Reductive acetylation has proven to be a powerful methodology primarily because its products are excellent substrates for carbon-carbon bond forming reactions. Since 2003, the Organic Syntheses article and the primary references have been cited over 100 times. This discussion addendum aims to provide a brief overview of recent developments in this methodology. Improvements and variations of α-acetoxy ether formation, as well as the synthetic utility of α-acetoxy ethers will be discussed. Recent applications in the context of the total synthesis of complex natural products are also included.

The original reductive acetylation protocol involves the addition of diisobutylaluminum hydride (DIBALH) as a 1.0 M solution in hexanes to the ester at -78 °C. The resulting aluminum alkoxide is then treated with pyridine, 4-dimethylaminopyridine (DMAP), and acetic anhydride (Ac₂O) sequentially. The internal temperature during these additions should not exceed -72 °C in order to maximize the yield and prevent undesired side reactions.² While this method is general, recent developments include the use of asymmetric electrophiles in order to generate more complex acyl ethers and the extension of reductive acetylation to lactams and imides.

Shortly after the original article, Rovis and Zhang reported the use of acid fluorides as competent reagents for the trapping of such aluminum alkoxides, the results of which are summarized in Figure 1.³ Aryl, vinyl, and alkyl acid fluorides are all effective trapping reagents (67-97% yield) and steric bulk is well tolerated (pivaloyl fluoride = 92% yield). This development allows access to more complex acyl acetal derivatives without sacrificing a full equivalent of the acid, which represents an improvement in atom economy over the use of symmetric anhydrides.

More recently, Dalla and co-workers have extended reductive acetylation strategy to the formation of α-acetoxy pyrrolidines (Figure 2).⁴ While DIBALH will reduce imides, the resultant aluminum alkoxide is not nucleophilic enough to react with acetic anhydride. Therefore, the reductant of choice for the preparation of α-acetoxy amines is lithium triethylborohydride (LiEt₃BH), whose lithium alkoxide is sufficiently nucleophilic for effective trapping with acetic anhydride.

A variety of N-alkylated imides, shown in Figure 3, afford α-acetoxy lactams in high yields (75-100%), with the notable exception of cases where there is α-branching with respect to the nitrogen substituent (e.g. the imide of α-methylbenzylamine, MeBn). Steric bulk on the imide also limits the conversion to the α-acetoxy lactams, as shown by the modest yield for the bis-OTBS imide. Despite these limitations, this reductive acetylation strategy offers rapid entry into N-acylimium ions for use in Mannich reactions.

Treatment of α-acetoxy ethers with a Lewis acid (commonly BF₃·OEt₂, MgBr₂·OEt₂, TMSOTf, SnCl₄ or TiCl₄) results in the formation of an oxocarbenium ion, which can be intercepted by a variety of nucleophiles to afford a new carbon-carbon or carbon-heteroatom bond adjacent to an ether linkage. The scope of such transformations has been investigated in the context of diastereoselective nucleophilic additions. α-Acetoxy ethers are also useful substrates for cascade sequences, such as oxonia Cope-Prins and Sakurai-Prins-Ritter cyclizations. The use of α-acetoxy ethers in enantioselective organocatalytic oxa-Pictet Spengler reactions have also been examined.

The use of α-(trimethylsilyl)benzyl alcohol as a chiral auxiliary has been investigated by Rychnovsky and Crossrow for diastereoselective additions to oxocarbenium ions generated from α-acetoxy ethers.⁵ This chiral auxiliary was chosen due to the ease of preparation of both enantiomers and facile deprotection or conversion to the benzyl ether. Treatment of the α-acetoxy ether with a variety of nucleophiles, including allyl silanes, silyl enol ethers, and silyl ketene acetals, in the presence of TMSOTf proceed in high yields (87-98%) and high diastereoselectivities (20:1 to 80:1), as shown in Figure 4. Similarly, (E)-crotyltrimethylsilane affords the syn product in high yield and diastereoselectivity (82%, 27:2.4:1). The addition of cyanide and ethyl nucleophiles proceed in high yields (97% and 75% respectively), albeit with modest diastereoselectivity (5:1 and 4:1).

Rychnovsky and Dalgard have reported on the expedient synthesis of tetrahydropyranones through an oxonia Cope-Prins cyclization.⁶ This strategy, outlined in Figure 5, involves a reductive acetylation of an ester 1, followed by treatment with TMSOTf to generate oxocarbenium ion 3. The pendant allyl moiety participates in a 2-oxonia Cope rearrangement to generate oxocarbenium ion 4, which is poised for a Prins cyclization (intramolecular Mukaiyama aldol reaction) with the silyl enol ether to afford tetrahydropyranone 5. This transformation is effective for a variety of substrates (Figure 6) affording the tetrahydropyranone product in high yields (77-99%), including those bearing quaternary centers adjacent to the ketone.

Rovis and Epstein have also utilized α-acetoxy ethers in a cascade sequence to provide 4-amino tetrahydropyrans through a Sakurai-Prins-Ritter cyclization.⁷ As shown in Figure 7, treatment of 4-acetoxy-1,3-dioxane 6 with TMSOTf generates oxocarbenium ion 7, which upon treatment with allyl silane affords alkene 8. In the presence of TfOH, acetal cleavage results in formation of oxocarbenium ion 9, which undergoes a Prins cyclization to give carbocation 10. Addition of a nitrile to the carbocation affords 4-amino tetrahydropyran 11 after hydrolysis.

The Sakurai-Ritter-Prins reaction is effective for a variety of dioxane derivatives, as shown in Figure 8. This transformation affords the 4-amino tetrahydropyran products in good yields (59-88%) and high diastereoselectivies (90:10 to 99:1). It should be noted that 2-substituted allyl silanes (Figure 9) and a variety of nitriles are effective partners in this transformation.⁷

Jacobsen and Doyle have utilized α-acetoxy ethers as substrates in the development of enantioselective organocatalytic oxa-Pictet-Spengler reactions (Figure 10).⁸ An ester derivative of tryptophol was reduced and trapped to give α-acetoxy ether 12. In the presence of a thiourea catalyst 13, TMSCl, and BaO, oxocarbenium ion formation and subsequent ring closure afforded tetrahydropyrano-indole 14 in good yield (82%) and good enantiomeric excess (79%).

Highlighted Applications in the Total Synthesis of Complex Natural Products: Intramolecular Allylation of α-Acetoxy Ethers

Kadota, Yamamoto and co-workers utilized reductive acetylation to unite two complex fragments in their highly convergent synthesis of marine neurotoxin gambierol (19).⁹ The strategy, shown in Scheme 1, begins with the coupling of ABC acid to FGH alcohol via Yamaguchi esterification. The resulting ester 15 is then subjected to reductive acetylation conditions. While

Ac₂O is an effective trapping reagent, chloroacetic anhydride provided increased yield and proper diastereoselectivity for the subsequent ring closure. Treatment of the resulting α-acetoxy ether 16 with boron trifluoride etherate in the presence of 4 Å molecular sieves afforded effective closure of the 6-membered D ring in high yield (87%) and modest diastereoselectivity (2:1) with respect to the acyclic ether. The resulting diene 17 is primed for a ring closing metathesis to forge the 7-membered E ring. The complex polycyclic ether framework 18 was then further elaborated to gambierol (19).

A similar approach was employed in Kadota and co-worker's total synthesis of the nontoxic brevetoxin antagonist brevenal (23).¹⁰ As shown in Scheme 2, the 7-membered D ring arose from the reductive chloroacetylation of ester 20, followed by treatment of α-acetoxy ether 21 with magnesium bromide etherate and 5 Å molecular sieves. The resulting oxocarbenium ion was then trapped by the allyl stannane to afford the tetracycle 22 in good yield as a single diastereomer (52% from the ester 20). This cyclization again sets the stage for a ring closing metathesis sequence to afford a pentacycle, which was elaborated to brevenal (23).

The authors also reported a second-generation strategy (Scheme 3) where acyclic a0cid 24 is coupled to ABC alcohol 25.^10-b This route employs the same reduction/cyclization sequence to forge the E ring in good yield as the single desired diastereomer (57% from the ester 26) and sets up the closure of the D ring in an analogous fashion.

Recently, the total synthesis of ciguatoxin CTX3C (34) by Yamashita and co-workers employed reductive acetylation to facilitate a radical cyclization to give the C ring of tridecacyclic natural product (Scheme 4).¹¹ The AB acid and E alcohol were subjected to Yamaguchi esterification conditions to afford the ester 29. Following reductive acetylation, α-acetoxy ether 30 underwent transacetylation in the presence of diisobutylaluminum phenylselenide to afford the α-seleno ether 31 in high yield (83% from the ester). The α-seleno ether 31 was carried through 3 steps before C-ring radical cyclization was initiated by triethylborane and oxygen in the presence of tributyltin hydride to provide sulfoxide 33 in good yield as a single diastereomer (86%). This approach offered increased stereoselectivity over a direct allylation strategy (as in gamberiol). Sulfoxide 33 was then carried forward to afford ciguatoxin CTX3C (34).

Reductive acetylation has proven to be a powerful method for the construction of complex cyclic ethers via intramolecular allylation. The strategy has played a key role in the preparation of brevetoxin-like ladder polyethers.¹² The method's utility is largely due to the ease with which substrates can be brought together by a Yamaguchi esterification. This protocol allows for a highly convergent and flexible approach to these marine natural products.

Intermolecular Couplings of α-Acetoxy Ethers and Silyl Enol Ethers

Crimmins and DeBaillie utilized reductive acetylation to install the α,β-unsaturated ketone moiety of the tetrahydropyran fragment of the marine cytotoxin bistramide A (38).¹³ The synthetic strategy is outlined in Scheme 5. The lactone 35 was reduced with DIBALH followed by trapping with Ac₂O to give the α-acetoxy ether 36 in high yield (87%) and good diastereoselectivity (7:1). Treatment of α-acetoxy ether 36 with (E)-3-penten-2-one in the presence of excess TMSOTf led to formation of tetrahydropyran 37, a key building block for the synthesis of bistramide A (38), in high yield (87%) and good diastereoselectivity (9:1).

Rychnovsky and co-workers used a related strategy to construct the western tetrahydropyran fragment of marine cytotoxin leucascandrolide A (43).¹⁴ As shown in Scheme 6, the lactone 39 was reduced with DIBALH followed by trapping with Ac₂O to give the α-acetoxy ether 40 in high yield (91%) and high diastereoselectivity (15:1). Treatment of α-acetoxy ether 40 with silyl enol ether 41 in the presence of catalytic zinc bromide led to formation of tetrahydropyran 42 in high yield (92%) and good diastereoselectivity (20:1). Tetrahydropyran 42 was then further elaborated to leucascandrolide A (43).

The most complex example of such intermolecular couplings comes from Crimmins and co-workers recent synthesis of the cancer cell growth inhibitor (+)-irciniastatin A (48).¹⁵ This convergent strategy is outlined in Scheme 7. Reduction of lactone 44 followed by trapping with Ac₂O proceeds to give α-acetoxy ether 45 in quantitative yield. Treatment of the sterically hindered α-acetoxy ether 45 with boron trifluoride etherate followed by a slight excess of the highly functionalized silyl enol ether 46 gave tetrahydropyran 47 in good yield (59%; 85% based on recovered ketone) and high diastereoselectivity (>20:1). Tetrahydropyran 47 was then carried forward to afford (+)-irciniastatin A (48).

Reductive acetylation followed by intermolecular coupling has proven to be a useful strategy for coupling complex fragments in total synthesis.¹⁶ The success of this methodology is largely due to the functional group compatibility of the reduction and mild conditions for oxocarbenium ion formation. Furthermore, the coupling itself often proceeds in high yield and high diastereoselectivity. These features validate this method as a highly convergent process in complex natural product synthesis.