Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Stereoselective Syntheses of (E)‑γ′,δ-Bisboryl-Substituted synHomoallylic Alcohols via Chemoselective Aldehyde Allylboration Mengzhou Wang,‡ Shang Gao,‡ and Ming Chen* Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, United States
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S Supporting Information *
ABSTRACT: The development of a novel (Z)-α,δ-bisboryl-substituted crotylboron reagent is reported. Ni-catalyzed 1,4-diboration of dienylboronate provided the targeted crotylboronate in good yield with high regio- and stereoselectivity. Chemo- and stereoselective addition of this crotylboron reagent to aldehydes followed by protection of the resulting secondary hydroxyl group gave TES-protected homoallylic alcohols bearing an alkyl and a vinyl boronate groups with high stereoselectivities. Scheme 2. Recent Development of α-Boryl-Substituted Allylboron Reagents
C
arbonyl addition with allylmetal reagents is an important transformation to synthesize acyclic molecules with contiguous stereocenters.1 However, the classic crotylation of carbonyl compounds, aldehydes, for instance, produces homoallylic alcohol products (e.g., II, Scheme 1) with a Scheme 1. Classic Aldehyde Crotylboration vs Reaction with α-Metal Substituted Crotylboron Reagents
terminal olefin unit that often requires a multistep manipulation to enable a subsequent C−C bond-forming event to give product III.2 In contrast, the reaction of carbonyl compounds with α-metal (B, Si, Sn) substituted (or 1,1-bismetallic) allylation reagents will provide homoallylic alcohols with a functionalized alkene group that can directly engage in a C−C bond formation reaction.3−7 In particular, reactions of α-metalsubstituted allylboron reagents5,6 (i.e., IV, Scheme 1) with carbonyl compounds proceed through the well-established Zimmerman−Traxler transition state8 to deliver homoallylic alcohol products V. The α-substituent (Met) in the starting reagent is transformed into a vinyl metal unit in product V, which under proper conditions, can directly cross couple with an electrophile to give product III by forging a C−C bond (Scheme 1). Therefore, by using such reagents (i.e., IV), the multistep functional group transformation can be eliminated, and synthetic strategies can often be substantially simplified. A new class of such 1,1-bismetallic allylation reagents that have recently emerged is α-pinacolatoboron-substituted crotylboronate B (Scheme 2).9 Murakami demonstrated © XXXX American Chemical Society
recently that reagent B, (E)-α-boryl-crotylboronate, can be generated via a Pd-catalyzed alkene transposition from the homoallylic bisboronate precursor. In the presence of a chiral Received: February 3, 2019
A
DOI: 10.1021/acs.orglett.9b00461 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters phosphoric acid catalyst, (R)-A, allylation of aldehydes with in situ generated reagent B formed (E)-δ-boryl-anti-homoallylic alcohols with high selectivities (eq 1, Scheme 2).9a A Rucatalyzed alkene transposition was also developed by the Murakami group to produce crotylboronate B with excellent (E)-selectivity. Subsequent one-pot chiral phosphoric acid (R)A catalyzed asymmetric aldehyde addition gave anti-1,2oxaborinan-3-enes with high enantioselectivities (eq 2, Scheme 2).9b Cho and co-workers independently showed that, by using [Ir(COD)2]OTf as the catalyst, crotylboron reagent B can be isolated in good yield with high (E)-selectivity through alkene transposition. Addition of crotylboron reagent B to aldehydes furnished racemic anti-1,2-oxaborinan-3-enes with high diastereoselectivities (eq 3, Scheme 2).9c In spite of these recent advances on the synthesis of (E)-αboryl-crotylboronate B, there is no available method that allows for efficient synthesis of (Z)-α-boryl-substituted crotylboronates (e.g., 2, Scheme 2), and stereoselective synthesis of boryl-substituted syn-homoallylic alcohols (e.g., 3) through allylation remains an unsolved problem. In line with our research interest in allylboron chemistry,10 we have developed and report herein stereoselective synthesis of (Z)α,δ-bisboryl crotylboronate 2 (Scheme 2) to address this challenge. Under the developed conditions, reagent 2 can be prepared with excellent stereoselectivity. Subsequent aldehyde allylboration with this novel reagent followed by protection of the resulting secondary hydroxyl group gave TES-protected (E)-syn-homoallylic alcohols 3 in good yields with excellent selectivities (eq 4, Scheme 2). This reaction is valuable because homoallylic alcohol product 3 has several functional groups. The vinyl boronate unit in 3 can be used directly in subsequent C−C bond forming reactions, and the alkyl-Bpin group also provides an additional handle for further functionalization. We envisioned a transition-metal-catalyzed dienylboronate 1,4-diboration approach to prepare of (Z)-α,δ-bisboryl crotylboronate 2.11,12 It has been shown by Miyaura that Ptcatalyzed diboration of penta-1,3-diene gave either 1,4- or 1,2diboration product selectively depending on the choice of a Pt catalyst.11b When Pt(PPh3)4 was used as the catalyst, 1,4diboration product was obtained with high regioselectivity at 80 °C in toluene. However, when the protocol was adopted with dienylboronate 113 as the substrate, a 3:1 inseparable mixture of 1,4-adduct 2 and 1,2-adduct C was obtained in a combined 65% yield (entry 1, Table 1). The Morken group demonstrated that 1,4-diboration of conjugated dienes can be achieved with high selectivity using a Ni catalyst.12 Inspired by this work, we conducted studies on Ni-catalyzed diboration of dienylboronate 1. In the presence of 10 mol % of Ni(COD)2, 10 mol % PCy3, and 1 equiv of B2Pin2, the reaction with 1 exclusively formed 1,4-diboration product 2 in THF at ambient temperature (2/C > 20:1). However, the conversion was moderate even after stirring for 48 h, and boronate 2 was isolated in 40% yield (entry 2, Table 1). Gratifyingly, the reaction was complete within 24 h when conducted at 50 °C, and 1,4-diboration product 2 was obtained in 63% yield with excellent selectivity (>20:1) (entry 3, Table 1). Increasing the loading of ligand to 20 mol % only marginally improved the yield of 2 (entry 4, Table 1). However, a 1 mmol scale reaction under identical reaction conditions provided 2 in 77% yield again with >20:1 stereoselectivity (entry 5).14 With boronate 2 in hand, subsequent studies on aldehyde allylboration with 2 were conducted. In theory, the reaction of boronate 2 with benzaldehyde followed by protection of the
Table 1. Synthesis of (Z)-α,δ-Bisboryl Crotylboronate 2
entry
conditions
ratio (2/C)c
yield (%) (2 + C)d
a
Pt(PPh3)4, toluene, 80 °C Ni(COD)2, PCy3, THF, rt Ni(COD)2, PCy3, THF, 50 °C Ni(COD)2, PCy3, THF, 50 °C Ni(COD)2, PCy3, THF, 50 °C
3:1 >20:1 >20:1 >20:1 >20:1
65 40 63 67 77
1 2b 3b 4e 5b,f a
Dienylboronate 1 (0.1 mmol, 1 equiv), Pt(PPh3)4 (3 mol %), B2pin2 (0.11 mmol, 1.1 equiv), toluene (0.2 mL), 80 °C. bDienylboronate 1 (0.1 mmol, 1 equiv), Ni(COD)2 (10 mol %), PCy3 (10 mol %), B2pin2 (0.1 mmol, 1 equiv), THF (0.2 mL). cThe regioselectivities were determined by 1H NMR analysis of the crude reaction products. d Yields of isolated products are listed. eDienylboronate 1 (0.1 mmol, 1 equiv), Ni(COD)2 (10 mol %), PCy3 (20 mol %), B2pin2 (0.1 mmol, 1 equiv), THF (0.2 mL). fThe reaction was conducted on a 1 mmol scale at 50 °C.
secondary hydroxyl group could produce a mixture of three protected homoallylic alcohol products 3a−5a (Scheme 3). In Scheme 3. Transition-State Analyses for Selective Formation of Allylation Product 3a
initial experiments, the reaction of benzaldehyde with 1.5 equiv of boronate 2 and subsequent protection of the hydroxyl group provided TES-protected (E)-γ′,δ-bisboryl-syn-homoallylic alcohol 3a as the major product (dr > 20:1) in 87% yield. A small quantity (∼3%) of 5a was also isolated. Formation of product 4a was not detected. The olefin geometry in product 3a was assigned as E based on 1H NMR analysis of the coupling constant of olefinic protons. The stereochemical B
DOI: 10.1021/acs.orglett.9b00461 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters relationship of 3a was assigned as syn based on 1H NMR analysis of the coupling constant of the corresponding acetonide 10 (see Scheme 6 for details). It should be noted that the unprotected homoallylic alcohol product is unstable toward flash column chromatography. The TES ethers (3a, 5a) are perfectly stable for chromatography purification (vide infra). The observed chemoselectivity of this reaction can be rationalized by the following transition-state analyses. Among the three competing transition states (TS-1−TS-3, Scheme 3) that lead to the formation of products 3a−5a, TS-2 suffers an A1,3 allylic strain15 between the pseudo axially oriented −Bpin group and the −CH2Bpin group (shown in light blue in TS-2). TS-3 suffers a nonbonding 1,3-syn-pentane interaction16 between one −Bpin group of the boron reagent 2 and the phenyl group of benzaldehyde (shown in light blue in TS-3). Therefore, formation of product 4a or 5a is disfavored. By contrast, no apparent steric interaction is involved in TS-1. As a result, allylation of benzaldehyde with reagent 2 proceeded through the lowest energy pathway TS-1 to give product 3a with high selectivity upon protection of the hydroxyl group. Next, we explored the scope of aldehyde that participates in the chemoselective allylation with boronate 2. As summarized in Scheme 4, a variety of aldehydes including aromatic, heteroaromatic, and aliphatic aldehydes all reacted with reagent 2 at ambient temperature in toluene. Subsequent protection of the secondary hydroxyl group with TESCl gave products 3a−o in 78−93% yield with excellent E/Z selectivities and high diastereoselectivities (3/5 > 10:1). In the case of 3p, a moderate selectivity (3p/5p = 6:1) was observed. As illustrated in Scheme 5, the moderate selectivity is presumably due to less severe steric interactions between the −Bpin group of reagent 2 and the −CH2 group of the aldehyde in transition state TS-4 (compared to the interaction between −Bpin and −Ph groups in TS-3 shown in Scheme 3). The reaction of 2 with α- or β-substituted aliphatic aldehydes, however, gave products 3m−o with much higher selectivities (>20:1). In these cases, the high selectivities are likely the results of a much more severe steric interactions between the −Bpin and a secondary alkyl groups in a transition state analogous to TS-4. The products generated from chemoselective allylation contain a vinyl- and an alkyl-Bpin group that can undergo a variety of further transformations. As shown in Scheme 6, the vinyl boronate unit in product 3d was converted into a vinyl iodide group in 84% yield.17 Vinyl iodide 6 should be able to react with aryl or vinyl nucleophiles in transition-metalcatalyzed cross-coupling reactions. On the other hand, the vinyl boronate unit can be directly used in cross-coupling reactions to form a C−C bond. For example, Pd-catalyzed Suzuki coupling of 3a with (Z)-vinyl iodide 7 gave diene 8 in 67% yield.18 Pd-catalyzed cross-coupling reaction of 3a with PhI provided product 9 in 76% yield with the alkyl-Bpin group intact.9b,19 Subsequently, a three-step reaction sequence furnished acetonide 10 in 75% yield. The syn-relative stereochemistry of 3a was supported by 1H NMR analysis of the coupling constant between Ha and Hb in acetonide 10 (Scheme 6). Additionally, the alkyl boronate unit in product 3 also provides a handle for further transformation. For instance, compound 9 underwent Matteson homologation20 to provide boronate 11 in 64% yield. Zweifel olefination21 of 9 gave 1,5diene 12 in 78% yield with excellent chemoselectivity; iodination of the alkene group in 9 was not observed.
Scheme 4. Scope of Aldehyde for Chemoselective Allylation with Boronate 2a−c
a
Reaction conditions: crotyl boronate 2 (0.15 mmol, 1.5 equiv), aldehyde (0.1 mmol, 1.0 equiv), toluene (0.3 mL), rt, then TESCl (0.15 mmol, 1.5 equiv), imidazole (0.2 mmol, 2 equiv), rt. bThe diastereoselectivities and E/Z selectivities were determined by 1H NMR analysis of the crude reaction products. cYields of isolated products are listed. dThe reactions were conducted at 0 °C.
In summary, we developed a Ni-catalyzed 1,4-diboration of dienylboronate to prepare (Z)-α,δ-bisboryl crotylboronate with high selectivity. Subsequent chemoselective allylboration of aldehydes with this novel allylboron reagent 2 followed by protection of the secondary hydroxyl group gave TESC
DOI: 10.1021/acs.orglett.9b00461 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
allylation using reagent 2 is currently ongoing.22 Synthetic application of this method will be reported in due course.
Scheme 5. Transition-State Analysis for the Moderate Selectivity in the Case of 3p (Formation of Byproduct 5p)
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00461. Experimental procedures; spectra for all new compounds (PDF)
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Scheme 6. Transformation of the Reaction Products
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shang Gao: 0000-0001-8166-5503 Ming Chen: 0000-0002-9841-8274 Author Contributions ‡
M.W. and S.G. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support provided by Auburn University is gratefully acknowledged. We thank AllylChem for a generous gift of B2pin2.
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REFERENCES
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protected (E)-γ′,δ-bisboryl-syn-homoallylic alcohols 3 in good yields with high diastereoselectivities. Transition-state analyses revealed that minimization of A1,3 allylic strain or nonbonding 1,3-syn-pentane interactions is the origin of the observed chemoselectivity. Importantly, products 3 have vinyl- and alkylBpin groups that are amenable to a variety of subsequent transformations. The vinyl boronate group in 3 can directly engage in C−C bond-forming reactions, and its chemical reactivities are often orthogonal to those of the alkyl-Bpin group. The alkyl boronate group in 3 also offers an additional handle for functional group transformations. Asymmetric D
DOI: 10.1021/acs.orglett.9b00461 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.9b00461 Org. Lett. XXXX, XXX, XXX−XXX
