Bronsted acid catalyzed asymmetric propargylation of aldehydes

Article abstract of DOI:10.1002/anie.201107407

Which gets activated? A versatile and highly enantioselective chiral Bronsted acid catalyzed method for the propargylation of aldehydes is described to provide a range of chiral homopropargylic alcohols. Computational studies support the belief that the c

Full text of DOI:10.1002/anie.201107407

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DOI: 10.1002/anie.201107407
Asymmetric Propargylation
Brønsted Acid Catalyzed Asymmetric Propargylation of Aldehydes**
Pankaj Jain, Hao Wang, Kendall N. Houk,* and Jon C. Antilla*
Enantiomerically pure homopropargylic alcohols are highly
useful intermediates, with broad synthetic utility. The termi-
nal alkyne functionality serves as a synthetic handle for cross-
coupling, metathesis, and heterocycle synthesis.[1] The addi-
tion of allenic or propargylic reagents to carbonyl compounds
is mechanistically similar to the analogous reaction with
allylic reagents. Though many useful and innovative methods
exist for the synthesis of homoallylic alcohols,[2] the enantio-
selective synthesis of homopropargylic alcohols remains
arduous. Two main complications are 1) the lower reactivity
of the allenylic and propargylic substrates in comparison to
allylic substrates, and 2) the difficulties associated with
controlling the reaction regioselectivity.[3] Herein, we describe
a highly enantioselective catalytic method for the preparation
of homopropargylic alcohols. Computational studies of the
reaction provide insight into the catalysis and stereochemistry
of the reaction.
proceeded smoothly in the presence of various chiral acid
catalysts,[8] with complete control over the regioselectivity
(Table 1). PA5[9] afforded product 3 with the highest enantio-
selectivity, when toluene was used as the reaction solvent. An
increase to 87% ee was seen with the use of higher catalyst
loading, in the presence of 4ꢀ M.S. (entry 13). The enantio-
selectivity could be further increased, when the reaction was
conducted at lower reaction temperatures of 08C (entry 14)
and À208C (entry 15), albeit with longer reaction times.
With the optimized conditions in hand,[10] a variety of
aldehydes with different electronic and steric properties were
tested to study the scope and limitation of the developed
Table 1: Catalyst screening and optimization for the propargylation of
benzaldehyde.[a]
Many current methods for enantioselective propargyla-
tion reactions rely upon the use of chiral reagents.[4] Alter-
native catalytic methods have been developed, but are limited
to the use of allenylic or propargylic metal-based reagents or
intermediates.[2a,5] Despite notable work, many of these
methods are restricted by one or more limitations. Among
them are 1) the use of reagents that are relatively difficult to
prepare or are unstable to air and/or moisture, 2) the use of
undesirable metal reagents or catalysts, and 3) regioselectivity
concerns.
In the past decade, Lewis and Brønsted acid-catalyzed
allylboration reactions have fascinated the synthetic com-
munity.[6,7] However, this methodology remains relatively
undeveloped for the more challenging allenylboration of
aldehydes. Following our recent report on the development of
a chiral phosphoric acid-catalyzed allylboration,[7] we exam-
ined the extension of our methodology to the enantioselective
propargylation of aldehydes. We began our investigation with
the reaction of benzaldehyde and allenyl boronic acid pinacol
ester. Boronate 2 is a relatively stable, non-toxic and
Entry
Catalyst[b]
Solvent
t
[h]
Yield
[%][c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PA1
PA2
PA3
PA4
PA5
PA6
PA7
PA5
PA5
PA5
PA5
PA5
PA5
PA5
PA5
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
DCM
40
40
40
40
40
40
40
40
40
40
40
40
24
64
72
94
93
92
95
91
93
94
89
87
94
92
92
93
96
94
0
7
20
9
74
4
16
62
43
68
75
77
87
90
91
À
commercially available reagent. The C C bond formation
[*] P. Jain, Prof. Dr. J. C. Antilla
Department of Chemistry, University of South Florida
4202 E. Fowler Avenue, Tampa, FL 33620 (USA)
E-mail: jantilla@usf.edu
PhCF3
p-xylene[e]
toluene[e]
toluene[e,f]
toluene[e,f,g]
toluene[e,f,h]
H. Wang, Prof. Dr. K. N. Houk
Department of Chemistry and Biochemistry
University of California, Los Angeles
607 Charles E. Young Drive East, Los Angeles, CA 90095 (USA)
E-mail: houk@chem.ucla.edu
[a] Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), catalyst
[**] We thank the National Institutes of Health (NIH GM-36700 and
GM-082935) and the National Science Foundation CAREER pro-
gram (NSF-0847108) for financial support.
(5 mol%), unless otherwise specified. [b] All catalysts were washed with
6m HCl after purification by column chromatography. [c] Yields of
isolated product. [d] Determined by chiral HPLC analysis. [e] Reaction
conducted in presence of 4ꢀ M.S. [f] 20 Mol% catalyst used. [g] Reaction
conducted at 08C. [h] Reaction conducted at À208C.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107407.
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methodology (Table 2). The reaction proved tolerant to
electron-donating and electron-withdrawing groups (1a–1j),
giving excellent yields and enantioselectivities (92–96% ee).
Table 2: Enantioselective propargylation of aldehydes.[a]
Scheme 1. Synthesis of important chiral moieties.
It is our belief that the propargylation proceeds through a
six-membered cyclic transition state, where catalyst activation
operates by hydrogen-bonding of the boronate oxygen. To
further understand the mechanism and stereoselectivity of
this phosphoric acid-catalyzed propargylation reaction, we
performed theoretical calculations. Calculated energies of
different pathways for allylboration[17] and propargylation
showed that Brønsted acids form a strong hydrogen bond with
the pseudo-equatorial oxygen of the allenyl boronate.[18]
A
computed transition state structure involving protonation is
shown in Figure 1.
[a] Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), PA5 (20 mol%).
Yields are of isolated product. Enantioselectivity was determined by
chiral HPLC. The product configurations were determined to be (R)
based on comparison to chiral HPLC analysis and optical rotation data
reported in the literature. [b] The product configurations were deter-
mined to be (R) by analogy. [c] (S) isomer was obtained. [d] Enantio-
selectivity was determined by 1H NMR spectroscopy after conversion to
the corresponding Mosher ester.
The methodology was extended to aliphatic aldehydes (1k–
1m), furnishing the corresponding homopropargylic alcohol
products 3k–m in 77–82% ee.
Figure 1. Transition state structure for the Brønsted acid-catalyzed
propargylation reaction.
We prepared several important synthetic scaffolds, pre-
viously unavailable from enantioenriched homopropargylic
alcohols (Scheme 1). Chiral dihydrofuran-3-ones, such as 4,
are important building blocks[11] for the synthesis of biolog-
ically active compounds. Despite their importance, a general
enantioselective synthesis for this class of molecule has yet to
be reported. We successfully transformed 3a[12] into dihydro-
furan-3-one 4, by employing gold-catalyzed reaction method-
ology developed by Zhang and co-workers,[13] with complete
preservation of the enantiomeric excess. Crabbꢁ homologa-
tion of 3a provided optically active 3,4-allenol 5, which has
the potential to serve as a substrate in natural product
synthesis.[14] Chiral dihydrofuran 6, currently dependent on
the Heck reaction for its synthesis,[15] was obtained through a
molybdenum-mediated cycloisomerization of 3a, based on
methodology developed by McDonald and co-workers.[16]
To explore the origins of the enantioselectivity, we studied
the transition state structures for the propargylation reaction,
where the phosphoric acid catalyst activates the pseudo-
equatorial oxygen of the allenyl boronate. Biphenol(bipol)-
derived phosphoric acid was used as the model, in place of the
fully derived binol phosphoric acid, to reduce the computa-
tional time. Catalyst PA5, bearing a 2,4,6-triisopropylphenyl
group at the 3,3’-positions, provides high experimental
enantioselectivity. Thus, the diastereomeric transition states
of the re-face and si-face attack involving the bipol model of
PA5 were compared. Transition states TSr1 and TSs1 are
represented in Figure 2. Re-face attack (TSr1) is predicted to
be more favored than si-face attack (TSs1) by 1.3 kcalmolÀ1.
This is in agreement with the 74% ee obtained experimen-
tally.
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Figure 2. Optimized structures of TSr1 and TSs1. Relative energies
(kcalmolÀ1) are shown in parentheses.
Figure 2 shows a lack of obvious steric differences in the
transition states. H–H distances are 2.4 ꢀ or more. However,
the distortion of the catalyst is larger in TSs1 than in TSr1 by
about 1.2 kcalmolÀ1. This distortion relieves steric repulsions
that would otherwise occur. The preference for re-facial
selectivity is therefore the result of the larger distortion of the
catalyst–boronate complex in TSs1. The origins of the differ-
ences in distortion energies of the catalyst–boronate complex
in the two TSs can be visualized from geometries of the
catalyst in the TSs. Figure 3a shows the catalyst–boronate
complex structure in TSr1. Here, the dioxaborolane ring has
no significant steric interaction with the catalyst, and the
dihedral angle between the 2,4,6-triisopropylphenyl substitu-
Figure 3. a) 3D structure of TSr1 without benzaldehyde. b) 3D struc-
ture of TSs1 without benzaldehyde.
with catalyst PA5 originates from steric interactions between
the methyl groups of the allenylboronate, the bulky catalyst
substituents, and the resulting distortion of the catalyst.
ent and the bipol core is 748, almost the same as the dihedral Experimental Section
General procedure for the propargylation of aldehydes: A screw-cap
angle of 728 in the optimized catalyst. Figure 3b shows the
catalyst–boronate complex structure in TSs1, with the dioxa-
borolane ring on the left. The methyl groups (circled in
Figure 3b) of the dioxaborolane ring and the isopropyl groups
of the catalyst (circled in Figure 3b) are close to each other. In
order to minimize such steric repulsions, the 2,4,6-triisopro-
pylphenyl substituent is rotated around the bond to the bipol
phenyl core with a dihedral angle of 788. This is a 68 rotation
away from the dihedral angle in the optimized catalyst (728).
The asymmetric induction can be rationalized by differences
in distortion energies originating from the steric interactions
between the substrates and the bulky 3,3’-substituents on the
catalyst.
reaction tube, with a stir bar and 4ꢀ MS (100 mg) was evacuated,
flame-dried, and back-filled with argon. The tube was charged with
(R)-trip-PA catalyst PA5 (20 mol%), freshly distilled aldehyde 1
(0.20 mmol) and 1.5 mL of dry toluene. The reaction mixture was
then cooled to À208C, followed by the addition of allenylboronic acid
pinacol ester 2 (0.30 mmol), slowly over 30 s. The mixture was stirred
96 h at this temperature, and then directly purified by silica gel
column chromatography (hexanes:EtOAC = 9:1) to afford product 3.
Received: October 20, 2011
Published online: December 28, 2011
Keywords: asymmetric catalysis · Brønsted acid ·
.
homopropargylic alcohol · propargylation
For other catalysts screened experimentally, calculations
showed the absence of an energy difference between re- and
si-attack diastereomeric transition states, suggesting why
these catalysts gave low enantioselectivities.
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highly efficient, demonstrating broad synthetic utility. Mech-
anistic studies show the catalyst activating the reaction by
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oxygen of the boronate. The high enantioselectivity obtained
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