A general, flexible, ring closing metathesis (RCM) based strategy for accessing the fused furo[3,2-b]furanone moiety present in diverse bioactive natural products

Article abstract of DOI:10.1016/j.tetlet.2013.08.021

A simple and straightforward methodology of general utility to construct sterically encumbered furo[3,2-b]furanone scaffolds present in a diverse range of bioactive natural products is delineated. The methodology emanates from readily available Morita-Baylis-Hillman adducts and employs sequential ring closing metathesis and oxy-Michael addition cascade as the key steps.

Full text of DOI:10.1016/j.tetlet.2013.08.021

Accepted Manuscript
A general, flexible, ring closing metathesis (RCM) based strategy for accessing
the fused furo[3,2-b]furanone moiety present in diverse bioactive natural prod‐
ucts
Ali Mohd Lone, Bilal Ahmad Bhat, Goverdhan Mehta
PII:
S0040-4039(13)01363-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.021
TETL 43383
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
24 June 2013
30 July 2013
1 August 2013
Please cite this article as: Lone, A.M., Bhat, B.A., Mehta, G., A general, flexible, ring closing metathesis (RCM)
based strategy for accessing the fused furo[3,2-b]furanone moiety present in diverse bioactive natural products,
Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.021
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Graphical Abstract
A general, flexible, ring closing metathesis (RCM) basedLeave this area blank for abstract info.
strategy for accessing the fused furo[3,2-b]furanone
moiety present in diverse bioactive natural products
Ali Mohd Lone,a Bilal Ahmad Bhata , Goverdhan Mehtab*
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Tetrahedron Letters
journal homepage: www.elsevier.com
A general, flexible, ring closing metathesis (RCM) based strategy for accessing the
fused furo[3,2-b]furanone moiety present in diverse bioactive natural products
Ali Mohd Lone,a Bilal Ahmad Bhata , Goverdhan Mehtab*
aIndian Institute of Integrative Medicine (CSIR), Sanatnagar-Srinagar190005, India
bSchool of Chemistry, University of Hyderabad, Hyderabad 500046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and straightforward methodology of general utility to construct sterically encumbered
furo[3,2-b]furanone scaffolds present in a diverse range of bioactive natural products is
delineated. The methodology emanates from readily available Morita-Baylis-Hillman adducts
and employs sequential ring closing metathesis and oxy-Michael addition cascade as the key
steps.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Ring closing metathesis
Furo[3,2-b]furanone
Natural products
Baylis-Hillman adducts
Sterically encumbered
Functionally embellished furo[3,2-b]furanone moiety has been
widely encountered as a distinctive sub-structure among a diverse
range of natural products of mixed biosynthetic origin.
Representative examples of natural products incorporating the
furo[3,2-b]furanone segment (in red) ) as part of their complex
architecture are neovibsanin A & B (1, 2),1 lactonamycin (3),2
exhibit a range of biological activities ranging from cytotoxic,
anti-HIV to cardiac SR-Ca2+ ATPase activators etc.3-5,8 Thus, the
furo[3,2-b]furanone core appears to be a promising and potent
pharmacophoric group that imparts considerable therapeutic
value to the natural products that embody it. This attribute along
with the complex, challenging & diverse natural product
schisandra nortriterpenoids (e,g micrandilactone
A
4),3
5
plumericin (5),4 pallavicinin (6) & neopallavicinin (7) and
plakortones (e,g plakortone E 8).6 All the natural products 1-8
displayed in Figure 1, exhibit wide ranging biological activities
and even 8, based exclusively on the furo[3,2-b]furanone
platform, displays an impressive bioactivity profile.6 For
example, vibsane-type7 natural products 1 & 2 bearing a fused
furo[3,2-b]furanone core along with many of their recently
reported structural siblings7h,k have been found to be potent
promoters of neurite growth with implications in
neurodegenerative disorders.7 By contrast, 3 exhibits significant
levels of antimicrobial activity against methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant
Enterococcus (VRE) strains apart from being cytotoxic against
various tumoral cell lines.2a Similarly, other natural products 4-8
———
Corresponding author. Tel.: +91-1942431253; fax: +91-1942441331; e-mail: bilal@iiim.ac.in (B.A. Bhat); gmsc@uohyd.ernet.in (G. Mehta)

2
H
OMe
O
R2
R1
O
O
A
B
O
OTBDPS
O
O
OTBDPS
O
OTBDPS
O
HO
O
O
C
O
HO
b
a
O
O
OH
9
11
10
Me
N
c
O
O
O
R 1 = OMe, R2 = Me (1)
OH
3
F
H
Ph
Ph
O
Si
R
1 = Me, R2 = OMe (2)
O
O
O
O
OTBDPS
d
e
O
O
H
H
HO
O
H
O
OH
OH
H
O
O
12
14
13
H
O
H
O
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0
°C, 1h, 92%; (b) Allyl bromide, KH, THF, 0 °C, 1h, 83%; (c) Grubbs-Ist,
CH2Cl2, rt, 2h, 93%; (d) Jones reagent, acetone, 0 °C -rt, 1h, 80%; (e) TBAF,
THF, rt, 30 minutes, 95%
H
O
O
O
O
O
O
O
H
OH
O
H
H
5
4
Bearing in mind the promise and relevance of neovibsanin based
scaffold 14 and desirability of creating diversity around it, the
generality of the protocol depicted in Scheme 1 had to be further
demonstrated. Towards this objective, bicyclic intermediate 12
was subjected to OTBDPS deprotection and the resulting allylic
alcohol on PDC oxidation furnished the aldehyde 1513 (Scheme
2). MeLi addition to aldehyde 15 led to a diastereomeric mixture
of secondary alcohols which upon PDC-oxidation directly
furnished the methylketone 16 ( Scheme 2). Jones oxidation in 16
afforded the spiro-fused -butenolide 17. 13 Chemoselective MeLi
addition of 17 furnished an intermediate carbinol 18 which
underwent concomitant oxa-Michael addition to afford ring-B
modified neovibsanin core 19 13 (Scheme 2).
R
H
O
O
O
O
O
O
H
R
H
R = α-H (6)
R = β-H (7)
8
Figure 1. Structure of furo[3,2-b]furanone harbouring natural products
architecture into which furo[3,2-b]furanone core is embedded,
has generated considerable interest in assembling this moiety.9
However, synthetic efforts in this arena have largely focused on
individual natural product targets4,6,7f,7g bearing the furo[3,2-
b]furanone moiety and generally applicable solutions to construct
this system, particularly in sterically constrained environment
have been relatively few.10 In an earlier report, we outlined the
synthesis of a range of furo[3,2-b]furanone scaffolds from
Morita-Baylis-Hillman (MBH) adducts of cyclic enones with
alkyne addition/lactonization and intramolecular oxy-Michael
addition constituting the key steps.11 However, keeping in view
the need for a simpler and versatile approach to furo[3,2-
b]furanone scaffold to enable diversity creation and mapping of
its therapeutic potential, an alternate approach of general utility
was devised. Herein, we disclose this simple and straightforward
methodology to construct a range of sterically constrained
furo[3,2-b]furanones wherein ring closing metathesis (RCM)
constitutes a key step.
O
O
O
a
b
12
O
16
15
O
c
O
O
H
O
O
O
O
d
OH
O
To test the viability of our methodology, the readily available
19
17
18
TBDPS-protected12 MBH-adduct of cyclohexenone and
Scheme 2. Reagents and conditions: (a) (i) TBAF, THF, rt, 30 minutes; (ii)
PDC, CH2Cl2, rt, 2h, 88% (over two steps); (b) (i) MeLi, THF, 0 °C, 30 min.;
(ii) PDC, CH2Cl2, rt, 2h, 90% (over two steps); (c) Jones reagent, acetone, 0
°C-rt, 2h, 82%; (d) MeLi, THF, 0 °C, 30 minutes, 92%.
formaldehyde
9
was subjected to vinylation with
vinylmagnesium bromide to furnish a tertiary alcohol 10, Scheme
1. Allylation of the hydroxyl group in 10 in the presence of
potassium hydride furnished the desired precursor 1113 and setup
the stage for the spiro-annulation of the carbonyl group of 9
through ring closing metathesis. Exposure of 11 to Grubbs-I
catalyst smoothly delivered the spiro-annulated compound 12 in
excellent yield. The spiro-fused dihydrofuran moiety in 12 now
Furthermore, commercially available dimedone was smoothly
converted to the TBDPS-protected MBH-adduct 20 through a
known procedure11b,
and further elaborated to a ring-A
16
substituted neovibsanin scaffold. Thus, 20 was subjected to
vinylation to 21, allylation of the tertiary hydroxyl group in it
yielded 2213 (Scheme 3). RCM in 22 to 23, Jones oxidation to
butenolide 24 and fluoride-mediated desilylation resulted in
concomitant oxa-Michael addition to furnish ring A modified
tricyclic furo[3,2-b]furanone derivative 25.13
required activation to act as
a Michael acceptor. After
considerable trials employing various oxidizing agents14 towards
allylic oxidation in 12, it was found that the classical Jones
reagent,15 readily delivered the required butenolide 1313 with
TBDPS protection remaining intact. TBAF-mediated desilylation
in 13 led to concomitant oxy-Michael addition to afford the
tricyclic furo[3,2-b]furanone 14 whose stereochemistry, as well
as of other oxy-Michael products to follow in the sequel, is based
11b,c
on earlier precedence7l,
and propensity towards preferred
formation of cis- ring junction involving a spiro carbon centre.
Thus, 14 is accessible in a short sequence bearing a segment
ubiquitous among many natural products (see, 1-3), particularly
constituting the ABC core of neovibsanins 1 and 2.

3
O
OH
O
O
O
a
b
O
O
O
O
O
H
d
O
a
b
c
32
OTBDPS
OTBDPS
OTBDPS
22
20
21
O
O
36
38
35
c
37
O
O
d
Scheme 5. Reagents and conditions: (a) (i) TBAF, THF, rt, 30 minutes; (ii)
PDC, CH2Cl2, rt, 2h, 85% (over two steps); (b) (i) MeLi, THF, 0 °C, 30 min.;
(ii) PDC, CH2Cl2, rt, 2h, 80% (over two steps); (c) Jones reagent, acetone, 0
°C-rt, 5h, 87%; (d) MeLi, THF, 0 °C, 30 minutes, 93%.
O
O
O
e
O
OTBDPS
OTBDPS
24
25
23
To further probe the generality of our strategy, it was of interest
to apply it for the construction of the tricyclic furo[3,2-
b]furanone core present in the natural product plumericin 5. This
endeavour emanated from the -OTBDPS protected MBH-adduct
of cyclopentenone and formaldehyde 39.11a Vinylation, O-
allylation, ring closing metathesis and Jones oxidation afforded
compound 43 smoothly via 40-42, Scheme 6. However, when 43
was subjected to TBAF-mediated desilylation, it only led to the
deprotected 44.13 The hydroxymethyl arm of 44 could not be
coaxed into oxa-Michael reaction to deliver 45 even when
hydroxyl activation was provided by exposure to bases like
DBU, KOtBu etc. It appeared that the hydroxylmethyl arm on the
planar, inflexible cyclopentene double bond of 43 could not
manoeuvre the requisite geometry for the intramolecular oxa-
Michael addition to eventuate in a highly strained tricyclic
furo[3,2-b]furanone 45. To substantiate this surmise, it was
decided to execute our strategy on the reduced derivative 46,
obtained by the hydrogenation of 39 (Scheme 7). Vinylation of
the carbonyl group in 46 was stereoselective and furnished 47. O-
allylation to 48 and RCM with Grubbs I catalyst led to 49 in
excellent yield. Jones oxidation on 49 resulted in the -butenolide
50 which on desilylation and subsequent treatment with DBU
underwent oxa-Michael addition to deliver 51,13 a structural
segment present in natural product 5 (Scheme 7).
Scheme 3. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0
°C, 30 min., 92%; (b) Allyl bromide, KH, THF, 0 °C-rt, 1h, 82%; (c) Grubbs-
Ist, CH2Cl2, rt, 2h, 92%; (d) Jones reagent, acetone, 0 °C -rt, 2h, 82%; (e)
TBAF, THF, rt, 30 minutes, 93%
With some degree of confidence in our simple strategy, we
decided to apply it for the construction of the ABC core of
schisandra nortriterpenoids (e,g micrandilactone A, 4 etc.).
Readily available compound 2617 was subjected to
phenylselenylation-H2O2 oxidative elimination to furnish
cycloheptenone 27. DIBAL-H reduction of 27 yielded a diol, in
which the primary hydroxyl group was chemoselectively
protected as TBDPS-derivative 2813 and further oxidation led to
29, formally a protected MBH adduct of cycloheptenone and
formaldehyde (Scheme 4). Compound 29 was smoothly
elaborated to 34 via 30-3313 following the vinylation, tertiary-
alcohol allylation, ring closing metathesis, Jones oxidation and
fluoride mediated deprotection protocol (Scheme 4) outlined
above.
In order to gain access to the ABC core of natural product 4,
installation of a gem-dimethyl substitution in ring-B was
mandated. This was achieved through a diversion, akin to that
described in Scheme 2, from the spiro-fused dihydrofuran
13
derivative 32. Elaboration of 32 to tricyclic 38, representing
ABC core of micrandilactone-A 4 through the intermediacy of
35-3713 is displayed in Schme 5 and reaffirms the efficacy of our
short sequence for the construction of the fused furo[3,2-
b]furanone system.
Finally, the methodology was tested to target the furo[3,2-
b]furanone scaffold present in plakortones represented by natural
product 8. In this endeavor, commercially available 3,5-
heptandione 52 was subjected to selective vinyl addition to afford
53. The tertiary hydroxyl group in 53 could be esterified with
acrolylchloride to 5413 and further ring closing metathesis using
Gubbs-II catalyst furnished the -butenolide 55. Chemoselective
O
HO
O
a
b
O
O
O
O
OTBDPS
28
OH
O
O
26
27
a
b
c
O
HO
O
d
e
OTBDPS
40
OTBDPS
OTBDPS
39
41
c
O
O
OTBDPS
OTBDPS
OTBDPS
O
O
O
31
30
29
O
d
X
f
O
O
OR
O
O
O
H
OTBDPS
45
42
43. R = TBDPS
44. R = H
g
h
e
O
Scheme 6. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0
°C, 30 min., 88%; (b) Allyl bromide, KH, THF, 0 °C, 1h, 89%; (c) Grubbs-
Ist, CH2Cl2, rt, 3h, 93%; (d) Jones reagent, acetone, 0 °C -rt, 2h, 83%; (e)
TBAF, THF, rt, 1h, 92% .
OTBDPS
OTBDPS
34
32
33
Scheme 4. Reagents and conditions: (a) (i) PhSeBr, LDA, THF, -78 °C; 2h;
(ii) H2O2, CH2Cl2, °C , 30 minutes, 85% (over two steps); (b) (i) DIBAL-H,
THF, rt, 2h; (ii) TBDPSCl, DMAP, imidazole, DMF, 6h, 70% (over two
steps); (c) PCC, CH2Cl2, rt, 2h, 91%; (d) vinylmagnesium bromide, THF, 0
°C, 30 minutes, 90%; (e) Allyl bromide, KH, THF, 0 °C-rt, 1h, 80%; (f)
Grubbs-Ist, CH2Cl2, rt, 3h, 89%; (g) Jones reagent, acetone, 0 °C -rt, 5h, 80%;
(h) TBAF, THF, rt, 30 minutes, 92%.

4
OTBDPS
OTBDPS
OH
TBDPSO
c
1999, 40, 6261; (c) Kubo, M.; Chen, I.-S.; Fukuyama, Y. Chem.
Pharm. Bull. 2001, 49, 242; (d) Fukuyama, Y.; Kubo,M.; Minami, H.;
Yuasa, H.; Matsuo, A.; Fujii, T.; Morisaki, M.; Harada, K.
Chem.Pharm. Bull. 2005, 53, 72; (e) Fukuyama, Y.; Fujii, H.; Minami,
H.; Takahashi, H.; Kubo, M. J. Nat. Prod. 2006, 69, 1098; (f) Gallen,
M. J.; Williams, C. M. Org. Lett. 2008, 10, 713; (g) Chen, A. P. J.;
Williams, C. M. Org. Lett. 2008, 10, 3441; (h) Fukuyama, Y.; Kubo,
M.; Esumi, T.;Harada, K.; Hioki, H. Heterocycles 2010, 81, 1571; (i)
Chen, A. P.-J.; Muller, C. C.; Cooper, H. M., Williams, C. M.
Tetrahedron 2010, 66, 6842; (j) Fykuyama, Y.; Kubo, M. Curr. Top.
Phytochem. 2011, 10, 39; (k) Imagawa, H.; Saijo, H.; Yamaguchi, H.;
Maekawa, K.; Kurusaki, T.; Yamamoto, H.; Nishizawa, M.; Oda, M.;
Kabura, M.; Nagahama, M.; Sakurai, J.; Kubo, M.; Nakai, M.; Makino,
K.; Ogata, M.; Takahashi, H.; Fukuyama, Y. Biorg. Med. Chem.Lett.
2012, 22, 2089; (l) Jeffrey, Y.; Mak, W.; Williams, C. M. Nat. Prod.
Rep. 2012, 29, 429.
(a) Xiao, W.-L.; Li, R.-T.; Huang, S. -X.; Pu, J. -X.; Sun, H.-D. Nat.
Prod. Rep. 2008, 25, 871; (b) Toyota, M.; Saito, T.; Asakawa, Y.
Chem.Pharm. Bull. 1998, 46, 178.
(a) Francisco, C. G.; Freire, R.; Herrera, A. J.; Perez-Martin, I.; Suarez,
E. Org. Lett. 2002, 4, 1959; (b) Henessian, S.; Marcotte, S.; Machaalani,
R.; Huang, G. Org. Lett. 2003, 5, 4277; (c) Mori, K.; Takaishi, H.
Tetrahedron 1989, 45, 1639; (d) Hayes, P. Y.; Kitching, W. J. Am.
Chem. Soc. 2002, 124, 9718; (e) Bhaket, P.; Morris, K.; Stauffer, C. S.;
Datta, A. Org. Lett. 2005, 7, 875; (f) Somfai, P. Tetrahedron 1994, 50,
11315; (g) Mallareddy, K.; Rao, S. P. Tetrahedron 1996, 52, 8535.
O
b
a
39
O
46
47
48
d
TBDPSO
TBDPSO
f
H
O
H
O
e
O
O
O
O
50
51
49
Scheme 7. Reagents and conditions: (a) H2, Pd/C, Hexane, rt, 2h, 92%; (b)
vinylmagnesium bromide, THF, 0 °C, 1h, 90%; (c) Allyl bromide, KH, THF,
0 °C, 1h, 89%; (d) Grubbs-Ist, CH2Cl2, rt, 3h, 93%; (e) Jones reagent,
acetone, 0 °C -rt, 5h, 90%; (f) (i) TBAF, THF, rt, 30 minutes; (ii) DBU, THF,
reflux; 6h, 70% (over two steps).
8.
9.
reduction of the carbonyl group in 5513 with NaBH4 was only
moderately stereoselective and through concomitant oxa-Michael
addition delivered plakortone-type frameworks 56a and 56b13 as
diastereomeric mixture (3:7 respectively), Scheme 8.
Stereostructures of 56a and 56b were deduced from the 2D-NMR
a
based NOE-analysis.
O
10. (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; (b) Kapitán,
P.; Gracza, T. ARKIVOC 2008, 8 and references cited therein.
11. (a) Mehta, G.; Bhat, B. A.; Kumara, T. H. S. Tetrahedron Lett. 2010,
51, 4069; (b) Mehta, G.; Bhat, B. A. Tetrahedron Lett. 2009, 50, 2474;
(c) Mehta, G.; Bhat, B. A.; Kumara, T. H. S. Tetrahedron Lett. 2009,
50, 6597.
O
O
O
O
OH
O
a
b
53
54
52
c
O
12. Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965.
13. All compounds reported here are racemic and were fully characterized
on the basis of IR, 1H NMR, 13C-NMR and HRMS spectral data.
Spectral data of selected compounds: compound 11 IR (neat) 3063,
3013, 2931, 2860, 1462, 1419, 1112, 701 cm-1; 1H NMR (400 MHz,
CDCl3 ) δ 7.68 (4H, m), 7.44-7.35 (6H, m), 6.34 (1H, bs), 5.76 (2H, m),
5.13-4.97 (4H, m), 4.16 (2H, m), 3.85 (1H, dd, J = 10.0 & 5.0 Hz ), 3.63
(1H, dd, J = 10 & 5.0 Hz ), 2.12 (2H, m), 1.92 (1H, m), 1.73-1.59 (3H,
m), 1.08 (9H, s); 13C NMR (100 MHz, CDCl3 ) δ 141.1, 136.9, 135.5
(4C), 133.8, 133.7, 129.5 (2C), 127.6 (4C), 127.5, 126.1, 115.3, 114.2,
79.0, 63.2, 62.2, 31.5, 27.4 (3C), 25.0, 19.5, 19.3; HRMS (ES):
455.2381 [M+Na]+; compound 13 IR (neat) 2931, 2860, 1758, 1101,
695 cm-1; 1H NMR (500 MHz, CDCl3 ) δ 7.71 (1H, d, J = 7.0 Hz), 7.61
(4H, m ), 7.43-7.35 (6H, m), 6.12 (1H, m), 5.97 (1H, d, J = 7.0 Hz),
3.92 (2H, m), 2.18 (2H, m), 1.84 (4H, m), 1.03 (9H, s); 13C NMR (125
MHz, CDCl3 ) δ 172.8, 160.4, 135.5 (4C), 134.8, 133.4, 132.5, 131.5,
129.7 (2C), 127.7 (4C), 120.0, 86.7, 62.8, 34.2, 26.7 (3C), 26.6, 24.9,
19.1; HRMS: 441.1862 [M+Na]+; compound 15 IR (neat) 2922, 2853,
1738, 1643, 1444, 1949 cm-1; 1H NMR (500 MHz, CDCl3 ) δ 9.44, (1H,
s), 6.93 (1H, m), 6.02 (m, 1H), 5.71 (m, 1H), 7.87-4.70 (m, 2H), 2.50-
2.20 (m, 2H), 1.87-170 (m, 4), 13C NMR (125 MHz, CDCl3 ) δ 192.2,
151.3, 141.3, 130.4, 127.0, 86.2, 75.4, 36.3, 26.5, 19.2; HRMS:
197.0721 [M+Na]+; compound 17 IR (neat) 3439, 3088, 2926, 2854,
1761, 1745, 1674, 1631, 1439 cm-1; 1H NMR (400 MHz, CDCl3 ) δ 7.42
(1H, d, J = 8.0 Hz), 7.19 (1H, m), 6.08 (1H, d, J = 8.0 Hz), 2.61-2.33
(2H, m), 2.25 (3H, s), 1.91-1.81 (4H, m); 13C NMR (100 MHz, CDCl3 )
δ 197.0, 173.0, 160.1, 147.2, 136.1, 119.6, 84.0, 35.4, 26.8, 26.2, 18.2;
HRMS: 215.0684 [M+Na]+; compound 19 IR (neat) 2974, 2932, 1774,
1687, 1439, 1406, 1379 cm-1; 1H NMR (400 MHz, CDCl3 ) δ 5.82 (1H,
m), 4.25 (1H, m), 2.75 (2H, bs), 1.87-1.79 (4H, m), 1.62-1.29 (2H, m),
1.33 (6H, s); 13C NMR (100 MHz, CDCl3 ) δ 175.2, 143.1, 124.8, 89.9,
83.2, 80.0, 37.5, 29.9, 29.8, 28.5, 24.3, 17.0; HRMS: 231.0997
[M+Na]+; compound 22 IR (neat) 3072, 3050, 2957, 2932, 2895, 2859,
1962, 1892, 1726, 1678 cm-1; 1H NMR (400 MHz, CDCl3 ) δ 7.72 (4H,
m), 7.44 (6H, m), 6.23 (1H, bs), 5.78 (2H, m), 5.20-4.98 (4H, m), 4.28
(2H, m), 3.81-3.62 (2H, m), 1.97 (2H, bs), 1.85 (1H, d, J = 14.0 Hz),
1.55 1H, d, J = 14.0 Hz), 1.10 (9H, s), 1.05 (3H, s), 0.95 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 141.5, 137.0, 135.7 (2C), 135.5, 133.9,
129.5 (2C), 127.6 (6C), 121.9, 114.9, 113.9, 113.8, 77.8, 62.7, 62.3,
43.8, 39.3, 30.5, 30.4, 26.9 (3C), 26.8, 19.3; HRMS: 483.2696
[M+Na]+; compound 25 IR (neat) 2953, 2870, 1778, 1137, 914 cm-1; 1H
NMR (400 MHz, CDCl3 ) δ 5.88 (1H, m), 4.56-4.51 (1H, m), 4.35 (1H,
d, J = 11.3 Hz), 4.23 (1H, m), 2.74 (2H, bs), 2.04 (2H, m), 1.79 (1H, d,
J = 14.1 Hz), 1.58 (1H, d, J = 14.1 Hz), 1.12 (3H, s), 1.06 (3H, s); 13C
NMR (100 MHz, CDCl3 ) δ 175.4, 133.5, 125.5, 88.7, 83.2, 70.1, 42.1,
39.2, 36.9, 31.8, 29.3, 27.1; HRMS: 231.0997 [M+Na]+; compound 28
IR (neat) 3320, 3034,1624 1613 cm-1; 1H NMR (400 MHz, CDCl3 ) δ
7.77 (4H, m), 7.44 (6H, m), 5.61 (1H, m), 4.58 (1H, m), 4.29 (2H, bs),
3.55 (1H, s), 2.19-1.66 (8H, m), 1.09 (9H, s); 13C NMR (100 MHz,
CDCl3 ) δ 144.1, 135.7, 135.6 (2C), 134.8, 133.1, 133.0, 129.8, 129.5,
128.4, 127.8, 127.7 (3C), 73.1, 69.1, 35.4, 27.2, 26.8 (3C), 26.4, 25.3,
O
O
O
O
KEY NOE
O
O
H
H
d
O
O
+
H
H
56b
55
56a
Scheme 8. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0
°C, 1h, 87%; (b) acrolylchloride, pyridine, THF, 0 °C, 1h, 84%; (c) Grubbs-
II, Toluene, 80 °C, 6h, 92%; (d) NaBH4, CeCl3.7H2O, MeOH, 1h, 80.
In summary, a short, simple and flexible methodology, based on
readily available building blocks has been developed to target
substituted and sterically congested furo[3,2-b]furanone scaffolds
present in a diverse range of bioactive natural products.
Acknowledgments
BAB acknowledges the financial support from the Department of
Science and Technology, India (Grant no. GAP 1199). AML
thanks University Grants Commission, India for the award of a
Junior research fellowship. GM thanks Eli-Lilly and Jubilant
Bhartia Foundations for the generous research support.
References and notes
1.
Fukuyama, Y.; Minami, H.; Takeuchi, K.; Kodama, M.; Kawazu, K.
Tetrahedron Lett. 1996, 37, 6767.
2.
(a) Isolation and biological evaluation: Matsumoto, Y.; Tsuchida, T.;
Maruyama, M.; Kinoshita, N.; Homma, Y.; Iinuma, H.; Sawa, T.;
Hamada, M.; Takeuchi, T.; Heida, N.; Yoshioka, T. J. Antibiot. 1999,
52, 269. (b) Structure determination: Matsumoto, Y.; Tsuchida, T.;
Nakamura, H.; Sawa, R.; Takahashi, Y.; Naganawa, H.; Inuma, H.;
Sawa, T.; Takeuchi, T.; Shiro, M. J. Antibiot. 1999, 52, 276.
(a) Li, R.; Zhao, Q.; Li, S.; Han, Q.; Sun, H.; Lu, Y.; Zhang, L.; Zheng, Q. Org.
Lett. 2003, 5, 1023; (b) Li, R. T.; Han, Q. B.; Zheng, Y. T.; Wang, R. R.;
Yang, L. M.; Lu, Y.; Sang, S. Q.; Zheng, Q. T.; Zhao, Q. S.; Sun, H. D. Chem.
Commun. 2005, 2936.
Trost, B. M.; Balkovec, J. M.; Mao, M, K.‐T. J. Am. Chem. Soc. 1983, 105,
6755.
Wu, C. L.; Liu, H. L.; Uang, H. L.; Phytochemistry, 1994, 35, 822; (b)
Asakawa, Y. Phytochemistry, 2001, 56, 297.
(a) Patil, A. D.; Freyer, A. J.; Bean, M. F.; Carte, B. K.; Westley, J. W.;
Johnson, R. K. Tetrahedron, 1996, 52, 377; (b) Cafieri, F.; Fattorusso,
E.; Taglialatela-Scafati, O.; Rosa, M. D.; Ianaro, A. Tetrahedron, 1999,
55, 13831.
(a) Fukuyama, Y.; Minami, H.; Yamamoto, I.; Kodama, M.; Kawazu,
K. Chem. Pharm. Bull. 1998, 46, 545; (b) Kubo, M.; Minami, H.;
Hayashi, E.; Kodama, M.; Kawazu, K.; Fukuyama, Y. Tetrahedron Lett.
3.
4.
5.
6.
7.

5
19.1; HRMS: 381.2172 [M+H]+; compound 31 IR (neat) 3072, 1892,
1
1678 cm-1; H NMR (400 MHz, CDCl3 ) δ 7.68 (4H, m), 7.41 (6H, m),
6.42 (1H, m), 5.79 (2H, m), 5.14-4.97 (4H, m), 4.15 (2H, m), 3.87-3.65
(2H, m), 2.34-2.19 (2H, m), 1.70-1.56 (6H, m), 1.09 (9H, s); 13C NMR
(100 MHz, CDCl3 ) δ 140.4, 140.1, 135.5 (4C), 135.4, 134.3, 133.9,
133.8, 129.4, 128.9, 127.5 (4C), 115.3, 114.2, 82.9, 64.3, 63.4, 35.3,
26.9 (3C), 26.0, 25.8, 22.8, 19.3; HRMS: 447.2641[M+H]+; compound
33 IR (neat) 3483, 3072, 2932, 2857, 1767, 1461, 1427, 1391, 1261 cm-
1; 1H NMR (400 MHz, CDCl3 ) δ 7.64 (4H, m), 7.60 (1H, d, J = 7.0 Hz),
7.45-7.36 (6H, m), 6.11 (1H, m), 5.94 (1H, d, J = 7.0 Hz), 4.01 (2H, m),
2.43-1.90 (4H, m), 1.81-1.56 (4H, m), 1.04 (9H, s); 13C NMR (100
MHz, CDCl3 ) δ 172.3, 158.1, 137.7, 135.5 (3C), 133.3, 131.1, 129.7,
129.7, 127.6 (6C), 119.5, 92.3, 64.5, 37.9, 26.8 (3C), 26.8, 26.1, 25.5,
19.2; HRMS: 455.2019[M+Na]+; compound 34 IR (neat) 2924, 1773,
1177, 1053 cm-1; 1H NMR (400 MHz, CDCl3 ) δ 5.93, (1H, m), 4.55
(1H, d, J = 12.0 Hz), 4.34(1H, d, J = 12.0 Hz), 4.29 (1H, bs), 2.70 (2H,
m), 2.44-2.20 (2H, m), 2.05-1.82 (4H, m), 1.80-1.42 (2H, m); 13C NMR
(100 MHz, CDCl3 ) δ 175.1, 139.8, 128.0, 93.2, 84.1, 72.1, 35.8, 33.7,
27.6, 27.0, 24.6; HRMS: 217.0841 [M+Na]+; compound 37 IR (neat)
1739, 1715, 1540, 1345 cm-1; 1H NMR (500 MHz, CDCl3 ) δ 7.42 (1H,
d, J = 7 Hz), 7.18 (1H, m), 6.07 (1H, d, J = 7 Hz), 2.54-2.30 (2H, m),
2.25 (3H, s), 1.96-1.76 (6H, m); 13C NMR (125 MHz, CDCl3 ) δ 197.0,
173.0, 160.1, 147.1, 136.0, 119.6, 83.9, 35.4, 29.3, 26.8, 26.2, 18.2;
HRMS: 206.0913 [M]+; compound 38 IR (neat) 2927, 1774, 1540, 1178
cm-1; 1H NMR (400 MHz, CDCl3 ) δ 5.80 (1H, m), 4.28 (1H, d, J = 4.0
Hz), 2.75 (1H, dd, J = 18.0 Hz, 5.0 Hz), 2.65 (1H, d, J = 18.0 Hz), 2.44-
2,33 (1H, m), 2.25-2.16 (1H, m), 2.00-182 (4H, m), 1.73-1.66 (1H, m),
1.57 (3H, s), 1.47-1.42 (1H, m), 1.36 (3H, s); 13C NMR (100 MHz,
CDCl3 ) δ 173.9, 148.4, 128.1, 84.3, 79.9, 77.1, 35.8, 34.6, 29.0, 28.4,
27.4, 27.1, 24.7; HRMS: 245.115 [M+Na]+; compound 44 IR (neat)
3217, 3035, 1737, 1463, 1430 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.39
(1H, d, J = 4.0 Hz), 6.19 (1H, s), 6.09 (1H, d, J = 4.0 Hz), 4.11 (1H, d, J
= 16.0 Hz), 3.99 (1H, d, J =16.0 Hz), 2.65 (1H, m), 2.51 (1H, m), 2.33
(2H, m), 1.7 (1H, s); 13C NMR (100 MHz, CDCl3 ) δ 172.5, 157.9,
140.4, 135.8, 120.5, 99.0, 57.9, 34.4, 30.0; HRMS: 166.1735 [M]+;
compound 51 IR (neat) 3856, 3752, 3397, 2927, 2855, 1785, 1598,
1458, 1261 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.80 (1H, m), 3.70 (1H,
m), 3.58 (1H, m), 2.56 (1H, m), 2.33-2.21 (2H, m), 1.81 (1H, m), 1.56
(3H, m), 1.45-1.29 (2H, m); 13C NMR (100 MHz, CDCl3 ) δ 175.4,
95.1, 91.6, 78.9, 53.2, 37.8, 36.1, 29.9, 25.4; HRMS: 191.0684 [M+Na]+
; compound 54 IR (neat) 3045, 1716, 1625, 1421 cm-1; 1H NMR (400
MHz, CDCl3) δ 6.40 (1H, d, J = 17.2 Hz), 6.12 (1H, dd, J = 10.4, 17.6
Hz), 5.94 (1H, dd, J = 11.2, 17.6 Hz), 5.82 (1H, d, J = 16.4Hz), 5.22
(2H, m), 3.26 (1H, d, J = 15.2 Hz), 3.13 (1H, d, J =15.6Hz), 2.40 (2H, q,
J = 7.2 Hz), 2.23 (1H, m), 1.90 (1H, m), 1.01 (3H, t, J = 7.6 Hz), 0.83
(1H, t, J = 7.6 Hz); HRMS: 233.1154 [M+Na]+; compound 55 IR (neat)
1
3033, 1734, 1617, 1511 cm-1; H NMR (400 MHz, CDCl3) δ 7.66 (1H,
d, J = 6.0 Hz), 6.05 (1H, d, J = 5.6 Hz), 3.10 (1H, d, J = 16.4 Hz), 2.73
(1H, d, J = 16.4 Hz), 2.45 (2H, q, J = 7.2 Hz), 1.89 (2H, m), 1.03 (3H, t,
J =7.2Hz), 0.83 (3H, t, J = 7.2Hz); 13C NMR (100 MHz, CDCl3 ): δ
207.4, 172.1, 159.1, 121.0, 89.1, 49.1, 37.2, 29.2, 7.6, 7.4; HRMS:
205.0841 [M+Na]+ ; compound 56b IR (neat) 2927, 2855, 1785, 1598,
1458 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.22 (1H, m), 3.88 (1H, m),
2.73 (2H, m), 2.22 (2H, m), 1.5-1.1 (10H, m); 13C NMR (100 MHz,
CDCl3): δ 175.3, 96.7, 81.1, 80.9, 42.4, 36.7, 29.6, 28.1, 10.1, 8.3;
HRMS: 185.1098[M+H]+
14. (a) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149;
(b) Muzart, Jacques. Tetrahedron Lett. 1987, 28, 4665 and references
cited therein.
15. Harding, K. E.; May, L. M.; Dick, K. F. J. Org. Chem. 1975, 40, 1664
16. Wińska, K.; Grudniewska, A.; Chojnacka, A.; Białońska, A.;
Wawrzeńczyk, C. Tetrahedron Asymmetry, 2010, 8, 670.
17. Liu, H,-J.; Yeh, W,-L.; Browne, E. N. C. Can. J. Chem. 1995, 73, 135.