Direct Zinc(II)-Catalyzed Enantioconvergent Additions of Terminal Alkynes to α-Keto Esters

Article abstract of DOI:10.1002/anie.201704226

The addition of terminal alkynes to racemic β-stereogenic α-keto esters was achieved in high levels of stereoselectivity, affording versatile tertiary propargylic alcohols containing two stereocenters. This environmentally benign enantioconvergent reaction proceeds with perfect atom economy, requires no solvent, and is catalyzed by a non-toxic zinc salt. The alkyne moiety can be leveraged in downstream transformations including hydrogenation to the corresponding saturated tertiary alcohol, which represents the product of a formal enantioconvergent aliphatic nucleophile addition.

Full text of DOI:10.1002/anie.201704226

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Accepted Article
Title: Direct Zn(II)-Catalyzed Enantioconvergent Additions of Terminal
Alkynes to alpha-Keto Esters
Authors: Jeffrey Scott Johnson and Blane Zavesky
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704226
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Angewandte Chemie International Edition
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COMMUNICATION
Direct Zn(II)-Catalyzed Enantioconvergent Additions of Terminal
Alkynes to -Keto Esters
Blane P. Zavesky and Jeffrey S. Johnson*
reaction to be rendered catalytic in zinc.[10] While this discovery
has led to a thorough investigation of compatible aldehyde
Abstract: The addition of terminal alkynes to racemic stereogenic
keto esters was achieved in high levels of stereoselectivity,

affording versatile tertiary propargylic alcohols containing two
stereocenters. This environmentally benign enantioconvergent
reaction proceeds with perfect atom economy, requires no
solvent, and is catalyzed by an abundant and non-toxic zinc salt.
The alkyne moiety can be leveraged in downstream
transformations including hydrogenation to the corresponding
saturated tertiary alcohol, which represents the product of a
formal enantioconvergent aliphatic nucleophile addition.
substrates, much less attention has been paid to ketone
electrophiles.[7a,7c,7d] A notable exception comes from the Jiang
group, who disclosed the alkynylation of keto esters (Scheme
[11]
1
B). Despite the reaction’s reported intolerance of enolizable
substrates, we were intrigued by the potential to construct
complex tertiary propargylic alcohols via enantioconvergent
acetylide additions.
Since the foundational report from Noyori and co-workers
describing the dynamic kinetic hydrogenation of keto esters,[1]
enantioconvergent reactions that proceed by addition to racemic,
configurationally labile electrophiles have been recognized for
their ability to furnish stereochemically complex alcohol building
blocks. Because of their high acidity, which facilitates substrate
enantiomerization, dicarbonyl derivatives have remained the
factotum substrate in enantioconvergent alcohol syntheses and
the majority of these reactions proceed via reduction to furnish
secondary alcohols.[2] In contrast, examples of enantioconvergent
reactions employing less activated substrates are underexplored.
Similarly, relatively few enantioconvergent additions proceed via
carbon-carbon bond formation to furnish tertiary alcohol
products.[3] We recently reported an enantioconvergent addition
employing arylboronic acids and keto ester electrophiles
catalyzed by a chiral(diene) rhodium(I) complex which furnishes
complex tertiary glycolate derivatives (Scheme 1A).[4] The
integration of other non-stabilized nucleophilic partners under this
reaction manifold carries with it the opportunity to generate novel,
stereochemically complex glycolate architectures. The purpose of
this communication is to convey experimental results regarding
the enantioconvergent addition of alkynes to configurationally
labile keto esters that furnishes tertiary alkynyl glycolates.
Scheme 1. Prior art relevant to the title reaction.
Our investigation began with the coupling of keto ester 1a
and phenyl acetylene (Table 1). Initially, we chose to carry out the
reaction using stoichiometric Zn(OTf) and ligand in order to first
2
to probe the diastereo- and enantioselectivity of the reaction.
[
5]
As a result of their versatility, propargyl alcohols are
routinely employed in total synthesis.[6] The addition of metal
acetylides to carbonyls is a venerable method for the synthesis of
propargyl alcohols.[7] Following Mukaiyama’s pioneering report
describing the asymmetric addition of lithium acetylides to
aldehydes,[8] many synthetically useful asymmetric acetylide
[9]
Following Carreira’s conditions, glycolate product 3a was
formed in 2.5:1 dr and 87:13 er (entry 1). When the ligand was
changed to the amino alcohol developed by the Jiang group,
which is accessible in 2 steps from commercially available
(1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol,[
11,12]
an
increase in both diastereo- and enantioselectivity was observed
entry 2). Encouraged by this result, we next turned to rendering
(
additions have been disclosed. The Zn(OTf)
catalyzed variant reported by Carreira and coworkers is a
preeminent example;[9] the use of Zn(OTf)
as a catalyst avoids
the use of pyrophoric dialkyl zinc promoters and allows the
2
/Nmethylephedrine
the process catalytic. Increasing the temperature while reducing
catalyst loading to 20 mol % resulted in low conversion to product
2
3
a (entry 3). Zinc acetylide additions are ligand accelerated,[13]
thus we probed the hypothesis that reactivity could be improved
by employing stoichiometric Zn(OTf) and catalytic ligand without
2
negatively impacting enantioselectivity (entry 4). Although
conversion was increased, a significant drop in enantioselectivity
led us to abandon this strategy. When the reaction was run neat
at 70 °C,[10] excellent conversion and enantioselectivity were
obtained (entry 5). Finally, lowering the temperature of the
reaction to 40 °C improved the diastereoselectivity of the reaction,
[
*]
B. P. Zavesky, Prof. Dr. J. S. Johnson
Department of Chemistry
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599-3290, United States
E-mail: jsj@unc.edu
Supporting information for this article is given via a link at the end of the
document
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Angewandte Chemie International Edition
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COMMUNICATION
affording product 3a in quantitative conversion, 8.7:1 dr, and 99:1
Table 2. Scope of alkynylation reaction.[a]
er (entry 6).
Table 1. Optimization of alkynylation reaction conditions.[a]
entry
1
mol % Zn
110
110
20
L
D[d]
C[d]
C
temp (°C) conv (%)
dr[b]
2.5:1
3.6:1
-
er[c]
87:13
98:2
-
rt
38
51
< 5
70
94
99
2
rt
3
70
70
70
40
4
110
20
C
3.7:1
3.8:1
8.7:1
64:36
96:4
99:1
5[e]
6[e]
C
20
C
[a]Unless otherwise noted, reactions conditions are as follows: 1.0 equiv of 1a,
.0 equiv of 2a, variable amounts of Zn(OTf) , 50 mol % NEt , 22 mol % ligand,
PhMe ([1a]
= 0.2 M), 24 h. [b]Determined by 1H NMR analysis of the crude
3
2
3
0
reaction mixture. [c]Determined by chiral HPLC analysis. Represents the
enantiomeric ratio of the major diastereomer. [d]120 mol % ligand employed.
[e]Reactions were conducted using no solvent.
Under our optimized conditions, a variety of terminal alkynes
were added to keto ester 1a (Table 2). Electron-rich aryl alkyne
2b was used to deliver alcohol 3b in good diastereo- and
enantiocontrol. 4-Fluorophenyl acetylene (2c) proved to be an
excellent coupling partner as well. Ene-yne product 3d was
obtained in 6.3:1 dr and 98.5:1.5 er. Alkyl substituted alkynes also
proved to be viable substrates. In general, forming these products
required slightly higher reaction temperatures. Alkyl alkynes
substituted with heteroatoms gave satisfactory results. The use of
a protected primary alcohol, as represented by product 3f, was
well tolerated. Acetal 3g was assembled with only modest
diastereoselectivity (4.6:1 dr) but almost perfect enantioselectivity
(
99.5:0.5 er). Amine 2h restored higher levels of
diastereoselectivity. When alkynes with tertiary centers (2i,
j) were added to 1a, the highest levels of diastereoselectivity
2
were obtained. A free alcohol was tolerated in the formation of 3i.
Finally, ()citronellal-derived alkyne 2k was employed, which
gave product 3k in excellent selectivity and yield.
Next, the generality of the keto ester partner was probed
(
Table 2). Keto ester 1l, which contains an electron-rich
substituent on the aryl ring, provided glycolate product 3l with
exquisite selectivity. The formation of product 3m in 78% yield,
8.2:1 dr, and 96.5:3.5 er indicates that this reaction is viable for
substrates containing electronegative substituents and arenes
bearing ortho substitution. When allyl keto esters were
empoyed (1n and 1o), an increase in temperature to 50 °C was
required, resulting in reduced levels of diastereoselectivity.
Glycolate product 3o, containing a meta-substituted aryl ring, was
formed with the lowest enantioselectivity (93.5:6.5 er), which
indicates that substitution about the arene can have a noticeable
[a]Reaction conditions: 1.0 equiv 1, 3.0 equiv 2, 20 mol % Zn (OTf)
mol % C, 50 mol % NEt , 24 h. All diastereomeric pairs were separated via
2
, 22
3
column chromatography on silica gel. The reported enantiomeric ratio is of the
major diastereomer. [b]Reaction conducted at 50 °C. [c]Reaction conducted at
60 °C. [d]Reaction time of 48 h. [e]Reaction conducted at 70 °C.
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Angewandte Chemie International Edition
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COMMUNICATION
effect on enantioselectivity. When keto esters containing
strongly electron-withdrawing groups on the arene or substitution
at the -position, poor conversions were observed, even at
elevated temperatures.
An X-ray diffraction study revealed the stereochemistry of 3b
to be (2S,3R).[14] The relative configuration indicates that the
favored transition state follows the Felkin–Ahn model (Figure 1)
[
15]
and the absolute stereochemistry agrees with the results of
Carreira[10] and Jiang.[11,12]
Figure 1. Determination of relative and absolute stereochemistries by X-ray
crystallography.
To evaluate the synthetic utility of the propargylic alcohol
products, a number of secondary transformations were carried
out (Scheme 3). Tetrabutylammonium fluoride (TBAF) mediated
removal of the trimethylsilyl group from compound 3j afforded the
terminal alkyne 4 in 59% yield. Compound 3a underwent nickel
boride-catalyzed partial hydrogenation to form syn-alkene 5 in
Scheme 3. Chemical transfomrations of propargyl alcohol products and
gram-scale reaction. Conditions: (a) TBAF (1 M solution in H
THF, 0 °C, 15 minutes; (b) Ni(OAc) (30 mol %), NaBH
ethylenediamine (1 equiv), H
2
O, 1.2 equiv),
2
4
(60 mol %),
t
high yield. Boron substituted alkene 6 was formed through the
method of Tsuji and coworkers.[16] Finally, a palladium on carbon
2
(1 atm), EtOH, rt, 8 h; (c) E (2 mol %), NaO Bu
(12 mol %), HBpin (1.5 equiv), toluene, 60 °C, 16 h; (d) Pd/C (10 wt. %), H
1 atm).
2
(
catalyzed hydrogenation furnished product 7 in excellent yield.
This hydrogenation shows that for these products, the alkyne
functionality can act as an alkane surrogate,[11] an important
feature due to a lack of alternative reliable methods for
accomplishing this net transformation stereoselectively.[17]
Furthermore, the enantioconvergent alkynylation reaction of 1a
and phenylacetylene was conducted on a gram scale. Since
excess alkyne served only the role of solubilizing the reaction
mixture, the amount of phenylacetylene was decreased to 1.5
molar equivalents. An equal volume amount of toluene was added
in place of excess alkyne to dissolve the reagents.[18] This
modification produced no significant decrease in yield or
stereoselectivity.
Acknowledgements
The project described was supported by Award R35 GM118055
from the National Institute of General Medical Sciences. We thank
Dr. Peter White for assistance during X-ray crystallography
experiments.
Keywords: alkynes • asymmetric catalysis • synthetic methods•
green chemistry • zinc
In conclusion, we have developed
a stereoconvergent
alkynylation reaction of stereogenic keto esters. The DKR
between keto esters and alkynes constitutes a rare example of
the addition of a nonstabilized carbon nucleophile to a C=O -
electrophile in an enantioconvergent fashion. The reaction
proceeds with 100% atom economy and is conducted neat. The
substituted glycolate products can be converted into useful alkene
and alkane products. Studies aimed at the use of this reaction in
the arena of total synthesis are ongoing.
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Entry for the Table of Contents
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Blane P. Zavesky, Jeffrey S. Johnson*
Page No. – Page No.
Direct Zn(II)-Catalyzed
Enantioconvergent Additions of
Terminal Alkynes to -Keto Esters
Text for Table of Contents
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