Asymmetric Claisen rearrangements enabled by catalytic asymmetric Di(allyl) ether synthesis

Article abstract of DOI:10.1021/ja058172p

Merging the catalytic asymmetric synthesis of di(allyl) ethers with ensuing olefin isomerization-Claisen rearrangement (ICR) reactions provides a convenient, two-step route to asymmetric aliphatic Claisen rearrangements from easily obtained starting mater

Full text of DOI:10.1021/ja058172p

Published on Web 03/11/2006
Asymmetric Claisen Rearrangements Enabled by Catalytic Asymmetric
Di(allyl) Ether Synthesis
Scott G. Nelson* and Kan Wang
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received December 1, 2005; E-mail: sgnelson@pitt.edu
Ester enolate (Ireland)-Claisen rearrangements are largely dif-
ferentiated from related [3,3] sigmatropic rearrangements by their
extensive applications in synthesis enterprises.1 The general utility
of Ireland-Claisen rearrangements can be attributed to the enhanced
functional group compatibility, superior stereocontrol, and facilitated
substrate preparation afforded by this activated Claisen variant
(Figure 1). We recently introduced olefin isomerization-Claisen
rearrangement (ICR) reactions as a means of imparting similarly
advantageous features to “unactivated” aliphatic Claisen rearrange-
ments.2,3 With the goal of broadening the utility of the ICR
methodology in asymmetric synthesis, we were interested in
exploiting the ICR reaction design to devise an efficient and
operationally simple strategy for affecting enantioselective Claisen
Figure 1. Two-step, enantioselective [3,3] sigmatropic rearrangements.
rearrangements. This report describes the integration of a catalytic
asymmetric synthesis of di(allyl) ether substrates into an expedient,
two-step protocol for realizing asymmetric aliphatic Claisen rear-
rangements from readily available starting materials.
Rigorous substrate-to-product chirality translation is among the
defining characteristics of [3,3] sigmatropic rearrangements.4
Thermal Claisen rearrangements routinely proceed via chairlike
transition states that orient substituents residing at the carbinol
stereocenter (Req) in pseudoequatorial positions (Figure 1). This
observation inspired a reaction design for asymmetric Claisen
rearrangements predicated on merging catalytic asymmetric orga-
nometallic-aldehyde addition reactions with in situ O-allylation of
the putative metal alkoxide reaction intermediate (step 1). The re-
sulting enantioenriched di(allyl) ethers 1 constitute direct progenitors
of asymmetric Claisen rearrangements by virtue of the ICR tech-
nology (step 2), thereby providing a simple two-step sequence to
enantioenriched Claisen adducts 2 from easily obtained precursors.
With the goal of using catalytic asymmetric transformations to
establish substrate chirality, amino alcohol-catalyzed dialkylzinc-
aldehyde additions were selected as conduits to the requisite
enantioenriched di(allyl) ether ICR substrates (eq 1). We envisioned
that catalyzed diethylzinc additions to conjugated enals would afford
enantioenriched allylic zinc alkoxides 3. Ensuing O-allylation of
the zinc alkoxide intermediate would deliver the desired ICR
substrates.5 Thus, (-)-MIB (4)-catalyzed addition of Et2Zn to
cinnamaldehyde (2 mol %, toluene, 0 °C) was used as a representa-
tive route to the enantioenriched zinc alkoxide 3 (93% ee).6
Attempted Pd(0)-catalyzed O-allylation directly on 3 afforded
minimal etherification. However, the zinc carboxylate 5, obtained
by selective protonation of the Et-Zn linkage with AcOH, proved
considerably more reactive toward O-allylation. Thus, reacting
alkoxide 3 directly with AcOH (1 equiv) followed by allyl acetate
and a catalyst system composed of Pd(OAc)2 (5 mol %) and PPh3
(25 mol %) (THF, 60 °C, 6 h) delivered the di(allyl) ether ICR
precursor 6a in 79% yield (93% ee).7 Subjecting ether 6a to the
Merging the one-step enantioselective di(allyl) ether synthesis
with subsequent ICR reactions provided access to a variety of
enantioenriched Claisen adducts from readily obtained Et2Zn and
conjugated enal reaction partners (Table 1). The merged addition-
allylation sequence affords di(allyl) ether ICR substrates 6a-f
incorporating C3 aryl (entries a, b, and f), alkenyl (entry c), aliphatic
alkyl (entry d), or oxygen-substituted alkyl substituents (entry e)
in good yields and with consistently high enantioselectivies (88-
98% ee). As anticipated, each of these di(allyl) ether substrates
participated in subsequent ICR reactions with faithful translation
of chirality, delivering the enantioenriched 2,3-syn-disubstituted
pentenal derivatives 7a-f with high absolute and relative stereo-
control (87-97% ee, 84-94% de). These di(allyl) ether syntheses
are not limited to unsubstituted allyl acetate alkylating agents as
1-acetoxy-3-trimethylsilylpropene affords di(allyl) ether 8 (77%
yield, 93% ee) (entry g). Subjecting 8 to the optimized ICR reaction
conditions provided the enantioenriched heptenal 9 in 91% ee (50%
yield).8
Enantioenriched di(allyl) ether ICR substrates can also be
assembled from easily obtained terminal alkyne precursors (eq 2).
For example, 1-heptyne and 3,3-dimethyl-1-butyne were trans-
formed to the alkenyl zinc reagents 10a/b by hydroboration and B
f Zn transmetalation.9 The alkenyl zinc reagents reacted with
benzaldehyde in the presence of 4 (2 mol %) followed by Pd(0)-
catalyzed O-allylation to generate di(allyl) ethers 11a (87% ee) or
+
ICR reaction conditions (1 mol % Ir(PCy3)3 then 3 mol % PPh3,
40 °C)2 delivered the 2,3-syn Claisen adduct 7a with enantiomeric
purity paralleling that of the di(allyl) ether precursor (92% ee).
9
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J. AM. CHEM. SOC. 2006, 128, 4232-4233
10.1021/ja058172p CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis and ICR of Enantioenriched Di(allyl) Ethers 6
Scheme 1 a
t
a (a) BuNdCHCH2PO(OEt)2, LDA; H+. (b) See text. (c) 1 mol %
Ir(PCy3)3+; 3 mol % PPh3, 80 °C; NaBH4. (d) NaH, BnBr. (e) 1.5 mol %
OsO4, NMO; NaIO4. (f) nC5H11CHCHZrClCp2, ZnEt2. (g) i. TBSCl, imid;
ii. O3; NaClO2, NaH2PO4. (h) i. H2, Pd/C then 5 mol % TPAP, NMO; ii.
TASF, DMF.
The asymmetric di(allyl) ether synthesis-ICR reaction sequence
provides convenient access to enantioselective aliphatic Claisen
rearrangements from easily obtained starting materials. The potential
of this reaction technology to simplify the execution of enantiose-
lective Claisen rearrangements should allow these reactions to be
readily integrated into asymmetric synthesis activities.
a Enantiomeric excess determined for allylic alcohol obtained by pro-
tonation of the zinc alkoxide prior to O-allylation. b Diastereomer ratios
determined by 1H NMR of crude product mixtures. c Enantiomer ratios
determined by chiral HPLC or GC. d Claisen adduct 7f was obtained as an
83:17 E:Z mixture of olefin isomers; enantiomer and diastereomer ratios
are reported for the E isomer.
Acknowledgment. Support from the National Institutes of
Health (P50 GM067082) for the University of Pittsburgh Center
for Chemical Methodologies and Library Development (UPCMLD),
the Bristol-Myers Squibb Foundation, and Eli Lilly & Co. is
gratefully acknowledged.
11b (92% ee);10 the ensuing ICR sequence provided the 2,3-syn-
disubstituted pentenals 12a and 12b in 86 and 93% ee, respectively
(12a: 80%; 12b: 80% yield).
Supporting Information Available: Experimental procedures and
1H and 13C spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
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An enantioselective synthesis of the (+)-calopin dimethyl ether
(13) highlights the potential utility of the ICR technology in
asymmetric synthesis activities (Scheme 1).11 Thus, reacting 2,3-
dimethoxy-4-methylbenzaldehyde12 with Meyers’ lithio enamino-
phosphonate reagent provided enal 14.13 Enal 14 was then converted
to the enantioenriched di(allyl) ether 15 using the optimized reaction
conditions described herein (90% yield, 90% ee). ICR reorganiza-
tion of 15 with in situ reduction of the intervening aldehyde function
generated the 2,3-syn-disubstituted 4-pentenol 16 (90% ee, syn/
anti ) 94:6). Alcohol protection was followed by oxidative olefin
cleavage to provide aldehyde 17 (70% for two steps). Aldehyde
17 participated in highly Felkin-selective alkenyl zinc addition with
the reagent obtained from 1-heptyne hydrozirconation and Zr f
Zn transmetalation to give allylic alcohol 18 (67%, 93:7 syn/anti).14
The allylic alcohol was protected prior to oxidative alkene cleavage
to afford aldehyde 19 (72%). Aldehyde oxidation to the corre-
sponding carboxylic acid preceded benzyl ether hydrogenolysis and
direct oxidation of the intervening lactol. Silyl ether deprotection
then completed the synthesis of the calopin dimethyl ether 13 (81%
for three steps).
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