Scandium-catalyzed allylboration of aldehydes as a practical method for highly diastereo- and enantioselective construction of homoallylic alcohols

Article abstract of DOI:10.1021/ja036807j

A general approach for the allylation of aldehydes using stable, air-tolerant camphor-based chiral allylboronates under Sc(OTf)₃ catalysis is described. This practical methodology provides both syn and anti propionate units and other homoallylic alcohols with very high levels of diastereo- and enantioselectivity for several substrates, including functionalized aliphatic aldehydes useful toward the elaboration of complex natural products. Copyright

Full text of DOI:10.1021/ja036807j

Published on Web 08/05/2003
Scandium-Catalyzed Allylboration of Aldehydes as a Practical Method for
Highly Diastereo- and Enantioselective Construction of Homoallylic Alcohols
Hugo Lachance, Xiaosong Lu, Michel Gravel, and Dennis G. Hall*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada
Received June 20, 2003; E-mail: dennis.hall@ualberta.ca
Carbonyl allylation chemistry is one of the most useful tools in
modern organic synthesis.1 Despite extensive investigations, there
is yet no general method using simple and stable allylation reagents
for the stereocontrolled formation of a wide variety of homoallylic
alcohol products (eq 1). Of particular significance is the challenging
Figure 1. Chiral allylboronates evaluated for enantioselective Lewis acid-
catalyzed additions onto aldehydes.
problem of controlling both diastereo- and enantioselectivity in
aldehyde crotylation, a process allowing the elaboration of syn and
anti propionate units ubiquitous in several classes of natural products
(eq 1, R1,R2 ) H,CH3 or CH3,H). Reagents of boron, silicon, and
tin have emerged as the most popular crotyl transfer agents for
achiral aldehydes.1 The most stereoselective methods,2-9 however,
suffer from one or many drawbacks such as air or moisture
sensitivity, the need for a multistep preparation of chiral reagents,
or incompatibility with aliphatic aldehydes. Thus, the search
continues for an efficient, practical solution to the problem of
stereoselective aldehyde crotylation and allylations in general.
We10 and others11 have recently reported the first examples of
metal-catalyzed additions of allylboronates. Further to the remark-
able rate enhancement, there are significant implications to the fact
that this novel catalytic manifold preserves the diastereospecificity
of uncatalyzed allylborations. These findings pave the way to the
development of more effective methods to access aldol-like adducts
with high enantiocontrol. Herein, we describe a general approach
for the allylation of aldehydes using stable, air-tolerant chiral
allylboronates under Sc(OTf)3 catalysis. This practical methodology
provides both syn and anti propionate units and other homoallylic
alcohols with very high diastereo- and enantioselectivity for several
substrates, including functionalized aliphatic aldehydes useful
toward the elaboration of complex natural products.
There are no chiral allylboronic esters known to afford practical
levels of enantioselectivity (>95% ee) in additions to achiral
aldehydes under typical low-temperature conditions (-78 °C).1 On
the basis of the potential beneficial effect of a lower reaction
temperature and the different mechanistic nature of the metal-
catalyzed manifold on the enantioselectivity, we planned to revisit
a number of known chiral diol auxiliairies for boronic acids. At
the outset, the allylation of benzaldehyde was investigated using
different solvents, temperatures, and Lewis acids identified from
our previous studies.10 A small set of allylboronates 1 derived from
chiral diol precursors a-e was compared under these variables
(Figure 1).
Table 1. Lewis Acid-Catalyzed Allylboration of Benzaldehydea
temp
(°C)
time
(h)
conv.d
(%)
ee e
(%)
entry
boronate
L. A.b
none
AlCl3
TiCl4
solvent c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
hexanes
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
-78
-78
-78
-40f
-40f
-78
-78
-78
-78
-78
-78
0
72
2
2
2
2
2
2
2
2
2
2
2
2
50
14
22
72
4
11
63
78
84
52
38
92
46
8
TfOH
Cu(OTf)2
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
4
90
30
20
62
100
100
0
9
10
11
12
13
84g
9
7
-
a
Reaction scale: approximately 0.4 mmol (>100 mg) of (-)-1 (1.1
b
c
equiv), and PhCHO (1 equiv). Lewis acid, 10 mol %. Typically 0.5 M
d
concentration in allylboronate. Measured by integration of representative
signals by 1H NMR on crude product obtained after an appropriate workup.
e
f
Measured by chiral HPLC (see Supporting Information for details).
No reaction observed at -78 °C. Opposite enantiomer is predominant.
g
efficient one both in terms of conversion and ee (entries 7-9).
Whereas pinanediol-derived 1c and the tartrate-based reagents 1d12
and 1e13 gave disappointing results (entries 11-13), the Hoffmann
camphor-based allylboronates 1a and 1b14 gave high enantioselec-
tivities under Sc(OTf)3 catalysis (entries 7, 10). Further optimization
confirmed that molecular sieves are not required and that the
preferred order of addition involves mixing the aldehyde with
Sc(OTf)3 in CH2Cl2 at -78 °C, followed by the allylboronate.
Developed more than two decades ago, the Hoffmann camphor-
based allylboronates were the first chiral allylboron reagents ever
reported.14 The advantages of the new, low-temperature catalytic
manifold are remarkable. In the absence of a catalyst (e.g., entry
1), 1a and 1b are unreactive at -78 °C and afford modest ee’s
(<75%) at higher temperatures.14 Interestingly, the diol precursor
of our most effective allylboronate, 1a, has been by far the least
Using allylboronate (-)-1a, these investigations revealed that
Sc(OTf)3 is significantly more active than other Lewis acids and
provided the highest enantiomeric excess in the formation of
homoallylic alcohol 5 (Table 1, entries 1-7). A pronounced solvent
effect was observed, with dichloromethane standing out as the most
9
10160
J. AM. CHEM. SOC. 2003, 125, 10160-10161
10.1021/ja036807j CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope for the Sc(OTf)3-Catalyzed
Enantioselective Addition of Allylboronates 1a-4a with Model
Aldehydesa
utility as early intermediates in the synthesis of complex natural
products. To demonstrate the potential of this methodology in
practical-scale preparation, the reaction of entry 9 was carried out
with a gram quantity of 2a. Using only 5 mol % of Sc(OTf)3,
alcohol 13 was obtained in a satisfying 71% yield and 96% ee.
To the best of our knowledge, this method represents the most
effective system for enantioselective methallyl transfer onto alde-
hydes,16 which suggests that a new generation of highly enanti-
oselective â-substituted allylating agents could be developed.
At this time, the precise mechanistic nature of this Lewis acid-
catalyzed process and the mode of stereoinduction are unknown.
On the basis of preliminary arguments presented earlier10 and the
fact that the diastereospecificity of the noncatalyzed reaction is
preserved, the allylboration is thought to proceed via the usual cyclic
transition state, with electrophilic boron activation by metal
coordination to the boronate oxygens.
In conclusion, we have reported a remarkably general and
practical aldehyde allylation methodology based on the Sc(OTf)3-
catalyzed reaction of stable chiral allylboronates. This approach is
unrivaled in many ways, in particular, its efficient control of both
diastereo- and enantioselectivity. We anticipate that this new metal-
catalyzed allylboration process will find use in the synthesis of
complex natural products, thereby giving new life to the camphor-
based allylboronates.
allylboronate
(R , R , R )
aldehyde
(R )
yield c
(%)
ee d
(%)
1
2
3
4
entry
product b
1
2
3
4
5
6
7
8
1a (H, H, H)
1a
1a
1a
1a
1a
2a (H, H, Me)
2a
2a
2a
Ph
5
6
7
8
85
64
86
62
76
61
64
76
77
70
90
60
71
63
74
53
52
57
57
92
97
93
77
90
90
98
97
97
97
95
97
96
94
95
59
96
96
96
PhCH2CH2
TBDPSOCH2CH2
BnOCH2
TBDMSOCH2
TBDPSOCH2
Ph
PhCH2CH2
TBDPSOCH2CH2
BnOCH2
TBDMSOCH2
Ph
PhCH2CH2
TBDPSOCH2CH2
TBDMSOCH2
Ph
PhCH2CH2
TBDPSOCH2CH2
TBDMSOCH2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
9
10
11
12
13
14
15
16
17
18
20
2a
3a (Me, H, H)
3a
3a
3a
4a (H, Me, H)
4a
4a
4a
Acknowledgment. This work was funded by the Natural
Sciences and Engineering Research Council (NSERC) of Canada
and the University of Alberta. H.L. thanks the Alberta Ingenuity
Fund, and M.G. thanks NSERC and the Alberta Heritage Founda-
tion for Medical Research (AHFMR) for graduate scholarships. The
authors thank Dr. Jason Kennedy for helpful advice and discussions.
a
Standard conditions: reaction scale: approximately 0.4 mmol of
aldehyde in CH2Cl2 (0.4-0.6M) with 10 mol % Sc(OTf)3 at -78 °C
followed by addition of allylboronate (entries 1-10: 1.1 equiv, entries 11-
14: 1.5 equiv). Entry 15 is with 3 equiv of aldehyde, entries 16-20 are
b
with 1.5 equiv of aldehyde. Reaction times: 12-24 h. The dr for 16-23
1
c
was always over 49:1 (determined by H NMR). Unoptimized yields of
Supporting Information Available: Full experimental details,
characterization data, and spectral reproduction for all compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
d
pure products isolated after flash chromatography. Measured by chiral
HPLC on the free alcohol or a derivative thereof (see Supporting Information
for details), or through NMR analysis of Mosher esters (entries 3,5,9,11).
The absolute configuration was determined by comparison of optical rotation
with known compounds.
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