Stereospecific Palladium-Catalyzed C-H Arylation of Pyroglutamic Acid Derivatives at the C3 Position Enabled by 8-Aminoquinoline as a Directing Group

Article abstract of DOI:10.1021/acs.orglett.7b01776

An efficient and stereospecific Pd-catalyzed protocol for the C-H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated cis products in good to high yields. Removal of the 8-aminoquinoline unit from these C-H arylation products enables access to synthetically useful cis and trans pyroglutamic acid-based building blocks.

Full text of DOI:10.1021/acs.orglett.7b01776

Letter
pubs.acs.org/OrgLett
Stereospecific Palladium-Catalyzed C−H Arylation of Pyroglutamic
Acid Derivatives at the C3 Position Enabled by 8‑Aminoquinoline as
a Directing Group
Oscar Verho, Micah Maetani, Bruno Melillo, Jochen Zoller, and Stuart L. Schreiber*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States;
Broad Institute, Cambridge, Massachusetts 02142, United States
S
* Supporting Information
ABSTRACT: An efficient and stereospecific Pd-catalyzed protocol
for the C−H arylation of pyroglutamic acid derivatives that uses 8-
aminoquinoline as a directing group is described. The reaction was
shown to proceed efficiently with a variety of aryl and heteroaryl
iodides bearing different functional groups, giving C3-arylated cis
products in good to high yields. Removal of the 8-aminoquinoline
unit from these C−H arylation products enables access to
synthetically useful cis and trans pyroglutamic acid-based building
blocks.
yroglutamic acid derivatives are an important class of
molecules in organic and medicinal chemistry given their
Since the pioneering work of Daugulis and coworkers in 2005,3
the combination of transition metal catalysis and directing group
chemistry has emerged as a powerful technique to promote direct
functionalization of a variety of unactivated primary and
secondary alkyl C−H bonds.2,4 This approach has proved
particularly useful for a number of cycloaliphatic or heterocyclic
substrates, as demonstrated by the recent protocols for the
C(sp3)−H arylation of benzodioxanes,5 cyclopropanes,6 cyclo-
butanes,6d,7 pyrrolidines,8 piperidines,8a,9 and cyclic ethers.5,6d,8a
For cyclic substrates, an attractive feature of these types of
reactions is that the arylation proceeds cis with respect to the
directing group, allowing for complete control of the stereo-
chemistry. Despite the remarkable progress within the field of C−
H functionalization in recent years, there exists, to the best of our
knowledge, no report of a method for the Pd-catalyzed C−H
arylation of pyroglutamic acid derivatives.
Our group recently developed a protocol for the Pd-catalyzed
C−H arylationofazetidinederivatives utilizing8-aminoquinoline
(8-AQ) as the directing group, which facilitated the synthesis of a
potent antimalarial compound.10 Initial trials with model
substrate 1 indicated that Pd(OAc)2 and AgOAc with the 8-AQ
auxiliary was an efficient combination for promoting C−H
arylation at the C3 position of the pyroglutamic acid scaffold in a
cis fashion. Further optimization efforts focused on the effects of
additives, solvent, reactionconcentration, andtemperatureonthe
C−H arylation of 1 (Table 1).11 The first set of reactions was
performed on a 0.1 mmol scale using Pd(OAc)2 (5 mol %),
AgOAc(1.5equiv), and4-iodotoluene(3equiv)asthearylsource
in DCE at 110 °C for 8 h (Table 1, entries 1−3). As observed in
previous C−H functionalization studies,8b,10,12 the addition of
P
prevalence as intermediates or targets in the synthesis of bioactive
compounds (Figure1).1 Anappealing feature of thepyroglutamic
Figure 1. L-Pyroglutamic acid and its derivatives exhibit a wide range of
bioactivities.
acid scaffold, particularly for applications inasymmetric synthesis,
is that it presents an inexpensive source of chirality that can be
conveniently accessed from glutamic acid. Most synthetic
manipulations that have been conducted on pyroglutamic acid
derivatives take advantage of the difference in stereoelectronic
influence of the two carbonyl moieties, which have allowed for
regioselective α-functionalization of either the C2 or C4
position.1b In contrast, functionalization of the C3 position of
these compounds constitutes a significant challenge, particularly
when attempted in the presence of other functional groups.
Inspired by modern C−H functionalization methods that allow
formoredirectwaystoformC−CandC−heteroatombonds,2 we
identified an opportunity to functionalize the C3 position
selectively using the carboxylic acid group as a handle for a
directing group. Such a synthetic approach would enable
straightforward access to a variety of C3-arylated pyroglutamic
acid derivatives, which could comprise interesting entries in
screening collections given the range of bioactivities exhibited by
this family of compounds.1
Received: June 12, 2017
© XXXX American Chemical Society
A
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Organic Letters
Letter
when 4-bromotoluene was employed as an aryl source (entry 15)
or when the C−H arylation was conducted on the corresponding
substrate with either afree lactam N−H or aBoc protecting group
(entries not shown).
Table 1. Selected Entries from the Optimization of the Pd-
Catalyzed C−H Arylation of Model Substrate 1
a
With optimized conditions in hand, we next explored the scope
of aryl iodides that could be used for the C−H arylation of 1
(Figure 2). The developed protocol was applicable to a wide
b
entry
additive (equiv)
solvent (M)
temp (°C) yield (%)
1
DCE (0.5)
110
110
110
110
110
110
110
110
110
110
110
110
120
120
120
9
2
PivOH (0.2)
DCE (0.5)
8
3
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.5)
(BnO)2PO2H (1.0)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
(BnO)2PO2H (0.2)
DCE (0.5)
65
16
57
60
65
60
68
71
73
62
80
nd
<5
4
i-PrOH (0.5)
toluene (0.5)
1,4-dioxane (0.5)
t-BuOAc (0.5)
MeCN (0.5)
CPME (0.5)
CPME (1.0)
CPME (1.0)
CPME (1.0)
CPME (1.0)
CPME (1.0)
CPME (1.0)
5
6
7
8
9
10
11
12
13
Figure 2. Scope of the Pd-catalyzed C−H arylation of pyroglutamic acid
derivative 1. Reaction conditions: substrate 1 (0.1 mmol, >99% ee),
Pd(OAc)2 (5mol%), AgOAc(1.5equiv), (BnO)2PO2H(0.2equiv), and
aryl iodide (3 equiv) dissolved in CPME (0.2 mL) and heated at 120 °C
under N2 atm for 8 h. All yields refer to isolated yields following silica gel
chromatography. b10 mol % of Pd(OAc)2 was used.
c
14
d
15
a
Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 (5 mol %), Ag(OAc)2
(1.5 equiv), additive, and 4-iodotoluene (3 equiv) were dissolved in
solvent and heated at the given temperature under N2 atm for 8 h.
b
Yield determined by 1H NMR using 1,3,5-trimethoxybenzene as
c
internal standard. Performed without Pd(OAc)2; nd = not detected.
d
Performed with 4-bromotoluene (3 equiv) instead of 4-iodotoluene.
variety of aryl and heteroaryl iodides, furnishing the correspond-
ing C3-arylated lactam products in good to high yields with either
5 or 10 mol % of Pd(OAc)2. C−H arylation reactions proceeded
most efficiently with aryl iodides bearing electron-donating
groups in the para position, as shown by reactions forming 2a and
2c. For aryl iodides containing electron-deficient groups or meta
substituents, reactions were less efficient, but the desired arylated
lactam products could still be isolated in satisfactory yields.
Notably, the protocol also allowed aryl iodides containing chloro-
and bromo-substituents to be used (2g−2i, 2q) without giving
rise to any side products originating from couplings over the C−
Cl or C−Br bonds. Interestingly, when 1,4-diiodobenzene was
usedforthearylation, itwaspossibletoobtain2jin53%yield. The
lower yield of this reaction was primarily due to a lower
conversion of 1, as only trace amounts were detected of the dimer
product arising from arylation of another equivalent of 1 by 2j.
The developed protocol was used for installment of other
synthetically useful functionalities such as carboxylic acid, ester
and nitro groups, and Boc-protected amine (2m−2p), though
these reactions typically proceeded in lower yields and required
increased catalyst loadings. Successful C−H arylation was
achieved with a number of different aryl and heteroaryl groups,
including naphthyl 2r, thiophene 2s, dihydrobenzofuran 2t, N-
tosylated indole 2w, and the more elaborately functionalized
pyridine 2u and chromene 2v. The described protocol was also
applied for synthesis of lactam 2x bearing a MIDA boronate
substituent in 50% yield, which is useful for further structural
elaborations through cross-coupling chemistry.16 Unfortunately,
the C−H arylation was less efficient for incorporation of ortho-
substituted aryl groups. With 10 mol % of Pd, we could prepare
ortho-fluoro-substituted lactam 2f in 69% yield; however, when
arylation was attempted with 2-iodotoluene instead, only trace
amounts of corresponding C3-arylated lactam was acquired (not
shown). Importantly, reactions were fully stereospecific and
dibenzyl phosphate had a positive impact on the performance of
this reaction, allowing for arylated product 2a to be obtained in
65% yield (vs 9% without). Pivalic acid (PivOH), a common
acidic additive in transition-metal-catalyzed C−H activation
reactions,13 was not found to have the same beneficial effect, and
2a was observed in only 8% yield. The reaction displayed a broad
tolerance for solvents, giving moderate to good yields in toluene,
1,4-dioxane, t-BuOAc, MeCN, and cyclopentyl methyl ether
(CPME) (entries 5−8). The reactions were generally highly
selective: only the desired cis product 2a14 and starting material 1
1
were observed by H NMR of the crude reaction mixture.
However, when i-PrOH was used as the solvent, the reaction
appearedtobelessselectiveandonly16%yieldof2awasobtained
(entry 4). Among the evaluated solvents, CPME was selected for
further experiments as it allowed for a high yield of 2a and
possessed a number of favorable, practical properties over the
other solvents, such as having a higher boiling point and good
safety profile.15 The reaction also worked well when the
concentration was increased, as demonstrated by the entry
performed at a 1 M concentration, which gave 71% yield (entry
10).
Although dibenzyl phosphate had a clear positive effect on the
performance of the reaction, no improvements in terms of yields
were seen when the stoichiometry of this additive was increased
beyond 0.2 equiv (Table 1, entries 11 and 12). Instead, the
reaction benefitted from being run at 1 M concentration and
120 °C, affording 2a in 80% yield (entry 13). Further efforts to
optimize the reaction by extending the reaction time had minimal
influence on the yield, which suggested that the catalytic system
becomes substantially deactivated after 8 h. As expected, a control
experiment without any Pd catalyst did not form any of the
anticipated product (entry 14). The protocol proved ineffective
B
DOI: 10.1021/acs.orglett.7b01776
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Letter
proceeded without erosion of the stereochemistry when
enantiomerically pure 1 (>99% ee; used in all reactions in Figure
2) was used.17
Scheme 1. Reductive and Nonreductive Conditions for
Removal of the Cbz Protecting Group from 2a and 2q
Next, weexaminediftheC−Harylation couldbeconductedon
a broader scope of pyroglutamic acid derivatives, so we prepared
3a−c bearing N-aryl substituents of varying electronic nature.
These substrates were conveniently synthesized from enantio-
pure L-pyroglutamic acid in two steps via Cu-catalyzed Chan-
Lam-type N-arylation18 followed by installation of the 8-AQ
directing group (see Supporting Information (SI)).
Forthisstudy, asmallsetofaryliodideswaschosen, comprising
one electron-rich, one electron-deficient, and one heteroaromatic
example(Figure3). N-Arylatedsubstrates3a−cwerelessreactive
Scheme2. Removalofthe8-AQDirectingGroupfrom4aand5
products epi-4a and epi-5 in 61 and 51% yield, respectively. With
P2-Et, complete epimerization was achieved after 24 h at 80 °C;
the isolated yield of the epimeric products was typically moderate
due to concomitant decomposition processes. For comparison,
the same epimerization reaction was very inefficient with
conventional bases, such as LiOtBu, DBU, and Et3N. In an
analogous manner, applying the ozonolytic directing group
cleavage method on epi-4a and epi-5 allowed access to trans-
configured primary amides epi-8 and epi-9 in 70 and 60% yield,
respectively.
Alternatively, the 8-AQ group can be cleaved to generate the
free carboxylic acid building blocks. Using the ozonolytic
conditions and cleaving the corresponding imide intermediate
of 5 with LiOH/H2O2 at rt, it was possible to generate the cis-
configured acid 11 in 54% yield. We observed significant amounts
of cis-amide 9 in this reaction because of moderate regioselectivity
in hydrolysis of the imide intermediate (Scheme S1). In the
cleavage of 4a, this side reaction was even more pronounced, and
cis-amide8wasformedalmostexclusivelyover cis-acid10. Instead
of optimizing this hydrolysis reaction, we prepared 10 from 11 by
the same Chan-Lam method used previously for the synthesis of
the N-arylated substrates 3a−c. This reactionallowed ustoobtain
cis-acid 10 in 57% yield, which shows that 11 could be used as a
potential building block for generating a diverse set of analogues
through Cu-catalyzed N-arylation. The trans-configured acid
productsepi-10andepi-11wereaccessed inhighyields bytreating
lactams4aand5withLiOHat75°C, whicheffectivelycleavedthe
8-AQ moiety with concomitant epimerization.
Figure 3. Pd-catalyzed C−H arylation of N-arylated pyroglutamic acid
derivatives 3a−c. Reaction conditions: substrate 3a−c (0.1 mmol),
Pd(OAc)2 (10 mol %), AgOAc (1.5 equiv), (BnO)2PO2H (0.2 equiv)
and aryl iodide (3 equiv) dissolved in CPME (0.2 mL) and heated at 120
°C under N2 atm for 8 h. All yields refer to isolated yields following silica
gel chromatography.
than 1, calling for the use of higher catalyst loadings: with 10 mol
% Pd(OAc)2, the nine N-arylated lactam products 4a−i were
obtained in 53−67% yield with excellent control of stereo-
chemistry.19 The trend observed in aryl iodide reactivity in the
reactions involving substrates 3a−c were consistent with that
observed for substrate 1, where the highest yields were obtained
with 4-iodotoluene. Although C−H arylation seemed to benefit
slightly from electron-deficient N-aryl substituents, there was a
very marginal difference in reactivity between 3a−c.
Having prepared a variety of C3-arylated pyroglutamic acid
derivatives, we next evaluated their synthetic utility. For example,
the Cbz-group of 2a was conveniently removed by Pd/C-
catalyzed hydrogenolysis to furnish unprotected lactam 5 in 87%
yield (Scheme 1a), with both relative and absolute stereo-
chemistry confirmed by X-ray crystallography. Although hydro-
genolysis constitutes an operationally simple way of removing the
Cbz group, it is incompatible with substrates containing reducible
substituents. For the dihalogenated lactam 2q, 3 equiv of
catecholborane bromide 620 can be used to remove the Cbz
group, giving 7 in 92% yield (Scheme 1b).
In summary, a new Pd-catalyzed protocol employing 8-AQ as
the directing group was developed that allows for the stereo-
specific arylation of the C3 position of different pyroglutamic acid
derivativesingoodtohighyields.Importantly, thisC−Harylation
proceeds efficiently with a diverse set of aryl and heteroaryl
iodides containing a variety of functional groups. The obtained
C3-arylated products were highly useful for a number of
subsequent chemical transformations, which highlights the
To establish the synthetic utility of our method more
completely, we focused on the cleavage of the 8-AQ directing
group (Scheme 2). Using an operationally simple single-flask
procedure,21 we removed the 8-AQ directing group effectively
from 4a and 5 to form primary amides 8 and 9, respectively. It was
also possible to epimerize 4a and 5 through the use of the
phosphazene-type superbase P2-Et22 to give the trans-configured
C
DOI: 10.1021/acs.orglett.7b01776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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3238. (c) Roman, D. S.; Charette, A. B. Org. Lett. 2013, 15, 4394.
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potential of this methodology to generate pyroglutamic acid
derived analogues for small-molecule screening.
(7) (a) Gutekunst, W. R.; Baran, P. S. J. Org. Chem. 2014, 79, 2430.
(b) Parella, R.; Gopalakrishnan, B.; Babu, S. A. J. Org. Chem. 2013, 78,
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(8) (a) Affron, D. P.; Bull, J. A. Eur. J. Org. Chem. 2016, 2016, 139.
(b) Feng, R.; Wang, B.; Liu, Y.; Liu, Z.; Zhang, Y. Eur. J. Org. Chem. 2015,
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ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01776.
■
S
Experimental procedures, compound characterization
data, and NMR spectra (PDF)
X-ray data for 5 (CIF)
(9) Yu, Q.-Y.; Zhong, H.-M.; Sun, W.-W.; Zhang, S.-J.; Cao, P.; Dong,
X.-P.; Qin, H.-B.; Liu, J.-K.; Wu, B. Asian J. Org. Chem. 2016, 5, 608.
(10) Maetani, M.; Zoller, J.; Melillo, B.; Verho, O.; Kato, N.; Pu, J.;
Comer, E.; Schreiber, S. L. J. Am. Chem. Soc. 2017, DOI: 10.1021/
jacs.7b06994.
(11) For a more comprehensive summary of the reaction condition
screening, please see Table S1.
(12) (a) Zhang, S.-Y; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J.
Am. Chem. Soc. 2013, 135, 2124. (b) Zhang, S.-Y; Li, Q.; He, G.; Nack, W.
A.; Chen, G. J. Am. Chem. Soc. 2013, 135, 12135.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stuart_schreiber@harvard.edu.
ORCID
Stuart L. Schreiber: 0000-0003-1922-7558
Notes
The authors declare no competing financial interest.
(13) Hamilton, G. S.; Ladd, C. L. Pivalic Acid. e-EROS Encyclopedia of
Reagents for Organic Synthesis; Wiley & Sons: Chichester, UK, 2015; pp
1−9.
ACKNOWLEDGMENTS
■
1
S.L.S. is an investigator at the Howard Hughes Medical Institute.
This work was supported by a grant form the National Institute of
General Medical Sciences (GM-038627). O.V. was supported by
the Wenner-Gren Foundations and the Swedish Chemical
Society (Stiftelsen Bengt Lundqvists Minne). M.M. was
supported by a fellowship from the National Science Foundation
(DGE1144152) and from Harvard University’s Graduate Prize
Fellowship. J.Z. was supported by a postdoctoral fellowship from
DAAD. B.M. was supported by a postdoctoral fellowship from
Harvard University. We thank the Broad Institute analytical team
for HRMS data, Tom Clinckemaillie for assistance with SFC, and
(14) The relatively large coupling constant of the H resonance for
proton α to the 8-AQ amide group was in line with those found for other
cis-configured pyroglutamic acid derivatives: Hartwig, W.; Born, L. J. Org.
Chem. 1987, 52, 4352. The corresponding trans product with smaller
coupling constant was not detected by 1H NMR. Also, 2D ROESY NMR
experiments support the respective stereochemistry.
(15) Watanabe, K.; Yamagiwa, N.; Torisawa, Y. Org. Process Res. Dev.
2007, 11, 251.
(16) (a) Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, 42, 17.
(b) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131,
6961.
(17) Determined by supercritical fluid chromatography (SFC) analysis
of 2a, 2d, and 2k (see SI for details).
Peter Muller (Massachusetts Institute of Technology) for X-ray
̈
(18) Berry, A.; Betageri, R.; Riether, D.; Eugene, R.; Wu, L.; Zindell, R.
M.; Khor, S. PCT Int. Appl. WO2010077836, 2010.
(19) SFC analysis showed that 4a, 4d, and 4g were all obtained in >98%
ee and > 20:1 dr (involving all three synthetic steps, starting from
enantiopure L-pyroglutamic acidto thefinalC−Harylation products; see
SI for more information).
crystallographic structural analysis.
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