Chiral Bronsted acid catalyzed enantioselective synthesis of anti -homopropargyl alcohols via kinetic resolution-aldehyde allenylboration using racemic allenylboronates

Article abstract of DOI:10.1021/ol4003459

A chiral phosphoric acid catalyzed kinetic resolution/allenylboration of racemic allenylboronates with aldehydes is described. Allenylboration of aldehydes with 2.8 equiv of allenylboronate (±)-1 in the presence of 10 mol % of catalyst (R)-2 provided anti-homopropargyl alcohols 3 in 83-95% yield with 9:1 to 20:1 diastereoselectivity and 73-95% ee. The catalyst enables the kinetic resolution of the racemic allenylboronate (±)-1 to set the methyl stereocenter and biases the facial attack of the aldehyde to set the stereochemistry of the hydroxyl group in 3.

Full text of DOI:10.1021/ol4003459

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Chiral Brønsted Acid Catalyzed
Enantioselective Synthesis of
anti-Homopropargyl Alcohols via Kinetic
ResolutionꢀAldehyde Allenylboration
Using Racemic Allenylboronates
Andy S. Tsai, Ming Chen, and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, United States
roush@scripps.edu
Received February 5, 2013
ABSTRACT
A chiral phosphoric acid catalyzed kinetic resolution/allenylboration of racemic allenylboronates with aldehydes is described. Allenylboration of
aldehydes with 2.8 equiv of allenylboronate (()-1 in the presence of 10 mol % of catalyst (R)-2 provided anti-homopropargyl alcohols 3 in 83ꢀ95%
yield with 9:1 to 20:1 diastereoselectivity and 73ꢀ95% ee. The catalyst enables the kinetic resolution of the racemic allenylboronate (()-1 to set
the methyl stereocenter and biases the facial attack of the aldehyde to set the stereochemistry of the hydroxyl group in 3.
Asymmetric crotylation of aldehydes with crotylboron
reagents is a well established method to generate stereo-
defined acyclic molecules bearing an olefinic handle.1
Similarly, allenylboration of 3-substituted allenylboron
reagents provides homopropargyl alcohols with an alkyne
moiety which are equally valuable in polyketide natural
product syntheses.2,3 Due to the closed transition states
involved in allenylboration reactions, the axial chirality of
3-substituted allenylboron reagents is directly transferred
to the stereochemistry of the propargylic position in the
product (e.g., the position that bears the methyl group in 3
and 4, Scheme 1).3,4 The stereochemistry of the hydroxyl
group in the homopropargyl products is controlled by the
facial approach of the allenylboronate to the aldehyde.
As shown in Scheme 1, allenylboration of an aldehyde
with (M)-1 can provide either anti-homopropargyl alcohol
ent-3 or the syn adduct 4 via the two competing transition
states TS-1 and TS-2. These two transition states, arising
from opposing diastereofacial approches of the reagent to
(2) For recent reviews on asymmetric propargylation of carbonyl
compounds, see: (a) Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111,
1914. (b) Marshall, J. A. J. Org. Chem. 2007, 72, 8153. For selected
asymmetric aldehyde propargylation reactions where only one stereo-
center is set, see: (c) Haruta, R.; Ishiguro, M.; Ikeda, N.; Yamamoto, H.
J. Am. Chem. Soc. 1982, 104, 7667. (d) Corey, E. J.; Yu, C.-M.; Lee,
D.-H. J. Am. Chem. Soc. 1990, 112, 878. (e) Hernandez, E.; Burgos,
C. H.; Alicea, E.; Soderquist, J. A. Org. Lett. 2006, 8, 4089. (f) Shi, S.-L.;
Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 6638.
(g) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; et al. J. Am. Chem.
Soc. 2010, 132, 7600. (h) Barnet, D. S.; Schaus, S. E. Org. Lett. 2011, 13,
4020. (i) Keck, G. E.; Krishnamurthy, D.; Chen, X. Tetrahedron Lett.
1994, 35, 8323. (j) Yu, C.-M.; Yoon, S.-K.; Choi, H.-S.; Baek, K. Chem.
Commun. 1997, 763. (k) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc.
2001, 123, 6199. (l) Even, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S.
J. Am. Chem. Soc. 2001, 123, 12095. (m) Chen, J.; Captain, B.;
Takenaka, N. Org. Lett. 2011, 13, 1654. (n) Woo, S. K.; Geary, L. M.;
Krische, M. J. Angew. Chem., Int. Ed. 2012, 51, 7830. (o) Jain, P.; Wang,
H.; Houk, K. N.; Antilla, J. C. Angew. Chem., Int. Ed. 2012, 51, 1391.
(p) Reddy, L. R. Org. Lett. 2012, 14, 1142. (q) Haddad, T. D.; Hirayama,
L. C.; Buckley, J. J.; Singaram, B. J. Org. Chem. 2012, 77, 889. (r)
Hirayama, L. C.; Daddad, T. D.; Oliver, A. G.; Singaram, B. J. Org.
Chem. 2012, 77, 4342. (s) Wan, H.; Jain, P.; Antilla, J. C.; Houk, K. N.
J. Org. Chem. 2013, 78, 1208.
(1) (a) Roush, W. R. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, p 1. (b)
Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763. (c) Lachance, H.;
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r
10.1021/ol4003459
XXXX American Chemical Society

the aldehyde substrates, often have similar energy and poor
anti/syn diastereoselectivity is generally observed.3b,c,h,4 Con-
sequently, in order to obtain homopropargyl alcohol
products with high diastereo- and enantioselectivity, single
enantiomer 3-substituted allenylboron reagents are required
as well as a means to control the diastereofacial selectivity of
the addition of the reagent to the aldehyde substrate.
resolution of a racemic allenylboronate, such as (()-1,7 in
reactions catalyzed by chiral phophoric acids such as 2
and would eliminate the need to synthesize enantioen-
riched allenylboron reagents for use in aldehyde allenyl-
boration reactions.2b,8 Thus, a single enantiomer phospho-
ric acid catalyst might be able both to select the more reactive
allenylboronate enantiomer from a racemic mixture and to
direct its addition to the aldehyde with high facial diaster-
eoselectivity. Accordingly, we are pleased to report that the
chiral, nonracemic Brønsted acid (R)-2 catalyzes the allenyl-
boration of aldehydes with racemic allene (()-1 with kinetic
resolution to obtain anti-homopropargyl alcohols 3 with
high diastereo- and enantioselectivity.
Scheme 1. Aldehyde Allenylboration Reactions with
Allenylboronate (M)-1
Scheme 2. Proposed Kinetic Resolution/Aldehyde
Allenylboration with Racemic Allenylboronate (()-1
We recently demonstrated that the chiral, nonracemic
phosphoric acid catalyst 25 can bias the two competing
transition states (e.g., TS-1 and TS-2) such that either syn-
or anti- products can be obtained with good to excellent
diastereoselctivity and with very high enantioselectivity.6
As illustrated in Scheme 2, allenylboration of aldehydes
with (M)-1 in the presence of 5 mol % of catalyst (S)-2
gave anti-homopropargyl alcohols ent-3 in 83ꢀ98% yield
and excellent diastereo- (>50:1 ds) and enantioselectivity
(>98% ee). We infer that this transformation is stereo-
chemically matched. On the other hand, mismatched
allenylborations of aldehydes with (M)-1 in the presence
of the enantiomeric catalyst (R)-2 provided the syn-adducts
4 with g9:1 ds and >98% ee. Importantly, the reaction of
(M)-1 and aldehydes in the presence of (S)-2 proceeded at a
faster rate than the reaction with the (M)-1/(R)-2 pairing.6
These differing rates form the basis of a possible kinetic
(3) For selected asymmetric propargylations of carbonyl compounds
where two stereocenters are set, see: (a) Marshall, J. A. Chem. Rev. 1996, 96,
31. (b) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008,
130, 15774. (c) Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T.
J. Chem. Soc., Chem. Commun. 1993, 1468. (d) Han, J. W.; Tokunaga,
N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915. (e) Marshall, J. A.;
Adams, N. D. J. Org. Chem. 1997, 62, 8976. (f) Marshall, H. A.; Maxson, K.
J. Org. Chem. 2000, 65, 630. (g) Brawn, R. A.; Panek, J. S. Org. Lett. 2007, 9,
2689. (h) Shimizu, M.; Kurahashi, T.; Kitagawa, H.; Hiyama, T. Org. Lett.
2003, 5, 225. (i) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1992, 57, 1242.
(j) Marshall, J. A.; Perkins, J. J. Org. Chem. 1994, 59, 3509. (k) Marshall,
J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201. (l) Marshall, J. A.; Grant,
C. M. J. Org. Chem. 1999, 64, 696. (m) Marshall, J. A.; Chobanian, H. R.;
Yanik, M. M. Org. Lett. 2001, 3, 3369. (n) Geary, L. M.; Woo, S. K.; Leung,
J. C.; Krische, M. J. Angew. Chem., Int. Ed. 2012, 51, 2972.
Initial studies of the chiral phosphoric acid catalyzed
kinetic resolutionꢀallenylboration reactions of (()-1 were
performed with hydrocinnamaldehyde as the substrate
(Table 1). Treatment of hydrocinnamaldehyde with 2.1 equiv
of allenylboronate (()-1 and 5 mol % of catalyst (R)-2 at
ambient temperature provided enantiomerically enriched
(71% ee) anti-homopropargyl alcohol 3a in 92% yield with
10:1 diastereoselectivity (Table 1, entry 2). The enantiomeric
excess of 3a was determined by using the Mosher ester
(4) Sasaki, Y.; Sawamura, M.; Ito, H. Chem. Lett. 2011, 40, 1044.
(5) For recent reviews of Brønsted acid catalysts, see: (a) Akiyama, T.
Chem. Rev. 2007, 107, 5744. (b) Rueping, M.; Kuenkel, A.; Atodiresei, I.
Chem. Soc. Rev. 2011, 40, 4539. (c) Rueping, M.; Nachtsheim, B. J.;
Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706.
(d) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc.
Rev. 2012, 41, 2406.
(7) For a recent study of kinetic resolution in the enantioselective
hydroboration of racemic allenylboronate (()-1 with diisopinocam-
pheylborane, see: Han, J.-L.; Chen, M.; Roush, W. R. Org. Lett. 2012,
14, 3028.
(8) The synthesis of these reagents have generally been derived from
the SN20 substitution of enantioenriched propargyl alcohol derivatives
or enantioselective hydrometalation of enynes amongst other methods;
see refs 2a and 3.
(6) Chen, M.; Roush, W. R. J. Am. Chem. Soc. 2012, 134, 10947.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Kinetic Resolution/Allenylboration Reactions of Hydrocinnamaldehyde Using Racemic Allenylboronate (()-1 and Chiral
Acid (R)-2a
temp
time
(h)
(R)-2
(()-1
(equiv)
entry
solvent
(°C)
(mol %)
dsb
yieldc
% eed
1
2
3
4
5
6
7
toluene
toluene
toluene
CH2Cl2
Et2O
55
23
24
24
24
24
38
24
16
0%
5%
5%
5%
5%
5%
10%
1.1
2.1
2.1
2.1
2.1
2.8
2.8
3.5:1
10:1
20:1
11:1
6:1
90%
92%
92%
89%
63%
89%
93%
ꢀ
71
78
80
49
84
90
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ50
toluene
toluene
20:1
20:1
a Reactions were performed with 0.15 mmol of aldehyde at a concentration of 0.2 M. b Product diastereoselectivities were determined by 1H NMR
analysis of the crude reaction mixture. c Combined isolated yield of both diastereomers. d Enantioselectivity of the major product was determined by
Mosher ester analysis.9
analysis.9 To confirm that the reaction indeed proceeded
via the kinetic resolution pathway, the remaining allenyl-
boronate was isolated and subjected to the uncatalyzed
allenylboration with hydrocinnamaldehyde. The homo-
propargyl alcohol product obtained from the reaction is a
3.5:1 mixture of anti- and syn-diastereomers ent-3a and
ent-4a. The enantiomeric excess of both diastereomers
obtained from this experiment was 60% ee.
When the allenylboration reaction of (()-1 and hydro-
cinnamaldehyde was performed in toluene atꢀ30 °C in the
presence of 5 mol % of catalyst (R)-2, anti-homopropargyl
alcohol 3a was obtained with 20:1 diastereoselectivity and
78% ee (entry 3). A solvent screen showed that while di-
chloromethane was a competent solvent (entry 4), reactions
performed in toluene provided better diastereoselectivity
with nearly equivalent enantioselectivity. Coordinating sol-
vents, such as diethyl ether, were detrimental (entry 5). In-
creasing the equivalents of allenylboronate (()-1 used in the
reaction to 2.8 equiv resulted in improved enantioselectivity
(84% ee; entry 6). Finally, by increasing the catalyst loading
to 10 mol % and by performing the reaction in toluene at
ꢀ50 °C for 16 h, the allenylboration reaction provided
homopropargyl alcohol 3a in 93% yield with 20:1 diaster-
eoselectivity and 90% ee (entry 7).
Figure 1. Kinetic resolution/allenylboration reactions of repre-
sentative aldehydes with allenylboronate (()-1. Reactions were
allenylboration of hydrocinnamaldehyde were then ap-
The conditions developed for the kinetic resolutionꢀ
performed with 0.2 mmol of aldehyde at a concentration
plied to the reactions of a variety of representative achiral
of 0.2 M. Product diastereoselectivities were determined by
1H NMR analysis of the crude reaction products. The combined
isolated yield of both diastereomers is provided. The enantio-
meric purity of the major product was determined by Mosher
aldehydes; the results of these experiments are summarized
in Figure 1. Unhindered aliphatic and R,β-unsaturated
aldehydes provided homopropargyl alcohols 3aꢀc with
ester analysis.9
excellent diastereo- and enantioselectivities. The homo-
propargyl alcohols derived from a range of substituted
aromatic aldehydes were obtained in 86ꢀ93% yield with
9ꢀ15:1 diastereoselectivities and 95% ee (3fꢀh). High
diastereoselectivities were obtained for the reactions lead-
(9) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
ingto3dand 3e; however, theenantioselectivitieswereonly
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
moderate in these cases (73ꢀ77% ee).
Org. Lett., Vol. XX, No. XX, XXXX
C

To further evaluate the synthetic utility of this kinetic
resolutionꢀallenylboration procedure, the allenylboration
reaction with the chiral, nonracemic aldehyde 5 was ex-
plored (Scheme 3). When the allenylboration of aldehyde 5
with 2.8 equiv of racemic 1 was performed in the presence
of 10 mol % of acid catalyst (S)-2, an 8:1 mixture of
homopropargyl alcohols 6 and 7 was obtained, favoring
the anti,anti-homopropargyl alcohol 6. This result demon-
states an exceedingly simple means to generate the anti,
anti-stereotriad from the racemic allenylboronate (()-1.10
Scheme 4. Kinetic Resolution/Allenylboration Reactions with
Racemic Allenylboronates 8 and 9
Scheme 3. Allenylboration of Chiral Aldehyde 5
kinetic resolutionꢀallenylboration reactions of substrates
such as (()-8 and (()-9.
In summary, we developed a chiral Brønsted acid cata-
lyzed kinetic resolutionꢀallenylboration reaction of race-
mic allenylboronate (()-1. When performed in the
presence of 10 mol % of acid (R)-2, the kinetic resolu-
tionꢀaldehyde allenylboration reaction of (()-1 provided
anti-homopropargyl alcohols 3 in 83ꢀ95% yield with 9:1
to 20:1 diastereoselectivity and 73ꢀ95% ee. The kinetic
resolution of racemic allene (()-1 and its controlled dia-
stereofacial addition to a chiral aldehyde was exemplified
by the chiral Brønsted acid catalyzed allenylboratin of 5,
which provided the anti,anti-homopropargyl alcohol 6
with 8:1 selectivity. Synthetic applications of this metho-
dology will be reported in due course.
Finally, racemic allenylboronates (()-8 and (()-9 were
tested in this kinetic resolutionꢀallenylboration reaction
sequence (Scheme 4). By using the conditions determined
to be optimal in our studies of the kinetic resolutionꢀ
allenylboration reactions of (()-1, the allenylboration of
hydrocinnamaldehyde with allene (()-8 provided a 6.5:1
mixture of homopropargyl alcohols 10 and 11 with a
terminal alkyne unit in 85% yield and 73% ee. Similarly,
the allenylboration of hydrocinnamaldehyde with allene
(()-9 (2.8 equiv) and 10 mol % of catalyst (R)-2 at ꢀ10 °C
afforded homopropargyl alcohols 12 and 13 in 78% yield
with 10:1 diastereoselectivity and 67% ee. These results
suggest that further optimization may be required in order
to achieve high diastereo- and enantioselectivity in the
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436 and CA162504)
is gratefully acknowledged. We thank Eli Lilly for a Graduate
Fellowship to M.C.
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Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX