Organic Letters
Letter
would avoid coordination to the more sterically hindered face
of a substituted cycloalkene, allowing for the stereoselective
synthesis by syn addition of the diboron reagent to the alkene.
In this study, we accomplish this with the use of catalytic
Pt(dba)3, incorporating substituted cyclopentane motifs and
both substituted and unsubstituted heterocycles into the Pt-
catalyzed diboration substrate scope.
Scheme 3. Pt(dba)3-Catalyzed Diboration of Cyclic
Alkenes
a
Initial studies employed the conditions originally established
by Miyaura and coworkers2a and focused on diboration of a
scaffold derived from cis-4-acetoxy-2-cyclopenten-1-ol (1) to
give 3, a derivative of a known building block for the synthesis
of carbocyclic nucleosides and prostaglandins (Table 1).10
Table 1. Impact of Reaction Conditions on the Diboration
of Functionalized Cyclopentenes
entry
R
equiv X
equiv Y
Pt(dba)3 (%)
% yield
1
2
3
4
H
1.5
1.5
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.2
1.2
3
3
0.5
0.5
0.5
0.5
<15
88
82
95
99
98
TBS
TBS
TBS
TBS
TBS
a
5
b
6
a
b
Reaction conducted in open atmosphere for 18 h. Reaction
a
Yields refer to isolated yield of purified material and are an average of
conducted in open atmosphere for 6 h.
two experiments. Diastereomer ratios were determined by analysis of
b
the crude NMR spectra. This product was oxidized prior to
purification because the alkene and the diboron product coelute.
Whereas initial experiments employing the unprotected
alcohol 1 resulted in low conversion (entry 1), masking of
the hydroxyl as a silyl ether (2) allowed for a successful
reaction. With a 3 mol % loading of Pt(dba)3 and
bis(pinacolato)diboron as the limiting reagent, an 88% isolated
enhanced by replacement of the benzyl ether with a more
sterically incumbered silyl ether (7). In a further examination
of this catalytic system, diboration of unsubstituted, mono- and
disubstituted 3-pyrroline derivatives could be accomplished
(10−13) in yields of 35−74% with diastereoselectivity of up to
>20:1. Notably, product 13, originating from an α,β-
unsaturated lactam, was formed exclusively as the mono-
boronic ester, with the α-boronic ester presumably undergoing
protodeborylation during workup or isolation. 2,5-Dihydrofur-
an substrates were also acceptable reaction partners.
Compound 15 containing an ester substituent was formed in
useful yield with high diastereoselectivity. These conditions
could also be applied to bicyclic substrates, delivering diboron
16 from Vince lactam by diboration of the less hindered face of
the bicycle.11 Bicyclic structures containing nitrogen (17) and
oxygen (18) heteroatoms could also be prepared with high
diastereoselectivity, although the yield for 18 was lowered due
to the competitive formation of naphthalene. So far, diboration
of cyclic enol ethers (i.e., 2,3-dihydrofuran) has been
ineffective.
Aspects of the diboration that pertain to practical preparative
synthesis utility were examined. First, an experiment was
conducted on the multigram scale, with all reagents handled in
an open atmosphere and without taking precautions to exclude
air and moisture during the course of the reaction. As depicted
in Scheme 4a, under these conditions, compound 7 could be
delivered in 74% yield on a scale that furnished 2.17 g of the
diboration product. In a second set of experiments (Scheme
4b), we probed the utility of a heterogeneous Pt catalyst for the
diboration reaction. These catalysts may be recoverable, and
1
yield of the diboration product 4 was obtained, and H NMR
analysis revealed the product to arise by a >95% trans addition
of the two boron groups relative to the pre-existing
substituents (entry 2). It was also found that the catalyst
loading could be lowered to 0.5 mol % with minimal reduction
in yield (entry 3). When the reaction was conducted with
bis(pinacolato)diboron in excess relative to the alkene
substrates, the reaction yield was increased, thereby allowing
for the more efficient transformation of the precious alkene
substrate (entry 4). Shortening the reaction time to 6 h and
conducting the reaction without an inert argon atmosphere
(entries 5 and 6, under air) were shown to have a minimal
impact on the isolated yield, allowing for a glovebox-free
operation.
When the conditions established in Table 1 were applied to
a range of alkenes, it was found that a variety of different
structures could undergo diboration efficiently and with good
selectivity. As depicted in Scheme 3, the reaction could
accommodate a variety of five-membered cyclic and bicyclic
compounds. For cyclopentene-derived compounds, tetrasub-
stituted diboration products were formed with yields ranging
from 60 to 98% and include functional groups such as silyl
ether and acetoxy groups (4), esters (5, 12, 15), a protected
hydroxymethyl group (6, 7), and a carbamate. Whereas
product 6 was formed with reduced stereoselectivity (4:1 dr)
compared with the others, it was discovered that the
stereoselectivity in the production of this scaffold could be
2864
Org. Lett. 2021, 23, 2863−2867