By
requirements for the degree of
Doctor of Philosophy
Committee in charge:
Professor F. Dean Toste, Chair Professor K. Peter C. Vollhardt Professor Benito O. de Lumen
Fall 2013
By
University of California, Berkeley
Professor F. Dean Toste, Chair
The activation of relatively unreactive carbon-carbon (C-C) multiple bonds is an important tool for the introduction of functional groups and stereochemical information in organic molecules. In recent years, the use of electrophilic cationic gold(I) complexes for the functionalization of alkynes and allenes has seen rapid development. An especially general application of gold catalysis is the nucleophilic trapping of gold-activated π bond to give a heterocyclic compound. In the case of allenes, chiral ligands have been used to generate product with excellent enantiocontrol. In the first part of this Thesis we report studies on the development of an enantioselective cyclization using the gold-catalyzed transformation of propargyl esters to generate allenes in situ. A subsequent gold-catalyzed dynamic kinetic asymmetric cyclization of a phenol onto the allene resulted in the generation of enantioenriched cyclized chromanone derivatives from racemic starting material. The optimal catalyst for this transformation was a (biscarbene)digold(I) complex, which delivered better enantioselectivities than previously known phosphine-gold and phosphoramidite-gold complexes.
Electrophilic sources of the halogens (fluorine, chlorine, bromine, and iodine) activate C-C multiple bonds in much the same way as gold(I) complexes, but the electrophilic atom of the reagent is incorporated into the final product. Because halogen atoms are amenable to further functional group manipulation and are also present in complex natural products, the enantioselective synthesis of halofunctionalized products from alkenes is an important synthetic goal. Typically, enantioselectivity is achieved using a chiral catalyst to activate the electrophilic reagent. However, high enantioselectivities may be hampered by uncatalyzed background reactivity. The Toste research group has introduced a new approach for electrophilic functionalization (chiral anion phase transfer catalysis) by inducing ion pairing between a phosphate anion chiral source and a cationic electrophilic reagent by phase transfer. This concept was initially demonstrated for fluorination, using the cationic reagent F-TEDA-BF4 (Selectfluor®). In the second part of the Thesis, we report studies on the extension of this strategy to the heavier halogens. With the successful development of bromination and iodination
1
reagents suitable for chiral anion phase transfer, we applied these reagents to the synthesis of halogenated benzoxazines with high levels of enantioselectivity.
2
i
and all subsequent teachers
Esters ……………………………………………………………………………………………1
Introduction …………………………………………………………………………….2
Carbene Ligands for Enantioselective Gold Catalysis ………………………….5
Results and Discussion ……………………………………………………………….6
Chapter 2. Development of Halogenation Reagents for Chiral Anion Phase-
Transfer Catalysis ………………………………………………………………………….42
Results and Discussion ……………………………………………………………...47
Appendix 1. Enantioselective Catalytic Fluorination of Allylic Alcohols by
Chiral Anion Phase Transfer and an In Situ Directing Group Strategy ……...83
iii
iv
Acknowledgements

The teacher is one who provides guidance, transmits a craft, and dispels confusion.
Han Yu “On Teaching”
·
The Master said, “Teachers are always among those you walk with.”
Analects 7:22
For me, graduate school was the ultimate learning experience. I look back with considerable
embarrassment at my abilities as a scientist when I started out, and with some satisfaction at my
improvements since then. To progress from naively enjoying chemistry, armed with only a little
book knowledge, to having enough perspective, intuition and experience to maybe consider
myself to be a chemist was only possible with the help of many teachers along the way. I would
like to thank these teachers in these Acknowledgements.
I would first like to convey my deepest gratitude to my advisor, Prof. Dean Toste. His
enthusiasm for chemistry and his lightning fast and incisive perception of vital aspects of a
chemical problem is as impressive to me now as it was five years ago. His mentorship and
interactions with me and fellow students and coworkers, however, are what made my graduate
experience a truly valuable one. From the beginning, Prof. Toste accorded me with the trust and
respect appropriate for a mature, independent researcher. I only recognize retrospectively what a
privilege that was. It was a privilege that I was clearly not ready for at the beginning, but
through the gentle prodding of countless informal conversations at the white board, or in the 6 th
floor hallways, Prof. Toste steadily put me on the path to thinking about the right ideas, asking
the right questions, and running the right experiments.
I would like to thank my qualifying exam committee, Profs. Peter Vollhardt, Richmond Sarpong,
Christopher Chang, and Benito de Lumen, for pushing the boundaries of my knowledge, and
kindly pointing out the deficiencies. They helped me see my research, as well as chemistry in
general, from a broader perspective. I would also like to thank Prof. Robert Bergman for the
knowledge and conceptual framework that I refer to time and again from Chem 200/260, as well
as the invaluable opportunity to review (and sometimes relearn) the course material as his GSI.
Of course, grad school would be tremendously more difficult without advice, knowledge and
friendship from labmates. First and foremost, it was an honor to work with and get to know
Jeffrey Wu, Aaron Lackner, and Mika Shiramizu. They’ve walked the same path with me, from
first year classes, to joining the lab and doing research, to graduation. They’ve always been the
v
first folks I turn to, whether it’s talk about (or complain) about chemistry, hang out, or go out for
a drink.
When I first joined the group, those lab members a few years ahead were tremendously
influential in how I approach the practical aspects of chemistry now. Just to name a few
individuals, they include Sunghee Son, Nathan Shapiro, Steven Sethofer, Asa Melhado, Vivek
Rauniyar, Gregory Hamilton, and Jane Wang. Besides transmitting to me virtually everything I
know about running a reaction or managing my research, they also offered me considerable
encouragement when prospects looked grim. More recently, as recent postdoctoral fellows,
David Nagib, Chung-Yeh Wu, Matthew Winston, Neal Mankad (UIC) and Hosea Nelson have
given me unique perspectives and knowledge from their graduate experiences, and I am grateful
for all the interesting conversations I’ve had with them.
Of course, I am humbled to learn quite a few things from those a few years behind me. The
conversations I’ve had with Miles Johnson, William Wolf, and Mark Levin, among others, have
often been on chemistry outside my areas of familiarity or intriguing ideas that I would never
have come across on my own.
Finally, I thank everyone who has ever played a game of foosball with me. Thanks for humoring
me, even though skill continues to elude me in this contest of surprising philosophical depth.
Thanks go out to Dean as well, for his remarkable wisdom in providing the group with the table.
1  
2  
Introduction. The development of gold(I)-catalyzed reactions is a major advance in the chemistry of alkynes and allenes in the past decade. The ability for cationic gold complexes to activate C-C multiple bond systems under mild air and moisture tolerant conditions has greatly increased the synthetic utility of these functional groups, which have previously proved challenging to functionalize selectively and in a catalytic sense. In the context of asymmetric catalysis, the intramolecular addition of nucleophiles to a pendant allene tether has been reported by the Toste and other research groups as a method for the generation of enantioenriched five- and six-membered heterocyclic rings of some generality. Although the cyclization products of these allene substrates are of considerable interest, the preparation of the substrates themselves can be tedious or synthetically challenging.1
In contrast, due in part to their synthetic accessibility, propargyl esters constitute another class of intensely studied substrates for gold catalysis. In the presence of cationic gold complexes, propargyl esters undergo facile rearrangement by either 1,2- or 1,3-migration of the ester moiety to generate a gold-stabilized vinylcarbene or a gold-coordinated allene complex, respectively.2 In general, selectivity for these modes of reactivity depends on the substitution on the alkyne. Terminal or electron-withdrawing group substituted alkynes preferentially undergo 1,2- rearrangement, while 1,3-rearrangement to give the gold-allene complex is the preferred pathway for alkyl or aryl substituted alkynes. Gold-stabilized vinylcarbene intermediates formed from propargyl esters precursors have been utilized by the Toste group for enantioselective inter- and intramolecular cyclopropanations3, as well as allylic ether rearrangements.4 On the other hand, the gold-allene complexes derived from propargyl esters had not previously been used as intermediates for enantioselective catalysis. We anticipated that these gold-allene complexes could undergo subsequent cyclization in the presence of an intramolecular nucleophile. While the in situ generation of an allene intermediate seems like an appealing strategy, both enantiomers of the unsymmetrical allene are formed, so a dynamic kinetic process is necessary to generate enantioenriched product.
In this Chapter, we recount investigations into the feasibility of this strategy using a phenol tethered propargyl ester, which would produce a chromenyl pivalate product. The removal of the pivalate would afford an enantioenriched chromanone, a class of products whose members have exhibited significant bioactivity.5 During the course of these investigations, a gold-carbene complex first synthesized by Dr. Christian Kuzniewski exhibited considerable promise. We followed this lead, further optimizing catalyst structure, among other parameters, to ultimately arrive at reaction conditions which gave products in good yields and enantioselectivities.
Propargyl ester rearrangements. The rearrangement of propargyl esters in the presence of transition metal complexes was first investigated by Saucy, Marbet, Lindlar, and Isler at Hoffmann-La Roche, who demonstrated that propargyl acetates undergo 1,3-ester migration to give allenyl acetates in the presence of copper or silver salts.6 Although the allenyl acetate
3  
products were in some cases isolable, upon prolonged reaction, the final products of the reaction were the geminal diacetates (eq 1.1).
AcO 5 wt. % Ag2CO3
The 1,2-migration of propargyl esters was first reported by Rautenstrauch, who demonstrated that propargyl esters rearranged and cyclized in the presence of PdCl2(MeCN)2 to give a cyclopentadienyl acetate product in good yields (eq 1.2).7 In the same report, Rautenstrauch mentions that a bishomologated substrate reacted under similar conditions to form the intramolecular cyclopropanation product (eq 1.3). Rautenstrauch proposed that both transformations proceeded through Pd(II)-vinylcarbene intermediates. Subsequently, Fensterbank, Malacria, Marco-Contelles and coworkers developed a more efficient PtCl2- catalyzed intramolecular cyclopropanation.8
The use of propargyl esters as precursors for intermolecular cyclopropanation was first disclosed by Miki, Ohe, and Uemura, who used [RuCl2(CO)3]2 to effect the cyclopropanation of styrene using propargyl ester 1.1 as the precursor (eq 1.4).9 Along with cyclopropanation product 1.2, allenic ester 1.3, formed via 1,3-rearrangement, was observed as a side product. The authors noted that AuCl3 was an exceptionally active catalyst for this transformation, although 1.2 and 1.3 were formed in comparable amounts (eq 1.5).
4  
Using well defined cationic gold(I) complexes, the Toste group was able to address the problem of regioselectivity, and by using chiral (bisphosphine)digold catalysts, render the cyclopropanation reaction enantioselective.10 The Toste group also reported the gold-catalyzed formation of cyclopentenones in analogy to the palladium-catalyzed transformation originally reported by Rautenstrauch.11 Although superficially similar, the gold-catalyzed transformation proceeded with efficient chirality transfer, suggesting concerted C-C bond formation and C-O bond cleavage, rather than the presence of a fully formed gold-carbene intermediate. Previous work in the Toste group has also investigated the mechanism of the 1,3-rearrangements of propargyl esters as well as the related vinyl ether system.12 Through the use of stereochemical probes, it was concluded that 1,3-rearrangement was a reversible process for propargyl esters but irreversible for vinyl ethers. An 18O-labeling experiment also provided experimental evidence for direct rearrangement, in contrast to previous computational suggestions that two successive 1,2-migrations may be favored to give the net 1,3-migration product.13
Intramolecular hydrofunctionalization of allenes. The gold-catalyzed hydrofunctionalization of allenes was first studied in the context of the cyclization of allenyl ketones by AuCl3 to form furans reported by Hashmi and coworkers.14 Soon after, Krause and coworkers reported the AuCl3-catalyzed cyclization of α-allenyl alcohols as the first examples of a gold-catalyzed transformation with axial-to-central chirality transfer (eq 1.6).15
Subsequent work by the Krause,16 Yamamoto,17 Widenhoefer,18 and Hashmi19 groups have further elaborated the hydrofunctionalization to include a variety of C, N, and O nucleophiles, exo- and endo- cyclization modes, and the formation of 5-, 6- and 7-membered rings. Many of these transformations also exhibited good to excellent chirality transfer.17,18 The de novo generation of enantioenriched compounds by hydrofunctionalization of allenes was first achieved independently by the Toste and Widenhoefer groups, who reported enantioselective hydroamination and hydroalkoxylation reactions, respectively (eq 1.7 and 1.8).20,21
5  
OH 2.5% (R)-DTBM-MeO-BIPHEP(AuCl)2
(1.7)
Ph
The Toste group subsequently developed the strategy of chiral counterions to expand the scope of the enantioselective hydrofunctionalization reaction to oxygen nucleophiles, including alcohols and carboxylic acids.22 The use of chiral rather than prochiral allene starting materials in enantioselective gold-catalyzed cyclizations is considerable less developed. The implementation of such a process requires a system in which racemization of the substrate is rapid compared to nucleophilic trapping, so that the product distribution is under Curtin- Hammett control. The rate of racemization of allenes in the presence of cationic gold(I) complexes has been studied computationally and experimentally, and depends heavily on the substitution pattern of the allene as well as the nature of the gold complex or associated counterions.23,24 Widenhoefer and coworkers reported the first examples of a gold-catalyzed dynamic kinetic transformation of allenes in an intramolecular hydroamination.25 In contrast to the Widenhoefer group’s earlier observation of good to excellent chirality transfer exhibited by disubstituted allenes, racemic trisubstituted allene 1.4 was found to undergo dynamic kinetic cyclization to yield a mixture of (Z) and (E) cyclization products 1.5 in overall good enantioselectivity (eq 1.9).
Carbene ligands for enantioselective gold catalysis. N-Heterocyclic carbenes (NHCs) have been highly versatile ligands for late transition metal catalysis and chiral versions have been successfully employed in enantioselective rhodium-, palladium-, and copper-catalyzed reactions. In gold catalysis, IPrAuCl (1,3-bis(2,6-diisopropylphenyl)imidazolylidenegold(I) chloride) and related complexes, first prepared by Herrmann and coworkers26 and popularized by Nolan,27 have been used in a variety of gold-catalyzed reactions. The observed reactivity and selectivity when NHC-Au(I) complexes are employed are often reflective of their strong σ-donating ability and large steric bulk.28 Thus, the development of chiral versions of these complexes would broaden the range of reactions amenable to enantioselective gold catalysis.
6  
However, extending the use of NHC-Au(I) complexes to enantioselective transformations has been challenging. For example, Tomioka and coworkers reported the use of C2-symmetric NHC ligands for the cyclization of 1,6-enynes in the presence of methanol to provide the product of a methoxycyclization with a maximum enantioselectivity of 59% ee (eq 1.10).29 Similarly, Shi and coworkers developed axially chiral biphenyl based complexes towards the enantioselective intramolecular hydroamination of allenes, achieving the highest enantioselectivity of 44% ee.30 Finally, shortly before the results of the present study were disclosed, Czekelius and coworkers reported the 7-endo-dig intramolecular desymmetrization of alkynes using a highly sterically- encumbered bis(tetrahydroisoquinoline) based NHC-Au(I) catalyst, with the achievement of enantioselectivities up to 51% ee.31
Espinet and coworkers reported chiral bis(acyclic carbene)digold(I) complexes, which exhibited poor enantiocontrol when evaluated for olefin cyclopropanation and allene hydroalkoxylation.32 The modular construction of these complexes by the reaction of gold-isocyanide complexes and amines, an approach pioneered by Balch and Parks,33 made them attractive for further structural optimization (eq 1.11). In the present work, a modification of one of the complexes reported by Espinet and coworkers served as the catalyst for the highly enantioselective dynamic kinetic transformation of propargyl esters.
Results and Discussion. The present study34 was initiated by a serendipitous finding by Dr. Vivek Rauniyar.35 The transformation was originally discovered as an achiral reaction catalyzed by AuCl3 (eq 1.12). On treatment of 1.6 with AuCl3, a single product, originally assigned as 1.7, was isolated in high yield. Based on later mechanistic insight, as well as nOe and x-ray crystallographic data on related compounds, it is likely that the product was in fact 1.7’.
7  
In any case, based on this initial finding, we prepared substrate 1.8, whose cyclization product was anticipated to contain a stereogenic center. As expected, treatment of 1.8 with the related gold(III) complex dichloro(pyridine-2-carboxylato)gold(III), PicAuCl2, resulted in the formation of a single product in moderate yield (eq 1.13). In order to distinguish between two regioisomers, analogous to 1.7 and 1.7’, a NOESY experiment was performed. The observation of a correlation between the two sets of benzylic protons led to the conclusion that 1.9 was the likely structure of the product. We postulated a plausible mechanism leading to 1.9 in which 1,3-ester migration first takes place to give a gold-coordinated allenyl acetate (A, Scheme 1.1). Nucleophilic attack of the ether oxygen (6-endo-trig) on this intermediate results in an oxonium intermediate (B), which would undergo O-to-C carbodemetalative migration to give the final product.
Due to the presence of π-donating substituents on the allene in intermediates of type A, we postulated that A might be configurationally labile, rapidly racemizing the axis of chirality through a planar intermediate or transition state of type A’. Based on this reasoning, we further speculated that the potentially slower nucleophilic attack to form B could allow for a dynamic kinetic asymmetric process. Consequently, we surveyed a few (bisphosphine)digold(I) complexes and silver salts to render the reaction enantioselective. Although promising levels of enantioselectivity were achieved, the desired cyclization product was isolated in low chemical yield (eq 1.14). Among the reaction side products, the major one was identified as protodemetalated (as opposed to carbodemetalated) product 1.10. Attempts to minimize this side product using molecular sieves or rigorously dry (glove box) technique were only partially successful.
8  
Scheme 1.1: Proposed intermediates in the transformation of 8 to 9.
Motivated by the adventitious production of 1.10, we investigated the possibility of designing a substrate that would lead to 1.10 as the major product. To this end, tert-butylated, tert- butoxycabonylated, silylated, and silylethylated substrates (1.11, 1.12, 1.13, 1.14, resp.) were prepared. However, in no case was desired product 1.10 observed when these substrates were subjected to cationic gold-catalyzed reaction conditions (eq 1.15). Interestingly, MOM protected phenol 1.15 reacted, but incompletely, to form a product identified as allene 1.16 by the characteristic 13C NMR signal of the allene moiety at δ 201.5. Since the reaction could not be driven to full conversion, we suspected that 1.15 and 1.16 were in equilibrium. Indeed, subjecting chromatographically purified 1.16 to cationic gold-catalyzed reaction conditions in CDCl3 resulted in the re-formation of 1.15; the equilibrium constant at room temperature was found to be ~1.3, in favor of the propargyl ester (eq 1.16).
OR
OPiv
Ph
O
OPiv
10
Ph
R = t-Bu (1.11), complex mixture, no 1.10 R = TBS (1.12), complex mixture, no 1.10 R = t-BuC(O), (1.13), no reaction R = CH2CH2SiMe3, (1.14), no reaction R = MOM, (1.15), formation of equilibrium mixture with 1.16
9  
With these negative results in hand, we considered the possibility of simply using the unprotected phenol 1.17 as substrate. We regarded phenol 1.17 as an unattractive substrate initially because of the possibility of competitive 5-endo-dig cyclization to give benzofuran 1.18. Fortunately, the desired product was formed with moderate enantioselectivity and yield upon subjection of 1.17 to cationic (bisphosphine)digold catalysts and NaBARF (sodium tetrakis(3,5- bis(trifluoromethyl)phenyl)borate) as the halide abstracting additive (eq 1.17).
In the course of catalyst optimization, Dr. Christian Kuzniewski generously provided a sample of hydrogen-bond stabilized (biscarbene)digold(I) catalyst 1.19 which afforded the desired product with encouraging enantioselectivity (eq 1.18).
Since 1.19 could be synthesized modularly by Suzuki coupling, we began a collaboration to explore catalyst structure in order to optimize enantioselectivity for the dynamic kinetic transformation of 1.17 to 1.10. In order to efficiently construct analogues of 1.19, we required diaminobinaphthyl derivative 1.20 (Scheme 1.2) in reasonable quantities. Although a highly attractive route would be tetrakislithiation of Boc-protected diamine 1.21, followed by electrophilic iodine quench, the formation of monoiodinated product along with the desired diiodinated product could not be suppressed despite drastic reaction conditions (Scheme 1.2, top).36 A slightly more circuitous approach, first reported by Maruoka and coworkers, was taken (Scheme 1.2, middle), in which the starting material (BINAM) was hydrogenated (to prevent 6,6’
10  
Scheme 1.2: Synthesis of complex 19 and its analogues.
Despite the less than optimal synthesis, key intermediate 1.20 could be prepared on gram scale and analogues of 1.19 (Scheme 2, bottom) with different aryl substituents at the 3,3’ position were evaluated for catalytic activity and enantioselectivity. Complex 1.23, previously reported by Espinet and coworkers,32 bearing no substituent at the 3,3’ position served as a point of comparison. Not surprisingly, this complex catalyzed the transformation with poor enantioselectivity. While 3,5 and 2,6 substitution on the 3,3’ aryl rings were detrimental (Table 1.1, entries 3 and 4), it was found that the 4-substituted analogues resulted in higher enantioselectivities (entries 6-8), although the reason for the variation in enantioselectivity between tert-butyl, methoxy, and trifluoromethyl substituents was not elucidated.
11  
Table 1.1: Effect of ligand structure on enantioselectivity.
With 1.29 chosen as the optimal catalyst, other reaction parameters were reinvestigated. A screen of halide abstracting additives revealed that AgOTf was superior to NaBARF, both in terms of yield (78% vs. 56%, by NMR) and enantioselectivity (85% vs. 73%). Other silver salts (AgBF4 and AgPF6) reacted sluggishly or gave poorer enantioselectivity (AgOTs, 60% ee). While the ratio of gold complex to silver salt was found to be important for some enantioselective gold-catalyzed reactions, ratios of Au:Ag between 1:1.5 and 1:2.5 gave the same reactivity and enantioselectivity, within 1%. Among the solvents evaluated, only CH2Cl2, ClCH2CH2Cl, and CHCl3 provided product with high enantioselectivities, while THF (39% ee), EtOAc (13% ee), and glyme (13% ee) gave low selectivities, and the use of MeNO2 resulted in a complex mixture of products. Deuterochloroform38 was chosen as the optimal solvent. Minor adjustment of other reaction parameters (0 C, 0.1 M in substrate) gave desired product in 85% isolated yield and 91% ee (eq 1.19).
With these optimized conditions, we explored the substrate scope of the reaction in collaboration with Dr. Christian Kuzniewski and undergraduate student Christina Hoong. Substrates with a number of substituents on the propargylic position of the substrate gave good to excellent enantioselectivities (Table 1.2). Notable unsuccessful substrates include one bearing a chloropyridyl substituent (entry 9, no reaction, although PicAuCl2 successfully catalyzed the transformation), and cyclohexyl substituent (entry 12, formed a 3:1 mixture of benzofuran product and desired product), as well as a tertiary alcohol derived substrate (entry 13, 11% ee).
12  
Table 1.2: Substrate scope of enantioselective cyclization of phenol-tethered propargyl esters.
We revisited p-methoxybenzyl ether substrate 1.8, using our optimized conditions and were pleased to find that not only was 1.8 cleanly converted to 1.9 with only trace formation of protodemetalation product 1.10, but also with exceptionally high levels of enantioselectivity (>99% ee, eq 1.20). We explored the scope of ethers that would similarly undergo carbodemetalative O-to-C migration and found that electron rich (hetero)arylmethyl ethers were similarly competent substrates for this reaction (Table 1.3). Unfortunately, under these conditions, 2-(N-tosyl)pyrrolylmethyl, 1-naphthylmethyl, and 2-naphthylmethyl ethers reacted sluggishly, while the 3-(N-tosyl)indolylmethyl ether was unreactive.
13  
14  
To gain some understanding of the nature of the dynamic kinetic process through which highly enantioenriched 1.10 was obtained, we subjected enantioenriched starting material 1.17 (enriched to 60% ee in the (S)-isomer) to reaction conditions and halted the reaction at partial conversion. At 70% conversion, starting material of lower enantioenrichment was recovered while desired product was isolated in essentially the same enantioselectivity as under standard conditions (eq 1.21, top). We envisioned two possibilities to explain the lower enantioenrichment of the recovered starting material (Scheme 1.3).
OH
OPiv
Ph
(R)-1.17
OH
OPiv
Ph
(S)-1.17
OH
OH
OPiv
Ph
(R)-1.17
OH
OPiv
Ph
(S)-1.17
OH
k1 k2
Scheme 1.3: Mechanistic scenarios for dynamic kinetic asymmetric transformation
In the first scenario, the enantiomers of 1.17 would rapidly equilibrate through the allene intermediate, so that 1.17 is racemized under reaction conditions (Scheme 1.3, A). Alternatively, the 1,3-rearrangement to the gold-allene complex could be a kinetic resolution in which the major enantiomer of the starting material reacted faster. In this situation, return to the starting material from the allene would be slow compared to further reaction of the allene to form the product (Scheme 3, B). To distinguish between the possibilities, racemic 1.17 was subjected to
15  
standard reaction conditions and halted at partial conversion. At 60% conversion, starting material in this case was enantioenriched in the opposite sense as the enantioenriched starting material in the earlier experiment (eq 1.21, bottom), suggesting that a kinetic resolution was operative, and equilibration between allene and propargyl ester was slow compared to subsequent nucleophilic attack by the phenol oxygen.
Finally, to demonstrate the potential synthetic applicability of this methodology, we showed that the pivalate ester products could be deprotected to give the chromanone. To this end, chromenyl pivalate 1.30 was subjected to LiAlH4 in ether at 0 C to provide chromanone 1.31, without any observable erosion of enantiomeric excess (eq 1.22).
Conclusions. In this study, we have developed a tandem 1,3-arrangement-cyclization of a propargyl ester, in which an allene intermediate undergoes 6-endo-trig hydroalkoxylation to form a chromenyl ester. This process was rendered enantioselective through a dynamic kinetic process by taking advantage of the propensity of electron-rich allenes to racemize in the presence of cationic gold(I) complexes. The in situ generation of configurationally-labile allene intermediates from readily accessible propargyl ester may serve as a new strategy for utilizing these racemic substrates for asymmetric gold catalysis. Crucial to the successful implementation of this process was the development of a new class of chiral hydrogen-bond stabilized (biscarbene)digold(I) complexes whose modular synthesis allowed for substituent tuning for reactivity and enantioselectivity.
16  
Experimental.
General Information. Unless otherwise noted, reagents were obtained from commercial sources and used without further purification. All reactions were carried out under N2 using Schlenk line techniques, unless otherwise stated. Dry and degassed THF, dichloromethane, diethyl ether, toluene, triethylamine, and dimethylformamide were obtained by passage through activated alumina columns under argon. All other solvents were dried by storage over 3A or 4A molecular sieves overnight. TLC analysis of reaction mixtures was performed on Merck silica gel 60 F254 TLC plates and visualized by UV, I2/silica, and/or ceric ammonium molybdate stain. Preparative TLC was carried out on the same plates. Flash chromatography was carried out with ICN SiliTech 32-63 D 60 Å silica gel. Standard aqueous workup refers to extraction with the indicated solvent, followed by drying of the combined organic layers with sodium sulfate (magnesium sulfate when extracting with diethyl ether), gravity filtration, and removal of solvent by rotary evaporation. 1H and 13C NMR spectra were recorded with Bruker AV-300, AVQ-400, AVB-400, AV-500, DRX-500, and AV-600 spectrometers and were referenced to 1H (residual) and 13C signals of the deuterated solvents, respectively.39 Mass spectral and microanalytical data were obtained at the Micro-Mass/Analytical Facility operated by the College of Chemistry, University of California, Berkeley. X-Ray crystallographic analysis was carried out by Dr. Antonio DiPasquale at the College of Chemistry X-Ray Crystallographic Facility (CHEXRAY, University of California, Berkeley).
Preparation of gold(I)-HBHC complexes. 3,3’-Diido-2,2’-diamino-1,1’-binaphthyl and 3,3’- aryl substituted 2,2’-diamino-1,1’-binaphthyls were prepared in procedures modified from Maruoka and coworkers.37 Gold(I)-HBHC complexes were prepared as described by Espinet and coworkers.32
(R)-3,3’-Diiodo-2,2’-diamino-1,1’-binaphthyl (1.20). To a solution of 1.22 (700 mg, 1.28 mmol, 1.00 equiv) in 50 mL benzene was added DDQ (1.20 g, 5.27 mmol, 4.10 equiv) in one portion. The reaction vessel was purged with nitrogen and the reaction mixture stirred in a preheated bath at 80 °C for 10 min. The reaction mixture was then concentrated to dryness and ground to a fine powder which was loaded directly onto a chromatography column. Purification
17  
by flash column chromatography (25:1 → 5:1 hexanes / ethyl acetate) afforded 1.20 as a slightly yellow powder (235 mg, 34%) whose spectral data were consistent with those previously reported.
(R)-3,3'-Bis(4-(trifluoromethyl)phenyl)-2,2’-1,1'-binaphthyl. A septum vial containing 1.20 (235 mg, 0.438 mmol, 1.00 equiv), 4-(trifluoromethyl)phenylboronic acid (250 mg, 1.31 mmol, 3.00 equiv), Pd(OAc)2 (2.0 mg, 0.0088 mmol, 0.02 equiv), SPhos (7.2 mg, 0.018 mmol, 0.04 equiv), and K3PO4 (372 mg, 1.75 mmol, 4.00 equiv) was evacuated and backfilled with nitrogen. Dry and degassed toluene (4 mL) was added and the mixture was stirred vigorously at 100 °C for 2.5 h. The reaction mixture was then filtered through a short plug of silica gel with dichloromethane eluent and concentrated. Purification by flash column chromatography (2:1 hexanes / dichloromethane) afforded the title compound as a colorless foam (245 mg, >95%).
1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.2 Hz, 2H), 7.80 – 7.72 (m, 10H), 7.34 – 7.21 (m, 4H), 7.14 (d, J = 7.6 Hz, 2H), 3.82 (s, 4H). 13C NMR (151 MHz, CDCl3) δ 142.95, 140.31, 133.32, 130.17, 129.92 (q, JCF = 32.6 Hz), 129.79, 129.25, 128.34, 128.22, 127.34, 125.85 (q, JCF
= 3.6 Hz), 124.14 (q, JCF = 272 Hz), 123.83, 123.04, 113.21. HRMS (ESI+): calcd for [C34H22N2F6+H]+: 573.1760, found: 573.1757.
Other 3,3’-disubstituted BINAM derivatives were prepared analogously.
1.29
Complex 1.29. To a solution of (R)-3,3'-bis(4-(trifluoromethyl)phenyl)-2,2’-1,1'-binaphthyl (240 mg, 0.419 mmol, 1.00 equiv) in dry THF (10 mL) was added 2-pyridylisocyanogold chloride40 (282 mg, 0.838 mmol, 2.00 equiv) in one portion. The mixture was stirred in the dark for 15 h, when an NMR aliquot showed complete consumption of the diamine. The mixture was then concentrated to dryness, redissolved in THF, and filtered through glass fiber to remove metallic gold and recrystallized twice by layering (THF/hexanes) to afford colorless needles. The crystals were washed with hexanes, dissolved in CH2Cl2, and filtered through glass fiber to afford 1.29 upon removal of solvent as a colorless powder. The mother liquor was recrystallized to yield another crop of crystals (292 mg, 53% yield).
18  
Figure 1.1: X-ray structure of 1.29.
1H NMR (400 MHz, CDCl3) δ 13.88 (s, 2H), 8.19 (s, 2H), 8.04 – 7.88 (m, 4H), 7.77 – 7.64 (m, 6H), 7.64 – 7.49 (m, 10H), 7.12 (d, J = 4.7 Hz, 2H), 6.89 – 6.80 (m, 2H), 6.76 (d, J = 8.3 Hz, 2H). HRMS (ESI+): calcd. for [C46H30F6N6Au2Cl2 – Cl]+: 1209.1450, found: 1209.1493.
Other gold(I)-HBHC complexes were prepared analogously.
Complex 1.19: 1H NMR (600 MHz, CD2Cl2) δ 13.84 (s, 2H), 8.10 (s, 2H), 8.00 (s, 2H), 7.97 – 7.92 (m, 2H), 7.72 – 7.65 (m, 6H), 7.56 (t, J = 7.7 Hz, 2H), 7.48 (d, J = 7.8 Hz, 4H), 7.33 (t, J = 7.6 Hz, 4H), 7.31 – 7.24 (m, 2H), 7.19 (d, J = 4.5 Hz, 2H), 6.85 (dd, J = 7.0, 5.4 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H). HRMS (ESI+): calcd. for [C44H32N6Au2Cl2+H]+: 1109.1469, found: 1109.1493. Complex 1.24: 1H NMR (500 MHz, CD2Cl2) δ 13.77 (s, 2H), 8.21 (s, 2H), 8.00 (s, 2H), 7.99 – 7.87 (m, 2H), 7.76 – 7.59 (m, 6H), 7.59 – 7.50 (m, 2H), 7.21 (d, J = 4.0 Hz, 2H), 6.84 (dd, J = 7.4, 5.2 Hz, 2H), 6.73 (d, J = 8.3 Hz, 2H), 6.64 (d, J = 2.2 Hz, 4H), 6.37 (t, J = 2.2 Hz, 2H), 3.67 (s, 12H). HRMS (ESI+): calcd. for [C48H40N6O4Au2Cl2 – Cl ]+: 1193.2131, found: 1193.2176. Complex 1.25: 1H NMR (600 MHz, CDCl3) δ 13.64 (s, 2H), 8.31 (s, 2H), 7.98 (s, 2H), 7.94 – 7.82 (m, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.60-7.52 (m, 4H), 7.50-7.44 (m, 2H), 7.37 (dd, J = 5.0, 1.3 Hz, 2H) , 7.22 (t, J = 8.4 Hz, 2H), 6.77 (dd, J = 7.1, 5.5 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H), 6.38 (d, J = 8.2 Hz, 2H), 3.77 (s, 6H), 3.72 (s, 6H). HRMS (ESI+): calcd. for [C48H40N6O4Au2Cl2 – Cl ]+: 1193.2131, found: 1193.2188. Complex 1.26: 1H NMR (600 MHz, CD2Cl2) δ 13.94 (s, 2H), 8.12 (s, 2H), 8.08 – 7.96 (m, 6H), 7.83 – 7.68 (m, 12H), 7.63-7.51 (m, 4H), 7.49 – 7.37 (m, 4H), 7.25 (dd, J = 5.0, 1.3 Hz, 2H),
19  
6.88 (dd, J = 8.8, 4.3 Hz, 2H), 6.66 (d, J = 8.2 Hz, 2H). HRMS (ESI+): calcd. for [C52H36N6Au2Cl2+H]+: 1209.1782, found: 1209.1805. Complex 1.27: 1H NMR (500 MHz, CD2Cl2) δ 13.82 (s, 2H), 8.12 (s, 2H), 7.97 (s, 2H), 7.95 – 7.90 (m, 2H), 7.71 – 7.63 (m, 6H), 7.59 – 7.53 (m, 2H), 7.42 (d, J = 8.5 Hz, 4H), 7.36 (d, J = 8.6 Hz, 4H), 7.23 (dd, J = 5.1, 1.3 Hz, 2H), 6.85 (ddd, J = 7.4, 5.1, 0.8 Hz, 2H), 6.71 (d, J = 8.3 Hz, 2H), 1.29 (s, 18H). HRMS (ESI+): calcd. for [C52H48N6Au2Cl2+H]+: 1221.2721, found: 1221.2733. Complex 1.28: 1H NMR (500 MHz, CDCl3) δ 13.79 (s, 2H), 8.01 (s, 2H), 7.95 (s, 2H), 7.92 – 7.87 (m, 2H), 7.69 – 7.60 (m, 6H), 7.53 (t, J = 7.0 Hz, 2H), 7.40 (d, J = 8.6 Hz, 4H), 7.14 (d, J = 5.1 Hz, 2H), 6.85 (d, J = 8.6 Hz, 4H), 6.81 (dd, J = 7.3, 5.1 Hz, 2H), 6.73 (d, J = 8.2 Hz, 2H), 3.78 (s, 6H). HRMS (ESI+): calcd. for [C46H36N6O4Au2Cl2 – Cl ]+: 1133.1914, found: 1133.1970. General procedure for gold(I)-catalyzed reactions. Gold(I) complex and silver triflate were weighed in a dram vial, and CDCl3 was added (0.2 M based on substrate). The heterogeneous mixture was then sonicated for 3 min using a commercial ultrasonic cleaner. The mixture was then added via syringe filter (0.2 micron) to a septum-capped dram vial containing substrate (0.03-0.06 mmol, 0.2 M solution in CDCl3) at 0 ºC over 1 min with constant swirling. The reaction mixture was maintained at 0 ºC for 4 h and then quenched with one drop of Et3N (ca. 50 μL). Solvent was removed, and the crude reaction mixture was purified directly by flash column chromatography (pentane/ethyl acetate, 4 mL Pasteur pipette column).
Determination of enantioselectivity. Enantioselectivity was determined by chiral HPLC using a Daicel Chiralpak IA column (0.46 cm x 25 cm). Racemic samples were prepared by treatment of the substrate with (2-pyridinecarboxylato)gold(III) dichloride (10-20 mol%) in DCM (0.05 M) for 4-24 h, or IPrAuCl/AgSbF6 (5 mol% each) in DCM for 1 h. An enantioenriched sample of substrate 17 (enriched in (S), 60% ee, 93:7 hexanes/isopropanol, 1.00 mL/min, major: 6.9 min, minor: 12.0 min) was obtained from 1-phenylprop-2-yn-1-ol that was partially resolved with phenylalanine.41
Removal of pivalate group: To a stirred solution of 1.30 (22.0 mg, >99% ee) in dry ether (1 mL) at 0 ºC was added lithium aluminum hydride in one portion (5.6 mg, 3.0 equiv). After 10 min, 50 mg of pulverized Na2SO4·10H2O and 10 mL ether was added, and stirring was continued for 15 min. Subsequently, the reaction mixture was filtered, and the precipitate was washed thoroughly with EtOAc. Solvent was removed, and the crude product was purified by column chromatography (25:1 to 20:1 pentane/EtOAc) to afford 1.31 (10.8 mg, 58% yield, >99% ee).
Characterization of substrates and products:
OH OPiv
20  
1.17: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.1 Hz, 2H), 7.48 – 7.38 (m, 3H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 – 7.23 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.57 (s, 1H), 6.04 (s, 1H), 1.26 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 177.83, 157.64, 136.51, 131.53, 131.01, 128.98, 128.78, 127.30, 120.14, 114.92, 108.36, 93.16, 81.67, 66.41, 38.95, 27.00. HRMS (ESI+): calcd. for [C20H20O3+Li]+: 315.1567, found: 315.1565.
1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.33 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 – 7.24 (m, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.52 (s, 1H), 6.07 (s, 1H), 1.24 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.69, 157.59, 135.57, 131.93, 131.62, 131.14, 129.01, 123.12, 120.18, 115.02, 108.12, 92.34, 82.10, 65.78, 38.91, 26.95. HRMS (EI+): calcd. for [C20H19O3Br]+: 386.0518, found: 386.0521.
1H NMR (600 MHz, CDCl3) δ 8.05 (s, 1H), 7.96 – 7.84 (m, 3H), 7.67 (dd, J = 8.5, 1.5 Hz, 1H), 7.59-7.51 (m, 2H), 7.37 (dd, J = 7.7, 1.3 Hz, 1H), 7.31 – 7.23 (m, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.88 (td, J = 7.7, 0.9 Hz, 1H), 6.74 (s, 1H), 6.09 (s, 1H), 1.27 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.83, 157.66, 133.83, 133.46, 133.07, 131.59, 131.04, 128.82, 128.28, 127.74, 126.82, 126.73, 126.54, 124.67, 120.17, 114.97, 108.39, 93.13, 81.97, 66.63, 38.99, 27.02. HRMS (EI+): calcd. for [C24H22O3]
+: 358.1569, found: 358.1572.
OH OPiv
1H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 8.0 Hz, 1H), 7.36 – 7.20 (m, 5H), 6.96 (d, J = 8.3 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.66 (s, 1H), 6.03 (s, 1H), 2.48 (s, 3H), 1.26 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.85, 157.68, 136.27, 134.41, 131.46, 130.95, 130.93, 129.05, 127.84, 126.34, 120.10, 114.90, 108.46, 92.97, 81.58, 64.79, 39.04, 27.04, 19.07. HRMS(EI+): calcd. for [C21H22O3]+: 322.1569, found: 322.1571.
21  
OH OPiv
1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 2H), 7.40 – 7.23 (m, 4H), 6.97 (d, J = 8.3 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.53 (s, 1H), 6.09 (s, 1H), 2.95 (sept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.26 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.94, 157.63, 149.80, 133.79, 131.49, 130.94, 127.35, 126.85, 120.10, 114.88, 108.43, 93.41, 81.43, 66.35, 38.94, 33.89, 27.01, 23.89. HRMS (EI+): calcd. for [C23H26O3]
+: 350.1882, found: 350.1888.
1H NMR (500 MHz, CDCl3) δ 7.70 (s, 4H), 7.34 (dd, J = 7.7, 1.4 Hz, 1H), 7.28 (td, J = 7.9, 1.6 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.88 (td, J = 7.7, 0.9 Hz, 1H), 6.61 (s, 1H), 5.99 (s, 1H), 1.26 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.70, 157.67, 140.44, 131.71, 131.33, 131.30, 131.04, 127.65, 125.86 (q, JCF = 3.7 Hz), 123.90 (q, JCF = 272.5 Hz) , 120.31, 115.10, 108.05, 92.14, 82.44, 65.73, 39.02, 27.01. HRMS (EI+): calcd. for [C21H19O3F3]
+: 376.1286, found: 376.1286.
OH OPiv
1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 6.5 Hz, 2H), 7.50 – 7.34 (m, 3H), 7.15 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 5.85 (s, 1H), 2.24 (s, 3H), 1.25 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 177.79, 155.45, 136.57, 131.78, 131.58, 129.36, 128.93, 128.75, 127.28, 114.65, 107.94, 92.77, 81.84, 66.37, 38.93, 26.99, 20.26. HRMS (EI+): calcd. for [C21H22O3]
+: 322.1569, found: 322.1569.
22  
1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 6.8 Hz, 2H), 7.48 – 7.38 (m, 4H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.52 (s, 1H), 6.13 (s, 1H), 1.25 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.94, 156.86, 136.06, 133.85, 133.67, 129.09, 128.83, 127.27, 116.73, 111.65, 110.37, 94.17, 80.42, 66.37, 38.98, 26.98. HRMS (EI+): calcd. for [C20H19O3Br]+: 386.0518, found: 386.0522.
1.10: 1H NMR (500 MHz, CDCl3) δ 7.60 – 7.49 (m, 2H), 7.41 – 7.36 (m, 2H), 7.36 – 7.31 (m, 1H), 7.16 (td, J = 8.0, 1.6 Hz, 1H), 7.08 (dd, J = 7.6, 1.5 Hz, 1H), 6.89 (td, J = 7.6, 0.9 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.10 (d, J = 3.7 Hz, 1H), 5.59 (d, J = 3.7 Hz, 1H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.22, 153.99, 142.70, 140.14, 130.34, 128.69, 128.62, 127.30, 121.26, 121.00, 118.55, 116.29, 111.38, 77.46, 39.43, 27.24. HRMS (EI+): calcd. for [C20H20O3]
+: 308.1412, found: 308.1409. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 9.0 min, minor: 7.9 min.
1H NMR (500 MHz, CD2Cl2) δ 7.54 – 7.46 (m, 2H), 7.45 – 7.35 (m, 2H), 7.16 (td, J = 7.9, 1.6 Hz, 1H), 7.07 (dd, J = 7.7, 1.6 Hz, 1H), 6.89 (td, J = 7.5, 1.0 Hz, 1H), 6.78 (dd, J = 8.1, 0.9 Hz, 1H), 6.04 (d, J = 4.0 Hz, 1H), 5.58 (d, J = 4.0 Hz, 1H), 1.37 (s, 9H). 13C NMR (126 MHz, CD2Cl2) δ 175.73, 153.16, 142.68, 138.78, 131.27, 130.01, 128.63, 122.10, 120.99, 120.75, 118.14, 115.80, 110.40, 75.99, 38.87, 26.53. HRMS(EI+): calcd. for [C20H19O3Br]+:386.0518, found: 386.0521. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 9.8 min, minor: 8.5 min.
23  
1H NMR (500 MHz, CDCl3) δ 7.97 (s, 1H), 7.91 – 7.79 (m, 3H), 7.67 (dd, J = 8.5, 1.7 Hz, 1H), 7.56 – 7.41 (m, 2H), 7.16 (td, J = 7.9, 1.6 Hz, 1H), 7.11 (dd, J = 7.7, 1.5 Hz, 1H), 6.90 (td, J = 7.6, 1.0 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.27 (d, J = 3.7 Hz, 1H), 5.67 (d, J = 3.7 Hz, 1H), 1.40 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.19, 154.03, 142.91, 137.40, 133.40, 133.16, 130.39, 128.64, 128.32, 127.65, 126.48, 126.32, 126.20, 125.05, 121.33, 121.05, 118.62, 116.32, 111.25, 77.57, 39.46, 27.27. HRMS (EI+): calcd. for [C24H22O3]
+: 358.1569, found: 358.1571. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 11.9 min, minor: 15.0 min.
1H NMR (500 MHz, CDCl3) δ 7.63 – 7.57 (m, 1H), 7.25 – 7.18 (m, 3H), 7.15 (td, J = 7.9, 1.6 Hz, 1H), 7.09 (dd, J = 7.6, 1.5 Hz, 1H), 6.88 (td, J = 7.5, 1.0 Hz, 1H), 6.79 (dd, J = 8.1, 0.8 Hz, 1H), 6.34 (d, J = 3.5 Hz, 1H), 5.52 (d, J = 3.5 Hz, 1H), 2.50 (s, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.24, 154.31, 143.06, 136.19, 130.84, 130.28, 128.55, 128.05, 126.24, 121.27, 120.96, 116.19, 111.12, 75.08, 39.43, 27.26, 19.22. HRMS (EI+): calcd. for [C21H22O3]
+: 322.1569, found: 322.1577. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 6.5 min, minor: 5.8 min.
1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.15 (td, J = 8.0, 1.6 Hz, 1H), 7.07 (dd, J = 7.6, 1.5 Hz, 1H), 6.87 (td, J = 7.6, 1.0 Hz, 1H), 6.80 (dd, J = 8.1, 0.8 Hz, 1H), 6.07 (d, J = 3.7 Hz, 1H), 5.57 (d, J = 3.7 Hz, 1H), 2.90 (sept, J = 6.9 Hz, 1H), 1.38 (s, 9H), 1.23 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 176.20, 154.07, 149.40, 142.60, 137.60, 130.26, 127.37, 126.76, 121.22, 120.89, 118.55, 116.29, 111.56, 77.43, 39.43, 33.90, 27.26, 23.92. HRMS (EI+): calcd. for [C23H26O3]
+: 350.1882, found: 350.1886. HPLC: 99:1 Hexanes/isopropanol, 0.75 mL/min, major: 8.6 min, minor: 7.5 min.
24  
1H NMR (500 MHz, CDCl3) δ 7.65 (q, J = 8.5 Hz, 4H), 7.18 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.14 (d, J = 3.8 Hz, 1H), 5.61 (d, J = 3.8 Hz, 1H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.22, 153.72 , 144.01, 143.13, 130.67 (q, JCF = 32.8 Hz), 130.61, 127.53, 125.68 (q, JCF = 11.3 Hz), 123.95 (q, JCF = 269.6 Hz), 121.48 , 121.39 , 118.47, 116.36, 110.51, 76.52, 39.51, 27.25. HRMS (EI+): calcd. for [C21H19O3F3]
+:376.1286, found: 376.1284. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 8.2 min, minor: 6.9 min.
1H NMR (500 MHz, CDCl3) δ 7.57 – 7.49 (m, 2H), 7.41 – 7.30 (m, 3H), 6.95 (dd, J = 8.2, 1.8 Hz, 1H), 6.86 (d, J = 1.7 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 6.05 (d, J = 3.7 Hz, 1H), 5.57 (d, J = 3.8 Hz, 1H), 2.25 (s, 3H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.27, 151.84, 142.93, 140.23, 130.81, 130.19, 128.65, 128.54, 127.29, 121.65, 118.31, 116.09, 111.44, 77.32, 39.43, 27.25, 20.79. HRMS (EI+): calcd. for [C21H22O3]+: 322.1569, found: 322.1573. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 11.3 min, minor: 8.0 min.
1H NMR (500 MHz, CDCl3) δ 7.52 – 7.47 (m, 2H), 7.41 – 7.31 (m, 3H), 7.23 (dd, J = 8.6, 2.4 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H), 6.09 (d, J = 3.8 Hz, 1H), 5.64 (d, J = 3.8 Hz, 1H), 1.39 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.08, 152.97, 141.58, 139.58, 132.89, 128.84, 128.76, 127.31, 124.14, 120.37, 118.11, 113.14, 112.37, 77.64, 39.48, 27.21. HRMS (EI+): calcd. for [C20H19O3Br]+: 386.0518, found: 386.0522. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 11.8 min, minor: 7.6 min.
25  
O
Ph
OPiv
OMe
1.8: 1H NMR (500 MHz, CDCl3) δ 7.56 (dd, J = 7.5, 1.7 Hz, 2H), 7.44 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.32 – 7.24 (m, 4H), 6.92 (t, 2H), 6.90 – 6.85 (m, 2H), 6.72 (s, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.21 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.23, 159.64, 159.26, 137.55, 133.74, 130.02, 128.82, 128.45, 127.58, 120.67, 113.89, 112.70, 112.35, 89.77, 83.34, 70.27, 66.04, 55.26, 38.77, 26.99. HRMS (ESI+): calcd. for [C28H28O4+Li]+: 435.2142, found: 435.2141.
1H NMR (600 MHz, CDCl3) δ 7.57 (dd, J = 7.5, 1.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.33 – 7.28 (m, 3H), 7.27 – 7.24 (m, 1H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 5.03 (s, 2H), 3.81 (s, 3H), 2.25 (s, 3H), 1.22 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.21, 159.24, 157.63, 137.63, 134.09, 130.58, 130.08, 129.06, 128.83, 128.45, 128.42, 127.58, 113.86, 113.04, 112.15, 89.42, 83.56, 70.55, 66.07, 55.24, 38.76, 26.99, 20.21. HRMS (ESI+): calcd. for [C29H30O4+Li]+: 449.2299, found: 449.2295.
1H NMR (500 MHz, CDCl3) δ 7.60 – 7.54 (m, 2H), 7.33 – 7.24 (m, 4H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.99 – 6.95 (m, J = 5.5, 1.8 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 6.72 (s, 1H), 5.04 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.25 (s, 3H), 1.20 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.20, 157.52, 148.96, 148.60, 137.43, 134.12, 130.60, 130.11, 129.43, 128.48, 128.40, 127.55, 119.85, 112.95, 112.04, 110.90, 110.61, 89.32, 83.57, 70.69, 65.99, 55.87, 55.71, 38.72, 26.94, 20.21. HRMS (ESI+): calcd. for [C30H32O5+Li]+: 479.2404, found: 479.2403.
26  
1H NMR (500 MHz, CDCl3) δ 7.62 – 7.54 (m, 2H), 7.45 (dd, J = 7.8, 1.7 Hz, 1H), 7.35 – 7.30 (m, 3H), 7.29 – 7.24 (m, 1H), 6.96 (d, J = 1.3 Hz, 1H), 6.94 – 6.88 (m, 3H), 6.78 (d, J = 7.9 Hz, 1H), 6.73 (s, 1H), 5.96 (s, 2H), 5.03 (s, 2H), 1.22 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.22, 159.46, 147.80, 147.26, 137.54, 133.76, 130.53, 130.00, 128.46, 128.44, 127.55, 120.90, 120.76, 112.71, 112.36, 108.15, 108.11, 101.01, 89.87, 83.26, 70.43, 66.01, 38.74, 26.96. HRMS (ESI+): calcd. for [C28H26O5+Li]+: 449.1935, found: 449.1934.
1H NMR (600 MHz, CDCl3) δ 7.61 – 7.55 (m, 2H), 7.46 – 7.43 (m, 2H), 7.37 – 7.32 (m, 3H), 7.32 – 7.27 (m, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.94 (td, J = 7.5, 0.9 Hz, 1H), 6.71 (s, 1H), 6.41 (d, J = 3.2 Hz, 1H), 6.38 (dd, J = 6.8, 3.6 Hz, 1H), 5.07 (s, 1H), 1.22 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.25, 159.33, 150.17, 142.92, 137.51, 133.79, 129.98, 128.46, 127.61, 121.22, 113.38, 112.75, 110.48, 109.87, 89.87, 83.14, 66.01, 63.51, 38.77, 26.98. HRMS (EI+): calcd. for [C25H24O4]
+: 388.1675, found: 388.1682.
1H NMR (600 MHz, CDCl3) δ 7.60 – 7.57 (m, 2H), 7.50 – 7.40 (m, 2H), 7.42 (t, J = 1.7 Hz, 1H), 7.36 – 7.33 (m, 3H), 7.31 – 7.27 (m, 1H), 6.94 (d, J = 7.9 Hz, 2H), 6.73 (s, 1H), 6.48 (d, J = 1.1 Hz, 1H), 5.00 (s, 2H), 1.23 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.22, 159.43, 143.28, 140.61, 137.54, 133.74, 130.02, 128.53, 128.45, 127.52, 121.17, 120.84, 112.52, 112.35, 110.01, 89.80, 83.17, 66.00, 62.84, 38.74, 26.96. HRMS (ESI+): calcd. for [C25H24O4+Li]+: 395.1829, found: 395.1828.
27  
1H NMR (600 MHz, CDCl3) δ 7.60 – 7.55 (m, 3H), 7.51 – 7.45 (m, 2H), 7.33 – 7.29 (m, 2H), 7.29 – 7.21 (m, 5H), 7.01 (d, J = 8.3 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.78 (s, 1H), 6.73 (s, 1H), 5.22 (s, 2H), 1.20 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.21, 159.17, 155.13, 152.72, 137.45, 133.85, 130.05, 128.47, 128.41, 128.08, 127.51, 124.46, 122.83, 121.39, 121.18, 113.11, 112.68, 111.36, 105.94, 90.10, 82.98, 77.21, 77.00, 76.79, 66.00, 63.99, 38.73, 26.93. HRMS (ESI+): calcd for [C29H26O4+Li]+: 445.1986, found: 445.1988.
1H NMR (500 MHz, CDCl3) δ 7.62 – 7.54 (m, 2H), 7.45 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.10 (d, J = 2.6 Hz, 1H), 7.00 (dd, J = 5.1, 3.5 Hz, 1H), 6.98 – 6.90 (m, 2H), 6.72 (s, 1H), 5.28 (s, 2H), 1.22 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.24, 159.17, 139.03, 137.50, 133.82, 129.98, 128.45, 127.63, 126.67, 126.64, 126.12, 121.16, 113.10, 112.66, 89.97, 83.09, 66.02, 65.92, 38.76, 26.99. HRMS (ESI+): calcd. for [C25H24O3S+Li]+: 411.1601, found: 411.1599.
1H NMR (500 MHz, CDCl3) δ 7.91 – 7.85 (m, 2H), 7.51 (d, J = 7.2 Hz, 2H), 7.49 – 7.44 (m, 2H), 7.39 – 7.34 (m, 2H), 7.34 – 7.28 (m, 2H), 7.25 (dd, J = 9.4, 5.4 Hz, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.95 (td, J = 7.5, 0.7 Hz, 1H), 6.70 (s, 1H), 5.36 (s, 2H), 1.21 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 177.19, 159.35, 140.53, 137.53, 137.49, 133.81, 131.43, 130.07, 128.51, 128.44, 127.40, 124.71, 124.54, 124.24, 122.74, 121.92, 120.93, 112.41, 112.31, 90.00, 83.08, 65.99, 65.60, 38.72, 26.95. HRMS (ESI+): calcd. for [C29H26O3S+Li]+:461.1757, found: 461.1755.
28  
1H NMR (600 MHz, CDCl3) δ 8.16 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (s, 1H), 7.50 – 7.43 (m, 3H), 7.34 (t, J = 7.7 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.27 – 7.23 (m, J = 7.4 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.6 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 6.67 (s, 1H), 5.28 (s, 2H), 1.67 (s, 9H), 1.17 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 177.18, 159.53, 149.60, 137.41, 133.82, 129.98, 129.43, 128.38, 128.30, 127.48, 124.78, 124.68, 122.88, 120.85, 119.84, 116.32, 115.20, 112.78, 112.50, 89.80, 83.81, 83.23, 65.99, 63.29, 38.69, 28.16, 26.91. HRMS (ESI+): calcd. for [C34H35O5N+Li]+: 544.2670, found: 544.2667.
1.9: 1H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 4.7 Hz, 2H), 7.35 – 7.29 (m, 3H), 7.07 (t, J = 7.7 Hz, 3H), 6.99 (d, J = 7.7 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.7 Hz, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 3.79 (s, 3H), 3.64 (d, J = 15.3 Hz, 1H), 2.74 (d, J = 15.3 Hz, 1H), 1.45 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 176.47, 158.45, 152.54, 138.81, 138.10, 129.92, 129.61, 129.19, 128.87, 128.71, 128.20, 122.03, 120.97, 120.89, 118.77, 116.32, 114.09, 79.27, 55.29, 39.39, 32.16, 27.40. HRMS (ESI+): calcd. for [C28H28O4+NH4
]+: 446.2326, found: 446.2337. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 11.9 min, minor: 10.2 min.
1H NMR (500 MHz, CDCl3) δ 7.49 – 7.42 (m, 2H), 7.35 – 7.28 (m, 3H), 7.06 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.60 (s, 1H), 3.79 (s, 3H), 3.63 (d, J = 15.3 Hz, 1H), 2.74 (d, J = 15.3 Hz, 1H), 2.24 (s, 3H), 1.46 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.53, 158.40, 150.31, 138.92, 138.12, 130.10, 130.01, 129.90, 129.29, 128.79, 128.66, 128.19, 122.02, 121.41, 118.46, 116.11, 114.06, 79.10, 55.29, 39.38, 32.18, 27.39, 20.85. HRMS(ESI+): calcd. for [C29H30O4+H]+: 443.2217, found: 443.2229. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 16.8 min, minor: 7.3 min.
29  
1H NMR (500 MHz, CDCl3) δ 7.43 (s, 2H), 7.34 – 7.27 (m, 3H), 6.88 (dd, J = 8.2, 1.7 Hz, 1H), 6.80 – 6.74 (m, 2H), 6.70 – 6.64 (m, 2H), 6.57 (d, J = 8.2 Hz, 1H), 5.62 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 3.65 (d, J = 15.2 Hz, 1H), 2.78 (d, J = 15.3 Hz, 1H), 2.24 (s, 3H), 1.46 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.61, 150.39, 149.11, 147.81, 139.06, 138.22, 130.19, 130.07, 129.77, 128.83, 128.66, 128.18, 122.01, 121.40, 120.97, 118.49, 116.19, 112.05, 111.24, 79.14, 55.96, 55.83, 39.42, 32.68, 27.42, 20.87. HRMS (ESI+): calcd. for [C30H32O5+NH4]
+: 490.2588, found: 490.2600. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 30.9 min, minor: 15.6 min.
O
Ph
OPiv
O O
1.30: 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 6.7 Hz, 2H), 7.39 – 7.27 (m, 3H), 7.08 (td, J = 7.9, 1.5 Hz, 1H), 6.99 (dd, J = 7.6, 1.4 Hz, 1H), 6.87 (td, J = 7.6, 0.7 Hz, 1H), 6.74 – 6.64 (m, 3H), 6.58 (d, J = 7.9 Hz, 1H), 5.93 (d, J = 1.6 Hz, 2H), 5.66 (s, 1H), 3.60 (d, J = 15.2 Hz, 1H), 2.72 (d, J = 15.2 Hz, 1H), 1.46 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.49, 152.50, 147.87, 146.36, 138.88, 137.99, 130.92, 129.70, 128.92, 128.72, 128.17, 121.91, 121.77, 121.00, 120.92, 118.64, 116.33, 109.27, 108.25, 100.92, 79.17, 39.37, 32.68, 27.37. HRMS (ESI+): calcd. for [C28H26O5+Li]+: 449.1935, found: 449.1933. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 13.3 min, minor: 12.3 min.
Figure 1.2: X-ray structure of 3-(furan-2-ylmethyl)-2-phenyl-2H-chromen-4-yl pivalate. The absolute configuration is (R). The stereochemistries of other products were assigned by analogy.
30  
1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 6.3 Hz, 2H), 7.36 – 7.27 (m, 4H), 7.08 (td, J = 8.0, 1.6 Hz, 1H), 6.97 (dd, J = 7.7, 1.5 Hz, 1H), 6.86 (td, J = 7.6, 1.0 Hz, 1H), 6.68 (dd, J = 8.1, 0.7 Hz, 1H), 6.26 (dd, J = 3.1, 1.9 Hz, 1H), 6.02 (d, J = 3.0 Hz, 1H), 5.81 (s, 1H), 3.55 (d, J = 16.1 Hz, 1H), 2.98 (d, J = 16.1 Hz, 1H), 1.44 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.18, 152.62, 150.65, 141.72, 139.61, 137.90, 129.80, 128.92, 128.69, 128.12, 121.03, 120.94, 118.90, 118.66, 116.35, 110.38, 107.11, 79.63, 39.40, 27.33, 26.02. HRMS (ESI+): calcd. for [C25H24O4 + H]+: 389.1747, found: 389.1750. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 9.1 min, minor: 7.3 min.
1H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 6.5 Hz, 2H), 7.37 – 7.28 (m, J = 33.4 Hz, 4H), 7.18 (s, 1H), 7.08 (td, J = 7.9, 1.6 Hz, 1H), 6.98 (dd, J = 7.7, 1.5 Hz, 1H), 6.87 (td, J = 7.6, 1.0 Hz, 1H), 6.68 (dd, J = 8.1, 0.8 Hz, 1H), 6.27 (d, J = 0.9 Hz, 1H), 5.76 (s, 1H), 3.36 (d, J = 15.5 Hz, 1H), 2.73 (d, J = 15.6 Hz, 1H), 1.44 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 176.27, 152.58, 143.20, 140.12, 138.96, 138.05, 129.67, 128.91, 128.69, 128.10, 120.90, 120.34, 118.72, 116.32, 111.20, 79.37, 39.35, 27.33, 22.63. HRMS (ESI+): calcd. for [C25H24O4+Li]+: 395.1829, found: 395.1828. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 8.9 min, minor: 7.9 min.
1H NMR (500 MHz, CDCl3) δ 7.52 – 7.45 (m, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.34 – 7.28 (m, 3H), 7.24 – 7.16 (m, 3H), 7.10 (td, J = 7.9, 1.6 Hz, 1H), 6.99 (dd, J = 7.7, 1.5 Hz, 1H), 6.88 (td, J = 7.6, 1.0 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.45 (s, 1H), 5.91 (s, 1H), 3.70 (d, J = 16.2 Hz, 1H), 3.11 (d, J = 16.2 Hz, 1H), 1.45 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.17, 154.87, 153.95, 152.73, 137.82, 129.98, 129.00, 128.73, 128.58, 128.12, 123.61, 122.61, 121.12, 121.00, 120.49, 118.59, 118.12, 116.43, 110.93, 104.02, 79.70, 39.45, 27.34, 26.56. HRMS (ESI+): calcd. for [C29H26O4+Li]+: 455.1986, found: 455.1984. HPLC: 99:1 Hexanes/isopropanol, 1.00 mL/min, major: 12.7 min, minor: 7.5 min.
31  
1H NMR (600 MHz, CDCl3) δ 7.49 (d, J = 6.7 Hz, 2H), 7.38 – 7.30 (m, 3H), 7.15 (d, J = 5.1 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.93 – 6.89 (m, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.81 (s, 1H), 3.74 (d, J = 15.8 Hz, 1H), 3.09 (d, J = 15.8 Hz, 1H), 1.45 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 176.30, 152.66, 139.61, 139.11, 137.98, 129.84, 128.98, 128.76, 128.18, 126.95, 126.11, 124.44, 121.14, 121.01, 120.95, 118.60, 116.38, 79.32, 39.41, 27.37, 27.31. HRMS (ESI+): calcd. for [C25H24O3S+Li]+: 411.1601, found: 411.1601. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 12.5 min, minor: 10.2 min.
1H NMR (500 MHz, CDCl3) δ 7.90 – 7.82 (m, 1H), 7.69 (dd, J = 6.4, 2.7 Hz, 1H), 7.51 – 7.42 (m, 2H), 7.39 – 7.28 (m, 5H), 7.15 (s, 1H), 7.10 (td, J = 8.0, 1.6 Hz, 1H), 7.04 (dd, J = 7.7, 1.5 Hz, 1H), 6.90 (td, J = 7.6, 1.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.69 (s, 1H), 3.77 (dd, J = 15.9, 1.1 Hz, 1H), 3.20 (d, J = 15.9 Hz, 1H), 1.44 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.40, 152.58, 140.49, 139.46, 138.63, 137.76, 131.07, 129.81, 128.98, 128.74, 128.16, 124.37, 124.13, 123.89, 122.84, 121.52, 120.98, 120.96, 120.27, 118.66, 116.42, 79.45, 39.44, 27.35, 26.43. HRMS (ESI+): calcd. for [C29H26O3S+Li]+: 461.1757, found: 461.1759. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 11.1 min, minor: 7.9 min.
1H NMR (600 MHz, CDCl3) δ 8.10 (s, 1H), 7.48 (d, J = 7.6 Hz, 3H), 7.34 – 7.28 (m, 5H), 7.23 – 7.17 (m, 1H), 7.07 (td, J = 7.9, 1.6 Hz, 1H), 7.01 (dd, J = 7.7, 1.5 Hz, 1H), 6.87 (td, J = 7.6, 1.0 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 5.74 (s, 1H), 3.63 (dd, J = 15.8, 1.3 Hz, 1H), 3.00 (d, J = 15.8 Hz, 1H), 1.67 (s, 9H), 1.47 (s, 9H). 13C NMR (151 MHz, CDCl3) δ 176.36, 152.64, 149.64, 139.19, 137.97, 135.54, 130.34, 129.71, 128.91, 128.70, 128.23, 124.49, 124.25, 122.63, 120.99, 120.91, 120.52, 118.98, 118.79, 116.40, 115.88, 115.22, 83.62, 79.41, 39.47, 28.23, 27.43, 22.90.
32  
HRMS (ESI+): calcd. for [C34H35O5N+Li]+: 544.2670, found: 544.2666. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 7.6 min, minor: 6.8 min.
1.31: 1H NMR (600 MHz, CDCl3) δ 7.91 (dd, J = 7.8, 1.5 Hz, 1H), 7.55 – 7.44 (m, 1H), 7.40 – 7.29 (m, 5H), 7.02 (dd, J = 15.7, 7.8 Hz, 2H), 6.66 (d, J = 7.9 Hz, 1H), 6.59 (d, J = 1.3 Hz, 1H), 6.49 (dd, J = 7.9, 1.3 Hz, 1H), 5.90 (d, J = 2.1 Hz, 2H), 5.28 (d, J = 8.7 Hz, 1H), 3.31 (dt, J = 8.6, 6.1 Hz, 1H), 2.94 (dd, J = 14.2, 5.8 Hz, 1H), 2.90 (dd, J = 14.2, 6.4 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 193.62, 160.34, 147.48, 145.98, 137.44, 136.15, 132.25, 128.81, 128.67, 127.54, 127.27, 122.35, 121.48, 120.63, 117.94, 109.65, 108.03, 100.79, 81.78, 52.62, 32.26. HRMS (ESI+): calcd for [C23H18O4+H]+: 359.1278, found: 359.1279. HPLC: 98:2 Hexanes/isopropanol, 0.75 mL/min, major: 25.7 min, minor: 22.6 min.
1.16: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 6.9 Hz, 2H), 7.34 - 7.45 (m, 3H), 7.24 - 7.34 (m, 2H), 7.15 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 6.5 Hz, 1H), 6.78 (s, 1H), 5.01-5.10 (m, 2H), 3.32 (s, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 201.5, 176.1, 154.3, 133.9, 129.5, 128.7, 128.4, 128.1, 127.5, 122.7, 121.9, 121.8, 114.9, 103.8, 94.4, 56.1, 39.4, 27.4.
X-ray crystallographic data:
Complex 1.29: A colorless rod 0.12 x 0.06 x 0.06 mm in size was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using phi and omega scans. Crystal-to-detector distance was 60 mm and exposure time was 20 seconds per frame using a scan width of 0.5°. Data collection was 100.0% complete to 25.00° in θ. A total of 144079 reflections were collected covering the indices, -13<=h<=13, -30<=k<=30, -24<=l<=24. 20989 reflections were found to be symmetry independent, with an Rint of 0.0391. Indexing and unit cell refinement indicated a primitive, monoclinic lattice. The space group was found to be P2(1) (No. 4). The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SIR-2008) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-97). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-97.
33  
X-ray ID toste39
Sample/notebook ID YMW-IV-179
Formula weight 1461.91
Temperature 100(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P2(1)
b = 25.4178(8) Å θ= 101.1600(10)°.
c = 20.5328(6) Å θ = 90°.
Volume 5809.4(3) Å3
Crystal color/habit colorless rod
Theta range for data collection 1.29 to 25.40°.
Index ranges -13<=h<=13, -30<=k<=30, -24<=l<=24
Reflections collected 144079
Max. and min. transmission 0.7454 and 0.5740
Refinement method Full-matrix least-squares on F2
34  
Goodness-of-fit on F2 1.081
R indices (all data) R1 = 0.0319, wR2 = 0.0791
Absolute structure parameter -0.002(4)
35  
(R)-3-(Furan-2-ylmethyl)-2-phenyl-2H-chromen-4-yl pivalate: A colorless prism 0.15 x 0.12 x 0.10 mm in size was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using phi and omega scans. Crystal-to-detector distance was 60 mm and exposure time was 5 seconds per frame using a scan width of 1.0°. Data collection was 99.9% complete to 67.00° in θ. A total of 25730 reflections were collected covering the indices, -7<=h<=9, -11<=k<=11, -29<=l<=31. 3756 reflections were found to be symmetry independent, with an Rint of 0.0210. Indexing and unit cell refinement indicated a primitive, orthorhombic lattice. The space group was found to be P2(1)2(1)2(1) (No. 19). The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SIR-2008) produced a complete heavy-atom phasing model consistent with the proposed structure. All non-hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-97). All hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-97. Absolute stereochemistry was unambiguously determined to be R at C9.
36  
X-ray ID toste43
Sample/notebook ID YMW-V-48B
Formula weight 388.44
Temperature 100(2) K
Wavelength 1.54178 Å
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
b = 9.6818(6) Å θ = 90°.
c = 26.1298(16) Å θ = 90°.
Volume 2083.7(2) Å3
Crystal color/habit colorless prism
Theta range for data collection 3.38 to 68.05°.
Index ranges -7<=h<=9, -11<=k<=11, -29<=l<=31
Reflections collected 25730
Max. and min. transmission 0.9362 and 0.9065
Refinement method Full-matrix least-squares on F2
37  
Goodness-of-fit on F2 1.065
R indices (all data) R1 = 0.0322, wR2 = 0.0834
Absolute structure parameter 0.04(17)
38  
References:
1. For a review on allene synthesis, see: Brummond, K. M.; DeForrest, J. E. Synthesizing Allenes Today (1982-2006). Synthesis 2007, 795-818; for a monograph, see: Brandsma, L. Synthesis of Acetylenes, Allenes, and Cumulenes. Elsevier: Oxford, 2004.
2. For a discussion of 1,2- vs. 1,3-rearrangement selectivity of propargyl esters, see Wang, S.; Zhang, G.; Zhang, L. Gold-Catalyzed Reaction of Propargylic Carboxylates via an Initial 3,3-Rearrangement. Synlett 2010, 692-706.
3. Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. Gold(I)-Catalyzed Stereoselective Olefin Cyclopropanation. J. Am. Chem. Soc. 2005, 127, 18002-18003; Watson, I. D. G.; Ritter, S.; Toste, F. D. Asymmetric Synthesis of Medium-Sized Rings by Intramolecular Au(I)-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 2009, 131, 2056-2057.
4. Uemura, M.; Watson, I. D. G.; Toste, F. D. Gold(1)-Catalyzed Enantioselective Synthesis of Benzopyrans via Rearrangement of Allylic Oxonium Intermediates. J. Am. Chem. Soc. 2009, 131, 3464-3465.
5. Nijveldt, R. J.; van Nood, E.; van Hoorn, D. E. C.; Boelens, P. G.; van Norren, K.; van Leeuwen, P. A. M. Flavanoids: A Review of Probable Mechanisms of Action and Potential Applications. Am. J. Clin. Nutrit. 2001, 74, 418-425.
6. Saucy, G.; Marbet, R.; Lindlar, H.; Isler, O. Über eine neue Synthese von Citral und verwandten Verbindungen. Helv. Chim. Acta. 1959, 42, 1945-1955.
7. Rautenstrauch, V. 2-Cyclopentenones from 1-Ethynyl-2-propenyl Acetates. J. Org. Chem. 1984, 49, 950-952.
8. Mainett, E.; Mouriès, V.; Fensterbank, L.; Malacria, M.; Marco-Contelles, J. The Effect of a Hydroxy Protecting Group on the PtCl2-Catalyzed Cyclization of Dienynes – A Novel, Efficient, and Selective Synthesis of Carbocycles. Angew. Chem. Int. Ed. 2002, 41, 2132-2135.
9. Miki, K.; Ohe, K.; Uemura, S. A New Ruthenium-Catalyzed Cyclopropanation of Alkenes Using Propargylic Acetates as a Precursor of Vinylcarbenoids. Tetrahedron Lett. 2003, 44, 2019-2022.
10. Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. Gold(I)-Catalyzed Stereoselective Olefin Cyclopropanation. J. Am. Chem. Soc. 2005, 127, 18002-18003.
11. Shi, X.; Gorin, D. J.; Toste, F. D. Synthesis of 2-Cyclopentenones by Gold(I)-Catalyzed Rautenstrauch Rearrangement. J. Am. Chem. Soc. 2005, 127, 5802-5803.
12. Mauleón, P.; Krinsky, J. L.; Toste, F. D. Mechanistic Studies on Au(I)-Catalyzed [3,3]- Sigmatropic Rearrangements using Cyclopropane Probes. J. Am. Chem. Soc. 2009, 131, 4513-4520.
13. Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.; Cavallo, L. Golden Carousel in Catalysis: The Cationic Gold/Propargylic Ester Cycle. Angew. Chem. Int. Ed. 2008, 47, 718-721.
39  
14. Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. A New Gold-Catalyzed C-C Bond Formation. Angew. Chem. Int. Ed. 2000, 39, 2285-2288.
15. Hoffmann-Röder, A.; Krause, N. Gold(III) Chloride Catalyzed Cyclization of α- Hydroxyallenes to 2,5-Dihydrofurans. Org. Lett. 2001, 3, 2537-2538.
16. Gockel, B.; Krause, N. Golden Times for Allenes: Gold-Catalyzed Cycloisomerization of β-Hydroxyallenes to Dihydropyrans. Org. Lett. 2006, 8, 4485-4488.
17. Patil, N. T.; Lutete, L. M.; Nishina, N.; Yamamoto, Y. Gold-Catalyzed Intramolecular Hydroamination of Allenes: A Case of Chirality Transfer. Tetrahedron Lett. 2006, 47, 4749-4751.
18. Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. Highly Active Au(I) Catalyst for the Intramolecular exo-Hydrofunctionalization of Allenes with Carbon, Nitrogen, and Oxygen Nucleophiles. J. Am. Chem. Soc. 2006, 128, 9066-9073.
19. Pflästerer, D.; Dolbundalchok, P.; Rafique, S.; Rudolph, M; Rominger, F.; Hashmi, A. S. K. On the Gold-Catalyzed Intramolecular 7-exo-trig Hydroamination of Allenes. Adv. Synth. Catal. 2013, 355, 1383-1393.
20. Lalonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. Gold(I)-Catalyzed Enantioselective Intramolecular Hydroamination of Allenes. J. Am. Chem. Soc. 2007, 129, 2452-2453.
21. Zhang, Z.; Widenhoefer, R. A. Gold(I)-Catalyzed Intramolecular Enantioselective Hydroalkoxylation of Allenes. Angew. Chem. Int. Ed. 2007, 46, 283-285.
22. Hamilton, G. L.; Kang, E. J.; Mba, M; Toste, F. D. A Powerful Counterion Strategy for Asymmetric Transition Metal Catalysis. Science 2007, 317, 496-499.
23. Gandon, V.; Lemière, G.; Hours, A.; Fensterbank, L.; Malacria, M. The Role of Bent Acyclic Allene Gold Complexes in Axis-to-Center Chirality Transfers. Angew. Chem. Int. Ed. 2008, 47, 7534-7538.
24. Sherry, B. D.; Toste, F. D. Gold(I)-Catalyzed Propargyl Claisen Rearrangement. J. Am. Chem. Soc. 2004, 126, 15978-15979.
25. Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. Gold(I)-Catalyzed Dynamic Kinetic Enantioselective Intramolecular Hydroamination of Allenes. J. Am. Chem. Soc. 2007, 129, 14148-14149.
26. Schneider, S. K.; Herrmann, W. A.; Herdtweck, E. Synthesis of the First Gold(I) Carbene Complex with a Gold-Oxygen Bond – First Catalytic Application of Gold(I) Complexes Bearing N-Heterocyclic Carbenes. Z. Anorg. Allg. Chem. 2003, 629, 2363-2370.
27. de Frémont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P. Synthesis and Characterization of N-Heterocyclic Carbene Gold(I) Complexes. Organometallics 2005, 24, 2411-2418.
28. For discussions on ligand effects in gold catalysis, see: Gorin, D. J.; Sherry, B. D.; Toste, F.D. Ligand Effects in Homogeneous Au Catalysis. Chem. Rev. 2008, 108, 3351-3378; Benitez, D.; Tkatchouk, E.; Gonzalez, A. Z.; Goddard, W. A.; Toste, F. D. On the Impact of Steric and Electronic Properties of Ligands on Gold(I)-Catalyzed Cycloaddition
40  
Reactions. Org. Lett. 2009, 11, 4798-3801; Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.; Goddard, W. A.; Toste, F. D. Nature Chem. 2009, 1, 482.
29. Matsumoto, Y.; Selim, K. B.; Nakanishi, H.; Yamada K.; Yamamoto, Y.; Tomioka, K. Chiral Carbene Approach to Gold-Catalyzed Asymmetric Cyclization of 1,6-Enynes. Tetrahedron Lett. 2010, 51, 404-406.
30. Liu, L.-J.; Wang, F.; Wang, W.; Zhao, M.-X.; Shi, M. Synthesis of Chiral Mono(N- Heterocyclic Carbene) Palladium and Gold Complexes with a 1,1’-Biphenyl Scaffold and Their Applications in Catalysis. Beilstein J. Org. Chem. 2011, 7, 555-564.
31. Wilckens, K.; Lentz, D.; Czekelius, C. Synthesis of Gold Complexes Bearing Sterically Highly Encumbered, Chiral Carbene Ligands. Organometallics 2011, 30, 1287-1290.
32. Bartolomé, C.; García-Cuadrado, D.; Ramiro, Z. Espinet, P. Inorg. Chem. Synthesis and Catalytic Activity of Gold Chiral Nitrogen Acyclic Carbenes and Gold Hydrogen Bonded Heterocyclic Carbenes in Cyclopropanation of Vinyl Arenes and in Intramolecular Hydroalkoxylation of Allenes. Inorg. Chem. 2010, 49, 9758-9764. Hashmi and coworkers reported similar complexes: Hashmi, A. S. K.; Hengst, T.; Lothschütz, C.; Rominger, F. New and Easily Accessible Nitrogen Acyclic Gold(I) Carbenes: Structure and Application in the Gold-Catalyzed Phenol Synthesis as well as the Hydration of Alkynes. Adv. Synth. Catal. 2010, 352, 1315-1337.
33. For early reports of the construction of gold-carbene complexes by nucleophilic addition to isocyanide complexes, see: Parks, J. E.; Balch, A. L. Gold Carbene Complexes as Intermediates in the α-Addition of Amines to Isocyanides. J. Organomet. Chem. 1973, 57, C103-C106; Parks, J. E.; Balch, A. L. Gold Carbene Complexes: Preparation, Oxidation and Ligand Displacement. J. Organomet. Chem. 1974, 71, 453-463.
34. A portion of this study has been published: Wang, Y.-M.; Kuzniewski, C.; Rauniyar, V.; Hoong, C.; Toste, F. D. Chiral (Acyclic Diaminocarbene)Gold(I)-Catalyzed Dynamic Kinetic Asymmetric Transformation of Propargyl Esters. J. Am. Chem. Soc. 2011, 133, 12972-12975.
35. The result was presented at the Aug. 9, 2010 Toste group problem set, as a mechanistic proposal problem.
36. This approach was first reported by Kitamura and coworkers, who also isolated a mixture of mono- and diiodinated products, which was cross coupled and resubjected to a second round of lithiation. However, this route was not amenable to rapid assembly of analogues of 19. Huang, H.; Okuno, T.; Tusda, K.; Yoshimura, M.; Kitamura, M. Enantioselective Hydrogenation of Aromatic Ketones Catalyzed by Ru Complexes of Goodwin-Lions- type sp2N/sp3N Hybrid Ligands R-BINAN-R’-Py. J. Am. Chem. Soc. 2006, 128, 8716- 8717.
37. Kano, T.; Tanaka, Y.; Osawa, K.; Yurino, T.; Maruoka, K. Facile Synthesis of Structurally Diverse 3,3’-Disubstituted 1,1’-Binaphthyl-2,2’-diamines in Optically Pure Forms. J. Org. Chem. 2008, 73, 7387-7389. Although the rearomatization step was
41  
reported to proceed in 74% yield, in our hands, yields higher than 45% were never obtained. This low yield was confirmed by an internal standard experiment.
38. Deuterochloroform (CIL), stored over 4A MS, was used as a source of preservative free and high purity chloroform.
39. Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics 2010, 29, 2176-2179.
40. Bartolomé, C.; Carrasco-Rando, M.; Coco, S.; Cordovilla, C.; Martín-Alvarez, J. M.; Espinet, P. Luminescent Gold(I) Carbenes from 2-Pyridylisocyanide Complexes: Structural Consequences of Intramolecular versus Intermolecular Hydrogen-Bonding Interactions. Inorg. Chem. 2008, 47, 1616-1624.
41. Künstler, T.; Schollmeyer, D.; Singer, H.; Steigerwald, M. Synthesis of Optically Pure Alkynols. Tetrahedron: Asymmetry 1993, 4, 1645.
42  
Chapter 2. Development of Halogenation Reagents for Chiral Anion Phase- Transfer Catalysis
43  
Introduction. The halofunctionalization of alkenes by an electrophilic halogen source in the presence of a nucleophilic trap is a synthetically versatile transformation with the potential to generate two stereogenic centers in addition to substantially increasing molecular complexity. In particular, intramolecular halofunctionalizations are especially efficient in the generation of five- and six-membered heterocyclic compounds. The development of catalytic enantioselective halofunctionalizations is a comparatively recent innovation, with the first examples giving high enantioselectivities reported around a decade ago.1 These recently reported methods are generally believed to operate through catalyst activation of the reagent and thus, nonselective background reactivity must be suppressed, often by high catalyst loadings or low reaction temperatures.
In 2011, the Toste group reported chiral anion phase transfer catalysis as an approach to address this difficulty.2 Through the use of an insoluble (and inactive) cationic reagent that is only rendered soluble (and reactive) upon ion pairing with a lipophilic chiral anion, background reactivity can be effectively suppressed. Although the well-known fluorination reagent F- TEDA-BF4 (Selectfluor®, Air Products and Chemicals) is a stable dicationic salt and well-suited for this mode of catalysis, suitable analogues for the heavier halogens were not known. In this Chapter, we detail efforts towards the development of reagents for the adaptation of this strategy to chlorination, bromination, and iodination.
Intramolecular halofunctionalization. The earliest example of a bromolactonization was reported by Hjelt and Fittig in 1883 (eq 2.1).3 Since then, this reactivity has been extended to the remaining three non-radioactive halogens,4 using a variety of O, N, and C nucleophiles.5 The development of enantioselective variants of halofunctionalizations, however, is a much more recent innovation.
Early approaches to enantioselective halofunctionalization were generally based on activation of either the halogen electrophile6 (eq 2.2) or latent nucleophile7 (eq 2.3) with Lewis acidic transition metal complexes. Early examples of halofunctionalization reactions that proceed through transition-metal rather than halonium activation of the olefin have also been reported.8
44  
Although the use of chiral amines for asymmetric induction in halofunctionalization was advanced as early at 1998, highly enantioselective metal-free halocyclization systems had not been reported until 2010, when Borhan and coworkers disclosed a cinchona alkaloid based system for asymmetric chlorolactonization (eq 2.4).9,10
The proposed mode of catalysis was reagent activation, either by hydrogen bonding between catalyst and reagent or electrophilic chlorine transfer from reagent to the catalyst. Since then, a flurry of activity has ensued and several classes of organocatalysts have been successfully applied to enantioselective halocyclization reactions, including thiocarbamate,11 aminourea,12
imidazoline,13 phosphoric acid (or phosphate anion),14 and amidine15 based catalysts. Most of these catalytic systems enhance reaction rate and induce enantioselectivity by activation of the electrophilic reagent, although Murai’s imidazoline system is believed to operate by nucleophile activation instead. As evidenced by the reaction temperatures required for these systems, which range from 78 C to 20 C, a challenge common to the development of enantioselective halocyclization reactions is the uncatalyzed background reaction between substrate and (unactivated) reagent, which requires lower reaction temperatures to suppress. To address this challenge, the Toste group developed the concept of chiral anion phase-transfer catalysis, in which solubility-enforced ion pairing between cationic reagent and an anionic source of chirality suppresses background reactivity.
45
Enantioselective catalysis using chiral ion pairs. The use of a “spectator” chiral counteranion
to induce enantioselectivity in reactions that involve cationic intermediates or reagents was
pioneered by Arndtsen and coworkers, who studied the effect of a BINOL-derived chiral borate
in the cationic copper-catalyzed aziridination of styrene. 16
Although effective enantiocontrol
could not be achieved, the observation of enantioselectivities up to 10% ee that tracked with
solvent polarity demonstrated the validity of the concept (eq 2.5).
Since then, List and coworkers introduced the use of chiral phosphate anions to the realm of
organocatalysis (eq 2.6), 17
while the Toste group developed the use of chiral phosphate anions as
an effective strategy for transition metal catalyzed transformations (eq 2.7). 18
In order to make the chiral anion approach suitable for cationic reagents or intermediates rather
than catalysts, a tactic was needed to enforce ion pairing between the substoichiometric chiral
anion and the stoichiometric reagent or intermediate. The Toste group developed chiral anion
phase transfer as one approach to contend with this difficulty. In this approach an ionic reagent
is physically segregated from substrate by virtue of its insolubility in nonpolar solvents. Ion
metathesis of the reagent with a chiral lipophilic phosphate anion brings the electrophile into
solution. In the ideal scenario, the electrophile is present in solution precisely when ion paired
with the source of chirality, eliminating the potential for nonselective background reaction.
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A precursor to the chiral anion phase transfer concept was first demonstrated in 2008, in the ring opening of meso-aziridinium and sulfonium ions.19 The insoluble reagent, Ag2CO3 undergoes phase transfer via acid-base reaction with the chiral phosphoric acid (TRIP20) to give the organic- soluble silver salt of the phosphate, AgTRIP, which reacts to further to deliver the crucial meso- aziridinium cation intermediate as an ion pair with the phosphate anion (eq 2.8).
A more generally applicable version of chiral anion phase transfer catalysis was reported by the Toste group in 2011 (Scheme 2.1). In this process, an ionic, insoluble (and, therefore, unreactive) halogenating reagent undergoes ligand exchange with a chiral phosphate salt to give the active electrophile in solution as a chiral ion pair. Reaction of the chiral ion pair with substrate affords the enantioenriched product, along with one proton equivalent to give the corresponding phosphoric acid. Reaction with a stoichiometric base regenerates the phosphate anion and completes the catalytic cycle. This new approach to enantioselective halofunctionalization was realized using F-TEDA-BF4 as a source of electrophilic fluorine and a C8H17-alkylated version of the TRIP phosphoric acid. Fluorocyclization of olefin-tethered amide furnished the fluoro- oxazoline with excellent yield and enantioselectivity (eq 2.9).2
Scheme 2.1: Generalized catalytic cycle for the electrophilic functionalization of alkenes using chiral anion phase transfer catalysis.
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In this study, we aimed to implement the extension of the fluorocyclization reaction to other halogens. Although seemingly straightforward, the lack of obvious ionic halogenating reagents for Cl, Br, and I analogous to F-TEDA-BF4 necessitated the development of a new class of tricationic brominating and iodinating reagents based on the 1,4-diazabicyclo[2.2.2]octane (dabco) framework, on which F-TEDA-BF4 is based.
Results and Discussion. When we initiated this study,21 our initial goal was to extend the Toste group’s recently reported chiral anion phase-transfer fluorination to the next heavier halogen chlorine. Based on a recent report that dabco could be chlorinated by Cl2 to give the bischlorinated adduct 2.1 (eq 2.10),22 we were inspired to prepare the chlorine analogue of F- TEDA-BF4, as a potential chlorination reagent. Although treatment of the direct precursor of F- TEDA-BF4, chloromethyldabconium tetrafluoroborate (2.2), with Cl2 resulted in sluggish conversion, heating 2.2 in the presence of iodobenzene dichloride in MeCN at 60 C resulted in clean conversion to a 9:1 mixture of halogenated product and starting material (eq 2.11). The spectroscopic data for the chlorinated product is consistent with 2.3,23 so the material, still containing 10% starting material, was evaluated for reactivity, along with the previously reported 2.1.
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Surprisingly, under conditions for fluorination phase-transfer with 2.1 or 2.3 in place of F- TEDA-BF4, no reaction was observed, and even under homogeneous conditions in MeCN, reaction with substrate gave low conversions (eq 2.12). Thus, further attempts to use these N- chloroammonium reagents for phase transfer chlorination were abandoned.
We next considered the development of a reagent for phase-transfer halogenation based on a quaternary ammonium analogue of N-bromosuccinimide. After unsuccessful attempts to adapt the chlorination conditions developed earlier to quaternary ammonium precursor 2.4 (eq 2.13), we turned to bromination as the next target. After some experimentation with typical conditions from the synthesis of N-bromo amides and imides, it was found that treatment of 2.4 with a mixture of KBrO3, aqueous HBr (48%), H2SO4 and water led to an N-brominated product, as an unstable orange solid.24 Although the exact identity of the anion was not known, it was felt that replacement with a more inert, non-reducing anion would be beneficial to stability. Thus the orange solid was treated with AgSbF6 to yield 2.5 as a colorless solid, which was always contaminated with some (at least 5%) starting material, despite extensive efforts to improve reaction conditions or purify by crystallization (eq 2.14). Qualitatively, 2.5 oxidized aqueous KI almost instantaneously, while bromolactonization was observed for carboxylic acid 2.6 in both toluene and acetonitrile (eq 2.15). The observation that strong background reactivity took place, even in nonpolar solvents, suggested that a different scaffold was necessary for a phase-transfer bromination reagent.
We speculated that although 2.3 was unreactive, the corresponding N-bromodabconium salt would be reactive. Thus, we treated 2.2 with Br2 as the source of electrophilic bromine and
49  
AgBF4 to effect counterion exchange.25 Filtration and concentration under reduced pressure gave a pale yellow solid, A which was one major product by 1H NMR (eq 2.16).
We were encouraged to find that subjecting 2.6 to A for 40 min in toluene resulted in <5% conversion to the bromolactonization product, although reaction took place rapidly under homogeneous conditions in MeCN. However, treatment of 2.6 with A did result in substantial conversion (33% in 40 min