Design of a new cascade reaction for the construction of complex acyclic architecture: The tandem acyl-claisen rearrangement

Full text of DOI:10.1021/ja005925t

2448
J. Am. Chem. Soc. 2001, 123, 2448-2449
Scheme 1
Design of a New Cascade Reaction for the
Construction of Complex Acyclic Architecture: The
Tandem Acyl-Claisen Rearrangement
Vy M. Dong and David W. C. MacMillan*,†
Department of Chemistry, UniVersity of California
Berkeley, California 94720
DiVision of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, California 91125
ReceiVed December 27, 2000
Tandem or domino reactions have long been established as
powerful chemical tools for the rapid formation of complex cyclic
and polycyclic architecture.1 Surprisingly, however, relatively few
tandem strategies have been directed toward the production of
acyclic structural motifs despite significant advances in the area
of acyclic stereocontrol. In our recent study, we reported the
development of the acyl-Claisen rearrangement, a catalytic [3,3]-
bond reorganization that allows the stereoselective synthesis of
R,â-disubstituted-γ,δ-unsaturated carbonyls.2,3 In this communica-
tion, we outline the development of the tandem acyl-Claisen
reaction, a highly stereoselective three-component coupling that
enables the rapid construction of complex acyclic systems in the
context of 2,3,6-trisubstituted-1,7-dioxoheptane architecture (eq
1). This versatile cascade sequence is conducted by using simple
Table 1. Lewis Acid Promoted Tandem Acyl-Claisen
Rearrangement between Propionyl Chloride and Allyl Dimorpholine
1 (Scheme 1)a
allyl diamines and acid chlorides, chemicals that are widely
available in a diverse range of structural formats. As such, we
expect this tandem reaction to be of broad utility to a number of
chemical fields that employ molecule construction including
natural product and parallel medicinal agent synthesis.
syn-anti/
entry
Lewis acid
equiv of LA
% yield of 9
anti-antib,c
1
2
3
4
Yb(OTf)3
TiCl4‚THF2
MgI2
2.0
2.0
4.0
2.0
97
93
70
93
98:2
Design Plan. In accord with our acyl-Claisen studies, we
envisioned that a variety of ketenes 2, generated in situ from acid
chloride 3 and i-Pr2NEt, would undergo Lewis acid-catalyzed
addition to either the (Z)- or (E)-amine component of allyl diamine
1 to provide the regioisomeric allyl vinylammonium complexes
4 and 5 (Scheme 1). Given that (i) the (Z)-amine derived
conformation 5 would be destabilized on the basis of 1,3-diaxial
interactions and (ii) the ketene-addition step is likely reversible,4
the primary Claisen event was expected to proceed selectively
by way of the (E)-ammonium topography 4. As a central design
element, this regioselective addition-rearrangement would provide
the 2,3-disubstituted intermediate 6 with high levels of syn
selectivity while revealing an allylamine component that can
participate in a second acyl-Claisen transform. In this context,
the addition of a further equivalent of ketene 2 to intermediate 6
would result in an ammonium enolate that can adopt two chair
rearrangement topographies 7 and 8. Minimization of A(1,2)
strain5 about the C(5)-C(5a) bond of conformer 7 was expected
98:2d
98:2
AlCl3
64:36
a Reactions performed in CH2Cl2 at 23 °C. b Ratios determined by
GLC. c The syn-syn and anti-syn isomers were isolated in <1% yield.
d Reaction performed at -20 °C.
to enforce transannular interactions between the C(5a)-amide
moiety and the axial methylene group, while the same torsional
constraints in topography 8 positions the bulky C(5a)-amide chain
away from the [3,3]-isomerization event. As such, the second
Claisen step was anticipated to proceed via conformer 8 to furnish
the complex 2,3,6-trisubstituted-1,7-diamidoheptane 9 with high
levels of 2,3-syn-3,6-anti diastereocontrol.
Scope Studies. Our tandem acyl-Claisen strategy was first
evaluated by using allyl dimorpholine 1 with propionyl chloride
in the presence of i-Pr2EtN and a series of metal salts. As revealed
in Table 1, this tandem sequence was successful with a variety
of Lewis acids including Yb(OTf)3, TiCl4‚THF2, and MgI2 to
provide the tandem adduct 9 in excellent yield and diastereo-
selectivity (entries 1-3, 70-97% yield, g98:2 dr). In all cases,
the major constituent of 9 was confirmed by X-ray analysis to
be the 2,3-syn-3,6-anti isomer in complete accord with our
† Current address: Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, CA 91125.
(1) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience: New York,
1992.
(2) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
1999, 121, 9726.
(3) This reaction is based upon the Bellus ketene-Claisen reaction: (a)
Malherbe, R.; Bellus, D. HelV. Chim. Acta 1978, 61, 3096. (b) Malherbe, R.;
Rist, G.; Bellus, D. J. Org. Chem. 1983, 48, 860.
(5) For examples of A(1,2) strain directed reactions see: (a) Johnson, F.
Chem. ReV. 1968, 68, 375. (b) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem.
ReV. 1993, 93, 1307.
(4) Tidwell, T. T. Ketenes; Wiley: New York, 1995.
10.1021/ja005925t CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2449
Table 2. Tandem Acyl-Claisen Rearrangement between Propionyl
Chloride and Representative Allyl Diamines
Table 3. Tandem Acyl-Claisen Rearrangement between
Representative Allyl Dimorpholines and Acid Chloridesa
a Ratios determined by GLC, HPLC, or 1H NMR. b The syn-syn and
anti-syn isomers were isolated in <1% yield. c Relative configurations
assigned by X-ray analysis. d Using TiCl4‚THF2.
mechanistic plan (Scheme 1). The superior levels of diastereo-
selectivity (98:2 dr) and reaction efficiency (97% yield) exhibited
by Yb(OTf)3 (Table 1, entry 3) defined this Lewis acid as the
optimal catalyst for further exploration.
Experiments that probe the scope of the allyl dimorpholine
substrate are summarized in Table 2. The reaction appears quite
general with respect to the nature of the tertiary amine component
(entries 1-3, 90-99% yield, g95:5 dr). Considerable variation
in the olefin substituent can also be tolerated to afford acyclic
arrays that incorporate alkyl, halo, cyano, alkoxy, and sulfanyl
substituents in excellent yield and diastereoselectivity (entries
4-7, 70-98% yield, 91:9 to 99:1 syn-anti:anti-syn). As revealed
with the cyano- and phenylthio-substituted amines (entries 6 and
7), the reaction exhibits broad latitude with respect to the
electronic contribution of the olefin substituent (g70% yield,
g93:7 dr).
a With 2 equiv of Yb(OTf)3 and i-Pr2NEt at 23 °C in CH2Cl2. b NR2
1
) N-morpholine. c Ratios determined by GLC, HPLC, or H NMR.
d The syn-syn and anti-syn isomers were isolated in <1% yield.
e Relative configurations assigned by X-ray analysis. f Using TiCl4‚THF2.
g The syn-syn isomer was isolated in 2% yield.
to note that regioselective hydrolysis of the R,â-disubstituted
amide of these dicarbonyl Claisen adducts is possible with use
of an iodolactonization-ring opening sequence.7
The effect of the acid chloride component on the tandem acyl-
Claisen rearrangement has also been examined (Table 3).
Significant structural variation in the ketene surrogate (R2 ) Me,
Bn, NPhth, or OPv) is possible without loss in yield or dia-
stereoselectivity (71-99% yield, 92:8 to 98:2 syn-anti:anti-syn,
entries 1-6). A powerful feature of this cascade reaction is
the capacity to build functional and stereochemical arrays that
are not readily available using conventional chemical methods.
As demonstrated in entry 3, implementation of R-phthalylglycyl
chloride allows the rapid construction of carbon-tethered R-amino
carbonyls. This tandem strategy also provides an attractive
alternative to iterative aldol processes. Indeed, the synthesis
of a variety of substitutionally divergent polyol systems can
be achieved by using R-pivaloyloxy chloride with alkyl-, halo-,
or alkoxy-substituted diamines (entries 4-6, 71-97% yield,
g92:8 dr).
A demonstration of the synthetic utility of the tandem acyl-
Claisen rearrangement and the accompanying 1,7-diamidoheptane
products is presented (eq 2). A stereochemical motif commonly
found throughout the architecture of macrolide antibiotics is
represented by 2,3-syn-3,6-anti-2,6-dimethyl-1,7-dioxo-3-hydroxy-
heptane.6 As revealed in eq 2, this acyclic stereochemical array
can be accessed in one step from allyl diamine 13 and propionyl
chloride by using our tandem Claisen protocol. Moreover, the
incorporation of an olefin moiety at C(4) renders these Claisen
adducts versatile substrates for oxidative or reductive elaboration
(cf. C(4)-erythronolide B, C(4)-neomethynolide). It also important
Last, preliminary studies have been completed that outline the
utility of the tandem acyl-Claisen reaction as a powerful tool for
natural product synthesis. Details of this work along with a full
account of this survey will be forthcoming.
Acknowledgment. V.M.D. is grateful for an NSF predoctoral fellow-
ship. Financial support was provided by the NIH (R01 GM61214-01).
Supporting Information Available: Experimental procedures and
spectral data for all compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA005925T
(7) This regioselective hydrolysis protocol appears quite general for a
number of tandem Claisen adducts.
(6) Macrolide Antibiotics. Chemistry, Biology, and Practice; Omura, S.,
Ed.; Academic Press: Orlando FL, 1984.