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Stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide from Phomopsis sp. HCCB03520 and its C-6 epimer
Tetrahedron Letters 55 (2014) 67–69
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide from Phomopsis sp. HCCB03520 and its C-6 epimer Cheruku Ravindra Reddy, Biswanath Das ⇑ Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e
i n f o
Article history: Received 5 August 2013 Revised 22 October 2013 Accepted 24 October 2013 Available online 1 November 2013
a b s t r a c t The (Z)-isomer of a phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone isolated from Phomopsis sp. HCCB03520 and its C-6 epimer have been synthesized through a common route starting from butyraldehyde. The synthesis involves enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring closing metathesis as the important steps. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Phytotoxic nonenolide (6S,7R,9R)-6,7-Dihydroxy-9-propylnon-4eno-9-lactone (Z)-Isomer C-6 epimer Total synthesis Common route
The nonenolides (10-membered lactonic compounds) with interesting structural features and impressive bioactivity have commonly been discovered from natural sources.1 A novel phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9lactone (1) has recently been isolated from solid cultures of the endophytic fungus Phomopsis sp. HCCB03520.2 The structure of the compound was determined by spectroscopic analysis and its absolute configuration was established by CD spectroscopy. In continuation of our work3 on the construction of bioactive natural products we were interested in the stereoselective synthesis of 1 and its C-6 epimer 1a. However, our efforts have resulted in the synthesis of their (Z)-isomers (2 and 2a) which we would like to describe here (see Fig. 1). The retrosynthetic analysis of the compounds 1 and 1a indicated that they can be synthesized from the esters 3 and 3a, respectively (Scheme 1). The ester 3, in turn, can again be prepared from the diol 4 while the ester 3a from the diol 4a. Both the diols 4 and 4a can be generated from the allylic alcohol 5 derived from butyraldehyde (6). In the present synthesis (Scheme 2) butyraldehyde (6) was subjected to enantioselective Maruoka allylation4 with titanium complex (S,S)-I (A) and allyltributyltin to produce the known homoallylic alcohol 55 (ee 97%-determined by chiral HPLC). The free hydroxyl group of 5 was protected as TBDPS ether 7 by
OH 6
HO
5
7 8 11 12
OH
4 3
O 9 10
2 1
HO
O O
12
3 2
8
11 10
HO
4
7
O
1
5
HO 6
HO
HO
9 O 1 O
O
2
1a
2a
Figure 1. Structures of the (6S,7R,9R)-6,7-dihydroxy-9-propylnom-4-eno-9-lactone (1), its C-6 epimer (1a) and (Z)-isomer (2) and its C-6 epimer (2a).
OH
O
HO
TBDPSO O
O
OH
O O
OH
O
1: 6S 1a: 6R
4: 3S 4a: 3R
3: 3S 3a: 3R
OH O
⇑ Corresponding author. Tel./fax: +91 40 27160512. E-mail address: [email protected] (B. Das). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.10.114
O
6 Scheme 1. Retrosynthetic analysis of 1 and 1a.
5
68
C. R. Reddy, B. Das / Tetrahedron Letters 55 (2014) 67–69
OTBDPS
OR
O
c
a O
6
8
5 R=H
b
d
O
7 R = TBDPS OTBDPS
9
f
O
TBDPSO O
OH
11
10 TBDPSO
g
TBDPSO
OH
4 TBDPSO
TBDPSO
e
OH
OH
OH
h
4a
70:30% TBDPSO
OH
O
OH
O O
OH
4
OH
O
i 13
12 O
OH O
O
j O
O
3 TBDPSO
OH
4a
h
TBDPSO
O O
OH
i
OH
O O
13a
12a O
OH
O
j O
O O
3a Scheme 2. Synthesis of the key esters 3 and 3a.
O O
O
O
3: 3S 3a: 3R
l
k
O
O O
OH
O
OH
O O 15: 6S 15a: 6R
14: 3S 14a: 3R k
X
Wittig olefination with Ph3PCH2Br in the presence of NaHMDS to yield the unsaturated epoxide 11.9 The epoxide ring of 11 was cleaved with Sc(OTf)3 in THF–H2O (10:1) to afford the diastereoisomeric diols 4 and 4a in the ratio of 70:30.10 These two compounds were separated by flash chromatography. Two hydroxyl groups of 4 were protected as acetonide 12 by treatment with 2,2-dimethoxy propane and PPTS and next, the TBDPS ether group of 12 was deprotected with TBAF to generate the alcohol 13. The alcohol 13 underwent Yamaguchi esterification11 with 4-pentenoic acid using 2,4,6-trichlorobenzoyl chloride, Et3N and DMAP to furnish the ester 3 required for the synthesis of the nonenolide 2.
l
HO
Reagents and conditions:
HO O
O
2: 6S 2a: 6R Scheme 3. Synthesis of nonenolide 2 and 2a.
treatment with TBDPSCl and imidazole. The compound 7 was then reacted with OsO4 in the presence of NMO and subsequently with NaIO4 in aqueous acetone. The resulting aldehyde underwent Wittig olefination6 with Ph3PCHCOOEt to produce the a,b-unsaturated ester 8. The reduction of the ester 8 with DIBAL-H afforded the allylic alcohol 9 which was subjected to Sharpless asymmetric epoxidation7 with Ti(OiPr)4, ()-DIPT and tBuOOH to form the epoxy alcohol 10 (de 96%). The alcohol was oxidized with IBX8 and the generated corresponding aldehyde was subjected to C-1
(a) Allyltributyltin, (S,S)-I (5.31 g, 6.66 mmol), dry DCM, –15 to 0 °C, 72 h, 86%; (b) TBDPSCl, imidazole, dry DCM, 0 °C to rt, 2 h, 92%. %; (c) (i) OsO4, NMO, NaIO4, acetone/H2O, 0 °C- to rt, 6 h; , (ii) Ph3PCHCOOC2H5, benzene, 65 °C, 8 h, 78% (2 two steps); (d) DIBAL-H, CH2Cl2, -78 °C, 2 h, 84%; (e) Ti(OiPr)4, (-)-()-DIPT, tBuOOH, CH2Cl2, -20 °C, 6 h, 79%; (f) (i) IBX, DMSO, Py, THF, rt, 4 h, (ii) Ph3P+CH3Br-, , NaHMDS, THF, 0 °C- to rt, 10 h, 71% (2 two steps); (g) Sc(OTf)3 (0.2 equiv), THF/H2O (10:1), 23 °C, 6.5 h, 95%; (h) 2,2-DMP, PPTS, 0 °C- to rt, 6 h, 92% (12), 89% (12a); (i) TBAF, THF, 0 °C- to rt, 2.5 h, 88% (13), 91% (13a); (j) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, THF, toluene, 0 °C- to rt, 1.5 h, 91% (3), 90% (3a). The other diol 4a produced by the cleavage of the epoxide ring of 11 was converted into another desired ester 3a (Scheme 2) for
C. R. Reddy, B. Das / Tetrahedron Letters 55 (2014) 67–69
the synthesis of C-6 epimer (3) of 2 by similar transformations as above (i.e., protection of the hydroxyl groups of 4a as acetonide 12a, deprotection of the TBDPS ether group of 12a to form the alcohol 13a and Yamaguchi esterification of 13a with 4-pentanoic acid to yield the ester 3a). The acetonide group of the esters 3 and 3a was separately deprotected with 4 N HCl in MeCN to generate the corresponding diols, 14 and 14a, respectively (Scheme 3). These diols (14 and 14a) were attempted to cyclize by ring-closing metathesis using Grubbs’ 2nd generation catalyst12 (B) but no conversion took place (Scheme 3). Next, directly the esters 3 and 3a were separately treated with Grubbs’ 2nd generation catalyst (B). We are satisfied to observe that both the esters 3 and 3a afforded the cyclization products 15 and 15a respectively in high yields. The deprotection of the acetonide group of 15 and 15a was carried out with 4 N HCl in MeCN to furnish the (Z)-isomer (2) of the nonenolide 1 (from 15) and also the (Z)-isomer (2a) of the C-6 epimer 1a (from 15a).13 Reagents and conditions (k) Grubbs-II, CH2Cl2, 50 °C, 8 h, 82% (15), 84% (15a), (l) 4 N HCl, CH3CN, 4 h, 91% (2), 89% (2a), 92% (14), 89% (14a).
O OiPr Ti O O O Ti iPrO O (S,S)-1
A
Mes N Cl Cl
N Mes H Ru Ph
PCy3 Grubbs' catalyst (2nd generation) B
In conclusion, we have described the stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide and its C-6 epimer through a common route. The second compound has been synthesized here for the first time. The inexpensive and commonly available butyraldehyde has been used as the starting material. The enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring-closing metathesis are important steps involved in the present synthesis. Acknowledgments The authors thank CSIR and UGC, New Delhi for financial assistance. References and notes 1. Sun, P.; Lu, S.; Ree, T. V.; Krohn, K.; Li, L.; Zhang, W. Curr. Med. Chem. 2012, 9, 3417. 2. Yang, Z.; Ge, M.; Yin, Y.; Chen, Y.; Luo, M.; Chen, D. Chem. Biodivers. 2012, 9, 403. 3. (a) Kumar, J. N.; Das, B. Tetrahedron Lett. 2013, 54, 3865; (b) Reddy, Ch. R.; Veeranjaneyulu, B.; Nagendra, S.; Das, B. Helv. Chem. Acta 2013, 96, 505; (c) Reddy, P. R.; Sudhakar, C.; Jayprakash, N. K.; Das, B. Helv. Chem. Acta 2013, 96, 289.
69
4. Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708. 5. Sudhakar, C.; Reddy, P. R.; Kumar, C. G.; Sujitha, P.; Das, B. Eur. J. Org. Chem. 2012, 6, 1253. 6. Das, B.; Veeranjaneyulu, B.; Balasubramanyam, P.; Srilatha, M. Tetrahedron: Asymmetry 2010, 21, 2762. 7. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. 8. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019. 9. Mohapatra, D. K.; Dasari, P.; Rahaman, H.; Pal, R. Tetrahedron Lett. 2009, 50, 6276. 10. Barluenga, S.; Moulin, E.; Lopez, P.; Winssinger, N. Chem. Eur. J. 2005, 11, 4935. 11. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. 12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. 13. Spectroscopic data for selected compounds are given below. Compound 10: Colorless oil, ½a25 D +38.4 (c 0.5, CHCl3); IR: 3446, 1467, 1428, 1266, 1107 cm1; 1H NMR (200 MHz, CDCl3): d 7.69 (4H, d, J = 8.0 Hz), 7.48– 7.34 (6H, m), 3.92 (1H, m), 3.81 (1H, m), 3.52 (1H, m), 3.23 (1H, m), 3.04 (1H, m), 2.79 (1H, br s), 1.82–1.61 (4H, m), 1.58–1.41 (2H, m), 1.05 (9H, s), 0.73 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 136.4, 134.1, 130.0, 127.9, 71.1, 62.0, 58.4, 53.1, 39.0, 38.2, 27.1, 22.0, 18.2, 14.1; ESIMS: m/z 399 [M+H]+. Anal. Calcd for C24H34O3Si: C, 72.32; H, 8.60. Found: C, 72.34; H, 8.57. Compound 13: Colorless oil, ½a25 D 19.40 (c 0.5, CHCl3); IR: 3423, 1645, 1460, 1376 cm1; 1H NMR (200 MHz, CDCl3): d 5.80 (1H, m), 5.40–5.22 (2H, m), 4.56 (1H, t, J = 7.0 Hz), 4.38 (1H, m), 3.82 (1H, m), 1.72–1.23 (12H, m), 0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 134.0, 119.0, 108.8, 80.0, 78.6, 71.2, 39.9, 37.1, 28.2, 25.8, 18.9, 14.0; ESIMS: m/z 215 [M+H]+. Anal. Calcd for C12H22O3: C, 67.26; H, 10.35. Found: C, 67.28; H, 10.33. Compound 13a: Colorless oil, ½a25 D +11.40 (c 0.5, CHCl3); IR: 3421, 1649, 1465, 1376 cm1; 1H NMR (200 MHz, CDCl3): d 5.80 (1H, m), 5.39–5.22 (2H, m), 4.60– 4.42 (2H, m), 3.83 (1H, m), 1.98 (1H, m), 1.66 (1H, m), 1.56–1.42 (7H, m), 1.39 (3H, s), 0.95 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 134.2, 118.1, 108.1, 80.0, 74.9, 68.8, 40.2, 37.2, 28.3, 25.0, 19.9, 14.1; ESIMS: m/z 215 [M+H]+. Anal. Calcd for C12H22O3: C, 67.26; H, 10.35. Found: C, 67.23; H, 10.38. Compound 3: Yellow oil, ½a25 D 19.80 (c 0.5, CHCl3); IR: 1736, 1642, 1375, 1216, 1048 cm1; 1H NMR (200 MHz, CDCl3): d 5.88–5.75 (2H, m), 5.37–5.25 (2H, m), 5.12–5.00 (3H, m), 4.52 (1H, t, J = 7.0 Hz), 4.21 (1H, t, J = 7.0 Hz), 2.41–2.32 (4H, m), 1.80 (1H, m), 1.62 (1H, m), 1.59–1.51 (2H, m), 1.49 (3H, s), 1.36 (3H, s), 1.32–1.26 (2H, m), 0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 173.2, 136.8, 134.6, 119.8, 116.2, 109.1, 80.4, 75.2, 71.5, 37.4, 35.8, 34.3, 29.5, 29.0, 25.4, 19.6, 14.8; ESIMS: m/z 297 [M+H]+ Anal. Calcd for C17H28O4: C, 68.89; H, 9.52. Found: C, 68.87; H, 9.54. Compound 3a: Yellow oil, ½a25 D +16.20 (c 0.5, CHCl3); IR: 1735, 1645, 1375, 1219, 1048 cm1; 1H NMR (200 MHz, CDCl3): d 5.89–5.76 (2H, m), 5.33–5.25 (2H, m), 5.09–4.99 (3H, m), 4.50 (1H, t, J = 7.0 Hz), 4.18 (1H, m), 2.45–2.36 (4H, m), 1.70–1.52 (4H, m), 1.49 (3H, s), 1.35 (3H, s), 1.33–1.24 (2H, m), 0.92 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 172.8, 137.2, 134.7, 118.8, 115.9, 108.5, 79.9, 74.6, 71.2, 37.4, 35.6, 34.0, 29.1, 28.4, 25.8, 18.2, 14.0; ESIMS: m/z 297 [M+H]+ Anal. Calcd for C17H28O4: C, 68.89; H, 9.52. Found: C, 68.92; H, 9.50. Compound 2: Yellow oil, ½a25 D 10.20 (c 0.1, MeOH); IR: 3423, 1731, 1436, 1291, 1027 cm1; 1H NMR (200 MHz, CDCl3): d 5.75–5.65 (2H, m), 4.99 (1H, m), 4.82 (1H, dd, J = 8.0, 1.7 Hz), 4.21 (1H, m), 2.80 (1H, m), 2.61 (1H, m), 2.29 (1H, m), 2.10 (1H, m), 1.90–1.78 (2H, m), 1.70 (1H, m), 1.56 (1H, m), 1.43–1.30 (2H, m), 0.94 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 171.3, 130.8, 128.3, 77.1, 71.3, 68.4, 37.5, 35.2, 31.9, 23.3, 19.3, 14.0 m/z 229 [M+H]+ Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.16; H, 8.85. Compound 2a: Yellow oil, ½a25 D +32.60 (c 0.1, MeOH); IR: 3415, 1725, 1459, 1264, 1028 cm1; 1H NMR (200 MHz, CDCl3): d 5.84 (1H, t, J = 10.5 Hz), 5.80 (1H, ddd, J = 10.5, 4.5, 1.8 Hz), 4.78 (1H, m), 4.32 (1H, dd, J = 8.0, 1.8 Hz), 4.02 (1H, m), 2.60 (1H, m), 2.40 (1H, m), 2.29 (1H, m), 2.12 (1H, m), 1.92–1.83 (2H, m), 1.71 (1H, m), 1.53 (1H, m), 1.34–1.28 (2H, m), 0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 172.8, 130.7, 129.8, 77.2, 72.5, 68.1, 38.0, 34.9, 30.0, 24.9, 19.8, 14.9 m/z 229 [M+H]+ Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.17; H, 8.81. Foot note: It is important to mention here that we have noted some discrepancies in NMR (1H and 13C) spectral values between our synthetic compounds and the natural product 1. However, while our manuscript was under revision an article appeared in the web-site of RSC Advances (Krishna, P. R.; Prabhakar, S.; Krishna, K. V. S. R. RSC Adv. 2013, doi: http://dx.doi.org/ 10.1039/C3RA44330B). The authors described the synthesis of the (Z)-isomer (2) through a different route. The spectral data and the figures of the spectra of their compound were identical to those of the compound (2) synthesized by us.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide from Phomopsis sp. HCCB03520 and its C-6 epimer Cheruku Ravindra Reddy, Biswanath Das ⇑ Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
a r t i c l e
i n f o
Article history: Received 5 August 2013 Revised 22 October 2013 Accepted 24 October 2013 Available online 1 November 2013
a b s t r a c t The (Z)-isomer of a phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone isolated from Phomopsis sp. HCCB03520 and its C-6 epimer have been synthesized through a common route starting from butyraldehyde. The synthesis involves enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring closing metathesis as the important steps. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Phytotoxic nonenolide (6S,7R,9R)-6,7-Dihydroxy-9-propylnon-4eno-9-lactone (Z)-Isomer C-6 epimer Total synthesis Common route
The nonenolides (10-membered lactonic compounds) with interesting structural features and impressive bioactivity have commonly been discovered from natural sources.1 A novel phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9lactone (1) has recently been isolated from solid cultures of the endophytic fungus Phomopsis sp. HCCB03520.2 The structure of the compound was determined by spectroscopic analysis and its absolute configuration was established by CD spectroscopy. In continuation of our work3 on the construction of bioactive natural products we were interested in the stereoselective synthesis of 1 and its C-6 epimer 1a. However, our efforts have resulted in the synthesis of their (Z)-isomers (2 and 2a) which we would like to describe here (see Fig. 1). The retrosynthetic analysis of the compounds 1 and 1a indicated that they can be synthesized from the esters 3 and 3a, respectively (Scheme 1). The ester 3, in turn, can again be prepared from the diol 4 while the ester 3a from the diol 4a. Both the diols 4 and 4a can be generated from the allylic alcohol 5 derived from butyraldehyde (6). In the present synthesis (Scheme 2) butyraldehyde (6) was subjected to enantioselective Maruoka allylation4 with titanium complex (S,S)-I (A) and allyltributyltin to produce the known homoallylic alcohol 55 (ee 97%-determined by chiral HPLC). The free hydroxyl group of 5 was protected as TBDPS ether 7 by
OH 6
HO
5
7 8 11 12
OH
4 3
O 9 10
2 1
HO
O O
12
3 2
8
11 10
HO
4
7
O
1
5
HO 6
HO
HO
9 O 1 O
O
2
1a
2a
Figure 1. Structures of the (6S,7R,9R)-6,7-dihydroxy-9-propylnom-4-eno-9-lactone (1), its C-6 epimer (1a) and (Z)-isomer (2) and its C-6 epimer (2a).
OH
O
HO
TBDPSO O
O
OH
O O
OH
O
1: 6S 1a: 6R
4: 3S 4a: 3R
3: 3S 3a: 3R
OH O
⇑ Corresponding author. Tel./fax: +91 40 27160512. E-mail address: [email protected] (B. Das). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.10.114
O
6 Scheme 1. Retrosynthetic analysis of 1 and 1a.
5
68
C. R. Reddy, B. Das / Tetrahedron Letters 55 (2014) 67–69
OTBDPS
OR
O
c
a O
6
8
5 R=H
b
d
O
7 R = TBDPS OTBDPS
9
f
O
TBDPSO O
OH
11
10 TBDPSO
g
TBDPSO
OH
4 TBDPSO
TBDPSO
e
OH
OH
OH
h
4a
70:30% TBDPSO
OH
O
OH
O O
OH
4
OH
O
i 13
12 O
OH O
O
j O
O
3 TBDPSO
OH
4a
h
TBDPSO
O O
OH
i
OH
O O
13a
12a O
OH
O
j O
O O
3a Scheme 2. Synthesis of the key esters 3 and 3a.
O O
O
O
3: 3S 3a: 3R
l
k
O
O O
OH
O
OH
O O 15: 6S 15a: 6R
14: 3S 14a: 3R k
X
Wittig olefination with Ph3PCH2Br in the presence of NaHMDS to yield the unsaturated epoxide 11.9 The epoxide ring of 11 was cleaved with Sc(OTf)3 in THF–H2O (10:1) to afford the diastereoisomeric diols 4 and 4a in the ratio of 70:30.10 These two compounds were separated by flash chromatography. Two hydroxyl groups of 4 were protected as acetonide 12 by treatment with 2,2-dimethoxy propane and PPTS and next, the TBDPS ether group of 12 was deprotected with TBAF to generate the alcohol 13. The alcohol 13 underwent Yamaguchi esterification11 with 4-pentenoic acid using 2,4,6-trichlorobenzoyl chloride, Et3N and DMAP to furnish the ester 3 required for the synthesis of the nonenolide 2.
l
HO
Reagents and conditions:
HO O
O
2: 6S 2a: 6R Scheme 3. Synthesis of nonenolide 2 and 2a.
treatment with TBDPSCl and imidazole. The compound 7 was then reacted with OsO4 in the presence of NMO and subsequently with NaIO4 in aqueous acetone. The resulting aldehyde underwent Wittig olefination6 with Ph3PCHCOOEt to produce the a,b-unsaturated ester 8. The reduction of the ester 8 with DIBAL-H afforded the allylic alcohol 9 which was subjected to Sharpless asymmetric epoxidation7 with Ti(OiPr)4, ()-DIPT and tBuOOH to form the epoxy alcohol 10 (de 96%). The alcohol was oxidized with IBX8 and the generated corresponding aldehyde was subjected to C-1
(a) Allyltributyltin, (S,S)-I (5.31 g, 6.66 mmol), dry DCM, –15 to 0 °C, 72 h, 86%; (b) TBDPSCl, imidazole, dry DCM, 0 °C to rt, 2 h, 92%. %; (c) (i) OsO4, NMO, NaIO4, acetone/H2O, 0 °C- to rt, 6 h; , (ii) Ph3PCHCOOC2H5, benzene, 65 °C, 8 h, 78% (2 two steps); (d) DIBAL-H, CH2Cl2, -78 °C, 2 h, 84%; (e) Ti(OiPr)4, (-)-()-DIPT, tBuOOH, CH2Cl2, -20 °C, 6 h, 79%; (f) (i) IBX, DMSO, Py, THF, rt, 4 h, (ii) Ph3P+CH3Br-, , NaHMDS, THF, 0 °C- to rt, 10 h, 71% (2 two steps); (g) Sc(OTf)3 (0.2 equiv), THF/H2O (10:1), 23 °C, 6.5 h, 95%; (h) 2,2-DMP, PPTS, 0 °C- to rt, 6 h, 92% (12), 89% (12a); (i) TBAF, THF, 0 °C- to rt, 2.5 h, 88% (13), 91% (13a); (j) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, THF, toluene, 0 °C- to rt, 1.5 h, 91% (3), 90% (3a). The other diol 4a produced by the cleavage of the epoxide ring of 11 was converted into another desired ester 3a (Scheme 2) for
C. R. Reddy, B. Das / Tetrahedron Letters 55 (2014) 67–69
the synthesis of C-6 epimer (3) of 2 by similar transformations as above (i.e., protection of the hydroxyl groups of 4a as acetonide 12a, deprotection of the TBDPS ether group of 12a to form the alcohol 13a and Yamaguchi esterification of 13a with 4-pentanoic acid to yield the ester 3a). The acetonide group of the esters 3 and 3a was separately deprotected with 4 N HCl in MeCN to generate the corresponding diols, 14 and 14a, respectively (Scheme 3). These diols (14 and 14a) were attempted to cyclize by ring-closing metathesis using Grubbs’ 2nd generation catalyst12 (B) but no conversion took place (Scheme 3). Next, directly the esters 3 and 3a were separately treated with Grubbs’ 2nd generation catalyst (B). We are satisfied to observe that both the esters 3 and 3a afforded the cyclization products 15 and 15a respectively in high yields. The deprotection of the acetonide group of 15 and 15a was carried out with 4 N HCl in MeCN to furnish the (Z)-isomer (2) of the nonenolide 1 (from 15) and also the (Z)-isomer (2a) of the C-6 epimer 1a (from 15a).13 Reagents and conditions (k) Grubbs-II, CH2Cl2, 50 °C, 8 h, 82% (15), 84% (15a), (l) 4 N HCl, CH3CN, 4 h, 91% (2), 89% (2a), 92% (14), 89% (14a).
O OiPr Ti O O O Ti iPrO O (S,S)-1
A
Mes N Cl Cl
N Mes H Ru Ph
PCy3 Grubbs' catalyst (2nd generation) B
In conclusion, we have described the stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide and its C-6 epimer through a common route. The second compound has been synthesized here for the first time. The inexpensive and commonly available butyraldehyde has been used as the starting material. The enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring-closing metathesis are important steps involved in the present synthesis. Acknowledgments The authors thank CSIR and UGC, New Delhi for financial assistance. References and notes 1. Sun, P.; Lu, S.; Ree, T. V.; Krohn, K.; Li, L.; Zhang, W. Curr. Med. Chem. 2012, 9, 3417. 2. Yang, Z.; Ge, M.; Yin, Y.; Chen, Y.; Luo, M.; Chen, D. Chem. Biodivers. 2012, 9, 403. 3. (a) Kumar, J. N.; Das, B. Tetrahedron Lett. 2013, 54, 3865; (b) Reddy, Ch. R.; Veeranjaneyulu, B.; Nagendra, S.; Das, B. Helv. Chem. Acta 2013, 96, 505; (c) Reddy, P. R.; Sudhakar, C.; Jayprakash, N. K.; Das, B. Helv. Chem. Acta 2013, 96, 289.
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4. Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 1708. 5. Sudhakar, C.; Reddy, P. R.; Kumar, C. G.; Sujitha, P.; Das, B. Eur. J. Org. Chem. 2012, 6, 1253. 6. Das, B.; Veeranjaneyulu, B.; Balasubramanyam, P.; Srilatha, M. Tetrahedron: Asymmetry 2010, 21, 2762. 7. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. 8. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019. 9. Mohapatra, D. K.; Dasari, P.; Rahaman, H.; Pal, R. Tetrahedron Lett. 2009, 50, 6276. 10. Barluenga, S.; Moulin, E.; Lopez, P.; Winssinger, N. Chem. Eur. J. 2005, 11, 4935. 11. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989. 12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. 13. Spectroscopic data for selected compounds are given below. Compound 10: Colorless oil, ½a25 D +38.4 (c 0.5, CHCl3); IR: 3446, 1467, 1428, 1266, 1107 cm1; 1H NMR (200 MHz, CDCl3): d 7.69 (4H, d, J = 8.0 Hz), 7.48– 7.34 (6H, m), 3.92 (1H, m), 3.81 (1H, m), 3.52 (1H, m), 3.23 (1H, m), 3.04 (1H, m), 2.79 (1H, br s), 1.82–1.61 (4H, m), 1.58–1.41 (2H, m), 1.05 (9H, s), 0.73 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 136.4, 134.1, 130.0, 127.9, 71.1, 62.0, 58.4, 53.1, 39.0, 38.2, 27.1, 22.0, 18.2, 14.1; ESIMS: m/z 399 [M+H]+. Anal. Calcd for C24H34O3Si: C, 72.32; H, 8.60. Found: C, 72.34; H, 8.57. Compound 13: Colorless oil, ½a25 D 19.40 (c 0.5, CHCl3); IR: 3423, 1645, 1460, 1376 cm1; 1H NMR (200 MHz, CDCl3): d 5.80 (1H, m), 5.40–5.22 (2H, m), 4.56 (1H, t, J = 7.0 Hz), 4.38 (1H, m), 3.82 (1H, m), 1.72–1.23 (12H, m), 0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 134.0, 119.0, 108.8, 80.0, 78.6, 71.2, 39.9, 37.1, 28.2, 25.8, 18.9, 14.0; ESIMS: m/z 215 [M+H]+. Anal. Calcd for C12H22O3: C, 67.26; H, 10.35. Found: C, 67.28; H, 10.33. Compound 13a: Colorless oil, ½a25 D +11.40 (c 0.5, CHCl3); IR: 3421, 1649, 1465, 1376 cm1; 1H NMR (200 MHz, CDCl3): d 5.80 (1H, m), 5.39–5.22 (2H, m), 4.60– 4.42 (2H, m), 3.83 (1H, m), 1.98 (1H, m), 1.66 (1H, m), 1.56–1.42 (7H, m), 1.39 (3H, s), 0.95 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 134.2, 118.1, 108.1, 80.0, 74.9, 68.8, 40.2, 37.2, 28.3, 25.0, 19.9, 14.1; ESIMS: m/z 215 [M+H]+. Anal. Calcd for C12H22O3: C, 67.26; H, 10.35. Found: C, 67.23; H, 10.38. Compound 3: Yellow oil, ½a25 D 19.80 (c 0.5, CHCl3); IR: 1736, 1642, 1375, 1216, 1048 cm1; 1H NMR (200 MHz, CDCl3): d 5.88–5.75 (2H, m), 5.37–5.25 (2H, m), 5.12–5.00 (3H, m), 4.52 (1H, t, J = 7.0 Hz), 4.21 (1H, t, J = 7.0 Hz), 2.41–2.32 (4H, m), 1.80 (1H, m), 1.62 (1H, m), 1.59–1.51 (2H, m), 1.49 (3H, s), 1.36 (3H, s), 1.32–1.26 (2H, m), 0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 173.2, 136.8, 134.6, 119.8, 116.2, 109.1, 80.4, 75.2, 71.5, 37.4, 35.8, 34.3, 29.5, 29.0, 25.4, 19.6, 14.8; ESIMS: m/z 297 [M+H]+ Anal. Calcd for C17H28O4: C, 68.89; H, 9.52. Found: C, 68.87; H, 9.54. Compound 3a: Yellow oil, ½a25 D +16.20 (c 0.5, CHCl3); IR: 1735, 1645, 1375, 1219, 1048 cm1; 1H NMR (200 MHz, CDCl3): d 5.89–5.76 (2H, m), 5.33–5.25 (2H, m), 5.09–4.99 (3H, m), 4.50 (1H, t, J = 7.0 Hz), 4.18 (1H, m), 2.45–2.36 (4H, m), 1.70–1.52 (4H, m), 1.49 (3H, s), 1.35 (3H, s), 1.33–1.24 (2H, m), 0.92 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 172.8, 137.2, 134.7, 118.8, 115.9, 108.5, 79.9, 74.6, 71.2, 37.4, 35.6, 34.0, 29.1, 28.4, 25.8, 18.2, 14.0; ESIMS: m/z 297 [M+H]+ Anal. Calcd for C17H28O4: C, 68.89; H, 9.52. Found: C, 68.92; H, 9.50. Compound 2: Yellow oil, ½a25 D 10.20 (c 0.1, MeOH); IR: 3423, 1731, 1436, 1291, 1027 cm1; 1H NMR (200 MHz, CDCl3): d 5.75–5.65 (2H, m), 4.99 (1H, m), 4.82 (1H, dd, J = 8.0, 1.7 Hz), 4.21 (1H, m), 2.80 (1H, m), 2.61 (1H, m), 2.29 (1H, m), 2.10 (1H, m), 1.90–1.78 (2H, m), 1.70 (1H, m), 1.56 (1H, m), 1.43–1.30 (2H, m), 0.94 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 171.3, 130.8, 128.3, 77.1, 71.3, 68.4, 37.5, 35.2, 31.9, 23.3, 19.3, 14.0 m/z 229 [M+H]+ Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.16; H, 8.85. Compound 2a: Yellow oil, ½a25 D +32.60 (c 0.1, MeOH); IR: 3415, 1725, 1459, 1264, 1028 cm1; 1H NMR (200 MHz, CDCl3): d 5.84 (1H, t, J = 10.5 Hz), 5.80 (1H, ddd, J = 10.5, 4.5, 1.8 Hz), 4.78 (1H, m), 4.32 (1H, dd, J = 8.0, 1.8 Hz), 4.02 (1H, m), 2.60 (1H, m), 2.40 (1H, m), 2.29 (1H, m), 2.12 (1H, m), 1.92–1.83 (2H, m), 1.71 (1H, m), 1.53 (1H, m), 1.34–1.28 (2H, m), 0.91 (3H, t, J = 7.0 Hz); 13C NMR (50 MHz, CDCl3): d 172.8, 130.7, 129.8, 77.2, 72.5, 68.1, 38.0, 34.9, 30.0, 24.9, 19.8, 14.9 m/z 229 [M+H]+ Anal. Calcd for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.17; H, 8.81. Foot note: It is important to mention here that we have noted some discrepancies in NMR (1H and 13C) spectral values between our synthetic compounds and the natural product 1. However, while our manuscript was under revision an article appeared in the web-site of RSC Advances (Krishna, P. R.; Prabhakar, S.; Krishna, K. V. S. R. RSC Adv. 2013, doi: http://dx.doi.org/ 10.1039/C3RA44330B). The authors described the synthesis of the (Z)-isomer (2) through a different route. The spectral data and the figures of the spectra of their compound were identical to those of the compound (2) synthesized by us.