Asymmetric pentenylation of aldehydes: A new benchmark for the preparation of ethyl-substituted homoallylic alcohol

Article abstract of DOI:10.1055/s-0028-1087641

A highly diastereo- and enantioselective boron-mediated pentenylation reaction is presented. The chiral pentenylborane reagents, which are derived from pinene, undergo addition to various aldehydes to afford ethyl-substituted homoallylic alcohols in good

Full text of DOI:10.1055/s-0028-1087641

LETTER
213
Asymmetric Pentenylation of Aldehydes: A New Benchmark for the
Preparation of Ethyl-Substituted Homoallylic Alcohol
A
symmetric Pent
a
enylation
o
v
f
A
ldehydesindra P. Sonawane, Shyamsunder R. Joolakanti, Stellios Arseniyadis,* Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: stellios.arseniyadis@espci.fr; E-mail: janine.cossy@espci.fr
Received 18 September 2008
O
Abstract: A highly diastereo- and enantioselective boron-mediated
pentenylation reaction is presented. The chiral pentenylborane
reagents, which are derived from pinene, undergo addition to vari-
ous aldehydes to afford ethyl-substituted homoallylic alcohols in
good yield and high stereoselectivity. The latter are then easily con-
verted into the corresponding a,b-unsaturated d-lactones using an
acylation/ring-closing metathesis sequence. The relative and abso-
lute stereochemistry is exclusively controlled by the reagent.
O
OH OMe
pironetin (1)
Key words: asymmetric pentenylation, a,b-unsaturated lactone,
ring-closing metathesis
OH
O
O
P
OH
O
O
OH
During the past two decades, carbonyl allylations and cro-
tylations have become important tools in modern organic
synthesis, especially for the construction of polyketide
natural products.1 In this context, a plethora of effective
protocols have been developed to provide excellent levels
of diastereo- and enantioselection. The methods devel-
oped by Brown,2 Roush3 and Duthaler4 are notable among
them, as the absolute and relative configurations of the re-
sulting homoallylic alcohols are mainly determined by the
choice of the reagent. Interestingly, whereas all these
methods allow an easy access to the propionate subunit,
there were no general methods leading to the homologous
butyrate subunit reported when we started this work.5
Since then, Hatakeyama et al. reported one example in
their synthesis of phoslactomycin B.6 The need for devel-
oping such a method is especially felt when trying to syn-
thesize molecules containing an a,b-unsaturated d-lactone
substituted at the g-position by an ethyl group, as this mo-
tif is present in a number of natural products such as
pironetin7 (1) and leustroducsin B8 (2), which exhibit in-
teresting antifungal, antibacterial and antitumoral activi-
ties (Figure 1).
HO
O
4
O
NH2
leustroducsin B (2)
Figure 1 Structure of pironetin (1) and leustroducsin B (2)
substituted homoallylic alcohols in good yields
(Scheme 1).9 The latter were further converted into the
corresponding a,b-unsaturated d-lactones through an acy-
lation/ring-closing metathesis sequence. Our strategy to
develop a reagent for the asymmetric pentenylation of al-
dehydes was based upon the crotylboron reagent devel-
oped by Brown and thus derived from diisopino-
campheylborane and either (Z)- or (E)-2-pentene. Also,
we expected that this new reagent would react in a similar
fashion and therefore operate via a rigid chair-like
Zimmerman–Traxler transition state, which should ensure
a highly stereochemical transfer of the reagent’s olefinic
geometry.
The chiral pentenylating reagent was generated in situ fol-
lowing Brown’s procedure10 starting from (+)-methoxydi-
isopinocampheylborane and (Z)-2-pentene in the presence
of the Schlosser base,11 and tested on 3-phenylpropion-
aldehyde (Table 1, entry 1). To our delight, the asymmet-
ric pentenylation process gave rise to the corresponding
In this communication, we wish to report a highly stereo-
selective boron-mediated pentenylation reaction which al-
lows a straightforward access to both syn- and anti-ethyl-
(+)-Ipc2B
OH
(+)-Ipc2B
OH
(Z)
(E)
O
R
R
R
H
Scheme 1 Synthesis of syn- and anti-ethyl substituted homoallylic alcohols through boron-mediated asymmetric pentenylation
SYNLETT 2009, No. 2, pp 0213–0216
x
x.
x
x.
2
0
0
9
Advanced online publication: 15.01.2009
DOI: 10.1055/s-0028-1087641; Art ID: G28408ST
© Georg Thieme Verlag Stuttgart · New York

214
R. P. Sonawane et al.
LETTER
homoallylic alcohol in high yield (71%), good diastereo- ported in Table 1. As a general trend, the syn diastereoiso-
selectivity (syn/anti = 15:1) and an excellent enantioselec- mer was formed as the major product (dr >15:1). In
tivity of 91% as determined by chiral SFC analysis (see addition, both the yields and the enantioselectivities were
footnote d in Table 1).
good ranging from 53% to 92% and from 64% to 92%, re-
spectively. Finally, we were able to confirm the absolute
With these conditions in hand, a close examination of the
reagent’s scope was undertaken with a set of aliphatic,
aromatic and propargylic aldehydes. The results are re-
1
stereochemistry of the products by performing H NMR
analyses on the corresponding mandelate derivatives.12
Table 1 Asymmetric Pentenylation of Aldehydes
OH
(+)-Ipc2B
O
(Z)
R
THF–Et2O, –78 °C
R
H
Entry Substrate
1
Product
Yield (%)a
ee (%)c
91d
syn/antib
OH
O
71
15:1
H
2
53
15:1
64e
86d
O
OH
H
3
4
62
15:1
O
OH
H
61
92f
O
OH
15:1
H
81d
85e
OH
O
5
6
60
15:1
Br
Br
H
64
O
OH
14:1
H
O2N
O2N
7
8
92
16:1
87f
72d
OH
O
H
71
OTBS
O
OTBS
OH
20:1
H
a Isolated yield.
b Determined by 1H NMR analysis of the crude reaction mixture.
c Enantiomeric excess was determined by SFC analysis using a chiral phase column.
d Chiralcel OD-H.
e Chiralcel OJ-H.
f Chiralpak AD-H.
Synlett 2009, No. 2, 213–216 © Thieme Stuttgart · New York

LETTER
Asymmetric Pentenylation of Aldehydes
215
Table 2 Synthesis of a,b-Unsaturated d-Lactones via an Acylation/
RCM Sequence
OTs OH
OTs OH
OTs
O
(+) or (–)-Ipc2B
(Z)
O
O
+
OH
H
THF–Et2O, –78 °C
1)
, CH2Cl2, 0 °C
Cl
2) [Ru]-II, CH2Cl2, 40 °C
O
*
*
*
R
(anti,syn)-4
OTs OH
(syn,syn)-5
OTs OH
3
*
R
N
N
Mes
Cl
Cl
Mes
Ph
Ru
PCy3
[Ru]-II
(syn,anti)-7
(anti,anti)-6
Entry Substrate
Product
Yield (%)a
58
(+)-Ipc2B
(–)-Ipc2B
: 4/5/6/7 = 10:1:0:0
O
OH
O
4/5/6/7 = 1:10:0:0
:
1
Scheme 2 syn-Pentenylation of an a-branched aldehyde
O
OH
In order to show that the selectivity of this pentenylation
process is solely dependant on the reagent, we successive-
ly applied the (+)- and the (–)-diisopinocampheylpente-
nylborane to aldehyde 3 bearing a substituent at the a-
position (Scheme 2). With these two reagents, moderate
yields (40–51%) and high selectivities were observed (4/
5/6/7 = 10:1:0:0 and 4/5/6/7 = 1:10:0:0, respectively).
More interestingly, the ratios obtained confirmed that the
reaction was totally under reagent control in a similar
fashion to Brown’s crotylation.2
O
2
3
4
5
6
55
60
71
80
80
O
OH
O
O
Following these initial results, we turned our attention to
the use of the analogous (E)-pentenylborane reagent
which should lead to the anti-ethyl substituted homoallyl-
ic alcohols. As expected, under a slightly modified proce-
dure,13 the corresponding anti product could be isolated in
high yield (78%) and reasonable enantioselectivity (76%
ee; Scheme 3).
OH
O
Br
Br
Br
Br
O
OH
O
OH
O
(+)-Ipc2B
THF–Et2O, –78 °C
78%
Br
Br
H
O
OH
76% ee
O
Scheme 3 anti-Pentenylation of 3-bromobenzaldehyde
Finally, the previously obtained homoallylic alcohols
were efficiently converted into the corresponding a,b-un-
saturated d-lactones through a two-step sequence involv-
ing an acylation and a ring-closing metathesis (Table 2).14
In conclusion, we have developed two highly enantio- and
diastereoselective reagents for the pentenylation of alde-
hydes, which offer a great alternative to the standard aldol
processes.15 While the (Z)-pentenylborane reagent allows
access to syn-ethyl substituted homoallylic alcohols, the
analogous (E)-pentenylborane analogue leads to the anti-
stereoisomer. We have also prepared a variety of a,b-un-
saturated d-lactones in good yields thus illustrating the
importance of this methodology in the synthesis of com-
plex natural products with interesting biological activities.
O
OH
O
7
8
80
77
O2N
O2N
O
OTBS
OH
OTBS
O
a Isolated yield.
Synlett 2009, No. 2, 213–216 © Thieme Stuttgart · New York

216
R. P. Sonawane et al.
LETTER
(9) It is noteworthy that optically active ethyl-substituted
References and Notes
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