Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective One-Pot Deconjugation, Aldol, and Stabilized Peterson Olefination of α‑Trialkylsilyl-β-alkyl-α,β-Unsaturated Esters Michael S. Probasco,† David A. Johnson,† and Michael P. Jennings* Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama 35487-0336, United States
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S Supporting Information *
ABSTRACT: A stereoselective reaction process including a one-pot deconjugation, aldol, and stabilized Peterson olefination of αtrialkylsilyl-β-alkyl-α,β-unsaturated esters coupled with aliphatic aldehydes is described. This sequential procedure afforded tri-and disubstituted conjugated diene ester products with dr values of 12− 20:1 for the newly established alkene moieties in modest to good isolated yields.
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and C3−C4 olefins as determined by 1H NMR and 1D NOE of the corresponding trimethylsilylketene acetal.9 With this information in hand, the addition of propanal post LDA deprotonation (in lieu of TMSCl) of 1a furnished the conjugated diene product 2a in 75% yield with dr values of >20:1 (E) for the C3−C4 and 4:1 (Z) for the C2−C3′ alkenes as noted in entry1 of Table 1. As shown in entries 2−5, varying the reaction solvents provided similar yields and dr for the C3−C4 alkene of 2a. However, erosion of the C2−C3′ stereochemistry from 4:1 to 1:1 was observed when less Lewis
equential, one-pot reactions that allow for multiple bond forming processes not only are creatively pleasing but also play a central role in synthetic organic chemistry. The history of such reactions span from Cu-catalyzed vicinal functionalization to Diels−Alder reactions and into the realm of transition metal catalyzed processes where numerous bonds are formed in a domino fashion.1−3 While successive reactions can rapidly produce structurally diverse scaffolds/products, unfortunately the task of controlling stereochemistry during such processes can be quite challenging. First disclosed in 1968, Peterson described an olefination process in which a β-hydroxy-α-trialkylorganosilane would eliminate under either basic or acidic conditions to provide the corresponding alkene.4 Unfortunately, olefins formed by means of nonstabilized Peterson reagents tend not to be stereoselective due to the diastereomeric mixture of the silyl alcohol precursors.5 In addition, stabilized Peterson reactions are known and typically more stereoselective than their nonstabilized counterparts.6 Unfortunately, both types of Peterson olefination sequences have significantly lagged behind their phosphorus counterparts with respect to synthetic utility and mechanistic examinations.7 With our recent reports on the syntheses of a variety of stereodefined α-trialkylsilyl-β-substituted-α,β-unsaturated esters and the subsequent stereoselective deconjugation (and concomitant enolate formation) of said compounds,8,9 we envisioned a sequential reaction process that would harness the in situ formed enolate and allow for the formation of olefin products, post aldol reaction, with high levels of dr. Herein, we wish to report on a highly efficient stereoselective one-pot deconjugation, aldol, and stabilized Peterson olefination of αtrialkylsilyl-β-alkyl(aryl)-α,β-unsaturated esters to afford conjugated diene products with dr values of 12−20:1 for both alkene geometries in modest to good isolated yields. We have shown previously that the initial deconjugation/ enolate formation of α-trimethylsilyl-β-benzyl-α,β-unsaturated ester 1a readily proceeded with LDA in THF at −78 °C and afforded the extended enolate with >20:1 dr for both C1−C2 © XXXX American Chemical Society
Table 1. Proof of Concept One-Pot Deconjugation, Aldol, and Stabilized Peterson Olefination of 1a with Amide Bases and Propanal
entry
solvent
base
yield (%)a
E/Z,b C3−C4
Z/E,b C2−C3′
1 2 3 4 5 6 7 8 9 10
THF Et2O toluene THP DME THF THF THF THF THF
LDA LDA LDA LDA LDA LiTMP LiCA LiNEt2 LiHMDS NaHMDS
75 66 60 64 72 65 48 32 74 42
>20/1 >20/1 >20/1 >20/1 >20/1 >20/1 >20/1 >20/1 >20/1 >20/1
4/1 1/1 1/1 4/1 2/1 3/1 4/1 2/1 3/1 2/1
a
Purified, isolated yield of the diene product. bDr determined by 1H NMR (360 or 500 MHz) integration of the olefin peaks in the crude reaction mixture. Received: January 7, 2019
A
DOI: 10.1021/acs.orglett.9b00069 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
As described in entries 5−8, a survey of reaction solvents provided generally higher yields (except toluene) and improved the dr (up to 6:1 for the Z isomer) for the C2− C3′ alkene of 2a while maintaining the >20:1 dr for the C3− C4 olefin. The greatest yield and dr values were observed with THF as the reaction medium. However, there was concern about complete transmetalation to the boron enolate under the previous reaction conditions. Thus, the addition of 3.2 equiv of Chx2BCl post LDA deprotonation at −78 °C and allowing the reaction to warm to −20 °C in THF, followed by propanal addition (5 equiv), furnished ester 2a in 61% yield with a drastic improvement in dr for the C2−C3′ olefin of >20:1 for the Z-isomer (as determined by 1H NMR and 1D NOE)! Further addition of 4.2 equiv of Chx2BCl post LDA deprotonation provided a higher yield, but had no effect on the dr of product ester 2a as shown in entry 10. With the standardized reaction conditions established from Table 2, attention was subsequently focused on exploring the sequential reaction scope by varying the aldehyde and vinyl silane coupling partners. As described in Table 3, ester 1a readily underwent deconjugation, transmetalation, and an ensuing aldol addition with isobutyraldehyde followed by the Peterson elimination to afford conjugated diene 2b in 64% overall yield (entry 2). The dr of both newly formed olefins at C3−C4 and C2−C3′ of 2b were >20:1 as determined by 1H NMR for the E and Z isomers, respectively. Likewise, exchanging isobutyraldehyde (while maintaining 1a as the nucleophilic coupling partner) for the linear TBS protected aldehyde (derived from 1,3propanediol) provided diene 2c in 67% yield combined with a slight reduction in dr with respect to the C2−C3′ olefin (12:1 for the Z-isomer). In addition, the deprotonation/ transmetalation/aldol/Peterson olefination sequence with ester 1b and isobutyraldehyde readily proceeded and provided conjugated diene 2d in 63% overall yield coupled with high levels of dr (>15:1) for both olefins geometries as noted in Table 3, entry 4. Lastly, the β-isopropyl ester 1c served as a competent nucleophilic substrate post enolization and the subsequent boron mediated aldol addition/elimination with propanal afforded diene 2e in 68% yield with a dr of >20:1 for the Z-C2−C3′ olefin. With the scope of the sequential reaction somewhat defined in Table 3, we were interested in investigating the bistrialkylsilyl esters 1d and 1e as nucleophilic coupling partners due primarily to the synthetic utility of the stereodefined olefinic vinyl silane products as shown in Table 4. Thus, the treatment of ester 1d with LDA at −78 °C, followed by transmetalation to the extended boron enolate with Chx2BCl and an ensuing addition of propanal, afforded the conjugated diene product 2f in 61% yield coupled with very high levels of dr (>20:1; C3−C4, E and C2−C3′, Z) for both of the generated olefins as described in entry 1. Similarly, substituting propanal with isobutyraldehyde, the linear TBS aldehyde (from Table 3) and 3-phenylpropanal provided conjugated diene products 2g, 2h, and 2i (with 1d as the nucleophilic coupling partner) in 67%, 62%, and 63% yields, respectively, with dr values of >20:1 for all of the established olefin moieties. Lastly, the triethylsilyl ester variant 1e readily underwent the deprotonation/transmetalation/aldol/Peterson olefination sequence with 3-phenylpropanal as the electrophilic counterpart to provide diene 2i with an improved yield of 72% (versus 62% with ester 1d) while maintaining the high level of dr (>20:1) for both newly created olefins (entry 5).
basic solvents (i.e., toluene, Et2O, and DME) were employed. Likewise, the investigation of other Li-amide bases provided diene 2a in similar to lower yields and dr for both formed olefins in entries 6−9. Lastly, by comparing LiHMDS to NaHMDS we observed a lower yield (74 vs 42%) and dr of the newly formed C2−C3′ alkene. With the proof of concept in hand from Table 1, albeit with moderate to low dr for the newly formed C2−C3′ olefin, our concerns centered on the initial stereospecificity of the aldol reaction. Unfortunately, tetrasubstituted Li-enolate aldol reactions tend not to be stereospecific, which might aid in explaining the low level of dr for the newly formed C2−C3′ alkene.10 However, a recent disclosure by Gleason has shown that stereodefined tetrasubstituted boron enolates derived from an amide precursor afforded aldol adducts with high levels of dr (>95:5) in a stereoselective and specific manner.11 Based on this report, we chose to transmetallate to a boron enolate post LDA mediated deprotonation with the hope of affording a stereospecific aldol reaction followed by an immediate stabilized Peterson olefination as delineated in Table 2. Thus, initial treatment of 1a with LDA in hexane at Table 2. Boron Mediated Aldol Reaction and Stabilized Peterson Olefination of 1a via an Extended Lithium Enolate Transmetallation
entrya
solvent
t (°C)
yield (%)b
E/Z,c C3−C4
Z/E,c C2−C3′
1 2 3 4 5 6 7 8 9d 10e
hexane hexane hexane hexane MTBE Et2O toluene THF THF THF
−78 → −40 −78 → −20 −78 → 0 −78 → rt −78 → −20 −78 → −20 −78 → −20 −78 → −20 −78 → −20 −78 → −20
35 40 15 0 44 50 20 55 61 68
>20/1 >20/1 >20/1 ND >20/1 >20/1 >20/1 >20/1 >20/1 >20/1
3/1 3/1 3/1 ND 6/1 5/1 4/1 6/1 >20/1 >20/1
a
Reactions ran with 1.1 equiv of LDA, 2.2 equiv of Chx2BCl, and 5.0 equiv of propanal, unless otherwise noted. bPurified, isolated yield of the diene product. cDr determined by 1H NMR (360 or 500 MHz) integration of the olefin peaks in the crude reaction mixture. d3.2 equiv of Chx2BCl were used. e4.2 equiv of Chx2BCl were used.
−78 °C followed by a sequential addition of B-Chlorodicyclohexylborane (Chx2BCl, 2.2 equiv) and propanal (5.0 equiv) provided diene 2a after warming to −40 °C and basic oxidation (NaOH and 30% H2O2) of the intermediate borinate ester in a low 35% yield. The dr of the C3−C4 olefin geometry of 2a in entry 1 remained high (>20:1 for the E alkene), while the dr of the C2−C3′olefin was a moderate 3:1 favoring the Z isomer. In entry 2, the reaction temperature was warmed from −40 to −20 °C post addition of Chx2BCl and propanal and a slightly higher yield of 40% was observed for 2a while maintaining the olefin dr values. Further warming of the reaction did not increase the yield or dr of the conjugated diene ester 2a (entries 3 and 4). B
DOI: 10.1021/acs.orglett.9b00069 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 3. One-Pot Deconjugation, Aldol, and Stabilized Peterson Olefination of Esters 1a−1c with Various Aldehydes
Table 4. One-Pot Deconjugation, Aldol, and Stabilized Peterson Olefination of bis-Trialkylsilyl Esters 1d and 1e with Various Aldehydes
a Reactions ran with 1.1 equiv of LDA, 4.2 equiv of Chx2BCl, and 5.0 equiv of aldehyde. bPurified, isolated yield of the diene product. cDr determined by 1H NMR (360 or 500 MHz) integration of the olefin peaks in the crude reaction mixture.
a
Reactions ran with 1.1 equiv of LDA, 4.2 equiv of Chx2BCl, and 5.0 equiv of aldehyde. bPurified, isolated yield of the diene product. cDr determined by 1H NMR (360 or 500 MHz) integration of the olefin peaks in the crude reaction mixture.
Based on the products observed in Tables 3 and 4, the proposed four-step sequential reaction pathway is delineated in Scheme 1. As previously described, the complex-induced proximity effect (CIPE) mediated LDA deprotonation of ester 1d via the eight-membered transition state (3) afforded the high levels of dr for both the alkene moieties (C1−C2 and C3−C4) resident in the extended lithium enolate 4.9 Subsequent complete transmetalation, by means of the
addition of Chx2BCl (4.2 equiv), allowed for the presumed formation of the boron dieneolate while retaining the important C1−C2 and C3−C4 olefin stereochemistries.12 Thus, upon the sequential addition of propanal to the boron enolate, it was postulated that the ensuing aldol addition proceeded via the Zimmerman−Traxler transition state (5), C
DOI: 10.1021/acs.orglett.9b00069 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
elimination mechanism post aldol addition. Results from these efforts will be reported in due course.
Scheme 1. Proposed Four-Step Reaction Pathway Elucidating the Stereoselective Formation of Diene 2f from Ester 1d
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00069. Experimental procedures and spectroscopic data for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Michael P. Jennings: 0000-0002-1069-6246 Author Contributions †
M.S.P. and D.A.J. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Support for this project was provided by the University of Alabama. REFERENCES
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thus transferring the enolate stereochemistry of 4 to the aldol adduct product 6.13,14 Final in situ basic oxidative workup of the borinate intermediate 6 furnished the conjugated diene product 2f in 61% yield. The dr of the product 2f was very high (>20/1) for both newly established alkenes. A few key points merit brief discussion. The aldol reaction was >99% regioselective for the more sterically congested α-carbon in lieu of the γ-carbon of the extended enolate.12 Second, isolation of the β-hydroxy aldol product was not possible; thus, the dr of the aldol adduct could not be directly determined (although postulated to be quite high based on literature precedence). Unfortunately, the precise mechanism of the stabilized Peterson elimination process remains unknown and open to conjecture.15 However, the dr of the newly formed olefins at C2−C3′ are highly dependent on the type of the enolate utilized for the aldol addition and/or covalent nature of the counterion of the aldol adduct (Li versus Chx2B).15 Our results strongly suggest that the final elimination pathway is highly stereospecific with respect to the stereochemistry of the initial aldol adduct 6. Regrettably, aromatic aldehydes do not provide the conjugated diene products in very high yields or dr at the C2−C3′ alkene moiety under the described reaction conditions in Tables 3 and 4. In conclusion, we have developed a stereoselective reaction process including a one-pot deconjugation, aldol, and stabilized Peterson olefination of α-trialkylsilyl-β-alkyl-α,β-unsaturated esters coupled with aliphatic aldehydes. The above-mentioned procedure afforded substituted conjugated diene products with dr values of 12−20:1 for the newly established alkene geometries in modest to good isolated yields. Future work will be centered on further elucidating the Peterson-type D
DOI: 10.1021/acs.orglett.9b00069 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.9b00069 Org. Lett. XXXX, XXX, XXX−XXX
