Regioselective trans-Carboboration of Propargyl Alcohols

Proper choice of the base allowed trans-diboration of propargyl alcohols with B2(pin)2 to evolve into an exquisitely regioselective procedure for net trans-carboboration. The method is modular as to the newly introduced carbon substituent (aryl, methyl, allyl, benzyl, alkynyl), which is invariably placed distal to the −OH group.

very functional group tolerant and has already stood the test of total synthesis. 3 For its exquisite regioselectivity, however, the procedure does not broker formation of the isomeric motif D (R = Me), which is equally prominent in the polyketide estate.
Inspired by a literature report, 4 we saw an opportunity to attain compounds of type D via formal trans-carboboration, although broadly applicable manifestations of this type of reactivity are exceedingly rare. 5−10 Specifically, it is known that propargyl alcohols such as 1a, on deprotonation with nBuLi, followed by reaction with B 2 (pin) 2 in THF at increased temperature, undergo trans-selective diboration to give 4borylated 1,2-oxaborolol derivatives 3a after hydrolytic workup (Scheme 2). 4,11 The reaction likely passes through the mixed ate-complex 2a; in one case, this putative intermediate has been subjected to subsequent Suzuki coupling 12 with 4-tolyl iodide in the presence of catalytic palladium and aqueous KOH as a promoter. In the present context, it is important to note that both boron sites of 2a reacted under these conditions to give the tetrasubstituted alkene 4a in 64% yield. 4 Because ate-complexes per se are competent intermediates for cross-coupling, 12 we surmised that addition of excess base might actually be unnecessary. Rather, advantage could be taken of the distinct chemical character to the two boron centers in a compound of type 2: cross-coupling should occur selectively at the endocyclic borate site, whereas the tricoordinate boron moiety is expected to persist in the absence of external base; if so, many opportunities for downstream functionalization can be envisaged. As the borate site does not survive workup (see the formation of product 3a), any such selective derivatization is contingent on the ability to generate and manipulate an atecomplex of type 2 in "one pot".
In most cases, the boracycle 3b was formed as the major product; it was accompanied by varying amounts of the protodeborylated compound 4b but only tracesif anyof the desired product 5b.
In an attempt to rationalize this renitence, we wondered whether the borate subunit in 2 actually subsists under the chosen conditions. Earlier work from this laboratory on the "9-MeO-9-BBN variant" of the Suzuki reaction showed that the stability of ate-complexes of type 7 derived from the highly Lewis acidic 6 and polar organometallic reagents R−M is strongly cation-dependent (Scheme 3). 13, 14 The ease of scrambling complex 7 as the competent nucleophile for crosscoupling into unproductive 8 and 9 roughly follows the order: Na + ≈ K + < Li + ≪ MgX + , ZnX + . The analogous equilibration of the borate unit in 2 is arguably more facile because it derives from an inherently much less Lewis acidic RB(OR) 2 entity. 15 Under this premise, a lithium counterion is unlikely to be the ideal escort as the neutral boron species 2′ might be favored, which will not engage in cross-coupling in the absence of an external base. Therefore, we rescreened different counterions with the hope of stabilizing the critical borate intermediate 2, even though the original report on trans-diboration had identified nBuLi as the optimal promoter. 4 In accord with the empirical order observed in our previous study, 13,14 replacement of nBuLi by NaHMDS 16 opened the doorway to the desired net trans-carboboration chemistry ( Table 1; for further details, see the Supporting Information). In a first foray, trans-diboration was merged with classical Suzuki-type sp 2 −sp 2 coupling: to this end, the use of diaryliodonium salts in combination with Pd 2 (dba) 3 /P(2furyl) 3 proved optimal. Although the reaction proceeded well in 1,4-dioxane in many cases, the use of 1,2-dichloroethane/ THF (10 equiv) was found to be more general (Figure 1). The crude products are usually very clean, but partial loss of material upon flash chromatography on silica diminishes the isolated yields. In the case of tert-propargyl alcohols as the substrates, the basic conditions can entail retro-alkynylation, leading to the formation of the corresponding ketones as minor impurities.
The functional group compatibility is remarkable in that preexisting aryl bromides or chlorides remained intact, regardless whether they originate from the propargyl alcohol substrate or from the transferred aryl substituent; conceivable oligomerization of the resulting products carrying a C−X as well as a C−B unit was not observed. This favorable outcome shows that the residual tricoordinate boron substituent in the product formed is "silent" in the absence of an external base, whereas the ate site of transient 2 (M = Na) readily engages in cross-coupling. 17 The excellent regioselectivity harnessed in reactions of 1,3-enyne or even 1,3-diyne substrates is an additional asset: only the propargylic triple bond undergoes carbometalation, whereas an additional site of unsaturation does not interfere.
The new procedure also lends itself to the introduction of a methyl substituent at the distal propargylic C atom; a slightly modified catalyst system (Pd 2 (dba) 3 /P(1-nap) 3 in 1,4-dioxane) in combination with MeI gave the best results (Figure 2 and Supporting Information). In all cases investigated, C−C bond    formation occurred exclusively distal to the alcohol substituent. Extensive NMR investigations and crystallographic data confirmed connectivity and double bond geometry of the products (for the structures of compounds 3b, 5b,n, and 10i in the solid state, see the Supporting Information). Once again, the observed regio-and stereoselectivities were excellent as were the functional group tolerance; moreover, the method scales well. It is important to note that O-methylation of the propargylic alcohol substrate did not interfere with productive transmethylboration to any noticeable extent, which indicates a perfect orchestration of events along the reaction coordinate. For this very reason, other reactive electrophiles are equally competent partners (Figure 3). Specifically, allyl and benzyl bromide could be used without O-alkylation intervening. Likewise, the incorporation of an alkynyl substituent was successful; the resulting enynes 13 are regioisomeric to the products formed by the transition-metal-free trans-alkynylboration using RCC−B(pin) as the reagent recently described in the literature. 5 Overall, these data show that the concept underlying this new trans-carboboration manifold is pleasingly general, although its different incarnations require some catalyst optimization. Further extensions are subject to ongoing investigations in our laboratory.
The alkenyl boronate products thus formed lend themselves to numerous downstream transformations; 18 only a few possibilities are shown in Scheme 4: (i) Although protodeborylation of 10 "wastes" the valuable C−B bond, it leads to the important polyketide motif D cited in the introduction; as shown for product 14, the reaction can be readily achieved using catalytic AgNO 3 . 19 (ii) Addition of aq NaOH "arms" the remaining boron atom in 10 for cross-coupling with a second electrophilic partner. In this manner, two dif ferent hydrocarbyl residues can be stitched trans to each other across the triple bond; 20 the resulting tetrasubstituted alkenes such as 15 are difficult to make in rigorously stereodefined format by other means. 21 This aspect is highlighted by the concise approach to compound 22, which is a key metabolite of the nonsteroidal estrogen receptor modulator idoxifen (Scheme 5); 22 this example further substantiates the compatibility of the method with alkyl as well as aryl halides. (iii) Oxidation of the C−B bond 23 in 10 unmasks the corresponding acyloin 16, whereas directed epoxidation affords the building block 17 with high diastereoselectivity. 24 (iv) Addition of catalytic amounts of Sc(OTf) 3 as an oxophilic Lewis acid activates the allylic −OH group of 5c without damaging the C−B bond as evident from the intramolecular Friedel−Crafts alkylation, furnishing the borylated indene 18. 25 (v) Finally, we note that the triple bond of compounds 13 constitutes yet another valuable handle for functionalization; the formation of the tetrasubstituted bory-    26,27 In summary, a robust yet modular procedure for net carboboration of propargyl alcohols is reported. The transformation is distinguished by the unorthodox trans-addition mode and benefits from exquisite regio-and chemoselectivity. For these virtues and for the multifaceted character of the resulting products, we expect that the new method qualifies for many applications. Studies along these lines are currently ongoing in our laboratory.

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01225.
Experimental section including characterization data, NMR spectra of new compounds, and supporting crystallographic data (PDF)

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
Generous financial support by the MPG is gratefully acknowledged. We thank Prof. C. W. Lehmann and Mr. J. Rust, at this institute, for solving the X-ray structures in the Supporting Information.