Stereocontrolled synthesis of 5-(1′-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones

Article abstract of DOI:10.1016/S0040-4039(01)00316-1

Diastereo- and enantioselective synthesis of 5-(1′-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones from 2-diethoxyphosphoryl-4-alkenoic acids or 2-diethoxyphosphoryl-4-alkenoates was readily accomplished using novel methodology involving syn- or anti-di

Full text of DOI:10.1016/S0040-4039(01)00316-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2919–2922
Stereocontrolled synthesis of
5-(1%-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones
Tomasz Janecki* and Edyta B*laszczyk
:
Institute of Organic Chemistry, Technical University, Zeromskiego 116, 90-924 L*o´dz´, Poland
Received 15 November 2000; revised 13 February 2001; accepted 21 February 2001
Abstract—Diastereo- and enantioselective synthesis of 5-(1%-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones from 2-
diethoxyphosphoryl-4-alkenoic acids or 2-diethoxyphosphoryl-4-alkenoates was readily accomplished using novel methodology
involving syn- or anti-dihydroxylation procedures combined with Horner–Wadsworth–Emmons olefination techniques. © 2001
Elsevier Science Ltd. All rights reserved.
Due to the wide spectrum of biological activity exhibited
by functionalised 3-methylidenetetrahydro-2-furanones
1, this class of compound has been the subject of
considerable synthetic effort.1–3 It has been established
that whereas the presence of a conjugated carbonyl
system is essential for activity, there are also other factors
which may enhance the biological properties of these
compounds, e.g. the presence of stereochemically defined
carbinol units at strategic positions.4
to optically active products they are usually not general
and have relatively low overall efficiency. Other strategies
such as the palladium-catalysed carbonylation of vinyl
halides,9 the reaction of a-acetoxyaldehydes with ethyl
2-(phenylthio)propionate,10 or the lactonisation of a-
methylidene-g-hydroxy-d-alkoxyesters11
have
been
shown to be of limited applicability and give racemic
products. In this respect, continuing our investigations
focused on the application of organophosphorus
reagents in the synthesis of 3-methylidenetetrahydro-2-
furanones,12,13 we now describe our newly developed
diastereo- and enantioselective techniques for the prepa-
ration of 5-(1%-hydroxyalkyl)-3-methylidenetetrahydro-
2-furanones 5 from non-sugar precursors.
Synthesis of 4-hydroxy and/or 5-hydroxyalkyl substi-
tuted furanones of general structure 2, 3, and 4 has been
so far accomplished chiefly by using carbohydrates as
starting materials.4–8 Although these methods give access
O
O
O
O
(EtO)2P
O
O
(EtO)2P
OH
R2
OEt
R2
b
a
R1
Br
(EtO)2P
OEt
R2
R1
R1
6
7
8
9
Scheme 1. Conditions: (a) NaH, THF, 0°C to rt, 20 h; (b) KOH (1.5 equiv.), EtOH/H2O=7:1, rt, 24 h.
Keywords: hydroxylation; Horner–Wadsworth–Emmons olefination; 2-furanones; diastereoselection; enantioselection.
* Corresponding author. Fax: +48 42 636 5530; e-mail: tjanecki@ck-sg.p.lodz.pl
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00316-1

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T. Janecki, E. B*laszczyk / Tetrahedron Letters 42 (2001) 2919–2922
Table 1. Synthesis of alkenoates 8 and alkenoic acids 9
acids 9 was performed using the excellent OsO4/NMO
protocol in aqueous acetone.16 Indeed, the diols 11
obtained lactonised spontaneously to the desired furan-
ones 12 (Scheme 2, Table 2). Furthermore we were
pleased to observe that the dihydroxylation is com-
pletely diastereoselective and gives access to lactones 12
with the l configuration at the newly formed vicinal
stereogenic centres. Due to the additional stereogenic
centre at C-3, all furanones 12 were obtained as mix-
tures of diastereoisomers with close to a 1:1 ratio.
Entry
Product
R1
R2
Yielda (%)
8
9
1
2
3
4
5
a
b
c
d
e
H
H
Me
n-Pr
Ph
H
Me
H
H
H
47
64
50
59
53
84
89
88
84
96
a All yields refer to pure, isolated products. All new compounds were
fully characterised by IR, 1H, 13C and 31P NMR spectroscopy and
elemental analysis.
anti-Dihydroxylation of alkenoates 8 was achieved by a
standard reaction sequence involving oxidation with
MCPBA, followed by cleavage of the epoxides with
perchloric acid to deliver diols 10.17 Pleasingly, these
diols underwent spontaneous transesterification to yield
furanones 12 with the u configuration at the newly
generated stereogenic centres.
The key intermediate components in our syntheses of l-
and u-hydroxyalkylfuranones 514 were the readily
accessible 2-diethoxyphosphoryl-4-alkenoates 8 and the
corresponding 4-alkenoic acids 9. As shown in Scheme
1 and Table 1, alkenoates 8 were obtained by alkylation
of ethyl diethoxyphosphorylacetate (6) with various
allyl bromides 7 using a known literature procedure.15
In turn, chemoselective hydrolysis of 8 gave acids 9.†
Having accessed a range of phosphorylated furanones
12 possessing complementary stereochemistry, Horner–
Wadsworth–Emmons techniques were then applied.
More specifically, olefination of formaldehyde13 yielded
a series of the target l- or u-3-methylidene-2-furanones
5‡ as defined diastereoisomers (Scheme 2, Table 2).§
In due course, syn-dihydroxylation of the carboxylic
O
O
O
O
O
O
O
(EtO)2P
(EtO)2P
(EtO)2P
d
a, b or c
OR
OH
R2
O
OR
R2
O
R1
R1
R2
R2
HO
R1
HO
R1
HO
8 (R=Et)
9 (R=H)
10 (R=Et)
11 (R=H)
12
5
Scheme 2. Conditions: (a) OsO4 cat., NMO, H2O/acetone, rt, 24 h; (b) MCPBA, CH2Cl2, rt, 24 h then 30% HClO4, rt, 24 h; (c)
AD-mix-a or AD-mix-b, 50% aqueous tert-BuOH, 0°C to rt, 48 h; (d) 36% formalin, K2CO3, 0–5°C, 15 min.
Table 2. Diastereoselective synthesis of 3-diethoxyphosphoryltetrahydrofuranones 12 and 3-methylidenetetrahydrofuranones 5
Entry
Product
R1
R2
Mode of dihydroxylation
Yielda (%)
12
5
1
2
3
4
5
6
7
8
a
b
c
H
H
H
Me
H
H
H
H
H
H
syn
syn
syn
anti
syn
anti
syn
anti
73
74
82
78
81
72
85
90
70
63
44
59
62
68
63
41
Me
Me
n-Pr
n-Pr
Ph
c
d
d
e
e
Ph
1
a All yields refer to pure, isolated products. All new compounds were fully characterised by IR, H, 13C and 31P NMR spectroscopy and elemental
analysis.
†
The procedure for chemoselective hydrolysis is described in Ref. 12.
‡
Compound l-5e: oil; IR wmax (cm−1) (film) 3432, 3095, 3064, 3032, 1764, 1664, 1496, 1452, 1439, 1128, 1040, 1020; 1H NMR (250 MHz, CDCl3)
4
4
l 2.62 (bs, 1H, OH), 2.65–2.86 (m, 2H, C-4H2), 4.63–4.73 (m, 2H, C-5H, C1%H), 5.59 (t, J=2.50 Hz, 1H, ꢀCH), 6.21 (t, J=2.5 Hz, 1H, ꢀCH),
7.34–7.42 (m, 5H, Ph); 13C NMR (62.9 MHz, CDCl3) l 28.56 (C-4), 75.13 (C-5), 79.11 (C-1%), 121.35 (ꢀCH2), 126.14, 127.59, 127.65 and 137.28
(Ph), 132.91 (C-3), 169.16 (C-2). Anal. calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.71; H, 5.80.
Compound u-5e: oil; IR wmax (cm−1) (film) 3425, 3090, 3065, 3030, 1665, 1766, 1496, 1440, 1128, 1050, 1022; 1H NMR (250 MHz, CDCl3) l
2.47 (bs, 1H, OH), 2.63 (ddt, 2J=17.50 Hz, 3J=8.25 Hz, 4J=2.50 Hz, 1H, C-4H), 3.02 (ddt, 2J=17.50 Hz, 3J=5.75 Hz, 4J=2.50 Hz, 1H,
C-4H), 4.73 (ddd, 3J=8.25 Hz, 3J=5.75 Hz, 3J=3.25 Hz, 1H, C-5H), 5.14 (d, 3J=3.25 Hz, 1H, C-1%H), 5.60 (t, 4J=2.50 Hz, 1H, ꢀCH), 6.21
4
(t, J=2.50 Hz, 1H, ꢀCH), 7.30–7.40 (m, 5H, Ph); 13C NMR (62.9 MHz, CDCl3) l 26.52 (C-4), 72.91 (C-5), 80.11 (C-1%), 121.94 (ꢀCH2), 125.96,
128.03, 128.56 and 138.21 (Ph), 134.46 (C-3), 170.58 (C-2). Anal. calcd for C12H12O3: C, 70.57; H, 5.92. Found: C, 70.57; H, 5.98.

T. Janecki, E. B*laszczyk / Tetrahedron Letters 42 (2001) 2919–2922
2921
Table 3. Enantioselective synthesis of 3-diethoxyphosphoryltetrahydrofuranones 12 and 3-methylidenetetrahydrofuranones 5
Entry
Product
R1
R2
AD-mix
12
5
Yielda (%)
[h]2D1
ee%
Configuration
Yielda (%)
1
2
3
4
5
6
a
a
d
d
e
H
H
n-Pr
n-Pr
Ph
H
H
H
H
H
H
a
b
a
b
a
b
73
75
64
68
61
60
–
–
B5
B5
30
40
70
–
–
72
59
58
69
65
71
+19.1
−26.5
+32.6
−42.7
5S,1%S
5R,1%R
5S,1%S
5R,1%R
e
Ph
90
1
a All yields refer to pure, isolated products. All new compounds were fully characterised by IR, H, 13C and 31P NMR spectroscopy and elemental
analysis.
Following the establishment of the described protocols
for preparation of l- and u-furanones 5, we attempted
to formulate methods for the enantioselective synthesis
of the same class of compounds. In this respect, the
commercially available Sharpless reagents18 (AD-mix-a
and AD-mix-b) were employed in syn-dihydroxylation
reactions of the phosphorylated alkenoic acids 9.¶ The
results obtained are shown in Table 3. Surprisingly, no
enantioselection was observed with the terminal olefin
(R1=R2=H, entries 1 and 2). On the other hand, the
alkyl (R1=n-Pr, entries 3 and 4) and aryl (R1=Ph,
entries 5 and 6) substituted olefins gave moderate to
high levels of enantioselection, respectively. The
observed enhancement in selectivity induced by aryl
substitution of the double bond is a well known phe-
nomenon and has been reported for the asymmetric
dihydroxylations of 1-alkenylphosphonates19 as well as
other olefins.18
of the methoxy groups in appropriate Mosher esters
derived from (+)- and (−)-5e (entries 5 and 6) were 3.61
and 3.47 ppm, respectively.
In summary, we have developed an efficient and stereo-
controlled route to a variety of 5-(1%-hydroxyalkyl)-3-
methylidene-2-furanones 5 by a unique combination of
syn- or anti-dihydroxylation of 4-alkenoic acids 9 or
alkenoates 8 and Horner–Wadsworth–Emmons olefina-
tion techniques. Importantly, this new methodology is
completely diastereoselective and gives access to l- or
u-2-furanones 5. Furthermore, the initial results from
our asymmetric dihydroxylation studies indicate that
l-2-furanones 5 of high enantiomeric purity can be
obtained from readily available 5-aryl substituted 4-
alkenoic acids 9. Work to enhance the overall efficacy
of these and other organophosphorus-based techniques
for the preparation of functionalised furanones is cur-
rently continuing in our laboratory.
The enantiomeric excesses and absolute configurations
of optically active furanones 5 were determined by their
transformation into Mosher’s esters,20 followed by the
Acknowledgements
1
analysis of the resulting diastereoisomers by H NMR.
In configurational assignments the shielding effects of
phenyl groups were diagnostic, e.g. the chemical shifts
This work has been supported by the Polish State
Committee for Scientific Research (KBN, Project No 3
TO9A 060 14).
§
Compounds 5c were obtained as a mixtures of diastereoisomers
(entry 3 l/u=80/20, entry 4 l/u=20/80). This is a consequence of
using commercially available E/Z mixture of crotyl bromide 7c
(E/Zꢀ85/15) in the alkylation of 6. For that reason alkenoate 8c
and alkenoic acid 9c were prepared as a mixtures of diastereoiso-
mers (E/Z=80/20) and also furanones 12c were mixtures of four
diastereoisomers.
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