Letter pubs.acs.org/OrgLett
Enantioselective Access to Bicyclo[3.2.1]octadienone Skeleton: Total Syntheses of (+)-Engelharquinone and Its Epoxide Takumi Fukazawa,† Yoshio Ando,† Ken Ohmori,*,† Tamio Hayashi,‡ and Keisuke Suzuki*,† †
Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore
‡
S Supporting Information *
ABSTRACT: The first enantioselective total syntheses of engelharquinone (2) and its epoxide 3 have been achieved. The key steps include (1) catalytic asymmetric 1,4-addition of a naphthylboronic acid derivative to a masked naphthoquinone derivative by using a chiral Rh-complex and (2) thiolate-promoted stereospecific construction of the bicyclo[3.2.1]octadienone scaffold.
B
icyclo[3.2.1]octadienone (yellow, Figure 1) is a structure seen in β-naphthocyclinone (1)1 and in plant-derived
Figure 2. Two-step approach to bicyclo[3.2.1]octadienone.
For application in total synthesis, we hoped to develop an enantioselective version. Because step 1 exploited the Rhmediated 1,4-addition of boronic acid F to enone E,4a we surmised its enantioselecive variants4b−e would provide us a viable entry. If the enantioselection proceeded well, an additional question was the stereochemical integrity at step 2 and subsequent conversions. We decided to address these issues in the context of total syntheses of 2 and 3, juglone dimers annulated in a head-to-tail manner as in G. We hoped that the synthesis would allow assignment of their unknown stereochemistry as well.
Figure 1. Bicyclo[3.2.1]octadienone motif in compounds 1−3.
natural products, engelharquinones 2 and 3, a pair of antituberculoutic compounds recently isolated from a Taiwan plant, Engelhardia roxburghiana.2 This structure is formally produced by assembly of two naphthoquinones through two bonds, I and II, and is intriguing due to the potential biological relevance and synthetic challenge. We became interested in developing synthetic access to this structural motif, and we previously reported a promising twostep approach (Figure 2):3 Step 1 forms the first bond (red) by assembling donor B and acceptor A to give keto-enone C, and another bond (blue) is formed at step 2 by thiolate-mediated reductive cyclization, giving the key structure D. © XXXX American Chemical Society
Received: February 15, 2017
A
DOI: 10.1021/acs.orglett.7b00464 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters In this communication, we wish to report the first enantioselective total syntheses of 2 and 3 using this strategy. Table 1 shows the initial search for the acceptor substrates in the 1,4-addition reaction. Quinone monoacetals 4a−d5 were
alcohol [t-BuMe2SiCl (1.1 equiv), room temperature, 1.5 h] gave silyl ether 9 in 96% yield. After treatment of phenol 9 with MeLi (1.2 equiv, 0 °C, 1 h), the bromine−lithium exchange [nBuLi (1.5 equiv), −78 °C, 30 min]7 followed by the reaction with i-PrOB(pin) [2 equiv, −78 °C → room temperature, 4 h] gave arylboronic acid ester 10 in quantitative yield. With coupling partners 4c and 10 in hand, their union was examined by using an achiral rhodium catalyst {[RhCl(cod)]2 (10 mol %), KOH (1 equiv), 1,4-dioxane, H2O (4/1, 0.3 M)} to give 1,4-adduct 11 in 80% yield (Table 2, entry 1).8
Table 1. Reactivity of Acceptors: C5-Substituent Effecta
Table 2. Rh-Catalyzed Enantioselective 1,4-Additiona entry
4
R
time/h
1 2 3 4
4a 4b 4c 4d
MeO AcO HO H
7 5 1.5 2
yield/% 15 44 75 81
(6a) (6b) (6c) (6d)
a Conditions: 5 (1.5 equiv), [Rh] (8 mol % of Rh), Et3N (1 equiv), 1,4-dioxane, H2O (4/1, 0.3 M).
subjected to the reaction with boronic acid 5 in the presence of a [RhCl(cod)]2 (4 mol %) and Et3N (1 equiv) [1,4-dioxane, H2O (4/1, 0.3 M)]. It turned out that the C5 substituent (R) poses a decisive effect on the reactivity. Substrates 4a (R = MeO) and 4b (R = AcO) were reluctant to undergo the reaction, giving low yields of the 1,4-adducts 6a and 6b, respectively (entries 1 and 2). By contrast, substrate 4c with a free phenol gave 1,4-adduct 6c in excellent yield (entry 3). The reactivity of 4c was comparable to enone 4d lacking the oxygen functionality (R = H, entry 4). Poor reactivities of 4a and 4b could be attributed to steric hindrance around the reaction site posed by the acetal moiety, where the buttressing effect of R is operative as shown in I.6 Scheme 1 shows the preparation of arylboronic acid ester 10 as the 1,4-addition donor. Reduction of bromonaphthoquinone
entry
[Rh]
ligand
yield/%
ee/%
1 2 3 4b 5b 6c
[RhCl(cod)]2 [RhCl(cod)]2 12 [RhCl(CH2CH2)2]2 [RhCl(coe)2]2 {RhCl[(R,R)-Ph-bod]}2
none (R)-(+)-BINAP none (R,R)-Ph-bod (R,R)-Ph-bod none
80 6 33 70 6 82
− 20 (R) 93 (R) 98 (R) 41 (R) >99 (R)
a Conditions: 10 (1.5 equiv), [Rh] (20 mol % of Rh), chiral ligand (30 mol %), KOH (1 equiv), 1,4-dioxane, H2O (4/1, 0.3 M). b1,4Dioxane, H2O (4/1, 0.1 M). c[Rh] (5 mol % of Rh), KOH (0.25 equiv).
As the initial attempt for the enantioselective reaction, (R)(+)-BINAP4b,d was used as a chiral ligand. However, the reaction was slow, giving a low yield of 1,4-adduct 11 in 20% ee (entry 2).9 The major enantiomer of 11 was R, as established at the stage of enone 13 (vide infra). On the other hand, the chiral diene−rhodium complex 124e led to excellent enantioselectivity, giving (R)-11 in 93% ee, albeit low chemical yield (entry 3). Furthermore, use of the (R,R)-Ph-bod ligand4c,d realized an excellent result, giving a 70% yield of (R)-11 in 98% ee (entry 4). The choice of the Rhcatalyst precursor was crucial, as the use of a cyclooctene complex [RhCl(coe)2]2 gave a poor yield and enantioselectivity (entry 5). Eventually, an optimal set of conditions were found by using a preformed chiral rhodium complex, {RhCl[(R,R)Ph-bod]}2, giving (R)-11 in 82% yield with near-perfect enantioselectivity (>99% ee, entry 6). Scheme 2 shows the conversion of 1,4-adduct 11 to enantiopure enone 139 in 88% yield in three steps: (1) methylation [dimethyl sulfate (1.1 equiv), K2CO3 (1.5 equiv), 12 h], (2) desilylation (HF·pyridine, 2 h), and (3) oxidation [PhI(OCOCF3)210 (1.2 equiv), 0 °C, 3.5 h]. At this stage, we were able to assign the absolute stereochemistry of 13 as R by X-ray diffraction analysis5,11,12 with oxygen as the heaviest atom (Persons quotient method).13
Scheme 1. Synthesis of Arylboronic Acid Ester 10
75 with Na2S2O4 (5 equiv, room temperature, 3 h) followed by the alkylation with ethyl bromoacetate (1 equiv) [K2CO3 (2 equiv), room temperature, 3 h] gave naphthol 8 in 89% yield. Reduction of the ester moiety in 8 [DIBAL (4 equiv), THF, −78 → 0 °C] and selective silylation of the resulting primB
DOI: 10.1021/acs.orglett.7b00464 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Conversion to Enone 13
Scheme 3. Endgame
The stage was set for the key reductive cyclization of enone 13. Several thiolates were examined as summarized in Table 3. Table 3. Optimization of Reductive Cyclization of 13a
a
The enantiomeric excess of 2 (>99% ee) was confirmed by HPLC analysis on a chiral stationary phase.9 Recrystallization (vapor diffusion, hexane, CHCl3) afforded dark red prisms of 2 (mp 233 °C, decomp., lit.2 247−250 °C), amenable to X-ray diffraction analysis to ascertain the absolute configuration of the synthetic material 2 as shown in Scheme 3.11,13 Notably, the optical rotation of the synthetic material 2 (>99% ee) was [α]D25 +340 (c 0.0645, CHCl3), opposite in sign and substantially larger in magnitude in comparison with that of the natural product 2, [α]D25 −14 (c 0.07, CHCl3). Thus, the natural product 2 is antipodal to the synthetic material (+)-2 and with low enantiopurity.17 Some natural products are known to be scalemic,18 i.e., nonracemic, but not enantiopure, and the present case is likely to be an additional example. Unfortunately, the natural samples of 2 (and also 3) are no longer available, 19 and the precise assessment of its enantiopurity remains elusive. We next examined the conversion of (+)-2 into the corresponding epoxide 3. The nucleophilic epoxidation [tBuOOH (5 equiv), TBD (20 mol %), CH2Cl2, 0 °C, 30 min]20 proceeded smoothly to give epoxide 3 as a single isomer (1H NMR) as an orange amorphous solid in 94% yield. All physical data for the synthetic material 3 (1H and 13C NMR, IR, UV− vis, and high-resolution mass spectra) coincided with those of the reported data for 3.2 Recrystallization of the synthetic material 3 (vapor diffusion, hexane, CH2Cl2) afforded orange prisms (mp 193 °C, decomp.). The X-ray diffraction analysis allowed assignment of the relative and absolute structure of epoxide 3 as shown in Scheme 3.11,13
Conditions: NaH (2.0 equiv), DMF (0.5 M).
Upon treatment of 13 with the monosodium salt of ethanedithiol [1,2-ethanedithiol (6.0 equiv), NaH (2.0 equiv)], bicyclic compound 14 was obtained in 66% yield (entry 1). The corresponding reaction using 1,3-propanedithiol led to a 60% yield (entry 2). The yield was improved by using sodium ethanethiolate [ethanethiol (12 equiv), NaH (2.0 equiv)], giving a 76% yield of (+)-14 (entry 3).14,15 Importantly, no racemization occurred as evidenced by the enantiomeric purity of (+)-14 (>99% ee),9 which assuaged our concern on the base lability of the stereogenic center at the γposition of the enone. Scheme 3 shows the endgame to the total synthesis of engelharquinone (2) and conversion to its epoxide 3. Acid hydrolysis of acetal (+)-149 [1 M aq. HCl, 2 h] and oxidation [PhI(OCOCF3)2 (1.5 equiv), 0 °C, 1 h] gave quinone monoacetal (+)-1511 in 85% yield in two steps. Finally, demethylation of quinone monoacetal (+)-15 [MgI216 (20 equiv), diethyl ether and THF (3/1), reflux, 12.5 h] followed by removal of the acetals (80% aq. TFA, room temperature, 1.5 h) gave engelharquinone (2) as an orange amorphous solid in 50% yield in two steps. All physical data of the synthetic material 2 (1H and 13C NMR, IR, UV−vis, high-resolution mass spectra) coincided with those of the reported data.2 C
DOI: 10.1021/acs.orglett.7b00464 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(8) Use of Et3N as base instead of KOH gave 1,4-adduct 11 in 54% yield. From studying 1,4-addition, use of arylboronic acid pinacol ester was determined to give better results than use of arylboronic acid. (9) Assessed by HPLC analysis with DAICEL columns (0.46 cm ϕ × 25 cm, flow rate 1.0 mL/min, λ = 280 nm, 25 °C) with a chiral stationary phase. 11; CHIRALPAK IA, hexane/i-PrOH = 85/15, tR = 8.8 min for (R)-isomer, 11.3 min for (S)-isomer. 13; CHIRALPAK IB, hexane/i-PrOH = 50/50, tR = 15.0 min for (R)-isomer, 22.7 min for (S)-isomer. 14; CHIRALPAK IB, hexane/EtOAc = 30/70, tR = 9.6 min for (+)-isomer, 21.8 min for (−)-isomer. 2; CHIRALPAK IB, hexane/EtOAc = 65/35, tR = 7.8 min for (+)-isomer, 8.5 min for (−)-isomer. 3; CHIRALPAK IB, hexane/i-PrOH = 90/10, tR = 15.9 min for (+)-isomer, 18.6 min for (−)-isomer. (10) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927−3930. (11) CCDC 1529303 (13), 1531668 (15), 1529304 (2), and 1529305 (3) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/ cif. (12) The (R)-stereochemistry of 1,4-adduct 11, correlated from (R)13, agreed with the stereochemical model for the 1,4-addition proposed by Hayashi et al. See ref 4d. (13) Parsons, S.; Flack, H. Acta Crystallogr., Sect. A: Found. Crystallogr. 2004, 60, s61. (14) The corresponding reaction using dodecanethiol led to a 51% yield. (15) In our previous report (ref 3), we noted the special efficacy of mono-Na+ salt of ethanedithiol (HSCH2CH2S− Na+) in a related twostep transformation: the first step was reduction of a dienone to a monoenone similar to 13, and the second step was cyclization to bicyclo[3.2.1]octadienone (like 13→14). The present observation strongly suggests that the special efficacy is related to the first step, a delicate step with a competing single-electron reduction, and the second step is better promoted by EtSNa, presumably by a simple steric factor. (16) Yamaguchi, S.; Sugiura, K.; Fukuoka, R.; Okazaki, K.; Takeuchi, M.; Kawase, Y. Bull. Chem. Soc. Jpn. 1984, 57, 3607−3608. (17) For a review, see: (a) Mori, K. Proc. Jpn. Acad., Ser. B 2014, 90, 373−388. For examples, see: (b) Mori, K.; Sugai, T. Synthesis 1982, 1982, 752−753. (c) Lu, Y.; Beeman, R. W.; Campbell, J. F.; Park, Y.; Aikins, M. J.; Mori, K.; Akasaka, K.; Tamogami, S.; Phillips, T. W. Naturwissenschaften 2011, 98, 755−761. (18) (a) Brewster, J. H. Chem. Eng. News 1992, 70 (May 18), 3. (b) Eliel, E. L. Chirality 1997, 9, 428−430. (19) Personal communication from Prof. Chen. (20) Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor, R. J. K. Synlett 1999, 1999, 795−797.
The completely stereoselective epoxidation is rationalized by the V-shaped structure of 2,11 where the peroxide anion attacked from the convex face. Again the optical rotation of the synthetic material 3 was by far larger in magnitude, [α]D25 +185 (c 0.0358, CHCl3), cf. natural 3 [α]D25 −49 (c 0.026, CHCl3), suggesting low enantiopurity of the natural material 3. In conclusion, the first total syntheses of (+)-engelharquinone (2) and its epoxide 3 have been accomplished via the Rhmediated enantioselective 1,4-addition and thiolate-mediated stereospecific reductive cyclization to the bicyclo[3.2.1]octadienone framework. This synthesis clarified the [α]D values of enantiopure 2 and 3.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00464. Full experimental procedure, characterization data, and NMR spectra for all new compounds (PDF) X-ray crystallographic data for 13, 15, 2, and 3 (ZIP)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Ken Ohmori: 0000-0002-8498-0821 Tamio Hayashi: 0000-0001-9187-3664 Keisuke Suzuki: 0000-0001-7935-3762 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank Prof. Ih-Sheng Chen (Kaohsiung Medical University) for giving the NMR data of the natural products as well as Prof. Hidehiro Uekusa and Dr. Kohei Jomoto (Tokyo Institute of Technology) for X-ray diffraction analysis. This work was supported by JSPS KAKENHI Grant Numbers JP16H06351, JP16H01137.
■
REFERENCES
(1) Zeeck, A.; Zähner, H.; Mardin, M. Justus Liebigs Ann. Chem. 1974, 1974, 1100−1125. (2) Wu, C.-C.; Peng, C.-F.; Tsai, I.-L.; Abd El-Razek, M. H.; Huang, H.-S.; Chen, I.-S. Phytochemistry 2007, 68, 1338−1343. (3) Ando, Y.; Hori, S.; Fukazawa, T.; Ohmori, K.; Suzuki, K. Angew. Chem., Int. Ed. 2015, 54, 9650−9653. (4) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229−4231. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579−5580. (c) Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503−2508. (d) Tokunaga, N.; Hayashi, T. Adv. Synth. Catal. 2007, 349, 513−516. (e) Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009, 4815−4817. (5) See the Supporting Information. (6) Todoroki, H.; Iwatsu, M.; Urabe, D.; Inoue, M. J. Org. Chem. 2014, 79, 8835−8849. (7) Obitsu, T.; Ohmori, K.; Ogawa, Y.; Hosomi, H.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1998, 39, 7349−7352. D
DOI: 10.1021/acs.orglett.7b00464 Org. Lett. XXXX, XXX, XXX−XXX
