Letter Cite This: Org. Lett. 2018, 20, 3810−3814
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Enantioselective Syntheses of Homopropargylic Alcohols via Asymmetric Allenylboration Mengzhou Wang, Shahriar Khan, Evangelos Miliordos, and Ming Chen* Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, United States
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S Supporting Information *
ABSTRACT: A chiral phosphoric acid catalyzed allenylboration reaction is reported. Homopropargyl alcohols with an internal alkyne unit were obtained in good yields with high enantioselectivities under the developed conditions.
C
would provide such molecules directly (eq 2, Scheme 1). Although many reagents have been developed to produce homopropargylic alcohols with a terminal alkyne moiety,4−7 approaches to access homopropargylic alcohols with an internal alkyne group (e.g., 2), particularly catalytic asymmetric variants, are generally lacking.8,9 Corey reported an allenyl boron reagent8a that produces alcohols 2 with high enantioselectivity, but the preparation of such a boron reagent requires a stoichiometric amount of chiral diamine and a propargyltin agent. Another chiral auxiliary-based allenyl boron reagent was developed by the Soderquist group.8b However, a multistep synthesis, including a resolution step, is required for the preparation of this air- and oxygen-sensitive boron reagent. A Sc(OTf)3-catalyzed asymmetric addition of an allenyl silicon reagent to a carbonyl group was reported by Evans, although the scope of the carbonyl compounds is limited to ethyl glyoxylate.8c Therefore, the development of a catalytic, asymmetric method to address this problem would be valuable. In connection with an ongoing problem in natural product synthesis, we became interested in asymmetric propargylation with 1-substituted allenylboronate reagents (1 in Scheme 1). We envisioned that enantioenriched homopropargylic alcohols 2 should be accessible from the addition of boronates 1 to aldehydes through the proper control of enantioselectivity by a suitable chiral catalyst. Inspired by the work of Antilla10a and Reddy10b on chiral, nonracemic phosphoric acid catalyzed allenylboration reactions,10,11 we report herein enantioselective syntheses of homopropargyl alcohols 2 via the reaction of aldehydes with allenylboronates 1 (eq 3, Scheme 1). We initiated our studies by examining the reaction conditions for asymmetric allenylboration of benzaldehyde with boronate
hiral, nonracemic homopropargylic alcohols (with an internal alkyne moiety, i.e. 2, Scheme 1) are highly
Scheme 1. Approaches to Enantioenriched Homopropargylic Alcohols with an Internal Alkyne Moiety
valuable intermediates in organic syntheses.1 Nucleophilic addition of lithiated terminal alkynes to enantioenriched epoxides is one traditional approach to synthesize these compounds (eq 1, Scheme 1).2 However, this method requires the syntheses of enantiomerically pure terminal epoxides, which often involves resolution or a multistep synthesis.2,3 Additionally, the strong basicity of organo-lithium reagents limits its functional group compatibility. On the other hand, asymmetric aldehyde addition with 1-substituted allenyl metal reagents © 2018 American Chemical Society
Received: May 3, 2018 Published: June 13, 2018 3810
DOI: 10.1021/acs.orglett.8b01399 Org. Lett. 2018, 20, 3810−3814
Letter
Organic Letters 1a. We chose phosphoric acid A1 as the catalyst, which is known for its superior enantioselection in asymmetric allylboration and allenylboration reactions.10,11a−d In the event, treatment of benzaldehyde with allenylboronate 1a (1.2 equiv) in toluene at −45 °C for 48 h in the presence of 5 mol % of phosphoric acid A112 and 4 Å molecular sieves provided homopropargyl alcohol 2a in 94% yield with 95% ee (entry 1, Table 1). The reaction without the addition of 4 Å
Scheme 2. Scope of the Asymmetric Allenylboration of Aldehydes with 1a Catalyzed by Phosphoric Acid (R)-A1a,b,c
Table 1. Evaluation of the Reaction Conditions of Allenylboronate 1a with Benzaldehydea
entry
variation of conditions
yield (%)b
ee (%)c
1 2 3 4 5
none no 4 Å MS Et2O as the solvent THF as the solvent CH2Cl2 as the solvent
94 94 88 75 81
95 83 80 50 55
a Reaction conditions: allenyl boronate 1a (0.12 mmol, 1.2 equiv), benzaldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A1 (5 mol %), 4 Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h. b Yields of isolated products were listed. cEnantioselectivities were determined by HPLC analysis using a chiral stationary phase.
molecular sieves under otherwise identical conditions gave product 2a in 94% yield with 83% ee (entry 2, Table 1). Reactions in other solvents such as diethyl ether, THF, or CH2Cl2 gave 2a in good yields, although with much lower enantioselectivity (entries 3−5, Table 1). The reaction conditions developed for the synthesis of 2a were then applied to allenylboration of a variety of aldehydes with boronate 1a, and the results are summarized in Scheme 2. Asymmetric allenylboration of aromatic aldehydes bearing either electron-donating or -withdrawing substituents at the para-position of the arene provided products 2b−f in 86−98% yields with 97−98% ee. para-Halogen-substituted aromatic aldehydes reacted to afford homopropargyl alcohols 2g−i in 70−84% yields with 97% ee. Similar results were obtained from aldehydes with other substitution patterns, and alcohols 2j−n were formed in 70−95% yields with 92−98% ee. Aldehydes that contain a heterocycle, for example, a thiophenyl group, reacted with 1a to furnish product 2o in 90% yield. Reactions with α, β-unsaturated aldehydes also occurred to give alcohols 2p−r in 79−91% yields with 81−98% ee. It should be noted that reactions with aliphatic aldehydes, such as hydrocinnamic aldehyde, provided products with low enantioselectivities under the current reaction conditions. It is well-established that a double stereodifferentiation reaction is a useful method to produce diastereomeric products with high selectivity.13 To probe whether different diastereomers can be formed selectively by utilizing either acid (R)-A1 or (S)-A1 as the catalyst under the current catalytic system, studies on reactions of enantioenriched aldehydes 3a and 3b with boronate 1a were conducted. As shown in Scheme 3, in the absence of any acid catalyst, the reaction of (S)perillaldehyde (3a) with 1a gave a 1:1 mixture of homopropargyl alcohols 4a and 5a in 88% yield. Similarly, the reaction of (R)-myrtenal (3b) with 1a provided a 1:1.2 mixture of alcohol products 4b and 5b in a combined 93%
a Reaction conditions: allenyl boronate 1a (0.12 mmol, 1.2 equiv), aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A1 (5 mol %), 4 Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h. b Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. cYields of isolated products were listed.
yield, slightly favoring isomer 5b. In the presence of 5 mol % of phosphoric acid (R)-A1, the reaction of (S)-perillaldehyde (3a) with 1a occurred with complete catalyst control to give product 4a in 83% yield with >20:1 diastereoselectivity. When the enantiomeric acid (S)-A1 was used as the catalyst, diastereomer 5a was obtained in 78% yield, and again with >20:1 diastereoselectivity. Similarly, asymmetric reactions of (R)myrtenal (3b) with 1a also proceeded under catalyst control. With (R)-A1 as the catalyst, alcohol 4b was obtained in 74% yield with 12:1 dr, while alcohol 5b was generated in 83% yield with 15:1 dr when acid (S)-A1 was utilized. Studies on asymmetric reactions with allenylboronates bearing other substituents (1b−c) were also conducted, and the results are summarized in Scheme 4. In the presence of 5 mol % of phosphoric acid (R)-A1, reactions of several aldehydes with boronate 1b or 1c occurred to give products 6a−h in 61− 92% yields with 90−96% ee. The absolute configuration of the 3811
DOI: 10.1021/acs.orglett.8b01399 Org. Lett. 2018, 20, 3810−3814
Letter
Organic Letters Scheme 3. Double Stereodifferentiation Reactions of Chiral Aldehydes with Boronate 1a Catalyzed by Acids A1a,b,c
a Reaction conditions: allenyl boronate 1a (0.12 mmol, 1.2 equiv), aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A1 or (S)-A1 or (5 mol %), 4 Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h. bDiastereoselectivities were determined by 1H NMR analysis of the crude reaction product. cYields of isolated products were listed.
Scheme 4. Scope of the Asymmetric Allenylboration with Boronates 1b−c Catalyzed by Phosphoric Acid (R)-A1a,b,c
a
Reaction conditions: allenyl boronate 1b or 1c (0.12 mmol, 1.2 equiv), aldehyde (0.1 mmol, 1.0 equiv), phosphoric acid (R)-A1 (5 mol %), 4 Å molecular sieves (50 mg), toluene (0.3 mL), −45 °C, 48 h. bEnantioselectivities were determined by HPLC analysis using a chiral stationary phase. cYields of isolated products were listed. dThe ee was determined by modified Mosher ester analysis.14 Pen: n-pentyl.
Figure 1. Computational studies of the transition states of the asymmetric allenylboration reaction.
secondary hydroxyl groups in the products was determined by modified Mosher ester analysis of 6f and 6g.14 To probe the origin of the asymmetric induction of the reaction, density functional theory (DFT) calculations of the transition states (TS-1−TS-4) of the allenylboration reaction were performed. As illustrated in Figure 1, in the four
competing transition states, catalyst (R)-A1 can either coordinate to the aldehyde−boronate complex through hydrogen bonding in a bidentate fashion (e.g., TS-1, TS-3) or only bind to the boronate oxygen atom in the pseudo-equatorial position (e.g., TS-2, TS-4).15 Among these transition states, TS-1 is favored over the other three by more than 2.5 kcal/mol, 3812
DOI: 10.1021/acs.orglett.8b01399 Org. Lett. 2018, 20, 3810−3814
Organic Letters
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which is in good accordance with the experimental data. The computational data support that the reaction proceeds through the lowest energy transition state TS-1 to give product 2. It is well documented that enantioenriched homopropargyl alcohols are highly valuable intermediates in the context of complex molecule syntheses, as well as the production of pharmaceutical agents.16 The alkyne group can be utilized in a variety of C−C forming reactions, such as cross-coupling reactions and alkyne ring-closing metathesis.16,17 Furthermore, the alkyne unit can also be conveniently transformed into several functional groups. For instance, reduction of homopropargyl alcohol 2a with LiAlH4 at 90 °C gave (E)-homoallylic alcohol 7 in 88% yield with 15:1 selectivity (eq 1, Scheme 5).
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ming Chen: 0000-0002-9841-8274 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support provided by Auburn University is gratefully acknowledged. We thank the Schneller, the Merner and the Gordon groups at Auburn University for sharing the chemicals, and AllylChem for a generous gift of B2Pin2.
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Scheme 5. Transformation of the Reaction Products
REFERENCES
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(Z)-Homoallylic alcohol 8 was also prepared from 2a with high Z-selectivity using Schwartz’s reagent (eq 2, Scheme 5). Under the conditions developed by the Ready group,18 2a was converted to vinyl iodide 9 in 56% yield with excellent selectivity (eq 3, Scheme 5). In addition, the alkyne moiety in homopropargyl alcohol 2 often exhibits orthogonal reactivities to other functional groups. For example, the aryl bromide moiety of homopropargyl alcohol 2h underwent Suzuki− Miyaura cross-coupling to give product 10 with the alkyne unit intact (eq 4, Scheme 5). In summary, we developed a chiral phosphoric acid catalyzed aldehyde allenylboration reaction. Under the optimized conditions, homopropargyl alcohols with an internal alkyne unit were obtained in good yields with high enantioselectivities. The alkyne moiety in the products can be readily converted into several functional groups. Computational studies were conducted to probe the origin of enantioselectivity of the reaction. Synthetic applications of this method will be reported in due course.
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Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01399. Experimental procedures, spectra for all new compounds (PDF) 3813
DOI: 10.1021/acs.orglett.8b01399 Org. Lett. 2018, 20, 3810−3814
Letter
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DOI: 10.1021/acs.orglett.8b01399 Org. Lett. 2018, 20, 3810−3814
