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This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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DOI: 10.1039/C5OB00376H www.rsc.org/xxxxxx | XXXXXXXX
A novel domino cyclization for the stereoselective synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran derivatives 5
B. V. Subba Reddy,a* N. Prudhvi Raju,a,b B. Someswarao,a,b B. Jagan Mohan Reddy,b B. Sridharc, Kanakaraju Marumudi,d A. C. Kunward
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX First published on the web Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 10
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A novel bicyclization of 2-(2-(hydroxymethyl)-1-methylene-2,3-dihydro-1H-inden-2-yl)ethanol with aldehydes in the presence of 10 mol% BF3.OEt2 in dichloromethane at 0-25 °C affords the biologically relavent indeno[2,1-c]pyran scaffolds in good yields with high selectivity. Similarly the bicyclization of 2-(1-(hydroxymethyl)-2-methylenecyclopentyl)ethanol with aldehydes generates the corresponding cyclopenta[c]pyran derivatives under similar conditions. This method is very useful to produce the hematoxylin and brazilin like scaffolds. Tandem reactions have received great attention because they are highly convergent and extremely useful for organic synthesis.1 They are also called as cascade reactions, which usually combine several transformations in a one-pot synthesis.2 More specifically, Prins cascade process is a highly stereoselective approach for the synthesis of fused/bridged tetrahydropyran systems.3 Recently, a few cascade cyclizations have been reported for the synthesis of novel oxacycles.4 It has been successfully employed for the total synthesis of biologically active natural products.5 Inspired by its versatility, we also reported the synthesis of fused tetrahydropyran derivatives by a domino Prins cyclization of homoallylic substrates with appended nucleophiles.6 However, there are no reports on the synthesis of indeno[2,1-c]pyran scaffolds by means of a tandem Prins strategy. The natural products, Hematoxylum campechianum L. and Caesalpiniasappan L. are used as a natural pigment, and also as a herbal medicine for the treatment of diarrhea, dysentery, dyspepsia, leucorrhea, and diabetic complications.7 Brazilin is a natural product, which is found to display a wide spectrum of biological activities such as hypoglycemic activity, antihepatotoxicity, inhibition of protein kinase C activity, antiplatelet aggregation, induction of immunological tolerance, and antiinflammatory activity (Figure 1).8
Figure 1. Biologically active natural products 60
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___________ 40
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a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India; Fax: +91-40-27160512; Email: [email protected]; Homepage: www.iictindia.org. b Department of Organic Chemistry, Adikavi Nannaya University, Rajahmundry, 533105, India. c Laboratory of Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007,India. d Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India. #Electronic Supplementary Information (ESI) available: Copies of 1H and 13C NMR spectrum of products. see DOI: 10.1039/b000000x/
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This journal is © The Royal Society of Chemistry [year]
Due to their inherent biological profiles and fascinating structural features, we herein report a novel cascade process for the synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran derivatives from aldehydes and exo-olefinic diols. It is an elegant approach for the synthesis of a novel series of dioxacycles with three contiguous stereocenters. At first, we attempted the condensation of exo-endiol (1) with benzaldehyde (2a) using a readily available BF3.OEt2 (10 mol%). To our delight, the reaction proceeded smoothly at room temperature to afford the corresponding indeno[2,1-c]pyran 3a in 80% yield with high selectivity. Encouraged by the above result, we turned our attention to examine the reactivity of different aldehydes. Interestingly, several aromatic aldehydes such as 3-nitro-, 4isopropyl-, 2,4-dichloro- derivatives participated well in this cyclization (entries c, d, e, Table 1). Notably, sterically hindered substrates like 1-naphthaldehyde and 2,4-dichlorobenzaldehyde also gave the desired products in good yields (entries b and e, Table 1). Aliphatic aldehyde, for example pivalaldehyde afforded the product reasonably in good yield (entry g, Table 1). In addition, heteroaromatic aldehyde, i.e. 5-bromothiophene-2carboxyaldehyde was also effective for this conversion (entry f, Table 1). The structure and stereochemistry of product 3d were established by extensive NMR experiments including 2-D Double Quantum Filtered Correlation Spectroscopy (DQFCOSY), Total Correlation Spectroscopy (TOCSY) and Nuclear Overhauser Effect Spectroscopy (NOESY) experiments. The distinctive double doublet at 3.98 ppm in 3d due to 1-H was used initiate the assignments with the help of DQF-COSY, TOCSY and NOESY experiments. It is an interesting molecule with several disconnected spin systems and consequently the TOCSY experiments were very useful. Thus 3-H(pro-S) - 3-H(pro-R) and 4-H(pro-S)-4-H(pro-S) form A-B systems, whereas 1-H, 2-H(proS) and 2-H(pro-R) form a 3-spin system while 5-H(pro-S), 5-
Journal Name, [year], [vol], 00–00 | 1
Organic & Biomolecular Chemistry Accepted Manuscript
ARTICLE TYPE
Organic & Biomolecular Chemistry
Page 2 of 4 View Article Online
DOI: 10.1039/C5OB00376H
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
10
15
RCHO (2) O
OH 10 mol% BF3.OEt 2 O
DCM, 0-25 o C 1
Entry
3 R= aryl, hetero, aliphatic
OH
Aldehyde (2)
Product (3) a
Time (min)
Yield (%) b
CHO a
O
30
80
O
30
85
20
73
45
76
40
75
35
75
40
70
O
CHO b O NO 2
CHO c
O O 2N
20
O
CHO d
O O
Cl
Cl
CHO O
25
Figure 2. Energy minimized structure with characteristic NOE correlations of 3d
30
O
Cl
e
Br
Cl
S
Further the relative stereochemistry of 3e was established by a single crystal X-ray diffraction (Figure 3).9
Br
f
S
O CHO
CHO
g
a All
O
O O
the products were characterized by 1H and 13C NMR spectroscopy. refers to pure product after column chromatography.
b Yield
40
35
Figure 3. ORTEP diagram of 3e Table 1. Synthesis of indeno[2,1-c]pyran derivatives
45
50
The scope of the reaction was further demonstrated using a different exo-endiol, i.e. 2-(1-(hydroxymethyl)-2methylenecyclopentyl)ethanol (4). Accordingly, treatment of 4 with 1-naphthaldehyde in the presence of 10 mol% BF3.OEt2 in dichloromethane at 0-25 °C gave the 3-naphthyltetrahydro1H,5H-4a,7a-(epoxyethano)cyclopenta[c]pyran 5h in 85% yield (entry h, Table 2). Other substrates such as 4-bromo-, 3,4dimethoxy-, 4-cyano-, and 2,4,5-trifluorobenzaldehydes reacted smoothly with 4 to furnish the cyclopenta[c]pyrans in good yields (entries i-l, Table 2). Thiophene-2-carboxaldehyde was also equally effective for this transformation (entry m, Table 2). Aliphatic aldehyde, i.e. isovaleraldehyde also afforded the isobutyl substituted cyclopenta[c]pyran in 70% yield (entry n, Table 2). Indeed, aliphatic aldehydes gave the product relatively in lower yield than aromatic counterpart.
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2 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]
Organic & Biomolecular Chemistry Accepted Manuscript
5
R
H(pro-R), 6-H(pro-S) and 6-H(pro-R) are part of a 4-spin system. It was easy to distinguish the two A-B spin systems, with the proximity of one of them in the pyran ring oxygen, resulting in chemical shifts (δ) around 4 ppm. In the three-spin system the three protons are all dd, with 1-H appearing at 3.98 ppm. Large di-axial coupling constant, 3J1-H/2-H(pro-S) = 12.2 Hz, and axial equatorial coupling constant, 3J1-H//2-H(pro-R) = 2.2 Hz and NOE correlations, 1-H/3-H(pro-R), and 3-H(pro-S)/4-H(pro-R) are consistent with the chair conformation of the six membered ring as shown in the energy minimized structure (Figure 2). The configurations at the quaternary centers and the proposed structure are further supported by characteristic NOE correlations, 4-H(pro-S)/5-H(pro-S), 2-H(pro-S)/5-H(pro-R) and 2-H(pro-S)/6-H(pro-R) provide emphatic support for the structure with six-membered ring taking chair conformation. The energy minimized structure adequately supports the proposed structure of 3d.
Page 3 of 4
Organic & Biomolecular Chemistry View Article Online
Table 2. Synthesis of cyclopenta[c]pyran derivatives
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TOCSY/ HSQC experiments. The prochiral assignments of these protons were made from the nOe correlations (1-H/4-H(pro-S), 2-H(pro-R)/4-H(pro-S), 3-H(pro-S)/5-H(pro-R), 3-H(pro-S)/6H(pro-R) and 6-H(pro-S)/8-H(pro-S)) shown in the energy minimized structure (Figure 4), which is consistent with all the NMR observations (couplings and nOe correlations).
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
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Figure 4. Energy minimized structure with characteristic NOE correlations of 5k 10
55
Mechanistically, we assume that the reaction proceeds through the formation of oxocarbenium ion from cyclic acetal, which is derived from aldehyde and unsaturated diol. A subsequent attack of exo-olefin on oxocabenium ion generates a more stable tertiary-carbocation, which is simultaneously trapped with a tethered hydroxyl group to afford the desired product (Scheme 1).
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The compound 5k, interestingly contains isolated 2-spin, 3-spin, 4-spin and 6-spin systems in the aliphatic region, which were identified with the help of TOCSY experiments. The distinctive double doublet at 4.36 ppm due to 1-H (additionally confirmed from HSQC experiments, as it is the only aliphatic methine proton, other aliphatic protons are from methylene groups.) was used to initiate the assignments with the help of DQF-COSY, TOCSY, NOESY and HSQC experiments. The TOCSY connectivities involving the distinct dd patterns of the 1-H and 2H protons, with large di-axial and small axial-equatorial coupling were assigned as 3J1-H/2-H(pro-S) = 12.2 Hz and 3J1-H//2-H(pro-R) = 2.9 Hz. The isolated two spin system of 3-H protons was identified easily with, having two coupled doublets at 4.05 ppm and 3.43 ppm. The one having strong nOe correlation (at 3.43 ppm) with 1-H was assigned as 3-H (pro-R). The four spin system containing protons H-7 and H-8, with H-7 adjacent to the pyran ring oxygen appearing at about 4 ppm. The prochiral assignments for these protons were made from the 2-H (pro-S)/7-H(pro-R) and 2-H(pro-S)/8-H(pro-R) nOe correlations. The six spin system of protons H-4, H-5 and H-6 is rather complex. However, the chemical shifts of the six protons could be obtained from the This journal is © The Royal Society of Chemistry [year]
Scheme 1. A plausible reaction pathway 65
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In this domino reaction, the tethered alcohol attacks preferentially from less hindered equatorial side to produce the dioxa-tricycle 5 with high stereoselectivity. Recent report of Barbero et al. supports the preferential equatorial attack of internal nucleophile, when trapping the tertiary-tetrahydropyranyl cation occurs intramolecularly.10
In conclusion, we have developed a novel bicyclization approach for the synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran scaffolds from aldehydes and exo-olefinic diols. It is a tandem process to generate dioxacycles in good yields with high selectivity. The use of readily available catalyst makes this method simple, convenient and practical. This method provides a direct access to the synthesis of natural products like oxacycles in a single-step process. Journal Name, [year], [vol], 00–00 | 3
Organic & Biomolecular Chemistry Accepted Manuscript
DOI: 10.1039/C5OB00376H
Organic & Biomolecular Chemistry
Page 4 of 4 View Article Online
T. Pheko, C. L. Willis, Angew. Chem., Int. Ed., 2012, 51, 3901; (e) B. D. Cons, A. J. Bunt, Bailey, C. L. Willis, Org. Lett., 2013, 15, 2046.
Experimental
5
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
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Dichloromethane was dried according to a standard literature procedure. Reactions were performed in an oven-dried round bottom flask, the flasks were fitted with rubber septa and the reactions were conducted under nitrogen atmosphere. Glass syringes were used to transfer the solvent. Crude products were purified by column chromatography on silica gel of 100-200 mesh. Thin layer chromatography plates were visualized by exposure to ultraviolet light and/or by exposure to iodine vapors and/or by exposure to methanolic acidic solution of panisaldehyde followed by heating (
Organic & Biomolecular Chemistry
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Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: V. S. R. Basireddy, N. Prudhvi raju, B. someswarao, J. M. Reddy, S. Balasubramanian, M. Kanakaraju and A. C.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Organic & Biomolecular Chemistry
CREATED USING THE RSC ARTICLE TEMPLATE (VER. 3.1) - SEE WWW.RSC.ORG/ELECTRONICFILES FOR DETAILS View Article Online
DOI: 10.1039/C5OB00376H www.rsc.org/xxxxxx | XXXXXXXX
A novel domino cyclization for the stereoselective synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran derivatives 5
B. V. Subba Reddy,a* N. Prudhvi Raju,a,b B. Someswarao,a,b B. Jagan Mohan Reddy,b B. Sridharc, Kanakaraju Marumudi,d A. C. Kunward
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX First published on the web Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 10
15
20
25
30
35
A novel bicyclization of 2-(2-(hydroxymethyl)-1-methylene-2,3-dihydro-1H-inden-2-yl)ethanol with aldehydes in the presence of 10 mol% BF3.OEt2 in dichloromethane at 0-25 °C affords the biologically relavent indeno[2,1-c]pyran scaffolds in good yields with high selectivity. Similarly the bicyclization of 2-(1-(hydroxymethyl)-2-methylenecyclopentyl)ethanol with aldehydes generates the corresponding cyclopenta[c]pyran derivatives under similar conditions. This method is very useful to produce the hematoxylin and brazilin like scaffolds. Tandem reactions have received great attention because they are highly convergent and extremely useful for organic synthesis.1 They are also called as cascade reactions, which usually combine several transformations in a one-pot synthesis.2 More specifically, Prins cascade process is a highly stereoselective approach for the synthesis of fused/bridged tetrahydropyran systems.3 Recently, a few cascade cyclizations have been reported for the synthesis of novel oxacycles.4 It has been successfully employed for the total synthesis of biologically active natural products.5 Inspired by its versatility, we also reported the synthesis of fused tetrahydropyran derivatives by a domino Prins cyclization of homoallylic substrates with appended nucleophiles.6 However, there are no reports on the synthesis of indeno[2,1-c]pyran scaffolds by means of a tandem Prins strategy. The natural products, Hematoxylum campechianum L. and Caesalpiniasappan L. are used as a natural pigment, and also as a herbal medicine for the treatment of diarrhea, dysentery, dyspepsia, leucorrhea, and diabetic complications.7 Brazilin is a natural product, which is found to display a wide spectrum of biological activities such as hypoglycemic activity, antihepatotoxicity, inhibition of protein kinase C activity, antiplatelet aggregation, induction of immunological tolerance, and antiinflammatory activity (Figure 1).8
Figure 1. Biologically active natural products 60
65
70
___________ 40
45
50
a Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India; Fax: +91-40-27160512; Email: [email protected]; Homepage: www.iictindia.org. b Department of Organic Chemistry, Adikavi Nannaya University, Rajahmundry, 533105, India. c Laboratory of Crystallography, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007,India. d Centre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India. #Electronic Supplementary Information (ESI) available: Copies of 1H and 13C NMR spectrum of products. see DOI: 10.1039/b000000x/
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This journal is © The Royal Society of Chemistry [year]
Due to their inherent biological profiles and fascinating structural features, we herein report a novel cascade process for the synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran derivatives from aldehydes and exo-olefinic diols. It is an elegant approach for the synthesis of a novel series of dioxacycles with three contiguous stereocenters. At first, we attempted the condensation of exo-endiol (1) with benzaldehyde (2a) using a readily available BF3.OEt2 (10 mol%). To our delight, the reaction proceeded smoothly at room temperature to afford the corresponding indeno[2,1-c]pyran 3a in 80% yield with high selectivity. Encouraged by the above result, we turned our attention to examine the reactivity of different aldehydes. Interestingly, several aromatic aldehydes such as 3-nitro-, 4isopropyl-, 2,4-dichloro- derivatives participated well in this cyclization (entries c, d, e, Table 1). Notably, sterically hindered substrates like 1-naphthaldehyde and 2,4-dichlorobenzaldehyde also gave the desired products in good yields (entries b and e, Table 1). Aliphatic aldehyde, for example pivalaldehyde afforded the product reasonably in good yield (entry g, Table 1). In addition, heteroaromatic aldehyde, i.e. 5-bromothiophene-2carboxyaldehyde was also effective for this conversion (entry f, Table 1). The structure and stereochemistry of product 3d were established by extensive NMR experiments including 2-D Double Quantum Filtered Correlation Spectroscopy (DQFCOSY), Total Correlation Spectroscopy (TOCSY) and Nuclear Overhauser Effect Spectroscopy (NOESY) experiments. The distinctive double doublet at 3.98 ppm in 3d due to 1-H was used initiate the assignments with the help of DQF-COSY, TOCSY and NOESY experiments. It is an interesting molecule with several disconnected spin systems and consequently the TOCSY experiments were very useful. Thus 3-H(pro-S) - 3-H(pro-R) and 4-H(pro-S)-4-H(pro-S) form A-B systems, whereas 1-H, 2-H(proS) and 2-H(pro-R) form a 3-spin system while 5-H(pro-S), 5-
Journal Name, [year], [vol], 00–00 | 1
Organic & Biomolecular Chemistry Accepted Manuscript
ARTICLE TYPE
Organic & Biomolecular Chemistry
Page 2 of 4 View Article Online
DOI: 10.1039/C5OB00376H
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
10
15
RCHO (2) O
OH 10 mol% BF3.OEt 2 O
DCM, 0-25 o C 1
Entry
3 R= aryl, hetero, aliphatic
OH
Aldehyde (2)
Product (3) a
Time (min)
Yield (%) b
CHO a
O
30
80
O
30
85
20
73
45
76
40
75
35
75
40
70
O
CHO b O NO 2
CHO c
O O 2N
20
O
CHO d
O O
Cl
Cl
CHO O
25
Figure 2. Energy minimized structure with characteristic NOE correlations of 3d
30
O
Cl
e
Br
Cl
S
Further the relative stereochemistry of 3e was established by a single crystal X-ray diffraction (Figure 3).9
Br
f
S
O CHO
CHO
g
a All
O
O O
the products were characterized by 1H and 13C NMR spectroscopy. refers to pure product after column chromatography.
b Yield
40
35
Figure 3. ORTEP diagram of 3e Table 1. Synthesis of indeno[2,1-c]pyran derivatives
45
50
The scope of the reaction was further demonstrated using a different exo-endiol, i.e. 2-(1-(hydroxymethyl)-2methylenecyclopentyl)ethanol (4). Accordingly, treatment of 4 with 1-naphthaldehyde in the presence of 10 mol% BF3.OEt2 in dichloromethane at 0-25 °C gave the 3-naphthyltetrahydro1H,5H-4a,7a-(epoxyethano)cyclopenta[c]pyran 5h in 85% yield (entry h, Table 2). Other substrates such as 4-bromo-, 3,4dimethoxy-, 4-cyano-, and 2,4,5-trifluorobenzaldehydes reacted smoothly with 4 to furnish the cyclopenta[c]pyrans in good yields (entries i-l, Table 2). Thiophene-2-carboxaldehyde was also equally effective for this transformation (entry m, Table 2). Aliphatic aldehyde, i.e. isovaleraldehyde also afforded the isobutyl substituted cyclopenta[c]pyran in 70% yield (entry n, Table 2). Indeed, aliphatic aldehydes gave the product relatively in lower yield than aromatic counterpart.
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2 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]
Organic & Biomolecular Chemistry Accepted Manuscript
5
R
H(pro-R), 6-H(pro-S) and 6-H(pro-R) are part of a 4-spin system. It was easy to distinguish the two A-B spin systems, with the proximity of one of them in the pyran ring oxygen, resulting in chemical shifts (δ) around 4 ppm. In the three-spin system the three protons are all dd, with 1-H appearing at 3.98 ppm. Large di-axial coupling constant, 3J1-H/2-H(pro-S) = 12.2 Hz, and axial equatorial coupling constant, 3J1-H//2-H(pro-R) = 2.2 Hz and NOE correlations, 1-H/3-H(pro-R), and 3-H(pro-S)/4-H(pro-R) are consistent with the chair conformation of the six membered ring as shown in the energy minimized structure (Figure 2). The configurations at the quaternary centers and the proposed structure are further supported by characteristic NOE correlations, 4-H(pro-S)/5-H(pro-S), 2-H(pro-S)/5-H(pro-R) and 2-H(pro-S)/6-H(pro-R) provide emphatic support for the structure with six-membered ring taking chair conformation. The energy minimized structure adequately supports the proposed structure of 3d.
Page 3 of 4
Organic & Biomolecular Chemistry View Article Online
Table 2. Synthesis of cyclopenta[c]pyran derivatives
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TOCSY/ HSQC experiments. The prochiral assignments of these protons were made from the nOe correlations (1-H/4-H(pro-S), 2-H(pro-R)/4-H(pro-S), 3-H(pro-S)/5-H(pro-R), 3-H(pro-S)/6H(pro-R) and 6-H(pro-S)/8-H(pro-S)) shown in the energy minimized structure (Figure 4), which is consistent with all the NMR observations (couplings and nOe correlations).
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
5
50
Figure 4. Energy minimized structure with characteristic NOE correlations of 5k 10
55
Mechanistically, we assume that the reaction proceeds through the formation of oxocarbenium ion from cyclic acetal, which is derived from aldehyde and unsaturated diol. A subsequent attack of exo-olefin on oxocabenium ion generates a more stable tertiary-carbocation, which is simultaneously trapped with a tethered hydroxyl group to afford the desired product (Scheme 1).
60
15
20
25
30
35
The compound 5k, interestingly contains isolated 2-spin, 3-spin, 4-spin and 6-spin systems in the aliphatic region, which were identified with the help of TOCSY experiments. The distinctive double doublet at 4.36 ppm due to 1-H (additionally confirmed from HSQC experiments, as it is the only aliphatic methine proton, other aliphatic protons are from methylene groups.) was used to initiate the assignments with the help of DQF-COSY, TOCSY, NOESY and HSQC experiments. The TOCSY connectivities involving the distinct dd patterns of the 1-H and 2H protons, with large di-axial and small axial-equatorial coupling were assigned as 3J1-H/2-H(pro-S) = 12.2 Hz and 3J1-H//2-H(pro-R) = 2.9 Hz. The isolated two spin system of 3-H protons was identified easily with, having two coupled doublets at 4.05 ppm and 3.43 ppm. The one having strong nOe correlation (at 3.43 ppm) with 1-H was assigned as 3-H (pro-R). The four spin system containing protons H-7 and H-8, with H-7 adjacent to the pyran ring oxygen appearing at about 4 ppm. The prochiral assignments for these protons were made from the 2-H (pro-S)/7-H(pro-R) and 2-H(pro-S)/8-H(pro-R) nOe correlations. The six spin system of protons H-4, H-5 and H-6 is rather complex. However, the chemical shifts of the six protons could be obtained from the This journal is © The Royal Society of Chemistry [year]
Scheme 1. A plausible reaction pathway 65
70
75
In this domino reaction, the tethered alcohol attacks preferentially from less hindered equatorial side to produce the dioxa-tricycle 5 with high stereoselectivity. Recent report of Barbero et al. supports the preferential equatorial attack of internal nucleophile, when trapping the tertiary-tetrahydropyranyl cation occurs intramolecularly.10
In conclusion, we have developed a novel bicyclization approach for the synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran scaffolds from aldehydes and exo-olefinic diols. It is a tandem process to generate dioxacycles in good yields with high selectivity. The use of readily available catalyst makes this method simple, convenient and practical. This method provides a direct access to the synthesis of natural products like oxacycles in a single-step process. Journal Name, [year], [vol], 00–00 | 3
Organic & Biomolecular Chemistry Accepted Manuscript
DOI: 10.1039/C5OB00376H
Organic & Biomolecular Chemistry
Page 4 of 4 View Article Online
T. Pheko, C. L. Willis, Angew. Chem., Int. Ed., 2012, 51, 3901; (e) B. D. Cons, A. J. Bunt, Bailey, C. L. Willis, Org. Lett., 2013, 15, 2046.
Experimental
5
Published on 16 March 2015. Downloaded by Mahidol University on 21/03/2015 02:57:37.
10
15
Dichloromethane was dried according to a standard literature procedure. Reactions were performed in an oven-dried round bottom flask, the flasks were fitted with rubber septa and the reactions were conducted under nitrogen atmosphere. Glass syringes were used to transfer the solvent. Crude products were purified by column chromatography on silica gel of 100-200 mesh. Thin layer chromatography plates were visualized by exposure to ultraviolet light and/or by exposure to iodine vapors and/or by exposure to methanolic acidic solution of panisaldehyde followed by heating (
