Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Syntheses of Unsymmetrical 1,4-Bifunctional Allylboron Reagents via Cu-catalyzed Highly Regio- and Stereoselective 1,4Protoboration of Dienylboronates and Analysis of the Origin of Chemoselective Aldehyde syn-(Hydroxymethyl)allylation Shang Gao, Mengzhou Wang, and Ming Chen*
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Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, United States S Supporting Information *
ABSTRACT: The syntheses of unsymmetrical 1,4-bifunctional allylboron reagents via Cu-catalyzed highly regio- and stereoselective 1,4-protoboration of dienylboronates were developed. The resulting allylboronates underwent chemoselective allylboration with aldehydes followed by oxidative workup to give diol products with high diastereoselectivity. Transition state analysis revealed that the disfavored transition states suffer from either a severe A1,3 allylic strain or 1,3-syn-pentane interactions. Minimization of such nonbonding 1,3-syn-pentane interactions is proposed to be the origin of observed chemoselectivity of the reaction.
A
bifunctional allylmetal reagents (Scheme 1) are particularly attractive because the product generated from the allyl addition to a carbonyl compound contains a homoallylic metal moiety that can engage in several classes of transformations.2 It offers a useful handle for further derivatization to give highly functionalized downstream products. While symmetrical 1,4bifunctional allylmetal reagents, such as A or B, can be prepared via olefin metathesis from the unsubstituted allylic reagents (Scheme 1),3,4 the syntheses of unsymmetrical ones (e.g., C or D) are more challenging. One important advance in this area was achieved by the Miyaura group using a Ptcatalyzed diboration of 1,3-conjugated dienes to synthesize (Z)-allylic boronates C ([Met] = Bpin, Scheme 1).5,6 More recently, an asymmetric variant of the reaction was developed by the Morken group.7 With a TADDOL-derived phosphonite7a or a chiral oxaphospholane as the ligand,7b unsymmetrical (Z)-1,4-dipinacolatoboron allylic reagents (e.g., 2, bottom panel, Scheme 1) were obtained with high enantioselectivities. We envisioned a complementary strategy that may also offer the entry to unsymmetrical (Z)-1,4-dipinacolatoboron allylic
llylic organometallics (B, Si, Sn) are highly important and versatile reagents in organic synthesis.1 Among these, 1,4-
Scheme 1. Approaches for the Syntheses of 1,4-Bifunctional Allylmetal Reagents
Received: November 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03483 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 2. Transition State Analysis for Chemoselective syn(Hydroxymethyl)allylation Reaction of 2a with PhCHO
Table 1. Evaluation of the Reaction Conditions for CuCatalyzed 1,4-Protoboration of Dienylboronate 1aa
entry
ligand
t (h)
Z:Eb
yield (%) (2a)c
1 2 3 4 5 6 7 8
Xantphos IMes·HCl ICy·HCl IPr·HCl SIPr·HCl IPr·HCld IPr·HCld,e no ligand
1 1 1 1 1 1 0.5 18
N.D. 4:1 5:1 10:1 9:1 >20:1 >20:1 N.D.
20:1) (Entry 6). A large-scale reaction (1 mmol) under the same reaction conditions provided (Z)-2a in 83% yield again with high Z/E ratio (Entry 7). In the absence of a ligand, the reaction did not form any appreciable amount of protoboration product even with prolonged reaction time (Entry 8). The optimal reaction conditions were then applied to 1,4protoboration of several dienylboronates (1b−e), and the results are summarized in Table 2. For dienylboronates 1b−d, the reactions were complete within 0.5 h, and the (Z)-isomers were obtained exclusively (Z:E > 20:1) in 68−87% yields. In the case of diene 1e, the conversion was very low; and only a trace amount of product 2e was observed after 24 h at ambient temperature. With allylboronates 2a−d in hand, studies on addition of these allyl reagents to aldehyde were conducted. As aforementioned, allylic boronates 2 have two sites (e.g., red and blue in 2a, Scheme 2) that in principle could add to a carbonyl compound to give a mixture of homoallylic alcohols. As depicted in Scheme 2, four alcohol products 3a−6a could be generated from the reaction between boronate 2a and benzaldehyde. Among the four competing transition states (TS-1 to TS-4) that lead to these four alcohol products, reactions via TS-1 or TS-2 occur at the less hindered site (red) to produce 3a or 4a, respectively, after oxidation. Reactions via
a
Reaction conditions: allyl boronate 2a (0.12 mmol, 1.2 equiv), aldehyde (0.1 mmol, 1.0 equiv), toluene (0.3 mL), rt. bThe diastereoselectivities were determined by 1H NMR analysis of the crude reaction products. cYields of isolated product are listed. dA small amount of Z isomer was observed (3−4%).
equiv of B2pin2, and 2 equiv of MeOH, protoboration of dienylboronate 1a at ambient temperature in toluene provided a complex mixture. Only a trace amount of product 2a (20:1 selectivity (Scheme 2). The data indicate that TS-1, which led to the formation of 3a, has the lowest energy among the four competing transition states, and the energy of TS-1 differs from TS-2, TS-3, or TS-4 by at least 1.8 kcal/mol at ambient temperature. Upon close examination of the four competing transition states, it is apparent that TS-2 is unfavorable because a severe A1,3 allylic strain12 is involved (shown in red in TS-2), and therefore, the formation of diol 4a is disfavored. In TS-3 and TS-4, the H atom at the secondary allylic carbon center of boronate 2a should project toward the six-membered ring of the transition states to minimize steric interactions. 14 Inevitably, 1,3-syn-pentane interactions13 between the phenyl group of the aldehyde and the methyl group of boronate 2 (TS-3), or the phenyl group of benzaldehyde and the pinacolatoboron unit of boronate 2 (TS-4), will be developed (shown in red in TS-3 and TS-4). Therefore, the formation of diol 5a or 6a is also disfavored. In contrast, no apparent nonbonding steric interaction is involved in TS-1. Consequently, the reaction of 2a and benzaldehyde proceeded through the favored transition state TS-1 to generate 3a selectively.15 Next we explored the scope of aldehydes that participate in the chemoselective (hydroxymethyl)allylation16 with boronate 2a. As summarized in Scheme 3, a variety of aldehydes including aromatic, heteroaromatic, and aliphatic aldehydes all reacted with 2a at ambient temperature to give diols 3a−p (after oxidative workup) in 60−96% yields with excellent diastereoselectivities and chemoselectivities (regioselectivity). In the cases of 3m−p, a small amount of Z isomers (e.g., 4) were also identified (∼3%). The olefin geometry of homoallylic alcohols 3 was assigned as E based on 1H NMR analysis of the coupling constant of the olefinic protons. The syn stereochemical relationship was assigned by 1H NMR and 13 C NMR analysis of the corresponding acetonides (please see Supporting Information for details). (Hydroxymethyl)allylation with other (Z)-1,4-dipinacolatoboron allylic reagents (2b−d in Table 2) was also examined, and the results are summarized in Scheme 4. The reactions between representative aldehydes and allylboronates 2b−d gave (E)-syn-adducts 3q−v in 59−95% yields with excellent diastereoselectivities. Formation of the Z isomers was not observed in these cases. It is worth noting that products 3u and 3v contain a benzyl-protected allylic alcohol unit, which, upon deprotection, can be used as a handle for C−C bond formation to elongate the carbon chain of diol products 3. In summary, we developed a Cu-catalyzed highly regio- and stereoselective 1,4-protoboration of dienylboronates to prepare unsymmetrical 1,4-bifunctional allylboronates. Subsequent chemoselective syn-(hydroxymethyl)allylation of aldehydes with these allylboronates followed by oxidative workup gave diol products with high chemo- and diastereoselectivities. Transition state analyses revealed that the disfavored transition states suffer from either an A1,3 allylic strain or 1,3-syn-pentane interactions. In contrast, these nonbonding steric interactions are not present in the favored transition state. Minimization of such unfavorable 1,3-syn-pentane interactions is presumably the origin of observed chemoselectivity of the syn(hydroxymethyl)allylation reaction. Synthetic application of this method will be reported in due course.
Letter
ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03483. Experimental procedures and spectra for all new compounds (PDF)
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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. Some of the high-resolution mass spectra were obtained from a spectrometer supported by NSF Award 1427720. We thank AllylChem for a generous gift of B2pin2.
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REFERENCES
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Letter
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DOI: 10.1021/acs.orglett.8b03483 Org. Lett. XXXX, XXX, XXX−XXX
