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Stereoselective synthesis of cryptomoscatone D2
Tetrahedron Letters 55 (2014) 5756–5758
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of cryptomoscatone D2 Atla Raju, Gowravaram Sabitha ⇑ Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 17 June 2014 Revised 11 August 2014 Accepted 13 August 2014 Available online 19 August 2014
Cryptomoscatone D2 was synthesized stereoselectively from trans-cinnamaldehyde. The synthesis of the triol frame work relied on the creations of the stereocenters independently by utilizing double Maruoka allylations and Sharpless epoxidation. The lactone moiety was constructed by RCM reaction. Ó 2014 Published by Elsevier Ltd.
Keywords: Maruoka allylation Sharpless asymmetric epoxidation Red-Al reduction Ring-closing metathesis
Molecules containing d-lactone motifs continue to attract the interest of chemists due to their significant biological activities. Cryptomoscatone D2 (Fig. 1) is part of a series of related 6-substituted 5,6-dihydroypyran-2-ones (d-lactones), which was first isolated from branch and stem bark of Cryptocarya moschata, Lauraceae in 2000 by Cavalheiro and Yoshida1 and its structure was established by spectroscopic methods. The compound contains an a,b-unsaturated d-lactone ring along with two hydroxyl groups having opposite stereostructure and an olefinic system with (E)-configuration. Later, it was also isolated from Cryptocarya mandioccana by the same group and has been evaluated for its cytotoxicity in HPV-infected (HeLa and SiHa) and non-infected (C33A) human cervical carcinoma cell lines, and in human lung’s fibroblast line (MRC-5).2 Cryptomoscatone D2 possesses high dose-dependent and time-dependent cytotoxicity in HeLa, SiHa, C33A, and MRC-5 cell lines. To date, however, only one synthesis of cryptomoscatone D23a and its Z-isomer3b has been reported. In
continuation of our efforts toward the total synthesis of biologically active lactone natural products,4 we have recently accomplished the total synthesis of d-lactones such as synrotolide, synparvolide C, hyptolide and gamahonolide A. Herein, we describe the total synthesis of cryptomoscatone D2 (1) (Fig. 1) starting from trans-cinnamaldehyde. Retrosynthetic analysis of the structure of cryptomoscatone D2 (1) envisioned that the pyranone could be obtained by acrylation followed by olefin ring-closing metathesis (RCM) of the homoallyl alcohol 2. Finally, di-MOM deprotection produced the target molecule. Compound 2 in turn could be prepared from trans-cinnamaldehyde by successive reactions (Scheme 1). To begin the synthesis, the commercially available trans-cinnamaldehyde was subjected to Maruoka asymmetric allylation5 with allyltributyl tin, in the presence of catalyst (R,R)-I, prepared from (R)-BINOL, Ti(OiPr)4, and Ag2O, to furnish (S)-homoallylic alcohol 36 in 94% yield (Scheme 2). The optical purity of 3 was found to
O OH
OH
O
O MOM OH
OH
O
MOM O O
OH
2
cryptomoscatone D2 (1)
cryptomoscatone D2 (1 ) CHO
Figure 1.
⇑ Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512. E-mail address: [email protected] (G. Sabitha). http://dx.doi.org/10.1016/j.tetlet.2014.08.057 0040-4039/Ó 2014 Published by Elsevier Ltd.
trans-cinnamaldehyde Scheme 1. Retrosynthetic analysis.
5757
A. Raju, G. Sabitha / Tetrahedron Letters 55 (2014) 5756–5758
OR
OMOM
a
CHO
CO 2Et
c
trans-cinnamaldehyde
5
3, R = H 4, R = MOM
b
OMOM
OMOM
O
e
d
OH
OH 6 MOM
O
7
MOM
OR1
MOM O O
k 2
8, R1 = R2 = H 9, R1 = H, R2 = TBS
h
10, R1= MOM, R2 = TBS
i
11, R1 = MOM, R2 = H O
O MOM
MOM O O
OH
j
OR2 g
f
MOM
O
l
12
MOM O O
O
13
O m
OH
OH
O
O Ti O
O i-P r O
i-P r O
O Ti O
cryptomoscatone D2 (1) (R, R) - I
Scheme 2. Reagents and conditions: (a) (R,R)-I, [(R)-BINOL, Ti(Oi-Pr)4, TiCl4, Ag2O], allyltributyl tin (1.1 equiv), CH2Cl2, 20 °C, 24 h (94%; 62% ee); (b) MOMCl, DIEPA, CH2Cl2, 0 °C–rt, 2 h, 85%; (c) ethyl acrylate, Grubbs’ II catalyst, CH2Cl2, rt, 86%; (d) DIBAL-H, CH2Cl2, 0 °C–rt , 1 h, 92%; (e) ( )-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, 20 °C, 24 h, 96%, 97:3 dr; (f) Red-Al, THF, 0 °C, 2 h, 90%; (g) TBSCl, imidazole, CH2Cl2, 0 °C, 1 h, 95%; (h) MOMCl, DIEPA, CH2Cl2, 0 °C–rt, 2 h, 87%; (i) TBAF, THF, 0 °C–rt, 3 h, 90%; (j) (i) IBX, CH3CN, reflux, 0.5 h; (ii) (R,R)-I, [(R)-BINOL, Ti(Oi-Pr)4, TiCl4, Ag2O], allyltributyl tin (1.1 equiv), CH2Cl2, 20 °C, 24 h (82% over two steps, 92.22:7.78 dr); (k) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C, 0.5 h, 85%; (l) Grubbs’ 1st generation catalyst, CH2Cl2, reflux, 6 h, 91%; (m) 4 N HCl, CH3CN, 0 °C, 0.5 h, 90% or CeCl37H2O, CH3CN/MeOH (9:1), 48 h, 70%.
be 62% ee by chiral HPLC. Protection of the secondary hydroxyl group in 3 as the MOM ether using MOMCl, and DIPEA in dry dichloromethane yielded 4. The compound 4 was subjected to an olefin cross metathesis (CM) reaction7 with ethyl acrylate using Grubbs’ second generation catalyst (6 mol %) to provide a,b-unsaturated ester 5 in 86% yield. DIBAL-H reduction of 5 gave allylic alcohol 6 in 92% yield. The second stereocenter was created through Sharpless asymmetric epoxidation and its reductive opening with Red-Al to give 1,3 diol 8. A sequence of selective protection/deprotection steps under standard conditions yielded the di-MOM protected triol 11. Oxidation of alcohol 11 with iodoxybenzoic acid (IBX) gave the corresponding aldehyde, which was then subjected to second Maruoka asymmetric allylation5 in the presence of the titanium complex (R,R-I) and allyltributyl tin to give the corresponding homoallylic alcohol 2 in 82% yield (dr 92.22:7.78).8 In this way, three stereogenic centers were independently generated. Now, esterification of alcohol 2 with acryloyl chloride, triethylamine, and a catalytic amount of 4-(N, N-dimethylamino)pyridine gave the acrylate 12 in 85% yield, which underwent RCM reaction utilizing first-generation Grubbs’ catalyst9 in refluxing CH2Cl2 to furnish a,b-unsaturated lactone 13 in 91% yield. Treatment of 13 with 4 N HCl in CH3CN at 0 °C for 30 min (90%) or CeCl37H2O in CH3CN/MeOH (9:1) (70%) provided the target molecule, cryptomoscatone D2 (1).10
In summary, we have reported a stereoselective synthesis of cryptomoscatone D2 (1) in 13 steps and in 23% overall yield that features independent stereocontrolled access to different chiral centers for building polyhydroxylated chain. Acknowledgment One of the authors, A.R. thanks UGC, New Delhi, India for the financial support. Supplementary data Supplementary data (experimental procedures, spectral data and copies of 1H NMR, 13C NMR spectra of all compounds) associated with this article can be found, in the online version, at http:// dx.doi.org/10.1016/j.tetlet.2014.08.057. References and notes 1. Cavalheiro, A. J.; Yoshida, M. Phytochemistry 2000, 53, 811–819. 2. Giocondo, M. P.; Bassi, C. L.; Telascrea, M.; Cavalheiro, A. J.; Bolzani, V. S.; Silva, D. H. S.; Agustoni, D.; Mello, E. R.; Soares, C. P. Rev. Ciênc. Farm. Básica Apl. 2009, 30, 315–322. 3. (a) Yadav, J. S.; Ganganna, B.; Bhunia, D. C. Synthesis 2012, 44, 1365–1372; (b) Reddy, G. C.; Balasubramanyam, P.; Salvanna, N.; Sreenivasulu Reddy, T.; Das, B. Bioorg. Med. Chem. Lett. 2012, 22, 2415.
5758
A. Raju, G. Sabitha / Tetrahedron Letters 55 (2014) 5756–5758
4. (a) Sabitha, G.; Rao, A. S.; Sandeep, A.; Yadav, J. S. Eur. J. Org. Chem. 2014, 455– 465; (b) Sabitha, G.; Sandeep, A. S.; Rao, A. S.; Yadav, J. S. Eur. J. Org. Chem. 2013, 6702–6709; (c) Sabitha, G.; Raju, A.; Reddy, C. N.; Yadav, J. S. RSC Adv. 2014, 4, 1496–1502; (d) Sabitha, G.; Reddy, K. P.; Reddy, S. P.; Yadav, J. S. Tetrahedron Lett. 2014, 55, 3227–3228. 5. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708; (b) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K. Chem. Eur. J. 2003, 9, 4405. 6. (a) de Fátima, Â.; Ronaldo Aloise Pilli, R. A. Tetrahedron Lett. 2003, 44, 8721– 8724; (b) de Fátima, A.; Kohn, L. K.; Antônio, M. A.; de Carvalho, J. A.; Pilli, R. A. Bioorg. Med. Chem. 2005, 13, 2927–2933. 7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956. 8. The diastereomeric ratio of the product was determined using a Shimadzu high-performance liquid-chromatography (HPLC) system equipped with a
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of 254 nm. ATLANTIS C18 150 4.6 mm, 5 l (column) and a solvent system of acetonitrile and water (7:3) at a flow rate of 1.0 ml/min were used. tR: 6.1 and 6.3 min. 9. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. 10. (R)-6-((2R,4R,E)-2,4-Dihydroxy-6-phenylhex-5-en-1-yl)-5,6-dihydro-2H-pyran-2one [cryptomoscatone D2 (1)]: [a]25 D +64.1 (c 1, CHCl3). IR (neat) mmax: 3417, 2927, 1708, 1391, 1258, 1056, 754 cm 1. 1H NMR (500 MHz, CDCl3): d 7.40– 7.18 (m, 5H), 6.92–6.83 (m, 1H), 6.62 (d, J = 15.8 Hz, 1H), 6.28 (dd, J = 15.8, 6.0 Hz, 1H), 5.99 (d, J = 9.8 Hz, 1H), 4.81–4.70 (m, 1H), 4.68–4.60 (m, 1H), 4.42– 4.31 (m, 1H), 3.79 (br s, 1H), 3.37 (br s, 1H), 2.37–2.28 (m, 2H), 1.92–1.68 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): d 164.7, 145.7, 136.5, 131.7, 129.9, 128.5, 127.5, 126.4, 121.0, 74.9, 70.1, 64.2, 43.3, 42.4, 29.8 ppm. HRMS (ESI): calcd for C17H20O4Na (M+Na)+ 311.1259, found 311.1250.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of cryptomoscatone D2 Atla Raju, Gowravaram Sabitha ⇑ Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 17 June 2014 Revised 11 August 2014 Accepted 13 August 2014 Available online 19 August 2014
Cryptomoscatone D2 was synthesized stereoselectively from trans-cinnamaldehyde. The synthesis of the triol frame work relied on the creations of the stereocenters independently by utilizing double Maruoka allylations and Sharpless epoxidation. The lactone moiety was constructed by RCM reaction. Ó 2014 Published by Elsevier Ltd.
Keywords: Maruoka allylation Sharpless asymmetric epoxidation Red-Al reduction Ring-closing metathesis
Molecules containing d-lactone motifs continue to attract the interest of chemists due to their significant biological activities. Cryptomoscatone D2 (Fig. 1) is part of a series of related 6-substituted 5,6-dihydroypyran-2-ones (d-lactones), which was first isolated from branch and stem bark of Cryptocarya moschata, Lauraceae in 2000 by Cavalheiro and Yoshida1 and its structure was established by spectroscopic methods. The compound contains an a,b-unsaturated d-lactone ring along with two hydroxyl groups having opposite stereostructure and an olefinic system with (E)-configuration. Later, it was also isolated from Cryptocarya mandioccana by the same group and has been evaluated for its cytotoxicity in HPV-infected (HeLa and SiHa) and non-infected (C33A) human cervical carcinoma cell lines, and in human lung’s fibroblast line (MRC-5).2 Cryptomoscatone D2 possesses high dose-dependent and time-dependent cytotoxicity in HeLa, SiHa, C33A, and MRC-5 cell lines. To date, however, only one synthesis of cryptomoscatone D23a and its Z-isomer3b has been reported. In
continuation of our efforts toward the total synthesis of biologically active lactone natural products,4 we have recently accomplished the total synthesis of d-lactones such as synrotolide, synparvolide C, hyptolide and gamahonolide A. Herein, we describe the total synthesis of cryptomoscatone D2 (1) (Fig. 1) starting from trans-cinnamaldehyde. Retrosynthetic analysis of the structure of cryptomoscatone D2 (1) envisioned that the pyranone could be obtained by acrylation followed by olefin ring-closing metathesis (RCM) of the homoallyl alcohol 2. Finally, di-MOM deprotection produced the target molecule. Compound 2 in turn could be prepared from trans-cinnamaldehyde by successive reactions (Scheme 1). To begin the synthesis, the commercially available trans-cinnamaldehyde was subjected to Maruoka asymmetric allylation5 with allyltributyl tin, in the presence of catalyst (R,R)-I, prepared from (R)-BINOL, Ti(OiPr)4, and Ag2O, to furnish (S)-homoallylic alcohol 36 in 94% yield (Scheme 2). The optical purity of 3 was found to
O OH
OH
O
O MOM OH
OH
O
MOM O O
OH
2
cryptomoscatone D2 (1)
cryptomoscatone D2 (1 ) CHO
Figure 1.
⇑ Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512. E-mail address: [email protected] (G. Sabitha). http://dx.doi.org/10.1016/j.tetlet.2014.08.057 0040-4039/Ó 2014 Published by Elsevier Ltd.
trans-cinnamaldehyde Scheme 1. Retrosynthetic analysis.
5757
A. Raju, G. Sabitha / Tetrahedron Letters 55 (2014) 5756–5758
OR
OMOM
a
CHO
CO 2Et
c
trans-cinnamaldehyde
5
3, R = H 4, R = MOM
b
OMOM
OMOM
O
e
d
OH
OH 6 MOM
O
7
MOM
OR1
MOM O O
k 2
8, R1 = R2 = H 9, R1 = H, R2 = TBS
h
10, R1= MOM, R2 = TBS
i
11, R1 = MOM, R2 = H O
O MOM
MOM O O
OH
j
OR2 g
f
MOM
O
l
12
MOM O O
O
13
O m
OH
OH
O
O Ti O
O i-P r O
i-P r O
O Ti O
cryptomoscatone D2 (1) (R, R) - I
Scheme 2. Reagents and conditions: (a) (R,R)-I, [(R)-BINOL, Ti(Oi-Pr)4, TiCl4, Ag2O], allyltributyl tin (1.1 equiv), CH2Cl2, 20 °C, 24 h (94%; 62% ee); (b) MOMCl, DIEPA, CH2Cl2, 0 °C–rt, 2 h, 85%; (c) ethyl acrylate, Grubbs’ II catalyst, CH2Cl2, rt, 86%; (d) DIBAL-H, CH2Cl2, 0 °C–rt , 1 h, 92%; (e) ( )-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, 20 °C, 24 h, 96%, 97:3 dr; (f) Red-Al, THF, 0 °C, 2 h, 90%; (g) TBSCl, imidazole, CH2Cl2, 0 °C, 1 h, 95%; (h) MOMCl, DIEPA, CH2Cl2, 0 °C–rt, 2 h, 87%; (i) TBAF, THF, 0 °C–rt, 3 h, 90%; (j) (i) IBX, CH3CN, reflux, 0.5 h; (ii) (R,R)-I, [(R)-BINOL, Ti(Oi-Pr)4, TiCl4, Ag2O], allyltributyl tin (1.1 equiv), CH2Cl2, 20 °C, 24 h (82% over two steps, 92.22:7.78 dr); (k) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C, 0.5 h, 85%; (l) Grubbs’ 1st generation catalyst, CH2Cl2, reflux, 6 h, 91%; (m) 4 N HCl, CH3CN, 0 °C, 0.5 h, 90% or CeCl37H2O, CH3CN/MeOH (9:1), 48 h, 70%.
be 62% ee by chiral HPLC. Protection of the secondary hydroxyl group in 3 as the MOM ether using MOMCl, and DIPEA in dry dichloromethane yielded 4. The compound 4 was subjected to an olefin cross metathesis (CM) reaction7 with ethyl acrylate using Grubbs’ second generation catalyst (6 mol %) to provide a,b-unsaturated ester 5 in 86% yield. DIBAL-H reduction of 5 gave allylic alcohol 6 in 92% yield. The second stereocenter was created through Sharpless asymmetric epoxidation and its reductive opening with Red-Al to give 1,3 diol 8. A sequence of selective protection/deprotection steps under standard conditions yielded the di-MOM protected triol 11. Oxidation of alcohol 11 with iodoxybenzoic acid (IBX) gave the corresponding aldehyde, which was then subjected to second Maruoka asymmetric allylation5 in the presence of the titanium complex (R,R-I) and allyltributyl tin to give the corresponding homoallylic alcohol 2 in 82% yield (dr 92.22:7.78).8 In this way, three stereogenic centers were independently generated. Now, esterification of alcohol 2 with acryloyl chloride, triethylamine, and a catalytic amount of 4-(N, N-dimethylamino)pyridine gave the acrylate 12 in 85% yield, which underwent RCM reaction utilizing first-generation Grubbs’ catalyst9 in refluxing CH2Cl2 to furnish a,b-unsaturated lactone 13 in 91% yield. Treatment of 13 with 4 N HCl in CH3CN at 0 °C for 30 min (90%) or CeCl37H2O in CH3CN/MeOH (9:1) (70%) provided the target molecule, cryptomoscatone D2 (1).10
In summary, we have reported a stereoselective synthesis of cryptomoscatone D2 (1) in 13 steps and in 23% overall yield that features independent stereocontrolled access to different chiral centers for building polyhydroxylated chain. Acknowledgment One of the authors, A.R. thanks UGC, New Delhi, India for the financial support. Supplementary data Supplementary data (experimental procedures, spectral data and copies of 1H NMR, 13C NMR spectra of all compounds) associated with this article can be found, in the online version, at http:// dx.doi.org/10.1016/j.tetlet.2014.08.057. References and notes 1. Cavalheiro, A. J.; Yoshida, M. Phytochemistry 2000, 53, 811–819. 2. Giocondo, M. P.; Bassi, C. L.; Telascrea, M.; Cavalheiro, A. J.; Bolzani, V. S.; Silva, D. H. S.; Agustoni, D.; Mello, E. R.; Soares, C. P. Rev. Ciênc. Farm. Básica Apl. 2009, 30, 315–322. 3. (a) Yadav, J. S.; Ganganna, B.; Bhunia, D. C. Synthesis 2012, 44, 1365–1372; (b) Reddy, G. C.; Balasubramanyam, P.; Salvanna, N.; Sreenivasulu Reddy, T.; Das, B. Bioorg. Med. Chem. Lett. 2012, 22, 2415.
5758
A. Raju, G. Sabitha / Tetrahedron Letters 55 (2014) 5756–5758
4. (a) Sabitha, G.; Rao, A. S.; Sandeep, A.; Yadav, J. S. Eur. J. Org. Chem. 2014, 455– 465; (b) Sabitha, G.; Sandeep, A. S.; Rao, A. S.; Yadav, J. S. Eur. J. Org. Chem. 2013, 6702–6709; (c) Sabitha, G.; Raju, A.; Reddy, C. N.; Yadav, J. S. RSC Adv. 2014, 4, 1496–1502; (d) Sabitha, G.; Reddy, K. P.; Reddy, S. P.; Yadav, J. S. Tetrahedron Lett. 2014, 55, 3227–3228. 5. (a) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708; (b) Hanawa, H.; Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K. Chem. Eur. J. 2003, 9, 4405. 6. (a) de Fátima, Â.; Ronaldo Aloise Pilli, R. A. Tetrahedron Lett. 2003, 44, 8721– 8724; (b) de Fátima, A.; Kohn, L. K.; Antônio, M. A.; de Carvalho, J. A.; Pilli, R. A. Bioorg. Med. Chem. 2005, 13, 2927–2933. 7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956. 8. The diastereomeric ratio of the product was determined using a Shimadzu high-performance liquid-chromatography (HPLC) system equipped with a
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of 254 nm. ATLANTIS C18 150 4.6 mm, 5 l (column) and a solvent system of acetonitrile and water (7:3) at a flow rate of 1.0 ml/min were used. tR: 6.1 and 6.3 min. 9. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. 10. (R)-6-((2R,4R,E)-2,4-Dihydroxy-6-phenylhex-5-en-1-yl)-5,6-dihydro-2H-pyran-2one [cryptomoscatone D2 (1)]: [a]25 D +64.1 (c 1, CHCl3). IR (neat) mmax: 3417, 2927, 1708, 1391, 1258, 1056, 754 cm 1. 1H NMR (500 MHz, CDCl3): d 7.40– 7.18 (m, 5H), 6.92–6.83 (m, 1H), 6.62 (d, J = 15.8 Hz, 1H), 6.28 (dd, J = 15.8, 6.0 Hz, 1H), 5.99 (d, J = 9.8 Hz, 1H), 4.81–4.70 (m, 1H), 4.68–4.60 (m, 1H), 4.42– 4.31 (m, 1H), 3.79 (br s, 1H), 3.37 (br s, 1H), 2.37–2.28 (m, 2H), 1.92–1.68 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3): d 164.7, 145.7, 136.5, 131.7, 129.9, 128.5, 127.5, 126.4, 121.0, 74.9, 70.1, 64.2, 43.3, 42.4, 29.8 ppm. HRMS (ESI): calcd for C17H20O4Na (M+Na)+ 311.1259, found 311.1250.