Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis and Configuration of Natural Dracaenones Mei-Mei Li,†,‡ Yikang Wu,*,‡ and Bo Liu*,† †
School of Materials Science and Engineering, Harbin University of Science and Technology, Harbin 150040, China State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
‡
Org. Lett. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/09/19. For personal use only.
S Supporting Information *
ABSTRACT: Several dracaenones were synthesized in enantiopure forms for the first time. The key chiral center at C-7 was installed with well-defined stereochemistry using either an Evans aldol condensation or a chiral oxidant-mediated asymmetric epoxidation, while and the critical oxidative coupling was achieved under the PIFA/PTA conditions. Comparison of optical rotations for the synthetic and natural samples allowed for unequivocal assignment of the absolute configurations of the natural dracaenones.
D
of 1 should be opposite to that of 2 and 3. It is noteworthy that compound 2 was also isolated5 (by Li and Hou, in 2014) from the resin of D. cochinchinensis. However, the optical rotation was reported to be +0.51 (c 0.4, MeOH), radically different from the data ([α]D −411 (c 0.0258, MeOH)) reported2 by Cordell. Compound 4 was isolated by Zhang and Yang6 (from fresh stems of D. cochinchinensis) with the gross structure and relative configuration assigned on the basis of the spectroscopic data. The absolute configuration was deduced through comparison of the sign of optical rotation with those of 1−3. Compounds 5 and 6 were isolated by Tu7 (from heartwood of Caesalpinia sappan L.). The NMR data for 5 were very similar to those for 1. With the aid of 2D NOE data, 5 was assigned as the C-13 epimer of 1. Similarly, the structure of 6 was deduced according to the high resemblance between the NMR for 6 and 3. In both cases, the absolute configuration was assigned by comparison of the optical rotation with that for 1− 3. While the assignments of the gross structures and relative configurations of those natural dracaenones seem to be impeccable, the absolute configurations were not beyond all doubtthe octant rule was originally established for cyclohexanone systems, with only a very limited number of known precedents of semiquinone systems. Besides, 1 and 3 are not exactly mirror images to one another. Therefore, assignment of the configuration of the bridge system of 1 by comparison of its sign of optical rotation with that of 3 was not really convincing; the contribution of the chiral center at C-13 should not be overlooked. To verify the absolute configuration of dracaenones, we performed the syntheses described below. Construction of the bridged ring is apparently a critical step in the whole synthesis of dracaenones. A survey of the literature revealed that the only precedent (racemic, Scheme 1)
racaenones are a group of bridged compounds with an uncommon homoisofavane skeleton. The first one ever known in this family was caesalpin J1a (1, Figure 1, with
Figure 1. Structures of 1 (caesalpin J), 2, 3, 4, 5 (epicaesalpin J), and 6 with the atom-numbering system adopted from ref 2.
relative configuration determined by X-ray crystallographic analysis1b of its triacetate), which was isolated (from dried heartwood of Caealpinia sappan L.) in 1985 by Nohara and coworkers. Shortly afterward, the closely related 2 and 3 (both were isolated from Dracaena loureiri) were reported2 by Cordell. The name dracaenone was then introduced and adopted in all subsequent publications on this family of natural products. On the basis of their analysis of the CD data (using the octant rule3), Cordell2 also proposed the absolute configurations of 2 and 3 as depicted in Figure 1.4 Because the sign of optical rotation for 1 was opposite to that for 2 and 3, they suggested that the absolute configuration of the bridge system © XXXX American Chemical Society
Received: December 12, 2018
A
DOI: 10.1021/acs.orglett.8b03965 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Synthesis of ent-4
Scheme 1. Construction of the Bridged Ring System
was that reported by Cordell8 in the late 1980s, which relied on a TTFA-mediated oxidative coupling to construct the C−C bond between the two quaternary carbon atoms. Although the yields were not really satisfactory (12−37%), the lack of any other existing choices prompted us to examine this protocol first. As shown in Table 1, the TTFA conditions were apparently not applicable to our substrates. Fortunately, the PIFA/PTA9 Table 1. Results of Synthesis of 8 (cf. Scheme 1)a entry
7
R1
1 2 3 4 5 6 7 8 9 10 11 12 13 14
a a b c c d d e f f g h i j
H H Me H H H H Me Me Me H Me Me Me
R2 H H H Me Me
R3
reagents
8 (yield, %)
H H H Me Me
TTFAb PIFA/PTAc PIFA/PTA TTFA PIFA/PTA TTFA PIFA/PTA PIFA/PTA TTFA PIFA/PTA TTFA PIFA/PTA PIFA/PTA PIFA/PTA
a (0%)d a (traces) a (10%) c (0%)e c (0%)e d (0%)e d (0%)e d (60%) f (0%)e f (89%) g (28%) g (12%) g (40%)f g (62%)g
−CH2− −CH2− −CH2− Me Me H H TBS MOM
Me Me Me Me Me Me
a
Scheme 3. Conversion of 12 into 16
conditions, which were broadly exploited by Kita and coworkers in the synthesis of other ring systems with great success, proved to be satisfactory (Table 1, entries 8, 10, 13, and 14) if the phenolic OHs were protected in proper forms. With the key step secured, we next performed the enantioselective total synthesis shown in Scheme 2. An Evans aldol condensation of 9 with 10, followed by reductive cleavage of the auxiliary and tosylation, gave 11. Removal of the TBS groups with n-Bu4NF led to concurrent etherification, giving 12. Direct deoxygenation of 12 failed completely. However, its diacetate (13) could be smoothly converted into 1510 by treatment with Et3SiH/TFA followed by saponification and methylation. Finally, PIFA/PTA-mediated9f cyclization and the cleavage9f of the OMe groups afforded the end product ent-4. It is noteworthy that direct exposure of 12 to PIFA/PTA led to a 1:1 mixture of 17a and 17b (Scheme 3).11 However, because only 17a could be acetylated and deoxygenated (leading to a rather low total yield), this route was abandoned. The NMR and optical rotation for natural 4 were reported6 to be determined in CD3OD and MeOH, respectively. However, ent-4 turned out to be insoluble in either CD3OD
or MeOH. We tested a range of commonly used organic solvents and found that only DMSO (and DMSO-d6) could dissolve ent-4. The 1H and 13C NMR of ent-4 recorded in DMSO-d6 were fully consistent with those for natural 4, showing that the corresponding data of natural 4 must be measured in DMSOd6. The optical rotation for ent-4 in DMSO (c = 0.7) had a sign opposite to that for natural 4, with a magnitude of approximately half of that for natural 4 (increased slightly with dilution, Table 2). The absolute configuration of 15 was clearly defined by the Evans aldol condensation. Therefore, it can be concluded beyond all doubts that the absolute configuration of ent-4 must be as depicted. Consequently, natural 4 must have the absolute configuration as shown in Figure 1. Using ent-9 instead of 9 as the starting material, natural 4 was also synthesized in a similar fashion (detailed in the Supporting Information).
Cf. also the Supporting Information; 7f = (±)-15, 7i = (±)-22a, 7j = (±)-22b. bTTFA = thallium trifluoroacetate. cPIFA = phenyliodine bis(trifluoroacetate) or bis(trifluoroacetoxy)iodo)benzene (in old documents), PTA = H3[PW12O40] (phosphotungstic acid). dAffords an unidentified (main) product. eA complex mixture. fIsolated yield after cleavage of the TBS group. gIsolated yield after cleavage of the MOM group.
B
DOI: 10.1021/acs.orglett.8b03965 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Optical Rotation of ent-4a entry
[α]D
c
T (°C)
SDb
CVc (%)
1 2 3 4
+139.9 +253.4 +256.4 +273.1
0.7 0.1 0.07 0.05
17.9 18.3 18.4 18.4
3.6693 4.1173 3.9581 4.9927
+2.62 +1.63 +1.54 +1.83
later increased to +100 (detailed in the Supporting Information). The [α]D +0.51 (c 0.4, MeOH) for natural 2 reported by Li and Hou5 thus could be reasonably explained. Synthesis of 5 was first attempted as shown in Scheme 5. The known 23 was converted into 25 as reported by Davis.12 Scheme 5. Synthesis of ent-6
a
Measured in DMSO, with no detectable changes with time observed. b Standard deviation. cCoefficient of variation.
The synthesis of 2 is outlined in Scheme 4. The key C-7 stereogenic center was installed using the same strategy as in Scheme 4. Synthesis of 2
Reduction of 25 with NaBH4 in MeOH−THF led to 26. Methylation of the C-13 OH was unexpectedly complicated by concurrent formation of 28. For instance, treatment of 26 with t-BuOK/MeI led to both the desired 29 (42%) and the unwanted 28 (34%). Use of NaHMDS/THF to replace tBuOK/MeCN gave more or less the same results. Conversion of 29 into 31 was feasible (cyclization of 28 to give 30 also occurred smoothly). However, deprotection of 31 led to a complex mixture rather than the expected 5. Conversion of 26 into 27 under the NaBH4/THF−TFA conditions was successful. The resulting 27 underwent cyclization readily on exposure to PIFA/PTA and, after cleavage of the methoxy groups, afforded ent-6 (the antipode of natural 6). The difficulty associated with cleavage of the methoxy groups in 31 later was circumvented by using MOM as the protecting group. As shown in Scheme 6, asymmetric epoxidation of 32 installed the C-7 OH (86% ee). Subsequent reduction with NaBH4/THF−MeOH afforded 34. Methylation of 34 was achieved using KOH (instead of t-BuOK) as the base. Slightly improved selectivity was thus obtained (i.e., 37% of the desired 36 and 28% of 35, along with 16% of recovered 34, which could be recycled). Treatment of 36 with PIFA/PTA led to the expected 37. Finally, exposure of 37 to F3CCO2H gave the desired end product 5, which showed 1H and 13C NMR identical to those for natural 5.
the synthesis of 4. However, removal of the redundant OH at C-8 of the intermediate aldol after formation of the benzodihydrofuran ring in this case was unsatisfactory (12− 27%). Fortunately, deoxygenation immediately after reductive removal of the chiral auxiliary proved feasible, which led to 20 in 79% yield. Tosylation and TBAF-mediated desilylation− cyclization gave 21, which could be converted into 2 directly (but only in 12% yield). Performing the oxidative coupling after protection of the phenolic OH in 21 with TBS or MOM remarkably improved the formation of the bridged ring system, affording 2 (40% from 22a or 62% from 22b, respectively), which showed 1H and 13C NMR identical to those for natural 2. The optical rotation of 2 had the same sign as that originally reported2 (−411 (c 0.0248, MeOH)) for natural 2. However, the magnitude was substantially smaller (than natural 2). We examined the time-dependence of the [α]D (with ent-2 as the substrate, synthesized using the same approach as detailed in the Supporting Information) and found that the [α]D did not change much with time at c = 0.025. However, at c = 0.4, the time dependence was very obvious: The [α]D measured immediately after preparation of the sample solution was −6.9. Three minutes later, it changed to +7.6. The data recorded 1 h C
DOI: 10.1021/acs.orglett.8b03965 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
Scheme 6. Synthesis of 5
Mei-Mei Li: 0000-0001-5492-3263 Yikang Wu: 0000-0003-4501-5401 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSF of China (21532002, 21672244) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20020200).
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The optical rotation of 5 (in MeOH at c = 0.15) was measured to be [α]D = +312.7, which was consistent with that (+371) for natural 5 and thus allowed for an unequivocal assignment of the absolute configuration of natural 5. In summary, enantioselective total synthesis of several dracaenones was achieved, with the key step of construction of the bridged ring system realized using PIFA/PTA conditions (which was proven much better than TTFA in the previous synthesis). The substituents on phenyl rings were shown to have critical influence on the PIFA/PTA-mediated construction of the bridged ring system; different combinations of these groups on the two phenyl rings may lead to radically different results. The absolute configurations of this family of natural products are thus unequivocally determined for the first time. A methoxy group at the bridged ring was shown to have huge influence on the optical rotation, not only the magnitude but also the sign. The time dependence of the optical rotation for some of these compounds (at relative high concentrations, even the sign might change) was also observed. These results may help to understand the discrepancies in the optical rotation data in the literature and in some cases even may prevent mis-assignment of the absolute configuration.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03965. Scanned NMR and IR spectra, HPLC, experimental details, time-dependence of [α]D for ent-2, and tabular comparison of 1H and 13C NMR for natural and synthetic samples (PDF)
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REFERENCES
(1) (a) Shimokawa, T.; Kinjo, J.-e.; Yamahara, J.; Yamasaki, M.; Nohara, T. Chem. Pharm. Bull. 1985, 33, 3545−3547. (b) Miyahara, K.; Kawasaki, T.; Kinjyo, J.-e.; Shimokawa, T.; Yamahara, J.; Yamasaki, M.; Harano, K.; Nohara, T. Chem. Pharm. Bull. 1986, 34, 4166−4169. (2) Meksuriyen, D.; Cordell, G. A.; Ruangrungsi, N.; Tantivatana, P. J. Nat. Prod. 1987, 50, 1118−1125. (3) (a) Snatzke, G.; Wollenberg, G. J. Chem. Soc. C 1966, 1681− 1685. (b) Kirk, D. N. Tetrahedron 1986, 42, 777−818. (4) Although in ref 2 Cordell mentioned the X-ray analysis of 3 as “reported elsewhere”, it cannot be found anywhere to date. (5) Li, N.; Ma, Z.; Li, M.; Xing, Y.; Hou, Y. J. Ethnopharmacol. 2014, 152, 508−521. No discussion on the assignment of the structure and absolute configuration was given therein. (6) Zheng, Q.-A.; Zhang, Y.-J.; Yang, C.-R. J. Asian Nat. Prod. Res. 2006, 8, 571−577. It seemed to be overlooked that the absolute configurations of 1−3 were deduced from the CD analysis of 2 and 3, rather than the X-ray data of triacetate of 1. (7) Zhao, M.-B.; Li, J.; Shi, S.-P.; Cai, C.-Q.; Tu, P.-F.; Tang, L.; Zeng, K.-W.; Jiang, Y. Molecules 2014, 19 (1), 1−8, DOI: 10.3390/ molecules19010001. (8) (a) Cordell, G. A.; Blasko, G. Heterocycles 1988, 27, 445−452. (b) Blasko, G.; Cordell, G. A. Tetrahedron 1989, 45, 6361−6366. (9) Cf., e.g.: (a) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem. Commun. 2002, 450−451. (b) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem. - Eur. J. 2002, 8, 5377−5383. (c) Hamamoto, H.; Shiozaki, Y.; Hata, K.; Tohma, H.; Kita, Y. Chem. Pharm. Bull. 2004, 52, 1231−1234. (d) Wada, Y.; Otani, K.; Endo, N.; Harayama, Y.; Kamimura, D.; Yoshida, M.; Fujioka, H.; Kita, Y. Org. Lett. 2009, 11, 4048−4050. (e) Hamamoto, H.; Shiozaki, Y.; Nambu, H.; Hata, K.; Tohma, H.; Kita, Y. Chem. - Eur. J. 2004, 10, 4977−4982. (f) Hata, K.; Hamamoto, H.; Shiozaki, Y.; Kita, Y. Chem. Commun. 2005, 2465−2467. For some other PIFA mediated couplings, cf., e.g.: (g) Song, L.; Yao, H.; Tong, R. Org. Lett. 2014, 16, 3740−3743. (h) Zhou, Y.; Zhang, X.; Zhang, Y.; Ruan, L.; Zhang, J.; Zhang-Negrerie, D.; Du, Y. Org. Lett. 2017, 19, 150−153. (i) Nakhla, M. C.; Wood, J. L. J. Am. Chem. Soc. 2017, 139, 18504−18507. (j) Guo, W.-S.; Zhang, Y.-A.; Wen, L.-R.; Li, M.; Gong, H. Org. Lett. 2018, 20, 6394−6397. (k) L’Homme, C.; Ménard, M.-A.; Canesi, S. J. Org. Chem. 2014, 79, 8481−8485. (10) Deprotection of the antipode of 15 (i.e., ent-15) led to a natural product, which has not been synthesized to date (cf. the Supporting Information). (11) It is noteworthy that the optical rotations for 17a and 17b were radically different (+225.6 for 17a vs −8.4 for 17b, cf. the Supporting Information). Therefore, the hidden presumption in the assignment of absolute configuration in previous studies (i.e., the sign of optical rotation of dracaenones is mainly decided by the absolute configuration of the bridged ring system) might not be always correct; the presence of an additional stereogenic center might have an unexpectedly strong influence on the magnitude and the sign of optical rotation. (12) Davis, F. A.; Chen, B.-C. J. Org. Chem. 1993, 58, 1751−1753.
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DOI: 10.1021/acs.orglett.8b03965 Org. Lett. XXXX, XXX, XXX−XXX
