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Mar 17, 2018 - ABSTRACT: The first total synthesis of selligueain A (4), a plant-derived sweet polyphenol, has been achieved. The key step was the de ...
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Letter Cite This: Org. Lett. 2018, 20, 2857−2861

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Total Synthesis of Selligueain A, a Sweet Flavan Trimer Yuka Noguchi, Rikako Takeda, Keisuke Suzuki,* and Ken Ohmori* Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan S Supporting Information *

ABSTRACT: The first total synthesis of selligueain A (4), a plant-derived sweet polyphenol, has been achieved. The key step was the de novo synthetic approach to the selectively protected epiafzelechin unit 10, which was divergently converted to three flavan units 7, 8, and 9. These components were combined by an orthogonal activation and annulation method, enabling assembly of the characteristic trimeric structure with single and double interflavan linkages.

installing the third flavan unit with a single linkage (middle− bottom).7 The viability of this approach has been demonstrated by the successful synthesis of cinnamtannin B1 (1),5 a representative sweet trimer constituted by three epicatechin units, confirming that the key trimeric structure is selectively assembled with rigorous control of the stereo- and regiochemistry. However, further application of this methodology to other congeners is hampered by two serious bottlenecks. The first issue is the limited availability of flavan monomers: commercially available flavan-3-ol is basically limited to (+)-catechin, and other congeners are scarce and could not be used as starting materials. Second, monomer units need to be selectively protected for the use in the trimer synthesis stated above. This situation indeed applies to selligueain A (4) isolated from the rhizomes of Selliguea feei.3 Although this compound is interesting in view of the pronounced sweetness, 35 times sweeter than sucrose, it has been obtained in only minute amounts from nature, so that availability by organic synthesis is highly desirable. The issue, however, is that the trimers are composed of two rare flavan monomer units, i.e., (−)-epiafzelechin (EZ, 5) and (+)-afzelechin (AZ, 6) (Figure 3). Concerning this issue, we had developed several viable synthetic methods of catechin monomers.8 Most relevant to the present problem is, among others, the approach to the epi-type catechins, relying on the synthetic sequence, including the

A

lthough bitterness is the general association with the catechin-class polyphenols,1 there is an interesting exception in that a class of “sweet catechins” has been reported, such as 1−32 and 43 (Figure 1). These compounds share a

Figure 1. Structure motif of sweet trimeric flavans.

characteristic trimeric structure with a unique connectivity: the top−middle units are connected by a double linkage,4,5 while the middle−bottom units are singly connected. In view of the lack of a general theory on the structure−activity relationship of sweetness,6 these compounds and their synthetic analogues would serve as an intriguing probe to gain insights. Toward this particular trimeric scaffold, we reported a viable synthetic access (Figure 2) by exploiting (1) an annulation method to construct the double-linkage between two catechin units (top−middle)5 and (2) the orthogonal activation for

Figure 3. Monomeric components of selligueain A (4). Received: March 17, 2018 Published: April 16, 2018

Figure 2. Strategy for the key trimeric scaffold. © 2018 American Chemical Society

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Organic Letters

Scheme 3 illustrates preparation of the common flavan unit 10. Starting from 1,3,5-trifluorobenzene, sequential substitu-

ortho-metalation of aryl fluoride I and reaction with epoxy alcohol II, followed by an SNAr oxycyclization of adduct III to give flavan IV (Scheme 1).8,9 We hoped that this de novo approach would provide sufficient amounts of the monomer unit required for the total synthesis of 4.

Scheme 3. Synthesis of the Common Monomeric Unit 10

Scheme 1. De Novo Synthetic Approach to Flavan-3-ols

With this plan in mind, we embarked on the total synthesis of selligueain A (4) by way of the de novo synthesis of monomeric flavan units and their assembly by the unified oligomerization strategy (vide supra, Figure 2); the successful implementation will be described in this paper. Scheme 2 outlines our retrosynthetic analysis of 4. Disconnections of the interflavan bonds suggested three Scheme 2. Synthesis Plan tions with t-BuOK (DMF, rt, 2 h) followed by sodium benzyl alkoxide (BnOH, NaH, DMF, rt, 12 h) gave monofluoride 115 in excellent yield (Scheme 3). Regioselective lithiation of 1110 (n-BuLi, THF, −78 °C, 1 h) followed by the reaction with epoxide 128b in the presence of BF3·OEt2 (THF, −78 °C, 0.5 h) gave adduct 13 in 99% yield. Protection of alcohol 13 as a MOM ether (MOMCl, i-Pr2NEt, n-Bu4NI, CH2Cl2, rt, 16 h) followed by removal of the silyl group gave alcohol 14 (90% yield, two steps), ready for the pyran cyclization. Treatment of 14 with KH (THF, rt, 24 h) cleanly gave pyran 15 in excellent yield, which was treated with PPTS in EtOH to detach the MOM and tert-butyl groups, giving phenol 10 in 92% yield.8 Note that the latter reaction was conducted in the presence of phloroglucinol as a scavenger of the electrophilic C1 species generated during the MOM deprotection.8d The compound 10, thus prepared de novo, is an ideal key intermediate in view of the well-discriminated protection pattern poised for divergent access to all requisite monomer units, 7−9, ready for the total synthesis of 4. Scheme 4 illustrates synthesis of the top flavan unit 7. Tetrabenzyl derivative 16 was obtained from 10 by using an excess of benzyl bromide (2.3 equiv) and NaH as a base (rt, 75% yield). Heating of 16 with DDQ (4.0 equiv) in the presence of ethylene glycol (1.5 equiv, CH2Cl2, reflux, 3 h) gave 66% yield of 17 with a 2,4-ethylenedioxy bridge.5 The C(8) position in 17 was masked by a bromine atom (N-

monomeric synthons A−C, to which we assigned the three monomer units 7−9 designed as respective synthetic equivalents. The top unit 7 is an epiafzelechin (EZ) derivative possessing two oxygen-leaving groups at the C(2) and C(4) positions, which would be amenable for a hard activation.7 A bromine substituent is installed at C(8) to decrease the nucleophilicity at this position.7 The middle unit 8 is also an EZ-derivative with a sulfur leaving group at C(4) that could be activated by a soft Lewis acid. The bottom unit 9 is an afzelechin (AZ) derivative displaying 2,3-trans-stereochemistry, which we planned to obtain from the C(3)-epimerization of an EZ-derivative. Given divergent synthetic elaboration, we intended to prepare selectively protected flavan 10 as a common intermediate, which would pave an effective de novo approach to the requisite monomer units 7−9, respectively.

Scheme 4. Synthesis of Top Flavan Unit 7

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Organic Letters bromosuccinimide, CH 2 Cl 2 , 0 °C), giving bromide 7 quantitatively. The middle unit 8 was prepared from diol 10 (Scheme 5). After silylation of 10 to give silyl ether 18, DDQ oxidation in

Table 1. Nucleophilic Substitution at the C(3)-Position

Scheme 5. Synthesis of Middle Flavan Unit 8

run

substrate

R

time

yield of 25 (23a/b) (%)

1 2 3

24a 24b 24c

Ms Ts Ns

3d 24 h 40 min

62 (10/15) 65 (18/15) 67 (13/10)

Syntheses of 24a [MsCl (2 equiv), Et3N (5 equiv), CH2Cl2, 0 °C, 2.5 h, quant], 24b [TsCl (3 equiv), DMAP (1 equiv), pyridine, rt, 40 h, 88%], and 24c [NsCl (2 equiv), DMAP (2 equiv), CH2Cl2, rt, 12 h, 83%].

a

desired product 25 in 62% yield (run 1). Formation of the βelimination products, however, was less serious (23a: 10%; 23b: 15%). In the case of tosylate 24b, the reaction proceeded faster (24 h) than that of 24a, giving 25 in 65% yield (run 2). Notably, nosylate 24c showed much higher reactivity. The reaction completed within 40 min, giving 25 in 67% yield (run 3). Having identified an optimal set of conditions, the bottom unit 9 was synthesized (Scheme 7). Tribenzyl ether 26 was

the presence of 2-ethoxyethanol (CH2Cl2, rt, 2 h) gave 4alkoxyflavan 19 (73% yield from 10), which was quantitatively converted to the corresponding sulfide 20 by treatment with 2,6-xylenethiol (HSXy) in the presence of BF3·OEt2 (CH2Cl2, −78 °C, 2 h). The silyl group attached to the phenol in 20 was selectively removed by treatment with n-Bu4NF buffered with acetic acid, giving the middle unit 8 in quantitative yield. The diagnostic NOE was observed between the hydrogen (Ha) at the C(2) position and the CH3 group in the SXy group, confirming the β-disposition of the C(4)-substituent. Prior to preparation of the bottom unit, a model study was conducted addressing the viability of epimerization at the C(3)position of the epi-type flavan unit (Scheme 6). Due to the

Scheme 7. Synthesis of Bottom Unit 9

Scheme 6. Attempted Mitsunobu Reaction of 21 prepared from the common intermediate 10 by selective Obenzylation (BnBr, K2CO3, rt, 88% yield). After nosylation of 26 to give 27, the nucleophilic substitution with cesium acetate in the presence of 18-crown-6 (toluene, reflux, 40 min) gave 66% yield of the afzelechin derivative 28. Removal of the acetyl group in 28 (K2CO3, MeOH, rt, 1 h) gave the bottom unit 9 in quantitative yield. Having all the required building blocks, the stage was set for their assembly (Scheme 8). The initial step was the annulation of the top unit 7 and the middle unit 8, which was achieved by using BF3·OEt25 (CH2Cl2, −78 → −40 °C, 4 h) to give the annulation product 29 as a sole product in 86% yield. The regiochemistry of the newly formed interflavan linkage was verified as the C(4) → C(8) connectivity based on the diagnostic NOE correlations. Importantly, no formation of the C(4) → C(6)-linked products was observed under these conditions, and the sulfide moiety remained intact under these hard Lewis acidic conditions. After detachment of the silyl group in 29 (n-Bu4NF, THF, 98%), the resulting sulfide 30 was activated under soft Lewis acidic conditions5,7 (I2 and Ag2O, CH2Cl2, −78 → 0 °C, 4 h) followed by union with the bottom unit 9, giving trimer 31 in

ready availability, commercially available (−)-epicatechin was used for this purpose. After preparation of the epicatechin derivative 21, the Mitsunobu reaction was initially tested (DIAD, PPh3, PhCO2H, CH2Cl2, rt). Unfortunately, the desired product 22 was obtained only in poor yield (33%) with considerable amounts of alkenes 23a (38%) and 23b (12%). As an alternative approach, a stepwise conversion was examined by converting alcohol 21 into the sulfonates 24a−c followed by the nucleophilic substitution by an oxygen nucleophile (Table 1). Upon treatment of mesylate 24a (R = Ms) with cesium acetate in the presence of 18-crown-6, the reaction was sluggish (toluene, reflux, 3 days) and gave the 2859

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Scheme 8. Assembly of Three Flavan Units via Orthogonal Activation

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00873. Full experimental procedures, characterization data, and NMR spectra for all new compounds (PDF)



AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Keisuke Suzuki: 0000-0001-7935-3762 Ken Ohmori: 0000-0002-8498-0821 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Nos. JP16H06351, JP16H01137, and JP16H04107. REFERENCES

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93% yield. It should be noted that the seemingly labile benzylic acetal moiety at the C(2) position of the top unit remained untouched during this coupling reaction. Finally, all benzyl groups and the bromine atom were simultaneously removed by hydrogenolysis [H2 (1 atm), 5% Pd(OH)2/C (ASCA2),11 MeOH−THF−H2O (v/v/v = 4:4:1), 2 h]. Anaerobic filtration through a membrane filter (argon) gave crude 4 as a pale pinkish amorphous solid, which was purified by the reverse-phase preparative HPLC (Mightysil RPGP II, 20 mm ϕ × 250 mm, MeOH/H2O = 35/65 containing 0.1% TFA) to give pure 4 as an off-white amorphous solid12 in 85% yield. For purpose of characterization, a synthetic sample of 4 was acetylated (Ac2O, pyridine, rt, 6.5 h), giving the corresponding peracetate 32 (55% yield from 31). The 1H and 13C NMR spectra of 32 were fully identical with the reported data of the peracetyl derivative of natural 4,3 confirming the target structure. In conclusion, the first total synthesis of selligueain A (4) has been achieved by exploiting an orthogonal activation method and annulation for assembly of three flavan components prepared by de novo syntheses. Further study is in progress on biological testing using synthetic samples, particularly focusing attention on sweetness. 2860

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Organic Letters (d) Stadlbauer, S.; Ohmori, K.; Hattori, F.; Suzuki, K. Chem. Commun. 2012, 48, 8425−8427. (9) For applications of SNAr oxycyclization for natural product syntheses, see: (a) Ho, T.-C.; Ohmori, K.; Suzuki, K. Org. Lett. 2016, 18, 4488−4490. (b) Nakamura, K.; Ohmori, K.; Suzuki, K. Angew. Chem., Int. Ed. 2017, 56, 182−187. (10) For ortho-lithiation of fluorobenzene derivatives, see: (a) Pleschke, A.; Marhold, A.; Schneider, M.; Kolomeitsev, A.; Röschenthaler, G.-V. J. Fluorine Chem. 2004, 125, 1031−1038. (b) Heiss, C.; Marzi, E.; Mongin, F.; Schlosser, M. Eur. J. Org. Chem. 2007, 2007, 669−675. (c) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63, 1568−1576. (d) Stratakis, M.; Wang, P. G.; Streitwieser, A. J. Org. Chem. 1996, 61, 3145−3150. (e) Seo, H.; Ohmori, K.; Suzuki, K. Chem. Lett. 2011, 40, 744−746. (11) Purchased from N. E. CHEMCAT Co. (12) The purity was assessed by HPLC analysis: Inertsil ODS-3 (5 μm), 4.6 mm ϕ × 250 mm, H2O/MeOH = 65/35 containing 0.1% TFA, flow rate = 1 mL/min, column temp = 25 °C, detected at 280 nm, tR = 9.3 min. For details, see the Supporting Information.

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