Palladium-catalyzed carbonyl allylation: Synthesis of enantiomerically pure α-substituted allylboronic esters

Article abstract of DOI:10.1055/s-0029-1217160

Palladium-catalyzed carbonyl allylation of stable alkenylboronic ester with SnCl₂ proceeded diastereoselectively to afford a-substituted allylboronic esters; the assignment of their configuration as well as allyl additions are presented. Georg

Full text of DOI:10.1055/s-0029-1217160

1474
LETTER
Palladium-Catalyzed Carbonyl Allylation: Synthesis of Enantiomerically Pure
a-Substituted Allylboronic Esters
Allylboronates nrique Fernández, Jörg Pietruszka*
Institut für Bioorganische Chemie , Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Im Stetternicher Forst,
Geb. 15.8, 52426 Jülich, Germany
Fax +49(2461)616196; E-mail: j.pietruszka@fz-juelich.de
Received 26 February 2009
Abstract: Palladium-catalyzed carbonyl allylation of stable alke-
Ph Ph
Ph Ph
nylboronic ester with SnCl2 proceeded diastereoselectively to af-
ford a-substituted allylboronic esters; the assignment of their
configuration as well as allyl additions are presented.
XO
O
O
O
O
O
O
O
O
B
B
B*
O
Key words: boron, allylation, asymmetric synthesis, allyl additions
Ph Ph
Ph Ph
1a X = H
1b X = Ms
Additions of allylboronic esters to carbonyl compounds
giving homoallyl alcohols is one of the most versatile
transformations in organic synthesis.1 Allylboronic esters
are nontoxic and easy to handle reagents that add to alde-
hydes passing through a predictable six-membered transi-
tion state, regularly inducing high selectivity. Particularly,
reagents with a stereogenic center a to the boronic moiety
often afford exceptionally high selectivity. The synthesis
of a-substituted allylboronates and their addition to alde-
hydes was pioneered by Hoffmann (Scheme 1).2 Different
B*
B*
R2
OH
R2
R1
R1
R1
R2CHO
R1
5
3
B*
OH
R1
R2
O
2a R1 = CH2CO2Et
2b R1 = CH(OH)R
R2
6
4
Scheme 1 Transition structures for the allyl addition of a-substitu-
methods have been reported for their synthesis.3 It was es- ted allylboronates 2 to aldehydes
tablished in our group that [3,3]-sigmatropic rearrange-
ment of the highly stable tartrate derivate 1a4 gives
OH
OH
allylboronic esters 2a with a stereogenic center a to boron.
Their addition to aldehydes gave homoallylic alcohols
with very high diastereo- and enantioselectivity forming
almost exclusively Z-isomers 3, with only minor amounts
of the E-isomer 4 detectable.3a–3d,5
1. MeLi, THF
2. 30% H2O2
B*
B*
OH
OH
7a
10
analytical
samples
OH
OH
1. MeLi, THF
2. 30% H2O2
The stereochemical course of the reaction depends on the
substituent in the a-position and the steric bulk of the bo-
ronic ester. The selectivity can be explained in terms of
steric and dipolar effects on the two competing transition
structures 5 and 6.2 In order to extend the approach, we
were interested in developing new a-substituted allylbo-
ronic esters 2 via the palladium-catalyzed carbonyl allyla-
tion reaction. This transformation has been extensively
investigated in the past few years.6 Particularly, the sys-
tem Pd0/SnCl2 proved to be very powerful, wherein SnCl2
is used as reducing reagent and various Pd2+ complexes as
catalyst.7 Herein, we report for the first time that interme-
diates 1b are indeed suitable precursors for the envisaged
reaction.
8a
ent-10
Scheme 2 Assignment of the configuration of boronic esters 7a and
8a by chemical correlation
mers 8a–f (anti) and 9a–f (syn) were detectable in most
cases, the phenyl-substituted reagent 7b was formed ex-
clusively. By increasing the amount of catalyst (from 2–5
mol%) and water (25 equiv), the reaction was accelerated
and conversion was complete after 2 hours instead of 20
hours, without any changes in the selectivity (Table 1).8
Water supports the hydrolysis of the Sn(IV)–Cl bond ac-
tivating the allyltin intermediate.9
In each case, the diastereoselectivity of the reaction was
estimated by examination of the 1H NMR spectrum of the
crude product. The configuration of the products was as-
signed by means of chemical correlations. Oxidation of 7a
and 8a (R1 = c-C6H11) gave the known10 diols 10 and ent-
10 (Scheme 2). The relative stereochemistry of the allyl
boronic esters 7 and 8 was also confirmed to be anti from
the J values for the CH(OH)CH(B) protons (3–6 Hz) in 1H
NMR spectrum. In contrast, the corresponding syn-
isomers 9 showed larger coupling constants (9–11 Hz) for
the CH(OH)CH(B) unit.
In analogy to a protocol reported by Takahara et al.,7f bo-
ronic ester 1b was treated with PdCl2(PhCN)2, SnCl2, and
DMF as solvent with different aldehydes, with anti-allyl-
boronic esters 7a–f being predominantly produced with
good yields and selectivity. While the minor diastereoiso-
SYNLETT 2009, No. 9, pp 1474–1476
x
x.
x
x.
2
0
0
9
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217160; Art ID: D06209ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Allylboronates
1475
mismatched interaction between the auxiliary (in B*) and
the configurations in the anti diastereomers thus leading
to preferred complementary facial attack to the aldehydes
with the a-substituent being in a pseudo-equatorial (7a) or
pseudo-axial (8a) position.
Table 1 Allylations with Boronic Ester 1b
OH
R1
syn
9
*B
OMs
PdCl2(PhCN)2
(5 mol%)
B*
+
OH
OH
R1
anti
1b
SnCl2
DMF–H2O
r.t., 2 h
Table 2 Addition of New Reagent 7a to Various Aldehydes
+
R1
R1CHO
B*
B*
8
7
7a
anti
1. R2CHO, CH2Cl2, 0 °C to r.t.
2. LiAlH4, THF, 1 h
Entry
R1
Yield (%)a
Ratio of 7/8/9b
78:18:4
a
b
c
d
e
f
c-C6H11
79
79
80
75
70
71
OH
OH
OH
R2
R2
Ph
100:0:0
+
OH
14
15
Ph(CH2)2
PhCHCH
Me2CH
75:18:7
Entry
R2
Yield (%)a Ratio (E/Z)b ee (%)c
89:11:0
a
b
c
c-C6H11
Ph
87
91
92
84:16
50:50
74:26
>99
>99
>99
78:22:0
Me2CHCH2
77:14:9
a Isolated mixture of diastereomers.
Ph(CH2)2
b As determined by 1H NMR spectroscopy.
a Isolated mixture of diastereomers.
b The ratio was determined by 1H NMR spectroscopy.
c Determined by the Mosher ester method.
SnCl2
OMs Pd0
*B
Sn(OX)3
*B
*B
H2O
1b
11
12
Pd+
Table 3 Addition of New Reagent 8a to Various Aldehydes
RCHO
H
8a
OH
R
1. R2CHO, CH2Cl2, 0 °C to r.t.
2. LiAlH4, THF, 1 h
Sn(OX)3
13
R
*B
O
OH
OH
OH
B*
7
R2
R2
+
Scheme 3 Proposed mechanism of the palladium-catalyzed allyla-
tion
OH
ent-14
ent-15
Entry
R2
Yield (%)a Ratio (E/Z)b ee (%)c
A plausible mechanism of the palladium-catalyzed allyla-
tion reaction is shown in Scheme 3. The principle of the
process relies on the transient formation of a h3-allyl pal-
ladium complex 11, which might be transformed into al-
lyltin intermediates 12 that would cause nucleophilic
attack to aldehydes furnishing homoallylic alcohols 7.
The carbonyl allylation reaction seems to proceed via a
six-membered transition state 13, with the carbonyl oxy-
gen coordinating to the Sn(IV) species leading to the anti
products 7.
a
b
c
c-C6H11
Ph
89
83
85
16:84
33:67
24:76
>99
>99
>99
Ph(CH2)2
a Isolated mixture of diastereomers.
b The ratio was determined by 1H NMR spectroscopy.
c Determined by the Mosher ester method.
In summary, the present study demonstrates that boronic
esters 1b can be applied in the palladium-catalyzed carbo-
nyl allylation of aldehydes producing a-substituted anti-
allylboronic esters 7 and 8; reagents 7a and 8a were dem-
onstrated to add to various aldehydes furnishing enediols
14 and 15. Further investigations are in progress demon-
strating the scope of the sequence and also evaluating the
precise nature for the change in facial selectivity during
the allyl additions.
The addition of 7 and 8 to different aldehydes produced 3-
alkene-1,5-diols with good yields (83–92%) and selectiv-
ity (dr up to 85:15, ee >99% for all diastereoisomers; Ta-
ble 2 and Table 3). The (R,S)-7a diastereomer gave
surprisingly selectively the E-isomers 14a–c, while dia-
stereomer (S,R)-8a produced the Z-isomers ent-15a–c.
The configuration of all diols 14 and 15 was determined
by comparison of the spectroscopic data observed with
those previously reported3k,l and by the Mosher ester
method.11 The configuration of the diols also indirectly
confirmed the assignment of the allylboronic esters 7 and
8. The observed results are a consequence of the matched/
Acknowledgment
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
for the generous support of our projects. Donations from the BASF
Synlett 2009, No. 9, 1474–1476 © Thieme Stuttgart · New York

1476
E. Fernández, J. Pietruszka
LETTER
AG, the Chemetall GmbH, and the Wacker AG were greatly appre-
ciated. We thank Colleen Kellenberger and Vera Ophoven for sup-
porting experiments.
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(8) General Procedure for the Palladium-Catalyzed
Carbonyl Allylation of Aldehydes with SnCl2 – Synthesis
of 7
To a solution of 1b (1.0 mmol) in DMF (3 mL) was added
SnCl2 (3.0 mmol), PdCl2 (PhCN)2 (5 mol%), H2O (25
mmol), and the appropriate aldehyde (1.0 mmol). The
solution was stirred at r.t. until the reaction was completed
(monitored by TLC, 2 h). The reaction mixture was diluted
with Et2O (120 mL) and washed successively with aq 10%
HCl soln (10 mL), sat. NaHCO3 (10 mL), H2O (10 mL), and
brine (10 mL). The extracts were dried over anhyd MgSO4,
the solvent was removed under reduced pressure and the
crude product subjected to flash column chromatography on
SiO2 (PE–EtOAc, 90:10) and MPLC (PE–EtOAc, 98:2)
affording a-substituted allylboronic esters 7, 8, and 9 as
colorless foams.
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Selected Data for 7b
Prepared according to the general procedure: 79% yield of
7b after flash column chromatography. [a]D20 –93.2 (c 1.02,
CHCl3). 1H NMR (600 MHz, CDCl3): d = 1.85 (dd, 3J2,1
=
6.0 Hz, 3J2,3 = 9.7 Hz, 1 H, 2-H), 2.02 (d, 3JOH,1 = 2.3 Hz, 1
H, OH), 2.97 (s, 6 H, OCH3), 4.57 (dd, 3J1,OH = 2.3 Hz,
3J1,2 = 6.0 Hz, 1 H, 1-H), 4.73 (ddd, 4J4-E,2 = 0.7 Hz,
2J4-E,4-Z = 1.9 Hz, 3J4-E,3 = 17.1 Hz, 1 H, 4-HE), 4.89 (dd, 2J4-
Z,4-E = 1.9 Hz, 3J4-Z,3 = 10.2 Hz, 1 H, 4-HZ), 5.29 (s, 2 H, 4¢-
H, 5¢-H), 5.53 (ddd, 3J3,2 = 9.9 Hz, 3J3,4-Z = 9.9 Hz, 3J3,4-E
=
17.1 Hz, 1 H, 3-H), 7.01–7.40 (m, 25 H, arom. CH). 13
C
NMR (151 MHz, CDCl3): d = 40.10 (C-2), 51.98 (OCH3),
72.65 (C-1), 78.22 (C-4¢, C-5¢), 83.60 (CPh2OMe), 117.78
(C-4), 126.58, 127.03, 127.62, 127.67, 127.79, 127.86,
128.05, 128.84, 129.89 (arom. CH), 134.25 (C-3), 141.20,
141.31, 143.18 (arom. Cipso). Anal. Calcd (%) for C40H39BO5
(610.29): C, 78.69; H, 6.44. Found: C, 78.26; H, 6.59.
(9) Furlani, D.; Marton, D.; Tagliavini, G.; Zordan, M. J.
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Trans. 1 1994, 1901.
(5) Applications of 2a in natural product syntheses:
(a) Pietruszka, J.; Rieche, A. C. M.; Schöne, N. Synlett 2008,
2525. (b) Pietruszka, J.; Rieche, A. C. M. Adv. Synth. Catal.
2008, 350, 1407.
(11) Freire, F.; Seco, J. M.; Quiñoa, E.; Riguera, R. J. Org. Chem.
2005, 70, 3778; attempts to separate the enantiomers by
chromatographic methods failed; however, since starting
from diastereomerically pure reagents with no racemization
expected during the addition, the Mosher method lends
additional support to the assignment.
Synlett 2009, No. 9, 1474–1476 © Thieme Stuttgart · New York

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