Highly (E)-selective BF3·Et2O-promoted allylboration of chiral nonracemic α-Substituted allylboronates and analysis of the origin of stereocontrol

Article abstract of DOI:10.1021/ol1007444

(Figure presented) δ-Methyl-substituted homoallylic alcohols 2 were prepared in 71-88% yield, E:Z >30:1 and 93% to >95% ee via BF ₃·Et₂O-promoted allylboration with α-Me-allylboronate 1. The origin of high (E)-selectivity is proposed

Full text of DOI:10.1021/ol1007444

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2706-2709
Highly (E)-Selective BF3·Et2O-Promoted
Allylboration of Chiral Nonracemic
r-Substituted Allylboronates and Analysis of
the Origin of Stereocontrol
Ming Chen and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458
roush@scripps.edu
Received March 30, 2010
ABSTRACT
δ-Methyl-substituted homoallylic alcohols 2 were prepared in 71-88% yield, E:Z >30:1 and 93% to >95% ee via BF3·Et2O-promoted allylboration
with r-Me-allylboronate 1. The origin of high (E)-selectivity is proposed.
The asymmetric carbonyl allylboration reaction is a valuable
method for C-C bond formation. In the vast majority of
cases that have been described, the asymmetric induction
derives from the use of chiral auxiliaries attached to boron.1,2
Although not as widely adopted in the literature, the addition
of enantioenriched R-substituted allylboronates to carbonyl
compounds is a useful alternative.3-5 Pioneered by Hoffmann
et al., carbonyl addition reactions of enantioenriched R-sub-
stituted allylboronates 3 proceed with near perfect chirality
(1) (a) Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1. (b) Denmark,
Figure 1. Competing transition states for carbonyl addition reaction
S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (c) Denmark, S. E.; Almstead,
N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; p 299. (d) Chemler, S. R.; Roush, W. R. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; p 403.
(e) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (f) Roush, W. R.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
of R-substituted allylboronates 3.
transfer.3,4 A mixture of (Z)- and (E)-homoallylic alcohols
4 and 5 can be generated from two competing transition states
TS-3 and TS-4 (Figure 1). The ratio of the two homoallylic
alcohols depends in part on the electronic property of the
Oxford, 1991; Vol. 2, p 1
.
(2) (a) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A. J. Am.
Chem. Soc. 2005, 127, 8044. (b) Canales, E.; Prasad, K. G.; Soderquist,
J. A. J. Am. Chem. Soc. 2005, 127, 11572
.
10.1021/ol1007444  2010 American Chemical Society
Published on Web 05/17/2010

group at the R-position. When the R-substituent is a polar
group,3 such as an alkoxy group or halogen atom, allylbo-
ration proceeds predominately via TS-3 to give (Z)-homoal-
lylic alcohol 4. Although the exact origin of the high (Z)-
selectivity remains unclear, several factors, including steric
effects, dipolar effects, and stereoelectronic minimization of
π-σ* delocalization in the transition states, have been
proposed3l and supported by computational studies.4s How-
workers, allylboration in the presence of a catalytic amount
of a chiral, nonracemic Lewis or Brønsted acid provides
homoallylic alcohols in high yields and excellent enantiose-
lectivities.8 However, Lewis or Brønsted acid promoted
allylboration with enantioenriched, R-substituted allylbor-
onates largely remains underdeveloped.9 Recently, Hall
reported the enantioselective synthesis and Lewis acid
promoted allylborations of R-TMSCH2-substituted allylbo-
ronates that generate (E)-δ-TMSCH2-substituted homoallylic
alcohols with excellent selectivities.9c
In connection with an ongoing problem in natural product
synthesis, we had occasion to explore Lewis acid promoted
allylborations of enantioenriched R-substituted allylboronates. We
found and report herein that (E)-δ-methyl-homoallylic alcohols 2
are obtained in good yields and excellent enantioselectivities from
BF3·Et2O-promoted allylboration reactions of 1.10 In addition, we
have found that δ-chloro-substituted homoallylic alcohols 14 can
also be obtained in good yield and 3-6:1 (E)-selectivity from
BF3·Et2O-promoted allylboration reactions of 13. The origin of (E)-
selectivity in these reactions is proposed.
ever, when the R-substitution is a nonpolar alkyl group,4,5
a
mixture of (Z)- and (E)-homoallylic alcohols 4 and 5 is often
obtained. Until recently,5l-n,9 synthetically useful selectivity
has proven challenging to achieve with enantioenriched
R-alkyl-substituted allyl- or (E)-crotylboronates.
Lewis or Brønsted acid promoted allylboration with allyl-
boronate reagents is an important emerging topic in carbonyl
allylation chemistry.6,7 As demonstrated by Hall and co-
(3) For carbonyl addition with R-hetero atom substituted allylboronates:
(a) Hoffmann, R. W.; Landmann, B. Tetrahedron Lett. 1983, 24, 3209. (b)
Hoffmann, R. W.; Landmann, B. Angew. Chem., Int. Ed. 1984, 23, 437
(c) Hoffmann, R. W.; Dresely, S. Angew. Chem., Int. Ed. 1986, 25, 189.
(d) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986, 119, 1039. (e)
Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986, 119, 2013. (f) Hoffmann,
R. W.; Dresely, S. Tetrahedron Lett. 1987, 28, 5303. (g) Hoffmann, R. W.;
Dresely, S.; Lanz, J. W. Chem. Ber. 1988, 121, 1501. (h) Hoffmann, R. W.;
Dresely, S.; Hildebrandt, B. Chem. Ber. 1988, 121, 2225. (i) Hoffmann,
R. W.; Dresely, S. Synthesis 1988, 103. (j) Hoffmann, R. W.; Dresely, S.
Chem. Ber. 1989, 122, 903. (k) Stu¨rmer, R.; Hoffmann, R. W. Synlett 1990,
759. (l) Hoffmann, R. W.; Wolff, J. J. Chem. Ber. 1991, 124, 563. (m)
Beckmann, E.; Hoppe, D. Synthesis 2005, 217. For synthetic applications:
(n) Andersen, M. W.; Hildebrandt, B.; Dahmann, G.; Hoffmann, R. W.
Chem. Ber. 1991, 124, 2127. (o) Andersoen, M. W.; Hildebrandt, B.;
Hoffmann, R. W. Angew. Chem., Int. Ed. 1991, 30, 97. (p) Hoffmann, R. W.;
Schlapbach, A. Tetrahedron 1992, 48, 1959. (q) Hoffmann, R. W.; Rohde,
T.; Haeberlin, E.; Schafer, F. Org. Lett. 1999, 1, 1713. (r) Hoffmann, R. W.;
Haeberlin, E.; Rohde, T. Synthesis 2002, 207.
R-Methyl-substituted allylboronate 8 was prepared from
methyl boronate 6,11 by using the Matteson homologation
(Scheme 1).12 Allylboration reactions of hydrocinnamaldehyde
with 8 are summarized in Table 1. The noncatalyzed reaction
provided a 1:1.4 mixture of ent-2a and 9 (entry 1). Similar
results were obtained when the reaction was performed in the
presence of 10% Sc(OTf)3 (entry 2). When the reaction was
(6) (a) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124,
11586. (b) Ishiyama, T.; Ahiko, T.; Miyaura, N. J. Am. Chem. Soc. 2002,
124, 12414. For computational studies: (c) Sakata, K.; Fujimoto, H. J. Am.
Chem. Soc. 2008, 130, 12519.
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Hoffmann, R. W.; Weidmann, U. J. Organomet. Chem. 1980, 195, 137. (b)
Andersen, M.; Hildebrandt, B.; Koester, G.; Hoffmann, R. W. Chem. Ber.
1989, 122, 1777. (c) Hoffmann, R. W.; Ditrich, K.; Koester, G.; Stu¨rmer,
R. Chem. Ber. 1989, 122, 1783. (d) Hoffmann, R. W.; Sander, T. Chem.
Ber. 1990, 123, 145. (e) Hoffmann, R. W.; Schlapbach, A. Liebigs Ann.
1991, 1203. For synthetic applications: (f) Ditrich, K.; Bube, T.; Stu¨rmer,
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R. W.; Ladner, W.; Ditrich, K. Liebigs Ann. 1989, 883. (h) Stu¨rmer, R.;
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69, 4412. (c) Rauniyar, V.; Hall, D. G. J. Am. Chem. Soc. 2004, 126, 4518.
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Rauniyar, V.; Hall, D. G. Synthesis 2007, 3421. (g) Rauniyar, V.; Zhai, H.;
Hall, D. G. J. Am. Chem. Soc. 2008, 130, 8481. (h) Rauniyar, V.; Hall,
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Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. J. Am. Chem. Soc.
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Org. Lett., Vol. 12, No. 12, 2010
2707

Scheme 1
.
Synthesis of Allylboronate 8
Table 2. Optimization for Allylboration Reactions with 1
entry
conditions
2a:ent-9a
yield (%)b
1
2
3
4
a
no catalyst, -78 °C to rt, 8 h
10% Sc(OTf)3, -78 °C to rt, 8 h
10% BF3·Et2O, -78 °C, 2 h
100% BF3·Et2O, -78 °C, 2 h
1
1.5:1
3:1
71
64
79
68
>30:1
>30:1
Based on H NMR analysis of the crude reaction mixture. b Yield of
isolated product(s).
carried out in the presence of either 10% or stoichiometric
BF3·Et2O, a 3:1 mixture of ent-2a and 9 was obtained (entries
3 and 4). Despite additional attempts to optimize this reaction,
we were unable to achieve synthetically useful selectivity in
allylboration reactions of 8.
Gratifyingly, when the reaction was carried out in the
presence of 10% BF3·Et2O, (E)-homoallylic alcohol 2a was
obtained as the only product (E:Z > 30:1) in 94% ee and
79% yield (entry 3).
As summarized in Table 3, BF3-mediated allylboration of
a variety of aldehydes using 1 proceeded with near perfect
Table 1. Optimization for Allylboration Reactions with 8
Table 3. Preparation of (E)-δ-Me-Homoallylic Alcohols 2a-2f
entry
conditions
ent-2a:9a
yield (%)b
1
2
3
4
a
no catalyst, -78 °C to rt, 8 h
10% Sc(OTf)3, -78 °C to rt, 8 h
10% BF3·Et2O, -78 °C, 2 h
100% BF3·Et2O, -78 °C, 2 h
1
1:1.4
1:1.5
3:1
67
63
78
71
3:1
Based on H NMR analysis of the crude reaction mixture. b Yield of
isolated mixture of products.
entry
RCHO
product
yield (%)a
ee (%)b
1
2
3
4
5
6
Ph(CH2)2CHO
PhCH2CHO
PhCHO
2a
2b
2c
2d
2e
2f
79
88
75
71
84
73
>95
>95
94
CyCHO
>95
93
Pinanediol is a useful chiral director for the Matteson
homologation.13 We hoped that allylboronate 1 would
provide access to the desired (E)-homoallylic alcohols with
excellent selectivity based on Hall’s work.9c Accordingly,
allylboronate 1 was prepared with high diastereoselectivity
from 10 (Scheme 2).14
BnO(CH2)2CHO
BnOCH2CHO
95
a Yield of isolated (E)-homoallylic alcohols. b Enantiomeric purity and
absolute stereochemistry of 2a-2f were determined by using the Mosher
ester analysis.15
chirality transfer. (E)-δ-Methyl-substituted homoallylic al-
cohols 2a-2f were obtained in 93% to >95% ee and
71-88% yield. The correspoding (Z)-isomers were not
detected in any of these experiments.
Scheme 2. Synthesis of Allylboronate 1
We suspect the high (E)-selectivity in these reactions
originates from minimization of 1,3-syn-pentane interactions
in the competing transition states.16 As shown in Figure 2,
it is conceivable that BF3 will coordinate to the lower lone
pair of electrons (in blue) of the oxygen atom distal to the
angular methyl group to minimize steric interactions.17 If
so, TS-1 is disfavored due to a 1,3-syn-pentane interaction
(11) (a) Matteson, D. S.; Man, H.-W. J. Org. Chem. 1994, 59, 5734.
(b) O’Donnell, M. J.; Cooper, J. T.; Mader, M. M. J. Am. Chem. Soc. 2003,
125, 2370.
Results of allylboration of hydrocinnamaldehyde with
reagent 1 are presented in Table 2. The reaction in the
absence of Lewis acid gave a 1.5:1 mixture of alcohols 2a
and ent-9 (entry 1). With the addition of 10% Sc(OTf)3, a
3:1 mixture of 2a and ent-9 was obtained (entry 2).
(12) (a) Midland, M. M.; Preston, S. B. J. Am. Chem. Soc. 1982, 104,
2331. (b) Tsai, D. J. S.; Matteson, D. S. Organometallics 1983, 2, 236.
(13) Matteson, D. S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590.
(14) (a) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem.
Soc. 1986, 108, 810. (b) Maurer, K. W.; Armstrong, R. W. J. Org. Chem.
1996, 61, 3106.
2708
Org. Lett., Vol. 12, No. 12, 2010

These data indicate that the strong preference of reagents
13 to react with aldehydes via a transition state analogous
to TS-5 (but lacking the BF3 ligand) can be overridden in
the presence of BF3·Et2O. As shown in Figure 3, TS-5 is
Figure 2. Competing transition states for BF3-catalyzed aldehyde
allylboration with R-methyl allylboronate 1.
between the pseudoaxial methyl group and the BF3 ligand;
this interaction is absent in TS-2. Accordingly, product
formation proceeds via TS-2 and homoallylic alcohols with
(E)-olefin geometry are obtained with excellent selectivity.
We were intrigued by the possibility that BF3·Et2O-
promoted aldehyde allylboration could be used to induce (E)-
selectivity with reagents that have much higher intrinsic
preference for positioning of the R-substituent in a pseudo-
axial position in the allylboration transition state. R-Chloro-
substituted allylboronates, such as 13, are known to give (Z)-
δ-chloro-substituted homoallylic alcohols, e.g., 15, with high
(Z)-selectivity in allylboration reactions.3
Figure 3. Competing transition states for BF3-catalyzed aldehyde
allylboration with R-chloro allylboronates 13.
disfavored owing to the 1,3-syn-pentane interaction. In the
competing (and now favored) transition state TS-6, the R-Cl
substitution is positioned in a pseudoequatorial arrangement
to minimize interactions with the chlorine substituent.
Ultimately, these reactions lead to the formation of (E)-
homoallylic alcohols 14 with 3-6:1 (E)-selectivity.
In summary, we have demonstrated the highly (E)-selective
allylboration of aldehydes with reagent 1 in the presence of a
catalytic amount of BF3·Et2O. (E)-δ-Methyl-substituted ho-
moallylic alcohols 2 were prepared in 71-88% yield and
excellent enantioselectivities. (E)-δ-Chloro-substituted homoal-
lylic alcohols 14 were also obtained in good yields and 3-6:1
(E)-selectivity from reagents 13a,b. We postulate that minimi-
zation of 1,3-syn-pentane interactions in the transition states is
responsible for the (E)-selectivity of these reactions.
The sensitive R-chloro-substituted allylboronates 13a and 13b
were synthesized, and their allylboration reactions were explored
(Table 4). The reaction of hydrocinnamaldehyde with 13a in
Table 4. Allylboration with R-Cl-Allylboronates 13
Acknowledgment. Financial support provided by the
National Institutes of Health (GM038436 and GM026782)
is gratefully acknowledged.
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.
yield
entry substrate
conditions
14:15a (%)b
OL1007444
1
2
3
4
a
13a
13b
13a
13b
1
No catalyst, -78 °C to rt, 24 h
No catalyst, -78 °C to rt, 24 h
10% BF3·Et2O, -78 °C, 24 h
10% BF3·Et2O, -78 °C, 24 h
1:12
1:10
6:1
72
70
63
52
(15) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
3:1
Based on H NMR analysis of the crude reaction mixture. b Yield of
(16) (a) Roush, W. R. J. Org. Chem. 1991, 56, 4151. For recent examples
where minimization of syn-pentane interactions plays an important role in
stereoselectivity: (b) Liu, J.; De Brabander, J. K. J. Am. Chem. Soc. 2009,
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Lett. 2006, 47, 3791.
isolated product(s).
the absence of BF3·Et2O provided (Z)-δ-chloro-homoallylic
alcohol 15a in 72% yield.18 Similarly, crotylboration with 13b
gave alcohol 15b in 70% yield.18 In both cases, high (Z)-
selectivity (g10:1) was observed, consistent with Hoffmann’s
report.3 However, when these reactions were performed in the
presence of 10% BF3·Et2O, reagent 13a provided a 6:1 mixture
of δ-chloro-homoallylic alcohols 14a and 15a,18 and reagent
13b provided a 3:1 mixture of alcohols 14b and 15b.18
(17) Coordination to the non-bonded electron pair (indicated in red) is
disfavored owing to a 1,3-interaction with the angular methyl group.
Coordination to the distal oxygen atom is disfavored for steric reasons.
(18) The enantiomeric purity of homoallylic alcohols 14 and 15 was
ca.15-30% ee, presumably due to epimerization of the R-chloro center
during preperations of reagents 13a and 13b. Matteson, D. S.; Erdik, E.
Organmetallics 1983, 2, 1083.
Org. Lett., Vol. 12, No. 12, 2010
2709