Triene formation by elimination

Our initial efforts focused on the formation of the C6-C11 triene unit. So far, the only successful approach involved the previously discussed Suzuki coupling with a protected dienyl iodide fragment (Scheme 7). Still, we wanted to explore other strategies for the formation of the triene aside from cross-coupling reactions. We envisioned that triene 52 could be synthesized by an elimination reaction of secondary alcohol 53 (Scheme 28).

Scheme 28. Construction of triene 52 by an elimination strategy.

This alcohol could be accessed by the addition of the existing C1-C7 fragment 36 to aldehyde 54. We assumed that a halogen metal exchange of the vinyl iodide 36 followed by addition to aldehyde 54 would be the most promising approach. Compound 54 should be obtained from known triene fragment 9 by selective removal of the C12 TES group, followed by oxidation and addition of the existing vinyl iodide fragment 29. The dual use of fragment 29 – both for

the synthesis of the C1-C7 as well as the C8-C11 unit – would make the strategy very convergent.

Our synthesis commenced with the selective deprotection of triene fragment 9 (provided by S.

Hackl) at the C12 position. Treatment of the compound with PPTS at –18 °C in a methanolic solution led to the desired alcohol in 72% yield (Scheme 29).

Scheme 29. Selective deprotection of the C12 TES group.

Alcohol 55 was oxidized using standard Dess-Martin conditions. The aldehyde turned out to be unstable on the column and was used without purification for the following experiments (Table 4).

To facilitate the halogen metal exchange, vinyl iodide 29 was treated with tert-butyllithium at –78 °C. After stirring for ten minutes, the freshly prepared aldehyde was added. To our delight, the desired product 56 was isolated in a moderate yield of 45% as a mixture of diastereomers (entry 1). We hypothesized that the formation of the organozinc reagent would lead to a mild reaction and an increased yield. Transmetallation of the lithiated compound to zinc was facilitated by the addition of dimethyl zinc.^[59] Unfortunately, the yield only marginally increased to 47%. However, the compound was isolated with an improved diastereomeric ratio of 8:1. While the diastereomeric ratio was inconsequential for further synthesis, it made NMR analysis much more convenient.

Table 4. Addition of the C5 fragment 29 via halogen metal exchange.

Conditions Solvent T t Yield d.r.

1

29 (1.50 eq.) t-BuLi (3.00 eq.)

then RCHO

Et2O –78 °C 20 min 45% 1:1

2

29 (4.00 eq.) t-BuLi (8.00 eq.) ZnMe2 (4.00 eq.)

then RCHO

Et2O –78 °C 5 min

45 min 47% 8:1

TES protection of the secondary alcohol was accomplished using TESCl, imidazole, and DMAP with 67% yield (Scheme 30). The primary TES group of compound 57 was then selectively removed using PPTS at low temperature with a yield of 75%.

Scheme 30. TES protection of addition product 56 followed by removal of the C8 TES group.

The introduction of the C1-C7 36 fragment was achieved by applying the same methodology as described above (Scheme 31). First, alcohol 58 was oxidized using Dess-Martin conditions.

Simultaneously, vinyl iodide 36 was treated with tert-butyllithium and dimethyl zinc to generate the corresponding vinyl zincate. The addition of the aldehyde cleanly delivered the desired product 53 in 69% yield. Due to the lack of adjacent stereogenic centers that would allow for substrate-induced stereoselectivity, the compound was obtained as a 1:1 mixture of diastereoisomers.

Scheme 31. Assembly of the C1-C23 fragment 53 by a metallation-addition-sequence.

With alcohol 53 in hand, the stage was set for the envisioned elimination reaction towards the desired triene fragment 52. Literature reports suggested the formation of the mesylate, followed by treatment with base.^[60] Indeed, treatment of the compound with mesyl chloride and a large excess of triethylamine led to the direct formation of the triene 52, albeit in a low yield of only 23% (Table 5, entry 1). Furthermore, the reaction was not reproducible and often led to the decomposition of the starting material.

Gratifyingly, treatment of compound 53 with an excess of the Burgess reagent at 50 °C reproducibly led to the formation of the product in an acceptable yield of 55% (entry 2).^[61]

Table 5. Elimination of alcohol 53 to triene 52.

Conditions Solvent T t Yield

1 MsCl (4.00 eq.)

NEt3 (100 eq.) CH2Cl2 –78 °C ⟶ r.t. 24 h 23%

2 Burgess reagent (8.75 eq.) toluene 50 °C 2 h 45%

The NMR showed two major diastereoisomers in a ratio of 3.6:1. These are probably caused by an E/Z mixture of the newly formed alkene, while the minor isomers, which stem from the C12 position, could not be detected anymore. A separation of the isomers was not possible at this point. Instead, the E/Z mixture was used for the next steps.

Deprotection of the primary TES group using PPTS only led to the decomposition of the material (Table 6, entry 1). To our delight, an excess of HF ‧ pyridine delivered the desired primary alcohol 54 with a moderate yield of 62% (entry 2).

Table 6. Conditions for the deprotection of the C1 alcohol.

Conditions Solvent T t Yield

1 PPTS (3.00 eq.) MeOH/CH2Cl2 –20 °C 2 h decomp.

2 HF ‧ pyridine (84.0 eq.) THF/Et2O 0 °C 4 h 45%

An oxidation sequence was intended to deliver carboxylic acid 55.^[62] While the oxidation under Dess-Martin conditions cleanly formed the aldehyde (according to TLC) within 40 minutes, the application of the Pinnick conditions only led to rapid decomposition of the material (Table 7, entry 1). Literature-known conditions for aerial oxidation using TEMPO also led to decomposition (entry 2).^[63] Pyridinium dichromate (PDC) did not show conversion of the starting material (entry 3).^[64]

Table 7. Attempts for the oxidation of alcohol 54 to carboxylic acid 55.

Around the time of these results, S. Wienhold discovered that the macrolactonization was not applicable to the C1-C40 fragment of Pulvomycin (see chapter 3). These new findings, along with the non-satisfying yield of the sequence (4.0% over seven steps from triene fragment 9 to

the primary alcohol 54), made an application in the late stage of the total synthesis not feasible.

Instead, we focused on macrocyclization strategies aside from lactonization approaches.