Total synthesis of hibispeptin A via Pd-catalyzed C(sp3)-H arylation with sterically hindered aryl iodides

Article abstract of DOI:10.1021/ol503347d

To access the key Ile-Hpa pseudodipeptide motif in hibispeptins, a series of bidentate carboxamide-based auxiliary groups have been explored to facilitate the palladium-catalyzed arylation of unactivated γ-C(sp³)-H bonds of Ile precursor with a

Full text of DOI:10.1021/ol503347d

Letter
pubs.acs.org/OrgLett
3
Total Synthesis of Hibispeptin A via Pd-Catalyzed C(sp )−H Arylation
with Sterically Hindered Aryl Iodides
Gang He, Shu-Yu Zhang, William A. Nack, Ryan Pearson, Javon Rabb-Lynch, and Gong Chen*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
*
S Supporting Information
ABSTRACT: To access the key Ile-Hpa pseudodipeptide motif in hibispeptins, a series of bidentate carboxamide-based auxiliary
3
groups have been explored to facilitate the palladium-catalyzed arylation of unactivated γ-C(sp )−H bonds of Ile precursor with
aryl iodides. A new pyridylmethylamine-based auxiliary group PR is introduced, which permits the use of more sterically hindered
3
ortho-substituted aryl iodide substrates and can be removed under mild conditions. Pd-catalyzed PR-directed γ-C(sp )−H
arylation enabled the first total synthesis of hibispeptin A.
3
he hibispeptins are pseudohexameric cyclic peptide
natural products isolated from the root bark of Hibiscus
Pd-catalyzed arylation of unactivated γ-C(sp )−H bonds of
isoleucine with sterically hindered ortho-substituted aryl
iodides. PR-directed C−H arylation of isoleucine enabled us
to accomplish the first total synthesis of hibispeptin A.
T
syriacus, which has long been used as antipyretic and
1
anthelmintic herbal medicine in Asia (Scheme 1). Their
Our synthesis of hibispeptin A commenced with an
investigation of the Pd-catalyzed γ-C−H arylation reaction of
Scheme 1. Structure of Hibispeptins Featuring an Ile-Hpa
Motif
7a
Ile substrate 8 directed by the N-linked picolinamide (PA)
auxiliary group (Scheme 2A). Our previous studies have shown
that the PA auxiliary group is effective at facilitating Pd-
3
catalyzed arylation of γ-C(sp )−H bonds of amino acid
2b
substrates with aryl iodides under mild reaction conditions.
These C−H arylation reactions likely proceed through a
kinetically favored five-membered palladacycle intermediate via
II/IV
a Pd
catalytic cycle (see 6 and 7 in Scheme 2) to give the γ-
arylated product. Our initial attempts at the arylation of Ile 8
with 1.5 equiv of 3-acylphenyl iodide 9 under our previously
2b
reported conditions (with 1.5 equiv of Ag CO in tAmylOH
2
3
at 80 °C) provided the desired product 10 in ∼30% yield. The
yield of 10 was improved to 51% by the addition of 20 mol %
10
of the dibenzyl phosphate ((BnO) PO H) additive at 50 °C
2
2
for 3 days. In addition to 10, γ,γ′-bis-arylated side product 11
was also obtained in 10% yield. In comparison, γ-C−H
arylation of Ile 8 with ary iodide 12 bearing an ortho methoxy
group gave a notably decreased yield of product 13 (31%),
along with ∼5% of bis-arylated product 14. Use of more forcing
reaction conditions, such as additional equivalents of aryl iodide
or a higher reaction temperature, led to a decreased yield of 13
with increased formation of 14 and other side products. The
structures feature a unique C−C cross-link between the γ-
methyl of an isoleucine (Ile) residue and the arene group of a 4-
hydroxy phenacylamine (Hpa) residue. We envisioned that we
could employ Pd-catalyzed auxiliary group directed arylation to
construct the key Ile-Hpa motif 3 (Scheme 1) via reaction of a
3
γ-methyl C(sp )−H bond of an Ile precursor (see 4) with a
2
−8
suitable aryl iodide (see 5).
Despite significant advances of
3
C(sp )−H arylation chemistry over the past decade, use of
complex and sterically hindered aryl coupling partners remains
a substantial challenge. Herein, we report the development of a
9
Received: November 18, 2014
removable pyridylmethylamine-based auxiliary group (PR) for
©
XXXX American Chemical Society
A
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Organic Letters
Letter
Scheme 2. γ-Me Arylation of Ile through a Five-Membered
Palladacycle Mediated by N-Linked Auxiliary Groups
Scheme 3. γ-Me Arylation of Ile through a Six-Membered
Palladacycle Mediated by C-Linked Auxiliary Groups
arylation of Ile 8 with a more complex aryl iodide (see 42 in
Scheme 5) gave an even further diminished yield (<20%). We
reasoned the first γ-Me arylation of 8 was sterically disfavored
due to the cis-configuration of the α-CO Me and β-Et groups
2
of palladacycle intermediate 6. Although methylene groups are
generally less reactive than methyl groups, the γ′-methylene C−
H arylation of 10 proceeds through palladacycle intermediate 7
with a more favorable trans-configuration of the α-CO Me and
2
11
the β-benzyl groups. Similarly, the arylation of Ile 15,
equipped with Carretero’s pyridyl sulfonamide (PS) directing
the PE auxiliary from product 25 under various conditions,
2d
7c
such as Boc activation and BF ·Et O treatment, failed to
3
2
5
a
group, with 12 gave product 16 in 23% yield (Scheme 2B).
To circumvent the undesired methylene arylation caused by
the unfavorable sterics of PA-coupled Ile 8, we turned our
attention to Daugulis’ aminoquinoline (AQ) directing group,
which was installed on the C terminus of Ile 19 (Scheme
give the desired products in acceptable yields and chiral
integrity. In comparison, C−H arylation of Ile 26 equipped
with Shi’s gem-dimethyl substituted pyridyl methylamine
17
directing group gave a 15% yield of product 27 (Scheme
18
3C).
7
,12
3A).
Recently, we have demonstrated that the γ-methyl
The resistance of the PE auxiliary group to intermolecular
amide cleavage prompted us to consider an intramolecular
3
C(sp )−H bonds of Ile 19 can undergo Pd-catalyzed
intramolecular amination with amide NH through a kinetically
less favored six-membered palladacycle intermediate (see 17)
2b
cleavage strategy. We reasoned that we could install a
protected OH group at the methyl position of PE (see TIPS
protected PR 30, Scheme 4A). Upon unmasking the TIPS
protecting group, a reversible intramolecular acyl transfer from
N to O might form a more labile ester intermediate (see 34,
Scheme 4B), which could be irreversibly cleaved to form an
ester or hydrolyzed to form a carboxylic acid. PR auxiliary 30
can be readily prepared on a multigram scale from
commercially available 2-vinylpyridine 28 using a sequence of
dihydroxylation via an epoxide intermediate, selective TIPS
13
to form γ-lactam products using the PhI(OAc) oxidant.
2
While the Pd-catalyzed AQ-directed γ-Me arylation of Ile 19
with simple aryl iodide 9 proceeded in >70% yield (results not
shown Scheme 3A), the same arylation reaction with aryl iodide
1
2 afforded the desired product 20 in a much lower yield
(
31%), along with a lactam side product 21 in 24% yield. In a
previous study, we also found that pyridyl methylamine (PM)
was an effective auxiliary group for Pd-catalyzed intramolecular
3
13
γ-C(sp )−H amination to form γ-lactams. However, arylation
of PM-coupled Ile 22 with 12 proceeded under the optimized
conditions A of 20 mol % (BnO) PO H and 1.5 equiv of
protection, N substitution, and reduction. Racemic PR 30 can
3
be readily installed onto Phth-Ile-OH using standard EDCI-
mediated amide coupling at rt to give Ile 31, preserving
excellent chiral integrity at Cα of Ile (>98%). To our delight,
PR-coupled Ile 31 underwent C−H arylation with 1.5 equiv of
12 to give product 32 in 69% yield under the general
2
2
AgOAc in dioxane at 110 °C to give the desired product 23 in
1
4,15
moderate yield (38%) (Scheme 3B).
To our delight, Ile 24
16
equipped with 2-pyridyl ethylamine (PE), a more conforma-
tionally constrained analogue of the PM group, underwent the
desired γ-Me arylation with 1.5 equiv of 12 under the general
conditions A to give product 25 in a much improved yield
19
conditions A (Scheme 4B). Treatment of compound 32 with
1.2 M HCl in MeOH or HF/pyridine in THF at rt gave TIPS
deprotected intermediate 33 in excellent yield. Heating
compound 32 with 1.2 M HCl in MeOH at 100 °C for 12 h
gave a mixture of compound 33 and the corresponding acyl
(
70%). Neither bis-arylated products nor C−N cyclization
products were observed. However, our attempts at removing
B
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Organic Letters
Letter
Scheme 4. Development of Removable PR Auxiliary for γ-Me Arylation of Ile with Sterically Hindered Aryl Iodides
Scheme 5. Total Synthesis of Hibispeptin A via Pd-Catalyzed PR-Directed γ-Me Arylation of Ile
transfer product 34 in ∼1:1 ratio. Disappointingly, the desired
transesterification of 34 with MeOH did not occur. However,
intermediate 33 can readily react with 1.5 equiv of triphosgene
at rt to form oxazolidone 36 in good yield. The oxazolidone
motif in 36 can be cleanly cleaved by treatment with 1.1 equiv
of LiOH/H O at 0 °C to give free carboxylic acid 37.
with 15 mol % of Pd(OAc) at 110 °C for 2 days. TIPS
deprotection of 42 with HF/pyridine, oxazolidone formation
2
with triphosgene, and subsequent cleavage of the acyl
oxazolidone with LiOH/H O gave the key Ile-Hpa residue
2
2
43 in good overall yield and excellent purity.
To our surprise, the seemingly straightforward macro-
2
2
Next, we proceeded to apply PR-mediated γ-Me C−H
arylation to the total synthesis of hibispeptin A (Scheme 5). 4-
cyclization of the C−C cross-linked pentapeptide scaffold of
21
hibispeptin was exceedingly challenging. To address the Cα
racemization problem of 43, the NPhth protecting group of Ile-
Hpa 43 was swapped with a Cbz group by treatment with
NH NH ·H O followed by CbzCl to give 44 in good yield.
Hydroxyl acetophenone 38 was first monoiodinated with I . An
2
azido group was then installed at the α-position of the carbonyl
group via CuBr -mediated α-bromination followed by S 2
2
N
2
2
2
substitution with NaN . Staudinger reduction of the N group,
Boc protection, and protection of the phenolic OH with BnBr
gave mono-Boc phenacylamine 40 in good yield. Treatment of
Saponification of 44 and followed by amide coupling with H-
Pro-OMe gave tripeptide 45 in excellent yield and with
complete retention of chiral integrity at Cα of Ile. The Boc
group of tripeptide 45 was removed with HCl in dioxane and
then coupled with dipeptide Boc-Leu-Phe-OH using EDCI/
HOBt to give pentapeptide 46. Hydrolysis of the methyl ester
of 46 with LiOH and Boc deprotection with HCl in dioxane at
rt gave the macrolactamization precursor. The desired macro-
3
3
compound 40 with excess Boc O/DMAP gave tri-Boc
2
20
protected compound 41 in 75% yield. To our delight,
arylation of PR-coupled Ile 31 with tri-Boc protected aryl
iodide 41 proceeded smoothly to give the desired γ-arylation
product 42 in 47% yield under slightly optimized conditions
C
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Organic Letters
Letter
lactamization at the Pro/Leu site mediated by pentafluoro-
phenyl diphenylphosphinate (FDPP) in dilute DMF solution
at rt for 2 days proceeded smoothly to give cyclic pentapeptide
Guo, K.; Liu, P.; Guan, M.; Yao, Y.; Zhao, Y.-S. Angew. Chem., Int. Ed.
22
2
(
014, 53, 9884.
6) For sporadic examples of C(sp )−H arylation with aryl iodides
bearing small ortho substituents, see: refs 2b, 5a, and 5e.
7) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
3
4
7. The Cbz and Bn groups of 47 were then deprotected by
(
Pd-catalyzed hydrogenolysis; subsequent coupling with pyro-
glutamic acid using EDCI/HOBt gave hibispeptin A 1 in
moderate yield after silica gel chromatography.
2
2
2
005, 127, 13154. (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
010, 132, 3965. (c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed.
012, 51, 5188.
In summary, we have explored a series of bidentate
carboxamide auxiliary groups for the palladium-catalyzed
arylation of the γ-methyl group of isoleucine to construct the
Ile-Hpa pseudodipeptide motif in hibispeptins. We successfully
introduced a new pyridylmethylamine-based auxiliary group
PR, which permits the use of more sterically hindered ortho-
substituted aryl iodide substrates and can be removed under
mild conditions. Finally, we applied the PR-directed Pd-
catalyzed C−H arylation reaction to the first total synthesis of
hibispeptin A.
(
8) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726.
(9) Noisier, A. F. M.; Brimble, M. A. Chem. Rev. 2014, 114, 8775.
(10) (a) Zhang, S.-Y.; He, G.; Zhao, Y.-S.; Wright, K.; Nack, W. A.;
Chen, G. J. Am. Chem. Soc. 2012, 134, 7313. (b) Zhang, S.-Y.; He, G.;
Nack, W. A.; Zhao, Y.-S.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135,
2
124.
(11) The D-allo-Ile substrate, a diastereomer of Ile 8 at the β-position,
underwent γ-Me arylation with 12 in excellent yield (>80%) and
monoselectivity under the same (BnO) PO H-promoted reaction
2
2
conditions at 80 °C.
12) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,
391.
13) He, G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Angew.
Chem., Int. Ed. 2013, 52, 11124.
14) The PM group was tested for Pd-catalyzed C(sp )−H arylation
with ArI but gave poor results in the earlier Daugulis report; see ref 7a.
15) For the first successful application of a PM directing group in
(
3
(
ASSOCIATED CONTENT
■
*
S
Supporting Information
3
(
1
13
Experimental procedures and H and C NMR spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
2
Ru-catalyzed C(sp )−H functionalization: (a) Inoue, S.; Shiota, H.;
Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 6898. For the
first Ru-catalyzed PM-directed carbonylation of unactivated C(sp )−H
bonds: (b) Hasegawa, N.; Charra, V.; Inoue, S.; Fukumoto, Y.;
3
AUTHOR INFORMATION
Corresponding Author
■
Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070.
*E-mail: guc11@psu.edu.
3
(
16) For sporadic examples of PE-directed Ru-catalyzed C(sp )−H
Notes
carbonylation: Hasegawa, N.; Shibata, K.; Charra, V.; Inoue, S.;
Fukumoto, Y.; Chatani, N. Tetrahedron 2013, 69, 4466.
(
The authors declare no competing financial interest.
17) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.;
Shi, B.-F. Chem. Sci. 2013, 4, 4187.
ACKNOWLEDGMENTS
We gratefully thank the Pennsylvania State University and NSF
CAREER CHE-1055795) for financial support of this work.
■
(18) Compared with PM, the constrained conformation of PE may
better facilitate the formation of a kinetically less favored six-
membered palladacycle intermediate. On the other hand, the high
rigidity of PiP may favor the formation of five-membered palladacycle
intermediate.
(
REFERENCES
■
(19) A single example of an OTBS-protected PR analogue used as a
(
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(
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(
20) Mono-Boc protected 40 is much less reactive for the C−H
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21) The difficulty of chemical cyclization of the pseudopentameric
3
(
(
(
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(
́
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(
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dx.doi.org/10.1021/ol503347d | Org. Lett. XXXX, XXX, XXX−XXX