Concise synthesis of (+)-β-benzyl γ-butyrolactones from butynediol

Article abstract of DOI:10.1055/s-2002-19339

The synthesis of optically active β-benzyl-γ-butyrolactones from butynediol via four transition metal catalysed reactions is reported. Key reactions are the hitherto unknown enantioselective hydrogenation of 2-benzyl-2-buten-1,4-diols using Ir(I) phosphinooxazoline catalysts and the regiocontrolled oxidation of the resulting 2-benzyl-1,4-butanediols to the β-substituted butyrolactones.

Full text of DOI:10.1055/s-2002-19339

LETTER
77
Concise Synthesis of (+)- -Benzyl -Butyrolactones from Butynediol
C
oncise Synth
t
esisof
e
(+)
-
-Benz
f
yl -But
a
yrolactones
n
from Butynediol Kamlage,a,1 Michael Sefkow,a Nicole Zimmermann,b,2 Martin G. Peter*a
a
Institut für Organische Chemie und Strukturanalytik, Universität Potsdam, Karl-Liebknecht-Str. 24–25, 14476 Golm, Germany
b
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
E-mail: peter@serv.chem.uni-potsdam.de
Received 15 October 2001
geneous hydrogenation in the presence of chiral catalysts
(Table 1). Thus, butenolides 3a,b were converted to lac-
tones 2a,b in about 20% and 12% ee (2 h, 100 bar H2) us-
ing Ir(I)-phosphinooxazoline catalyst A9 (Table 1, entries
Abstract: The synthesis of optically active -benzyl- -butyrolac-
tones from butynediol via four transition metal catalysed reactions
is reported. Key reactions are the hitherto unknown enantioselective
hydrogenation of 2-benzyl-2-buten-1,4-diols using Ir(I)-phos-
phinooxazoline catalysts and the regiocontrolled oxidation of the 1 and 3). The conversion was 58% after 18 hours while the
resulting 2-benzyl-1,4-butanediols to the -substituted butyro-
ee remaining low at 12% (entry 2). Similarly, reduction of
3b or 3d in presence of R-(+)-BINAP-Ru(II)10 (120 h, 20–
lactones.
Key words: (+)- -benzyl -butyrolactones, butynediol, enantiose-
lective hydrogenation
30 bar) afforded lactones 2b and 2d in 55 and 95% con-
version, again with low ee (entries 4 and 5).11
It was reported that yeast reduction of butenolides afford-
ed the corresponding lactones with good ee.12 In our case,
substrate 3c was reduced by yeast in the presence12 or in
the absence13 of saccharose. The conversion of 3c to lac-
tone 2c was 20% in each instance and the product was ob-
tained as a racemic mixture (entries 6 and 7).
Butyrolactone lignans 13 are an important class of natural
products possessing notable biological activities, in par-
ticular antiviral,4 cytotoxic5 and canceroprotective6 prop-
erties. We have recently reported a short synthesis of
racemic butyrolactone lignans 1 via -alkylation of -sub-
stituted butyrolactones 2 (Scheme 1).7 These lactone in-
termediates were prepared by Raney-Nickel or Pd/C
catalysed hydrogenation of the corresponding unsaturated
lactones 3, which were obtained from butynediol 4 in
three transition metal catalysed reactions.7
hydrogenation or
yeast reduction
Ar
Ar
*
see Table 1
O
O
O
O
3a-d
2a-d
OMe
OMs
Me
Me
OMe
Me
OMe
OMe
a = Ph b =
c =
d =
R
R'
R
alkylation
O
O
O
O
Scheme 2 Attempted enantioselective reductions of lactones 3a–d
1
2
hydrogenation
Since neither asymmetric hydrogenation nor yeast reduc-
tion gave lactones 2 in acceptable yields and enantioselec-
tivities, a different synthetic strategy was necessary. Thus,
lactones 2 should be obtained by regioselective TPAP ox-
idation of optically active diols 5, prepared by asymmetric
hydrogenation of butenediols 6 (Scheme 3).
R
OH
3 steps
HO
O
O
4
3
Scheme 1 Retrosynthesis of lactone lignans 1
R
R
ref14
*
4
2
Since natural lignans 1 are generally non-racemic, an
asymmetric hydrogenation of 3a–d to 2a–d using chiral
catalysts was envisioned to provide optically active lign-
ans and analogs (Scheme 2). Transition metal catalysed
asymmetric hydrogenation of - or -methylene butyro-
lactones have been described.8 However, we observed
that butenolides 3a–d gave poor conversions upon homo-
HO
OH
HO
OH
5
6
Scheme 3 New strategy for the preparation of optically active lac-
tones 2
A series of substituted butenediols, 6a–g, were synthe-
sised according to an earlier reported procedure.14 These
compounds were subsequently hydrogenated in presence
of chiral catalysts (Scheme 4 and Table 2). Diol 6a was
reduced under different conditions, varying the catalyst
and the catalyst loading (Table 2, entries 1–6). Quantita-
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0077,0080,ftx,en;G30101ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

78
S. Kamlage et al.
LETTER
Table 1 Conditions employed for the attempted enantioselective Hydrogenation of Lactones 3a–d
Entry
Substrate Catalyst (mol%)
Solvent
p [bar]
Temp [°C] t [h]
conversion ee (%)a
(%)
18
58
20
55
95
20
20
1
2
3
4
5
6
7
3a
3a
3b
3b
3d
3c
3c
[Ir(COD)(PHOX)]BARF A (5)
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
EtOH
H2Od
100
100
100
20
30
–
23
23
23
23
23
37
37
2
18
12
12
–
[Ir(COD)(PHOX)]BARF A (5)
[Ir(COD)(PHOX)]BARF A (5)
R-(+)-BINAP-Ru(II) B (5)
R-(+)-BINAP-Ru(II) B (5)
yeastb,c
2
120
120
144
96
10
–
< 2
< 2
yeastb,e
H2O
–
a Enantiomeric excess determined by HPLC on Chiralcel OD-H.
b Yeast from UNIFERM GmbH & Co.
c Without saccharose according to ref.13
d Containing 5% EtOH.
e With saccharose according to ref.12
CF3
CF3
Ph2
P
O
O
O
O
Ru
B
Ph2P
N
P
Ir
COD
O
Ph2
4
A
B
tive conversion of 6a to 5a was observed in the presence Aryl-substituted butenediols 6b–g were hydrogenated
of 3–5 mol% of Ir(I)-phosphinooxazolines9 (H2, 100 bar, with varying results (entries 8–13). The sterically hin-
2 h). Lower catalyst loading (1 mol%) gave low conver- dered substrate 6c or compounds bearing a methanesulfo-
sion of 6a to 5a. The enantioselectivities ranged between nyl group in para position 6b,f gave low conversion under
68–82% ee.15 The highest ee (82%) was found with standard reaction conditions. On the other hand, diols with
[Ir(COD)(PHOX)]BARF C. [Ir(COD)(PHOX)]BARF D, p-alkoxy-substituted arenes, 6d,e,g, afforded quantita-
gave also notable ee (68%). We also tried R-(+)-BINAP- tively the diols 5d, 5e, and 5g with moderate ee for 5e
Ru(II) which moderately converted diol 5a, even after (58%) and for 5g (67%) (5d could not be separated on
prolonged reaction times (60 h). A racemic sample of 5a Chiralcel OD-H).
was prepared by hydrogenation of 6a with a 1:1 mixture
The absolute configuration of diol 5e ([ ]D28 = +2,76 (c
of R- and S-[Ir(COD)(PHOX)]BARF A (entry 7). All oth-
031 1.10, EtOH) was established as R, based on the obser-
er attempts to obtain rac-5a by using conventional cata-
vation that (S)-5e shows [ ]D22 = –1,9 (c 1.1, EtOH).17
lysts (e.g. Pd/C, Pd(OH)2, PtO2, Crabtree catalyst16)
failed.
Diols 5a,e were oxidised with TPAP/NMO.7,18 Lactones
2a,e and the regioisomers 8a,e were obtained in 67 and
82% yield, respectively, without decrease of optical purity
(Scheme 5). The isomers 2a,e and 8a,e (ratio about 2:1)
were separated by column chromatography. Lactone 2a
was alkylated to lignan 1a (R, R’ = Ph) in 30% yield using
BnBr and LHMDS/DMPU19 (reaction conditions not op-
timised).
Ar
H
Ar
H2/cat. L*M
HO
OH
HO
OH
6a-g
5a-g
OMe
OMs
Me
OMe
In conclusion, we have shown a concise synthesis (four
steps from butynediol 4) of optically active -benzyl- -
butyrolactones 2, key precursors for the preparation of
lactone lignans 1. Synthesis of 2 was achieved in accept-
able yields and enantiomeric excess from optically active
butanediols 5 which were obtained by Ir-phosphinoox-
azoline-catalysed asymmetric hydrogenation of butene-
diols 6.
Me
a = Ph b =
c =
d =
Me
OMe
OMe
OMe
OMe
O
O
OMs
OMe
e =
f =
g =
Scheme 4 Asymmetric hydrogenation of butenediols 6a–g
Synlett 2002, No. 1, 77–80 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Concise Synthesis of (+)- -Benzyl -Butyrolactones from Butynediol
79
Table 2 Conditions for the Asymmetric Hydrogenation of Butenediols 6a–g
Entry
1
Substrate Catalyst (mol%)
[Ir(COD)(PHOX)]BARF C (1)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
p [bar]
95
t [h]
2
conversion (%)
ee (%)a
n.d.
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
6f
24
100
100
100
100
80
2
[Ir(COD)(PHOX)]BARF C (3)
[Ir(COD)(PHOX)]BARF C (5)
[Ir(COD)(PHOX)]PF6b (4)
100
100
100
100
80
2
82 (R)
n.d.
3
2
4
2
n.d.
5
[Ir(COD)(PHOX)]BARF D (5)
R-(+)-BINAP-Ru(II)c B (5)
2
68 (R)
62 (R)
rac
6
60
1
7
R-and S-[Ir(COD)(PHOX)]BARF Ad (2/2)
[Ir(COD)(PHOX)]BARF D (5)
[Ir(COD)(PHOX)]BARF D (5)
[Ir(COD)(PHOX)]BARF D (5)
[Ir(COD)(PHOX)]BARF D (5)
[Ir(COD)(PHOX)]BARF D (5)
[Ir(COD)(PHOX)]BARF D (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
100
100
100
100
100
85
100
30
8
2
n.d.
9
2
0
–
10
11
12
13
2
100
100
30
n.d.e
58 (R)
n.d.
2
2
6g
2
100
67 (R)
a Enantiomeric excess determined by HPLC on Chiralcel OD-H.
b Structure C, counterion PF6 .
–
c Structure B (Table 1).
d Structure A, both enantiomers (Table 1).
e No separation on Chiralcel OD-H.
CF3
CF3
CF3
O
O
B
P
N
B
Ph2P
N
Ir
COD
Ir
COD
CF3
4
4
C
D
Acknowledgement
Ar
Ar
TPAP/NMO
CH2Cl2
This research was supported by the Deutsche Forschungsgemein-
schaft (DFG) (INK A26/1-1 and B26/1-1) and by the Fonds der
Chemischen Industrie. MS acknowledge a habilitation grant of the
DFG (Se875/1-1). NZ thanks the Fonds der Chemischen Industrie
for a Kekulé-fellowship. We thank Prof. A. Pfaltz for helpful dis-
cussions.
5a,e
+
:
O
O
O
8a,e
O
2a,e
67 - 82%
~ 2
1
LHMDS, DMPU
BnBr, THF, -78 °C
a = Ph
e =
30%
r.t.
O
O
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(+)-1a
Scheme 5 TPAP-catalysed oxidation of 5a,e to lactones 2a,e and
synthesis of lignan (+)-1a
Synlett 2002, No. 1, 77–80 ISSN 0936-5214 © Thieme Stuttgart · New York

80
S. Kamlage et al.
LETTER
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Synlett 2002, No. 1, 77–80 ISSN 0936-5214 © Thieme Stuttgart · New York