Diastereo- and enantio-selective crotylation of α-ketoesters using crotyl boronic acid ester complexes

Article abstract of DOI:10.1016/j.tetlet.2004.09.082

A diastereo- and enantio-selective crotylation of ethyl pyruvate has been achieved using a chiral boronic acid auxiliary-based approach. This reaction creates two contiguous stereogenic centers, one of which is a quaternary carbon with complete diastereoselectivity and with enantioselectivities up to 7:1 (73% ee).

Full text of DOI:10.1016/j.tetlet.2004.09.082

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8285–8288
Diastereo- and enantio-selective crotylation of a-ketoesters using
crotyl boronic acid ester complexes
Yanping Chen,a Laxman Eltepua and Paul Wentworth, Jr.a,b,
*
aDepartment of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
bOxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Received 23 August 2004; revised 9 September 2004; accepted 10 September 2004
Abstract—A diastereo- and enantio-selective crotylation of ethyl pyruvate has been achieved using a chiral boronic acid auxiliary-
based approach. This reaction creates two contiguous stereogenic centers, one of which is a quaternary carbon with complete dia-
stereoselectivity and with enantioselectivities up to 7:1 (73% ee).
Ó 2004 Published by Elsevier Ltd.
Despite the ubiquitous methodologies available for
efficient enantioselective addition of alkyl groups to
aldehydes, yielding stereochemically-defined secondary
alcohols,1 the corresponding asymmetric addition of
alkyl groups to ketones, to yield homochiral tertiary
alcohols has been much less investigated.
involves the simultaneous control of two contiguous
stereogenic centers one of which is a quaternary carbon.
Crotyl dialkylboranes and crotyl boronic acid esters
have both been useful in the asymmetric crotylation of
aldehydes leading to adducts with high diastereo- and
enantioselective control. By analogy, the crotylation of
pyruvates with crotyl dialkylboranes, such as crotyl-9-
BBN, was investigated and resulted in good to excellent
diastereoselectivities.5 However, an investigation of the
utility of crotyl boronic acid esters to the crotylation
of a-ketoesters has not yet been investigated (Scheme
1).6 Crotyl boronic acid esters are attractive as auxil-
iary intermediates because of the wide variety and
availability of chirally-defined 1,2-diols.7 Thus, by mod-
ulation of the crotylation reagent, it is theoretically pos-
sible for the four possible crotylation products to be
obtained. Herein we report the diastereospecific and
Asymmetric allylation and crotylation of aldehydes is
one of the most extensively studied processes for the
carbon–carbon bond formation, driven in part by the
versatility of homoallylic alcohols as synthetic interme-
diates.2,3 We are particularly interested in expanding this
methodology to ketones, specifically in the context of
asymmetric crotylation of a-ketoesters such as pyruvate.
Such a stereoselective reaction would be of tremendous
utility, because it leads to the generation of chirally-
defined a-hydroxy-esters, which are versatile synthetic pre-
cursors.4 This reaction is particular challenging because it
R1 OH
R1 OH
R3
O
OR2
OR2
OR2
OR2
B
O
O
R3
Me
O
Me
O
OR2
R1
O
R3
R3
HO R1
HO R1
O
O
B
Me
O
Me
O
Scheme 1. Strategy for asymmetric crotylation of a-ketoesters utilizing crotyl boronic acid esters.
Keywords: Enantioselective; Boronic acid ester; Asymmetric.
*
Corresponding author. Tel.: +1 858 784 2576; fax: +1 858 784 2590; e-mail: paulw@scripps.edu
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.09.082

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Y. Chen et al. / Tetrahedron Letters 45 (2004) 8285–8288
highly enantioselective crotylation of ethyl pyruvate 7
with chirally-defined crotyl boronic acid esters.
À78°C (Table 1). Changing to the more sterically
hindered borate 6 resulted in a complete loss of reaction.
The (E)- and (Z)-crotylboronate diethanolamine com-
plexes (1 and 2) were prepared according to RoushÕs
procedure, starting from (E)- or (Z)-butene, respec-
tively, (Scheme 2).8 These crotylboronate diethanol-
amine complexes are stable crystalline compounds and
were sufficiently stable that they could be stored at
4°C for more than three months without any detectable
decomposition. Additional chiral crotylboronate com-
plexes (3–6) were prepared in high-yield (>85% yield)
by transesterification that involved shaking a mixture
of the respective chiral 1,2-diol and crotyl diethylanol-
amine complex (1 or 2) in diethyl ether with an aqueous
solution of sodium chloride.
The reaction between 7 and chiral borate 5 gave the a-
hydroxyesters 10 and 11 as a pair of enantiomers in high
diastereoselectivity.11 The enantiomeric ratio of 10 and
11 had to be measured via a MosherÕs ester method
because 10 and 11 could not be separated by GC. Thus,
the mixture of 10 and 11, generated from the asymmetric
crotylation reaction, was reduced by LiAlH4 and then
treated with S-(+)-Mosher chloride (Scheme 4). The
enantiomeric excess was then easily measured by proton
NMR (Table 1).
The relative configuration of each crotylation product
was established by NMR analysis in a two-step process.
Primarily, the mixture of esters 8 and 9 was saponified
(NaOH aq/EtOH) and the resulting a-ketoacids were
converted into their corresponding diastereomeric iodo-
lactones 14 and 15 (I2/acetonitrile). NOE experiments
With the chiral crotylborates 3–6 in hand, the crotyl-
ation of ethyl pyruvate 7 was investigated (Scheme 3).
Crotylation of 7 with borate 3 in toluene at À78°C gave
the crotylation products 8 and 9 as an enantiomeric
pair9 in good yield (84%) and with high diastereoselec-
tivity (>98% de, determined by NMR), but with only
a 7% ee (the ratio of 8 to 9 was determined by chiral
GC10) (Scheme 3).
Table 1. Reaction of chiral boronates with ethyl pyruvate
Entry
Chiral
borate/solvent
Product
8:9a/% ee
Product
10:11b/% ee
Yield/%
1
2
3
4
5
6
3/toluene
4/toluene
4/THF
53:47/6
7:1/73
3.2:1/53
5:1/62
2:1/33
NA
NA
NA
86
84
82
80
83
87
More favorably however, the asymmetric crotylation of
ethyl pyruvate with (R,R)-diisopropyl tartrate derived
boronate (4) had a much-improved enantioselectivity
(73% ee) again with the same high diastereoselectivity
(>98% de). An investigation of the effect of solvent on
the crotylation of 7 with boronate 4 revealed that the
highest enantioselectivity was achieved in toluene at
NA
NA
4/Et2O
4/CH2Cl2
5/toluene
NA
5.4:1/69
a Determined by chiral GC.
b Determined by the MosherÕs ester method outlined in Scheme 4.
CO2i-Pr
CO2i-Pr
Ph
Ph
O
O
O
B
B
O
4
R4
O
B
3
1,2-diol
R5
NH
MeO Ph
O
CO2i-Pr
CO2i-Pr
O
O
Ph
Ph
1, R4= Me, R5= H
2, R4= H, R5= Me
B
B
O
O
Ph
MeO
5
6
Scheme 2. Preparation of homochiral boronic acid esters 3–6.
HO Me
Me OH
OEt
OEt
OEt
OEt
Me
O
Me
O
3 or 4
O
9
8
OEt
Me
5
O
Me OH
HO Me
7
Me
10
O
Me
11
O
Scheme 3. Crotylation of ethyl pyruvate 7 with chiral borates 3–5.

Y. Chen et al. / Tetrahedron Letters 45 (2004) 8285–8288
8287
Me OH MeO CF3
HO Me MeO CF3
O
1. LiAlH4, THF
2. S-Mosher chloride
O
+
10 + 11
Me
12
O
Me
O
13
Scheme 4. MosherÕs esters 12 and 13 were formed to elucidate the enantiomeric excess of 10 and 11.
O
O
O
Me
HO
Me
1. NaOH, EtOH
2. I2, CH3CN
HO
+
O
8 + 9
Me
Me
CH2I
CH2I
14
15
1. LiAlH4
2. Pd-C, H2
HO Me
Me OH
OH
OH
+
Me
16
Me
17
Scheme 5. Determination of relative and absolute stereochemistry of the a-hydroxy acids 8 and 9 formed in the asymmetric crotylation reaction.
molecular sieves (60mg) and then cooled to À78°C. A
CO2i-Pr
solution of ethyl pyruvate (0.11mL,1mmol) in dry tolu-
O
CO2i-Pr
ene (1mL) was then added dropwise over 30min. The
reaction mixture was stirred for 6h at À78°C and then
allowed to warmed to room temperature. The crude
material was purified by silica gel chromatography
(10–20% diethyl ether in hexanes) to give the crotylation
product in analytically pure form.
Me
B
O
RE
O
CO2Et
Rz
Figure 1. Hypothesized transition-state for crotylation of
crotylboronate ester 4.
7 by
revealed that the methyl groups are anti with respect to
the faces of the five-membered lactone ring, as shown in
compound 14 and 15 (Scheme 4). To elucidate the abso-
lute configuration of the enantiomers, esters 8 and 9
were reduced by LiALH4 to afford the corresponding
1,2-diols, which were hydrogenated to yield 16 and 17
as a mixture of diols. Comparison of the optical rotation
of this mixture with the known optical rotation of
compound 16,12 revealed that the major enantiomer
formed during this asymmetric crotylation reaction
with 4 corresponds to the (S,S)-absolute stereochemistry
(Scheme 5).
Acknowledgements
We would like to thank Mr. Neal Reed of the Janda Lab
at The Scripps Research Institute for assistance during
the chiral GC analyses. This work was supported by
The Skaggs Institute for Chemical Biology.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.09.082.
In conclusion, we have established that chiral boronates
can react with ethyl pyruvate to yield crotylation prod-
ucts in a diastereospecific manner. By far the best enan-
tioselectivity (up to 73% ee) was achieved with chiral
diisopropyl tartrate-derived boronates. Thus, by starting
with (E) or (Z)-butene and D or L-diisopropyl tartrate,
the four possible crotylation products with two contigu-
ous stereogenic centers can be generated. The major
enantiomer formed in this asymmetric crotylation
is consistent with the transition-state model shown
(Fig. 1).
References and notes
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Y. Chen et al. / Tetrahedron Letters 45 (2004) 8285–8288
125MHz (d, ppm, CDCl3): 176.8, 139.2, 115.9, 61.7,
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4.25 (m, 2H), 3.04 (br s, 1H), 2.40–2.46 (m, 1H), 1.32 (s,
3H), 1.27–1.29 (t, J = 7.0Hz, 3H), 0.92–0.94 (d,
J = 7.0Hz); 13C NMR 125MHz (d, ppm, CDCl3): 176.9,
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4.22 (m, 2H), 2.43–2.49 (m, 1H), 1.36 (s, 3H), 1.26–1.29 (t,
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