Catalytic enantioselective alkylation of substituted dioxanone enol ethers: ready access to C(α)-tetrasubstituted hydroxyketones, acids,and esters

Article abstract of DOI:10.1002/anie.200801424

(Chemical Equation Presented) Adaptive Alkylation: Palladium-catalyzed asymmetric alkylation enables access to fully substituted enantioenriched oxygenated stereocenters, which can be transformed easily to α-hydroxyketones, esters, and acids, providing a catalytic, enantioselective synthesis for natural products.

Full text of DOI:10.1002/anie.200801424

Angewandte
Chemie
DOI: 10.1002/anie.200801424
Stereoselective Catalysis
Catalytic Enantioselective Alkylation of Substituted Dioxanone Enol
Ethers: Ready Access to C(a)-Tetrasubstituted Hydroxyketones,
Acids,and Esters**
Masaki Seto, Jennifer L. Roizen, and Brian M. Stoltz*
The catalytic enantioselective formation of tetrasubstituted
a-alkoxycarbonyl compounds is an ongoing challenge to
synthetic chemists.[1] Fully substituted a-hydroxyesters and
acids comprise essential components of, and building blocks
for, many bioactive natural products (see Figure 1). These
synthesis of C(a)-tetrasubstituted hydroxy carbonyl com-
pounds.[7]
For this application, we chose to incorporate the a-
oxygenation into a cyclic motif, the 2,2-dimethyl-1,3-dioxan-
5-one framework,[8] and employ this platform for the enan-
tioselective synthesis of a-dialkyl ketones (Scheme 1, 6, for
Figure 1. Natural products containing a-hydroxyesters and acids.
Scheme 1. Alkylation strategies using the dioxanone framework.
include quinic acid (1), cytotoxic leiodolide A (2),[2] and the
anticancer agents in the harringtonine series (3a–f), whose
activities depend dramatically on the presence and composi-
tion of an a-hydroxyester side-chain.[3] While many
approaches to these important moieties exist,[4,5] we envi-
sioned applying our recently developed palladium-catalyzed
methods for the formation of enantioenriched all-carbon
quaternary stereocenters in cyclic alkanones[6] to a general
example). Dioxanones are challenging alkylation substrates
because standard conditions do not permit alkylation, but
instead facilitate ketone reduction (e.g. lithium diisopropyla-
mide, LDA, À788C), or self-condensation (e.g., lithium
hexamethyldisilazide, LHMDS), accompanied by decompo-
sition.[9] A technology that avoids this undesirable reactivity
would represent a marked advance in dioxanone chemistry.
For this purpose, Enders and co-workers have developed a
diastereoselective a-alkylation that relies on chirality
imparted by (+)-S-1-amino-2-methoxymethylpyrrolidine
hydrazones, which can be cleaved in a subsequent step
[Scheme 1, Eq. (1)]. We believed our catalytic palladium
technology would be an ideal platform to provide access to
valuable tetrasubstituted a-hydroxyketones, esters, and acids
[Scheme 1, Eq. (2)].
[*] Dr. M. Seto, J. L. Roizen, Prof. B. M. Stoltz
The Arnold and Mabel Beckman Laboratories of Chemical Syn-
thesis, Division of Chemistry and Chemical Engineering, California
Institute of Technology
1200 E. California Boulevard MC 164-30, Pasadena, CA 91125 (USA)
Fax: (+1)626-564-9297
E-mail: stoltz@caltech.edu
[**] The authors thankthe Takeda Pharmaceutical Company Limited of
Japan (postdoctoral fellowship to M.S.), the California Tobacco-
Related Disease Research Program of the University of California,
Grant Number 14DT-0004 (predoctoral fellowship to J.L.R.), the
NIH-NIGMS (R01 GM 080269-01), and Caltech for financial
support, Materia, Inc. for their generous donation of catalyst 9 used
in these studies, and Dr. S. Virgil, A. Silberstein, and Y. Segawa for
experimental assistance.
We examined the conversion of silyl enol ether 4a[10] into
enantioenriched tetrasubstituted ketone 6a under a variety of
palladium-catalyzed conditions, beginning with the standard
conditions developed for the all-carbon system (Table 1).[6]
Triethylsilyl derivative 4a was chosen for its stability and ease
of synthesis, compared to the related trimethylsilyl com-
pound. Treatment of silyl ether 4a with Pd(dmdba)2 (5 mol%,
dmdba = bis(3,5-dimethoxybenzylidene)acetone),
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801424.
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Table 1: Optimization of the enantioselective allylation of silyl enol ether
ates a variety of substituents at the a-position, including alkyl
(Table 2, entries 1 and 2), benzyl (Table 2, entry 3), and
alkenyl (Table 2, entries 7–9)moieties. Additionally, the
reaction proceeds when the allyl group is substituted inter-
nally by methyl, chloro, or phenyl (Table 2, entries 4–7)to
afford products in high yields and high entantiomeric excess.
Having established a general route to the enantioenriched
tetrasubstituted dioxanone 6, we developed a straightforward
sequence to transform the a-alkoxyketone into the corre-
sponding a-hydroxyester 8 (Table 3). To effect acetonide
cleavage, enantioenriched product 6 is treated with catalytic
p-toluenesulfonic acid (TsOH·H2O)in methanol or ethanol.
Dihydroxyketone 7 is oxidatively cleaved in the presence of
periodic acid, selectively removing the primary alcohol,[13] to
generate the a-hydroxyacid. Subsequent methylation fur-
nishes the tetrasubstituted enantioenriched a-hydroxyester 8.
These operations are tolerant of a number of substitutents,
including alkyl (Table 3, entries 1–4), chloro (Table 3,
entry 5), and aryl (Table 3, entries 3 and 6) groups. Further-
4a.[a]
Entry
Solvent
Yield [%][b]
ee [%][c]
1
THF
Et2O
1,4-dioxane
benzene
toluene
40
59
65
67
74
81
89
67
84
88
2[d]
3
4
5
[a] Reactions were performed using 0.1 mmol of substrate in solvent
(0.033m) at 258C over 5–7 h unless stated otherwise. [b] Yields of
isolated product. [c] Measured by chiral HPLC following conversion to
6b.[12] [d] Performed at 308C and 0.0167m.
Table 3: Substrate scope for methyl ester formation.[a]
(S)-tBuPHOX (5, 5.5 mol%),[11] Bu4NPh3SiF2 (TBAT,
1 equiv), and diallyl carbonate (1.05 equiv) in THF at 258C
(Table 1, entry 1)produced enantioenriched 6a in 40% yield
and 81% ee. Interestingly, the choice of solvent played a
significant role in the selectivity of tertiary ether formation. In
the optimal case, use of toluene as solvent furnished
dioxanone 6a in 74% yield and 88% ee (Table 1, entry 5).
We applied the optimized conditions to silyl enol ethers
with diverse a-substituents, in combination with substituted
allyl carbonates (Table 2). The asymmetric alkylation toler-
Entry
Substrate
R2
Yield 7 [%][b,c]
Yield 8 [%][b,c]
R1
1
2
Me
Et
PhCH2
Me
Me
H
H
H
Me
Cl[e]
Ph[f]
90
97
91
97
97
92
54
60
85
84
76
77
3[d]
4
5
6
Me
Table 2: Substrate scope for enantioselective allylation.[a]
7[g]
80
51
R1
R2
Yield [%][b]
ee [%][c]
8
–
48[h]
Entry
1
2
3
Me
Et
PhCH2
Me
Me
Me
allyl
2-methallyl
1-butenyl
H
H
H
Me
Cl[g]
Ph
Me
H
86
79
85
59
59
73
93
88
83
87
93
86
89
92
94
88
85
92
4[d,e]
5[f]
6[h]
7[e]
8
9[i]
–
61[h]
[a] Acetonides 6 (1.0 equiv) were cleaved with TsOH·H2O (0.1 equiv) in
MeOH (0.1m) over 2–3 h unless otherwise noted. Diols 7 were oxidized
with H5IO6 (1.5 equiv) in 2:1 THF:H2O (0.033m) unless otherwise noted.
TsOH=p-toluenesulfonic acid [b] Yields of isolated product. [c] There is
no measurable change of ee value through this sequence. [d] Acetonide
cleavage was performed in EtOH over 6 h. [e] Absolute stereochemistry
has been assigned by analogy, except in this case, which was assigned by
conversion into (+)-(S)-citramalic acid dimethyl ester.[12] [f] Direct
treatment with H5IO6 and subsequent methylation provided the ester
in 47% yield over two steps. [g] See the Supporting Information for a
description of the preparation of 6b from 6a by cross-metathesis.
[h] Three-step yield. [i] Oxidation performed with H5IO6 (1.0 equiv).
9
H
[a] Reactions were performed with silyl enol ether (0.5 mmol) and diallyl
carbonate (1.05 equiv) in PhMe (0.033m) unless stated otherwise. When
R1 =R2 =H, the reaction proceeds in 13% yield and 82% ee. [b] Yields of
isolated product. [c] Measured by chiral GC or HPLC.[12] [d] Performed
with trimethylsilyl precursor, 35 mol% TBAT in Et2O (0.0167m) at 258C.
[e] Performed with dimethallyl carbonate (1.05 equiv). [f] Performed with
dichloroallyl carbonate (1.05 equiv) at 358C. [g] Absolute stereochemis-
try has been assigned by analogy, except in this case, which was assigned
by conversion into (+)-(S)-citramalic acid dimethyl ester.[12] [h] Per-
formed with diphenylallyl carbonate (1.05 equiv).
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Angewandte
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more,the tetrasubstituted dioxanone derivative 6 may incor-
porate enolizable a,b-unsaturated esters (Table 3, entry 7), or
cyclic structures (Table 3, entries 8 and 9)as substituents.
Notably, assembly of acid (S)-10 (see Scheme 2)consti-
tutes a catalytic enantioselective formal synthesis of (À)-
quinic acid (1),[14] a useful chiral building block that has been
Keywords: alcohols · allylic compounds · asymmetric catalysis ·
enantioselectivity · palladium
.
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Scheme 2. Formal synthesis of (À)-quinic acid (1) and (À)-dragmaci-
din F (11).
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3-methylcyclopentene 6c in 95% yield and 85% ee. Likewise,
enantioenriched a,w-diene 6 f furnishes cyclohexene 6d in
90% yield and 92% ee. Cyclohexene 6d readily undergoes
acetonide cleavage and periodic acid oxidation to provide
pure, isolable acid (S)-10, completing the formal synthesis of
(À)-quinic acid (1).
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transformed the enantioenriched products into a-hydroxyke-
tones, acids, and esters. This mild, straightforward sequence
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(1.3 equiv)in acetonitrile (0.63 m)and isolated by silica gel
Received: March 25, 2008
Revised: May 1, 2008
Published online: July 24, 2008
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Communications
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