Total Synthesis of Auripyrone A Using a Tandem Non-Aldol Aldol-Paterson Aldol Process as a Key Step

Abstract

A tandem non-aldol aldol-Paterson aldol generates the polypropionate 12 from the epoxy alcohol 8 and the ketone 9 in only two steps and 74% overall yield as a single diastereomer, due to double stereodifferentiation, where the stereoinduction from the enolate and the α-methyl substituent of the aldehyde are reinforcing. This compound was used for an efficient synthesis of the natural product auripyrone A, 1, in only 18 steps and 17% overall yield, using a highly regioselective hemiketalization of a keto diol and a late stage spiroketalization onto a stable hemiketal as the final key steps.

In 1996, Yamada, et al., reported the isolation of auripyrones A 1 and B 2 from the methanol extracts of the sea hare Dolabella auricularia (Aplysiidae) (Figure 1).^[1] Extensive NMR investigation of the compounds revealed a complex spiroketal core, capped at one end by a tetrasubstituted γ-pyrone, residing in an anomerically favored configuration where all the substituents are positioned equatorially except the C10 methyl and the C11 acyloxy groups. Auripyrones A 1 and B 2 showed cytotoxicity against HeLa S₃ cells with IC₅₀ values of 260 and 480 ng/mL, respectively. To date one total synthesis^[2] of auripyrone A 1 has been reported by Perkins and coworkers, utilizing an elegant biomimetic cyclization of an acyclic triketone intermediate to generate the spiroketal moiety.^[3] The major drawback of this approach, however, is the late stage formation of the γ-pyrone in the presence of the sensitive spiroketal moiety which proceeded with poor yield (39% BRSM). Nonetheless, Perkins’ convergent total synthesis of auripyrone A 1 constitutes the only established synthetic route, and led to the determination of the absolute stereochemistry of the natural product. Herein, we report our convergent approach for the total synthesis of auripyrone A 1 as a single diastereomer in high chemical yield.

Figure 1.

In our retrosynthetic analysis (Scheme 1), the sensitive spiroketal moiety of auripyrone A 1 could be derived from a late stage cyclization of the C-17 ketone onto the hemiketal 3, which should be available from the aldolate 4. The key intermediate 4 could be obtained from a fully matched^[4] double stereodifferentiating^[5] anti aldol reaction of the boron enolate of the ketone 6 and the aldehyde 5. The γ-pyrone moiety of 5 would result from the aldehyde 7 following the protocol of Hoveyda and coworkers.^[6] Finally, the stereopentad 7 was envisioned to arise from the known epoxide 8^[7] by a novel tandem non-aldol aldol^[8]/Paterson lactate-derived aldol^[9] reaction with the ketone 9.

Scheme 1.

The synthesis commenced with the assembly of 7, using a highly convergent tandem non-aldol aldol/Paterson lactate-derived aldol reaction (Scheme 2). Epoxidation of the allylic alcohol 10 (synthesized in 5 steps from (S)-Roche ester)^[10] under reagent-controlled Sharpless conditions,^[11] or substrate controlled conditions with mCPBA,^[12] furnished the epoxide 8 in 85% yield and 20:1 diastereomeric ratio (dr), or 90% yield and 16:1 dr, respectively. Protection of 8 with TESCl provided the corresponding silyl ether which was treated with TESOTf at −45 °C to give, via the non-aldol aldol rearrangement, the syn-aldol adduct 11 in 86% yield and 20:1 dr. Unlike conventional auxiliary based aldol methods which require a protection step followed by removal of the chiral auxiliary to generate the protected aldehyde, the non-aldol aldol reaction provides direct access to pure silyl protected aldehydes without flash column purification^[13] for an iterative aldol process. To that end, the subsequent anti aldol reaction of the aldehyde 11 with the E-boron enolate of Paterson’s lactate-derived ketone 9^[9c] furnished the desired anti-aldolate 12 in 86% yield as a single diastereomer. The remarkable stereoselectivity of this reaction is due to double stereodifferentiation,^[5] where the stereoinduction from the enolate^[9c] and the α-methyl substituent of the aldehyde^[14] are reinforcing. Mild Lewis acid catalyzed^[15] protection of the alcohol 12 as the PMB ether proceeded smoothly without deprotection of the acid sensitive TES group to afford the ketone 13 in 93% yield. Reduction of 13 and concomitant removal of the α′-benzoate with LiBH₄ followed by periodate cleavage of the resulting diol^[16] afforded the desired aldehyde 7 in 83% yield over 2 steps. This novel tandem non-aldol aldol/Paterson lactate-derived aldol protocol constitutes a highly efficient, convergent approach for the synthesis of the desired stereopentad 7, generating four aldol stereocenters in two steps. Conversion of the aldehyde 7 in three steps to the meso-polypropionate 14, which possessed no optical rotation and displayed only twelve ¹³C NMR resonances indicating a symmetrical structure, confirmed the assigned stereochemistry of 7.

Scheme 2.

Reagents and conditions: a) Ti(OiPr)₄, tBuOOH, (+)-DIPT, DCM, −10 °C, 85%, 20:1 dr or mCPBA, K₂HPO₄, DCM, −10 °C, 90%, 16:1 dr; b) TESCl, Imidazole, DCM, 98%; c) TESOTf, DIPEA, DCM, −45 °C, 86%, 20:1 dr; d) 9, cHex₂BCl, Me₂NEt, Et₂O, −78 °C → 0 °C, 2 h; 0 °C → −78 °C; 11, −78 °C → −25 °C, 15 h; H₂O₂, MeOH, pH 7 buffer, 0 °C, 1 h, 86%, one isomer; e) PMBOC(=NH)CCl₃, Sc(OTf)₃, toluene 93%; f) LiBH₄, THF, 97%, 8:1 dr; g) NaIO₄, MeOH:pH 7 buffer (2:1), 86%. h) NaBH₄, EtOH, 0 °C, 81%; i) TBDPSCl, Imidazole, DCM; j) CAN, CH₃CN:H₂O (9:1), 78% two steps.

Next, we turned to the synthesis of the γ-pyrone moiety^[17] (Scheme 3). Following the protocol of Hoveyda,^[6] we obtained, via the aldol reaction of the lithium enolate of the silyloxy enone 15^[6] with the aldehyde 7, the aldolate 16 in 94% yield as a mixture of isomers.^[18] Oxidation of the isomeric mixture of 16 with Dess-Martin periodinane (DMP)^[19] and subsequent heating of the resulting diketone in DMF^[20] provided the desired γ-pyrone 17 in 68% yield over two steps. Acid promoted deprotection of the TES ether furnished the alcohol 18 which was subjected to Yamaguchi esterification^[21] with isovaleric acid to give the ester 19 in 98% yield. Treatment of the silyl ether 19 with HF·pyridine provided the primary alcohol 20^[22] which was oxidized with DMP to afford the aldol precursor, the aldehyde 5. The other component of the aldol reaction, the α-methyl-β-hydroxy ketone 6, was also readily available from TES protection of the known ketone 21^[2a] in 96% yield. The E-boron enolate of the ketone 6 underwent a highly diastereoselective anti aldol reaction with 5 to provide the Felkin product 4 in 94% yield and 21:1 diastereomeric ratio. The excellent diastereoselectivity of this double stereodifferentiating^[5] aldol reaction could be attributed to a fully matched^[4] reactant pair, where the stereoinduction from the β- hydroxy^[23] and the α-methyl^[14] substituent of the aldehyde and the α-methyl stereocenter of the ketone^[24] are reinforcing.

Scheme 3.

Reagents and conditions: a) 15, LDA, −78 °C, 7, 94%; b) DMP, DCM, NaHCO₃; c) DMF, 55 °C μw, 6 h, 68% two steps; d) PPTS, DCM:MeOH (3:1), 96%; e) 2,4,6-trichlorobenzoyl chloride, DMAP, Et₃N, isovaleric acid, 98%; f) HF·pyr, CH₃CN/pyr, 94%; g) DMP, DCM, NaHCO₃, 98%; h) TESCl, imidazole, DCM, 96%; i) 6, cHex₂BCl, Me₂NEt, Et₂O, −78 °C → 0 °C, 2 h, 0 °C → −78 °C, 5, −78 °C → −25 °C, 15 h, H₂O₂, MeOH, pH 7 buffer, 0 °C, 1 h, 94%, 21:1 dr.

With the key intermediate 4 in hand, we set out to investigate the formation of the spiroketal moiety of auripyrone A 1 (Scheme 4). Our initial attempts at generating the desired spiroketal by acid-catalyzed cyclization of the C-9 hydroxyl group onto either a γ-pyrone^[25] or an acyclic triketone^[2a] failed and led to rapid 1,5-acyl migration. The high propensity of our system for acyl migration presumably arises from the inherent preference of the acyclic polyketide^[26] to populate the local conformation I where the C-9 and C-11 oxygen moieties are in close spatial proximity. To circumvent this problem, we decided to mask the C-9 hydroxy substituent and attempt spiroketalization from a hemiketal platform.^[27] Oxidation of the alcohol 4 afforded the corresponding diketone as a single isomer^[28] which was deprotected with DDQ to furnish the hemiketal 23 as the major product by crude ¹H and ¹³C NMR. However, purification on silica gel gave the desired cyclic isomer 23 only in 66% yield as a single isomer, along with the open chain isomer 22 in 21% yield as a mixture of two C-14 methyl epimers.^[29] Deprotection of the TES ether of the hemiketal 23 with HF·pyridine provided the hemiketal 24 in 86% yield as a single isomer^[30] which was stable to column chromatography. Interestingly, the TES deprotection of the acyclic diketone 22 also afforded the hemiketal 24 exclusively, as a mixture of C-14 epimers, in 78% yield. The mixed configuration of the C-14 stereocenter in the hemiketal 24 is not critical since both diastereomers could equilibrate under thermodynamic cyclization conditions to the natural product. Nonetheless, to circumvent having to purify the unstable hemiketal 23 and recycle the acyclic diketone 22, a variety of conditions were screened for the deprotection of the ethers. We were gratified to find that oxidation of the aldolate 4 followed by treatment with CAN in acetonitrile and water (9:1) for 15 minutes led to concurrent removal of the PMB and TES ethers, providing exclusively the stable hemiketal 24 as a single diastereomer in 74% yield over two steps.^[31] The selectivity of this reaction is remarkable and yet difficult to explain since the deprotection of the PMB and TES ethers unveils two alcohols which could potentially cyclize on the C-13 ketone to form a hemiketal. Simple thermodynamic MM2 calculations proved ineffective and higher level calculations will be necessary to elucidate the remarkable selectivity of this reaction for exclusive formation of the hemiketal 24.

Scheme 4.

Reagents and conditions: a) DMP, DCM, NaHCO₃, 94%; b) DDQ, DCM:pH 7 buffer (9:1), 66% 23, 21% 22; c) HF·pyr, CH₃CN/pyr, 86%; d) HF·pyr, CH₃CN/pyr, 78%; e) DMP, DCM, NaHCO₃; f) CAN, CH₃CN:H₂O (9:1), 74% two steps; g) DMP, DCM, NaHCO₃; h) Amberlyst-15, DCM, 0 °C → 25 °C, 80% two steps.

Having successfully prepared the hemiketal 24 as a single diastereomer from the aldolate 4 in 2 steps in excellent yield, we next oxidized the alcohol of 24, and the resulting diketone^[32] was treated with Amberlyst-15 to afford the natural product auripyrone A 1 as a single diastereomer in 80% yield over two steps. The remarkably high chemical yield of this spiroketalization could presumably be attributed to the lower entropic cost of cyclization onto a conformationally limited hemiketal platform, or the increase in the rate of the acid-catalyzed cyclization, since the configuration of the C-14 stereocenter of the isomerically pure starting material 24 matches the desired configuration in the natural product.

The chemistry described here constitutes a highly convergent approach for the synthesis of auripyrone A 1 from the known epoxide 8 in 18 steps and 17% overall yield. Our strategy employs a novel tandem non-aldol aldol/Paterson lactate-derived aldol to generate the stereopentad backbone, a highly regioselective hemiketalization of a keto diol, and a late stage spiroketalization onto the stable hemiketal.