Diastereoselective synthesis of enantiopure γ-butenolide- butyrolactones towards Pseudopterogorgia lactone furanocembranoid substructures

Article abstract of DOI:10.1055/s-0032-1317555

A diastereoselective methodology for preparing trans-γ-lactone- γ-butenolides through vinylogous aldol additions of siloxyfuranes to enantiopure cyclopropylcarbaldehyde followed by a tin-catalyzed retroaldol-lactonization cascade is reported. This synthet

Full text of DOI:10.1055/s-0032-1317555

LETTER
▌2909
lDettierastereoselective Synthesis of Enantiopure γ-Butenolide-butyrolactones
towards Pseudopterogorgia Lactone Furanocembranoid Substructures
Diastereoselective Synthesis of Enantiopure γ-Butenolide-butyrolactones
Allan Patrick G. Macabeo,a,b Christian W. Lehmann,c Oliver Reiser*a
a
Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Fax +49(941)9434631; E-mail: Oliver.Reiser@chemie.uni-regensburg.de
b
Organic Synthesis Laboratory, Research Center for the Natural and Applied Sciences, University of Santo Tomas, Espana St., Manila 1015,
Philippines
c
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Received: 04.10.2012; Accepted after revision: 19.10.2012
We report here the enantio- and diastereoselective synthe-
sis of such substructures via a highly selective vinylogous
aldol addition of 2-siloxyfurans 6 to enantiopure cyclo-
propylcarbaldehyde 4, the latter being readily available
Abstract: A diastereoselective methodology for preparing trans-γ-
lactone-γ-butenolides through vinylogous aldol additions of siloxy-
furanes to enantiopure cyclopropylcarbaldehyde followed by a tin-
catalyzed retroaldol–lactonization cascade is reported. This syn-
thetic approach is applied to a short synthesis of an exo-trienol furan from ethyl 2-furoate in a two-step sequence (Scheme 1).4
lactone substructure relevant to bielschowskysin and other related
coral diterpenoid natural products.
Previous investigations from our group demonstrated the
diastereoselective addition of allylsilanes 5 to 4, leading
Key words: marine furanocembranoids, asymmetric synthesis,
vinylogous Mukaiyama addition, lactones, furans
after a retroaldol–lactonization sequence to 7 in stereo-
pure form. We envisioned that the construction of trans-
γ-lactone-γ-butenolides 8, which appear to be suitable
precursors for the synthesis diterpenoids 1–3, can be
Adjacently linked oxygenated heterocycles and γ-butyro- achieved via Lewis acid catalyzed vinylogous Mukaiya-
lactone motifs are prominent substructures in a number of ma aldol addition5 of 6 followed by our previously estab-
complex natural products. These moieties are present in lished retroaldol–lactonization protocol.4
various furanocembranoid diterpenes isolated from Pseu-
dopterogorgia species such as 1–3.1 The segments high-
SiMe3
lighted (Figure 1) feature a 2,5-dihydrofuran or furan ring
attached to a 4,5-disubstituted butyrolactol or butyrolac-
tone. With special attention to diterpenoids 1 and 2,
strategies2 towards the synthesis of these substructures
have been developed motivated by the unique frame-
works, intriguing biogenetic origins3 and biological activ-
ity of the underlying natural products.
CO2Me
O
n
H
O
ref. 4
O
n
R
5
H
OHC
ref. 4
RO
OHC
7
R1
R2
CO2Et
(this work)
R2
R1
OH
3
OH
4
H
*
HO
H
7
H
O
O
3
R = C(O)CO2Me
O
2
1
O
O
HO
9
O
16
O
8
H
OH
O
O
O
6
H
H
O
O
15
R3
14
OSi
H
O
H
O
OAc
8
O
6
bielschowskysin (1)
verrilin (2)
Scheme 1
MeO
HO
O
Our investigation was initiated by reacting 2-trimethylsi-
loxyfurans 6 with cyclopropane 4 in the presence of
BF3·OEt2 (Table 1). Employing 6a, good conversion and
diastereoselectivity to 9a was achieved based on TLC and
1H NMR analysis of the crude, however, no attempts to
purify and isolate this intermediate were made, but rather
its direct conversion to lactone aldehyde 8a was investi-
gated. Substantial decomposition was observed when
Ba(OH)2·8H2O or triethylamine, which has been success-
ful in other transformations of this type,4 were employed
to initiate the retroaldol–lactonization cascade. Switching
to Otera’s catalyst6 10 in the presence of methanol or eth-
ylene glycol smoothly afforded 8a or 8b with perfect anti
O
O
OAc
O
O
bippinatin K (3)
Figure 1 Pseudopterogorgia diterpenoids with 2,5-dihydrofuran, fu-
ran-linked butyrolactone, and butyrolactol framework
SYNLETT 2012, 23, 2909–2912
Advanced online publication: 16.11.2012
DOI: 10.1055/s-0032-1317555; Art ID: ST-2012-D0850-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2910
A. P. G. Macabeo et al.
LETTER
selectivity (C1/C2) and a 6:1 diastereoselectivity at C2/C3
(Table 1, entries 1 and 2). When the silyl group in 6 was
switched to a TBS group, a substantial improvement in di-
astereoselectivity for the formation of 8b (99:1) was ob-
served (Table 1, entry 3). Having established the reaction
sequence, several substituted siloxylated furan nucleo-
philes were investigated giving rise to 8c–f in acceptable
overall yields starting from 4 (Table 1, entries 4–7). Espe-
cially gratifying was that 8d,7 which is most relevant as a
precursor towards 1–3, was obtained as a single stereoiso-
mer (>99:1 de, 65% yield). The relative and absolute ste-
reochemistry of 8 was unambiguously established by X-
ray crystal structure analysis (Figure 2 for 8d)8 and chiral
ellipticity evidence.9 The butenolides displayed negative
and positive Cotton shifts for the π–π* and n–π* transi-
tions, respectively, revealing M helicity ascribed to deriv-
atives with S configuration at C3 (see the Supporting
Information). Noteworthy, from the anti arrangement of
substituents in the γ-butyrolactone moiety (C1/C2 in 8), it
is clear that addition pathways leading to the cyclopropyl
carbinol butenolides 9 are identical with those of the cy-
clic allylsilanes in accordance with the Felkin–Anh para-
digm (Scheme 2).10
Figure 2 X-ray crystal structure of 8d8
furan C6 with an additional aldehyde unit under Vilsmei-
er–Haack conditions was unsuccessful. A Heck-inspired
Csp2–Csp2 coupling between the furan moiety of 12 and
methacrylate ethyl ester under reaction conditions de-
scribed by Miaura and co-workers11 was next investigat-
ed. Treatment of a DMF solution of 12 with ethyl
methacrylate, 5 mol% Pd(OAc)2, LiOAc (4 equiv), and
Cu(OAc)2·5H2O (2 equiv) afforded 13 (52% yield).12
Noteworthy in this transformation was the preferential
elimination of the β-hydrogen attached to the least hin-
dered carbon (C9). Finally, oxidation of the furan moiety
using bromine in methanol afforded 14 as a diastereomer-
Starting with butenolide-lactone 8d, transformations di-
rected towards the diterpenoids 1–3 were investigated.
DIBAL-H reduction furnished lactol-furan 11 (63%,
Scheme 3), which was reoxidized under Ley’s conditions
to afford furan lactone 12 quantitatively. Extension at the
Table 1 Butenolide-lactones 8 from Sequential Vinylogous Mukaiyama Aldol Reaction and Retro-Aldol–Lactonization Cascades
..
RO
Cl
n-Bu n-Bu
Sn Cl
Sn
Cl
OHC
n-Bu
n-Bu
Sn
O
CO2Et
n-Bu
n-Bu
4
Cl Sn
n-Bu n-Bu
10
MeOH or
O
R2
R1
RO
OH
R = C(O)CO2Me
R2
H
H
BF3⋅OEt2
3
O
O
+
R1
O
2
1
O
CH2Cl2, –78 °C
R2
R1
CO2Et
H
H
ethylene gylcol
O
R3O
O
R3O
9a–f
8a–f
OSi
O
6
Entry
Si
R1
R2
Lactonization
conditionsa
R3
Yield of 8
(%)
drb,c
1
2
3
4
5
6
7
6a TMS
6a TMS
6b TBS
6c TBS
6d TBS
6e TBS
6f TBS
H
H
A
B
B
B
B
B
B
8a Me
38
40
40
44
65
42
50
83:17
H
H
8b (CH2)2
8b (CH2)2
8c (CH2)2
8d (CH2)2
8e (CH2)2
8f (CH2)2
86:14
99:1
H
H
Me
H
H
87:13
>99:1
91:9
Me
Ph
Ph
4-t-BuPh
4-t-BuPh
90:10
a A: catalyst 10 (5 mol%), MeOH, reflux, 12 h; B: catalyst 10 (5 mol%), ethylene glycol, PhMe, reflux, 12 h.
b Ratio of 1S,2S,3S and 1S,2S,3R diastereomers.
c Determined by 1H NMR integral analysis.
Synlett 2012, 23, 2909–2912
© Georg Thieme Verlag Stuttgart · New York

LETTER
Diastereoselective Synthesis of Enantiopure γ-Butenolide-butyrolactones
2911
Acknowledgment
‡
Si
The Deutscher Akademischer Austauschdienst (DAAD) for the gra-
duate fellowship awarded to APGM is gratefully acknowledged.
R1
O
O
R1
R2
O
O
H
R2
H
4
Supporting Information for this article is available online at
BF3
BF3
+
H
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
O
8
H
H
OH
CO2Et
OR
H
H
6
CO2Et
OR
References and Notes
H
(1) For the isolation of 1–3, see: (a) Marrero, J.; Rodriguez, A.
D.; Baran, P.; Raptis, R. G.; Sanchez, J. A.; Orteg-Barria, E.;
Capson, T. L. Org. Lett. 2004, 6, 1661. (b) Rodriguez, A. D.;
Shi, Y.-P. J. Org. Chem. 2000, 65, 5389. (c) Marrero, J.;
Benitez, J.; Rodriguez, A. D.; Zhao, H.; Raptis, R. G. J. Nat.
Prod. 2008, 71, 381.
9
R = C(O)CO2Me
Scheme 2 Stereochemical model for the formation of 9 followed by
retroaldol–lactonization cascade to 8
(2) For the partial synthesis of 1, see: (a) Doroh, B.; Sulikowski,
G. A. Org. Lett. 2006, 8, 903. (b) Miao, R.; Gramani, S. G.;
Lear, M. J. Tetrahedron Lett. 2009, 50, 1731. (c) Nicolau,
K. C.; Adsool, V. A.; Hale, C. R. H. Angew. Chem. Int. Ed.
2011, 50, 5149. (d) Macabeo, A. P. G.; Kreuzer, A.; Reiser,
O. Org. Biomol. Chem. 2011, 9, 3146. (e) Farcet, J. P.;
Himmelbauer, M.; Mulzer, J. Org. Lett. 2012, 14, 2195.
(3) (a) Li, Y.; Pattenden, G.; Rogers, J. Tetrahedron Lett. 2010,
51, 1280. (b) Kimbrough, T. J.; Roethle, P. A.; Mayer, P.;
Trauner, D. Angew. Chem. Int. Ed. 2010, 49, 2619.
(c) Roethle, P. A.; Trauner, D. Nat. Prod. Rep. 2008, 25,
298.
(4) (a) Böhm, C.; Schinnerl, M.; Bubert, C.; Zabel, M.; Labahn,
T.; Parisini, E.; Reiser, O. Eur. J. Org. Chem. 2000, 2955.
(b) Böhm, C.; Reiser, O. Org. Lett. 2001, 3, 1315.
(c) Bandichhor, R.; Nosse, B.; Sörgel, S.; Böhm, C.; Seitz,
M.; Reiser, O. Chem.–Eur. J. 2003, 9, 1. (d) Schinnerl, M.;
Böhm, C.; Seitz, M.; Reiser, O. Tetrahedron: Asymmetry
2003, 14, 765. (e) Kalidindi, K.; Jeong, W. B.; Schall, A.;
Bandichhor, R.; Nosse, B.; Reiser, O. Angew. Chem. Int. Ed.
2007, 46, 6361.
ic mixture of dimethoxylated products which, upon treat-
ment on silica, gave lactone 15.13 The Z configuration of
the newly formed alkene moiety was unambiguously as-
signed based on the H5/H7 NOESY correlation. Thus, the
exo-olefinated dihydrofuran moiety being useful as a po-
tential precursor for 1 and in core structures of other diter-
penoidal natural products such as 1614 can be easily
accessed through the aforementioned oxidative transfor-
mation utilized in this study.
In conclusion, we have developed a new stereoselective
strategy for constructing butenolide-butyrolactone and fu-
ran-butyrolactone units present in complex natural prod-
uct structures such as 1–3 through vinylogous Mukaiyama
addition of heterosiloxydienes to highly functionalized
cyclopropane carbaldehyde 4 and a lactonization se-
quence, demonstrating in a new way the power of donor–
acceptor-substituted cyclopropane building blocks.15 In
addition, the synthesis of a (Z)-exo-trienolfuran lactone
substructure 15 representing the northeastern sector of
bielschowskysin (1) was accomplished.
(5) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929. (b) Denmark, S. E.; Heemstra,
J. R. Jr.; Beutner, G. L. Angew. Chem. Int. Ed. 2005, 44,
4682; Angew. Chem. 2005, 117, 4760.. (c) Kalesse, M. Top.
Curr. Chem. 2005, 244, 43. (d) Hosokawa, S.; Tatsuta, K.
H
H
O
H
O
O
O
O
OH
b
a
c
O
O
d
O
8d
EtO2C
O
O
O
O
O
O
13
12
11
CO2Me
OMe
6
7
OMe
MeO
OMe
O
2
1
O
HO
6
O
O
O
7
O
e
2
1
O
H
OAc
EtO2C
EtO2C
9
O
O
9
O
O
O
O
16
14
15
Scheme 3 Reagents and conditions: (a) DIBAL-H, THF, –78 °C, 63%; (b) TPAP, NMO, MS 4 Å, DMF, r.t., quant.; (c) ethyl methacrylate,
Pd(OAc)2, LiOAc, Cu(OAc)2·5H2O, DMF, 117 °C, 52%; (d) Br2, MeOH, NH3 (g), –40 °C; e) column chromatography (silica gel), 55%
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2909–2912

2912
A. P. G. Macabeo et al.
LETTER
Mini-Rev. Org. Chem. 2008, 5, 1. (e) Zanardi, F.; Battistini,
L.; Curti, C.; Casiraghi, G. Chemtracts 2010, 123.
(11) Maehara, A.; Satoh, T.; Miura, M. Tetrahedron 2008, 64,
5982.
(6) (a) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56,
5307. (b) Orita, A.; Sakamoto, K.; Hamada, Y.; Mitsutome,
A.; Otera, J. Tetrahedron 1999, 55, 2899.
(7) Representative Procedure for Butenolide-Lactone
Synthesis (8d)
(12) A mixture of 12 (50 mg, 0.21 mmol), ethyl methacrylate
(105 μL, 0.84 mmol), Pd(OAc)2 (2.4 mg, 0.011 mmol),
Cu(OAc)2·H2O (84 mg, 0.42 mmol), and LiOAc (55 mg,
0.84 mmol) was stirred in DMF (1 mL) at 117 °C under air.
After cooling, the reaction mixture was extracted with
EtOAc and dried (Na2SO4). Compound 13 was purified by
preparative reversed-phase HPLC using a gradient-elution
method with increasing amounts of MeCN in H2O.
2-{(2′S,3′S)-3′-[1,3]Dioxolan-2-yl-3-methyl-5′-oxo-
2′,3′,4′,5′-tetrahydro[2,2′]bifuranyl-5-ylmethyl}acrylic
Acid Ethyl Ester (13)
Under a nitrogen atmosphere, BF3·OEt2 (0.28 mL, 2.21
mmol) was added via syringe to a solution of
cyclopropylcarboxaldehyde (+)-4 (500 mg, 2.01 mmol) in
anhyd CH2Cl2 (20 mL) at –78 °C. After stirring for 30 min,
a solution of 6d in CH2Cl2 (2.11 mmol) was added slowly,
resulting in an orange-colored solution. After stirring for 16
h at –78 °C, sat. aq NaHCO3 (45 mL) was added, and the
mixture was allowed to warm to r.t. The layers were
separated, and the aqueous layer was extracted three times
with EtOAc (45 mL each). The combined organic layers
were washed with brine (45 mL), H2O (45 mL), dried
(Na2SO4), filtered, and concentrated in vacuo to give the
carbinol cyclopropane 9d which was used for the next step
without further purification. A round-bottomed flask,
equipped with Dean–Stark trap was charged with crude
cyclopropyl carbinol 9d (approx. 1 equiv) followed by
ethylene glycol (224 μL, 4.02 mmol, 2 equiv) and Sn catalyst
10 (5 mol%). The mixture was gently refluxed for 12 h, after
which the crude mixture was evaporated and purified by
chromatography on silica gel (EtOAc–hexanes = 3:1) to
furnish compound 8d.
Yield 38 mg (52%). [α]D25 +54.4 (c 0.4, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 6.24 (t, J = 3.3 Hz, 1 H), 5.91 (s, 1
H), 5.52 (t, J = 4.2 Hz, 1 H), 5.41 (m, 1 H), 4.92 (t, J = 3.9
Hz, 1 H), 4.22 (m, 2 H), 4.05–3.87 (m, 4 H), 3.57 (d, 2 H),
3.13 (m, 1 H), 2.87 (m, 1 H), 2.63 (m, 1 H), 2.03 (t, 3 H), 1.30
(t, 3 H). 13C NMR (75 MHz, CDCl3): δ = 174.9, 165.8, 152.1,
143.0, 135.9, 125.5, 119.8, 109.5, 101.6, 72.2, 64.3, 59.4,
41.2, 29.6, 28.3, 13.0, 8.9. HRMS (EI): m/z calcd for
C18H22O7 [M]+: 350.1366; found: 350.1364. IR (neat): 2962,
2904, 1779, 1714, 1634, 1406, 1260, 1196, 1024, 947, 795
cm–1.
(13) A solution of 13 (15 mg, 0.042 mmol) in a mixture of MeOH
(50 μL) and Et2O (35 μL) was stirred and cooled to –40 °C.
Bromine (7.1 μL, 0.044 mmol) in dry MeOH (0.1 mL) was
added dropwise over 5 min. After addition, stirring was
continued for an additional 10 min. The mixture was
saturated with NH3 gas to pH 8, allowed to warm to r.t.,
diluted with Et2O and concentrated. The residue was purified
by flash chromatography (silica gel, 1:1 EtOAc–hexanes) to
afford a 1:1 mixture of 15 and 3-epi-15.
(2S,3S,2′S)-3-[1,3]Dioxolan-2-yl-3′-methyl-3,4-dihydro-
2H,2′H-[2,2′]bifuranyl-5,5′-dione (8d)
Yield 331 mg (65%), [α]D25 +3.6 (c 0.3, MeOH), colorless
crystals, mp 97–98 °C. 1H NMR (300 MHz, CDCl3): δ =
5.87 (m, 1 H), 4.94 (d, J = 4.1 Hz, 2 H), 4.69 (dt, J = 11.7,
5.8 Hz, 1 H), 4.10–3.86 (m, 4 H), 3.03 (td, J = 9.9, 4.4 Hz, 1
H), 2.79 (m, 1 H), 2.49 (dd, J = 18.0, 5.4 Hz, 1 H), 2.16 (dd,
J = 12.3, 1.0 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ =
175.1, 172.2, 164.3, 118.3, 103.3, 84.5, 75.7, 65.8, 40.1,
29.4, 14.0. HRMS (EI): m/z calcd for C12H13O6 253.0712 [M
– H]+; found: 253.0710. IR (neat): 2932, 2902, 2864, 1779,
1730, 1646, 1402, 1266, 1188, 1147, 1089, 1019, 975, 899
cm–1.
2-[(2S,2′S,3′S)-3′-[1,3]Dioxolan-2-yl-2-methoxy-3-
methyl-5′-oxo-2′,3′,4′,5′-tetrahydro-2H-[2,2′]bifuranyl-
(5Z)-ylidenemethyl]acrylic Acid Ethyl Ester (15)
Yield 8.8 mg, 55%. 1H NMR (300 MHz, CDCl3): δ = 6.34 (s,
1 H), 6.18 (q, J = 1.4 Hz, 1 H), 5.41 (d, J = 5.1 Hz, 1 H), 4.85
(d, J = 3.5 Hz, 1 H), 4.50 (d, J = 2.1 Hz, 1 H), 4.28–4.18 (m,
2 H), 4.00–3.85 (m, 4 H), 3.47 (s, 2 H), 3.14 (s, 2 H), 2.84
(m, 1 H), 2.68 (m, 1 H), 2.42 (m, 1 H), 1.95 (s, 3 H), 1.31 (t,
J = 3.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 176.7,
166.9, 157.6, 141.2, 133.7, 127.1, 124.1, 115.0, 103.9, 94.0,
81.1, 65.8, 61.3, 50.9, 50.4, 38.4, 28.9, 14.1, 12.4. HRMS
(EI): m/z calcd for C19H24O8 [M]+: 380.1471; found:
380.1478. IR (neat): 2904, 1782, 1710, 1636, 1447, 1366,
1244, 1130, 1021, 957, 942, 852 cm–1.
(8) Details on this X-ray crystal structure can be obtained from
the Cambridge Crystallographic Data Center quoting CCDC
901653; see also the Supporting Information.
(9) (a) Gawronski, J. K.; Chen, Q. H.; Geng, Z.; Huang, B.;
Martin, M. R.; Mateo, A. I.; Brzotowska, M.; Rychilewska,
U.; Feringa, B. L. Chirality 1997, 9, 537. (b) Gawrosnki, J.
K.; van Oeveren, A.; van der Deen, H.; Leung, C. W.;
Feringa, B. L. J. Org. Chem. 1996, 61, 1513. (c) Zanardi, F.;
Battistini, L.; Rassu, G.; Pinna, L.; Mor, M.; Culeddu, N.;
Casiraghi, G. J. Org. Chem. 1998, 63, 1368. (d) Jefford, C.
W.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1987, 28,
4037. (e) Figadere, B.; Chaboche, C.; Peyrat, J. F.; Cave, A.
Tetrahedron Lett. 1993, 34, 8093. (f) Zanardi, F.; Battistini,
L.; Rassu, G.; Auzzas, L.; Pinna, L.; Marzocchi, L.;
Acquotti, D.; Casiraghi, G. J. Org. Chem. 2000, 65, 2048.
(10) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
(14) (a) Kamel, H. N.; Ferreira, D.; Garcia-Fernandez, L. F.;
Slattery, M. J. Nat. Prod. 2007, 70, 1223.
(b) Venkateswarlu, Y.; Sridevi, K. V.; Rama Rao, M. J. Nat.
Prod. 1999, 62, 756. (c) Epifánio, R. de A.; Maria, L. F.;
Fenical, W. J. Braz. Chem. Soc. 2000, 11, 584. (d) Sánchez,
M. C.; Ortega, M. J.; Zubia, E.; Carballo, J. L. J. Nat. Prod.
2006, 69, 1749. (e) Grote, D.; Dahse, H.-M.; Seifert, K.
Chem. Biodiversity 2008, 5, 2449.
(15) Leading review: Reissig, H.-U.; Zimmer, R. Chem. Rev.
2003, 103, 1151.
Synlett 2012, 23, 2909–2912
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