Catalytic enantioselective 1,2-diboration of 1,3-dienes: Versatile reagents for stereoselective allylation

Article abstract of DOI:10.1002/anie.201105716

More with boron: The development of catalytic enantioselective 1,2-diboration of 1,3-dienes enables a new strategy for enantioselective carbonyl allylation reactions (see scheme). These reactions occur with outstanding levels of stereoselection and can be applied to both monosubstituted and 1,1-disubstituted dienes. The carbonyl allylation reactions provide enantiomerically enriched functionalized homoallylic alcohol products. Copyright

Full text of DOI:10.1002/anie.201105716

Angewandte
Chemie
DOI: 10.1002/anie.201105716
Asymmetric Catalysis
Catalytic Enantioselective 1,2-Diboration of 1,3-Dienes: Versatile
Reagents for Stereoselective Allylation**
Laura T. Kliman, Scott N. Mlynarski, Grace E. Ferris, and James P. Morken*
Polyketides are an important class of natural products that
often possess potent biological activity and intriguing chem-
ical structures. Among the methods for constructing these
ensembles, the stereoselective addition of allyl metal
reagents[1]—particularly allyl boron reagents[2]—to prochiral
carbonyls holds particular prominence. With Type I allylation
reagents,[3] which react through closed transition states, this
reaction not only delivers functionality that is strategically
Scheme 1. Strategy for chain-extending polyketide synthesis using
1,2-diboration of 1,3-dienes.
positioned for establishing appropriate oxygenation patterns,
but its stereochemical predictability allows ready access to
acetate, propionate, and isobutyrate synthetic equivalents. A
limitation of many allylation reactions, however, is that they
deliver products bearing a terminal alkene; if one desires
additional substitution or functionality on the olefin, addi-
tional synthetic manipulations are often required.[4] In this
regard, the vinylogous aldol reaction has proven particularly
important as it delivers enoate-derived homoallylic alcohols.
Unfortunately, even with the tremendous emphasis placed on
the development of catalytic enantioselective vinylogous
aldol reactions, an efficient syn-selective asymmetric propio-
nate version is still unavailable, as is a version that delivers
quaternary centers.[5] Herein, we document the first examples
of the enantioselective catalytic 1,2-diboration of 1,3-dienes
(Scheme 1). As depicted in Scheme 1, the 1,2-diboration of
1,3-dienes delivers allyl boron reagents (A) that are perfectly
configured to participate in highly selective allylation reac-
tions.[6–8] Importantly, with an appropriate oxidative work-up,
these reactions deliver vinylogous aldol equivalents that
directly address the above-described synthesis limitations.
Also of significant consequence, is that the allyl boron in the
allylation product B may be subject to other useful bond-
forming reactions,[9] which allow for chain-extending poly-
ketide synthesis.
that furnished the desired 1,2-diboration, the selectivity was
suboptimal. A more reliable strategy for obtaining the 1,2-
diboration product was to replace the trans-diene substrate
with cis-1,3-dienes. This approach furnished 1,2-diboration
products (3:1 to > 20:1 1,2/1,4 selectivity) across a range of
substrates and generally occurred with excellent enantio-
selection. After optimization, the ligand structures and
reaction conditions depicted in Scheme 2 were found to be
optimal. With respect to polypropionate synthesis, the
diboration of cis pentadiene is paramount and this was
found to occur in excellent enantioselectivity (95:5 e.r.) and
good yield with ligand L2 (Scheme 2; 1).[13] Aside from the
phenyl-substituted diene, all other cis dienes examined
reacted with outstanding enantiocontrol when employing
ligand L1. The diboration of 1,1-disubstituted dienes employ-
ing ligand L3 occurred with uniformly high levels of
stereocontrol (compounds 9–14). Notably, allylic silyl ethers
do not engage in allylic borylation under the reaction
conditions and tethered alkenes do not appear to perturb
the reaction in a detrimental way.
Significant features of the 1,2-bis(boronate) resulting
from the diboration of cis-1,3-dienes are an embedded a-
chiral allylboronate and a cis alkene. According to the
seminal studies by Hoffmann and co-workers, it was antici-
pated that these features would render allylation reactions
highly selective.[14] In an initial experiment, commercially
available cis-piperylene was subjected to catalytic diboration
with [Pt(dba)3] and the ligand L2 in THF. The solvent was
then removed in vacuo, CH2Cl2 added, and benzaldehyde
introduced to the reaction mixture. Upon oxidative work-up,
the allylation product was obtained in moderate yield upon
isolation (48%); however, the stereoisomeric purity was
excellent (> 20:1 syn/anti, 94:6 e.r.). Examination of the
unpurified reaction mixture revealed significant amounts of a
bis(allylation) product presumably arising from addition of
the initial adduct 15 (Table 1) to a second equivalent of
aldehyde. To minimize the amount of bis(allylation), the
diboration was executed on a scale that delivered a twofold
To develop the catalytic synthesis strategy in Scheme 1,
efforts were first extended toward the development of an
enantioselective 1,2-diboration of terminal dienes.[10] A recent
study in our laboratory showed that enantioselective 1,4-
diboration of trans-1,3-dienes could be accomplished with
[Pt(dba)3] and a chiral phosphonite ligand.[11,12] Although
evaluation of alternate phosphorous donors revealed ligands
[*] L. T. Kliman, S. N. Mlynarski, G. E. Ferris, Prof. Dr. J. P. Morken
Department of Chemistry, Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: morken@bc.edu
[**] We are grateful to the NIH (NIGMS GM-59417) and the NSF (DBI-
0619576, BC Mass. Spec. Center; CHE-0923264, BC X-ray Facility)
for support, and to AllyChem for a donation of B2(pin)2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105716.
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Table 1: Asymmetric allylboration of carbonyl groups.[a]
Entry
1
Product
Yield [%][b]
71
e.r.[c]
94:6
es[d]
98
16
17
18
19
20
21
22
2
3
4
5
6
7
66
64
66
72
62
72
94:6
95:5
96:4
94:6
93:7
94:6
98
>99
>99
98
96
98
8
9
23
24
90
68
97:3
96:4
>99
>99
Scheme 2. Catalytic enantioselective 1,2-diboration of 1,3-dienes. Reac-
tions carried out at 608C for 12 h, with subsequent oxidation using
30% H2O2 and 3m NaOH for 4 h. For products 1–8, 3 mol% of
[Pt(dba)3], 6 mol% of ligand, and THF were employed. For products
9–14 3 mol% of [Pt(dba)3] and 3.6 mol% of ligand employed. Yield is
that of the purified 1,2-diol (average of two experiments). Enantiomeric
purity determined by GC analysis of a derivative employing a chiral
stationary phase (see the Supporting Information for details). dba=di-
benzylideneacetone, pin=pinacol, TBDPS=tert-butyldiphenylsilyl.
[a] Diboration reaction carried out at 608C for 12 h with ligand L2 for
entries 1–7 and ligand L1 for entries 8 and 9; allylation at room
temperature for 12 h with 2:1 ratio of diboron to aldehyde; oxidation with
30% H2O2 and 3m NaOH for 12 h. [b] Percent yield of purified material
(average of two experiments). [c] Enantiopurity determined by GC or SFC
analysis employing a chiral stationary phase. [d] Enantiospecificity (es)
calculated as follows: (%ee allylation product/%ee diboration prod-
uct)*100. The values of ꢀ100% for entries 4 and 8, are likely a result of
error in the measurement of the e.r.
excess of 1,2-bis(boronate) relative to the aldehyde. This
strategy provided good yields of the monoallylation product
for a range of aldehyde substrates (Table 1). As might be
expected, the allylation products were found to possess syn-
relative stereochemistry (> 20:1 in all cases) and the product
alkene was found to be in the trans configuration. With
respect to synthetic utility, it is significant that aromatic,
aliphatic, and a,b-unsaturated aldehydes (entries 1–5) all
participate and the level of chirality transfer from the
allylboronate is excellent. Other notable features are that a-
branched aldehydes react (entry 6) as do those that bear
a oxygenation (entries 7–9). Importantly, the regioisomeric
1,4-diboration product is not only less reactive in allylation
reactions, but any derived allylation product is easily removed
by silica gel chromatography. A stereochemical model that
correlates reactant configuration with product configuration
is depicted as TS-1 (Table 1). Most likely to avoid an A1,3
interaction with the cis substituent, the CH2B(pin) occupies
an equatorial position in the chairlike transition structure.
Bond reorganization then delivers the observed enantiomer
of product with syn stereoselection and with a trans alkene.
As exemplified by the production of the compounds 9–14
(Scheme 2), 1,2-diboration of 1,1-disubstituted dienes occurs
with excellent selectivity. Similar to the case of cis dienes, it
was anticipated that the intermediate bis(boronate) esters
would participate in highly selective carbonyl allylation
reactions. However, with 1,1-disubstitued dienes, the overall
reaction sequence would furnish products bearing all-carbon
quaternary centers.[15,16] Notably, the added steric encum-
brance of these allylation products appeared to diminish the
rate of secondary allylation such that high yields were
obtained even when equimolar amounts of diene, B2(pin)2,
and aldehyde were employed (Scheme 3). Also worth men-
tion is that both the diboration and the allylation reactions
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Scheme 4. Diboration/allylation/functionalization sequence. TBAF=
tetra-n-butylammonium fluoride.
furnished the allylic alcohol 27. Alternatively, subsequent to
the allylation reaction, the intermediate allylboronate was
subjected to homologation according to the protocol from
Sadhu and Matteson [Eq. (2)].[17a] This reaction delivered the
homoallylic alcohol 39, also in excellent yield and stereo-
selection. Lastly, it was found that the allylboronation
product, when subjected to protodeboronation conditions
similar to those described by Aggarwal and co-workers,[9d] was
converted into the simple alkene product 40 [Eq. (3)]. In this
case, the protonation event occurred predominantly by an
SE2’ pathway and delivered the bis(homoallylic) alcohol 40 as
the major product. Considering the range of transformations
that are available to organoboronates, and the fact that the
diboration/allylation sequence occurs cleanly in aprotic
solvent, allylation intermediates may be directly transformed
into a number of other useful building blocks.
Scheme 3. Asymmetric allylboration of carbonyls groups with g,g-
disubstituted allylboronates. Diboration reaction carried out at 608C
for 12 h with ligand L3 and with [substrate]=1.0m in toluene.
Allylations were conducted at 608C for 24 h with 1 equiv of aldehyde
relative to diene and B2(pin)2. Oxidation conducted with 30% H2O2
and 3m NaOH for 4 h. Yield is that of purified material (average of
two experiments). Enantiomer ratio determined by HPLC or SFC
analysis employing a chiral stationary phase. [a] Used 3 equiv of
iPrCHO.
In conclusion, we have described the catalytic enantio-
selective 1,2-diboration of 1,3-dienes and have found that the
1,2-bis(boronate) products can be employed in versatile
stereoselective allylation reactions and deliver a range of
functionalized chiral building blocks. Additional studies on
the use of these reactions in complex molecule synthesis are in
progress and will be reported in due course.
proceeded cleanly in toluene solvent and this allowed the
entire sequence to be accomplished in a single flask without
solvent-swapping operations. Of particular note, either dia-
stereomer of the product could be obtained in excellent yield
and enantioselectivity simply by employing the appropriate
diastereomer of diene substrates. For example, whereas
diboration/allylation employing the neral-derived diene 38
furnished product 26 in excellent selectivity, diboration/
allylation employing the geranial-derived diene 37 delivered
diastereomer 27 with excellent levels of stereocontrol. Similar
observations were made with the propionaldehyde-derived
products 28 and 29.
An attractive feature of the synthesis strategy described
above is that the allylation product can be subjected to bond-
forming reactions other than oxidation. As depicted in
Scheme 4 [Eq. (1)], when diene 37 was subjected to dibora-
tion and then employed in an allylation, oxidative work-up
Received: August 12, 2011
Published online: December 1, 2011
Keywords: allylation · asymmetric catalysis · boron ·
.
enantioselectivity · synthetic methods
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