Enantioselective Halolactonizations with Z-Alkenes: Model Studies

Due to the lack of success within these initial saponification-halolactonization attempts, it was determined that the next approach to be taken would be the investigation of a model system. Model studies of a smaller, more accessible substrate would provide insight into the feasibility of achieving halolactonizations with unsaturated carboxylic acids bearing Z-alkenes. Thus, cyclopentenyl cyanocarboxylic acid 576 was seen as an attractive model substrate due to its ease of availability from previously synthesized material. Saponification of ethyl ester 569 with NaOH in aqueous ethanol furnished cyanoacid 576 in good yield (Scheme 194). To our delight, subsequent treatment of acid 576 with NIS and catalytic quantities of DMAP in the presence of DCM delivered the desired iodolactone (577) albeit in modest yield (37%). Acquisition of lactone 577 now set the stage for enantioselective investigations.

Based on the high degree of success in their respective halolactonization system, reaction conditions described by Dobish and Johnston were used as a template for initial enantioselective studies.245 Herein, PBAM was employed as the chiral organocatalyst, NIS as the iodine source, and toluene (0.05 M) as the solvent. The first variable that was examined was reaction time. When cyanoacid 576 was subjected to the lactonization protocol, iodolactone 577 was afforded in low yield and with minimal levels of enantioselection (12% yield, 5% ee) (Table 29, entry 1). Prolonged reaction times of 12 hours, 24 hours, and 48 hours did not result in any significant change as 577 was acquired in comparable yields and ee’s (Table 29, entries 2-4). Yet when this lactonization was run over the course of 72 hours, lactone 577 was furnished in 4% yield and 17% ee (Table 29, entry 5). Despite this minor improvement in enantioselection, subsequent studies utilized a 24 hour reaction time for the sake of acquiring data in a more timely manner.

The next variable that was probed was solvent concentration. Increasing the concentration from 0.05 M to 0.1 M resulted in higher yield, but minimal loss in enantioselection as iodolactone 577 was furnished in 11% yield and 5% ee (Table 29, entry 6). Further concentrated systems (0.5 M and 1.0 M) confirmed the trends of improved yield and diminished ee (Table 29, entries 7 and

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8). Due to the gradual decrease in enantioselection upon increased solvent concentration, 0.05 M remained as the optimal concentration up to this point.

Introduction of counterions ensued as Brønsted acid salts of BAM ligands led to higher selectivity in previous work.245 When the triflic acid salt of PBAM (19•HOTf) was used as the catalyst for this system, little change was seen relative to the free base as lactone 577 was afforded in 9% yield and 3% ee (Table 30, entry 2). The triflimide salt of PBAM (19•HNTf2) performed

similarly (Table 30, entry 3). Since acid salts proved ineffective in promoting reactivity and/or selectivity, efforts then shifted towards the use of more Brønsted basic organocatalysts.

8_{(MeO)PBAM (19d) was employed delivering iodolactonization product 577 in increased yield} and diminished ee (11% yield, 1% ee) (Table 30, entry 4).6_{(MeO)PBAM (19e) furnished 577 in}

Table 29. Preliminary Time and Concentration Studies

entry time (h) conc. (M) yield (%) ee (%) 1 6 0.05 12 5 2 12 0.05 8 5 3 24 0.05 6 6 4 48 0.05 8 3 5 72 0.05 4 17 6 24 0.1 11 5 7 24 0.5 13 2 8 24 1.0 12 1

Table 30. Effects of Acid Salts and More Brønsted Basic Organocatalysts

entry catalyst yield

(%) ee (%) 1 PBAM 6 6 2 PBAM•HOTf 9 3 3 PBAM•HNTf2 4 6 4 8_{(MeO)PBAM 11 1} 5 6_{(MeO)PBAM 8 7} 6 6,7_(MeO) 2PBAM 0 N/A 7 -- 7 0

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8% yield and 7% ee and 6,7(MeO)2PBAM (19c) failed to provide product (Table 30, entries

5 and 6). Furthermore, when this lactonization was run in the absence of catalyst, iodolactone 577 was isolated in 7% yield as a racemate (Table 30, entry 7). This indicates that the use of organocatalysts, thus far, have had little or no effect on reactivity and/or selectivity as previously acquired yields are comparable to that of the background reaction.

When the racemic version of this iodolactonization was run, CH2Cl2 was employed as the

solvent resulting in the acquisition of lactone 577 in 37% yield (Scheme 194). Since a reasonable yield was observed with CH2Cl2, this solvent was used in the enantioselective variant with

ambitions of increasing product formation. Unfortunately, CH2Cl2 performed poorly in the

presence of PBAM as lactone 577 was furnished in only 10% yield and 3% ee (Scheme 195). Toluene, therefore, remained as the solvent of choice.

It should be noted that a 5 mol% loading of PBAM performed similarly relative to when a 10 mol% loading was employed (Table 31, entry 1). Because of these comparable results and for the sake of catalyst economy, 5 mol% catalyst loadings were to be used for subsequent studies.

Scheme 195. Iodolactonization Attempt with CH2Cl2 as the Solvent

entry catalyst T (°C) iodine source yield (%) ee (%) 1 PBAM 25 NIS 8 8 2 StilbPBAM 25 NIS 23 19 3 3,5_{(CF3)2BenzAM 25 NIS 8 6} 4 PivalAM 25 NIS 1 0 5 StilbPBAM 0 NIS 21 22 6 StilbPBAM -20 NIS 15 30

7 StilbPBAM -50 NIS 0 N/A

8 StilbPBAM -20 DIDMH 19 28

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Amidine catalysts possessing different backbones were submitted to the halolactonization protocol with the hope of introducing different bite angles that can ultimately promote enantioselection. When StilbPBAM (88) was used as the catalyst, noticeable improvements in yield and selectivity were seen as iodolactone 577 was furnished in 23% yield and 19% ee (Table 31, entry 2). Amidine-amide catalysts in 3,5_(CF

3)2BenzAM (78a) and PivalAM (78m) performed

poorly, however, as loss in yield and/or enantioselection were observed for both of these cases (Table 31, entries 3-4). Encouraged by these results seen with StilbPBAM, lower temperatures were reevaluated in order to see if selectivity could be further improved. When the reaction was chilled to 0 °C and -20 °C respectively, we were delighted to see consistent improvement in ee albeit the gradual depression in yield (Table 31, entries 5 and 6). Unfortunately, running the reaction at -50 °C completely mitigated product formation as no sign of lactone 577 could be detected (Table 31, entry 7). Nevertheless, these improved degrees of enantioselection clearly indicate that the StilbPBAM catalyst is influential in this iodolactonization reaction. Additionally, DIDMH was also reapplied as the iodo source, but still proved inferior relative to NIS (Table 31, entry 8).

Acid salts were employed once more with the ambition of further enhancing selectivity. Unfortunately, both the triflic acid and triflimide salts of StilbPBAM (88•HOTf and 88•HNTf2)

gave lower yield and diminished enantioselection reaffirming the superiority of the free base catalyst (Table 32, entries 2 and 3). These results led to the examination of more Brønsted basic stilbene diamine-derived ligands. When 6(MeO)StilbPBAM (88a) was employed as the organocatalyst, mild improvement was observed as lactone 577 was furnished in 24% yield and

entry catalyst solvent yield

(%) ee (%) 1 StilbPBAM toluene 15 30 2 StilbPBAM•HOTf toluene 7 19 3 StilbPBAM•HNTf2 toluene 9 28 4 6_{(MeO)StilbPBAM toluene 24 32} 5 7_{(MeO)StilbPBAM toluene 11 26}

6 6_{(MeO)StilbPBAM xylenes 0 N/A}

7 6_{(MeO)StilbPBAM THF 0 N/A}

8 6_{(MeO)StilbPBAM CH3CN 4 3}

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32% ee (Table 32, entry 4). 7(MeO)StilbPBAM (88b) did not fare as well as 577 was acquired in only 11% yield and 26% ee (Table 32, entry 5).

With 6(MeO)StilbPBAM (88b) chosen as the new optimal catalyst, the effects of different solvents were examined more extensively. Interestingly, xylenes, a solvent similar to that of toluene, failed to yield any product when subjected to the halolactonization protocol (Table 32, entry 6). The same was observed with an ethereal solvent in THF (Table 32, entry 7). CH3CN was

also used, but proved inferior relative to toluene as lactone 577 was afforded in only 4% yield and 3% ee (Table 32, entry 8). Once again, toluene remained the solvent of choice.

Non-BAM catalysts were submitted next in order to see their respective influence on product yield and enantioselection. 2,4,6-Triisopropyl-phenyl-based binaphthol phosphoric acid (TRIP) catalyst 578247 was ineffective as no product was furnished upon its use (Table 33, entry 2). Deng’s248 and Takemoto’s249 thiourea organocatalysts (579 and 68) were also employed, but to no avail as lactone 577 was isolated in minimal yield and as a racemate in both cases (Table 33, entries 3 and 4).

247 _{Čorić, I.; Vellalath, S.; List, B. J. Am. Chem. Soc. 2010, 132, 8536-8537.} 248 _{Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128,6048-6049.}

249 _{Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625-627.}

entry catalyst yield

(%) ee (%) 1 6_{(MeO)StilbPBAM 24 32} 2 TRIP 0 N/A 3 Deng Thiourea 1 0 4 Takemoto Thiourea 1 0

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At this point, every variable within this reaction system has been examined to an extent with the optimal result being a 24% isolated yield of lactone 577 with 32% ee. Since modification of these variables did not provide good yields and promising levels of enantioselection, efforts then shifted towards the use of other electrophilic halogen sources (i.e. bromine and chlorine). With aspirations of achieving bromolactonization, cyanoacid 576 was treated with N- bromosuccinimide (NBS) and DMAP in the presence of CH2Cl2. Gratifyingly, the desired

bromolactone 580 was successfully acquired albeit in 19% yield (Scheme 196).

Investigation of the enantioselective variant of this bromolactonization commenced when acid 576 was treated with PBAM (5 mol%) and NBS in the presence of toluene at -20 °C. After a 24 hour reaction period, no sign of bromolactone 580 could be detected (Table 34, entry 1). The same result was seen when StilbPBAM was employed as the catalyst (Table 34, entry 2). The use of a different bromine source in N-bromophthalimide (NBP) also proved fruitless as this too failed to provide product (Table 34, entry 3).

Due to the limitations of this bromolactonization reaction, efforts shifted towards the development of a chlorolactonization system. This approach was even more problematic as treatment of cyanoacid 576 with N-chlorosuccinimide (NCS) and DMAP in the presence of CH2Cl2 failed to deliver racemic chlorolactone 581 (Scheme 197). Since chlorolactone 581 could

not be isolated as a racemate, no analytical assay could be developed ultimately preventing enantioselective studies.

Scheme 196. Racemic Synthesis of Bromolactone 580

entry catalyst bromine

source yield (%) ee (%) 1 PBAM NBS 0 N/A 2 StilbPBAM NBS 0 N/A 3 StilbPBAM NBP 0 N/A

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Selenolactonization with acid 576 was the next avenue that was explored. Subjection of acid 576 to N-(phenylseleno)phthalimide (PSP) and DMAP in the presence of CH2Cl2 provided

selenolactone 582 in 21% yield as a racemate (Scheme 198). Acquisition of this selenolactone set the stage for the enantioselective variation of this reaction system.

Enantioselective investigations began when cyanoacid 576 was treated with PBAM (5 mol%) and PSP in the presence of toluene at room temperature. After 24 hours, no promising levels of enantioselection were observed as selenolactone 582 was furnished in 26% yield and 2% ee (Table 35, entry 1). Replacing PBAM with StilbPBAM did not show any improvement as a racemic mixture of 582 was delivered in 23% yield (Table 35, entry 2). Both PBAM and StilbPBAM were reemployed in the selenolactonization protocol at -20 °C. Chilled temperatures did not show improvement as selenolactone 582 was isolated but as a racemate in 18% and 21% yields, respectively (Table 35, entries 3 and 4). Furthermore, the triflic acid and triflimide salts of StilbPBAM also proved ineffective as no improvement in yield and/or ee were observed (Table 35, entries 5 and 6).

Scheme 197. Failed Attempt Towards Chlorolactonization

Scheme 198. Racemic Synthesis of Selenolactone 582

entry catalyst T (°C) yield (%) ee (%) 1 PBAM 25 26 2 2 StilbPBAM 25 23 0 3 PBAM -20 18 0 4 StilbPBAM -20 21 0 5 StilbPBAM•HOTf -20 13 2 6 StilbPBAM•HNTf2 -20 23 0

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The focus then centered upon the development of a 6-membered model system as multiple variations of the 5-membered system showed little or no promise. The substrate of choice for these 6-membered model studies was that of cyanoacid 583, the homologated analog of cyanoacid 576. Thus, compound 583 could be readily accessed upon subjecting acid 576 to an Arndt-Eistert homologation process.250 _{Treatment of 576 with SOCl}

2 provided acid chloride 584 (Scheme 199).

Subsequent exposure of this acyl chloride to diazomethane in diethyl ether furnished diazoketone 585 in modest yield (38% over 2 steps). 585 then underwent homologation when treated with silver benzoate (AgOBz) under basic conditions ultimately delivering methyl ester 586 in 64% yield. Saponification of ester 586 with hydroxide in aqueous methanol afforded the desired precursor acid 583 (88% yield). Acid 583 was successfully converted to [6.5]-bicyclic iodolactone 587 in moderate yield when treated with NIS and DMAP in the presence of CH2Cl2 (37%).

Investigation of the enantioselective version of this 6-membered iodolactonization began when acid 583 was treated with PBAM (5 mol%) and NIS in toluene at room temperature. Lactone 587 was acquired in 12% yield and 4% ee after a 24 hour reaction time (Table 36, entry 1). StilbPBAM showed no improvement as lactone 587 was obtained in 14% yield as a racemate (Table 36, entry 2). Triflic acid and triflimide salts of StilbPBAM also proved fruitless as yields and enantioselection remained relatively unchanged (Table 36, entries 3 and 4).

Various solvents were examined next in order to see their respective influence on this lactonization protocol. CH2Cl2 resulted in an improvement in yield as lactone 587 was furnished

in 25% yield (Table 36, entry 5). However, the enantiopurity was similar to that observed with toluene (3% ee). Nitromethane (MeNO2) did not show any enhancement as iodolactone 587 was

delivered in 19% yield as a racemate (Table 36, entry 6). Alcoholic (MeOH) and nitrile (CH3CH2CN) solvents performed similarly to that of MeNO2, and THF failed to give product

250 _{Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.-P. Tetrahedron-Asummetr.}

2005, 16, 857-864.

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completely (Table 36, entries 7-9). Although CH2Cl2 led to improved yield, toluene was taken onto

further studies as noticeable levels of enantioselection were achieved with this solvent in the 5- membered lactonization system.

Other non-amidine organocatalysts were also employed with aspirations of increasing yield and selectivity. When 3,5-(bistrifluoromethyl)phenyl-based binaphthol (BINOL) 588 was used as the catalyst, little change was seen relative to PBAM as lactone 587 was isolated in 14% yield and 3% ee (Table 37, entry 2). BINOL phosphoric acid 589 and phenanthrene-derived BINOL phosphoric acid 590 performed similarly (Table 37, entries 3 and 4). Anthracene-derived BINOL phosphoric acid catalyst 591 showed mild improvement as the iodolactone product was isolated in 17% yield and 8% ee (Table 37, entry 5). 2,6-Dimethyl-4-methoxy-phenyl-based BINOL phosphoric acid 592 did not fare as well as this catalyst delivered lactone 587 in 7% yield as a racemate (Table 37, entry 6). TRIP as well as Deng’s and Takemoto’s thioureas also proved

entry catalyst solvent yield

(%) ee (%) 1 PBAM toluene 12 4 2 StilbPBAM toluene 14 0 3 StilbPBAM•HOTf toluene 17 -5 4 StilbPBAM•HNTf2 toluene 17 1 5 PBAM CH2Cl2 25 3 6 PBAM MeNO2 19 0 7 PBAM MeOH 11 1 8 PBAM CH3CH2CN 8 1 9 PBAM THF 0 N/A

Table 36. 6-Membered Iodolactonization: Catalyst and Solvent Studies

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ineffective as diminished yields and selectivities were observed relative to when PBAM was used (Table 37, entries 7-9).

The inability to achieve promising levels of enantioselection with a multitude of Z-alkene substrates resulted in the analysis of potential problems. One commonality between the starting materials employed throughout the course of these lactonization studies is that they all possess a cyano motif. Also, the fact that 32% ee was observed within the 5-membered iodolactonization system suggests that the starting cyanoacid is indeed binding to the organocatalyst (Table 32, entry 4). With these observations in mind, it is reasonable to infer that the cyano group of the acid may be involved in an unwanted electronic interaction when binding to the organocatalyst (Figure 36). In other words, the cyano motif may be preventing the acid from orienting itself with the catalyst in such a way that favors higher levels of enantioselection. In order to neutralize this potential problem, the cyano functionality should be replaced with a moiety less prone to undesired electronic interaction (i.e. a phenyl group). Therefore, phenyl cyclopentene carboxylic acid 593 was the next substrate of interest.

entry catalyst yield

(%) ee (%) 1 PBAM 12 4 2 BINOL 588 14 0 3 phosphoric acid 589 17 -5 4 phosphoric acid 590 17 1 5 phosphoric acid 591 25 3 6 phosphoric acid 592 19 0 7 TRIP 11 1 8 Deng Thiourea 8 1

9 Takemoto Thiourea 0 N/A

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Acid 593 was synthesized via a known procedure as described by Takacs and colleagues.251 Treatment of commercially available methyl phenylacetate (594) with NaH and cis-1,4-dichloro- 2-butene in the presence of N,N’-dimethylpropylene urea (DMPU) and THF at elevated temperature provided methyl phenylcyclopentene carboxylate 595 in 42% isolated yield (Scheme 200). Subsequent saponification of 595 with KOH in ethanol furnished known acid 593 in 95% yield. When this acid was treated with NIS and DMAP in CH2Cl2, iodolactone 596 was afforded

setting the stage for enantioselective studies.

With a phenyl motif in place of the cyano group, we were hopeful that acid 593 would achieve a binding mode that would ultimately increase selectivity. When PBAM was used as the organocatalyst, we were disappointed to see that this substrate was not immediately better behaved as lactone 596 was acquired in 9% yield and 1% ee (Table 38, entry 1). However, when StilbPBAM was employed, increased yield and promising levels of enantioselection were observed as the lactone product was isolated in 25% yield and 48% ee (Table 38, entry 2). This jump in selectivity between the PBAM and StilbPBAM entries indicates that the bite angle of the catalyst is critical for inducing high levels of enantioselection. Encouraged by the StilbPBAM result, the triflic acid and triflimide salts of StilbPBAM were also submitted with aspirations of further enhancing enantioselection. Unfortunately, neither of these fared as well relative to the free base catalyst (Table 38, entries 3 and 4).

With StilbPBAM taken on as the catalyst, the effects of temperature were examined next. Subjection of StilbPBAM to the reaction protocol at 0 °C led to an increase in both yield and enantioselection as lactone 596 was afforded in 41% yield and 58% ee (Table 38, entry 5). A -20 °C reaction temperature provided the lactone product in 30% yield and 65% ee confirming that

251 _{Hoang, G. L.; Yang, Z.-D.; Smith, S. M.; Pal, R.; Miska, J. L.; Pérez, D. E.; Pelter, L. S. W.; Zheng, X. C.;}

Takacs, J. M. Org. Lett. 2015, 17, 940-943.

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lower temperatures correlate to higher ee (Table 38, entry 6). However, when the lactonization was further chilled to -50 °C and -78 °C, product formation was completely mitigated (Table 38, entries 7 and 8).

After identifying -20 °C as the optimum temperature, organocatalysts with higher Brønsted basicity profiles were studied next. When 7_{(MeO)StilbPBAM was employed as the catalyst, we} were disappointed to see a dramatic drop in yield and selectivity as lactone 596 was provided in only 11% yield and 12% ee (Table 38, entry 9). An anthracenyl-bearing analog, dubbed 7_{(MeO)AnthPBAM (597), was also examined in the iodolactonization system. Unfortunately, this} catalyst also proved fruitless as lactone 596 was delivered in 10% yield and -3% ee (Table 38, entry 10).

With promising levels of enantioselection achieved, other variables are to be examined in order to further improve this system. These variables include different iodine sources, solvents, and other catalysts modifications. These efforts are currently ongoing within our laboratory by Matthew Knowe and Zachary Carter.