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Stereoselective synthesis of Heliannuol G
Tetrahedron Letters 58 (2017) 4336–4339
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of Heliannuol G Debayan Sarkar ⇑, Manoj Kumar Ghosh Department of Chemistry, National Institute of Technology, Rourkela, Odisha 769008, India
a r t i c l e
i n f o
Article history: Received 30 August 2017 Revised 22 September 2017 Accepted 27 September 2017 Available online 5 October 2017
a b s t r a c t The first stereoselective synthesis of Heliannuol G has been achieved employing an o-quinone methide intermediate. The present synthesis triumphs over all the drawbacks associated with the reported one and reveals an impressive overall yield of 12.37%. Ó 2017 Elsevier Ltd. All rights reserved.
Keywords: Sulfur ylide Heliannuol Dihydroenzofuran o-Quinone methide Economic
Introduction Heliannuols are unique class of benzooxacyclic allelopathic sesquiterpenes obtained from sunflowers. Recent synthetic approaches and structural studies have demanded for an amendment to the dihydrobenzofuran ring framework for Heliannuols G and H rather than the earlier predicted benzoxocane ring system.1 Heliannuols G and H were isolated by Macias et al.2 from the aqueous fresh leaf extract of Helianthus annuus L. SH-222 and YPP. The group reported that heliannuol G and H as eight membered benzoxacycles, whereas the recent anomalies arising out of the reported and found NMR data led to the structural revision. Interestingly, the Shishido group had earlier executed an enantioselective total synthesis of benzoxocane Heliannuol G and H and also highlighted the difference observed in the isolation and synthesized data.3 The same group, later came up with their proposition of the revised structure on the reported coupling constant of olefinic protons for Heliannuols G and H to be 15.7 Hz and 15.5 Hz respectively which pointed the presence of a trans-olefin rather than prescribed cyclic olefin. The structural anomaly was solved by the Shishido group4 in their followed-up synthesis, where the Heliannuols G and H were assigned as substituted dihydrobenzofurans with an external trans-olefin intact (Fig. 1). Albeit, Shishido’s synthesis has been ascribed with major disadvantages. First of all, the key step of synthesis ends up with a diastereomeric mixture of 2:1. Secondly, two protection groups have been employed in the synthesis. Thirdly, expensive transition metal catalysts like Grubbs ⇑ Corresponding author. E-mail address: [email protected] (D. Sarkar). https://doi.org/10.1016/j.tetlet.2017.09.081 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
2nd Generation and Pd(PPh3)4 have been employed which brands this synthesis as non-economic. The synthesis ends up with a mixture of both Heliannuols G and H and requires a HPLC separation which points out towards unsatisfactory overall yield. These reasons along with our interest in the Heliannuol family5 attracted our attention and we planned to develop a straightforward as well as economic synthesis of at least one of these structurally amended Heliannuols which would also compensate the existing issues. Herein, we report a stereoselective metal free synthesis of Heliannuol G with an impressive overall yield of 12.37% in only seven linear steps. Retrosynthetically, we envisaged that a chiral auxiliary (L⁄) bestowed dihydroxylation of hydroxy-2,3-dihydrobenzofuran-carboxylate (9) which can be achieved via intramolecular aldol reaction of keto-ester (8) and would furnish the Heliannuols via a stereoselective pathway. However, it was preferred to check the model reaction first (Scheme 1). Methyl hydroquinone (4) was chosen as the model substrate which was acylated to the corresponding diacetate (5) followed by the thermal Fries rearrangement to deliver the hydroxyl ketone (6). The distal hydroxyl group of the ketone was then selectively protected to the corresponding methyl ether (7). The ether was then alkylated with ethylbromoacetate to deliver the keto ester (8). The ester underwent an intramolecular aldol type reaction at 78 °C in presence of catalytic CeCl37H2O as an activator, to provide ethyl 3-hydroxy-3-methyl-2,3-dihydrobenzofuran-2-carboxylate (9) as a diastereomeric mixture (dr = 1:1) with an overall yield of 82% (Scheme 2). Before proceeding further, we decided to envisage the possibilities of the key dehydroxylation reaction. Unfortunately, repeated
4337
D. Sarkar, M.K. Ghosh / Tetrahedron Letters 58 (2017) 4336–4339
Me
Table 1 Trials towards dehydroxylation.
OH
HO Me
O Me Me Heliannuol G (1) Me
HO
O
Me OH O R H 3C Me 3a. R = β-H, Heliannuol G
OH
HO Me
Me H
MeO
Me
MeO
3b. R = α -H, Heliannuol H
O Me Me
X
HO Me H
OEt
10
Me O
O
MeO O
OEt
9
Heliannuol H (2)
O
Me
O
Me 11
OEt
After Structural Revision
Before Structural Revision
Fig. 1. Structure of Heliannuols G & H.
Me H
HO Me
PGO
Me O Me OH 18 Me Me H PGO L* O Dehydroxylation O Me OEt O
O 3a PGO Me
Me H
10
Intrmolecular aldol PGO
Me O
Reagent
Product
1 2 3 4 5 6 7
H2, HClO4, Pd-C (10%) H2/Pd-C (5%), MeOH Wilkinson’s catalyst/H2 BF3OEt2, NaCNBH3, 90 °C H2/Pd-C (5%), MeOH, PTSA Et3SiH, BF3OEt2 HCOONH4, MeOH, reflux
11, 60% No reaction No reaction No reaction 11, 50% 11, 70% No reaction
O O
OEt
9 O
Me
HO Me H
MeO
OEt
O
8
HO Me H
HO
Me
Me
OEt O
Entry
O
L Me
Chiral auxiliary
12,
HO Me H
MeO
b
OH
O
OEt
9,
HO *=
O
O
OH
6
HO Me H
MeO
a
4
O 13,65 %
Scheme 1. Initial retrosynthetic plan.
Me
a
AcO
OH
Me
4
b OAc
OH 7, 80%
OH 6, 53%
O Me MeO d
Me
Me
Me
5, 95% O
c MeO
HO
Me
Me O 8, 94%
e MeO OEt
O
78 °C (b) Ph3PCHCOOEt,
Scheme 3. Reaction conditions: (a) DIBAL-H, toluene, DCM, 0 °C.
O HO
COOEt
HO Me H O O 9, 82% (a:b = 1:1)
OEt
dearomatization reactions.6 Therefore, we hinged upon the generation of a trans-benzofuran employing the reactive o-quinone methide reactive intermediate via oxidative dearomatization. The o-quinone intermediate have been less explored in construction of trans benzofurans. The o-quinone intermediate can be synthesized from treatment of appropriately designed 2-tosylphenols with the sulphur ylides7 (Scheme 4).
Scheme 2. Reaction conditions: (a) AcCl, Py, DCM, 0 °C (b) AlCl3, 120–165 °C (c) MeI, K2CO3, acetone, reflux, 6 h (d) Ethylbromo acetate, K2CO3, acetone, reflux, 6 h (e) LiHMDS, CeCl37H2O, THF, 78 °C.
Me H
HO
trials and screening of different reaction conditions did not deliver the 2,3-disubstituted benzofuran (10). In most cases, it either did not react or delivered the furan carboxylate (11) or a complex mixture was obtained. The synthetic efforts are enlisted below (Table 1). Further, hydroxyl-2,3-dihydrofuran-2-carboxylate (9) was treated with DIBAL-H at 78 °C to generate the aldehyde (12) followed by an immediate Wittig Horner olefination to afford the desired a, b-unsaturated ester (13) as a diastereomeric mixture (1:1) with 65% overall yield in two steps and ester was confirmed by NMR and HPLC. Repeated trials of dehydroxylation with the ester was unsuccessful (Scheme 3). It was this moment, when we realized that attempts towards the present endeavors may be replaced with a new strategy where these hindrances can be easily eliminated in the due course of transformations. Our group has been focusing on oxidative
Me
Me H
PGO Me OH Me
O 1
PGO
S O O OH 15 O
O O
Me 10 PGO
OEt OH Me
Me
O
18 Me
Me H
PGO
OEt O
Me
OH 14
Me HO
Me
Me
OH 6
HO
Me
MeO
Me
OH 4
Me
O
Scheme 4. Followed-up Retrosynthetic plan via o-quione intermediate.
4338
D. Sarkar, M.K. Ghosh / Tetrahedron Letters 58 (2017) 4336–4339
O MeO
HO Me a
Me
OH
7
S
Me Me
Me
O
e
MeO
S
Me MeO Me
Me Br S Me 16 COOEt MeO
d
MeO
Me H
OEt
SN 2
o-quinone methide
Me
O 17, 71%
H
Me
=
g, h,i
Me H
MeO
f
O
Br Me
O
Me
19, 72%
O HO
Me OH
Me H O Heliannuol G(1)
Me MeO
S COOEt
Me
Me
Me 2S
S Me 16 COOEt
H MeO
Me
Me OH
Scheme 5. Reaction conditions: (a) NaBH4, MeOH, 4 h, (b) PTSA, PhSO2Na, DCM, 2 h (c) 16, Cs2CO3, DCM, 12 h (d) DIBAL-H, toluene, 78 °C, 3 h (e) Ph3PCHCOOEt, DCM, 0 °C–rt, 6 h (f) MeMgI, THF, rt, 10 h (g) BBr3, DCM, 78°C to rt (h) EtSNa, DMF (i) MeMgI (excess), THF, reflux.
(II)
o-quinone methide SN2
Me
H
MeO
MeO COOEt
Me
O
Me
The ketone (7) was now reduced by sodium borohydride to the corresponding secondary alcohol (14) and it was converted to the corresponding sulfonyl phenol (15) with excellent yield of 70%. The sulfonyl phenol (15) was then exposed with the sulfur ylide (2ethoxy-2-oxoethyl)dimethylsulfonium bromide (16) in presence of cesium carbonate (Cs2CO3) as a base which afforded our key compound dihydrobenzofuran (10) via o-quinone methide intermediate7 with satisfactory yield of 83% as a single diastereomer. At this point, the relative cis-configuration of the dihydrobenzofuran was confirmed by NOE studies, although final conformation could easily be achieved after the completion of the entire reaction sequence. The dihydro-furan carboxylate was reduced with diisobutylaluminium hydride to the desired aldehyde (17) with 71% yield. The aldehyde (17) underwent a Wittig-Horner olefination to provide the a,b-unsaturated ester (18) and was further subjected to a Grignard reaction to achieve the desired tertiary methyl alcohol (19). Repeated trials towards deprotection of this alcohol employing ethane thiolate or boron tribromide solution resulted in a complex mixture (Scheme 5). The key reaction which generates the dihydrobenzofuran core involves an SN2 mechanism. The probable reactive intermediates involved in this reaction may be designated as (I) and (II). During the sulphur ylide attack to the o-quinone methide intermediate, the formation of intermediate (I) seems more suitable than (II) as the former suffers from less non-bonding and Gauche Butane interactions as compared to (II) as shown (Scheme 6). The more stable reactive intermediate delivered the more stable cis-stereoisomer via intramolecular nucleophilic displacement reaction (Scheme 6). In summary, the first stereoselective synthesis of Heliannuol G has been achieved. This is the second synthesis of the natural product after the Shishido group’s report and the methodology described has removed the drawbacks associated with the earlier synthesis. The synthesis is straightforward, economic and does not require any high pressure separations as well as delivers an impressive overall yield of 12.37% in only linear seven steps. The products are easily separated and characterized. The NMR spectra
COOEt H O
O Me
Me Me
O
H
Effective Gauche Butane NonInteraction bonding interaction
O
OEt 18
Me
O
Me
10 OEt
Me
H
MeO
MeO Me
O 18, 79%
Me H
COOEt O
O
Me H
MeO
SMe2
Me
O
COOEt
Me
Me
H
(I) O
O 10, 83%
Ph
O O OH 15, 70%
OH 14, 80% Me H
Br 16 MeO COOEt c
Me b MeO
Me
MeO
Me
MeO
Me COOEt H S Me O Me
10
Scheme 6. A planned pre-scheduled deprotection of the unsaturated ester (18) employing BBr3 solution furnished the deprotected ester (20) in 65% yield. Finally a successful Grignard reaction with the ester (20) delivered Heliannuol G8 (3a) as the sole product in 73% yields (Scheme 7).
Me H
MeO
OEt O
Me
18
b
Me H
HO
a
OEt O
Me
20, 65%
O
O
Me H
HO
Me 73%
O
Me
Heliannuol G(1) Scheme 7. (a) BBr3, DCM,
Me OH
78 °C to rt (b) MeMgI, THF, rt, 10 h.
matched well with isolated natural product report which further confirms the structural amendment. It is also anticipated that the methodologies described herein will prove wider applications in future towards related natural products. Acknowledgments We sincerely acknowledge Department of Science and Technology (DST), Govt. of India (Grant nos SB/FT/CS-076/2012) & EEQ/2016/000518, Board of Research in Nuclear Sciences (BRNS) (2013/20/37C/2/BRNS/2651), and INSPIRE-DST, Govt. of India (Grant No. 04/2013/000751). MKG thanks NIT Rourkela, India for research fellowship. A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.2017.09.081.
D. Sarkar, M.K. Ghosh / Tetrahedron Letters 58 (2017) 4336–4339
References 1. 2. 3. 4. 5. 6. 7. 8.
Sarkar D, Ghosh MK. Curr Org Chem. 2017. ref.-BSP-COC-2016-969. Macias FA, Varela RM, Torres A, Molinillo JMG. J Nat Prod. 1999;62:1636–1639. Morimoto S, Shindo M, Shishido K. Heterocyles. 2005;66:69–73. Morimoto S, Shindo M, Yoshida M, Shishido K. Tetrahedron Lett. 2006;47:7353–7356. Sabui S, Ghosh S, Sarkar D, Venkateswaran RV. Tetrahedron Lett. 2009;50:4683–4684. (a) Sarkar D, Ghosh MK, Rout N. Org Biomol Chem. 2016;14:7883–7898; (b) Sarkar D, Ghosh MK, Rout N, Kuila P. New J Chem. 2017;41:3715–3718. Chen M-W, Cao L-L, Ye Z-S, Jiang G-F, Zhou Y-G. Chem Commun. 2013;49:1660–1662. and reference therein. All new compounds reported here gave analytical and spectral data consistent with assigned structures. Selected spectral data For Heliannuol G (3a): Colourless oil, 1H NMR (400 MHz, CDCl3) d = 6.59(s, 1H), 6.57(s, 1H), 6.00(d, J = 15.6 Hz, 1H), 5.89(dd, J = 15.4 Hz, 7.2 Hz, 1H), 4.56(t, J = 8 Hz, 1H), 3.22–3.15 (m, 1H), 2.21(s, 3H), 1.37(s, 6H), 1.30(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d = 152.6, 147.7, 141.6, 130.4, 125.0, 122.8, 110.9, 110.5, 91.2, 70.7, 43.0,
4339
29.5, 17.3, 14.0; HRMS (ESI) calc’d for C15H20NaO3 [M+Na]+ = 271.1310, Found: 271.1304.For 19: 1H NMR (400 MHz, CDCl3) d = 6.65(s, 1H), 6.61(s, 1H), 6.01(d, J = 15.6 Hz, 1H), 5.88(dd, J = 15.4, 7.6 Hz, 1H), 4.58(t, J = 8 Hz, 1H), 3.80(s, 3H), 3.25–3.18(m, 1H), 2.19(s, 3H), 1.37 (s, 6H), 1.35(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d = 152.3, 152.1, 141.5, 129.2, 126.3, 125.0, 111.4, 106.6, 91.3, 70.4, 56.2, 43.3, 29.5, 17.4, 16.40; HRMS (ESI) calc’d for C16H22O3 [M]+ = 262.1569, Found: 262.1561.For 20: Pale Yellow oil, 1H NMR (400 MHz, CDCl3) d = 7.04(dd, J = 15.6 Hz, 5.6 Hz, 1H), 6.61(s, 1H), 6.59(s, 1H), 6.14(dd, J = 15.8 Hz, 1.6 Hz, 1H), 4.77–4.73(m, 1H), 4.56(brs, 1H), 4.23(q, J = 7.2 Hz, 2H), 3.28–3.21(m, 1H), 2.22(s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.31(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d = 166.1, 152.4, 148.0, 144.9, 129.2, 123.3, 121.3, 111.2, 110.6, 88.6, 60.5, 42.9, 18.4, 16.0, 14.1; HRMS (ESI) calc’d for C15H18O4 [M]+ = 262.1205, Found: 262.1210. For 18: Pale yellow oil, 1H NMR (400 MHz, CDCl3) d = 6.66(s, 1H), 6.64(s, 1H), 6.38–6.33(m,1H), 5.89–5.82(m, 2H), 4.23(q, J = 7.2 Hz, 2 Hz), 3.80(s, 3H), 3.25–3.18(m, 1H), 2.20(s, 3H), 1.43(d, J = 6.8 Hz, 3H), 1.33(t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) d = 165.6, 152.3, 151.8, 148.3, 129.4, 126.5, 120.5, 111.7, 106.5, 85.8, 60.3, 56.1, 44.7, 19.5, 16.4, 14.1; HRMS (ESI) calc’d for C16H20NaO4 [M+Na]+ = 299.1259, Found: 299.1258.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of Heliannuol G Debayan Sarkar ⇑, Manoj Kumar Ghosh Department of Chemistry, National Institute of Technology, Rourkela, Odisha 769008, India
a r t i c l e
i n f o
Article history: Received 30 August 2017 Revised 22 September 2017 Accepted 27 September 2017 Available online 5 October 2017
a b s t r a c t The first stereoselective synthesis of Heliannuol G has been achieved employing an o-quinone methide intermediate. The present synthesis triumphs over all the drawbacks associated with the reported one and reveals an impressive overall yield of 12.37%. Ó 2017 Elsevier Ltd. All rights reserved.
Keywords: Sulfur ylide Heliannuol Dihydroenzofuran o-Quinone methide Economic
Introduction Heliannuols are unique class of benzooxacyclic allelopathic sesquiterpenes obtained from sunflowers. Recent synthetic approaches and structural studies have demanded for an amendment to the dihydrobenzofuran ring framework for Heliannuols G and H rather than the earlier predicted benzoxocane ring system.1 Heliannuols G and H were isolated by Macias et al.2 from the aqueous fresh leaf extract of Helianthus annuus L. SH-222 and YPP. The group reported that heliannuol G and H as eight membered benzoxacycles, whereas the recent anomalies arising out of the reported and found NMR data led to the structural revision. Interestingly, the Shishido group had earlier executed an enantioselective total synthesis of benzoxocane Heliannuol G and H and also highlighted the difference observed in the isolation and synthesized data.3 The same group, later came up with their proposition of the revised structure on the reported coupling constant of olefinic protons for Heliannuols G and H to be 15.7 Hz and 15.5 Hz respectively which pointed the presence of a trans-olefin rather than prescribed cyclic olefin. The structural anomaly was solved by the Shishido group4 in their followed-up synthesis, where the Heliannuols G and H were assigned as substituted dihydrobenzofurans with an external trans-olefin intact (Fig. 1). Albeit, Shishido’s synthesis has been ascribed with major disadvantages. First of all, the key step of synthesis ends up with a diastereomeric mixture of 2:1. Secondly, two protection groups have been employed in the synthesis. Thirdly, expensive transition metal catalysts like Grubbs ⇑ Corresponding author. E-mail address: [email protected] (D. Sarkar). https://doi.org/10.1016/j.tetlet.2017.09.081 0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
2nd Generation and Pd(PPh3)4 have been employed which brands this synthesis as non-economic. The synthesis ends up with a mixture of both Heliannuols G and H and requires a HPLC separation which points out towards unsatisfactory overall yield. These reasons along with our interest in the Heliannuol family5 attracted our attention and we planned to develop a straightforward as well as economic synthesis of at least one of these structurally amended Heliannuols which would also compensate the existing issues. Herein, we report a stereoselective metal free synthesis of Heliannuol G with an impressive overall yield of 12.37% in only seven linear steps. Retrosynthetically, we envisaged that a chiral auxiliary (L⁄) bestowed dihydroxylation of hydroxy-2,3-dihydrobenzofuran-carboxylate (9) which can be achieved via intramolecular aldol reaction of keto-ester (8) and would furnish the Heliannuols via a stereoselective pathway. However, it was preferred to check the model reaction first (Scheme 1). Methyl hydroquinone (4) was chosen as the model substrate which was acylated to the corresponding diacetate (5) followed by the thermal Fries rearrangement to deliver the hydroxyl ketone (6). The distal hydroxyl group of the ketone was then selectively protected to the corresponding methyl ether (7). The ether was then alkylated with ethylbromoacetate to deliver the keto ester (8). The ester underwent an intramolecular aldol type reaction at 78 °C in presence of catalytic CeCl37H2O as an activator, to provide ethyl 3-hydroxy-3-methyl-2,3-dihydrobenzofuran-2-carboxylate (9) as a diastereomeric mixture (dr = 1:1) with an overall yield of 82% (Scheme 2). Before proceeding further, we decided to envisage the possibilities of the key dehydroxylation reaction. Unfortunately, repeated
4337
D. Sarkar, M.K. Ghosh / Tetrahedron Letters 58 (2017) 4336–4339
Me
Table 1 Trials towards dehydroxylation.
OH
HO Me
O Me Me Heliannuol G (1) Me
HO
O
Me OH O R H 3C Me 3a. R = β-H, Heliannuol G
OH
HO Me
Me H
MeO
Me
MeO
3b. R = α -H, Heliannuol H
O Me Me
X
HO Me H
OEt
10
Me O
O
MeO O
OEt
9
Heliannuol H (2)
O
Me
O
Me 11
OEt
After Structural Revision
Before Structural Revision
Fig. 1. Structure of Heliannuols G & H.
Me H
HO Me
PGO
Me O Me OH 18 Me Me H PGO L* O Dehydroxylation O Me OEt O
O 3a PGO Me
Me H
10
Intrmolecular aldol PGO
Me O
Reagent
Product
1 2 3 4 5 6 7
H2, HClO4, Pd-C (10%) H2/Pd-C (5%), MeOH Wilkinson’s catalyst/H2 BF3OEt2, NaCNBH3, 90 °C H2/Pd-C (5%), MeOH, PTSA Et3SiH, BF3OEt2 HCOONH4, MeOH, reflux
11, 60% No reaction No reaction No reaction 11, 50% 11, 70% No reaction
O O
OEt
9 O
Me
HO Me H
MeO
OEt
O
8
HO Me H
HO
Me
Me
OEt O
Entry
O
L Me
Chiral auxiliary
12,
HO Me H
MeO
b
OH
O
OEt
9,
HO *=
O
O
OH
6
HO Me H
MeO
a
4
O 13,65 %
Scheme 1. Initial retrosynthetic plan.
Me
a
AcO
OH
Me
4
b OAc
OH 7, 80%
OH 6, 53%
O Me MeO d
Me
Me
Me
5, 95% O
c MeO
HO
Me
Me O 8, 94%
e MeO OEt
O
78 °C (b) Ph3PCHCOOEt,
Scheme 3. Reaction conditions: (a) DIBAL-H, toluene, DCM, 0 °C.
O HO
COOEt
HO Me H O O 9, 82% (a:b = 1:1)
OEt
dearomatization reactions.6 Therefore, we hinged upon the generation of a trans-benzofuran employing the reactive o-quinone methide reactive intermediate via oxidative dearomatization. The o-quinone intermediate have been less explored in construction of trans benzofurans. The o-quinone intermediate can be synthesized from treatment of appropriately designed 2-tosylphenols with the sulphur ylides7 (Scheme 4).
Scheme 2. Reaction conditions: (a) AcCl, Py, DCM, 0 °C (b) AlCl3, 120–165 °C (c) MeI, K2CO3, acetone, reflux, 6 h (d) Ethylbromo acetate, K2CO3, acetone, reflux, 6 h (e) LiHMDS, CeCl37H2O, THF, 78 °C.
Me H
HO
trials and screening of different reaction conditions did not deliver the 2,3-disubstituted benzofuran (10). In most cases, it either did not react or delivered the furan carboxylate (11) or a complex mixture was obtained. The synthetic efforts are enlisted below (Table 1). Further, hydroxyl-2,3-dihydrofuran-2-carboxylate (9) was treated with DIBAL-H at 78 °C to generate the aldehyde (12) followed by an immediate Wittig Horner olefination to afford the desired a, b-unsaturated ester (13) as a diastereomeric mixture (1:1) with 65% overall yield in two steps and ester was confirmed by NMR and HPLC. Repeated trials of dehydroxylation with the ester was unsuccessful (Scheme 3). It was this moment, when we realized that attempts towards the present endeavors may be replaced with a new strategy where these hindrances can be easily eliminated in the due course of transformations. Our group has been focusing on oxidative
Me
Me H
PGO Me OH Me
O 1
PGO
S O O OH 15 O
O O
Me 10 PGO
OEt OH Me
Me
O
18 Me
Me H
PGO
OEt O
Me
OH 14
Me HO
Me
Me
OH 6
HO
Me
MeO
Me
OH 4
Me
O
Scheme 4. Followed-up Retrosynthetic plan via o-quione intermediate.
4338
D. Sarkar, M.K. Ghosh / Tetrahedron Letters 58 (2017) 4336–4339
O MeO
HO Me a
Me
OH
7
S
Me Me
Me
O
e
MeO
S
Me MeO Me
Me Br S Me 16 COOEt MeO
d
MeO
Me H
OEt
SN 2
o-quinone methide
Me
O 17, 71%
H
Me
=
g, h,i
Me H
MeO
f
O
Br Me
O
Me
19, 72%
O HO
Me OH
Me H O Heliannuol G(1)
Me MeO
S COOEt
Me
Me
Me 2S
S Me 16 COOEt
H MeO
Me
Me OH
Scheme 5. Reaction conditions: (a) NaBH4, MeOH, 4 h, (b) PTSA, PhSO2Na, DCM, 2 h (c) 16, Cs2CO3, DCM, 12 h (d) DIBAL-H, toluene, 78 °C, 3 h (e) Ph3PCHCOOEt, DCM, 0 °C–rt, 6 h (f) MeMgI, THF, rt, 10 h (g) BBr3, DCM, 78°C to rt (h) EtSNa, DMF (i) MeMgI (excess), THF, reflux.
(II)
o-quinone methide SN2
Me
H
MeO
MeO COOEt
Me
O
Me
The ketone (7) was now reduced by sodium borohydride to the corresponding secondary alcohol (14) and it was converted to the corresponding sulfonyl phenol (15) with excellent yield of 70%. The sulfonyl phenol (15) was then exposed with the sulfur ylide (2ethoxy-2-oxoethyl)dimethylsulfonium bromide (16) in presence of cesium carbonate (Cs2CO3) as a base which afforded our key compound dihydrobenzofuran (10) via o-quinone methide intermediate7 with satisfactory yield of 83% as a single diastereomer. At this point, the relative cis-configuration of the dihydrobenzofuran was confirmed by NOE studies, although final conformation could easily be achieved after the completion of the entire reaction sequence. The dihydro-furan carboxylate was reduced with diisobutylaluminium hydride to the desired aldehyde (17) with 71% yield. The aldehyde (17) underwent a Wittig-Horner olefination to provide the a,b-unsaturated ester (18) and was further subjected to a Grignard reaction to achieve the desired tertiary methyl alcohol (19). Repeated trials towards deprotection of this alcohol employing ethane thiolate or boron tribromide solution resulted in a complex mixture (Scheme 5). The key reaction which generates the dihydrobenzofuran core involves an SN2 mechanism. The probable reactive intermediates involved in this reaction may be designated as (I) and (II). During the sulphur ylide attack to the o-quinone methide intermediate, the formation of intermediate (I) seems more suitable than (II) as the former suffers from less non-bonding and Gauche Butane interactions as compared to (II) as shown (Scheme 6). The more stable reactive intermediate delivered the more stable cis-stereoisomer via intramolecular nucleophilic displacement reaction (Scheme 6). In summary, the first stereoselective synthesis of Heliannuol G has been achieved. This is the second synthesis of the natural product after the Shishido group’s report and the methodology described has removed the drawbacks associated with the earlier synthesis. The synthesis is straightforward, economic and does not require any high pressure separations as well as delivers an impressive overall yield of 12.37% in only linear seven steps. The products are easily separated and characterized. The NMR spectra
COOEt H O
O Me
Me Me
O
H
Effective Gauche Butane NonInteraction bonding interaction
O
OEt 18
Me
O
Me
10 OEt
Me
H
MeO
MeO Me
O 18, 79%
Me H
COOEt O
O
Me H
MeO
SMe2
Me
O
COOEt
Me
Me
H
(I) O
O 10, 83%
Ph
O O OH 15, 70%
OH 14, 80% Me H
Br 16 MeO COOEt c
Me b MeO
Me
MeO
Me
MeO
Me COOEt H S Me O Me
10
Scheme 6. A planned pre-scheduled deprotection of the unsaturated ester (18) employing BBr3 solution furnished the deprotected ester (20) in 65% yield. Finally a successful Grignard reaction with the ester (20) delivered Heliannuol G8 (3a) as the sole product in 73% yields (Scheme 7).
Me H
MeO
OEt O
Me
18
b
Me H
HO
a
OEt O
Me
20, 65%
O
O
Me H
HO
Me 73%
O
Me
Heliannuol G(1) Scheme 7. (a) BBr3, DCM,
Me OH
78 °C to rt (b) MeMgI, THF, rt, 10 h.
matched well with isolated natural product report which further confirms the structural amendment. It is also anticipated that the methodologies described herein will prove wider applications in future towards related natural products. Acknowledgments We sincerely acknowledge Department of Science and Technology (DST), Govt. of India (Grant nos SB/FT/CS-076/2012) & EEQ/2016/000518, Board of Research in Nuclear Sciences (BRNS) (2013/20/37C/2/BRNS/2651), and INSPIRE-DST, Govt. of India (Grant No. 04/2013/000751). MKG thanks NIT Rourkela, India for research fellowship. A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.2017.09.081.
D. Sarkar, M.K. Ghosh / Tetrahedron Letters 58 (2017) 4336–4339
References 1. 2. 3. 4. 5. 6. 7. 8.
Sarkar D, Ghosh MK. Curr Org Chem. 2017. ref.-BSP-COC-2016-969. Macias FA, Varela RM, Torres A, Molinillo JMG. J Nat Prod. 1999;62:1636–1639. Morimoto S, Shindo M, Shishido K. Heterocyles. 2005;66:69–73. Morimoto S, Shindo M, Yoshida M, Shishido K. Tetrahedron Lett. 2006;47:7353–7356. Sabui S, Ghosh S, Sarkar D, Venkateswaran RV. Tetrahedron Lett. 2009;50:4683–4684. (a) Sarkar D, Ghosh MK, Rout N. Org Biomol Chem. 2016;14:7883–7898; (b) Sarkar D, Ghosh MK, Rout N, Kuila P. New J Chem. 2017;41:3715–3718. Chen M-W, Cao L-L, Ye Z-S, Jiang G-F, Zhou Y-G. Chem Commun. 2013;49:1660–1662. and reference therein. All new compounds reported here gave analytical and spectral data consistent with assigned structures. Selected spectral data For Heliannuol G (3a): Colourless oil, 1H NMR (400 MHz, CDCl3) d = 6.59(s, 1H), 6.57(s, 1H), 6.00(d, J = 15.6 Hz, 1H), 5.89(dd, J = 15.4 Hz, 7.2 Hz, 1H), 4.56(t, J = 8 Hz, 1H), 3.22–3.15 (m, 1H), 2.21(s, 3H), 1.37(s, 6H), 1.30(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d = 152.6, 147.7, 141.6, 130.4, 125.0, 122.8, 110.9, 110.5, 91.2, 70.7, 43.0,
4339
29.5, 17.3, 14.0; HRMS (ESI) calc’d for C15H20NaO3 [M+Na]+ = 271.1310, Found: 271.1304.For 19: 1H NMR (400 MHz, CDCl3) d = 6.65(s, 1H), 6.61(s, 1H), 6.01(d, J = 15.6 Hz, 1H), 5.88(dd, J = 15.4, 7.6 Hz, 1H), 4.58(t, J = 8 Hz, 1H), 3.80(s, 3H), 3.25–3.18(m, 1H), 2.19(s, 3H), 1.37 (s, 6H), 1.35(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d = 152.3, 152.1, 141.5, 129.2, 126.3, 125.0, 111.4, 106.6, 91.3, 70.4, 56.2, 43.3, 29.5, 17.4, 16.40; HRMS (ESI) calc’d for C16H22O3 [M]+ = 262.1569, Found: 262.1561.For 20: Pale Yellow oil, 1H NMR (400 MHz, CDCl3) d = 7.04(dd, J = 15.6 Hz, 5.6 Hz, 1H), 6.61(s, 1H), 6.59(s, 1H), 6.14(dd, J = 15.8 Hz, 1.6 Hz, 1H), 4.77–4.73(m, 1H), 4.56(brs, 1H), 4.23(q, J = 7.2 Hz, 2H), 3.28–3.21(m, 1H), 2.22(s, 3H), 1.35 (d, J = 6.8 Hz, 3H), 1.31(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d = 166.1, 152.4, 148.0, 144.9, 129.2, 123.3, 121.3, 111.2, 110.6, 88.6, 60.5, 42.9, 18.4, 16.0, 14.1; HRMS (ESI) calc’d for C15H18O4 [M]+ = 262.1205, Found: 262.1210. For 18: Pale yellow oil, 1H NMR (400 MHz, CDCl3) d = 6.66(s, 1H), 6.64(s, 1H), 6.38–6.33(m,1H), 5.89–5.82(m, 2H), 4.23(q, J = 7.2 Hz, 2 Hz), 3.80(s, 3H), 3.25–3.18(m, 1H), 2.20(s, 3H), 1.43(d, J = 6.8 Hz, 3H), 1.33(t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) d = 165.6, 152.3, 151.8, 148.3, 129.4, 126.5, 120.5, 111.7, 106.5, 85.8, 60.3, 56.1, 44.7, 19.5, 16.4, 14.1; HRMS (ESI) calc’d for C16H20NaO4 [M+Na]+ = 299.1259, Found: 299.1258.