Tandem SN2-Michael addition to vinylogous carbonates for the stereoselective construction of 2,3,3,5-tetrasubstituted tetrahydrofurans

Article abstract of DOI:10.1016/j.tetlet.2010.09.008

A stereoselective method for the synthesis of substituted tetrahydrofuran derivatives employing a tandem alkylation-Michael addition sequence to vinylogous carbonates is developed. The method could be used to synthesize THFs bearing tertiary ethers. Further, the method is extended to the synthesis of adjacent bis-THFs.

Full text of DOI:10.1016/j.tetlet.2010.09.008

Tetrahedron Letters 51 (2010) 6093–6097
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem SN2-Michael addition to vinylogous carbonates for the stereoselective
construction of 2,3,3,5-tetrasubstituted tetrahydrofurans
⇑
Santosh J. Gharpure , S. Raja Bhushan Reddy
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective method for the synthesis of substituted tetrahydrofuran derivatives employing a tan-
dem alkylation-Michael addition sequence to vinylogous carbonates is developed. The method could
be used to synthesize THFs bearing tertiary ethers. Further, the method is extended to the synthesis of
adjacent bis-THFs.
Received 10 August 2010
Revised 30 August 2010
Accepted 1 September 2010
Available online 17 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Tetrahydrofuran
Tandem reactions
Alkylation reaction
Michael reaction
Adjacent bis-tetrahydrofurans
1. Introduction
they generate several bonds in a ‘single pot’ operation thereby
minimizing the amount of waste that is generated.6 Recently, a
The tetrahydrofuran (THF) moiety is present in a variety of natu-
ral products with important biological activity and this has provided
impetus to the research directed at new methods for the synthesis of
THF derivatives.1 Vinylogous carbonates or b-(alkoxy)acrylates have
been proven to be excellent radical acceptors. As a result, a large
number of methods have been developed for the construction of
THF derivatives using alkyl and acyl radical cyclization to vinylogous
carbonates under a variety of conditions.2 Recently, our group has
utilized alkyl radical cyclization to vinylogous carbonates for the
stereoselective synthesis of new oxa-cage compounds.3 In contrast,
vinylogous carbonates have been sparingly used for the synthesis of
THFs under non-radical conditions. Recently, examples have shown
that vinylogous carbonates participate in intramolecular Michael
additions involving carbanion intermediates—most notable being
the use of Stetter reaction for the synthesis of THFs.4 We have
developed a stereoselective intramolecular cyclopropanation of
vinylogous carbonates using carbenes for the construction of
donor–acceptor cyclopropafuranones which were converted into
THF derivatives by opening the cyclopropane ring under radical
conditions.5 However, in general, the utility of vinylogous carbon-
ates as Michael acceptors under non-radical conditions for the
synthesis of THFs is still largely underdeveloped.
stereoselective synthesis of 1,2,2-trisubstituted indane derivatives
employing a tandem SN2-Michael addition sequence was reported
from our lab.7 In a program directed at the synthesis of cyclic
ethers using vinylogous carbonates, we used this tandem SN2-
alkylation-Michael addition to vinylogous carbonates for the ster-
eoselective construction of THP derivatives.8 Herein, we describe
an extension of this approach to the stereoselective synthesis of
2,3,3,5-tetrasubstituted tetrahydrofurans.9 This study further
demonstrates that vinylogous carbonates are excellent acceptors
in Michael addition even under non-radical conditions.
2. Results and discussion
It was envisaged that THF 1 can be assembled by reaction of
the iodide 2 with the active methylene compound 3 in the
presence of appropriate base via a tandem SN2-Michael addition
sequence (Scheme 1). The C3–C4 bond of the THF would be
formed by alkylation reaction whereas the C2–C3 bond would
SN2 alkylation
E1
E2
E1
I
Michael addition
Over the years, tandem reactions have proved to be an effective
tool in developing the environmentally benign processes since
CO2Et
E2
3
R
O
1
R
O
H
H
CO2Et
2
E1, E2 = Electron withdrawing groups
⇑
Corresponding author. Tel.: +91 44 22574228; fax: +91 44 22574202.
E-mail address: sjgharpure@iitm.ac.in (S.J. Gharpure).
Scheme 1. Retrosynthesis for tetrasubstituted tetrahydrofurans.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.008

6094
OH
S. J. Gharpure, S. R. B. Reddy / Tetrahedron Letters 51 (2010) 6093–6097
Table 3
OTs
OTs
O
I
a
c
b
Synthesis of the iodide 2f–h precursors from epoxides 7f–h
CO2Et
CO2Et
OH
OH
O
CO2Et
4a
5a
6a
2a
NaI, AcONa
AcOH
I
I
NMM, CH2Cl2
O
Scheme 2. Reagents, conditions, and yields: (a) TsCl, Py, CH2Cl2, 0 °C–rt, 12 h, 54%;
(b) ethyl propiolate, NMM, CH2Cl2, rt, 3 h, 85%; (c) NaI, acetone, reflux, 12 h, 92%.
CO2Et
R
(Step 1)
(Step 2)
R
OH
R
O
2f-h
8f-h
7f-h
Table 1
Entry
R
Yield (%)
Tandem alkylation-Michael addition for the synthesis of THFs: scope of the
nucleophiles
Step 1
Step 2
E1
1
2
3
Me
BnOCH2
Cy
f
g
h
73
88
74
72
72
77
E2
K2CO3
I
E1
E2
+
CO2Et
CO2Et
1aa-ae
DMF, rt
O
O
H
2a
E1
3a-h
Entry
E2
CN
Product
Time (h)
Yield (%)
dra
1ac in good yield and moderate diastereoselectivity. On the other
hand, when sulfone-nitrile 3d and sulfone-ester 3e were used as
nucleophiles, the corresponding THF derivatives 1ad and 1ae were
obtained in good yields with excellent diastereoselectivity.
1
2
3
4
5
CN
3a
3b
3c
3d
3e
1aa
1ab
1ac
1ad
1ae
3.5
3.5
2.5
12
6.5
79
56
60
71
40
—
—
5:1
P19:1
P19:1
CO2Me
CN
CO2Me
CO2Et
SO2Ph
SO2Ph
CN
The diastereoselectivity in these cases appears to be dependent
on the relative bulk of the susbstituents on the active methylene
compound—higher the difference in the relative bulk, higher the
diastereoselectivity. The stereochemistry shown is on the basis
that the bulkier substituents on the C2 and C3 would occupy the
pseudo-equatorial orientation whereas the smaller substituents
would occupy pseudo-axial positions.7 It is also apparent that un-
der the reaction conditions employed, the retro-oxy-Michael reac-
tion is sufficiently slow allowing for the isolation of the THFs.
After establishing the scope of the reaction with different nucle-
ophiles, we turned our attention to expand the scope of this strat-
egy for the synthesis of 2,3,3,5-tetrasubstituted THF derivatives.
The requisite iodides 2b–e required for the study were prepared
from the vicinal diols 4b–e in a similar manner to that described
for the iodide 2a. Thus, monotosylation of the primary alcohols
4b–e using tosyl chloride and catalytic dibutyltin oxide gave the
tosylates 5b–e, respectively, in good yields.12 Reaction of the alco-
hols 5b–e furnished the vinylogous carbonates 6b–e, which upon
displacement of tosyl group with iodide furnished the correspond-
ing iodides 2b–e in good overall yields. The reactions were
uneventful and are summarized in the Table 2.
CO2Me
Determined on crude reaction mixtures by 1H NMR.
a
be formed by the Michael addition of the active methylene moi-
ety to the vinylogous carbonate.
To test the feasibility of the proposed THF synthesis, preparation
of the iodide 2a (R = H) was undertaken. Thus, ethylene glycol (4a)
on monotosylation furnished the tosylate 5a (Scheme 2). Michael
addition of the alcohol 5a to ethyl propiolate in the presence of
N-methyl morpholine (NMM) resulted in the formation of the corre-
sponding vinylogous carbonate 6a in good yield. Displacement of to-
syl group in the vinylogous carbonate 6a with iodide using
Finkelstein conditions resulted in the formation of the iodide 2a.
Having the requisite iodide 2a in hand, attention was turned to-
ward testing the feasibility of the proposed THF synthesis. Toward
this end, the iodide 2a was treated with malononitrile (3a) in DMF
inthe presence ofK2CO3 atroom temperature, which gratifyingly lead
to the formation of 2,3,3-trisubstituted THF derivative 1aa in
excellent yield (Table 1, entry 1).10,11 To study the scope of the
nucleophiles, the reaction was carried out with a variety of active
methylene compounds. The results are summarized in Table 1.
Dimethyl malonate (3b) was also found to be a good nucleophile in
this transformation leading to the formation of triester 1ab in good
yield (Table 1, entry 2). Even unsymmetrically substituted active
methylene compounds could be used as nucleophiles for the
synthesis of the THF derivatives. Thus, ethyl cyanoacetate (3c) on
reaction with the iodide 2a under optimized condition gave the THF
In another direction, the iodides 2f–h were prepared from the
epoxides 7f–h by a shorter reaction sequence. In this strategy, the
epoxides 7f–h were opened with sodium iodide to the correspond-
ing iodo-alcohols 8f–h in acetic acid. The iodo-alcohols 8f–h on
reaction with ethyl propiolate in the presence of NMM furnished
the corresponding vinylogous carbonates 2f–h in excellent overall
yields (Table 3).
Table 2
Synthesis of the iodides 2b–e from 1,2-diols 4b–e
nBu2SnO
TsCl
CH2Cl2
CO2Et
NMM
NaI
OH
OH
OTs
OH
OTs
I
CH2Cl2
acetone
(Step 3)
CO2Et
CO2Et
(Step 1)
(Step 2)
R
R
R
O
R
O
4b-e
5b-e
6b-e
2b-e
Entry
R
Yield (%)
Step 2
Step 1
Step 3
1
2
3
4
Et
b
c
d
e
90
88
90
76
93
95
76
90
71
79
76
68
iPr
Ph
p-Me-C6H4

S. J. Gharpure, S. R. B. Reddy / Tetrahedron Letters 51 (2010) 6093–6097
6095
Table 4
Tandem alkylation-Michael addition for the synthesis of 2,3,3,5-tetrasubstituted THFs: substrate scope
E1
H
E1
E2
E2
K2CO3
I
+
E1
E2
CO2Et
CO2Et
CO2Et
+
R
DMF, rt
R
O
R
O
O
H
H
H
2b-h
3a-e
cis-1ba-gd
trans-1ba-gd
Entry
R
E1
E2
Product
Time (h)
Yieldsb (%)
dr (cis:trans)a
1
2
3
4
5
6
7
8
9
Et
2b
2c
2d
2e
2f
2g
2h
2f
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CO2Me
SO2Ph
SO2Ph
SO2Ph
SO2Ph
3a
3a
3a
3a
3a
3a
3a
3b
3d
3d
3d
3d
1ba
1ca
1da
1ea
1fa
1ga
1ha
1fb
1cd
1dd
1fd
1gd
3
2.5
3.5
5
4
5
3
5
6
6
79
67
45
47
72
61
69
64
55
41
51
60
2:1
2:1
iPr
Ph
2.3:1
2.1:1
2.5:1
2.4:1
2.4:1
2.7:1
3:1
2.3:1
2.8:1
2:1
p-Me-C6H4
Me
BnOCH2
Cy
Me
CO2Me
iPr
2c
2d
2f
CN
CN
CN
CN
10
11
12
Ph
Me
BnOCH2
10.5
5
2g
a
Determined on crude reaction mixtures by 1H NMR.
Isolated yields.
b
Table 4 outlines the scope of this tandem alkylation-Michael
addition to vinylogous carbonates for the synthesis of 2,3,3,5-tetra-
substituted tetrahydrofurans. The iodides 2b–h were subjected to
the reaction with symmetrically substituted active methylene
compounds like malononitrile (3a) and dimethyl malonate (3b)
to furnish the corresponding THF derivatives 1ba–fb (Table 4,
entries 1–8). In all the cases, the product was formed in good to
excellent yield albeit with moderate diastereoselectivity. With a
view to improve the diastereoselectivity, unsymmetrically substi-
tuted active methylene compound sulfone nitrile 3d was chosen
as the nucleophile. It was reasoned that not only would it expand
scope of the methodology by introducing an additional stereocen-
ter, but it would lead to the tetrasubstituted THF derivatives with
better diastereoselectivity owing to large difference in the relative
bulk of the substituents on the active methylene compound. Thus,
the iodides 2c–g were subjected to reaction with sulfone nitrile 3d
to result in the THF derivatives 1cd–gd, respectively, in good yields
but with only marginal to moderate improvement in diastereose-
lectivity (Table 4, entries 9–12). This was in sharp contrast to what
we had observed for the THP derivatives where the diastereoselec-
tivities obtained with unsymmetrical active methylene com-
pounds as nucleophiles were excellent.8
The low selectivity obtained in the case of THF derivatives can
be attributed to the conformation of THF ring wherein there is
no significant preference for the substituents to be in the pseu-
do-equatorial orientation unlike that for the THP derivatives. The
stereochemistry of major isomer was assigned as cis on the basis
of the NOE experiments. Further, the minor trans isomer of the ni-
trile 1da was subjected to single-crystal X-ray diffraction studies to
unambiguously ascertain the relative stereochemistry of the sub-
stituents in the THF derivatives.13 These studies revealed that the
substituents at C-2 and C-5 on the THF ring occupy the pseudo-
equatorial and pseudo-axial positions, respectively (Fig. 1). In the
other cases, the stereochemistry shown is by analogy to this
example.
Figure 1. ORTEP diagram of the THF derivative trans-1da.
OTs
CO2Et
CN
CN
I
CO2Et
CO2Et
OTs
a
c
b
CO2Et
CO2Et
O
O
OH
O
CO2Et
H
H
5a
9
10
11
Scheme 3. Reagents, conditions, and yields: (a) diethyl acetylene dicarboxylate,
DABCO, CH2Cl2, rt, 4 h, 85%; (b) NaI, acetone, reflux, 12 h, 92%; (c) CH2(CN)2, K2CO3,
DMF, rt, 1 h, 62%.
10. Reaction of the iodide 10 with malononitrile (3a) in the pres-
ence of K2CO3 as base gave the THF derivative 11 with carbethoxy
group as the tertiary substitution (Scheme 3). It is interesting to
note here that the reaction proceeds through alkylation followed
by 5-exo Michael addition to vinylogous carbonate rather than
6-endo Michael addition to a-alkoxy acrylate motif.
Synthesis of cyclic ethers with a tertiary ether is a challenging
task. To highlight the utility of our strategy, it was decided to syn-
thesize the cyclic ether 11 with carbethoxy group as the tertiary
substitution. To this end, the mono-tosyl ethylene glycol (5a)
was reacted with diethyl acetylene dicarboxylate in the presence
of DABCO to furnish the ester 9 as a mixture of geometrical
isomers. Displacement of the tosyl group of the ester 9 with so-
dium iodide in acetone furnished the requisite iodide precursor
The adjacent bis-THF motif is present in a variety of natural
products belonging to annonaceous acetogenin family.14 We envi-
sioned that synthesis of densely substituted adjacent bis-THF
derivative would be challenging and thereby highlight the utility
of the developed tandem alkylation-Michael reaction. Toward this
D-glucose (12), was
converted into the iodide 2i following a sequence which is slightly
different than that described for synthesis of the iodides 2. Thus,
end, the known15 diol 4i, prepared from

6096
S. J. Gharpure, S. R. B. Reddy / Tetrahedron Letters 51 (2010) 6093–6097
O
OH
OH
O
O
O
O
O
O
HO
HO
HO
Me
Me
Me
Me
HO
HO
a
I
MeO
4i
MeO
OH
D-glucose (12)
8i
b
CO2Et
CO2Et
EtO2C
O
O
O
O
Me
Me
O
O
O
O
O
O
O
c
Me
Me
Me
Me
+
I
O
NC
NC
NC
NC
MeO
2i
MeO
cis-1ia
MeO
trans-1ia
Scheme 4. Reagents, conditions, and yields: (a) I2, PPh3, DMF, 0 °C–rt, 12 h, 39%; (b) ethyl propiolate, NMM, CH2Cl2, rt, 7 h, 79%; (c) CH2(CN)2, K2CO3, DMF, rt, 3 h, 67%, dr 1.4:1
(cis:trans).
structures of natural products has been highlighted. This study
has further proved that reactivity of vinylogous carbonates are
not limited to radical reactions but they are excellent Michael
acceptors even under anionic conditions. Further efforts to ex-
pand the scope of the reaction and its application in target direc-
ted synthesis are underway in our laboratory and will be
reported in due course.
Acknowledgments
The authors thank the DST and CSIR, New Delhi for the financial
support. The authors highly appreciate the NMR instrumentation
facility provided by the DST under the IRPHA program to the
Department of Chemistry, IIT Madras. The authors thank the
Department of Chemistry, IIT Madras for providing the X-ray
facility and Mr. Ramkumar for collecting the crystallographic data.
References and notes
1. For reviews on tetrahydrofuran synthesis, see: (a) Boivin, T. L. B. Tetrahedron
1987, 43, 3309; (b) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321; (c)
Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711; (d) Koert,
U. Synthesis 1995, 115; (e) Miura, K.; Hosomi, A. Synlett 2003, 143; (f) Wolfe, J.
P.; Hay, M. B. Tetrahedron 2007, 63, 261; (g) Piccialli, V. Synthesis 2007, 2585.
2. For some selected examples, see: (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M.
Tetrahedron Lett. 1993, 34, 4831; (b) Lee, E. Pure Appl. Chem. 2005, 77, 2073; (c)
Ko, H. M.; Lee, C. W.; Kwon, H. K.; Chung, H. S.; Choi, S. Y.; Chung, Y. K.; Lee, E.
Angew. Chem., Int. Ed. 2009, 48, 2364; (d) Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim,
D. S.; Jung, C. K.; Kwak, H. S.; Park, J. H.; Lee, E.; Hong, C. Y.; Jeong, S. W.; Jeon,
K.; Park, J. H. J. Org. Chem. 2003, 68, 8080; (e) Matsuo, G.; Kadohama, H.; Nakata,
T. Chem. Lett. 2002, 2, 148; (f) Evans, P. A.; Murthy, V. S.; Roseman, J. D.;
Rheingold, A. L. Angew. Chem., Int. Ed. 1999, 38, 3175; (g) Evans, P. A.; Roseman,
J. D. J. Org. Chem. 1996, 61, 2252; (h) Leeuwenburgh, M. A.; Litjens, R. E. J. N.;
Codée, J. D. C.; Overkleeft, H. S.; Van der Marel, G. A.; Van Boom, J. H. Org. Lett.
2000, 2, 1275; (i) Sibi, M. P.; Patil, K.; Rheault, T. R. Eur. J. Org. Chem. 2004, 372;
(j) Chakraborty, T. K.; Samanta, R.; Ravikumar, K. Tetrahedron Lett. 2007, 48,
6389. and references therein.
Figure 2. ORTEP diagram of the THF derivative trans-1ia.
selective monoiodination of the diol 4i gave the iodo-alcohol 8i
which on reaction with ethyl propiolate yielded the requisite
iodo-vinylogous carbonate 2i. Gratifyingly, the reaction of this
iodide 2i under optimized conditions led to the formation of the
adjacent bis-THF derivative 1ia in good yields albeit with only
moderate diastereoselectivity (Scheme 4). However, the two dia-
stereomers could be readily separated by silica gel column
chromatography.
The stereochemistry of trans-isomer trans-1ia was unambigu-
ously established by single-crystal X-ray diffraction studies
(Fig. 2). It is pertinent to mention here that the bis-THF derivative
1ia contains an acetal linkage in one of the THF rings which could
be further functionalized using Lewis acid mediated oxonium gen-
eration followed by trapping with various nucleophiles leading to
C-alkyl/aryl substituted furanoside derivatives.
3. Gharpure, S. J.; Porwal, S. K. Synlett 2008, 242.
4. Henderson, D. A.; Collier, P. N.; Gregoire, P.; Rzepa, P.; White, A. J. P.; Burrows, J.
N.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 2434; For some selected examples of
Stetter reaction in the synthesis THF and THPs, see: (a) Ciganek, E. Synthesis
1995, 1311; (b) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002,
124, 2404; (c) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298; (d) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876; (e) McErlean,
C. S. P.; Willis, A. C. Synlett 2009, 233. and references therein.
5. Gharpure, S. J.; Shukla, M. K.; Vijayasree, U. Org. Lett. 2009, 11, 5466.
6. Reviews: (a) Bunce, R. A. Tetrahedron 1995, 51, 13103; (b) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134; (c) Nicolaou,
K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
3. Conclusion
7. Gharpure, S. J.; Reddy, S. R. B.; Sanyal, U. Synlett 2007, 1889.
8. Gharpure, S. J.; Reddy, S. R. B. Org. Lett. 2009, 11, 2519.
In conclusion, we have developed an efficient synthesis of the
2,3,3,5-tetrasubstituted THF derivatives employing tandem
alkylation-Michael addition to vinylogous carbonates. This
study showed that this method could be used for installing ter-
tiary ether centre in THFs. Further, the utility of this strategy for
the synthesis of adjacent bis-THF derivatives which are part
9. For some selected examples of tandem alkylation-Michael reaction sequence
for the synthesis of heterocycles and carbacycles, see: (a) Bunce, R. A.; Peeples,
C. J.; Jones, P. B. J. Org. Chem. 1992, 57, 1727; (b) Bunce, R. A.; Kotturi, S. V.;
Peeples, C. J.; Holt, E. M. J. Heterocycl. Chem. 2002, 39, 1049; (c) Bunce, R. A.;
Allison, J. C. Synth. Commun. 1999, 29, 2175; (d) Goff, D. A. Tetrahedron Lett.
1998, 39, 1473; (e) Watanabe, H.; Onoda, T.; Kitahara, T. Tetrahedron Lett. 1999,

S. J. Gharpure, S. R. B. Reddy / Tetrahedron Letters 51 (2010) 6093–6097
6097
40, 2545; (f) Le Dreau, M.-A.; Desmaele, D.; Dumas, F.; dAngelo, J. J. Org. Chem.
1993, 58, 2933; (g) Desmaele, D.; Louvet, J.-M. Tetrahedron Lett. 1994, 35, 2549;
(h) Srikrishna, A.; Reddy, T. J.; Kumar, P. P. Synlett 1997, 663; (i) Prabhu, K. R.;
Sivanand, P. S.; Chandrasekaran, S. Angew. Chem., Int. Ed. 2000, 39, 4316; (j) Liu,
H.-J.; Han, Y. J. Chem. Soc., Chem. Commun. 1991, 1484.
81.27 (CH), 80.53 (CH), 76.08 (CH), 61.62 (CH2), 57.97 (CH3), 40.59 (CH2), 39.28
(C), 36.97 (CH2), 26.98 (CH3), 26.36 (CH3), 14.19 (CH3). THF derivative cis-1ia:
mp 92–94 °C; ½a 2D3
ꢀ19.0 (c 1.0, CHCl3); IR (neat) 2987, 2936, 2852, 2252, 1738,
ꢂ
1596, 1459, 1384, 1317, 1257, 1217, 1193, 1166, 1124, 1083, 1022, 889,
857 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 5.85 (d, J = 3.6 Hz, 1H), 4.52 (d,
10. All the compounds exhibited spectral data consistent with their structures.
Melting point, IR, NMR (1H and 13C) and HRMS spectral data for some of the
compounds are as follows: THF derivative 1aa: IR (neat) 2983, 2931, 2183,
1732, 1625, 1450, 1401, 1384, 1369, 1315, 1186, 1147, 1083, 1025, 944,
J = 4.0 Hz, 1H), 4.49 (d, J = 6.4 Hz, 1H), 4.35 (td, J = 7.2, 6.2 Hz, 1H), 4.24 (dd,
J = 5.6, 4.0 Hz, 1H), 4.23 (q, J = 7.2 Hz, 2H), 3.73 (d, J = 3.3 Hz, 1H), 3.40 (s, 3H),
2.96 (ABX, J = 16.8, 7.2 Hz, 1H), 2.90 (ABX, J = 13.6, 7.6 Hz, 1H), 2.89 (ABX,
J = 16.8, 6.0 Hz, 1H), 2.81 (ABX, J = 13.6, 7.2 Hz, 1H), 1.48 (s, 3H), 1.32 (t,
J = 7.2 Hz, 3H), 1.31 (s, 3H); 13C NMR (100 MHz, CDCl3, DEPT) d 168.75 (C),
114.45 (C), 113.52 (C), 112.29 (CH), 105.35 (CH), 83.92 (CH), 81.40 (CH), 81.39
(CH), 80.21 (CH), 76.31 (CH), 61.71 (CH2), 58.17 (CH3), 41.07 (CH2), 38.19 (C),
36.78 (CH2), 26.97 (CH3), 26.38 (CH3), 14.23 (CH3); HRMS (ESI, M+Na+) m/z
calcd. for C18H24N2O7Na 403.1481, found 403.1477.
857 cmꢀ1 1H NMR (400 MHz, CDCl3) d 4.47 (t, J = 6.4, 1H), 4.30–4.15 (m, 1H),
;
3.99 (q, J = 7.7 Hz, 1H), 2.94 (ABX, J = 16.9, 7.1 Hz, 1H), 2.88 (ABX, J = 16.9,
6.1 Hz, 1H), 2.79 (t, J = 6.9 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3, DEPT) d 168.68 (C), 114.15 (C), 113.35 (C), 82.18 (CH), 66.83 (CH2), 61.75
(CH2), 39.49 (CH2), 38.30 (C), 36.82 (CH2), 14.20 (CH3); HRMS (ESI, M+Na+) m/z
calcd. for C10H12N2O3Na 231.0746, found 231.0750. THF derivative cis-1da: IR
(neat) 2986, 2930, 2252, 1805, 1735, 1605, 1494, 1448, 1403, 1372, 1312, 1260,
11. Representative experimental procedure: To a 10 mL oven dried round bottom
flask charged with K2CO3 (256 mg, 1.85 mmol) was added dry DMF (0.2 mL)
1123, 1033, 850, 760, 701 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.45–7.30 (m,
followed by malononitrle (3a) (73.3 mg, 73 lL, 1.11 mmol) under nitrogen
5H), 5.07 (dd, J = 8.8, 6.8 Hz, 1H), 4.68 (t, J = 6.8 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H),
3.18 (ABX, J = 14.0, 6.8 Hz, 1H), 3.14 (ABX, J = 17.2, 6.8 Hz, 1H), 3.03 (ABX,
atmosphere and the mixture was allowed to stir for 15 min. A solution of the
iodo-vinylogous carbonate 2a (100 mg, 0.37 mmol) in dry DMF (0.3 mL) was
added to the reaction mixture over a period of 15 min and allowed to stir at rt
for 3.5 h (TLC control). Reaction mixture was diluted with diethyl ether
(25 mL), washed with water (3 ꢁ 5 mL) and brine and the organic layer was
dried (anhyd Na2SO4). Evaporation of the solvent and purification of the
reisdue on a silica gel column using ethyl acetate/hexanes (1:12) as eluent
furnished the THF derivative 1aa (61 mg, 79%) as a colourless oil.
J = 17.2, 6.8 Hz, 1H), 2.67 (ABX, J = 14.0, 8.8 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3, DEPT) d 168.68 (C), 137.05 (C), 129.26 (CH), 129.11
(2 ꢁ CH), 126.27 (2 ꢁ CH), 114.57 (C), 113.77 (C), 81.94 (CH), 80.59 (CH), 61.86
(CH2), 47.12 (CH2), 38.50 (C), 36.88 (CH2), 14.22 (CH3); HRMS (ESI, M+Na+) m/z
calcd. for C16H16N2O3Na 307.1059, found 307.1056. THF derivative trans-1da:
mp 76–78 °C; IR (neat) 2983, 2924, 2853, 2252, 1736, 1592, 1452, 1407, 1368,
1316, 1186, 1123, 1078, 1022, 764, 704 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d
12. (a) Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V.; Košmrlj, B. J. Am.
Chem. Soc. 2002, 124, 3578; (b) Guillaume, M.; Lang, Y. Tetrahedron Lett. 2010,
51, 579. and references cited therein.
7.45–7.30 (m, 5H), 5.40 (dd, J = 8.6, 6.6 Hz, 1H), 4.88 (dd, J = 7.4, 5.8 Hz, 1H),
4.30–4.20 (m, 2H), 3.26 (ABX, J = 13.4, 6.6 Hz, 1H), 3.04 (ABX, J = 16.4, 7.5 Hz,
1H), 2.98 (ABX, J = 16.4, 5.8 Hz, 1H), 2.74 (ABX, J = 13.4, 8.8 Hz, 1H), 1.32 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3, DEPT) d 168.69 (C), 138.83 (C),
129.22 (2 ꢁ CH), 128.85 (CH), 125.26 (2 ꢁ CH), 113.21 (C), 112.99 (C), 81.15
(CH), 79.43 (CH), 61.81 (CH2), 46.40 (CH2), 39.62 (C), 37.06 (CH2), 14.23 (CH3);
HRMS (ESI, M+Na+) m/z calcd. for C16H16N2O3Na 307.1059, found 307.1056.
THF derivative 11: IR (neat) 2982, 2164, 1736, 1459, 1376, 1298, 1196, 1087,
13. Crystal data for THF derivative trans-1da: Formula: C16H16N2O3; Unit cell
parameters: a 7.3930(3) b 10.1937(4) c 10.5704(5)
a
75.305(2) b 89.822(2)
81.379(2) space group P1; CCDC No. 787425. Crystal data for THF derivative
trans-1ia: formula: 18H24N2O7 unit cell parameters: 10.6929(12) b
c
ꢀ
C
a
8.5506(10) c 11.5532(15) b 107.922(5) space group P21 CCDC No. 787426.
CCDC Nos. 787425 and 787426 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
1024, 855 cmꢀ1 1H NMR (400 MHz, CDCl3) d 4.42 (td, J = 8.4, 5.2 Hz, 1H), 4.40–
;
4.15 (m, 5H), 3.30 (AB, J = 16.0 Hz, 1H), 3.08 (AB, J = 16.0 Hz, 1H), 3.00–2.80 (m,
2H), 1.33 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3,
DEPT) d 167.86 (C), 167.40 (C), 112.97 (C), 112.45 (C), 87.78 (C), 67.76 (CH2),
63.35 (CH2), 61.72 (CH2), 42.09 (C), 40.47 (CH2), 38.39 (CH2), 14.10 (CH3), 13.94
14. (a) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.;
Cortes, D. Nat. Prod. Rep. 2005, 22, 269; (b) Li, N.; Shi, Z.; Tang, Y.; Chen, J.; Li, X.
Beilstein J. Org. Chem. 2008, 4, 48; (c) McLaughlin, J. L. J. Nat. Prod. 2008, 71,
1311; (d) Alali, Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504. and
references cited therein.
15. (a) Chen, C.; Yu, B. Bioorg. Med. Chem. Lett. 2009, 19, 3875; (b) Yadav, J. S.;
Satyanarayana, M.; Raghavendra, S.; Balanarsaiah, E. Tetrahedron Lett. 2005, 46,
8745. and references therein.
(CH3). THF derivative trans-1ia: mp 82–84 °C; ½a D30
ꢀ60.9 (c 1.0, CHCl3); IR
ꢂ
(neat) 2990, 2937, 2825, 2360, 2256, 1745, 1452, 1382, 1312, 1256, 1218, 1190,
1155, 1078, 1022, 882, 850, 645 cmꢀ1 1H NMR (400 MHz, CDCl3) d 5.92 (d,
;
J = 3.6 Hz, 1H), 4.69 (t, J = 6.8 Hz, 1H), 4.59–4.50 (m, 2H), 4.37 (t, J = 3.6 Hz, 1H),
4.30–4.15 (m, 2H), 3.75 (d, J = 3.2 Hz, 1H), 3.38 (s, 3H), 3.00–2.80 (m, 4H), 1.50
(s, 3H), 1.32 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3, DEPT) d
168.50 (C), 113.54 (2 ꢁ C), 112.28 (C), 105.53 (CH), 84.38 (CH), 81.54 (CH),