Total Synthesis of (+)-SCH 351448

Abstract

A convergent synthesis of (+)-SCH 351448 (1), a monosodium salt of a C₂-symmetric macrodiolide, is described. Our approach is based on a [4+2] annulation with a chiral allyl silane (anti-5c) to assemble the pyran subunits. Homodimerization was carried out in a stepwise fashion; initial esterification at C29′ followed by macrocyclization at C29 afforded the desired macrodiolide.

In 2000, Hedge and coworkers reported the bioassay-guided isolation of a microbial metabolite, named SCH 351448 (1), from the organic extract of Micromonospora sp.¹ SCH 351448 is a novel activator (ED₅₀ = 25 μM) for low-density lipoprotein receptor promoter, which is important for the treatment of hypercholesterolemia.²

The structure of SCH 351448 (1) was determined by single-crystal X-ray analysis, and exhibited a hepta-coordinated sodium ion positioned in the interior cavity of the hydrophobic skeletal array.¹ Its structure consisted of a 28-membered macrodiolide comprised of two identical hydroxy carboxylic acid monomeric subunits. The intriguing structure and unique bioactivity of 1 has led to several total synthesis programs being initiated by the synthetic community.³

Our retrosynthetic analysis of this target (Figure 1) began with a disconnection of the C29/C29′ ester bonds to yield the monomeric subunit 2. The latter was envisioned to come from an olefin cross metathesis of fragments 3 and 4. Fragment 3 could arise from an asymmetric allylation and crotylation of the cis-2,6-dihydropyran core, which would be formed from a [4+2] annulation reaction⁴ of allylsilane anti-5c with aldehyde 6a. Similarly, fragment 4 would be derived from silane anti-5c and aldehyde 6b.

Figure 1. Retro synthetic analysis of SCH 351448 (1).

We have previously reported a highly diastereo- and enantio-selective [4+2] annulation between aldehydes and syn allylsilanes.⁴ However, early experiments at applying the annulation to form dihydropyran products 7 from silanes syn-5b/syn-5c and aldehyde 6a (Scheme 1, eq 1) gave inconsistent results and thus were not synthetically useful. Previously, Roush had reported the construction of cis-2,6-disubstituted dihydropyrans using anti-allylsilanes derived from the asymmetric γ-silyl allylboration of an aldehyde.⁵ In that report, the favored pathway was thought to proceed via a boat-like TS-A which fashioned the cis-isomer as the major product, while the trans-isomer was suggested to form via the unfavored chair-like TS-B (Scheme 1). In that context, we have observed that anti-silanes such as 5, participate in a [4+2]-annulation with aldehydes to produce 2,6-cis dihydropyrans 7; the results are summarized in Table 1. One proposed mechanism that accounts for the stereochemical course of the annulation involves the equilibration between a twist boat-like TS-C and a chair-like TS-D, where TS-C avoids the steric destabilizing trans-diaxial orientation versus TS-D (Scheme 1, eq 4 and eq 5).

Scheme 1. Possible transition states for the [4+2] annulation.

Table 1. Synthesis of cis-dihydropyrans via [4+2] annulation.

entry	aldehyde	anti-silane	major isomera	yield(%)b	dr (cis:trans)c
1	R = PhCH2	5a	7a	30	10:1
2	R = PhCH2	5b	7b	60	13:1
3	R = PhCH2	5c	7c	83	17:1
4	R = n-C4H9	5a	7d	25	10:1
5	R = n-C4H9	5b	7e	58	12:1
6	R = n-C4H9	5c	7f	81	18:1

^aStereochemistry of the dihydropyrans was assigned by NOE experiments.

^bYields were based on pure materials isolated by chromatography on SiO₂.

^cThe product ratios were determined by ¹H NMR (400 MHz).

Synthesis of the C1-C13 fragment began with the known α,α′-dimethyl aldehyde 6a⁶ (Scheme 2). Annulation of silane anti-5c and aldehyde 6a proceeded smoothly in the presence of TMSOTf to afford the desired dihydropyran 8 in 83% yield (dr 13:1). Hydrogenation of 8 afforded a primary alcohol which was later oxidized to aldehyde 9 in 80% yield over two steps. Further oxidation under Pinnick oxidation conditions⁷ and protection afforded benzyl ester 10. An S_N2 displacement of the mesitylate in compound 10 with NaCN followed by Raney-nickel mediated partial reduction⁸ of the resulting nitrile afforded aldehyde 11 in 60% yield, after hydrolysis of the intermediate imine. Asymmetric allylation of 11 using Brown's protocol ⁹ furnished the desired secondary homoallylic alcohol, which was subsequently protected as benzyl ether 12. Oxidative cleavage of alkene 12 followed by asymmetric crotylation of the resulting aldehyde using Brown's (E)-crotyl borane¹⁰ afforded the anti-homoallylic alcohol, which was protected as its TBS ether to provide olefin 3 as one of the coupling partners in 60% yield over three steps.

Scheme 2. Synthesis of C1-C13 fragment.

Synthesis of the C14-C29 fragment (Scheme 3) began with aryl triflate 13,¹¹ which was subjected to a Sonogashira cross-coupling to afford propargylic alcohol 14 in 85% yield. Catalytic hydrogenation of alkyne 14 in the presence of Pd/C followed by PCC oxidation provided aldehyde 6b. Annulation between aldehyde 6b and silane anti-5c furnished the desired dihydropyran, which was hydrogenated to give 15 in 70% yield over two steps. Subsequent S_N2 displacement of the mesitylate in 15 yielded an iodide, which was further converted to acetate 16 in 60% yield over two steps. A Sc(OTf)₃ catalyzed hydrolysis¹² of acetate 16 provided primary alcohol 17 in 91% yield, which was then subjected to a Swern oxidation, followed by a Julia-Kociénski olefination^3e with sulfone 18,¹³ to give alkene 19 in 80% yield. Opening of the dioxinone ring in 19 afforded the intermediate phenol, which was converted to the β-silyl ester 4.

Scheme 3. Synthesis of C14-C29 fragment.

With advanced intermediates 3 and 4 available in useful amounts, we were now positioned to investigate methods for their union. Cross metathesis between 3 and 4 (Scheme 4) proceeded smoothly using the Grubbs-Hoveyda second generation catalyst,¹⁴ which delivered the (E)-olefin. This material was then subjected to diimide reduction^3a to afford advanced intermediate 20. Deprotection of 20 provided seco acid 2, which was poised for the homodimerization experiments.

Scheme 4. Attempted template-directed macrodimerization.

A synthetic strategy to construct the C₂-symmetrical macrodiolide core of cycloviracin B₁ has been described by Furstner. ¹⁵ It involved a template-directed macrodilactonization reaction promoted by 2-chloro-1,3-dimethylimidazolinium chloride (DMC). ¹⁶ Inspired by this work, we investigated a similar strategy for macrodiolide formation. Unfortunately, treatment of seco acid 2 with DMC/DMAP and suitable additives¹⁷ only led to the undesired 14-membered lactone 23 ¹⁸ without formation of dimeric product 22. After these disappointments, we evaluated a stepwise pathway to complete the synthesis, as illustrated in Scheme 5.

Scheme 5. Assemly of 1 by dioxinone ring-opening and macrocyclization.

The reaction sequence that ultimately proved successful utilized Lee's method of esterification, ^3a which was facilitated by dioxinone ring-opening. Cross metathesis between 19 and 3 afforded the intermediate alkene, which was reduced with diimide to deliver dioxinone 24. TBS deprotection of 20 gave alcohol 21 in 91% yield (Scheme 4). Deprotonation of alcohol 21 with NaHMDS and addition of dioxinone 24 led to the desired mono-ester product, which was protected to afford 25 in 60% yield over two steps. Deprotection of the monoester provided the seco acid, which was subjected to a DMC/DMAP-promoted esterification¹⁶ reaction to achieve mycrocycle 22 in 50% yield over two steps. Lastly, deprotection followed by work up with 4 M HCl saturated with NaCl, ^3a delivered SCH 351448 (1) as its monosodium salt in 70% yield. The spectral data for our synthetic material matched those reported for the natural product.³

In summary, we have described a convergent, enantioselective total synthesis of (+)-SCH 351448 with a 2.3% overall yield from readily available allylsilane anti-5c. Synthetic highlights of our route include a [4+2] annulation strategy using silane anti-5c to ultimately construct the tetrahydropyran ring systems in fragments 3 and 4. Olefin cross metathesis was utilized in the union of two advanced fragments to generate the monomeric subunit. A metal-template directed macrodilactonization strategy proved unsuccessful. Thus, the macrodiolide was assembled through a two-step sequence involving dioxinone ring-opening with concomitant esterification followed by DMC/DMAP-mediated macrocyclization.