were prepared by
reacting [(cC8H14)2IrCl]2 38 with varying amounts of phosphine
ligand followed by halide abstraction to afford the reactive cationic
The method used for halide abstraction in preparing the reactive
cationic Ir(I) catalysts also proved critical in defining the efficiency
of the isomerization-Claisen rearrangement reactions. Cationic Ir(I)
complexes obtained using AgSbF6 achieved highly selective allyl
ether isomerizations; however, these reactions produced equimolar
mixtures of the expected Claisen adduct 2a and pentenal 7 derived
from competing allyl ether migration, each as a stereorandom
mixture (eq 2). In general, Lewis acidic contaminants present during
the thermal Claisen rearrangements, whether they are derived from
Lewis acidic Ir(I)-phosphine species or Ag(I) salt byproducts, lead
to poor diastereoselection in the putative Claisen adducts.
These investigations identified the complex obtained by reacting
[(cC8H14)2IrCl]2 with PCy3 (3 equiv/Ir) and NaBPh4 as the halide
abstractor in 50:1 CH2Cl2/acetone (or 1,2-DCE/acetone) as the
9
13000
J. AM. CHEM. SOC. 2003, 125, 13000-13001
10.1021/ja037655v CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. ICR Reactions of Substituted Bis(allyl) Ethers 1 (Figure 1)
Enantioenriched (S)-E-1-phenyl-1-penten-3-ol was prepared by the
N-methyl-R,R-diphenylprolinol (9)-catalyzed addition of Et2Zn to
cinnamaldehyde (84% ee).15,16 Following O-allylation, subjecting
the resulting (S)-bis(allyl) ether (S)-1l to the optimized ICR
conditions delivered pentenal (2S,3R)-2l in 84% ee with excellent
diastereoselection (syn:anti ) 95:5).
c
entry
bis(allyl) ether 1a
syn:antib
% yield
a
b
c
d
e
f
g
h
i
R1 ) H, R2 ) CH3, R3 ) Ph (1a)
R1 ) H, R2 ) R3 ) Ph (1b)
94:6
98:2
95:5
97:3
95:5
93:7
96:4
92:8
93:7
86:8d
96:4
95:5
80
92
93
70
84
84
93
86
62
85
62
93
R1 ) H, R2 ) iPr, R3 ) Ph (1c)
R1 ) H, R2 ) nPr, R3 ) Ph (1d)
R1 ) CH3, R2 ) R3 ) Ph (1e)
R1 ) H, R2 ) CH3, R3 ) CH2SiMe3 (1f)
R1 ) H, R2 ) Ph, R3 ) CH2SiMe3 (1g)
R1 ) H, R2 ) CH3, R3 ) tBu (1h)
R1 ) R2 ) CH3, R3 ) tBu (1i)
j
k
l
R1 ) H, R2 ) CH3, R3 ) nBu (1j)
R1 ) H, R2 ) Ph, R3 ) nBu (1k)
R1 ) H, R2 ) Ph, R3 ) CH2CH3 (1l)
a Claisen rearrangement conducted at 23 °C (entries b,e), 39 °C (entries
1
a,c,d,f,g), or 80 °C (entries h-l). b Diastereomer ratios determined by H
The ICR reaction technology provides convenient access to
highly diastereoselective aliphatic Claisen rearrangements from
easily prepared starting materials. This reaction methodology also
offers an efficient entry to enantioenriched syn-2,3-dialkyl 4-pen-
tenal derivatives by merging asymmetric dialkyl zinc additions with
the ensuing ICR transformations.
NMR of crude product mixtures (entry i determined by GC). c Isolated yields
i
are reported for the primary alcohols derived from Bu2AlH reduction of
the initial aldehyde products 2a-l. d Reaction afforded 6% of the 2,3-syn,
4Z diastereomer.
optimum catalyst for merging allyl ether isomerization with ensuing
[3,3] sigmatropic rearrangement.10 In the standard test reaction, di-
(allyl) ether 1a was reacted with 1 mol % 5a (30 min, 23 °C) to
afford the Claisen substrate 6 (g95:5 E,E:Z,E); directly warming
6 to 39 °C for 12 h afforded 4-pentenal derivative 2a (80%) as a
85:15 (syn:anti) mixture of diastereomers. Claisen diastereoselection
was substantially higher for reactions employing the putative Ir(I)-
tris(phosphine) complex 5a relative to the analogous bis(phosphine)
complex 4a.11 Presumably, utilizing 3 equiv of ligand attenuates
the Lewis acidity of the derived Ir(I) complex, thereby limiting
the potential for Lewis acid-accelerated aldehyde epimerization
during the Claisen rearrangement. Catalyst preparations employing
NaBPh4 also eliminate AgCl contaminants that mediate competing
ether migration and function to attenuate Claisen diastereoselection.
On the basis of the preceding analysis, we reasoned that Claisen
diastereoselection could be further improved by rigorously ensuring
that the Ir(I)-phosphine complex could not participate in epimerizing
the R-chiral aldehyde Claisen products. With the goal of passivating
any residual Lewis acidic character in the Ir catalyst, additional
phosphine ligand was added to saturate the metal’s coordination
sphere prior to thermolysis. Thus, ether 6 was reacted with 1 mol
% 5a prior to adding PPh3 (3 mol %) and warming the resulting
reaction mixture to 39 °C (12 h). Under these conditions, pentenal
2a was obtained with excellent syn diastereoselection (syn:anti )
94:6) in 80% yield from the bis(allyl) ether 1a.12
Under the optimized isomerization-Claisen rearrangement (ICR)
reaction conditions, a variety of structurally diverse bis(allyl) ethers
1a-l participate in highly diastereoselective Claisen rearrangements.
Ether substrates incorporating various linear or branched alkyl
substituents at the allylic (R2) or carbinol carbon (R3) positions
exhibit uniformly high syn diastereoselection (syn:anti ) 91:9 to
98:2) (Table 1). Internal allyl ether substrates prepared as E,Z-olefin
mixtures are also effective ICR substrates due to the high E-
selectivity that characterizes Ir(I)-catalyzed allyl ether isomerization
(entries e, i). Substrates incorporating R3 substituents capable of
labilizing the adjacent C-O σ-bond (cf., Ph, CH2SiMe313) require
temperatures only as high as 39 °C to achieve useful Claisen
reaction rates (entries a-g). While most substrates exhibited equally
high selectivity for delivering the (E)-pentenal products, ether 1j
combining small alkyl groups at both R2 and R3 delivered a
measurable amount of the (Z)-2,3-syn diastereomer (6%) (entry j).14
This stereochemical leakage may result from the higher reaction
temperatures (80 °C) required for substrates possessing simple alkyl
R3 substituents.
Acknowledgment. Support from the National Institutes of
Health (P50 GM067082) for the University of Pittsburgh Center
for Chemical Methodologies and Library Development (UPCMLD)
and from Eli Lilly & Co. is gratefully acknowledged.
Supporting Information Available: Experimental procedures and
representative 1H and 13C spectra (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Ziegler, F. E. Chem. ReV. 1988, 88, 1423. (b) Ito, H.; Taguchi, T.
Chem. Soc. ReV. 1999, 28, 43. (c) Hiersemann, M.; Abraham, L. Eur. J.
Org. Chem. 2002, 1461. (d) Nubbemeyer, U. Synthesis 2003, 961.
(2) (a) Wipf, P. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 5, p 827. (b) Wilson, S. R. Org.
React. (New York) 1993, 43, 93. (c) Paquette, L. A. Tetrahedron 1997,
53, 13971.
(3) For extensive development of aliphatic Claisen rearrangements, see:
Nonoshita, K.; Maruoka, K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1992,
65, 541 and references therein.
(4) For alternative vinyl ether preparations in Claisen rearrangements, see:
(a) Mikami, K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1987, 28,
5879. (b) Sugiura, M.; Yanagisawa, M.; Nakai, T. Synlett 1995, 447. (c)
Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122, 3785. (d)
May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426. (e)
Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978.
(5) For the use of functionalized allyl vinyl ether substrates derived from
R-dicarbonyl substrates in asymmetric Claisen rearrangements, see: (a)
Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem., Int. Ed.
2001, 40, 4700. See also: (b) ref 4c.
(6) (a) Ni(0) catalysts: Wille, A.; Tomm, S.; Frauenrath, H. Synthesis 1998,
305. (b) Ir(I) catalysts: Higashino, T.; Sakaguchi, S.; Ishii, Y. Org. Lett.
2000, 2, 4193. (c) Reuter, J. M.; Salomon, R. G. J. Org. Chem. 1977, 42,
3360. (d) Ru(II) catalysts: Ben Ammar, H.; Le Noˆtre, J.; Salem, M.;
Kaddachi, M. T.; Dixneuf, P. H. J. Organomet. Chem. 2002, 662, 63.
(7) For a detailed investigation of Ir(I)-catalyzed allylic ether isomerization,
see: Ohmura, T.; Yamamoto, Y.; Miyaura, N. Organometallics 1999, 18,
413 and references therein.
(8) Onderdelinden, A. L.; van der Ent, A. Inorg. Chim. Acta 1972, 6, 420.
(9) Catalysts prepared from the more commonly used [(COD)IrCl]2 employing
various methods for reductive removal of the diene ligand uniformly
provided Ir(I)-phosphine catalysts exhibiting inferior activity relative to
analogous complexes prepared from dimer 3.
(10) Acetone was added to solubilize the NaBPh4. Miyaura has also found
acetone to accelerate related catalyzed isomerizations; see ref 7.
(11) Complex 5a is formulated as the tris(phosphine) complex on the basis of
reaction stoichiometry and is not necessarily intended to represent the
reactive catalyst complex that may be accessed by reversible phosphine
dissociation.
i
(12) Isolated yields are reported for the primary alcohols derived from Bu2-
AlH reduction of the initial Claisen products due to epimerization of the
R-chiral aldehydes during attempted chromatographic purification. See
Supporting Information for full procedural details.
(13) Wilson, S. R.; Price, M. F. J. Am. Chem. Soc. 1982, 104, 1124.
(14) A similar observation was made in Claisen rearrangements involving
substrates prepared by Hg(II)-mediated ether exchange. See ref 3.
(15) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987,
109, 7111.
(16) Enantioselectivity in the Et2Zn addition was not optimized.
The success of the ICR reactions suggested an operationally
simple strategy for realizing asymmetric reaction variants (eq 3).
JA037655V
9
J. AM. CHEM. SOC. VOL. 125, NO. 43, 2003 13001