Highly enantioselective catalytic alkyl propiolate addition to aliphatic aldehydes

Article abstract of DOI:10.1021/ol900667g

A novel H₈BINOL-based chiral ligand (S)-3 is found to catalyze the alkyl propiolate addition to aliphatic aldehydes in the presence of ZnEt2 and Ti(OiPr)₄ at room temperature with excellent enantioselectivity (89-97% ee).

Full text of DOI:10.1021/ol900667g

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2441-2444
Highly Enantioselective Catalytic Alkyl
Propiolate Addition to Aliphatic
Aldehydes
Mark Turlington, Albert M. DeBerardinis, and Lin Pu*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
lp6n@Virginia.edu
Received March 31, 2009
ABSTRACT
A novel H8BINOL-based chiral ligand (S)-3 is found to catalyze the alkyl propiolate addition to aliphatic aldehydes in the presence of ZnEt2 and
Ti(OiPr)4 at room temperature with excellent enantioselectivity (89-97% ee).
γ-Hydroxy-R,ꢀ-acetylenic esters contain three adjacent but
chemically distinct functional groups and are versatile
synthetic precursors to many organic compounds.1 Racemic
γ-hydroxy-R,ꢀ-acetylenic esters are usually prepared ac-
cording to Midland’s original report by treating an alkynoate
with nBuLi at low temperatures, followed by addition of an
aldehyde.2 Direct access to optically active γ-hydroxy-R,ꢀ-
acetylenic esters proved to be more challenging. Although
significant strides had been made in the catalytic asymmetric
addition of monoaryl or monoalkyl alkynes to aldehydes,3
no catalytic asymmetric alkyl propiolate addition was
reported before our recent work.4,5 This could be attributed
to the higher sensitivity and dissimilar reactivity of alkynoates
in comparison with simple alkyl and aryl alkynes. In
particular, our original 1,1′-bi-2-naphthol (BINOL)-Ti(OiPr)4
system for the asymmetric alkyne addition to aldehydes6
proved unsuitable for propiolate addition. This is because
the conditions for the alkynylzinc formation, stirring the
alkyne with ZnEt2 in refluxing toluene, led to decomposition
of methyl propiolate. A solution to the problem was realized
when our laboratory discovered that the addition of HMPA
facilitated the formation of alkynylzinc reagents at room
temperature for asymmetric alkyne additions.4 It is thought
that HMPA, acting as a Lewis base, coordinates with ZnEt2
and activates it toward deprotonation of the alkyne. This
methodology was successfully applied in the addition of
methyl propiolate to aromatic aldehydes to generate γ-hy-
droxy-R,ꢀ-acetylenic esters with high enantioselectivity.5
The development of other catalytic systems quickly
followed. In 2006, Trost demonstrated a highly enantiose-
lective addition of methyl propiolate to R,ꢀ-unsaturated
aldehydes using a proline-derived catalyst and ZnMe2.7 In
2007, Wang reported the use of a ꢀ-sulfonamide ligand in
(1) For examples, see: (a) Noyori, R.; Yamada, T.; Nishizawa, M. J. Am.
Chem. Soc. 1984, 106, 6717–6725. (b) Molander, G. A.; St. Jean, D. J. J.
Org. Chem. 2002, 67, 3861–3865. (c) Trost, B. M.; Ball, Z. T. J. Am. Chem.
Soc. 2004, 126, 13942–12944. (d) Albert, B. J.; Sivaramakrishnan, A.; Naka,
T.; Koide, K. J. Am. Chem. Soc. 2006, 128, 2792–2793.
(2) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28–29.
(3) (a) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.; Carreira, E. M. Acc.
Chem. Res. 2000, 33, 373–381. (b) Pu, L. Tetrahedron 2003, 59, 9873–
9886. (c) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem. ReV.
2005, 249, 1736–1744.
(5) (a) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew. Chem.,
Int. Ed. 2006, 45, 122–125. (b) Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8,
2019–2021.
(4) Gao, G; Xie, R.-G.; Pu, L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
(6) (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855–1857. (c) Gao, G.;
Moore, D.; Xie, R.-G.; Pu, L. Org. Lett. 2002, 4, 4143–4146.
5417–5420
.
10.1021/ol900667g CCC: $40.75
Published on Web 05/07/2009
 2009 American Chemical Society

combination with ZnEt2 and Ti(OiPr)4 for the addition of
methyl propiolate to aromatic aldehydes.8 Later that year,
You further modified the BINOL-Ti(OiPr)4 system by
substituting HMPA with NMI, which reduced the amount
of the Lewis base and BINOL required for the catalysis.9
Wang recently reported the use of ZnMe2 and a chiral
cyclopropane based amino alcohol for the addition of methyl
propiolate to aromatic aldehydes without Ti(OiPr)4.10
Whereas several systems have been developed for the
highly enantioselective addition of methyl propiolate to
aromatic aldehydes, aliphatic aldehydes remain challenging
substrates. Only one aliphatic aldehyde was reported to react
with methyl propiolate in the presence of a chiral catalyst to
give >90% ee.11 Our BINOL-HMPA system afforded
81-89% ee for a small range of aliphatic aldehyde
substrates.5b Wang’s sulfonamide system could catalyze the
addition of methyl propiolate to cyclohexanecarboxaldehyde
with only 79% ee.8 Our attempts to catalyze the addition of
methyl propiolate to valeraldehyde with a bifunctional
H8BINOL ligand without the use of Ti(OiPr)4 resulted in 70%
ee.12 Given these unsatisfactory results, we set out to explore
the addition of methyl propiolate to aliphatic aldehydes.
Herein, we report a catalytic system capable of promoting
the addition of alkyl propiolates to a variety of aliphatic
aldehydes with excellent enantioselectivity.
Ligand (S)-3 is designed as a structurally modified analog
of (S)-1 (Scheme 2). In (S)-3, a partially hydrogenated
Scheme 2. Synthesis of H8BINOL-Based Ligand (S)-3
BINOL unit, H8BINOL, is incorporated. The nonplanar
tetrahedral CH2 units in (S)-3 are expected to increase the
steric bulkiness of the ligand as well as the central biaryl
dihedral angle. This could potentially lead to improved chiral
induction in asymmetric catalysis.14 As shown in Scheme
2, (S)-3 can be readily synthesized from (S)-H8BINOL by
bromination followed by the Suzuki coupling with the
boronic ester 2 via modification of a literature procedure.15
The two-step reaction can be completed with an overall yield
of 86%. The ee of the resulting (S)-3 is determined to be
98% by HPLC analysis (Chiralcel OD column).
We have tested the use of (S)-3 to catalyze the reaction
of methyl propiolate with octyl aldehyde under various
conditions. The screening experiments are summarized in
Table 1. A large solvent effect on the enantioselectivity of
this reaction is observed (entries 1-5). It is found that in
THF, (S)-3 can catalyze the highly enantioselective reaction
of methyl propiolate with octyl aldehyde (91% ee and 70%
yield, entry 5). The other less coordinative solvents such as
CH2Cl2, Et2O, and toluene give poorer results. The enanti-
oselectivity in dioxane (87% ee) is found to be close to that
in THF but in a lower yield (entry 4). The effect of various
amounts of Ti(OiPr)4 on the reaction is examined (entries
5-9). When no or only 10 mol % of Ti(OiPr)4 is used, no
enantioselectivity is observed also with low yields (entries
7 and 8). Increasing the amount of Ti(OiPr)4 from 50 to 100
mol % (entry 9) leads to reduced yield while maintaining
the enantioselectivity. Thus, 50 mol % of Ti(OiPr)4 is optimal
(entry 5). Dilution and concentration (entries 10 and 11) have
no effect on enantioselectivity, though both diminish the
yield. Addition of Ti(OiPr)4 in the first step decreases the
yield (entry 12). Finally, when the amount of the chiral ligand
(S)-3 is increased from 10 to 20 mol %, both the yield and
ee are increased (84% yield and 95% ee, entry 13).
To improve the enantioselectivity of BINOL for the
asymmetric reaction of alkyl propiolates with aliphatic
aldehydes,5b we have examined the 3,3′-bisanisyl substituted
BINOL ligand (S)-1. Previously, (S)-1 was found to catalyze
the reaction of phenylacetylene with benzaldehyde in the
presence of ZnEt2 and Ti(OiPr)4 to generate 1,3-diphenyl-
2-propyn-1-ol with 88% ee.13 When (S)-1 20 mol% is used
to catalyze the reaction of methyl propiolate with pentyl
aldehyde, it gives the desired product with 62% yield and
85% ee (Scheme 1). This reaction is carried out at room
Scheme 1. Asymmetric Addition of Methyl Propiolate to Pentyl
Aldehyde Catalyzed by (S)-1 in Combination with ZnEt2 and
Ti(OiPr)4
(10) Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin, M.-M.; Na, R.-S.;
Zheng, B.; Li, Z.-Y.; Liu, S.-Z.; Wang, M. Chem.sEur. J. 2009, 15, 3069–
3071.
temperature without the use of a Lewis base additive.
Encouraged by this result, we have conducted a further
modification of the catalyst structure.
(11) Trost, B. M.; O’Boyle, B. M. J. Am. Chem. Soc. 2008, 130, 16190–
16192.
(12) Qin, Y.-C.; Liu, L.; Sabat, M.; Pu, L. Tetrahedron 2006, 62, 9335–
9348.
(7) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc.
2006, 128, 8–9.
(13) Moore, D.; Huang, W.-S.; Xu, M.-H; Pu, L. Tetrahedron Lett. 2002,
43, 8831–8834.
(8) Lin, L.; Jiang, X.; Liu, W.; Qui, L.; Xu, Z.; Xu, J.; Chan, A. S. C.;
Wang, R. Org. Lett. 2007, 9, 2329–2332.
(14) For a review on H8BINOL, see: Au-Yeung, T.T.-L.; Chan, S.-S.;
Chan., A. S. C. AdV. Synth. Catal. 2003, 345, 537–555.
(15) Bartoszek, M.; Beller, M.; Deutsch, J.; Klawonn, M.; Kockritz, A.;
Nemati, N.; Pews-Davtyan, A. Tetrahedron 2008, 64, 1316–1322.
(9) Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 5457–5460.
2442
Org. Lett., Vol. 11, No. 11, 2009

Table 1. Optimization of Conditions for the Reaction of Methyl
Propiolate with Octyl Aldehyde Catalyzed by (S)-3a
Table 2. Addition of Methyl Propiolate to Aliphatic Aldehydes
Catalyzed by (S)-3a
(S)-3
solvent
Ti(OiPr)4 yield
ee
(%)f
entry (mol %) (aldehyde concn M)
(mol %)
(%)
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
10
10
10
10
20
CH2Cl2 (0.1)
Et2O (0.1)
toluene (0.1)
1,4-dioxane (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
50
50
50
50
50
0
10
25
100
50
50
50
50
51
73
44
49
70
28
27
51
47
65
40
48
84
78
37
69
87
91
0
0
76
91
90
90
90
95
9
10b
11c
12d
13e
THF (0.2)
THF (0.05)
THF (0.1)
THF (0.1)
a Unless otherwise indicated, the following conditions were employed:
0.025 mmol (S)-3 (10 mol %), 2.5 mL solvent, 0.5 mmol ZnEt2 (2 equiv),
and 0.5 mmol methyl propiolate (2 equiv) were combined and stirred for
16 h at rt. Then 0.125 mmol Ti(OiPr)4 (0.5 equiv, 50 mol %) was added,
and the mixture was stirred for 1 h, followed by the addition of 0.25 mmol
octyl aldehyde (1 equiv). After consumption of the aldehyde the reaction
was quenched with 1.0 mmol acetic anhydride (4 equiv) for ease of
d
purification and HPLC analysis. b 1.25 mL THF. c 5 mL THF. Ti(OiPr)4
was added in the first step. e 0.5 mmol octyl aldehyde was used; 0.1 mmol
(S)-3 (0.2 equiv, 20 mol %) was used. The equivalents of the other reagents
remained the same, i.e., their quantities were doubled. f Enantiomeric excess
was determined by HPLC analysis (Chiralpak AD-H column).
We have applied the optimized conditions in entry 13 in
Table 1 to the asymmetric reaction of methyl propiolate with
various aliphatic aldehydes. The results are summarized in
Table 2. In general, good yields and excellent enantioselec-
tivities are obtained for linear, R-branched, and ꢀ-branched
aliphatic aldehydes (entries 1-6). The more bulky trimethy-
lacetaldehyde shows reduced reactivity, requiring higher
loadings of the ligand (40 mol %) and other reagents to give
55% yield and 97% ee (entry 7). In comparison, 40% yield
is obtained using the general conditions. Functionalized
aliphatic aldehydes are also examined and high enantiose-
lectivity is achieved (entries 8-10). In entry 11, the reaction
of ethyl propiolate with 4-pentenal gives the corresponding
product with the same high enantioselectivity as that of
methyl propiolate in entry 8.
a ZnEt2/methyl propiolate/(S)-3/Ti(OiPr)4/aldehyde ) 2:2:0.2:0.5:1.
b Determined by HPLC analysis on Chiralcel OD or Chiralpak AD-H colum.
c The reaction was quenched with 2.0 mmol acetic anhydride (4 equiv) to
yield the acetate product for ease of purification and HPLC analysis.
d Determined by 1H NMR analysis of mandelate acetate. e ZnEt2/methyl
f
propiolate/(S)-3/Ti(OiPr)4/aldehyde ) 4:4:0.4:1:1. 100 mol % Ti(OiPr)4.
g Ethyl propiolate was used in place of methyl propiolate.
matography on silica gel. First eluting with 2:1 CH2Cl2/
hexanes cleanly separates the ligand from the product,
providing an efficient means of recovering the ligand. After
removal of the ligand, the column was eluted with hexanes/
ethyl acetate (10-30% ethyl acetate) to give the desired
product. The ee was determined by HPLC analysis (Chiralcel
OD or Chiralpak AD-H column).
The absolute configuration of the product in entry 11 of
Table 2 is determined to be S by comparing its optical
rotation with that in the literature.16 By analogy, all other
products in Table 2 are assigned to be S. The absolute
configuration of the γ-hydroxy-R,ꢀ-acetylenic esters obtained
by using (S)-3 as the catalyst is opposite to that by using
(S)-BINOL.5b Thus, using this structurally modified BINOL
ligand provides stereocontrol very different from using
BINOL.
The following gives the general procedure for the reaction
catalyzed by (S)-3. Under nitrogen, (S)-3 (61.9 mg, 0.1 mmol,
20 mol %) was dissolved in THF (5 mL) in a 10 mL flame-
dried flask. ZnEt2 (103 µL, 1 mmol, 2 equiv) and methyl
propiolate (89 µL, 1 mmol, 2 equiv) were added sequentially,
and the mixture was stirred at room temperature for 16 h,
yielding a light yellow solution. Ti(OiPr)4 (74 µL, 0.25 mmol,
50 mol %) was then added, and the mixture was stirred for
1 h. To the resulting dark orange solution was added an
1
aldehyde, and the reaction was monitored by TLC or H
NMR. Upon consumption of the aldehyde, the reaction was
quenched with ammonium chloride (saturated aqueous). The
reaction mixture was extracted three times with CH2Cl2, and
the organic layer was dried with sodium sulfate and
concentrated. The resultant oil was purified by flash chro-
Ligands (S)-4 and (S)-5 are prepared in order to study the
t
effects on the reaction by replacing the Bu groups of (S)-3
(16) Johansson, M.; Kopcke, B.; Anke, H.; Sterner, O. Tetrahedron 2002,
58, 2523–2528.
Org. Lett., Vol. 11, No. 11, 2009
2443

with a smaller group like Me in (S)-4 or a bigger group like
adamantanyl in (S)-5. When these ligands (10 mol %) are
used to catalyze the reaction of methyl propiolate with octyl
aldehyde under the conditions of entry 5 in Table 1, the
corresponding products are obtained with 90% ee in both
cases. That is, the enantioselectivity of (S)-4 and (S)-5 is
very close to that of (S)-3 with little influence by the size of
the alkyl substituents. Ligands (S)-4 and (S)-5 lead to product
yields of 59% and 63%, respectively.
the 3,3′-bisanisyl groups of (S)-3, the resulting ligand (S)-8
gives both poor enantioselectivity (34% ee) and poor yield
(48%).
In summary, we have developed a catalytic system capable
of catalyzing the addition of alkyl propiolates to aliphatic
aldehydes with high enantioselectivity. This system’s ef-
fectiveness for aliphatic substrates under simple and mild
reaction conditions makes it especially useful, as no system
has currently been shown to afford high enantioselectivities
for a wide range of aliphatic aldehydes. We are currently
working on further expanding the substrate scope for the
reaction in both the alkynes and aldehydes.
The electronic effects are also investigated with the
preparation of ligands (S)-6 and (S)-7. Under the conditions
of entry 5 in Table 1, the electron-withdrawing fluorine
substituents in (S)-6 lead to a reduced enantioselectivity (70%
ee) for the reaction of methyl propiolate with octyl aldehyde,
whereas the more electron-donating ligand (S)-7 gives 86%
ee, closer to that of (S)-3. The yield using (S)-7 (52%) is
also better than that using (S)-6 (34%). The poorer enanti-
oselectivity of (S)-6 versus those of (S)-3 and (S)-7 indicates
that the coordination of the Lewis basic MeO groups of these
ligands to a metal center should be important for the
stereocontrol of the reaction. When pyridine is used to replace
Acknowledgment. Partial support of this work from the
U.S. National Science Foundation (CHE-0717995) and the
donors of the Petroleum Research Fund, administered by
the American Chemical Society, is gratefully acknowledged.
We also thank Mr. Yang Yue for the initial data on the use
of (S)-1.
Supporting Information Available: Synthesis and char-
acterization of new compounds and ee determination of the
chiral alcohol products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL900667G
2444
Org. Lett., Vol. 11, No. 11, 2009