An expeditious, bidirectional synthesis of furofuranones: A new application of Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2009.09.059

A concise, flexible approach of general utility to the furo[3,2-b]furanones from readily available Morita-Baylis-Hillman adducts is delineated. In an expeditious variant of this approach, a four-step cascade process is executed in a one-pot operation to g

Full text of DOI:10.1016/j.tetlet.2009.09.059

Tetrahedron Letters 50 (2009) 6597–6600
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expeditious, bidirectional synthesis of furofuranones: a new application
of Morita–Baylis–Hillman adducts
*
Goverdhan Mehta , Bilal Ahmad Bhat, T. H. Suresha Kumara
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2009
Revised 3 September 2009
Accepted 11 September 2009
Available online 13 September 2009
A concise, flexible approach of general utility to the furo[3,2-b]furanones from readily available Morita–
Baylis–Hillman adducts is delineated. In an expeditious variant of this approach, a four-step cascade pro-
cess is executed in a one-pot operation to generate the furofuranoid framework containing two quater-
nary centers.
Ó 2009 Elsevier Ltd. All rights reserved.
Natural products based on the furo[3,2-b]furanone framework
such as goniofufurone 11 and plakortones A and B 22 have period-
ically surfaced in the literature. However, the furofuranone motif
has been widely encountered as a dominant sub-structure in a di-
verse range of complex natural products of mixed biosynthesis
including pallavicinin 3,3 norrisolide 4,4 dendrillolide A 5,5 and
more recently, micrandilactone A 66 and its siblings, Figure 1.
Interestingly, not only goniofufurone 1 and plakortones A and B
2, based exclusively on the furo[3,2-b]furanone platform, but even
others such as 3–6, containing this moiety as part of their struc-
ture, exhibit a wide range of biological activities. For example,
plant-derived 1 is known to be cytotoxic to several human cancer
cell lines1 and marine-derived 2 displayed activation of cardiac SR-
Ca2+-pumping ATPase at micromolar concentrations.2,7 Com-
pounds 3–6 have also been found to exhibit a range of biological
activities.8 Thus, the furo[3,2-b]furanone core appears to be a
promising pharmacophoric group and this attribute, along with
the complex natural product architecture into which it is embed-
ded, has generated considerable interest in assembling this moiety.
However, synthetic efforts in this area have mainly focused on a
particular natural product target bearing the furo[3,2-b]furanone
moiety,9,10 and generally applicable solutions to this system are
lacking, barring an approach based on the Pd-mediated carbonyl-
ation of 1,3-diols.11 We report herein a simple, concise methodol-
ogy for assembling diverse furo[3,2-b]furanones from readily
available Morita–Baylis–Hillman (MBH) adducts.12,13
tial propargylation reaction and its manifestation provides access
to either furo[3,2-b]furanone 10 or 12 with swapping of the R1
and R2 substituents. This protocol gives considerable latitude in
terms of the placement of the substituents, particularly with qua-
ternary centers on the furo[3,2-b]furanone framework.
To test the viability of the methodology depicted in Scheme 1,
the readily available TBS-protected MBH adduct 13,13 from methyl
vinyl ketone and formaldehyde, was smoothly propargylated to
H
H
HO
Ph
O
O
O
O
O
O
R
H
HO
1
2 Plakortone A (R = Et),
Plakortone B (R = Me)
H
O
O
H
AcO
O
O
H
O
O
H
H
O
O
H
H
H
3
H
4
H
O
An outline of the methodology is delineated in Scheme 1 involv-
ing propargylation of the MBH adduct (7?8), elaboration to a
O
O
OH
AcO
O
c
-butenolide (8?9) and an oxy-Michael addition (9?10), to
O
H
H
generate the requisite furo[3,2-b]furanone moiety.10 Bi-direction-
ality can be imparted to this overall process by exploiting either
of the two oxygen functionalities of the MBH adduct 7 for the ini-
O
O
H
H
O
H
O
H
O
H
O
H
H
H
OH
5
6
* Corresponding author.
E-mail address: gm@orgchem.iisc.ernet.in (G. Mehta).
Figure 1. Structural diversity in furofuranone-containing natural products.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.059

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G. Mehta et al. / Tetrahedron Letters 50 (2009) 6597–6600
HO
OH
HO
OH
OTBS
Ph
OH
HO HO
R1
R3
O
OTBS
Ph
OTBS
R2
O
OTBS
Ph
HO
R1
HO
HO
a
b
R2
R1
R2
8
7
11
19
20
21
c
O
O
O
O
O
O
O
H
H
O
H
H
O
O
O
d
OTBS
Ph
O
O
O
Ph
O
O
OTBS
R2
+
R1
R3
R2
R2
R1
Ph
R1
24
23
22
10
9
12
Scheme 3. Reagents and conditions: (a) propargyl alcohol, n-BuLi, THF, 0 °C, 6 h,
62%; (b) Lindlar catalyst, H2, MeOH, rt, 2 h, 85%; (c) MnO2, CH2Cl2, rt, 20 h, 92%; (d)
TBAF, THF, rt, 20 min, 94% (23:24, 55:45).
Scheme 1. A general bidirectional approach for the construction of furo[3,2-
b]furanones.
give adduct 14. Regio- and stereoselective hydrogenation of 14 fur-
nished the Z-allylic alcohol 15 and MnO2 oxidation led to the but-
enolide 16. Silyl deprotection in 16 led to concomitant oxy-Michael
addition and generation of the furofuranone 1714 in four steps,
Scheme 2. The placement of the terminal methylene on the furof-
uranone framework was quite useful as it could be oxidatively
cleaved to deliver a versatile bicyclic ketone 18.14 The preceding
sequence emanating from 13 could also be implemented on the
TBS-protected MBH adduct 19,13 derived from methyl vinyl ketone
and benzaldehyde, via propargylation (19?20), regio- and stereo-
selective alkyne reduction (20?21), MnO2 oxidation (21?22) and
silyl deprotection to furnish the readily separable furofuranoid dia-
stereomers 23 and 24 (55:45),14 Scheme 3. The stereochemistry of
23 and 24 was confirmed by X-ray crystal structure analysis of
furofuranone 24.15
The generality of this version of the furofuranone synthesis was
further demonstrated through the preparation of adducts 25 and
26, readily obtainable in two steps from the TBS-protected
acrolein-formaldehyde MBH adduct 27,13 Scheme 4. Implementa-
tion of the above described four-step protocol on 25
(25?28?29?30?31) and 26 (26?32?33?34?35) led to the
furofuranones 31 and 35,14 respectively.
In a bidirectional variant of our furofuranone approach, the
MBH adduct 3613 of methyl vinyl ketone and propionaldehyde
was transformed into hydroxyketone 38 through Grignard addition
to give 37 and further chemoselective oxidation, Scheme 5. Propar-
gylation of 38 to 39 and selective alkyne reduction led to the key
precursor triol 40.14 MnO2 oxidation of 40 triggered a four-step
cascade process in a one-pot operation to deliver furo[3,2-b]fura-
none derivative 4114 in near quantitative yield, Scheme 5. Interest-
ingly, access to furofuranone 41 is free of any protecting group
manoeuver and its framework has two quaternary centers in place,
a structural feature reminiscent of plakortones 2 and micrandilac-
tone A 6. The efficacy of this cascade process to furofuranone sys-
tems was further demonstrated employing the MBH adduct 4213 of
methyl vinyl ketone and benzaldehyde. Elaboration of 42 to
hydroxyketone 44 via 43 was followed by propargylation to 45
and stereocontrolled partial reduction furnished the triol 46 to
set the stage for the four-step cascade cyclization. Indeed, exposure
of 46 to MnO2 resulted in furofuranone 47 in quantitative yield,14
OH
O
OTBS
OTBS
HO
R
OTBS
a
OHC
b
R
OH
OH
OTBS
25 R =
26 R = Bn
28 R =
32 R = Bn
27
O
OTBS
OTBS
HO
HO
a
e
c
b
O
OH
O
13
14
15
H
O
e
d
c
O
R
O
OTBS
OTBS
HO
R
O
O
O
R
H
H
d
Si
O
O
O
O
O
O
_
31 R =
35 R = Bn
29 R =
30 R =
34 R = Bn
F
33 R = Bn
O
Scheme 4. Reagents and conditions: (a) (i) homoprenyl bromide, Mg, THF, 0 °C,
30 min; benzyl chloride, Mg, THF, 0 °C, 1 h; (ii) Dess–Martin periodinane, CH2Cl2, rt,
2 h, 83% (25) and 52% (26) [over two steps]; (b) propargyl alcohol, n-BuLi, THF, 0 °C,
6 h, 60% (28) and 62% (32); (c) Lindlar catalyst, H2, MeOH, rt, 2 h, 92% (29) and 88%
(33); (d) MnO2, CH2Cl2, rt, 20 h, 90% (30) and 92% (34); (e) TBAF, THF, rt, 20 min, 94%
(31) and 92% (35).
18
17
16
Scheme 2. Reagents and conditions: (a) propargyl alcohol, n-BuLi, THF, 0 °C, 4 h,
66%; (b) Lindlar catalyst, H2, MeOH, rt, 2 h, 94%; (c) MnO2, CH2Cl2, rt, 20 h, 92%; (d)
TBAF, THF, rt, 20 min, 98%; (e) (i) OsO4/NMMO, acetone/H2O (4:1), 55 °C, 20 h, 90%;
(ii) NaIO4, THF/H2O (3:1), 30 min, 60%.

G. Mehta et al. / Tetrahedron Letters 50 (2009) 6597–6600
6599
Scheme 6. Further amplification of this theme with the intent to
probe stereochemical preferences during the installation of the
quaternary center led us to ketone 49 via 48, obtainable in turn
from the MBH adduct 36.13 Propargylation of 49 led to a separable
mixture of diastereomers 50 (7:3) and further selective alkyne
reduction of the major diastereomer led to 51. An MnO2-mediated
oxidative cascade cyclization of 51 furnished 52 (stereostructure
delineated through NOESY)14 in which the ethyl and the homopre-
nyl arms on the furofuranone are trans-disposed, Scheme 7.
In conclusion, a general approach to structurally embellished
O
OH
OH OH
OH
O
b
a
36
37
38
c
OH
HO
HO
O
HO
OH
OH
d
e
HO
OH
furo[3,2-b]furanones,
a motif widely present among natural
products, from readily available Morita–Baylis–Hillman adducts,
involving cascade cyclizations has been outlined. Application of
the methodology delineated here towards the synthesis of micran-
dilactone A 6 as well as the development of its asymmetric variant
is being actively pursued and will be reported shortly.
40
39
O
O
OH
H
O
O
HO
O
HO
O
Acknowledgments
B.A.B. thanks UGC for support through a Dr. D. S. Kothari post-
doctoral fellowship. X-ray data were collected at the CCD facility at
IISc, supported by DST, India, and we thank Mr. Saikat Sen for his
help in crystal structure determination. This research was also sup-
ported by the CBU of JNCASR, Bangalore. G.M. thanks CSIR for the
award of Bhatnagar Fellowship and research support.
41
Scheme 5. Reagents and conditions: (a) CH3I, Mg, Et2O, rt, 1 h, 75%; (b) Dess–
Martin periodinane, CH2Cl2, rt, 2 h, 93%; (c) propargyl alcohol, n-BuLi, THF, 0 °C, 6 h,
62 %; (d) Lindlar catalyst, H2, EtOAc, rt, 30 min, 92%; (e) MnO2, CH2Cl2, rt, 6 h, 96%.
References and notes
O
OH
Ph
OH OH
Ph
OH
O
b
a
1. Fang, X.; Anderson, J. E.; Chang, C.; Fanwick, P. E.; McLaughlin, J. L. J. Chem. Soc.,
Perkin Trans. 1 1990, 1655–1661.
Ph
2. Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.; Westley, J. W.; Johnson, R. K.;
Lahouratate, P. Tetrahedron 1996, 52, 377–394.
42
43
44
3. (a) Wu, C. L.; Liu, H. L.; Uang, H. L. Phytochemistry 1994, 35, 822–824; (b)
Asakawa, Y. Phytochemistry 2001, 56, 297–312.
4. Hochlowski, J.; Faulkner, D. J.; Matsumoto, G.; Clardy, J. J. Org. Chem. 1983, 48,
1141–1142.
5. Sullivan, B. J.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3204–3209.
6. Li, R. T.; Zhao, Q. S.; Li, S. H.; Han, Q. B.; Sun, H. D.; Lu, Y.; Zhang, L. L.; Zheng, O.
T. Org. Lett. 2003, 5, 1023–1026.
7. Caffierei, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Di Rosa, M.; Ianaro, A.
Tetrahedron 1999, 55, 13831–13840.
c
OH
OH
O
HO
HO
H
O
HO
OH
Ph
O
d
e
Ph
Ph
8. (a) Takizawa, P. A.; Yucel, J. K.; Veit, B.; Faulkner, D. J.; Deerinck, T.; Soto, G.;
Ellisman, M.; Malhotra, V. Cell 1993, 73, 1079–1090; (b) Toyota, M.; Saito, T.;
Asakawa, Y. Chem. Pharm. Bull. 1998, 46, 178–180.
47
46
45
9. Selected references: (a) Kim, C.; Hoang, R.; Theodorakis, E. A. Org. Lett. 1999, 1,
1295–1297; (b) Peng, X. S.; Wong, H. N. C. Chem. Asian. J. 2006, 1–2, 111–120;
(c) Semmelhack, M. F.; Hooley, R. J.; Kraml, C. M. Org. Lett. 2006, 8, 5203–5206.
and references cited therein; (d) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008,
73, 2–11 and references cited therein.
Scheme 6. Reagents and conditions: (a) CH3I, Mg, Et2O, rt, 1 h, 80%; (b) Dess–
Martin periodinane, CH2Cl2, rt, 2 h, 90%; (c) propargyl alcohol, n-BuLi, THF, 0 °C, 6 h,
80%; (d) Lindlar catalyst, H2, EtOAc, rt, 30 min, 98%; (e) MnO2, CH2Cl2, rt, 8 h, 99%.
10. (a) Mehta, G.; Bhat, B. A. Tetrahedron Lett. 2009, 50, 2472–2477; (b) Imagawa,
H.; Saijo, H.; Kurisaki, T.; Yamamoto, H.; Kubo, M.; Fukuyama, Y.; Nishizawa, M.
Org. Lett. 2009, 11, 1253–1255; (c) Chen, A. P.-J.; Muller, C. C.; Cooper, H. M.;
Williams, C. M. Org. Lett. 2009, 11, 3758–3761.
11. (a) Paddon-Jones, G. C.; McErlean, C. S. P.; Hayes, P.; Moore, C. J.; Konig, W. A.;
Kitching, W. J. Org. Chem. 2001, 66, 7487–7495; (b) Kapitán, P.; Gracza, T.
ARKIVOC 2008, 8–11 and references cited therein.
O
OH
OH OH
OH
O
a
b
12. For a recent review, see: Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev.
2007, 36, 1581–1588.
13. (a) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539–1552; (b) Shi,
M.; Liu, Y. H. Org. Biomol. Chem. 2006, 4, 1468–1470.
36
48
49
14. All new compounds were fully characterized on the basis of IR, 1H NMR, 13C
NMR and HRMS spectral data. Spectral data of selected compounds: compound
c
OH
O
17 IR (neat) 2924, 2853, 1778, 1233, 1097, 1055, 937 cmÀ1 1H NMR (300 MHz,
;
HO
HO
H
CDCl3) d 5.42 (m, 1H), 5.27 (m, 1H), 4.66–4.60 (m, 1H), 4.44–4.34 (m, 2H), 2.84
(dd, J = 18.3, 5.1 Hz, 1H), 2.74 (d, J = 18.3 Hz, 1H), 1.54 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 174.4, 147.4, 109.9, 89.8, 83.1, 71.2, 36.4, 20.2; HRMS (ES) m/
z calcd for C8H10O3Na (M+Na+): 177.0528; found: 177.0524; compound 18: IR
O
O
OH
OH
OH
e
d
(neat) 2926, 2855, 1777, 1061 cmÀ1 1H NMR (400 MHz, CDCl3) d 4.58 (d,
;
J = 4.2 Hz, 1H), 4.39 (d, J = 18.0 Hz, 1H), 4.06 (d, J = 18.0 Hz, 1H), 2.91–2.89 (m,
2H), 1.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 206.3, 173.5, 83.3, 81.2, 70.2,
36.1, 14.1; HRMS (ES) m/z calcd for C7H8O4Na (M+Na+): 179.1258; found:
52
51
50
179.1261; compound 23: IR (neat) 2956, 2925, 2855, 1784, 1463 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d 7.38–7.26 (m, 5H), 5.49 (s, 1H), 5.36 (s, 1H), 4.96 (s, 1H),
4.42 (d, J = 4.4 Hz, 1H), 2.94–2.82 (m, 2H), 1.62 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 174.9, 152.2, 139.7, 129.1 (3C), 128.3 (2C), 113.6, 91.0, 84.9, 82.4, 36.7,
21.7; HRMS (ES) m/z calcd for C14H14O3Na (M+Na+): 253.0841; found:
Scheme 7. Reagents and conditions: (a) homoprenyl bromide, Mg, THF, 0 °C, 1 h,
80%; (b) Dess–Martin periodinane, CH2Cl2, rt, 2 h, 93%; (c) propargyl alcohol, n-BuLi,
THF, 0 °C, 6 h, 60%; (d) Lindlar catalyst, H2, EtOAc, rt, 30 min, 90%; (e) MnO2, CH2Cl2,
rt, 6 h, 96%.
253.0854; compound 24: IR (neat) 2956, 2925, 2855, 1784, 1463 cmÀ1 1H
;

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G. Mehta et al. / Tetrahedron Letters 50 (2009) 6597–6600
NMR (400 MHz, CDCl3) d 7.40–7.28 (m, 5H), 5.61 (s, 1H), 5.51 (s, 1H), 5.00 (s,
4.8 Hz, 1H), 2.68 (d, J = 18.3 Hz, 1H), 2.02–1.89 (m, 4H), 1.77–1.60 (m, 2H), 1.66
(s, 3H), 1.56 (s, 3H), 1.24 (s, 3H), 0.96 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 174.8, 153.5, 131.8, 123.9, 110.3, 94.4, 86.2, 77.1, 41.0, 37.2, 28.0, 27.1,
25.6, 22.4, 17.6, 8.5; HRMS (ES) m/z calcd for C16H24O3Na (M+Na+): 287.0000;
found: 287.0032.
1H), 4.60 (t, J = 5.4 Hz, 1H), 2.95–2.82 (m, 2H), 1.61 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 174.7, 150.5, 139.6, 128.6 (2C), 128.3 (2C), 126.9, 113.1, 90.3, 83.0,
81.8, 36.6, 20.1; HRMS (ES) m/z calcd for C14H14O3Na (M+Na+): 253.0841;
found: 253.0854; compound 31: IR (neat) 2923, 2855, 1781, 1059 cmÀ1 1H
;
NMR (300 MHz, CDCl3) d 5.38 (s, 1H), 5.29 (s, 1H), 5.07 (t, J = 5.4 Hz, 1H), 4.58
(d, J = 13.5 Hz, 1H), 4.51 (d, J = 5.7 Hz, 1H), 4.35 (d, J = 11.8 Hz, 1H), 2.82 (dd,
J = 18.6, 6.0 Hz, 1H), 2.70 (d, J = 18.5 Hz, 1H), 2.06–1.84 (m, 4H), 1.69 (s, 3H),
1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) d 174.6, 147.0, 133.2, 122.4, 110.1, 92.3,
80.9, 71.2, 36.9, 34.8, 25.6, 22.6, 17.7; HRMS (ES) m/z calcd for C13H18O3Na
(M+Na+): 245.1154; found: 245.1158; compound 35: IR (neat) 2927, 2853,
15. X-ray data were collected at 291 K on a SMART CCD–BRUKER diffractometer
with graphite monochromated Mo K
a radiation (k = 0.7107 Å). The crystal
structure was solved by direct methods (SIR92) and refined by full-matrix least-
squares method on F2 using SHELXL-97. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre, CCDC 727573.
Compound 24: C14H14O3, MW = 230.25, crystal system: Orthorhombic, space
group: P212121, cell parameters: a = 5.4657(8) Å, b = 8.7936(12) Å,
1779, 1054 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.36–7.23 (m, 5H), 5.50 (s, 1H),
;
5.35 (s, 1H), 4.61 (d, J = 12.3 Hz, 1H), 4.44–4.33 (m, 2H), 3.43 (d, J = 14.4 Hz,
1H), 2.93 (d, J = 14.1 Hz, 1H), 2.33 (d, J = 18.6 Hz, 1H), 1.59 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 173.3, 147.7, 134.2 (2C), 130.2, 128.8 (2C), 127.6, 110.2, 91.4,
81.4, 71.1, 40.9, 36.9; HRMS (ES) m/z calcd for C14H14O3Na (M+Na+): 253.0841;
found: 253.0848; compound 41: IR (neat) 2966, 2926, 2854, 1778, 1462, 1198,
c = 25.119(3) Å, V = 1207.3(3) Å3, Z = 4,
= 0.089 mmÀ1
reflections with I > 2
q
calc = 1.267 g cmÀ3
,
F(0 0 0) = 488,
number of l.s. parameters = 155, R1 = 0.0529 for 1023
(I) and 0.0749 for 1341 data. wR2 = 0.1127, GOF = 1.099
l
,
r
for all data. An ORTEP diagram of 24 with 30% ellipsoidal probability is
depicted below.
1054 cmÀ1 1H NMR (300 MHz, CDCl3) d 5.30 (s, 1H), 5.17 (s, 1H), 4.46 (d,
;
J = 5.1 Hz, 1H), 2.79 (dd, J = 18.3, 5.1 Hz, 1H), 2.68 (d, J = 18.3 Hz, 1H), 1.99–1.88
(m, 2H), 1.27 (s, 3H), 1.25 (s, 3H), 0.97 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 174.9, 154.9, 139.2, 109.9, 94.5, 83.6, 37.4, 28.8, 28.1, 27.8, 8.4; HRMS
(ES) m/z calcd for C11H16O3Na (M+Na+): 219.0000; found: 219.0000; compound
47: IR (neat) 2927, 1780, 1187, 1059, 1027 cmÀ1 1H NMR (300 MHz, CDCl3) d
;
7.43–7.35 (m, 5H), 5.24 (s, 1H), 4.99 (s, 1H), 4.62 (m, 1H), 2.73–2.59 (m, 2H),
1.51 (s, 3H), 1.49 (s, 3H); 13C NMR (75 MHz, CDCl3) d 175.0, 158.0, 137.4, 128.6
(2C), 128.4, 125.7 (2C), 113.5, 95.5, 84.6, 82.2, 35.7, 29.3, 28.3; HRMS (ES) m/z
calcd for C15H17O3 (M+H+): 245.1177; found: 245.1182; compound 52: IR (neat)
2961, 2927, 2855, 1780, 1733 cmÀ1 1H NMR (300 MHz, CDCl3) d 5.36 (s, 1H),
;
5.13 (s, 1H), 5.07 (t, J = 7.2 Hz, 1H), 4.47 (d, J = 4.8 Hz, 1H), 2.78 (dd, J = 18.3,