Enantioselective synthesis of tertiary α-hydroxyketones from unfunctionalized ketones: Palladium-catalyzed asymmetric allylic alkylation of enolates

Article abstract of DOI:10.1002/anie.201203663

Aiming high: The title reaction for the synthesis of tertiary α-hydroxyketones is reported. Protected 1,2-enediol carbonates, the starting materials, were accessed from simple and readily available enol carbonates. Highly functionalized tertiary α-hydroxyketones can be obtained in high yield with excellent enantioselectivity using this method (see scheme). Copyright

Full text of DOI:10.1002/anie.201203663

Angewandte
Chemie
DOI: 10.1002/anie.201203663
Synthetic Methods
Enantioselective Synthesis of Tertiary a-Hydroxyketones from
Unfunctionalized Ketones: Palladium-Catalyzed Asymmetric Allylic
Alkylation of Enolates**
Barry M. Trost,* Raffael Koller, and Benjamin Schꢀffner
Tertiary a-hydroxyketones are found in many biologically
active compounds. These include the phytolexin lacineline C
and the homoisoflavanone eucomol, both of which have
a tetralone ring system.
Despite their presence in a variety of biologically active
targets, only a few catalytic methods are known to generate
this functionality in an enantioselective fashion. Phase-trans-
fer-catalyzed oxidations of simple ketones using molecular
oxygen have been reported.[1] However, in general, these
methods require high catalyst loadings and only moderate
Scheme 1. Synthesis of 1,2-endiol carbonates from simple enol carbo-
nates. mCPBA=meta-chloroperbenzoic acid, PG=protecting group.
enantioselectivities are obtained. Suzuki and co-workers
developed an intramolecular crossed aldehyde–ketone ben-
zoin cyclization with chiral triazolium salts as catalysts to
access tertiary a-hydroxyketones in moderate to excellent
yield and enantiomeric excess, but this strategy required high
catalyst loadings (10–20 mol%).[2] Sharpless and co-workers
reported the osmium-catalyzed dihydroxylation of cyclic silyl
enol ethers to give tertiary a-hydroxyketones.[3] However,
Scheme 2. Pd-DAAA for the synthesis of tertiary a-hydroxyketones.
slight structural variation in the substrates resulted in large
changes in the enantioselectivity using this method.
Previously, we reported palladium-catalyzed decarboxy-
lative asymmetric allylic alkylation (Pd-DAAA) of enolcar-
bonates to access both tertiary and quaternary stereocen-
ters.[4] To demonstrate the power of this transformation, we
envisioned the oxidation of the enol carbonate, such that an
additional oxygen functionality was present, for use as
substrates in the Pd-DAAA to access highly oxygenated
chiral products.
We envisaged that simple, readily accessible allyl enol
carbonates[5] could be chemoselectively oxidized to yield the
corresponding keto carbonates. Oxidation using m-CPBA
should initially yield the corresponding epoxides, which could
rearrange to give the more stable keto carbonates
(Scheme 1). To our surprise, such an oxidation/rearrangement
protocol was unprecedented in the literature. In a second step,
these substrates could be enolized and protected to give the
desired substrates for the Pd-DAAA reaction as shown in
Scheme 2.
As model substrates, tetralones and benzosuberones were
chosen. The corresponding enol allyl carbonates were syn-
thesized by selective O-acylation using allyl imidazole
carboxylate along with boron trifluoride etherate, a high
yielding method previously reported by our group (Table 1).[5]
Epoxidation of the enolcarbonates was achieved using
m-CPBA in CH2Cl2 at room temperature (Scheme 3). For the
encolcarbonates 2a–f, which are derived from tetralones, full
conversion was observed after one hour. The reactions of the
benzosuberone-derived substrates 2g and 2h were somewhat
slower and the reaction was stopped after two hours at room
temperature. The resulting epoxides are surprisingly stable
even under aqueous conditions. The epoxide opening was
facilitated by using BF3·OEt2 as the Lewis acid in Et2O. Under
the described reaction conditions complete acyl migration
was observed.
Upon deprotonation of 4a–h with NaHMDS, the resulting
enolates undergo complete acyl migration to form the
thermodynamically favored regioisomer even at À788C. The
enolate was then treated with MOMI, thus yielding the
MOM-protected 1,2-endiol carbonate (Scheme 4). Similarly,
the enolate could be treated with BOMI,[6] thus affording the
protected carbonate. Both the MOM- and BOM-protected
1,2-endiol carbonates were obtained in good to excellent
yield. The carbonates 5a–l are stable and can be stored for
[*] Prof.Prof. B. M. Trost, Dr. R. Koller, Dr. B. Schꢀffner
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 (CHE 0948222) for their generous support of our
programs. R.K. acknowledges support from the Schweizerische
Nationalfonds (SNF); B.S. is grateful to the Alexander von
Humboldt Foundation for a Feodor Lynen Fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203663.
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Table 1: Synthesis of the enol carbonates 2a–h.[a]
Entry
2
R1
R2
R3
R4
n
Yield [%][b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
TMS
H
H
CH3
1
1
1
1
1
1
2
2
88
97
91
99
84
80
74
86
7-OCH3
5-Br
H
H
H
-CH2CH2CH2-
H
H
2g
2h
H
H
H
H
[a] Reaction conditions: 1 (1.00 equiv), NaHMDS (1.20 equiv), allyl
.
imidazole carboxylate (1.20 equiv), BF3 OEt2 (1.20 equiv) in DME at
À788C for 1 h. [b] Yields refer to yields of isolated product. DME=di-
methoxyethane, HMDS=hexamethyldisilamide, TMS=trimethylsilyl.
Scheme 4. Synthesis of the protected 1,2-endiol carbonates. Reaction
conditions for the synthesis MOM-protected 5: 4a–h (1.00 equiv),
NaHMDS (1.20 equiv), MOMI (1.20 equiv) in THF at À788C. Reaction
conditions for the synthesis BOM protected 5: 4a–d (1.00 equiv),
NaHMDS (1.20 equiv), (BnO)2CH2 (1.60 equiv), TMSI (1.50 equiv) in
THF at À788C. Yields refer to yields of isolated product. BOM=
benzyloxymethyl, MOM=methoxymethyl, THF=tetrahydrofuran.
results in terms of enantioselectivity, were obtained with the
anthracenyl-diamine-derived ligand (R,R)-L4 (Table 2,
entries 1–4). Full conversion of the starting material 5a was
observed after 12 hours at room temperature. The product
could be isolated with an enantiomeric excess of 96%. (R,R)-
L1 and (R,R)-L3 showed a higher reactivity albeit with lower
enantiodiscrimination. Screening of different solvents
revealed that the initially used THF was the solvent of
Table 2: Selected results for the palladium-catalyzed DAAA of 5a.[a]
Scheme 3. Epoxidation and subsequent ring opening. Reaction condi-
tions for the synthesis of 3a–h: 2a–h (1.00 equiv), mCPBA
Entry
Solvent
Ligand
Conversion [%][b]
ee [%]
1
2
3
4
5
6
7
THF
THF
THF
THF
DME
1,2-DCE
1,4-dioxane
(R,R)-L1
(R,R)-L2
(R,R)-L3
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
>99
17
>99
>99
>99
29
71
60
42
96
88
75
93
(1.50 equiv) in CH2Cl2 (1.20 equiv) at RT for 1–2 h. Reaction conditions
for the synthesis of 4a–h: 3a–h (1.00 equiv), BF3·OEt2 (1.00 equiv) in
Et2O at À788C for 1 h. Yields refer to yields of isolated product.
weeks and even up to several months at low temperatures, if
protected from moisture.
>99
The 1,2-endiol carbonate 5a was chosen for optimization
studies (Table 2) and subjected to the Pd-DAAA using the
standard dppba ligands (Figure 1) developed in our group.
Initial optimization studies were conducted in THF. The best
[a] Reaction conditions: 5a (1.00 equiv), [Pd2(dba)3·CHCl3] (2.5 mol %),
Ligand (6 mol %) in the indicated solvent (0.1m in 5a) at RT for 16 h.
[b] Determined by 1H NMR. dba=dibenzylideneacetone, DCE=
dichloroethane.
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Electron-rich substrates gave excellent yields (93% to 99%)
with slightly lower enantioselectivities in the range of 90%.
The brominated tetralones 6e and 6 f were obtained in
a slightly lower yield. However, no dehalogenation product
was observed. These compounds are attractive starting
materials which can be derivatized using cross-coupling
chemistry. The reaction also tolerates substituents on the
allyl moiety. For the sterically more demanding substrates 5g
and 5h, the more reactive ligand (R,R)-L3 along with a slightly
elevated reaction temperature (458C) were used to give
excellent yields and enantioselectivities. For the sterically
even more demanding carbonate 5i, the ligand (R,R)-L1 was
used to give the desired product in 72% yield and 85% ee.
Variation of the allyl moiety to cyclohexenyl gave the desired
ketone 6j in excellent enantiomeric excess as a single
diastereoisomer, albeit in only 50% yield. Interestingly, as
a side product, the O-allylated product was obtained in 34%
yield and 65% ee. These numbers can be explained by the
steric demand of both the nucleo- and the electrophile upon
oxidative addition which leads to allylation at the oxygen
atom, which is sterically less demanding. The benzosuberone-
derived substrates 5k and 5l gave the best results with (R,R)-
L3.
Figure 1. The most commonly used dppba ligands L1–L4.
choice even though 1,4-dioxane gave comparable results to
that of THF (Table 2, entry 7). The absolute stereochemistry
is assigned by analogy to the DAAA of 2-substituted
tetralones and benzsuberones.
With the optimized reaction conditions in hand, a variety
of 1,2-endiol carbonates were subjected to Pd-DAAA
(Scheme 5). In general, good to excellent yields and enantio-
selectivities were obtained. We were pleased to see that the
BOM-protected 5b gave a comparable enantioselectivity to
5a, that is, 93% compared to 96%. Tolerance of both MOM
and BOM groups allows several protecting group strategies,
which is advantageous in synthesis. A similar observation was
made for the yield of the reaction (82% compared to 85%).
As shown for 6c in Scheme 6, the MOM-protected
hydroxylketones can easily be deprotected under relatively
mild reaction conditions using a cationic exchange resin
Scheme 6. Deprotection of 6c using a cationic exchange resin.
(Dowex-50W) in aqueous methanol, a method reported by
Seto et al.[7] The resulting hydroxyketone was obtained in
excellent purity without need for further purification after
filtration through silica.
To conclude, we have demonstrated a highly region- and
enantioselective palladium-catalyzed decarboxylative asym-
metric allylic alkylation to access highly functionalized
tertiary a-hydroxyketones from simple ketones. The starting
materials for the reaction were accessed using an unprece-
dented chemoselective epoxidation of enolcarbonates with
a subsequent Lewis acid mediated ring opening. We are
currently investigating the extension of this methodology to
acyclic substrates.
Experimental Section
General Procedure for the Pd-DAAA: Freshly distilled and degassed
THF (0.5 mL) was added to the ligand (R,R)-L1, (R,R)-L2, or (R,R)-
.
L4 (0.006 mmol, 6 mol%) and [Pd2(dba)3 CHCl3] (0.0025 mmol,
Scheme 5. Pd-DAAA of 1,2-endiol carbonates 5a–l in THF. [a] Reaction
conditions for the Pd-DAAA: 5a–l (1.00 equiv), [Pd2(dba)3·CHCl3]
(2.5 mol%), (R,R)-L4 (6 mol%) in THF (0.1m in 5a–l) at RT for 16 h.
Yields refer to yields of isolated product. [a] (R,R)-L3 was used at 458C.
[b] (R,R)-L1 was used at 458C. [c] Determined after hydrolysis to the
free alcohol.
2.5 mol%) under Ar. The resulting suspension was stirred at 458C
until a clear, bright-orange color was obtained, and it was then cooled
to RT. The catalyst solution was then added to the substrate 5
(0.10 mmol, 1.00 equiv) under Ar in freshly distilled and degassed
THF (0.5 mL). The reaction turns yellow immediately and is then
stirred for 16 h at the given temperature. After full conversion the
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reaction turns bright orange, thus indicating the presence of the Pd0/
phosphine complex. The solution was concentrated and purified by
flash column chromatography on silica gel (petroleum ether/EtOAc)
to give the desired protected hydroxy ketone.
[2] H. Takikawa, Y. Hachisu, J. W. Bode, K. Suzuki, Angew. Chem.
2006, 118, 3572; Angew. Chem. Int. Ed. 2006, 45, 3492.
[3] K. Morikawa, J. Park, P. G. Andersson, T. Hashiyama, K. B.
Sharpless, J. Am. Chem. Soc. 1993, 115, 8463.
[4] B. M. Trost, J. Xu, J. Am. Chem. Soc. 2005, 127, 2846; B. M. Trost,
J. Xu, J. Am. Chem. Soc. 2005, 127, 17180; B. M. Trost, J. Xu, M.
Reichle, J. Am. Chem. Soc. 2007, 129, 282; B. M. Trost, J. Xu, T.
Schmidt, J. Am. Chem. Soc. 2008, 130, 11852; B. M. Trost, J. Xu, T.
Schmidt, J. Am. Chem. Soc. 2009, 131, 18343; B. M. Trost, K. Lehr,
D. J. Michaelis, J. Xu, A. K. Buckl, J. Am. Chem. Soc. 2010, 132,
8915; B. M. Trost, B. Schꢀffner, M. Osipov, D. A. A. Wilton,
Angew. Chem. 2011, 123, 3610; Angew. Chem. Int. Ed. 2011, 50,
3548; B. M. Trost, D. J. Michaelis, J. Charpentier, J. Xu, Angew.
Chem. 2012, 124, 208; Angew. Chem. Int. Ed. 2012, 51, 204.
[5] B. M. Trost, J. Xu, J. Org. Chem. 2007, 72, 9372.
Received: May 11, 2012
Published online: && &&, &&&&
Keywords: alcohols · allylic compounds · asymmetric catalysis ·
.
ketones · palladium
[1] M. Masui, A. Ando, T. Shioiri, Tetrahedron Lett. 1988, 29, 2835;
E. V. Dehmlow, V. Knufinke, Liebigs Ann. Chem. 1992, 283; E. V.
Dehmlow, M. Romero, J. Chem. Res. 1992, 400; E. F. J. de Vries,
L. Ploeg, M. Colao, J. Brussee, A. van der Gen, Tetrahedron:
Asymmetry 1995, 6, 1123.
[6] BOMI was prepared prior to its use from (BnO)2CH2 and TMSI;
for additional information see the Supporting Information.
[7] H. Seto, L. N. Mander, Synth. Commun. 1992, 22, 2823.
4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Chemie
Communications
Synthetic Methods
Aiming high: The title reaction for the
synthesis of tertiary a-hydroxyketones is
reported. Protected 1,2-enediol carbo-
nates, the starting materials, were
accessed from simple and readily avail-
able enol carbonates. Highly functional-
ized tertiary a-hydroxyketones can be
obtained in high yield with excellent
enantioselectivity using this method (see
scheme).
B. M. Trost,* R. Koller,
B. Schꢁffner
&&&& — &&&&
Enantioselective Synthesis of Tertiary a-
Hydroxyketones from Unfunctionalized
Ketones: Palladium-Catalyzed
Asymmetric Allylic Alkylation of Enolates
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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