Tandem alkylation - Michael addition to vinylogous carbonates for the stereoselective construction of 2,3,3,6-tetrasubstituted tetrahydropyrans

Article abstract of DOI:10.1021/ol900721q

A stereoselective method for the synthesis of substituted tetrahydropyran derivatives employing a tandem S_N2-Michael addition sequence to vinylogous carbonates is developed. The method is extended to the synthesis of bicyclic ether motifs present in polyether ladder toxins.

Full text of DOI:10.1021/ol900721q

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2519-2522
Tandem Alkylation-Michael Addition to
Vinylogous Carbonates for the
Stereoselective Construction of
2,3,3,6-Tetrasubstituted
Tetrahydropyrans
Santosh J. Gharpure* and S. Raja Bhushan Reddy
Department of Chemistry, Indian Institute of Technology Madras,
Chennai - 600036, India
sjgharpure@iitm.ac.in
Received April 5, 2009
ABSTRACT
A stereoselective method for the synthesis of substituted tetrahydropyran derivatives employing a tandem SN2-Michael addition sequence to
vinylogous carbonates is developed. The method is extended to the synthesis of bicyclic ether motifs present in polyether ladder toxins.
The ubiquitous presence of tetrahydropyran (THP) moieties
in important bioactive cyclic ethers has provided impetus to
the research directed at new methods for the synthesis of
THP derivatives. Over the years, vinylogous carbonates or
ꢀ-(alkoxy)acrylates have come to the fore as excellent radical
acceptors. Consequently, a plethora of methods have been
developed for the construction of THP derivatives using alkyl
and acyl radical cyclization to vinylogous carbonates under
a variety of conditions.1 Recently, we were able to demon-
strate the utility of alkyl radical cyclization to vinylogous
carbonates for the stereoselective synthesis of new oxa-cage
compounds.2 In contrast, vinylogous carbonates have been
sparingly used for the synthesis of THPs under nonradical
conditions; e.g., acid-promoted Prins cyclization to vinylo-
gous carbonates has been used for the construction of the
2,4,6-trisubstituted THP derivatives.3 Vinylogous carbonates
have been shown to participate in intramolecular Setter
reaction involving carbanion intermediates in a Michael
fashion in the synthesis of tetrahydrofurans (THFs)4 and very
recently in the synthesis of THPs.5 These reports not
withstanding, in general, the utility of vinylogous carbonates
as Michael acceptors under nonradical conditions for the
synthesis of THPs is still largely underdeveloped.
(1) 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) Kang, E. J.; Cho, E. J.; Ji, M. K.; Lee, Y. E.; Shin,
D. M.; Choi, S. Y.; Chung, Y. K.; Kim, J. S; Kim, H. J.; Lee, S. G.; Lah,
M. S.; Lee, E. J. Org. Chem. 2005, 70, 6321. (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) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811. (f) Evans, P. A.; Raina, S.; Ahsan, K. Chem. Commun.
2001, 2504. (g) Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61,
2252. (h) Leeuwenburgh, M. A.; Litjens, R. E. J. N.; Code´e, 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.
(2) Gharpure, S. J.; Porwal, S. K. Synlett 2008, 242.
(3) (a) Nussbaumer, C.; Frater, G. HelV. Chim. Acta 1987, 70, 396. (b)
Kozmin, S. A. Org. Lett. 2001, 3, 755. (c) Hart, D. J.; Bennett, C. E. Org.
Lett. 2003, 5, 1499. (d) Kwon, M. S.; Woo, S. K.; Na, S. W.; Lee, E. Angew.
Chem., Int. Ed. 2008, 47, 1733.
(4) For some selected examples, 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, and references therein.
10.1021/ol900721q CCC: $40.75
Published on Web 05/15/2009
 2009 American Chemical Society

In the present day when the environmental concerns are very
high, tandem reactions are highly desirable since they generate
several bonds in a “single-pot” operation thereby minimizing
the amount of waste that is generated.6 Recently, we developed
a stereoselective synthesis of 1,2,2-trisubstituted Indane deriva-
tives employing a tandem SN2-Michael addition sequence.7
Herein, we now describe the tandem SN2-alkylation-Michael
addition to vinylogous carbonates for the stereoselective con-
struction of THP derivatives.8 This study further demonstrates
that vinylogous carbonates can act as good Michael acceptors
under nonradical conditions as well.
Table 1. Tandem Alkylation-Michael Addition for the
Synthesis of THPs: Scope of the Nucleophiles
entry
E1
CN
E2
CN
product time (h) yield (%) dra
1
2
3
4
5
6
7
8
3a
CO2Me CO2Me 3b
1aa
1ab
1ac
1ad
1ae
1af
3
8
85
83
0b
68
65
74
0c
-
-
We envisaged that the THP derivative 1 could be
synthesized from the iodide 2 and the active methylene
compound 3 employing a tandem SN2-Michael addition
sequence (Scheme 1). In this transformation, the C3-C4
PhSO2 PhSO2
3c
3d
3e
3f
12
4
-
CN
CN
PhSO2
CO2Et
g19:1
g19:1
g19:1
n.a.
n.a.
8
CO2Me PhSO2
12
12
12
H
CH2NO2 3g
1ag
1ah
CO2Me Ph 3h
0d
a Determined on crude reaction mixtures by 1H NMR. b Only the
alkylation product was obtained even at higher temperature (80 °C). c A
complex mixture of products obtained.10 d Only the alkylation product was
obtained in 25% yield.
Scheme 1. Retrosynthesis for Tetrasubstituted Tetrahydropyrans
found to be a good nucleophile in this transformation leading
to the formation of triester 1ab in good yield (Table 1, entry
2). On the other hand, the reaction of the bis-sulfone 3c
furnished quantitatively only the alkylation product; the
subsequent Michael addition to furnish 1ac did not take place
(Table 1, entry 3). Similarly, the reaction of methyl pheny-
lacetate (3h) with the iodide 2a furnished only the alkylated
product in 25% yield (Table 1, entry 8). These examples
suggested that the alkylation is indeed the first step in this
tandem reaction sequence. Moreover, it is apparent that under
the reaction conditions employed the retro-oxy-Michael
reaction is sufficiently slow allowing for the isolation of the
THPs.9
The iodide 2a was then subjected to reaction with
unsymmetrically substituted nucleophiles such as sulfone-
nitrile 3d, ethyl cyanoacetate (3e), and sulfone-ester 3f which
also gave the corresponding THP derivatives 1ad-af,
respectively, in good yield with excellent diastereoselectivity
(Table 1, entries 4-6). On the other hand, reaction of the
iodide 2a with nitromethane (3g) led to the formation of a
complex mixture (Table 1, entry 7). This is surprising given
that Desmaele et al. have found nitromethane to be a good
nucleophile in a tandem alkylation-Michael reaction se-
quence for the formation of cyclohexane derivatives.8g To
establish the relative stereochemistry of the substituents at
C-2 and C-3, the sulfone-ester 1af was subjected to single-
crystal X-ray diffraction studies, and it was found that the
bulky PhSO2 and CH2CO2Me groups occupy the equatorial
positions whereas the less bulky CN and H occupy the axial
orientation (see Supporting Information). This is presumably
due to the fact that these bulky substituents want to occupy
the equatorial position reducing the 1,3-diaxial interaction.
The relative stereochemistry of the substituents in other cases
was assigned by analogy.
bond of the THP would be formed by an alkylation reaction,
whereas the C2-C3 bond would be formed by the Michael
addition of the active methylene moiety to vinylogous
carbonate. To test the feasibility of the proposed THP
synthesis, the iodide 2a was treated with malononitrile (3a)
in DMF in the presence of Cs2CO3 at room temperature,
which gratifyingly led to the formation of 2,3,3-trisubstituted
THP derivative 1aa in excellent yield. 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
(5) (a) McErlean, C. S. P.; Willis, A. C. Synlett 2009, 233. For an
example of attempted sulfonium ylide annulation of vinylogous carbonates
leading to chromenes, see: Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang, Y. J.
Org. Chem. 2007, 72, 1335. (b) Ye, L.-W.; Sun, X.-L.; Zhu, C.-Y.; Tang,
Y. Org. Lett. 2006, 8, 3853.
(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.
(7) Gharpure, S. J.; Reddy, S. R. B.; Sanyal, U. Synlett 2007, 1889.
(8) 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, 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.
After establishing the scope of the reaction with various
nucleophiles, we turned our attention to using this reaction
for the synthesis of 2,3,3,6-tetrasubstituted tetrahydropyran
(9) This is in contrast to the observation by Tang and coworkers (ref 5)
who found that the Michael addition of sulphonium ylide to vinylogous
carbonates derived from phenol derivatives lead to 2H-chromenes and 4H-
chromenes via a retro-oxy-Michael reaction followed by SN2′ substitution
rather than the cyclopropabenzofuran derivatives.
(10) The complete characterization of some of the products obtained is
underway.
2520
Org. Lett., Vol. 11, No. 12, 2009

derivatives. Initially, the iodides 2b-i were subjected to
reactions with symmetrically substituted active methylene
compounds such as malononitrile (3a) and dimethyl malonate
(3b) to furnish, after tandem alkylation-Michael addition
sequence, the corresponding 2,3,3,6-tetrasubstituted THPs
1ba-hb (Table 2, entries 1-10). The reactions, in general,
Table 2. Tandem Alkylation-Michael Addition for the
Synthesis of 2,3,3,6-Tetrasubstituted THPs: Substrate Scope
Figure 1. ORTEP diagram for the sulfone nitrile 1gd.
time yield
product (h) (%)b dra
entry
R
E1
E2
though the reaction of the iodide 4 with malononitrile (3a)
using cesium carbonate as the base furnished the 2,2,3,3-
tetrasubstituted THP derivative 5 in moderate yield, changing
the base to potassium carbonate improved the yield of the
THP derivative 5 which contained tertiary ether with a
carbethoxy group substitution (Scheme 2). It is also interest-
1
2
3
4
5
6
7
8
9
Me
iPr
2b CN
2c CN
CN
3a
3a
3a
3a
3a
3a
3a
3a
1ba
1ca
1da
1ea
1fa
1ga
1ha
1ia
1bb
1hb
1be
1bd
1bf
1 cd
1gd
1hd
4
6
7
12
5
12
4
70
85
92
7:1
8:1
9:1
CN
CN
CN
CN
CN
CN
CN
PhCH2CH2 2d CN
2-furyl
Cy
2e CN
2f CN
2g CN
80 g10:1
90 g19:1
79 g19:1
74 g19:1
84 g19:1
71 g19:1
81 g19:1
62 g19:1
66 g19:1
55 g19:1
74 g10:1
88 g19:1
81 g19:1
Ph
p-MeO-C6H4 2h CN
p-Me-C6H4 2i CN
7
Me
2b CO2Me CO2Me 3b
12
12
4
10 p-MeO-C6H4 2h CO2Me CO2Me 3b
11 Me
12 Me
13 Me
14 iPr
15 Ph
2b CN
2b CN
2b CO2Me SO2Ph 3f
2c CN
2g CN
CO2Et 3e
SO2Ph 3d
7
Scheme 2
.
2,2,3,3-Tetrasubstituted THP Derivative with
Angular Substitution
12
12
12
10
SO2Ph 3d
SO2Ph 3d
SO2Ph 3d
16 p-MeO-C6H4 2h CN
a Determined on crude reaction mixtures by 1H NMR. b Isolated yields.
were found to be quite efficient and gave the THP derivatives
with excellent diastereoselectivity in most cases (Table 2,
entries 4-10). In a few cases, where the substituent at C-6
was relatively less bulky, moderate selectivities for the THP
derivatives were observed (Table 2, entries 1-3). The cis
stereochemistry of the major diastereomers was confirmed
with the help of NOE experiments.
ing to note here that the reaction proceeds through alkylation
followed by 6-exo Michael addition to “vinylogous carbon-
ate” rather than 7-endo Michael addition to “R-alkoxyacry-
late” motif..
To expand the scope of this tandem alkylation-Michael
addition reaction by incorporating one more stereocenter in
the THP fragment, these iodides were subjected to the
reaction with unsymmetrically substituted active methylene
nucleophiles 3d-f (Table 2, entries 11-16). In all the cases,
the corresponding product was obtained in good yields with
excellent diastereoselectivity. Interestingly, the comparison
of the entry 1 vs 11-13, and entry 2 vs 14 reveals that there
is an increase in the diastereoselectivity while using unsym-
metrical nucleophiles than with symmetrical nucleophiles.
To unambiguously ascertain the relative stereochemistry of
the substituents in the case of unsymmetrical nucleophiles,
the nitrile 1gd was subjected to single-crystal X-ray diffrac-
tion studies (Figure 1). It revealed that the bulkier substituents
at C-2, C-3, and C-6 on the THP ring occupy the equatorial
position, presumably to avoid the 1,3-diaxial interactions.
In the other cases (Table 2, entries 11-14 and 16), the
stereochemistry shown is by analogy to this example.
We envisioned that the construction of the tertiary ether
would be challenging and thereby highlight the synthetic
utility of the developed tandem SN2-Michael reaction. Even
In recent years, there is significant effort directed toward
the synthesis of fused polycyclic ethers.11 Many ladder like
polyether toxins contain trans-fused tetrahydropyran motifs.
To further the scope of our tandem SN2-Michael protocol,
we decided to employ it for the synthesis of fused bicyclic
THP fragments on the iodide 6, which was readily synthe-
sized from tri-O-acetyl-(D)-glucal. We were delighted to see
that the reaction of the iodide 6 with sulfone nitrile 3d under
reoptimized conditions led to the formation of bis-THP
derivative 7 in good yield with excellent diastereoselectivity
Scheme 3. Synthesis of trans-Fused Bicyclic THPs
Org. Lett., Vol. 11, No. 12, 2009
2521

(Scheme 3) The relative orientations of various substitutions
were confirmed with the help of single-crystal X-ray dif-
fraction studies on the sulfone nitrile 7 (Figure 2). This
reaction demonstrated that the method is useful for the
assembly of trans-fused THP rings applicable to polyether
ladder toxins.
tetrasubstituted THP derivatives employing a tandem
SN2-Michael addition sequence. We have demonstrated that
the diastereoselectivity of the reaction can be enhanced by
using unsymmetrical active methylene compounds. It has
been shown that tertiary ether can be introduced on the THP
fragment. Finally, the method has been extended to the
synthesis of fused bis-THP derivatives applicable in poly-
cyclic ether fragments of ladder toxins.
Acknowledgment. We thank CSIR and DST, New Delhi,
for financial support. We appreciate the NMR facility
provided by the DST under the IRPHA program to the
Department of Chemistry, IIT Madras. We thank Indian
National Science Academy, New Delhi, for INSA Medal for
Young Scientist to SJG. We thank Mr. Ramkumar of X-ray
facility of the Department of Chemistry, IIT Madras, for
collecting the crystallographic data.
Supporting Information Available: Synthetic schemes
for the iodide precursors 2, 4, and 6, the spectral data for
the compounds 1, 2, and 4-7, and X-ray analysis of the
sulfones 1af, 1gd, and 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL900721Q
Figure 2. ORTEP diagram for the sulfone nitrile 7.
(11) For some recent reviews, see: (a) Sasaki, M.; Fuwa, H. Nat. Prod.
Rep. 2008, 25, 401. (b) Valentine, J. C.; McDonald, F. E. Synlett 2006,
1816. (c) Clark, J. S. Chem. Commun. 2006, 3571. (d) Inoue, M. Chem.
ReV. 2005, 105, 4379. (e) Nakata, T. Chem. ReV. 2005, 105, 4314. (f)
Marmsater, F. P.; West, F. G. Chem.sEur. J. 2002, 8, 4346.
In conclusion, we have developed a concise, stereoselec-
tive, and efficient approach toward the synthesis of 2,3,3,6-
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Org. Lett., Vol. 11, No. 12, 2009