Arynes and Cyclic Alkynes as Synthetic Building Blocks for Stereodefined Quaternary Centers

Article abstract of DOI:10.1021/jacs.8b02875

We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates using β-ketoester-derived substrates. The conversion of β-ketoesters to chiral enamines is followed by reaction with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enantiomeric excesses as high as 96%. We also describe the one-pot conversion of a β-ketoester substrate to the corresponding enantioenriched α-arylated product. Computations show how chirality is transferred from the N-bound chiral auxiliary to the final products. These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides a solution to the challenging problem of stereoselective β-ketoester arylation/alkenylation, with formation of a quaternary center.

Full text of DOI:10.1021/jacs.8b02875

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Article
Arynes and Cyclic Alkynes as Synthetic Building
Blocks for Stereodefined Quaternary Centers
Elias Picazo, Sarah M. Anthony, Maude Giroud, Adam
Simon, Margeaux A. Miller, Kendall N. Houk, and Neil K. Garg
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02875 • Publication Date (Web): 01 May 2018
Downloaded from http://pubs.acs.org on May 2, 2018
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Arynes and Cyclic Alkynes as Synthetic Building Blocks for
Stereodefined Quaternary Centers
Elias Picazo,† Sarah M. Anthony,† Maude Giroud, Adam Simon, Margeaux A. Miller, K. N. Houk*, and
Neil K. Garg*
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Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
ABSTRACT: We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related
strained intermediates using β-ketoester-derived substrates. Conversion of β-ketoesters to chiral enamines is followed by reaction
with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enanti-
omeric excesses as high as 96%. We also describe the one-pot conversion of a β-ketoester substrate to the corresponding enantioen-
riched α-arylated product. Computations show how chirality is transferred from the N-bound chiral auxiliary to the final products.
These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides the
most general known solution to the challenging problem of stereoselective β-ketoester arylation/alkenylation, with formation of a
quaternary center.
methylacetates with 2-iodotrifluoroacetanilides,17 and the Pd-
INTRODUCTION
catalyzed α-arylation of malonates and cyanoacetates (race-
mic).18 A general method for the stereocontrolled α-arylation
Arynes have historically been avoided as synthetic interme-
diates as a result of their high reactivity.1,2 However, recent
or -alkenylation of β-ketoesters has not been disclosed.
studies have demonstrated that arynes can be generated under
mild reaction conditions,3 trapped regioselectively using pre-
a) Utility of arynes
dictive models,4 and employed in a host of synthetic applica-
i-Pr
tions. The utility of arynes is evident, as they have now been
i-Pr
OH
used to synthesize natural products, ligands, materials, agro-
Me
chemicals, and pharmaceutical agents (e.g., 1–3, Figure 1a).1,5
Me
O
i-Pr
i-Pr
NH
HF2C
N
The majority of reported synthetic applications of arynes are
intermolecular reactions that lead to achiral or racemic prod-
ucts.6 We questioned if arynes and related strained intermedi-
ates could instead serve as building blocks to generate enanti-
oenriched products bearing quaternary centers. Only two
methodologies leading to intermolecular, stereoselective aryne
trappings have been reported and are limited to the synthesis
of tertiary stereocenters.7,8
PCy2
H
N
Me
N
Me
Me
1
2
3
Tubingensin B
(Natural product)
XPhos
(Ligand)
Isopyrazam
(Agrochemical)
b) Present study
R'''
R'''
5
O
O
CO2R''
R
We considered the reaction manifold in which β-ketoesters
49 would be trapped with strained alkynes 5, to give their cor-
responding α-arylated products 6 with formation of a quater-
nary stereocenter (Figure 1b).10 As prior efforts to achieve this
direct functionalization in a racemic sense were accompanied
by an undesired C–C bond fragmentation,11 we considered a
two-step, alternative approach. First, β-ketoesters 4 would be
treated with amines 7 to afford the corresponding enamines
8.12 Trapping of the enamines 8 with in situ-generated arynes
(or strained cyclic alkynes) would give the α-arylated or
alkenylated products 6 after hydrolysis in the same pot.13 The
use of a chiral amine (i.e., 7) in this process would ultimately
give rise to enantioenriched products 6 bearing quaternary
stereocenters.10,14 It should be noted that the enantioselective
α-arylation of β-ketoesters has remained a challenging syn-
thetic problem.15 Promising developments include the use of
hypervalent iodine reagents (racemic or modest enantioen-
richment),16 the Cu-catalyzed, enantioselective coupling of 2-
*
R
R'
R' CO2R''
Direct arylation fails
4
6
Xc
NH
Xc
aq.
NH2
5
workup
CO2R''
R
7
R'
8
Arynes to generate stereodefined quaternary centers
Figure 1. Synthetic applications of arynes and strategy for the
stereoselective arylation of β-ketoesters.
We report the development of the synthetic sequence shown
in Figure 1b, which provides a facile method to achieve the
stereoselective α-arylation/alkenylation of β-ketoesters.9 In
addition to providing access to adducts bearing stereodefined
quaternary centers, this methodology demonstrates that highly
reactive arynes and related intermediates can serve as building
blocks to access enantioenriched products by intermolecular
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trapping. In addition, the origins of stereoselectivity have been
Page 2 of 7
21, which provided 12 in 80% and 56% ee (entries 3 and 4,
respectively). With improved results in the case of 20, we ex-
amined anthracenyl amines 22–24 (entries 5–7). As the use of
ethyl derivative 23 furnished 12 with the best combination of
yield and ee (entry 6), 23 was selected for subsequent studies.
It should be noted that the Ellman-approach provides both
enantiomers of 23, which, in turn, permits access to each enan-
tiomer of the products depicted subsequently.26,27
1
2
3
4
5
6
7
8
revealed by a computational investigation of these reactions.
RESULTS AND DISCUSSION
Development of a Racemic and Stereospecific Reaction
to Generate Quaternary Centers. To commence our studies,
we selected β-ketoester 9 as an initial substrate for the two-
step arylation procedure (Figure 2). As the use of enamines
and arynes to construct quaternary stereocenters was un-
known, we first pursued a racemic transformation. Benzyla-
mine was condensed with ketoester 9 to yield enamine 10
quantitatively. Next, enamine 10 was used to trap benzyne,
which was generated in situ from silyl triflate 11 (1.5 equiv) in
DME at 30 °C (6 h). After quenching with 1 M HCl(aq), we
were delighted to obtain the desired α-arylated product 12 in
92% yield with introduction of a quaternary center.19 Further-
more, we surveyed several other highly reactive intermediates
to gauge the possibility of utilizing substituted benzynes and
cyclic alkynes. The use of fused arynes 2,3-naphthalyne and
N-Boc-4,5-indolyne20 provided arylated products 13 and 14,
respectively.21 In addition, trapping with known heterocyclic
alkynes22 delivered tetrahydropyridine 15 and dihydropyran 16
in 67% and 74% yields, respectively. Regioselectivities for the
formation of 14–16 were in accord with the distor-
tion/interaction model.20,22 These results represent a facile
means to install aryl and vinyl moieties onto a cyclic β-
ketoester with quaternary center formation.
Table 1 Survey of chiral auxiliaries to give optically enriched
ketone 12.a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
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Xc
NH
O
Me3Si
TfO
O
i. CsF, DME, 30 °C
ii. 1 M HCl(aq)
+
OEt
*
CO2Et
17
11
12
Entry
Xc–NH2
ee
Entry
Xc–NH2
ee
Yield
Yield
Me
1
87%
74%
Ph
NH2
Me
5
71%
94%
18
9-anth
22
NH2
Me
2
64%
30%
Cy
NH2
Et
19
6
96%
84%
9-anth
23
NH2
Me
3
4
72%
79%
80%
56%
i. CsF, DME, 30 °C
1-naphth
20
NH2
Bn
O
Me3Si
NH
O
benzylamine
Na2SO4
CO2Et
11
CO2Et
iPr
NH2
TfO
*
CO2Et
7
100% 66%
benzene
Me
9-anth
ii. 1 M HCl(aq)
(quant. yield)
(92% yield)
24
9
10
12
2-naphth
21
NH2
Boc
N
NCbz
O
a
O
O
Reaction conditions: i. enamine 17 (1.0 equiv), silyl triflate 11
O
O
(1.5 equiv), CsF (7.5 equiv), DME (0.1 M), 30 °C, 6 h; ii. 1 M
HCl(aq), 23 °C, 30 min.
*
*
CO2Et
CO2Et
*
CO2Et
*
CO2Et
13
92% yield
14
42% yield a
15
67% yield
16
74% yield
Scope of Methodology. With a suitable chiral amine identi-
fied, we evaluated several cyclic alkynes in the stereoselective
arylation/alkenylation reaction to form quaternary stereocen-
ters (Figure 3). The reaction was tolerant of substituted ben-
zyne intermediates and extended aryl units, giving rise to ary-
lated products 28 and 13, respectively.28 Moreover, trapping of
an indolyne intermediate delivered heterocycle-containing
product 14. When applied to non-aromatic, strained alkynes,
the methodology provided alkenylated products in good yields
and stereoselectivities. For example, trapping of cyclohexyne29
provided cyclohexene derivative 29 in good yield and 86% ee.
Additionally, by employing heterocyclic alkynes, products 15
and 16 were obtained in excellent yields and comparable ste-
reoselectivities.
Figure 2. Discovery of methodology for the arylation/vinylation
of β-ketoesters in racemic fashion. Conditions for enamine for-
mation: ketoester 9 (1.0 equiv), benzylamine (1.5 equiv), Na2SO4
(5:1 by wt.), benzene (0.7 M), 80 °C, 16 h. Conditions for aryla-
tion/alkenylation unless otherwise stated: i. enamine 10 (1.0
equiv), silyl triflate 11 (1.5 equiv), CsF (7.5 equiv), DME (0.1 M),
30 °C, 6 h; ii. 1 M HCl(aq), 23 °C, 30 min. Yields reflect the aver-
a
age of two isolation experiments. Aryne trapping performed for
3 h.
Having developed the racemic arylation/alkenylation reac-
tion, we turned our attention to the discovery of a diastereose-
lective variant to access enantioenriched products (Table 1).23
Thus, a series of enantioenriched chiral amines, readily pre-
pared using Ellman auxiliary chemistry (i.e., 18–24),24,25 were
condensed with ketoester 9 to access enamines 17. Subsequent
arylation under the conditions depicted in Figure 2 furnished
12 in enantioenriched form. Utilization of phenyl derivative 18
resulted in the formation of 12 in good yield and 74% enanti-
omeric excess (ee) (entry 1). Employing amine 19, bearing a
cyclohexyl moiety, gave the desired product in a lower ee of
30% (entry 2). Recognizing the importance of the aryl frag-
ment, we examined 1- and 2-naphthyl derived amines 20 and
As shown in Figure 4, the methodology is also tolerant of
variation in the nucleophilic component. For example, re-
placement of the ethyl ester with a benzyl ester in the parent
substrate gave rise to arylated product 32 in 71% yield and
86% ee. Furthermore, piperidinone and tetrahydropyranone
derivatives could be employed to access heterocyclic products
(i.e., 33–35). Enamines derived from 7-membered ring β-
ketoesters could also be utilized, as shown by the formation of
arylated products 36 and 37 with excellent stereoselectivity.
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Lastly, the formation of ketoester 38 demonstrates the viability
arylated product 36, with recovery of the chiral auxiliary (Fig-
ure 5). β-Ketoester 39 was reacted with amine 23 to generate
enamine 40 in situ. Addition of CsF and silyl triflate 11, fol-
lowed by stirring at 30 °C for 6 h, and subsequent acid-
mediated hydrolysis yielded the desired α-arylated product 36.
When performed on mmol scale, the reaction gave 36 in 68%
yield and 92% ee, in addition to 67% recovered amine 23.
This protocol provides a promising means to achieve the di-
rect, asymmetric α-arylation of β-ketoesters.
1
2
3
4
5
6
7
8
of utilizing this methodology for the α-arylation of acyclic β-
ketoesters.
R
Et
Me3Si
TfO
O
9-anth
NH
O
i. CsF, DME, 30 °C
ii. 1 M HCl(aq)
+
R
OEt
*
CO2Et
25
26
27
Boc
9
Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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52
53
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N
i. CsF, DME, 30 °C
O
9-anth
NH
O
Me
Me3Si
23
O
CO2Me
CO2Me
11
O
CO2Me
O
benzene
80 °C
TfO
*
*
CO2Et
*
CO2Et
ii. 1 M HCl(aq)
CO2Et
*
mmol scale
one-pot
39
40
not isolated
36
68% yield, 92% ee
28
13
14
74% yield a
80% ee
(67% recovered 23)
80% yield
84% ee
94% yield
76% ee
Figure 5. One-pot, mmol-scale arylation reaction to furnish 36.
Conditions for enamine formation: ketoester 39 (1.0 equiv), amine
23 (1.0 equiv), benzene (0.7 M), 80 °C, 16 h, followed by evapo-
ration of benzene solvent. Conditions for arylation: i. silyl triflate
11 (1.5 equiv), CsF (7.5 equiv), DME (0.1 M), 30 °C, 6 h; ii. 1 M
HCl(aq), 23 °C, 12 h.
NCbz
O
O
O
O
*
CO2Et
CO2Et
*
CO2Et
*
29
15
16
97% yield a
86% ee
68% yield
86% ee
94% yield
86% ee
Computational Analysis of Chirality Transfer. Density
functional theory (DFT) calculations were performed to un-
derstand how stereochemical information is transferred from
the chiral auxiliary to the newly formed quaternary stereocen-
ter. Our laboratories have studied reactions of arynes in nucle-
ophilic additions using computations,4 but no theoretical stud-
ies of aryne trapping by chiral nucleophiles to set new stereo-
centers have been reported. All calculations described here
Figure 3. Variation of the electrophile. Conditions unless other-
wise stated: i. enamine 25 (1.0 equiv), silyl triflate 26 (1.5 equiv),
CsF (7.5 equiv), DME (0.1 M), 30 °C, 6 h; ii. 1 M HCl(aq), 23 °C,
30 min. Yields reflect the average of two isolation experiments.
Aryne or cyclic alkyne trapping performed for 3 h.
a
Et
M06-2X30/def2-TZVPP–SMD31
(diethyl
Me3Si
utilize
the
O
i. CsF, DME, 30 °C
ii. 1 M HCl(aq)
9-anth
NH
O
ether)//B3LYP32/6-31+G(d,p) level of theory (see the SI for a
discussion of the computational methods and results with other
density functionals).
+
*
R
R
OR’’
TfO
R' CO2R’’
R’
30
11
31
We first calculated the stereo-controlling transition struc-
tures for the reaction of benzyne and the S enantiomer of the
chiral enamine derived from amine 20, which possesses the 1-
naphthyl group at the chiral center. The stereochemistry-
controlling transition structures are shown in Figure 6. Each
pathway has a low barrier (∆G‡ = 9.6 and 11.6 kcal/mol, re-
spectively). TS1 leads to the experimentally preferred stereoi-
somer, (S)-12, whereas TS2 yields the minor enantiomer, (R)-
12.33 The difference in free energy of activation (∆∆G‡) is 2.0
kcal/mol, within error of the experimentally observed selectiv-
ity of 80% ee (∆∆G‡ = 1.3 kcal/mol). In both TS1 and TS2, an
intramolecular hydrogen bond between the NH and ester car-
bonyl is present. Axial-attack by benzyne occurs in both cases,
as expected from the preference the forming bond to be stag-
gered with respect to the allylic CH bonds (known previously
as the Fürst-Plattner rule).34 While attack is axial in both cases,
and the chiral group is in its favored conformation, the interac-
tion of the CH at the stereogenic center is disfavorable in the
minor TS.
O
N
O
O
O
O
CO2Et
*
*
CO2Me
*
CO2Et
*
CO2Bn
N
Ns
Boc
32
71% yield a
86% ee
33
34
35
83% yield a
86% ee
77% yield
88% ee
99% yield
86% ee
O
O
O
*
CO2Me
CO2Me
Me
*
*
Me CO2Et
O
36
69% yield
96% ee
37
78% yield a
96% ee
38
84% yield
78% ee
Figure 4. Variation of the nucleophilic component 30 in the trap-
ping with 11. Conditions unless otherwise stated: i. enamine 30
(1.0 equiv), silyl triflate 11 (1.5 equiv), CsF (7.5 equiv), DME
(0.1 M), 30 °C, 3 h; ii. 1 M HCl(aq), 23 °C, 30 min. Yields reflect
the average of two isolation experiments. Aryne trapping per-
formed for 6 h.
a
One-pot, Stereoselective Arylation. As one final applica-
tion of this methodology, we developed a one-pot variant of
the methodology to convert ketoester substrate 39 to α-
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Journal of the American Chemical Society
structed by the anthracene group. This conformation yields a
Page 4 of 7
R
1
O
higher-energy penalty than the torsional strain found in TS2,
R’
N
HCl (aq)
which enables an increase in enantiospecificity.
2
3
4
5
6
7
8
CO2Et
CO2Et
*
*
R
+
Favored
Major
(S)-12
R’
NH
9-anth biases
facial
selectivity
CO2Et
R
O
R’
N
HCl (aq)
(S)-20
R = Me;
R’ = 1-naphthyl
CO2Et
CO2Et
*
2.28 Å
*
9
2.38 Å
(S)-25
R = Et;
R’ = 9-anth
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Disfavored
Minor
(R)-12
hydrogen
bond
ΔΔG‡ = 2.5
TS3 (Major)
ΔG‡ = 9.5
TS4 (Minor)
ΔG‡ = 12.0
2.42 Å
Figure 7. Lowest-energy transition structures TS3 and TS4 for
the addition of benzyne and chiral enamine 25 (M06-2X/def2-
TZVPP–SMD (diethylether)//B3LYP/6-31+G(d,p)). Free energy
activation barriers (∆G‡) are compared to separated intermediates.
The difference in free energies of activation (∆∆G‡), relative to
TS1, are reported in kcal/mol.
2.37 Å
2.33 Å
2.13 Å
ΔΔG‡ = 2.0
TS1 (Major)
ΔG‡ = 9.6
TS2 (Minor)
ΔG‡ = 11.6
CONCLUSIONS
Figure 6. Lowest-energy transition structures TS1 and TS2 for
the addition of benzyne and the chiral enamine derived from
amine 20 (M06-2X/def2-TZVPP–SMD (diethylether)//B3LYP/6-
31+G(d,p)). Free energy activation barriers (∆G‡) are compared to
separated intermediates. The difference in free energies of activa-
tion (∆∆G‡), relative to TS1, are reported in kcal/mol.
We have developed the first methodology that allows for
arynes and related strained intermediates to be trapped inter-
molecularly for the formation of stereodefined quaternary
centers. The strategy relies on the facile conversion of β-
ketoesters to chiral enamines, which undergo nucleophilic
trapping of in situ generated strained arynes or cyclic alkynes.
Hydrolysis in the same pot provides the arylated products in
good to excellent enantiomeric excesses (up to 96% ee). This
strategy circumvents a previously known undesired C–C bond
fragmentation, while providing the most general solution to
the challenging problem of stereoselective β-ketoester aryla-
tion/alkenylation, with formation of a quaternary center. In
addition, a one-pot procedure for the conversion of a β-
ketoester substrate to the corresponding enantioenriched α-
arylated product was developed. Finally, computations show
how chirality transfer is achieved from the chiral auxiliary to
the final products, a type of conformational transmission oper-
ating in the trapping of arynes by chiral nucleophiles. We ex-
pect these studies will enable further developments of intermo-
lecular, stereoselective reactions of highly reactive aryne and
cyclic alkyne intermediates.
In TS2, there is a close-contact H–H interaction of 2.1 Å be-
tween the chiral center of the enamine and methylene of the
six-membered ring. This contact is alleviated in TS1, with an
H–H interaction distance of 2.4 Å. Our laboratory has previ-
ously examined the transmission of chirality in the reaction of
a similar chiral enamine with acrylonitrile, which similarly
revealed the importance of torsional interactions between
forming bonds and allylic bonds.34 In that case, the same con-
formations and their energies were found for the chiral
enamine with a phenyl ring instead of naphthyl. Torsional
strain35 controls the stereoselectivity of this reaction, where the
enamine conformations remain the same for both stereoiso-
meric transition states.
One might expect that the stereoselectivity cannot be modu-
lated by the size of the substituent, but as found here, enamine
25 has improved enantioselectivity with the larger 9-
anthracenyl substituent. We calculated the stereochemistry-
controlling transition structures for the reaction of chiral
enamine 25 and benzyne using methyl groups in place of ethyl
groups to simplify computations.36 The two lowest-energy
transition structures leading to the major and minor stereoiso-
mers are shown in Figure 7. TS3 leads to the experimentally
preferred stereoisomer, (S)-12, whereas TS4 yields the minor
enantiomer. The difference in free energy of activation (∆∆G‡)
is 2.5 kcal/mol, within error of the experimentally observed
selectivity of 84% ee (∆∆G‡ = 1.5 kcal/mol) and 0.5 kcal/mol
higher than observed with 20. Axial-attack by benzyne again
occurs for the two half-chair conformers of the cyclohexene.
However, here the conformation of the enamine stereogenic
group differs between the stereoisomeric transition structures.
Whereas the conformation of TS3 is analogous to that in TS1,
the enamine in TS4 is in a higher-energy conformation be-
cause the face being blocked to form the (R)-isomer is ob-
ASSOCIATED CONTENT
Supporting Information Available. Detailed experimental
procedures, compound characterization data, and computa-
tional analysis. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
houk@chem.ucla.edu; neilgarg@chem.ucla.edu
Author Contributions
†E.P. and S.M.A. contributed equally.
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ACKNOWLEDGMENT
1
The authors are grateful to the University of California, Los An-
geles for financial support. We are grateful to the NIH-NIGMS
(F31-GM117945 to E.P.), the Foote Family (E.P.), the Swiss Na-
tional Science Foundation for an Early Mobility Postdoctoral
Fellowship (M.G.), the UCLA Cota-Robles Fellowship Program
(E.P.), and the CBI training program (USPHS National Research
Service Award 5T32GM008496 to M.A.M. and A.S.). Dr. J.
Moreno (UCLA) is acknowledged for experimental assistance and
we thank the Nelson laboratory (UCLA) for use of instrumenta-
tion. These studies were supported by shared instrumentation
grants from the NSF (CHE-1048804) and the National Center for
Research Resources (S10RR025631). This work used computa-
tional and storage services associated with the Hoffman2 Shared
Cluster provided by UCLA Institute for Digital Research and
Education’s Research Technology Group.
stereocenters, see: a) Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.;
Lautens, M. J. Am. Chem. Soc. 2005, 127, 15028–15029. b) Webster, R.;
Lautens, M. Org Lett. 2009, 11, 4688–4691.
2
3
4
5
6
7
8
9
8 For the intermolecular trapping of arynes with Schöllkopf reagents (with
later hydrolysis) to generate tertiary stereocenters, see: a) Jones, E. P.;
Jones, P.; Barrett, A. G. M. Org. Lett. 2011, 13, 1012–1015. b) Jones, E.
P.; Jones, P.; White, A. J. P.; Barrett, A. G. M. Beilstein J. Org. Chem.
2011, 7, 1570–1576.
9
β-keto esters are commonly seen in bioactive molecules, so methods to
synthesize functionalized derivatives are valuable. A Reaxys search re-
veals there are 53,683 known β-keto esters with biological activity. Janu-
ary 24, 2018.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
Methodologies to generate quaternary stereocenters, especially with
control of absolute stereochemistry, remain highly sought after. For perti-
nent reviews, see: a) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516,
181–191. b) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem.
Res. 2015, 48, 740–751. c) Shockley, S. E.; Holder, J. C.; Stoltz, B. M.
Org. Process Res. Dev. 2015, 19, 974–981. d) Zeng, X.-P.; Cao, Z-Y.;
Wang, Y-H.; Zhou, F.; Zhou, J. Chem. Rev. 2016, 116, 7330–7396.
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12
1 For reviews regarding benzyne and related reactive intermediates, see: a)
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Enamines derived from β-ketoesters were considered well suited, as
they are stable on neutral alumina and can be purified prior to use.
13
For pioneering studies of racemic enamine arylations, see: a) Kuehne,
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A related breakthrough, albeit not using β-ketoesters, is the α-arylation
of oxindoles using Pd catalysis; see: a) Altman, R. A.; Hyde, A. M.;
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2
For the quantification of benzyne’s high electrophilicity, see: Fine
Nathel, N. F.; Morrill, L. A.; Mayr, H.; Garg, N. K. J. Am. Chem. Soc.
2016, 138, 10402–10405.
3 For Kobayashi’s generation of arynes from o-silyltriflate precursors, see:
Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–1214.
16
a) Beringer, F. M.; Forgione, P. S.; Yudis, M. D. Tetrahedron 1960, 8,
4
For the aryne distortion/interaction model, see: a) Cheong, P. H.-Y.;
49–63. b) Ochiai, M.; Kitagawa, Y.; Takayama, N.; Takaoka, Y.; Shiro,
M. J. Am. Chem. Soc. 1999, 121, 9233–9234. c) Oh, C. H.; Kim, J. S.;
Jung, H. H. J. Org. Chem. 1999, 64, 1338–1340.
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Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K. J.
Am. Chem. Soc. 2010, 132, 17933–17944. c) Goetz, A. E.; Bronner, S. M.;
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17 Xie, X.; Chen. Y.; Ma. D. J. Am. Chem. Soc. 2006, 128, 16050–16051..
18
For the Pd-catalyzed α-arylation of malonates, see: Beare, M. A.; Hart-
wig, J. F. J. Org. Chem. 2002, 67, 541–555.
19
By employing the N-deutero derivative of 10 in this transformation, we
observe deuterium incorporation on the ortho position of the aromatic ring
of 12. For details, see the SI.
20
For the synthesis and regioselective trappings of indolynes accessed
from silyltriflate precursors, see references 4a and 4b.
5
21
For select examples of synthetic applications, see: a) Mauger, C. C.;
For reasons not fully understood, the racemic arylation of the indolyne
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Shah, T. K.; Goetz, A. E.; Garg, N. K.; Houk, K. N. J. Am. Chem.
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Chem., Int. Ed. 2008, 47, 6338–6361. d) Ross, S. P.; Hoye, T. R. Nat.
Chem. 2017, 9, 523–530. e) Corsello, M. A.; Kim, J.; Garg, N. K. Nat.
Chem. 2017, 9, 944–949.
was lower yielding than the corresponding stereoselective arylation reac-
tion.
22
For the synthesis and regioselective trappings of these strained cyclic
alkynes, see: a) McMahon, T. C.; Medina, J. M.; Yang, Y.-F.; Simmons,
B. J.; Houk, K. N.; Garg, N. K. J. Am. Chem. Soc. 2015, 137, 4082–4085.
b) Shah, T. K.; Medina, J. M.; Garg, N. K. J. Am. Chem. Soc. 2016, 138,
4948–4954.
6
Intramolecular aryne trappings, although less common, have been used
23
to construct complex natural product frameworks. See references 1, 5, and
the following recent examples: a) Goetz, A. E.; Silberstein, A. L.;
Corsello, M. A. J. Am. Chem. Soc. 2014, 136, 3036–3039. b) Neog, K.;
Borah, A.; Gogoi, P. J. Org. Chem. 2016, 81, 11971−11977. c) Corsello,
M. A.; Kim, J. Garg, N. K. Nat. Chem. 2017, 9, 944–949. d) Ross, S.P.;
Hoye, T.R. Nat. Chem. 2017, 9, 523–530. e) Neumeyer, M.; Kopp, J.;
Brückner, R. Eur. J. Org. Chem. 2017, 2883–2915.
Other strategies for this transformation were pursued, such as the use of
Cu/BOX as a catalyst for the arylation reaction. Additionally, many other
classes of amines, such as amino acids and amino acid derivatives were
examined in the arylation reaction, but led to either poor yields and/or
poor stereochemical outcomes.
24
For a review on Ellman’s chiral sulfinamides, see: Ellman, J. A.; Ow-
ens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. Procedure followed
to synthesize chiral anthracenyl amines: Rodriguez–Hernandez, R.; Her-
nandez–Castillo, T.; Huizar–Trejo, K. E. Synthesis 2011, 17, 2817–2821.
7
For the intermolecular trapping of benzyne with dienes bearing the Op-
polzer sultam (with later cleavage of the auxiliary) to generate tertiary
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25
Chiral auxiliaries have seen widespread use to install important stereo-
centers in drugs and complex targets. For a recent review, see: Farina, V.;
Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev. 2006, 106, 2734–
2793. For examples using chiral sulfinamides, see: a) Pflum, D. A.; Krish-
namurthy, D.; Han, Z.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett.
2002, 43, 923–926. b) Han, Z. S.; Herbage, M. A.; Mangunuru, H. P. R.;
Xu, Y.; Zhang, L.; Reeves, J. T.; Sieber, J. D.; Li, Z.; DeCroos, P.; Zhang,
Y.; Li, G.; Li, N.; Ma, S.; Frinberg, N.; Wang, X.; Goyal, N.; Krishna-
murthy, D.; Lu, B.; Song, J. J.; Wang, G.; Senanayake, C. H. Angew.
Chem., Int. Ed. 2013, 52, 6713–6717. For examples of chiral auxiliaries
used in drug development see: Zhang, W.-Y.; Sun, C.; Hunt, D.; He, M.;
Deng, Y.; Zhu, Z.; Chen, C.-L.; Katz, C. E.; Niu, J.; Hogan, P. C.; Xiao,
X.-Y.; Dunwoody, N.; Ronn, M. Org. Process Res. Dev. 2016, 20, 284–
296.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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35
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44
45
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49
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26 For the crystallographic data used to assign the absolute stereochemistry
of amine 23 and its enantiomer, see the SI.
27
The choice of enantiomer of 23 used in subsequent experiments was
made arbitrarily, as both were prepared in gram quantities.
28
The regioselective formation of 28 is consistent with previously ob-
served trends in the trapping of 3-methylbenzyne; see: Aithagani, S. K.;
Dara, S.; Munagala, G.; Aruri, H.; Yadav, M.; Sharma, S.; Vishwakarma,
R. A.; Singh, P. P. Org. Lett. 2015, 17, 5547–5549.
29
For a study involving the generation and trapping of cyclohexyne, see:
Medina, J. M.; McMahon, T. C.; Jiménez-Osés, G.; Houk, K. N.; Garg, N.
K. J. Am. Chem. Soc. 2014, 136, 14706–14709.
30 Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215−241.
31
Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009,
113, 6378–6396.
32
a) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58,
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33
The stereochemical outcome predicted by the computational analysis
was validated experimentally. For the determination of product absolute
stereochemistry, see the SI.
34 Lucero, M. J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 826–827.
35
Wu, Y. D.; Houk, K. N.; Paddon-Row, M. N. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1019–1021.
36
From the results provided in Table 1, entries 5 and 6, the use of methyl
vs ethyl has a negligible impact on stereoselectivity.
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SYNOPSIS TOC
1
2
3
4
5
6
R’
Arynes &
Cyclic Alkynes
Xc
NH
X
O
R’
O
X
+
OR
Quaternary
Stereocenters
*
CO2R
n
7
up to 96% ee
n
8
9
O
One-Pot
Conversion
O
CO2Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2Me
92% ee
+
*
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