Zinc-catalyzed enantiospecific sp3-sp3 cross-coupling of α-hydroxy ester triflates with grignard reagents

Article abstract of DOI:10.1002/anie.200800733

(Chemical Equation Presented) Zinc chloride does the trick and efficiently catalyzes the enantiospecific cross-coupling of α-hydroxy ester triflates with Grignard reagents under mild conditions. Enantiopure α-hydroxy esters are directly available from the chiral pool or by diazotization of α-amino acids. Substantial variations in both reacting partners are tolerated making this methodology an attractive alternative to enolate alkylation featuring a reversal of polarity.

Full text of DOI:10.1002/anie.200800733

Angewandte
Chemie
DOI: 10.1002/anie.200800733
Synthetic Methods
Zinc-Catalyzed Enantiospecific sp3–sp3 Cross-Coupling of a-Hydroxy
Ester Triflates with Grignard Reagents**
Christopher Studte and Bernhard Breit*
Skeleton-expanding operations that provide control of all
levels of selectivity are among the most valuable transforma-
tions in organic synthesis.[1] One important example is the
alkylation of ester or amide enolates which requires either a
chiral auxiliary or stoichiometric amounts of a chiral base in
order to control the absolute configuration of the final
alkylation product.[2–5]
As an alternative, one might start from an a-hydroxy ester
derivative (Scheme 1), a number of which are available in
enantiomerically pure form from the chiral pool or are readily
come corresponded to complete inversion of configuration.
Unfortunately, yields were low owing to side reactions arising
from electron-transfer processes.
To find an improved and widely applicable method for the
synthesis of optically active a-alkylcarbonyl compounds on a
large scale and under mild conditions, we examined the
reaction of organometallic reagents with secondary alkyl
electrophiles. We report herein the development of a zinc-
catalyzed cross-coupling reaction of Grignard reagents with
a-hydroxy ester triflates.
Initial investigations of the reaction between lactic acid
derived triflate 1a[19] and a Grignard reagent in the absence of
any catalyst resulted in a low yield of coupling product 2a as a
result of competitive side reactions such as the formation of
chloride 3 (Table 1, entry 1). Adding an iron catalyst led to
Table 1: Cross-couplingof 1a with organometallic reagents.
Scheme 1. Syntheses of enantiopure a-alkylesters.
prepared from either a-amino acids (vide infra) or enzymati-
cally generated chiral cyanohydrins.[6] Thus, the transforma-
tion of the hydroxy function into a leaving group followed by
an sp3–sp3 cross-coupling reaction with an organometallic
nucleophile could become an attractive alternative if the
reaction occurs with control of the stereochemistry.
Unfortunately, known cross-coupling protocols employ-
ing stereogenic secondary electrophiles occur as stereoran-
dom processes.[7–14] An elegant solution to this problem is to
use racemic substrates in combination with a chiral nickel
catalyst in order to achieve good levels of enantioselectiv-
ity.[15,16] To the best of our knowledge the stereoselective sp3–
sp3 cross-coupling of a-hydroxy ester derivatives is restricted
to the use of stoichiometric amounts of transition-metal salts,
employing cuprate reagents.[17,18] The stereochemical out-
Entry
Cat. MXn
nBu-M
2a [%][a]
Conv. [%][b]
1
2
3
4
5
6
–
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgBr
nBuLi
46
0
56
>99
11
62
>99
>99
>99
>99
>99
[Fe(acac)3]
Li2CuCl4
ZnCl2
ZnCl2
ZnCl2
0
[a] Yield determined by GC with an internal standard. [b] Determined by
1H NMR spectroscopy.
the formation of homocoupling product 4, while the presence
of a copper salt[20] resulted in only a slightly higher yield of 2a
as well as the reduction of the triflate to ester 5 (Table 1,
entry 3). Finally, the addition of a catalytic amount of ZnCl2
resulted in a quantitative yield of 2a with complete inversion
of configuration (Table 1, entry 4).[21,22] When n-butylmagne-
sium bromide was used instead of the corresponding chloride,
only low yields of the desired product could be obtained
(Table 1, entry 5). The presence of magnesium salts proved
critical, as Mg-free systems were ineffective (Table 1, entry 6).
Under optimized reaction conditions, the cross-coupling
reaction of triflate 1a or nonaflate 1b at 08C with 1.4 equiv-
alents of chloromagnesium reagent and 2.5 mol% of zinc
catalyst resulted in a quantitative yield of the coupling
product after 3 h (Scheme 2). Reducing the amount of either
[*] C. Studte, Prof. Dr. B. Breit
Institut für Organische Chemie und Biochemie
Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg(Germany)
Fax: (+49)761-203-8715
E-mail: bernhard.breit@chemie.uni-freiburg.de
[**] This work was supported by the Fonds der Chemischen Industrie,
the DFG International Research Traininggroup “Catalysts and
Catalytic Reactions for Organic Synthesis” (GRK 1038), and the
Krupp Foundation (Alfried Krupp Award for younguniversity
teachers to B.B.). We thank DSM for generous gifts of chemicals, Dr.
J. Wörth and G. Fehrenbach for analytical support, and S.
Mundinger for laboratory assistance.
Supportinginformation for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200800733.
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Table 3: Zn-catalyzed cross-couplingof 1a with Grignard reagents.
Entry
R[a]
Product
Yield [%][b]
ee [%][c]
CT [%][d]
Scheme 2. Determination of the absolute configuration of 2a. a) TFA
(trifluoroacetic acid), CH2Cl2, RT, >99%. Tf=trifluoromethanesulfonyl,
Nf=nonafluorobutanesulfonyl.
1
2
3
4
5
6
7
8
9
Et
iPr
(+)-2b
(+)-2c
(+)-2a
(+)-2d
(+)-2e
(+)-2 f
(+)-2g
(+)-2h
(+)-2i
(+)-2j
(+)-2k
>99
98
>99
>99[e]
96[f]
>99
>99
>99
>99
>99[g]
>99
>99[i]
>99[i]
>99[j]
>99
>99
100
100
100
100
100
100
100
100
100
100
100
nBu
iBu
sBu
Cy
Oct
lauryl
Bn
90[h]
>99
>99
>99
94[k]
the Grignard reagent or ZnCl2 led to the formation of small
amounts of chloride 3 (Table 2, entries 1 and 4). The absolute
configuration of ester 2a was determined by its conversion to
10
11
>99
Table 2: Optimization of the reaction conditions for the cross-coupling
of 1a with nBuMgCl.
[a] Cy=cyclohexyl, Bn=benzyl. [b] Yield of isolated product. [c] Deter-
mined by GC on a chiral phase. [d] The chirality transfer (CT) was
calculated as CT=[ee(2)/ee(1)]”100%. [e] 20 mol% ZnCl2. [f] Com-
bined yield of a 1:1 mixture of diastereomers. [g] Each diastereomer is
enantiopure. [h] 10 mol% ZnCl2. [i] The enantiomeric excess was deter-
mined after conversion of the reduced ester to the acetate. [j] Deter-
mined by HPLC on a chiral phase. [k] 2.3 equiv of Grignard reagent led to
a quantitative yield.
Entry
nBuMgCl
ZnCl2 [mol%]
2a [%][a]
3 [%]
1
2
3
4
1.1 equiv
1.4 equiv
1.4 equiv
1.4 equiv
5.0
5.0
2.5
1.0
98
>99
>99
96
2
–
–
4
[a] Combined quantitative yield; ratio was determined by 1H NMR
spectroscopy.
the known carboxylic acid 6, an important building block of
the high-potency sweetener NC-00637.[23] This proved the
course of the transformation to proceed by inversion of
configuration.
Using the optimized conditions, we next investigated the
reaction of 1a with a variety of organomagnesium nucleo-
philes to explore the scope and generality of this process
(Table 3). Not only primary (entries 1, 3, 4, 7, and 8), but also
secondary acyclic (entries 2and 5), secondary cyclic (entry 6),
and functionalized (entries 9–11) Grignard reagents were
found to be suitable coupling partners, affording the target
compounds 2a–k in excellent yields and with complete
inversion of configuration.
Thus, enantiospecific carbon–carbon bond formation
proceeds smoothly with 1a and an array of different alkyl
chloromagnesium reagents under mild conditions.[24] The
generality of this cross-coupling reaction makes 1a an
important building block in organic synthesis,[25] as it is
easily prepared and stable, and it can be stored at À208C for
several months.
After having examined different variations of the nucleo-
philic partner in the zinc-catalyzed cross-coupling reaction
with lactic acid derived triflate 1a, we turned our attention to
other electrophiles, investigating several structurally diverse
a-hydroxy ester derivatives. Starting from inexpensive and
commercially available a-amino acids 7a–f we obtained the
a-hydroxy acids 8a–f by a known diazotization protocol
(Scheme 3).[26] Subsequent straightforward conversions of
8a–f to a-hydroxy ester triflates 9a–f[19] yielded the electro-
philic coupling partners in enantiopure form. Substrate 9g
was obtained directly from l-malic acid.
Scheme 3. Synthesis of enantiopure a-hydroxy ester triflates 9a–f from
a-amino acids 7a–f.
The zinc-catalyzed cross-coupling is general and can be
extended to a wide variety of substrates, generating the
coupling products with complete inversion of configuration.
a-Hydroxy ester derived electrophiles with a linear alkyl
chain (9a), a b-branched alkyl chain (9b), or a benzyl
substituent (9c) in the a position could be coupled with
primary Grignard reagents to quantitatively yield the corre-
sponding products (Table 4, entries 2, 5, and 8). When less-
reactive MeMgCl was used, the cross-coupling proceeded
sluggishly and an excess of Grignard reagent had to be used to
minimize competing side reactions (Table 4, entries 1, 4, and
7). The cross-coupling with secondary Grignard reagents
resulted in very good yields (Table 4, entries 3, 6, and 9) but
was accompanied by the formation of small amounts of the
corresponding reduction products.
Even more challenging b-substituted a-hydroxy ester
triflates 9d and 9e could be coupled quantitatively with
EtMgCl (Table 4, entries 11 and 14), although an excess of
nBuMgCl was required to drive the reaction to complete
conversion (entries 12and 15). In the case of MeMgCl an
increase of the reaction temperature to 208C, an excess of
organomagnesium reagent, and higher catalyst loading were
needed to ensure complete conversion and a good yield
(Table 4, entries 10 and 13).
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Table 4: Zn-catalyzed cross-couplingof a-hydroxy ester triflates 9a–g with Grignard reagents.[a]
Entry
Substrate
Product
R
ZnCl2 [mol%]
Yield [%][b]
ee [%][c]
CT [%][d]
1
2
3
(À)-2a, R=Me
(À)-10a, R=Et
(À)-10b, R=iPr
20
5
15
92[e]
>99
88
99
99
99
100
100
100
4
5
6
(À)-2d, R=Me
(À)-11a, R=Et
(À)-11b, R=iPr
20
10
15
81[e]
>99
79
>99
>99
>99
100
100
100
7
8
9
(À)-2i, R=Me
(À)-12a, R=Et
(À)-12b, R=iPr
20
5
20
72[e]
>99
84
98[f]
98[f]
98[f]
100
100
100
10
11
12
(À)-2c, R=Me
(À)-13a, R=Et
(+)-10b, R=nBu
50
15
20
76[g]
>99
>99
>99
>99
100
100
100
>99[h]
13
14
15
(À)-2e, R=Me
(À)-14a, R=Et
(+)-14b, R=nBu
50
20
20
73[g]
>99
99[i]
99[i]
99[i]
100
100
100
>99[j]
16
17
(À)-15, R=Et
(À)-16, R=Me
20
20
95[k]
97[f]
100
100
74[e]
>99
[a] Unless otherwise noted, reactions were carried out on a 1 mmol scale in THF (0.3m) with 1.4 equiv of a Grignard solution in THF (1.0–2.5m) for 3 h
at 08C. [b] Yield of isolated product. [c] Unless otherwise noted, determined by GC on a chiral phase. [d] The chirality transfer (CT) was calculated as
CT=[ee(2)/ee(1)]”100%. [e] 2.3 equiv MeMgCl. [f] Determined by HPLC on a chiral phase. [g] 5.0 equiv MeMgCl, slow addition (3 mLhÀ1) of the
Grignard reagent at 208C. [h] 4.5 equiv nBuMgCl. [i] de, >99% ee. [j] 2.5 equiv nBuMgCl. [k] 2.0 equiv EtMgCl.
b-Functionalized a-hydroxy ester substrates, such as
serine-derived triflate 9 f and malic acid derivative 9g
proved compatible with the cross-coupling reaction condi-
tions as well, generating excellent yields of the coupling
products (Table 4, entries 16 and 17) and thereby extending
the scope of the reaction.[27] The zinc-catalyzed cross-coupling
of chloromagnesium reagents with a-hydroxy ester triflates
tolerates substantial variations in both reaction partners. The
resulting coupling products can be used for further synthetic
manipulations, making this methodology a valuable and
practical tool in organic synthesis.
In summary, we have documented the first stereospecific
zinc-catalyzed sp3–sp3 cross-coupling reaction employing
Grignard reagents. As an ideal catalyst, inexpensive and
nontoxic anhydrous zinc chloride was identified. Readily
available a-hydroxy esters served as electrophilic coupling
partners. They are available in enantiomerically pure form
from the chiral pool either directly (l- and d-lactic acid, l-
malic acid, etc.) or in a one-step protocol by the diazotization
of the corresponding a-amino acids. This methodology offers
an attractive alternative to enolate alkylation and features a
reversal of polarity. This allows for the preparation of
compounds having sterically crowded tertiary carbon centers
in excellent yield and enantioselectivity that are not acces-
sible by classical techniques.
Experimental Section
Typical procedure: (+)-2a (Table 2, entry 3): A solution of anhydrous
ZnCl2 (3.4 mg, 2.5 mol%) in dry THF (3 mL) at 08C was treated
successively with triflate (À)-1a (278 mg, 1.00 mmol) and nBuMgCl
(2.0m in THF; 0.70 mL, 1.4 mmol, 1.4 equiv) in an argon atmosphere.
After the reaction mixture had been stirred for 3 h at this temper-
ature, it was diluted with n-pentane and quenched by the addition of a
saturated aqueous NH4Cl solution. The reaction mixture was then
extracted three times with n-pentane, and the combined organic
layers were applied directly to a pad of silica gel. The filter was rinsed
with n-pentane, the product was eluted with a mixture of n-pentane/
Et2O (10:1), and the solvent was distilled off at atmospheric pressure
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to give (+)-2a (186 mg, > 99% yield, > 99% ee). The enantiomeric
excess was determined by GC on a chiral phase (Chiraldex G-TA
column 30 m ” 0.25 mm, 1.2 bar He, isothermal 408C); retention
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times: 69.9 min (minor R enantiomer) and 72.0 min (major
S
enantiomer). [a]2D0 = + 11.5 (c = 0.83, CHCl3). The absolute config-
uration of the product was determined by converting (+)-2a to
carboxylic acid (+)-6 [a]2D0 = + 18.1 (c = 0.84, CHCl3) and comparing
with reported data:[28] [a]D20 = + 15.8 (c = 1.0, CHCl3).
Received: February 13, 2008
Published online: June 18, 2008
Keywords: alkylation · C–C coupling· chiral pool ·
.
Grignard reaction · zinc
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Angewandte
Chemie
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[20] For copper-catalyzed sp3–sp3 cross-couplings of primary triflates
with Grignard reagents, see: a) C. Herber, B. Breit, Eur. J. Org.
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[24] Unfortunately, aryl, alkenyl, and allyl Grignard reagents could
not be coupled efficiently so far and furnished only mediocre
yields of the desired products.
[25] The opposite enantiomers are easily accessible from commer-
cially available d-lactic acid tert-butyl ester.
[21] For an example of zinc-catalyzed Grignard additions to carbonyl
compounds, see: M. Hatano, S. Suzuki, K. Ishihara, J. Am. Chem.
Soc. 2006, 128, 9998 – 9999.
[22] Nonhygroscopic ZnCl2·TMDA complex (TMDA = trimethyl-
hexamethylenediamine), Zn(OAc)2, and Zn(OTf)2 were appli-
cable as catalysts as well, whereas other zinc halides were less
successful.
[26] S. Deechongkit, S.-L. You, J. W. Kelly, Org. Lett. 2004, 6, 497 –
500.
[27] Mandelic ester triflate could not be coupled successfully under
the present reaction conditions. It is known to be prone to
racemization and unstable, as it decomposes at room temper-
ature (see Ref. [19]).
[28] H. Iwamoto, N. Inukai, I. Yanagisawa, Y. Ishii, T. Tamura, T.
Shiozaki, T. Takagi, K.-I. Tomoika, M. Murakami, Chem. Pharm.
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[23] For an account of different synthetic methods to access (S)-2-
methylhexanoic acid 6, see: D. J. Ager, S. Babler, D. E. Froen,
Angew. Chem. Int. Ed. 2008, 47, 5451 –5455
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