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A convenient access to the tricyclic core structure of hippolachnin A
Accepted Manuscript A convenient access to the tricyclic core structure of Hippolachnin A Ritabrata Datta, Ryan Joseph Dixon, Subrata Ghosh PII: DOI: Reference:
S0040-4039(15)30353-1 http://dx.doi.org/10.1016/j.tetlet.2015.11.045 TETL 46985
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
19 October 2015 5 November 2015 14 November 2015
Please cite this article as: Datta, R., Dixon, R.J., Ghosh, S., A convenient access to the tricyclic core structure of Hippolachnin A, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.045
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Tetrahedron Letters
A convenient access to the tricyclic core structure of Hippolachnin A Ritabrata Datta, Ryan Joseph Dixon and Subrata Ghosh* Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
A concise route for the synthesis of the enantiopure oxacyclobutapentalene core structure present in hippolachnin A has been developed. The key steps involve ring closing metathesis to construct butenolide and its intramolecular [2+2] photocycloaddition.
Keywords: Asymmetric synthesis Metathesis Lactone Photochemistry
Hippolachnin A 1 is a polyketide isolated1 recently from the South China Sea sponge Hippospongia lachne. Initial bioassay indicates2 that it is not only a potent antifungal agent but also capable of curing various diseases such as renal failure, chronic heart failure etc. Hippolachnin A having an unprecedented oxacyclobutapentalene skeleton possesses a highly sterically congested cage structure with six contiguous stereocentres. Structural novelty combined with its therapeutic potential elicited considerable interest in its synthesis. A recent report2 of the total synthesis of (±)-hippolachnin A by Carreira et al prompted us to report our initial results on the development of an asymmetric route towards its synthesis.
We envisioned that a Wittig reaction3 of the tricyclic lactone 2 with (methoxycarbonylmethylene)triphenylphosphorane would directly provide 1 (Scheme 1). Thus our approach to 1 was initially targeted on the construction of the lactone 2. Our continued interest4 in the application of intramolecular [2+2] photocycloaddition reaction for the synthesis of natural products which led us to consider the possibility of adopting this technique for accomplishing the synthesis of 2 from the dienone 3. The latter was anticipated to be obtained from a ring closing metathesis5-oxidation sequence of the diene 4. Preliminary result based on this synthetic plan is presented here.
We focused on development of a general route that can provide 1 as well as its analogues in enantiomerically pure form.
.
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805; E-mail address: [email protected] (S. Ghosh).
Scheme 2. Reagents and conditions: (a) LiAlH4, Et2O, 0 °C, 1 h, 90%; (b) (i) Pd/C (10%), H2, EtOH, rt, 2 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 2 h (87% overall in two steps); (c) (i) EtMgBr, THF, 0 °C, 12 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, 78 °C, 2 h, (71% overall in two steps); (d) CH2=CHMgBr, THF, 0 °C, 12 h, 73%.
2
Tetrahedron
The feasibility of this protocol was demonstrated by the synthesis of the lactone 2 (R = H). The synthesis commenced with the known unsaturated ester 5a,6 prepared from D-mannitol and employed earlier in several syntheses.7 Lithium aluminum hydride reduction of the ester 5a afforded the unsaturated hydroxy compound 5b. Catalytic (10% Pd/C) hydrogenation of 5b followed by Swern oxidation of the primary hydroxyl group provided the aldehyde 6 (Scheme 2). Addition of ethyl magnesium bromide to the aldehyde 6 and oxidation of the resulting carbinol provided the ketone 78 in overall 71% yield. For synthesis of the diene required for RCM, vinyl magnesium bromide was added to the ketone 7 leading to a diastereoisomeric mixture (ca. 1:1) of the carbinol 8. We next attempted the etherification of tertiary alcohol with allyl bromide. However, allylation of the alcohol 8 to produce the diene 4 (R = H) failed under a variety of reaction conditions. It appeared to us that the inertness of 8 towards allylation is possibly due to the steric crowding around the tert-OH.
presence of anhydrous CeCl3 to produce the carbinol 10 in reasonably good yield (70%). As expected the carbinol 10 underwent smooth allylation (NaH-allylbromide) to produce the triene 11 in 85% yield. RCM of the triene 11 with Grubbs’ 1st generation catalyst [Cl2(PCy3)2Ru=CHPh] produced an inseparable mixture (ca. 1:1) of the dihydrofuran derivatives 12 and 13 in 95% yield. The mixture of the dihydrofuran derivatives 12 and 13 was then transformed to the trienes 14 and 15 through a sequence of three steps involving deprotection of the ketal, periodate cleavage of the liberated diol and Wittig olefination with the ylide generated from n-propyl triphenyl phosphonium bromide in 64% over all yield in three steps. Finally allylic oxidation of the dihydrofurans afforded the butenolides 16 and 17 in 79% yield.
We thought that replacing Et group by a vinyl group may facilitate etherification by reducing the steric bulk around tertOH. The vinyl group can be reduced to Et at a suitable stage in the synthesis. With this idea the aldehyde 6 was transformed to the unsaturated ketone 9 through addition of vinyl magnesium bromide followed by Swern oxidation in 75% yield (Scheme 3). Addition of a second vinyl group appeared to be troublesome. After considerable experimentation it was found that vinyl magnesium bromide could be added to the ketone 9 in the
Scheme 4. Reagents and conditions: (a) hν, acetone, rt, 3.5 h, 41%; (b) Pd/C (10%), H2, EtOAc, rt, 2 h, 85%.
Scheme 3. Reagents and conditions: (a) (i) CH2=CHMgBr, THF, 0 °C, 12 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 2 h, (75% overall in two steps); (b) CH2=CHMgBr, CeCl3, THF, -78 °C, 1 h, 70%; (c) NaH, HMPA, CH2=CHCH2Br, THF, 0 °C, 14 h, 85%; (d) Cl2(PCy3)2Ru=CHPh, toluene, 65 °C, 24 h, 95%; (e) (i) AcOH: H2O (4:1), rt, 30 h; (ii) NaIO4-SiO2, CH2Cl2, rt, 0.5 h; (iii) CH3CH2CH2PPh3Br, KHMDS, THF, 0 °C, 1 h (64% overall in 3 steps); (f) PDC, DMF, 65 °C, 12 h, 79%.
With the photo precursors ready in hand, a solution of the mixture of the butenolides 16 and 17 in acetone was irradiated externally in a pyrex cold finger for 3.5 h. Photocycloaddition of 16 and 17 was expected to provide adducts 18 and 19 along with their C-3 epimers respectively. Column chromatography of the crude product afforded 18 in 41% yield as the only isolable photoadduct as a colorless volatile liquid (Scheme 4).9 The gross structure of the photoadduct was established through 1H and 13C NMR spectra. The stereochemical assignment is based on analysis of 2D (HSQC, HMBC, COSY and NOESY) NMR spectra. In COSY spectrum of compound 18 (Figure 1), C-8 H was found to have cross peaks with C-2 and C-4 H’s indicating their syn relationship with each other. The most characteristic information about the syn orientation of C-3, C-4 and C-5 substituents was obtained from the cross peaks observed for C-4 H with C-11 H (CH2 protons of C-5 Et) and C-13 H (CH2 protons of C-3 Et) in NOESY spectrum (Figure 1). Cross peaks found for C-2 H with C-13 H as well as with C-14 H gave additional support to the structure 18. This stereochemical assignment is corroborated by NOESY spectra (Figure 2) of compound 20. The compound 20 was obtained in 85% yield as a colorless volatile liquid by catalytic hydrogenation of 18. Cross peaks observed for the pairs C-8, C-9 H’s, C-8, C-10 H’s, C-2, C-13 H’s, C-2, C-14 H’s and C-4 , C-11 H’s in NOESY spectra of 20 clearly reveals the syn orientation of C-8 H with C-7 Et, C-2 H with C-3 Et and C-4 H with C-5 Et. The cross peaks observed between the pairs C-4, C-12 H’s and C-4, C-13 H’s in NOESY of 18 (Figure 1) correspond to the cross peaks found between C-9, C-18 H’s and C-9, C-11 H’s respectively in Hippolachnin A 1 (Figure 3).1,2 Similarly the cross peaks between the pairs C-4, C-14 H’s, C-8, C-9 H’s and C-8, C-10 H’s in NOESY of the compound 20
3 (Figure 2) corresponding to the cross peaks observed for the pairs C-9, C-12 H’s, C-5, C-15 H’s and C-5, C-16 H’s of 1 (Figure 3) confirmed the stereochemical assignment to 18 and 20.
Supplementary data Supplementary data associated with this article can be found, in the online version, at References and notes 1.
The observed stereochemical outcome in the photocycloaddition of the butenolide 16 may be explained by the well-accepted pathway10 for sensitized enone-alkene photoaddition which, in this case, initially leads to the biradical intermediate 21 (Scheme 5). 5-Exo-trig addition of the highenergy radical β to the lactone carbonyl to the double bond gives rise to a new biradical intermediate 22 which finally collapses in a manner to produce the cyclobutane 18 in which all the bulky substituents at C-3, C-5 and C-7 occupies less sterically crowded exo positions rather than its C-3 epimer in which the C-3 Et group occupies a sterically congested endo position.
Scheme 5. In conclusion we have developed a convenient route for the construction of a tricyclic lactone with three ethyl groups in the desired orientation in enantiomerically pure form en route to hippolachnin A. The key steps involve a RCM-oxidation sequence to form butenolide and a sensitized intramolecular [2+2] photocycloaddition to afford the tricyclic core.
Acknowledgement We are grateful to Department of Science and Technology, Government of India for financial support through J. C. Bose National Fellowship (SR/S-2/JCB-83/2011) awarded to SG. RD thanks Council of Scientific and Industrial Research, New Delhi for a research fellowship.
Piao, S.-J.; Song, Y.-L.; Jiao, W.-H.; Yang, F.; Liu, X.-F.; Chen, W.-S.; Han, B.-N.; Lin, H.-W. Org. Lett. 2013, 15, 3526. 2. Ruider, S. A.; Sandmeier, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2015, 54, 2378. 3. (a) Lakhrissi, M.; Chapleur, Y. Angew. Chem., Int. Ed. 1996, 35, 750; (b) Sabitha, G.; Reddy, M. M.; Srinivas D.; Yadov, J. S. Tetrahedron Lett., 1999, 40, 165; (c) Richard, M.; Didierjean, C.; Chapleur, Y.; Moise, N. P. Eur. J. Org. Chem. 2015, 2632. 4. (a) Ghosh, S.; Patra, D.; Saha, G. J. Chem. Soc., Chem. Commun., 1993, 783; (b) Ghosh, S.; Patra, D. Tetrahedron Lett., 1993, 34, 4565; (c) Patra, D.; Ghosh, S. J. Chem. Soc., Perkin Trans. 1, 1995, 2635; (d) Patra, D.; Ghosh, S. J. Org. Chem., 1995, 60, 2526; (e) Ghosh, S.; Patra, D.; Samajdar, S. Tetrahedron Lett., 1996, 37, 2073; (f) Holt, D. J.; Barker, W. D.; Jenkins, P. R.; Ghosh, S.; Russell, D. R.; Fawcett, J. Synlett, 1999, 1003; (g) Ghosh, S.; Banerjee, S.; Chowdhury, K.; Mukherjee, M.; Howard, J. A. K. Tetrahedron Lett., 2001, 42, 5997; (h) Mondal, S.; Yadav, R. N.; Ghosh, S. Org. Biomol. Chem., 2011, 9, 4903; (i) Jana, A.; Mondal, S.; Ghosh, S. Org. Biomol. Chem., 2015, 13, 1846. 5. For excellent accounts on RCM see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446; (b) Fürstner, A. Top. Catal. 1997, 4, 285; (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2036; (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413; (e) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371; (f) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012; (g) Kotha, S.; Sreenivasachary, N. Indian J. Chem. 2001, B40, 763; (h) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199; (i) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490; (j) Ghosh, S.; Ghosh, S.; Sarkar, N. J. Chem. Sci. 2006, 118, 223; (k) Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919. 6. Nayek, A.; Banerjee, S.; Sinha, S.; Ghosh, S. Tetrahedron Lett. 2004, 45, 6457. 7. (a) Sarkar, N.; Nayek, A.; Ghosh, S. Org. Lett. 2004, 6, 1903; (b) Banerjee, S.; Ghosh, S.; Sinha, S.; Ghosh, S. J. Org. Chem. 2005, 70, 4199; (c) Ghosh, S.; Sinha, S.; Drew, M. G. B. Org. Lett. 2006, 8, 3781; (d) Ghosh, S.; Bhaumik, T.; Sarkar, N.; Nayek, A. J. Org. Chem. 2006, 71, 9687; (e) Matcha, K.; Ghosh, S. Tetrahedron Lett. 2008, 49, 3433; (f) Ghosh, M.; Bose, S.; Ghosh, S. Tetrahedron Lett. 2008, 49, 5424; (g) Mondal, S.; Malik, C. K.; Ghosh, S. Tetrahedron Lett. 2008, 49, 5649; (h) Mondal, S.; Ghosh. S. Tetrahedron 2008, 64, 2359; (i) Ghosh, M.; Bose, S.; Maity, S.; Ghosh, S. Tetrahedron Lett. 2009, 50, 7102; (j) Matcha, K.; Ghosh, S. Tetrahedron Lett. 2010, 51, 6924; (k) Maity, S.; Matcha, K.; Ghosh, S. J. Org. Chem. 2010, 75, 4192; (l) Bose, S.; Ghosh, M.; Ghosh, S. J. Org. Chem. 2012, 77, 6345. 8. All new compounds were characterized through spectroscopic data (see supplementary material). 9. Neither the butenolide 17 nor any of its photoadducts could be detected in the NMR spectra of the crude reaction mixture. The instability of the expected product 19 or its C-3 epimer with C-3 and/or C-5 Et occupying sterically crowded endo position probably inhibited cycloaddition of 17 and led to its decomposition during irradiation. cf. Ghosh, S.; Raychowdhuri, S. R.; Salomon, R. G. J. Org. Chem 1987, 52, 83. 10. (a) Brown, M. J. Org. Chem. 1968, 33, 162; (b) Banerjee, S.; Ghosh, S. J. Org. Chem. 2003, 68, 3981.
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A convenient access to the tricyclic core structure of Hippolachnin A Ritabrata Datta, Ryan Joseph Dixon and Subrata Ghosh*
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S0040-4039(15)30353-1 http://dx.doi.org/10.1016/j.tetlet.2015.11.045 TETL 46985
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
19 October 2015 5 November 2015 14 November 2015
Please cite this article as: Datta, R., Dixon, R.J., Ghosh, S., A convenient access to the tricyclic core structure of Hippolachnin A, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.11.045
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Tetrahedron Letters
A convenient access to the tricyclic core structure of Hippolachnin A Ritabrata Datta, Ryan Joseph Dixon and Subrata Ghosh* Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
A concise route for the synthesis of the enantiopure oxacyclobutapentalene core structure present in hippolachnin A has been developed. The key steps involve ring closing metathesis to construct butenolide and its intramolecular [2+2] photocycloaddition.
Keywords: Asymmetric synthesis Metathesis Lactone Photochemistry
Hippolachnin A 1 is a polyketide isolated1 recently from the South China Sea sponge Hippospongia lachne. Initial bioassay indicates2 that it is not only a potent antifungal agent but also capable of curing various diseases such as renal failure, chronic heart failure etc. Hippolachnin A having an unprecedented oxacyclobutapentalene skeleton possesses a highly sterically congested cage structure with six contiguous stereocentres. Structural novelty combined with its therapeutic potential elicited considerable interest in its synthesis. A recent report2 of the total synthesis of (±)-hippolachnin A by Carreira et al prompted us to report our initial results on the development of an asymmetric route towards its synthesis.
We envisioned that a Wittig reaction3 of the tricyclic lactone 2 with (methoxycarbonylmethylene)triphenylphosphorane would directly provide 1 (Scheme 1). Thus our approach to 1 was initially targeted on the construction of the lactone 2. Our continued interest4 in the application of intramolecular [2+2] photocycloaddition reaction for the synthesis of natural products which led us to consider the possibility of adopting this technique for accomplishing the synthesis of 2 from the dienone 3. The latter was anticipated to be obtained from a ring closing metathesis5-oxidation sequence of the diene 4. Preliminary result based on this synthetic plan is presented here.
We focused on development of a general route that can provide 1 as well as its analogues in enantiomerically pure form.
.
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805; E-mail address: [email protected] (S. Ghosh).
Scheme 2. Reagents and conditions: (a) LiAlH4, Et2O, 0 °C, 1 h, 90%; (b) (i) Pd/C (10%), H2, EtOH, rt, 2 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 2 h (87% overall in two steps); (c) (i) EtMgBr, THF, 0 °C, 12 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, 78 °C, 2 h, (71% overall in two steps); (d) CH2=CHMgBr, THF, 0 °C, 12 h, 73%.
2
Tetrahedron
The feasibility of this protocol was demonstrated by the synthesis of the lactone 2 (R = H). The synthesis commenced with the known unsaturated ester 5a,6 prepared from D-mannitol and employed earlier in several syntheses.7 Lithium aluminum hydride reduction of the ester 5a afforded the unsaturated hydroxy compound 5b. Catalytic (10% Pd/C) hydrogenation of 5b followed by Swern oxidation of the primary hydroxyl group provided the aldehyde 6 (Scheme 2). Addition of ethyl magnesium bromide to the aldehyde 6 and oxidation of the resulting carbinol provided the ketone 78 in overall 71% yield. For synthesis of the diene required for RCM, vinyl magnesium bromide was added to the ketone 7 leading to a diastereoisomeric mixture (ca. 1:1) of the carbinol 8. We next attempted the etherification of tertiary alcohol with allyl bromide. However, allylation of the alcohol 8 to produce the diene 4 (R = H) failed under a variety of reaction conditions. It appeared to us that the inertness of 8 towards allylation is possibly due to the steric crowding around the tert-OH.
presence of anhydrous CeCl3 to produce the carbinol 10 in reasonably good yield (70%). As expected the carbinol 10 underwent smooth allylation (NaH-allylbromide) to produce the triene 11 in 85% yield. RCM of the triene 11 with Grubbs’ 1st generation catalyst [Cl2(PCy3)2Ru=CHPh] produced an inseparable mixture (ca. 1:1) of the dihydrofuran derivatives 12 and 13 in 95% yield. The mixture of the dihydrofuran derivatives 12 and 13 was then transformed to the trienes 14 and 15 through a sequence of three steps involving deprotection of the ketal, periodate cleavage of the liberated diol and Wittig olefination with the ylide generated from n-propyl triphenyl phosphonium bromide in 64% over all yield in three steps. Finally allylic oxidation of the dihydrofurans afforded the butenolides 16 and 17 in 79% yield.
We thought that replacing Et group by a vinyl group may facilitate etherification by reducing the steric bulk around tertOH. The vinyl group can be reduced to Et at a suitable stage in the synthesis. With this idea the aldehyde 6 was transformed to the unsaturated ketone 9 through addition of vinyl magnesium bromide followed by Swern oxidation in 75% yield (Scheme 3). Addition of a second vinyl group appeared to be troublesome. After considerable experimentation it was found that vinyl magnesium bromide could be added to the ketone 9 in the
Scheme 4. Reagents and conditions: (a) hν, acetone, rt, 3.5 h, 41%; (b) Pd/C (10%), H2, EtOAc, rt, 2 h, 85%.
Scheme 3. Reagents and conditions: (a) (i) CH2=CHMgBr, THF, 0 °C, 12 h; (ii) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 2 h, (75% overall in two steps); (b) CH2=CHMgBr, CeCl3, THF, -78 °C, 1 h, 70%; (c) NaH, HMPA, CH2=CHCH2Br, THF, 0 °C, 14 h, 85%; (d) Cl2(PCy3)2Ru=CHPh, toluene, 65 °C, 24 h, 95%; (e) (i) AcOH: H2O (4:1), rt, 30 h; (ii) NaIO4-SiO2, CH2Cl2, rt, 0.5 h; (iii) CH3CH2CH2PPh3Br, KHMDS, THF, 0 °C, 1 h (64% overall in 3 steps); (f) PDC, DMF, 65 °C, 12 h, 79%.
With the photo precursors ready in hand, a solution of the mixture of the butenolides 16 and 17 in acetone was irradiated externally in a pyrex cold finger for 3.5 h. Photocycloaddition of 16 and 17 was expected to provide adducts 18 and 19 along with their C-3 epimers respectively. Column chromatography of the crude product afforded 18 in 41% yield as the only isolable photoadduct as a colorless volatile liquid (Scheme 4).9 The gross structure of the photoadduct was established through 1H and 13C NMR spectra. The stereochemical assignment is based on analysis of 2D (HSQC, HMBC, COSY and NOESY) NMR spectra. In COSY spectrum of compound 18 (Figure 1), C-8 H was found to have cross peaks with C-2 and C-4 H’s indicating their syn relationship with each other. The most characteristic information about the syn orientation of C-3, C-4 and C-5 substituents was obtained from the cross peaks observed for C-4 H with C-11 H (CH2 protons of C-5 Et) and C-13 H (CH2 protons of C-3 Et) in NOESY spectrum (Figure 1). Cross peaks found for C-2 H with C-13 H as well as with C-14 H gave additional support to the structure 18. This stereochemical assignment is corroborated by NOESY spectra (Figure 2) of compound 20. The compound 20 was obtained in 85% yield as a colorless volatile liquid by catalytic hydrogenation of 18. Cross peaks observed for the pairs C-8, C-9 H’s, C-8, C-10 H’s, C-2, C-13 H’s, C-2, C-14 H’s and C-4 , C-11 H’s in NOESY spectra of 20 clearly reveals the syn orientation of C-8 H with C-7 Et, C-2 H with C-3 Et and C-4 H with C-5 Et. The cross peaks observed between the pairs C-4, C-12 H’s and C-4, C-13 H’s in NOESY of 18 (Figure 1) correspond to the cross peaks found between C-9, C-18 H’s and C-9, C-11 H’s respectively in Hippolachnin A 1 (Figure 3).1,2 Similarly the cross peaks between the pairs C-4, C-14 H’s, C-8, C-9 H’s and C-8, C-10 H’s in NOESY of the compound 20
3 (Figure 2) corresponding to the cross peaks observed for the pairs C-9, C-12 H’s, C-5, C-15 H’s and C-5, C-16 H’s of 1 (Figure 3) confirmed the stereochemical assignment to 18 and 20.
Supplementary data Supplementary data associated with this article can be found, in the online version, at References and notes 1.
The observed stereochemical outcome in the photocycloaddition of the butenolide 16 may be explained by the well-accepted pathway10 for sensitized enone-alkene photoaddition which, in this case, initially leads to the biradical intermediate 21 (Scheme 5). 5-Exo-trig addition of the highenergy radical β to the lactone carbonyl to the double bond gives rise to a new biradical intermediate 22 which finally collapses in a manner to produce the cyclobutane 18 in which all the bulky substituents at C-3, C-5 and C-7 occupies less sterically crowded exo positions rather than its C-3 epimer in which the C-3 Et group occupies a sterically congested endo position.
Scheme 5. In conclusion we have developed a convenient route for the construction of a tricyclic lactone with three ethyl groups in the desired orientation in enantiomerically pure form en route to hippolachnin A. The key steps involve a RCM-oxidation sequence to form butenolide and a sensitized intramolecular [2+2] photocycloaddition to afford the tricyclic core.
Acknowledgement We are grateful to Department of Science and Technology, Government of India for financial support through J. C. Bose National Fellowship (SR/S-2/JCB-83/2011) awarded to SG. RD thanks Council of Scientific and Industrial Research, New Delhi for a research fellowship.
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A convenient access to the tricyclic core structure of Hippolachnin A Ritabrata Datta, Ryan Joseph Dixon and Subrata Ghosh*
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