Enantioselective Transformations of Carbon-Carbon Multiple Bonds Using Electrophilic Catalysts and Reagents By Yiming Wang A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor F. Dean Toste, Chair Professor K. Peter C. Vollhardt Professor Benito O. de Lumen Fall 2013
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Enantioselective Transformations of Carbon-Carbon Multiple Bonds Using Electrophilic Catalysts
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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
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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.
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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.
46
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.
47
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.
48
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