Conjugate Addition to Acylketene Acetals Derived from 1,8

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Conjugate Addition to Acylketene Acetals Derived from 1,8Dihydroxynaphthalene and Its Application To Synthesize the Proposed Structure of Spiropreussione A Hirokazu Tsukamoto, Yumi Nomura, Koichi Fujiwara, Shogo Hanada, and Takayuki Doi* Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan S Supporting Information *

ABSTRACT: A conjugate addition of diverse nucleophiles to acylketene acetals derived from 1,8-dihydroxynaphthalene (DHN) is developed for the formation of its 3-oxoalkan-1-one acetals. The initial acylketene acetals are prepared via double oxa-Michael addition of DHN to 1-bromo-1-propyn-3-ones. Carbonucleophiles, including organocopper reagents and active methylene compounds, and heteroatom nucleophiles were introduced under basic conditions. This method is applied for synthesizing spiropreussione A; the proposed structure does not correspond to that of the authentic natural product.

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pirobisnaphthalenes containing two naphthalene-derived C10 units bridged by a spiroacetal linkage are an important class of compounds, because of their interesting biological activities.1 Diverse biosynthetic pathways generate structural complexity and diversity in the class of compounds,2 including the cytotoxic spiromamakone A3 (1, IC50 = 0.33 μM against the murine leukemia cell line P388) and spiropreussione A4 (2, IC50 = 2.4 μM against the human ovarian carcinoma cell line A2780 and 3.0 μM against the human liver carcinoma cell line BEL-7404), wherein both have a unique spiro[4,4]nonadiene skeleton resulting from the loss of one carbon atom during biosynthesis (Figure 1). The discovery of such biologically active compounds highlights the lack of an efficient and general method for the formation of naphthyl acetals, which are required to synthesize these compounds.5 However, the polymerization of 1,8-dihydroxynaphthalene (DHN) accompanies acetal formation under acidic conditions.6 Recently, a spiromamakone A benzo-analog equipotent to the natural

product 1 was synthesized via the double oxa-Michael addition of DHN to oxidized vinylogous thioesters derived from 1,3cyclopentanedione.7 However, the method was deemed unsuitable for the construction of the naphthyl acetal in 2, given its location at the γ- and/or δ-positions, relative to the cyclopentenedione carbonyl groups. Therefore, a general and efficient method must be developed to construct DHN-derived acetals under neutral or basic conditions. Kinetically favored five-membered cyclic acetals derived from catechol under neutral and basic conditions can be constructed using several methods;8−10 however, the formation of kinetically less-favored six-membered acetals derived from 1,8dihydroxynaphthalene is limited to sodium-methoxide-catalyzed double hydroalkoxylation of highly electrophilic dimethyl acetylenedicarboxylate.11 First, double hydroalkoxylation of both natural and 3-substituted methyl propiolates 3a, 3b, and 6a with DHN (Scheme 1) was examined. Unsubstituted 3a was subjected to the double oxa-Michael addition12 of 4 in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to afford acetal 5a in high yields; however, the conversion of alkylsubstituted propiolates 3b to their corresponding acetals 5b was not observed under catalysis using either sodium methoxide or tertiary amine- or phosphine-based catalysts. Interestingly, a stoichiometric amount of DABCO affected the addition and elimination reaction of 3-bromo propiolate 6a, affording acylketene acetal 7a in high yields. To the best of our

Figure 1. Spiromamakone A and spiropreussione A.

Received: April 20, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.8b01259 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

with 30% yield of a byproduct 10aA (Table 1, entry 3). An allylic substitution reaction between the organocopper reagent and 9aA yielded 10aA. The introduction of methyl substituents into the terminal carbon of the vinyl Grignard reagent considerably increased the yield of the conjugate addition products (Table 1, entries 4 and 5). The in situ formation of an enol silyl ether was occasionally observed post-aqueous workup; however, it was readily converted to the parent carbonyl compound upon treatment with K2CO3 in methanol. Phenylmagnesium bromide and allylmagnesium bromide participated in the conjugate addition to 7a to afford 9aD and 9aE in moderate yields (Table 1, entries 6 and 7). The addition of alkyl groups, such as methyl and butyl, also proceeded well (Table 1, entries 8 and 9); electrophiles, such as methyl ketone 7b and aldehyde 7c, underwent the conjugate addition of butylmagnesium bromide to afford 9bG and 9cG in 80% and 47% yields, respectively (Table 1, entries 10 and 11). Unfortunately, phenyl- and tert-butyl ketones 7d and 7e underwent elimination reactions to afford 3,3-dibutyl-1-phenylheptan-1-one (11) and 5-butyl-2,2-dimethyl-4-nonen-3-one (12) as byproducts (Table 1, entries 12 and 13). The steric demands of these functional groups hampered the in situ formation of the enol silyl ether and caused the elimination of DHN. The subsequent second and third conjugate additions afforded 11 and 12, respectively. In addition to organocopper reagents, other nucleophiles were examined (Table 2).18 The use of acetone cyanohydrin and a catalytic amount of KCN allowed the introduction of a cyano group (Table 2, entry 1). Both unsubstituted and substituted nitromethanes were successfully added to 7a in the presence of DBU (Table 2, entries 2 and 3). Sodium salts of malonate, cyanoacetate, and malononitrile underwent a conjugate addition to 7a to afford 9aK−9aM in good to moderate yields (Table 2, entries 4−6). Unfortunately, the conjugate additions of α-substituted malonate and β-ketoester were not observed (data not shown). Nucleophilic addition of five-membered carbocycles, including cyclopentane-1,3-dione and sodium cyclopentadienylide, occurred successfully (Table 2, entries 7 and 8). Methoxide and various amines participated in the conjugate addition reaction to afford 9aP−9aR in excellent yields (Table 2, entries 9−11). In addition, sulfide and selenide anions generated in situ via the reduction of disulfide and diselenide with NaBH4 in DMF19 were introduced into the products 9aS and 9aT with high efficiency (Table 2, entries 12 and 13). The structural similarity between the spirocyclopentenol unit of spiropreussione A (2) and a synthetic intermediate obtained via the synthesis of (−)-O-methylshikoccin and (+)-Omethylepoxyshikoccin, as reported by Paquette et al.,20 reminded us that a Knoevenagel reaction of aldehyde 16 obtained from either 9aC or 9aI in the presence of thiophenol21 or benzeneselenol20 could be employed for the synthesis of 2 (see Scheme 2). However, the Knoevenagel reaction of 16 with cyclopentane-1,3-dione, in the presence of thiophenol, followed by the deprotection of the cyanohydrin acetate in 17 under basic conditions, eliminated thiol and did not afford cyclopentanol 18.22 An alternative approach to construct cyclopentanol 21 via intermolecular and intramolecular aldol reactions using aldehyde 14 was investigated to synthesize 2 (see Scheme 3). To effectively introduce cyclopent-4-en-1,3-dione without the dehydration of the resulting aldol,23 lithium enolate of 4silyloxy-2-cyclopenten-1-one was selected as the nucleophile.24

Scheme 1. Double oxa-Michael Addition of DHN (4) to Methyl Propiolate Derivatives

knowledge, this is the first synthesis of acylketene acetal using 3-bromo-2-propyn-1-ones, which are easily prepared via bromination of the parent 2-propyn-1-ones derived from esters, ketones, and aldehydes.13,14 Furthermore, the conjugate addition of various nucleophiles to 7a led to the formation of diverse groups of acetals.15 To probe the reaction requirements for a conjugate addition to β,β-disubstituted unsaturated carbonyls 7a−7e, a variety of Grignard reagent and copper salt combinations in the absence or presence of various additives were examined (Table 1). Table 1. Conjugate Addition of Organocopper Reagents 8A−8G to 7a−7ea

entry

7

X

nucleophile R

product 9

yield (%)

1b,c 2b,d 3 4 5 6 7b 8 9 10 11 12 13

7a 7a 7a 7a 7a 7a 7a 7a 7a 7b 7c 7d 7e

OMe OMe OMe OMe OMe OMe OMe OMe OMe Me H Ph t-Bu

CHCH2 (A) CHCH2 (A) CHCH2 (A) CHCHCH3 (B) CHC(CH3)2 (C) Ph (D) allyl (E) Me (F) Bu (G) Bu (G) Bu (G) Bu (G) Bu (G)

9aA 9aA 9aA 9aB 9aC 9aD 9aE 9aF 9aG 9bG 9cG 9dG 9eG

0 15 17e 50 65 57 40 85 61 80 47 29f 13g

a

Grignard reagent (4 equiv), CuI (2 equiv), DMAP (4 equiv), and TMSCl (4 equiv) were employed. bAll reagent equivalents increased by 2.5 times in reference to the substrate. cDMAP and TMSCl were omitted. dBF3·OEt2 was used instead of DMAP and TMSCl. eSN2′ adduct 10aA was obtained in 30% yield. f3,3-Dibutyl-1-phenylheptan1-one (11) was obtained in 25% yield. g5-Butyl-2,2-dimethyl-4-nonen3-one (12) and the 1,4-reduction product 3,3-dimethyl-1-(naphtho[1,8-de][1,3]dioxin-2-yl)butan-2-one were obtained in 34% and 19% yields, respectively.

Initially, the least reactive ester 7a and vinylmagnesium bromide (8A) were chosen as the electrophile and nucleophile, respectively, because the resulting functionality present in 9aA provided useful chemical handles for the synthesis of spiropreussione A (2). The organocopper reagents prepared from CuI or CuBr·SMe2 did not react in the absence of additives (Table 1, entry 1). The addition of a Lewis acid, such as BF3·OEt2,16 provided the conjugate addition product 9aA in 15% yield (Table 1, entry 2), whereas a combination of TMSCl and DMAP as an additive17 afforded 9aA in 17% yield, along B

DOI: 10.1021/acs.orglett.8b01259 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Conjugate Addition of C-, O-, N-, S-, and Se-Nucleophiles to 7a

a

entry

R (product)

conditionsa

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

CN (9aH) CH2NO2 (9aI) (MeO)2CHCH2−CHNO2 (9aJ) CH(CO2Et)2 (9aK) NCCHCO2Et (9aL) CH(CN)2 (9aM) CH(COCH2−)2 (9aN) 1- and 2-cyclo-pentadienyl (9aO) OMe (9aP) NEt2 (9aQ) N(CH2)4 (9aR) SPh (9aS) SePh (9aT)

Me2C(CN)OH, cat. KCN, CH3CN, 1 h CH3NO2, DBU, 1 h (MeO)2CHCH2CH2NO2, CH3CN, DBU, 6 h CH2(CO2Et)2, NaH, THF, 0.5 h CH2(CN)(CO2Et), NaH, THF, 2 h CH2(CN)2, NaH, THF, 1 h cyclopentane-1,3-dione, DCE, 80 °C, 3 d sodium cyclopentadienylide, THF, 0.5 h NaOMe, MeOH, 15 min NHEt2, CH2Cl2, 50 °C, 19 h pyrrolidine, CH2Cl2, 2 h PhSSPh, NaBH4, DMF,12 h PhSeSePh, NaBH4, DMF, 12 h

83 96 78 73 73 43 59 45 88 87 83 95 96

Reaction was performed at room temperature unless otherwise noted.

reactions, affording a diastereomeric mixture of cyclopentanol 21. Treatment of 21 with the Martin sulfurane dehydrating reagent facilitated dehydration in the presence of the highly electrophilic cyclopentenedione moiety in the B ring.25 Finally, the deprotection of the MOM ether furnished the proposed structure of spiropreussione A (2). However, NMR spectra of the synthetic compound 2 were different, compared with those of the natural product. The absence of HMBC correlation of H9′ with C1′ and the presence of COSY correlations of H2′ and H3′ with H9′ reported for the natural product4 should be inconsistent with the structure 2.26 In summary, a reaction implementing the conjugate addition of various nucleophiles to acylketene acetals derived from 1,8dihydroxynaphthalene was developed, which afforded various 3oxoalkan-1-one acetals. The carbonyl groups in the resulting products can be functionalized even further. The resultant product was then used to generate an intermediate in the synthesis of the proposed structure of spiropreussione A. The synthesized structure did not match that of the natural product, and the synthesis of a revised structure is now in sight.

Scheme 2. Unsuccessful Transformation of 9aC into Proposed Structure of Spiropreussione A (2)

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Scheme 3. Synthesis of the Proposed Structure of 2

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01259. Detailed experimental procedures, spectroscopic data, and copies of NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +81 22 795 6865. Fax: +81 22 795 6864. E-mail: doi_ [email protected].

The aldol reaction of 14 afforded a diastereomeric mixture of 19 without any loss of water or silanol. MOM protection of the resulting alcohol and Bu4NF/AcOH-mediated TBS deprotection afforded alcohol 20 in a high yield. The oxidation of 20 with Dess−Martin periodinane and subsequent deprotection of the dimethyl acetal caused simultaneous intramolecular aldol

ORCID

Takayuki Doi: 0000-0002-8306-6819 Notes

The authors declare no competing financial interest. C

DOI: 10.1021/acs.orglett.8b01259 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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(17) (a) Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4025−4028. (b) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 4029−4032. (c) Matsuzawa, S.; Horiguchi, Y.; Nakamura, E.; Kuwajima, I. Tetrahedron 1989, 45, 349−362. (18) For conjugate addition of diverse carbonucleophiles to β,βdisubstituted α,β-unsaturated esters, see: Wuitschik, G.; Carreira, E. M.; Wagner, B.; Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.; Müller, K. J. Med. Chem. 2010, 53, 3227−3246. (19) Hong, I. S.; Greenberg, M. M. Org. Lett. 2004, 6, 5011−5013. (20) (a) Paquette, L. A.; Backhaus, D.; Braun, R. J. Am. Chem. Soc. 1996, 118, 11990−11991. (b) Paquette, L. A.; Backhaus, D.; Braun, R.; Underiner, T. L.; Fuchs, K. J. Am. Chem. Soc. 1997, 119, 9662−9671. (21) For Knoevenagel reaction in the presence of thiol, see: (a) Fuchs, K.; Paquette, L. A. J. Org. Chem. 1994, 59, 528−532. (b) Inomata, K.; Barragué, M.; Paquette, L. A. J. Org. Chem. 2005, 70, 533−539. (c) Hong, B.-C.; Chen, S.-H.; Kumar, E. S.; Lee, G.-H.; Lin, K.-J. J. Chin. Chem. Soc. 2003, 50, 917−926. (d) Eberle, M.; Lawton, R. G. Helv. Chim. Acta 1988, 71, 1974−1982. (e) Yadav, J. S.; Syamala, M. Chem. Lett. 2002, 31, 688−689. (22) Cyanohydrin acetate was used for the aldehyde protecting group, since it was difficult to remove dimethyl acetal at the α-position of the naphthyl acetal carbon under acid catalysis. (23) Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Vel’der, Y.; Spirikhin, L. V. Zh. Org. Khim. 1989, 25, 438−439. (24) (a) Dias, L. C.; Shimokomaki, S. B.; Shiota, R. T. J. Braz. Chem. Soc. 2005, 16, 482−489. (b) Sugiura, S.; Hazato, A.; Tanaka, T.; Okamura, N.; Bannai, K.; Manabe, K.; Kurozumi, S.; Suzuki, M.; Noyori, R. Chem. Pharm. Bull. 1985, 33, 4120−4123. (c) Miller, C. M.; Benneche, T.; Tius, M. A. Org. Biomol. Chem. 2015, 13, 4051−4058. (25) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003− 5010. (26) We have recently achieved the total synthesis of spiromamakone A and found that its spectra data in CDCl3 agreed with those reported for spiropreussione A. A paper entitled “Total Synthesis of Spiromamakone A and Structure Revision of Spiropreussione A” will be reported soon.

ACKNOWLEDGMENTS This work was partly supported by the Suntry Foundation for Life Sciences, the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (under Grant Nos. JP18am0101095 and JP18am0101100) and JSPS KAKENHI (Grant No. JP15H05837 in Middle Molecular Strategy).

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DOI: 10.1021/acs.orglett.8b01259 Org. Lett. XXXX, XXX, XXX−XXX