Engers taught me the basics of the laboratory when I was a junior student, from running reactions to reading a 2D spectrum. The absolute configuration of C9 was tentatively assigned a 9S configuration, determined by the observed NOE between the Cl'-methine of the 6-deoxy-L-glucose sugar.
Nicolaou’s synthesis of the C12-C28 region of apoptolidin A
Nicolaou and co-workers synthesized the C12–C28 fragment (1.6) incorporating the C21–C25 pyranketal moiety with the deprotection of C25 (1.7). Koert and co-workers completed the synthesis of apoptolidin A through an intermolecular Stille coupling with C1-C11 (1,9) and C12-C28 (1,10) in the presence of copper(I) thiophene carboxylate11.
Koert’s synthesis of the pyran system of apoptolidin A
In 2009, Crimmins and co-workers12 completed the synthesis of apoptolidine A using an olefin metathesis reaction with a Grubbs13 heterocyclic carbene catalyst between 1.13 and 1.14 in high yield and olefin metathesis stereoselectivity. Crimmins continued the synthesis with a glycosylation at C9 and hydrolysis of the ethyl ester and Yamaguchi cyclization completed the carbon framework (Figure 1.8).
Crimmins’ synthesis of the C13-C28 (1.16) Fragment
In 2002, Roush's14 synthesis of bafilomycin A1 contained an acid-base-sensitive hemiacetal moiety that was cleaved off, resulting in the ketone functionality in 1.17 (Scheme 1.4). Roush completed the synthesis of bafilomycin A1 by carefully balancing the basicity of the tris-(dimethylamino)sulfonium difluorosilicate (TAS-F) reagent with aqueous DMF, yielding the hemiacetal in bafilomycin A1 (Scheme 1.5).
Hanessian’s formation of bafilomycin A
Retrosynthetic analysis of ammocidin D
Sulikowski's retrosynthetic analysis of the northern hemisphere (1.19) leads to decouplings to provide the sugarless methyl ester fragment C1-13 (1.21). Sulikowski's southern hemisphere retrosynthetic analysis leads to a decoupling providing an asymmetric aldol adduct (C14-C28 1.25).
Envisioned cyclization to form ammocidin D pyran acetal 1.20
Our retrosynthetic analysis of ammocidinone began with an uncoupling at the hemiacetal bond, indicating that ketone 2.1 was a penultimate intermediate. Finally, the hemiacetal functionality would be formed at a late stage after the global deprotection of ketone 2.1 (Scheme 2.2).
Anticipated global deprotection providing ammocidinone
Crimmins has proposed that transition state 1 (TS 1) for the boron enolate and the titanium enolate gives the “Evans” syn aldol adduct. Therefore, the preparation of the Evans syn or non-Evans syn can be achieved by simply changing the stoichoimetry of the Lewis acid and the amine base, as illustrated in Scheme 2.5.
Transition state model for Evans and non Evans syn aldols
If chloride ion is sequestered by excess TiCl4, the titanium enolate can also proceed through transition state 2 (TS 2), where both the aldehyde and the auxiliary are coordinated to titanium6. These aldol additions are very sensitive to the amount of Lewis acid used and to the nature of the amine base used in the reaction.
Application of Crimmins’ syn aldol
Formation of aldehyde 2.16
Auxiliary approach towards ethyl ketone C22-C28 1.26
Open transition state rationale for 2.20
Evans’ unexpected product via auxiliary approach towards cytovaricin B
Upon joining the lab, I sought to continue our synthetic efforts on the ethyl ketone fragment 1.26 via an open transition state via the Mukaiyama intermolecular aldol reaction14. Another route to the C22-C28 fragment 1.26 involved a Mukaiyama intermolecular variant that required the silyl enol 2.22 and the key aldehyde 2.16.
Mukaiyama aldol based approach towards C22-C28
The anti Mukaiyama glycolate aldol adduct 2.23 can be rationalized through a Felkin-Ahn model15 (Figure 2.3) where diastereofacial selectivity is achieved when the nucleophile approaches the aldehyde opposite the benzyl ether substituent. While experimental data support the Felkin-Ahn approach, application of the chelation control model proposed by Mukaiyama16 (Figure 2.4) predicts the desired synchronous stereochemistry.
Attempted chelation control between silyl enol 2.22 and aldehyde 2.16
Furthermore, the methoxy substituent should avoid unfavorable gauche interactions with the Lewis acid, thereby providing the desired syn stereochemistry. Alternatively, fragment 1.26 can be cleaved via an intramolecular Mukaiyama aldol reaction to provide the silyl ketene acetal 2.35.
Mukaiyama’s fluoride mediated aldol addition
Synthesis of the intramolecular Mukaiyama precursor
Fluoride ion mediated intramolecular Mukaiyama addition
Rationalization for the desired diasteromer
The E-geometric isomer, which experiences an undesired synpentane interaction in the chair conformer (TS 10 Scheme 2.18), is instead protonated by water, leading to 2.34. In general, the transition state model illustrates the importance of the Z-geometric isomer, which ultimately provides the desired stereoisomer (Scheme 2.18).
Synthesis of lactol 2.39
Therefore, we began to modify the synthesis to avoid this problem following the seminal work by Porco in a key step in the synthesis of the quinamycins.
Porco’s synthesis of kinamycin C
Revised synthetic strategy towards ethyl ketone fragment 2.47
Expedited synthesis of the Mukaiyama precursor
The reaction was stirred for 20 minutes and washed with water, extracted with CH 2 Cl 2 (3 x 50 ml). The reaction was stirred for 1 hour and washed with NaHCO3 (15 ml), extracted with diethyl ether (3 x 10 ml). The resulting solution was stirred at room temperature for 24 hours and washed with NaHCO3, extracted with CH2Cl2 (3 x 10 ml).
The reaction was warmed to room temperature and stirred for 1 hour, washed with NaHCO3, extracted with CH2Cl2 (5 ml). The reaction was stirred at room temperature for 24 hours, washed with water and extracted with CH2Cl2 (3 x 10 mL).
Paterson’s approach towards zaragozic acid C
Wasserman’s studies on γ,δ-epoxy, δ,ε-epoxy ketone openings
Nelson’s synthesis of intermediate 3.23 towards hemibrevetoxin B
Ketoepoxide ring opening with isomerization of the furan acetal to the pyran acetal
Application of the Horner Wadsworth Emmons4 protocol with the known ethyl 2-(diethoxyphosphoryl)propanoate 3.28 provided 2.43 in a 12:1 E:Z ratio in 85% yield. The reduction-oxidation sequence was followed by Evans' asymmetric glycolate aldol 5 with the help of the norephedrine-based auxiliary 3.30 to produce the aldol adduct 3.31 in high diastereomeric ratio (20:1 dr). Ethylation and deprotection of the TES ether provided the key δ,γ-unsaturated β-hydroxy ethyl ketone 3.34 (Scheme 3.6).
Synthesis of Ketone Fragment 3.34
In addition, anti-epoxy ketone 3.24 can reach the desired product through a 5-exo pathway followed by an isomerization to the desired pyranose ring system. However, Merck Molecular Force Field calculations (MMFF94) surprisingly predicted that furanacetal 3.25 is 3.6 kcals/mol more stable than the desired pyranacetal 3.26 system (Scheme 3.7).
Mechanistic rationale towards 3.26
As illustrated in Scheme 3.7, the undesired isomers of pyran acetals 3.37 and furan 3.36 are also possible products. According to MMFF94 calculations, the pyran acetal 3.37 can rearrange to the more stable furan acetal 3.36 due to the sterically charged axial substituents (Scheme 3.7).
Transition state models for peracid and metal catalyzed epoxidations
For the peracid oxidant9, the allylic alcohol hydrogen bonds with an estimated dihedral angle of ±120°. In contrast, in the vanadium oxidant, the metal alcohol bond between the allylic oxygen atom and the metal center favors a dihedral angle of ±40° for efficient oxygen transfer, and the preferred anti or erythro diastereoselectivity is determined by the A(1,2) strain. found in TS 3.
Smith’s synthesis of (+)-13-Deoxytedanolide
Taylor11 and colleagues also investigated peracid epoxidations in the synthesis of myriaporone 1, a class of natural products related to the tedanolides. A late phase reduction of isoxazoline 3.44 with Mo(CO)6 successfully unmasked the β-hydroxy ketone and paved the way for the major epoxidation. Under the optimized conditions of less than one equivalent of mCPBA at -50°C, the desired syn-2,3-epoxide 3.45 was obtained as a single diastereomer and unreacted starting material (Scheme 3.10).
Taylor’s synthesis of myriaporone via late stage peracid epoxidation
Further evidence for furan 3.36 was provided by two-dimensional NMR analysis where a NOE cross-peak between H22 and Me24 was observed and an HMBC cross-peak between C21 and H25 was absent. Therefore, furan 3.36 possessed not only the undesirable ring tautomer, but also the reverse stereochemistry at C24 and C25 to that required for the ammocidines. Interestingly, metal-catalyzed epoxidations (mechanistically different from the peracid) with VO(acac)2 and Sharpless epoxidations14 also directly yielded furan 3.36.
In view of the two separate epoxidation mechanisms, this outcome was unique and unexpected (Scheme 3.11).
Peracid and metal catalyzed epoxidation of 3.34
With the determined stereochemistry and ring size, two possible reaction pathways could account for the unexpected production of furan 3.36. Based on literature precedent, we assumed that furan 3.36 arrived from syn-epoxy ketone 3.35 via a 5-exo opening (Path A). The cyclization of O18 3.34 will allow path A and path B to be distinguished by assigning the O18-induced shift relative to the abundant O16 carbon signal in the 13C NMR spectrum16 (Scheme 3.12).
Examination of the 13C NMR spectrum indicated that resonances corresponding to C21 and C24 were accompanied by O18-induced carbon shifts at 110 and 84 ppm, respectively (Figure 3.1, Scheme 3.13). The combination of the assigned stereochemistry and isotope position in furan acetal O18 3.36 revealed that syn-2,3-epoxyketone 3.35 underwent 5-exo opening to form 3.36 in support.
Jamison’s work on water epoxide opening cascades
Required fragments for the assembly of 3.46
Examining the 1,3 asymmetric induction Felkin-Ahn polar model, we speculate that the selectivity of the aldehyde face is governed by steric and electrostatic dipole repulsions. The model proposes that the β-methoxy substituent reduces the dipole interaction with the aldehyde, allowing the preferred transition state TS 5 (Figure 3.3), leading to the preferred 1,3-anti diastereomer. The steric interaction between the aldehyde and the sterically demanding β-alkyl substituent (RL) is expected to be minimized if they are oriented periplanar to the Cα-C=O bond.
Enolsilane approach is expected to be in a staggered conformation where the sterically demanding Lewis acid and RL of enolsilane are minimized22 (Figure 3.3). Epoxidation of O18 3.46 by the VO(acac)2 protocol gave a single 2,3-epoxy ketone O18 3.55, which could be isolated by flash chromatography, indicating that the hydrogen bond of the C19 hydroxyl group slowed the rate of cyclization , as previously assumed.
Cyclization to pyran acetal 3.56
Combining both the stereochemistry in 3.57 and the O18 labeling study provided evidence for the generation of anti-ketoepoxide 3.55 that upon heating in water yielded pyranacetal 3.56 via a 5- exo opening. It is noteworthy that this epoxide formation with VO(acac)2 provided the opposite stereoisomer compared to that of its keto epoxide 3.35 (Scheme 3.11). Therefore, we deduced from the preceding experiments that it is essential for the C19 hydroxyl group to hydrogen bond with the C21 ketone in order for the desired keto-epoxide cyclization to afford the apropos pyranose ring system found in the family of ammocidins.
Isomerization of pyran acetal 3.55 to furan acetal 3.59
Revised Mechanism for the formation of pyran acetal 3.56
Isomerization of myriaporone 1 to myriaporone 2
Plausible mechanism from myriaporone 1 to 2
Crimmin’s anti selective aldol reactions with titanium enolates
Synthesis vinyl bromide 1.27 via Crimmins anti aldol reaction
Vinyl bromide C14-C28 southern hemisphere
In order to study the multiple substrates required for the fusion of the northern and southern fragments, we developed three new versions of the southern hemisphere. Starting with the known aldehyde25 3.76, Grignard addition provided the syn propargyl alcohol in 2:1 dr ratio in 60% yield for the desired diastereomer. We hypothesized that the Grignard addition would proceed via a chelate model26 that may provide the epimer required at C16 for the amocidin family.
Protection of secondary alcohol as the TBS ether in 94% yield and removal of the PMB ether with DDQ afforded primary alcohol 3.79 in 89% yield. Oxidation with IBX yielded the unstable aldehyde 3.80, which was immediately used in the next reaction (Scheme 3.25).
Synthesis of propargylic aldehyde 3.80
Propargylic C14-C28 southern hemisphere 3.4
Smith’s synthesis of fragment 3.90 towards (+) phorboxazole A
Vinyl stannane C14-C28 southern hemisphere
Vinyl iodide aldehyde synthesis
Vinyl iodide C14-C28 southern hemisphere
The solution was stirred for 2 h, washed with aqueous NaHCO 3 (10 mL) and extracted with diethyl ether (3 x 15 mL). The solution was extracted with CH2Cl2 (3 x 50 mL), the combined organic layers were dried (MgSO4) and concentrated in vacuo. The resulting solution was extracted with CH2Cl2 (3 x 15 mL) and the combined extracts were dried (MgSO4).
The solution was extracted with CH2Cl2 (3 x 50 mL), the combined organic layers were dried and concentrated in vacuo to give a clear oil. The resulting solution was extracted with CH2Cl2 (3 x 15 mL) and the combined organic layers were dried and concentrated in vacuo to give a clear oil.
H MeO
