Intramolecular Wittig Cyclization

24. For isolation of rameswaralide (8) and initial biosynthetic speculation, see

2.4 Intramolecular Wittig Cyclization

Faced with this challenge, we envisioned preparation of cyclopentenone 250 by an intramolecular Wittig cyclization (Scheme 2.4.1).

¹³

The introduction of an oxidized allyl fragment during the alkylation event to generate ketone 251 could facilitate the olefinic oxidation. Subsequent nucleophilic substitution with a phosphine would generate Wittig precursor 252. Exposure to basic conditions could generate the phosphonium ylide, thereby enabling an intramolecular Wittig cyclization to form cyclopentenone 250.

Scheme 2.4.1. Proposed Construction of Cyclopentenone 250 Using Intramolecular Wittig Cyclization

To explore this pathway, we began with chloroallylketone 254, which was prepared by palladium-catalyzed asymmetric allylic alkylation in 82% yield and 91% ee by a known procedure (Scheme 2.4.2).

¹⁴

Epoxidation of ketone 254 with m-CPBA generated intermediate epoxide 255. Nucleophilic epoxide opening then formed the α- phosphinoketone in situ, enabling the construction of enone 250 by intramolecular Wittig cyclization. Although the yield for the two-step sequence was low and varied unpredictably, desired cyclopentenone 250 could be isolated in small quantities.

O O

O

O O

O

O O

O

X O

PR₃ 1) oxidation

2) PR₃

then base

251 252 250

+

Scheme 2.4.2. Construction of Enone 250 by Epoxidation of Chloroallylketone 254

Having accomplished a proof of principle, we turned our attention to optimization.

Despite the fact that a variety of epoxidation conditions had been screened,

¹⁵

the synthesis of intermediate 255 proved difficult and remained low yielding. The Wittig cyclization had similar constraints, furnishing cyclopentenone 250 in variable, unsatisfactory yields.

In spite of these failed attempts, we remained inspired by the successful isolation of the desired enone 250. As an alternative, we decided to explore the synthesis of other Wittig cyclization precursors. One appealing option was to target intermediate α- bromoketone 256 (Scheme 2.4.3).

¹³

Oxidative bromination of vinyl chloride 254 with NaOBr in AcOH resulted in the formation of intermediate bromide 256. In situ displacement of the bromide by triphenylphosphine and subsequent intramolecular Wittig cyclization furnished cyclopentenone 250 with no erosion of enantiomeric excess, albeit in unpredictable yields.

Scheme 2.4.3. Construction of Enone 250 by Oxidative Bromination of Chloroallylketone 254

Synthetic advancement of dioxanone 254 through α-bromoketone 256 was plagued by vast inconsistencies, and optimization proved difficult. The two-step sequence offered

O O

O

O O

O

Cl O

Cl O O

O

Ph3P, Et3N toluene, 110 °C

5 h

(8% yield, 2 steps)

254 255 250

91% ee

m-CPBA CH₂Cl₂

9 d TBAT

Pd₂(dmdba)₃ (5 mol %) (S)-CF₃-t-BuPhox (5.5 mol %)

toluene 35 °C, 7 h

(82% yield) Cl

OMs

248

O O

OTES

253

O O

O

O Br

O O

O

Cl O O

O

Ph₃P, Et₃N toluene, 110 °C

5 h

(35% yield, 2 steps)

254 256 250

91% ee

NaOBr, AcOH acetone, 0 °C

1.5 h

92% ee

a range of yields from 0% to 82%. A variety of oxidative bromination conditions were attempted,

¹⁵

yet consistent yields could not be achieved. Importantly, when intermediate 256 was successfully formed,

¹⁶

conversion to cyclopentenone 250 could be reproducibly achieved with moderate success, indicating that the oxidative bromination was the problematic step in the sequence.

Upon closer inspection of the oxidative α-bromination procedure, we identified two possible sources of inconsistency. First, we suspected that exposure of substrate 254 and intermediate 256 to acetic acid was causing the ketal cleavage of both compounds throughout the reaction, resulting in decomposition. Direct observation of this hypothesis was challenging, as the cleavage of the acetonide simply generated additional quantities of the reaction solvent, acetone. An additional source of variability arose as the scale of the reaction was increased. During prolonged reaction times, a consequence of operating on greater scale (ca. 2 h), the bright yellow NaOBr solution suspended over the reaction flask in an addition funnel (Figure 2.4.1.A) decomposes due to the acetic acid vapors in the reaction headspace (Figure 2.4.1.B). This decomposition hinders reproducibility and lowers the reaction yield.

Figure 2.4.1. Decomposition of NaOBr Stock Solution

A. B.

T = 0 h Addition begins, stock solution is

bright yellow, homogenous T = 1 h Stock solution has become hetero- genous with white precipitate

In order to address these concerns, we first sought to alter the ketal. The introduction of additional steric bulk was hypothesized to impart additional stability to the protecting group and thus its tolerance to the oxidative bromination conditions.

Gratifyingly, the selection of the cyclohexyl ketal proved to have no deleterious effects on the asymmetric allylic alkylation of enol ether 257 (Scheme 2.4.4).

¹⁷

Under optimized conditions,

¹⁸

chloroallylketone 258 was generated in a greatly improved 82% yield and increased 92% ee in comparison to acetonide allylic alkylation product 254.

Scheme 2.4.4. Synthetic Route Enabled by the Crucial Choice of the Cyclohexyl Ketal Group

With vinyl chloride 258 in hand, we set about developing an improved procedure for the formation of α-bromoketone 259. In order to avoid suspending the NaOBr stock solution over the headspace of the reaction for any prolonged period, we divided vinyl chloride 258 into equal portions in a solution of acetone and AcOH among a series of vials cooled to 0 °C (Figure 2.4.2.A). The addition of NaOBr was then accomplished dropwise from a needleless plastic syringe, adding one drop (ca. 40 µL) of the bright yellow stock solution to each vial every 30 seconds.

¹⁹

As the addition commences, the transparent colorless solution of vinyl chloride 258 immediately took the bright yellow color of the NaOBr stock solution (Figure 2.4.2.B). As the addition proceeded, the vials progressed through light orange (Figure 2.4.2.C) to deep red-orange (Figure 2.4.2.D) at the completion of the addition. Attempts to convert cyclohexyl ketal 258 to α- bromoketone 259 employing this procedure were met with consistent success and

O O

O

O O

O

O O

O

92% ee 258

Cl O

Br

O O

OTES

NaOBr AcOH acetone 0 °C, 1.5 h

(n-Bu)₃P Et₃N toluene 110 °C, 16 h

(94% yield 2 steps)

257 259 260

TBAT Pd₂(pmdba)₃ (1.5 mol %) (S)-t-BuPhox (3.5 mol %)

toluene 35 °C, 20 h

(82% yield) Cl

OMs

253

complete conversion could be reliably accomplished under optimized conditions, affording bromide 259 in nearly quantitative yield.

²⁰

Figure 2.4.2. Improved Technique for Conversion of Vinyl Chloride 258 to α-Bromoketone 259

With α-bromoketone 259 in hand, the silica sensitive intermediate was immediately

advanced as a crude oil to cyclopentenone 260. Application of standard conditions for

this transformation afforded enone 260, albeit in 35–40% yield.

²¹

Modification of these

conditions, including the use of (n-Bu)

3

P, enabled the conversion of bromide 259 to the

desired cyclopentenone 260 in 94% yield over two steps from chloroallylketone 258.