Total Synthesis of (-)-Maximiscin

Article abstract of DOI:10.1021/jacs.0c03202

A short, enantioselective synthesis of (-)-maximiscin, a structurally intriguing metabolite of mixed biosynthetic origin, is reported. A retrosynthetic analysis predicated on maximizing ideality and efficiency led to several unusual disconnections and tac

Full text of DOI:10.1021/jacs.0c03202

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Communication
Total Synthesis of (–)-Maximiscin
Kyle S. McClymont, Feng-Yuan Wang, Amin Minakar, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03202 • Publication Date (Web): 25 Apr 2020
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Journal of the American Chemical Society
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Total Synthesis of (–)-Maximiscin
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Kyle S. McClymont, Feng-Yuan Wang, Amin Minakar, and Phil S. Baran*
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Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
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Supporting Information Placeholder
sequence (Tactic 2) to forge the hindered C-3,7-bond and set its
ABSTRACT: A short, enantioselective synthesis of (–)-
maximiscin, a structurally-intriguing metabolite of mixed
biosynthetic origin, is reported. A retrosynthetic analysis
predicated on maximizing ideality and efficiency led to
several unusual disconnections and tactics. Formation of the
central highly-oxidized pyridone ring through a convergent
coupling at the end of the synthesis simplified the route
considerably. The requisite building blocks could be
prepared from feedstock materials (derived from shikimate
and mesitylene). Strategies rooted in hidden symmetry
relative trans-orientation. During this process, a remarkably
efficient radical cascade was developed to achieve not only this
bond formation but also a redox relay11 to set the proper C-13
oxidation state. Recognizing that if the C-13 position were simply a
methyl group, an enantiocontrolled desymmetrizing C–H activation
could be invoked (Tactic 3) to cement the absolute configuration of
four centers in one step.12 Such a tactic is not without risk, as the
required C-H activation would enlist a challenging 6-membered
palladacycle intermediate.13 Finally, the all-cis stereochemistry
needed for this step could originate from the hydrogenation of an
inexpensive mesitylene-derived carboxylic acid 714 (Tactic 4).
recognition,
C–H
functionalization,
and
radical
retrosynthesis played key roles developing this concise route.
A. Biosynthetic building blocks:
NH2
Me
O
2: shikimate
3: Tyr
4: PK
Natural products derived from mixed biosynthetic lineages have
historically provided chemists with some of the most exotic
molecular architectures imaginable (e.g. staurosporine, hyperforin,
and reserpine).1 The unique structure of (–)-maximiscin 1 (Figure
1A) is no exception, resulting from the rare union of three separate
metabolic pathways.2 Thus, a central 1,4-dihydroxy-2-pyridone
(derived from tyrosine 3) is linked to both a shikimate derivative
(derived from shikimic acid 2) and a trisubstituted cyclohexyl
fragment of polyketide origin (derived from 4). As such, 1 exists as
an equilibrating mixture of atropisomers about the C-3,7 bond. The
challenge associated with synthesizing such a structure is
compounded by its documented instability, as it tends to fragment
between the shikimate and pyridone residues.3 4-hydroxy-2-
pyridone alkaloids such as 1 have historically represented an
exciting class of natural products for chemical synthesis, due to their
intriguing structural properties, and biological activiites.4 Although
no synthesis of 1 has been reported, simpler variants lacking the
shikimate subunit have been prepared.5 In this Communication, an
abiotic, convergent, enantioselective preparation of 1 is reported;
this synthesis is enabled by exploiting hidden symmetry and
leveraging the logic of C–H functionalization6 and radical
retrosynthesis strategies7.
CO2H
CO2Me
Me
O
A
B
C
HO
OH
HO
OH
CO2Me
OH
Me
Me
Me
O
C
7
O
N
3
A
B
HO
OH
OH
(–)-maximiscin (1)
OH
B. Convergent, symmetry guided approach:
7:
5:
6:
3
2
O
OH
Me
Me
HO2C
O
Me
Me
R
N
1
HO2C
13
(<$1/g)
4
Si
Me
Enabled by 4 Key Tactics
[1] “Aza-Sakurai”
[2] Radical cross-coupling translocation cascade
[3] Enantiocontrolled desymmetrizing C–H activation
[4] Syn-selective hydrogenation
To maximize convergency, retrosynthetic scission of the central
pyridone ring produced two equally sized fragments (R=shikimate
derivative 5, and 6). Their union through a non-canonical
Guareschi-Thorpe-type condensation (Tactic 1, Figure 1B) could
potentially forge this core motif at a late-stage. While such
condensations normally require an electron-withdrawing group on
the enamine fragment,8 in this variant a b-silicon atom was
employed, reminiscent of the Sakurai-type allylation.9 This
provided the added benefit of building in the requisite N-oxide
motif, which would otherwise require subsequent oxidation from
the parent pyridone.5, 10 Fragment 5 could be traced back to a known
shikimate-derived epoxide in a few simple steps. Fragment 6 was
envisaged to arise from a decarboxylative radical homologation
Figure 1. (A) (–)-Maximiscin (1): biosynthesis; (B) key strategies
and tactics employed.
The successful execution of these tactics to access synthetic 1 for
the first time is outlined in Scheme 1. Preparation of fragment 6
(Scheme 1A) began with hydrogenation of 7 using Adam’s catalyst,
which furnished the all-cis carboxylic acid 8 with complete
selectivity in 97% isolated yield (gram-scale).15 This set the stage
for the development of a desymmetrizing C–H activation reaction
that was to define four chiral centers from this meso-acid.16 An
exhaustive set of directing groups and C–H functionalization
conditions were explored (see SI), culminating in the identification
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Journal of the American Chemical Society
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of a chiral PIP-type directing group (9, X = H, inset table 1).17
Amide 10d, derived from acid 8 and amine 9 (84% isolated yield,
gram-scale), conferred reasonable yield and high
diastereoselectivity under Pd-catalyzed methoxylation conditions to
deliver 11.18 The influence of various substituents on the pyridyl
ring of the directing group was then explored. Although
diastereoselectivity remained high, ring electronics exerted a
profound effect on reaction yield (inset table 1). A 4-Cl substituted
analog was identified as the optimal directing group, and upon
Synthesis of fragment 5 was accomplished starting from known
epoxide 16, which is derived from shikimic acid (Scheme 1B).28
Opening of the epoxide intermediate to furnish 17 was achieved
using N-Boc-hydroxylamine assisted by DBU in methylene chloride
(70% isolated yield, gram-scale); use of Lewis acids led to mixtures
of SN2/SN2’ products, while elimination/aromatization pathways
dominated in different solvents. X-ray analysis confirmed the
regioselectivity of the epoxide opening process. Intermediate 17
was converted to a TBS-protected hydroxylamine intermediate
(72% isolated yield, gram-scale), which was condensed with
acetaldehyde to give des-TMS-5 (not shown, 82% isolated yield).
The final bond-forming step involved union of this fragment with 6
using a bold late-stage pyridone synthesis to forge the central ring
of 1. Initial conditions surveyed for this step were based on a report
for the synthesis of alkyl-fused hydroxypyridones, derived from
diacid chlorides and ketoxime ethers.29 Combination of oxime ether
des-TMS-5 with the diacid chloride derivative of 6 in toluene at
90°C generated intractable mixtures of decomposition products,
with significant recovery of unreacted des-TMS-5. It was reasoned
that the poor nucleophilicity of the oxime ether, combined with
elevated reaction temperatures, promoted decomposition of the
diacid chloride before it could engage with the oxime. To remedy
this, two modifications were implemented: (1) The TMS derivative
5 was prepared, inspired by the venerable Hosomi-Sakurai
reaction30 as it was envisaged that a β-silicon effect could enhance
the nucleophilicity at nitrogen via σ(Si–C) to π donation.31 (2) The
reaction was conducted at lower temperature, using AgOTf to
promote activation of the diacid chloride electrophile. Ultimately,
this push-pull system of Si/Ag+ activation delivered the
condensation product 18 in moderate yield with surprising speed
(reaction quenched after 7 minutes, see inset table 3 for selected
optimization conditions). The reaction benefited from elevated
temperature, although by-products became predominant above 50
°C. Acetonitrile proved to be the optimal solvent, and a methanol
quench was employed to liberate product which had been acylated
on the pyridone 4-OH by starting material. This enabled the facile
recovery of the diacid fragment as a mixture of the mono- and di-
methyl esters (25% + 22% respectively) which could be recycled to
access additional 6. A reasonable mechanistic proposal involves
silver mediated activation of the diacid chloride derived from 6, to
produce a transient diacyl triflate, which is intercepted by oxime 5,
assisted by the appended TMS moiety. This would produce an
enamine intermediate which could rapidly engage the second acyl
electrophile in an intramolecular fashion to generate the pyridone
ring. Additionally, TMSOTf generated in situ may serve to further
enhance the reactivity of the electrophile (TMS derivatization is
observed by LCMS). The importance of the silyl substituent on 5 is
highlighted by the observation that des-TMS-5 provides 18 in much
lower yield (14%) under the same reaction conditions (see SI). This
represents a unique pyridone synthesis and enables the construction
of a remarkably hindered ring system, which exists as a mixture of
interconverting atropisomers. Deprotection using TFA/MeOH
afforded (–)-maximiscin 1 ([ꢀ]ꢁꢀꢂ.ꢂ = –147), completing a 10-step
(LLS) total synthesis of this natural product (60% ideality).32 All
spectral data were wholly consistent with the original isolation
report.2
1
2
3
4
5
6
7
8
further refinement of the reaction conditions,
a scalable
desymmetrizing methoxylation to access 11 was realized (58%
isolated yield + 23% recovered 10d, gram-scale). This, to the best
of our knowledge, represents the most complex desymmetrizing C–
H activation reported to-date.19 It defines 4 stereocenters in a single
step, including the distal δ-methyl substituent, which is remote from
the directing group. Removal of the directing group from 11 was
accomplished using HBr at elevated temperature (99% isolated
yield, gram-scale). This reaction cleanly delivered lactone 12, along
with a substantial amount of recovered directing group 9 (80%). The
latter material could be recycled, and used to prepare another batch
of amide 10d for the C–H activation sequence, without any erosion
in enantiopurity (see SI). With lactone 12 in hand, the next tactic
involved effecting a decarboxylative homologation for a key C–C
bond forming step, drawing further utility from the C–H
functionalization handle. Phenyl vinyl sulfone was selected as the
homologation reagent of choice. It represents a simple, inexpensive
2-carbon extension unit, and has precedent for such applications.20
Initial success was achieved using a Ni-catalyzed decarboxylative
Giese addition protocol21 (performed on a derivative of 12, see SI),
but the yield was hampered by competing 1,5-hydrogen atom
transfer (1,5-HAT) from C–2 to C–13 which resulted in double
addition of the radical acceptor onto C–13 (see SI). It was
hypothesized that transitioning from a reductive to oxidative
decarboxylative manifold could enable this transposed radical to be
oxidized, thus producing aldehyde 14.22 A number of exotic redox
strategies were evaluated before a simple solution emerged (see SI)
using Minisci-type conditions23 directly from lactone 12, which was
hydrolyzed in-situ. Thus, following saponification of lactone 12
with NaOH (1.2 equiv), sequential addition of AgNO3 (0.3 equiv),
Na2S2O8 (2.5 equiv), NaHSO4 (1.13 equiv), Fe2(SO4)3 (0.2 equiv),
and the vinyl sulfone led to the formation of aldehyde 14. The
reaction was exceptionally clean (see SI for crude NMR) and proved
scalable, resulting in a 91% yield of 14 on gram scale. Some features
of this radical translocation cascade are worth noting. The addition
of NaHSO4 enabled the tandem hydrolysis/decarboxylation by
buffering the resulting carboxylate. Without it, a heterogeneous
mixture resulted, leading to aggregate formation and diminished
product yield. The standard Ag+/persulfate combination proved
ineffective (ca. 6% yield), prompting the exploration of additives
(inset table 2). Fe2(SO4)3 uniquely served as a highly efficient co-
catalyst, the first use we are aware of in concert with a Ag-catalyzed
Minisci-reaction.24 The reaction requires both metals to be present,
as no desired product is formed in the absence of Ag. Literature on
the reactivity of Fe-salts in free radical chemistry suggest that the
Fe3+ can assist in the selective oxidation of the intermediate α-oxy
alkyl radical.25 With aldehyde 14 in hand, access to key building
block 6 could be rapidly achieved. Classical Wittig conditions
provided an olefin intermediate which was elaborated to 15 through
a one-pot sulfone oxidation and methyl ester formation sequence
(50% yield overall).26 Next, acylation of 15 proved challenging,
with most acyl electrophile/base combinations leaving the hindered
ester untouched. Use of LDA with Mander’s reagent in diethyl ether
proved uniquely effective,27 and in-situ hydrolysis of the resulting
diester provided 6 in 74% isolated yield. The crude diacid could be
purified by simple trituration, and yielded crystals suitable for x-ray
diffraction, which confirmed its absolute configuration.
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Several unusual steps in this synthesis are worthy of note: (1) a
scalable enantiocontrolled C–H activation-desymmetrization
defined 4-stereocenters in a single step and enabled access to a
highly-functionalized carbocycle from simple aromatic feedstock;
(2) a radical disconnection, leveraging a Ag/Fe co-catalyzed
stereoinvertive decarboxylative Giese addition, constructed a
hindered C–C bond with concomitant radical translocation to a
remote site; (3) a non-intuitive disconnection through the central
hydroxypyridone ring enabled a highly convergent synthesis of 1
and led to the development of a new tactic to assemble such systems.
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Journal of the American Chemical Society
Scheme 1. Total synthesis of maximiscin (–)-1. a
1
2
3
4
5
6
7
8
9
A. Synthesis of fragment X
B. Synthesis of fragment X
DGHN
Me
O
CO2Me
CO2H
CO2H
2. (COCl)2, DMF
then Et3N,
Me
Me
Me
Me
Me
1. PtO2, H2
O
(97%)
[gram scale]
t-Bu
O
O
R
Me
7
Me
8
Me
10a-f
3. cat. [Pd],
X
H2N
•
N
R
16: R = cyhex
2 HCl
(9, X = 4-Cl 84%)
[gram scale]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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43
44
45
46
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48
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50
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60
(table 1)
a. Boc-NHOH,
DBU (70%)
5. NaOH,
N
then, cat. [Ag],
NaHSO4,
Na2S2O8,
SO2Ph
2
t-Bu
HN
Cl
O
H
additive (table 2)
H
O
O
[x-ray]
13
4. aq. HBr
SO2Ph
Me
Me
Me
N
HO
Me
(91%
d.r. = >20:1)
[gram scale]
(99%)
[gram scale]
H
MeO
13
Me
17 [gram scale]
c.
Me
12
b. H+;
TBSCl
(72%)
Me
11 (from 10d)
[gram scale]
1,5-HAT;
radical [O]
O
TMS
O
(80%)
SO2Ph
O
TMS
MeO
O
MeO
8. LDA;
6. Ph3P=CH2
[gram scale]
O
N
Me
NC
OMe
5:
6:
O
then, aq. KOH
(74%)
7. KHMDS; O2
then, Me2SO4
(50% 2 steps)
OTBS
O
R
[x-ray]
O
Me
14
Me
15
R
9. (COCl)2
(table 3)
AgOTf,
base
Me
O
Me
Me
Me
Me
TfO
Me
CO2Me
CO2Me
O
O
O
O
N
N
OTBS
18
O
(41%)
OH
O
TfO
TMS
O
O
R
O
NH2
TfO
O
O
R
R
R
10. TFA,
MeOH
(70%)
table 1
step 3 optimization
table 2
step 5 optimization
table 3
step 9 optimization
Me
O
Me
(X =)
10a (H)
10b (6-OMe) n.d.
yield d.r.
co-cat.
none
Cu(OAc)2
yield
solvent
PhMe
PhMe
PhMe
temp. (ºC) yield
CO2Me
44% >10:1
6%
22%
28%
48%
71%
91%*
RT
50
50
50
50
50
9%
12%
21%*
26%*
28%*
41%*
-
O
N
10c (4-Me) 31% >10:1 Co(ClO4)2
10d (4-Cl)* 58% 20:1 Fe(OAc)2
10e (5-Cl) 53% >10:1 Fe2(SO4)3
10f (quin.) 23% >10:1 Fe2(SO4)3
PhMe/MeNO2
CH3CN
CH3CN; MeOH
HO
OH
OH
(–)-maximiscin (1)
[ca. 100 mg prepared]
OH
* using (R)-DG * gram scale
* AgOTf added last
aReagents and conditions: (1). PtO2 (5 mol%), H2 (450 psi), AcOH, rt, 14 h. (2) (COCl)2 (1.20 equiv), DMF (0.05 equiv), CH2Cl2, 0 °C to rt,
1 h, then 9 (1.00 equiv), Et3N (3.70 equiv.), DMAP (0.05 equiv), PhMe, 70 °C, 2.5 h. (3) Pd(OAc)2 (15 mol%), LiOAc (1.00 equiv), NaIO4
(4.00 equiv), Ac2O (2.00 equiv), PhMe/MeOH (2:1), 90 °C, 24 h. (4) aq. HBr, 100 °C, 15 h. (5) aq. NaOH (1.20 equiv), THF, MeOH, rt, 12
h, then AgNO3 (30 mol%), Fe2(SO4)3•5H2O (20 mol%), NaHSO4•H2O (1.13 equiv), Na2S2O8 (2.50 equiv), phenyl vinyl sulfone (1.40 equiv),
H2O/CH3CN (4:1), 40 °C, 3 h. (6) CH3PPh3Br (2.50 equiv), n-BuLi (2.30 equiv), THF, –5 °C to rt, 1 h. (7) KHMDS (2.50 equiv), O2
(balloon), THF –78 °C to rt, 45 min, then Me2SO4 (3.50 equiv), rt, 1 h, then morpholine (3.00 equiv), rt, 30 min. (8) LDA (3.00 equiv), Et2O,
–78 °C to 0 °C, 1 h, then methyl cyanoformate (4.00 equiv), –78 °C, then methanol (excess), aq. KOH (8.20 equiv), EtOH, 80 °C, 12 h. (9)
(COCl)2 (2.50 equiv), DMF (0.08 equiv), CH2Cl2, rt, 2.5 h, then 5 (1.20 equiv), DTBMP (2.20 equiv), AgOTf (1.90 equiv), CH3CN, 50 °C,
7 min. (10) TFA/MeOH (1:1), 0 °C to rt, 22 h. (a) N-Boc-NHOH (1.20 equiv), DBU (1.00 equiv), CH2Cl2, rt, 5 min. (b) TFA/CH2Cl2 (1:4),
0 °C, 15 min, then TBSCl (3.00 equiv), Imid. (4.00 equiv), DMAP (0.10 equiv), CH2Cl2, 12 h. (c) TMS-acetaldehyde (1.20 equiv), CH2Cl2,
rt, 30 min. Abbreviations: DBU = 1,8-diazobicyclo[5.4.0]undec-7-ene; DMAP = N,N-dimethyl-4-aminopyridine; DMF = N,N-
dimethylformamide; DTBMP = 2,6-Di-tert-butyl-4-methylpyridine; imid. = imidazole; KHMDS = potassium bis(trimethylsilyl)amide; LDA
= lithium diisopropylamide; TFA = trifluoroacetic acid; THF = tetrahydrofuran.
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Damage, Activates DNA Damage Response Pathways, and Has
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ASSOCIATED CONTENT
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Selective Cytotoxic Activity against a Subtype of Triple-Negative
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(c) Fürstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Synthesis and
evaluation of the antitumor agent TMC-69-6H and a focused
library of analogs. Tetrahedron 2004, 60, 9543–9558.
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The Journal of Organic Chemistry 1994, 59, 8065–8070; (b) Jones,
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Cordypyridones A and B and Related Epimers. Organic Letters
2009, 11, 5526–5529.
Supporting Information. Experimental procedures,
analytical data (1H and 13C NMR, MS) for all new
compounds as well as optimization tables. This material
is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
9
Corresponding Authors
(6) Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Innate and
Guided C–H Functionalization Logic. Accounts of Chemical
Research 2012, 45, 826–839.
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E-mail: pbaran@scripps.edu (P.S.B.).
Notes
(7) Smith, J. M.; Harwood, S. J.; Baran, P. S. Radical
Retrosynthesis. Accounts of Chemical Research 2018, 51, 1807–
1817.
(8) (a) Guareschi Reaction. In Comprehensive Organic Name
Reactions and Reagents, pp 1294–1297; (b) Joule, J. A.; Mills, K.
Heterocyclic Chemistry. 5th ed.; John Wiley & Sons: 2010.
(9) Hosomi-Sakurai Allylation. In Comprehensive Organic Name
Reactions and Reagents, pp 1491–1495.
(10) (a) Snider, B. B.; Lu, Q. Total Synthesis of (±)-Leporin A.
The Journal of Organic Chemistry 1996, 61, 2839–2844; (b)
Fürstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Total Synthesis
and Reassessment of the Phosphatase-Inhibitory Activity of the
Antitumor Agent TMC-69-6H. Angewandte Chemie International
Edition 2003, 42, 5361–5364.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was provided by NIH
(GM-118176), Tsinghua Xuetang Talent Program
(predoctoral fellowship to F. W.), Fulbright Scholar
Program (predoctoral fellowship to A. M.). NIH
(1S10OD025208) for OSR instrument. We thank Johnson
Matthey for providing samples of solid supported
rhodium catalysts. Crystallographic structures were
rendered using PyMOL, a product of Schrödinger LLC. We
are grateful to Dr. D.-H. Huang and Dr. L. Pasternack
(Scripps Research) for NMR spectroscopic assistance,
Prof. A. L. Rheingold, Dr. C. E. Moore, Dr. M. Gembicky and
Dr. J. B. Bailey and Gary J. Balaich (University of California
San Diego) for X-ray crystallographic analysis. Dr. Jason
Chen, Ms. Brittany Sanchez and Ms. Emily Sturgell
(Scripps Research) for analytical support. Prof. Robert
Cichewicz and Dr. Lin Du (University of Oklahoma) for
providing samples of authentic (–)-maximiscin and
useful discussion. David Hill (Scripps Research) for
assistance with chiral GCMS analysis. Prof. Keary Engle
(Scripps Research) for glovebox access. We also thank
Yuzuru Kanda, Solomon Reisberg, Stephen Harwood,
Tyler Saint-Denis, David Peters and Dr. Julien Vantourout
(Scripps Research) for useful discussions.
(11) Renata, H.; Zhou, Q.; Dünstl, G.; Felding, J.; Merchant, R.
R.; Yeh, C.-H.; Baran, P. S. Development of a Concise Synthesis
of Ouabagenin and Hydroxylated Corticosteroid Analogues.
Journal of the American Chemical Society 2015, 137, 1330–1340.
(12) for examples of desymmetrizing C–H activation in total
synthesis see: (a) Johnson, J. A.; Li, N.; Sames, D. Total Synthesis
of (−)-Rhazinilam:ꢀ Asymmetric C−H Bond Activation via the Use
of a Chiral Auxiliary. Journal of the American Chemical Society
2002, 124, 6900–6903; (b) Siler, D. A.; Mighion, J. D.; Sorensen,
E. J. An Enantiospecific Synthesis of Jiadifenolide. Angewandte
Chemie International Edition 2014, 53, 5332–5335; (c) Sharpe, R.
J.; Johnson, J. S. A Global and Local Desymmetrization Approach
to the Synthesis of Steroidal Alkaloids: Stereocontrolled Total
Synthesis of Paspaline. Journal of the American Chemical Society
2015, 137, 4968–4971; for a review of C–H activation in total
synthesis see: (d) Abrams, D. J.; Provencher, P. A.; Sorensen, E. J.
Recent applications of C–H functionalization in complex natural
product synthesis. Chemical Society Reviews 2018, 47, 8925–8967.
(13) for selected examples of C–H activation proceeding via a 6-
membered palladacycle see: (a) Reddy, B. V. S.; Reddy, L. R.;
Corey, E. J. Novel Acetoxylation and C−C Coupling Reactions at
Unactivated Positions in α-Amino Acid Derivatives. Organic
Letters 2006, 8, 3391–3394; (b) Lafrance, M.; Gorelsky, S. I.;
Fagnou, K. High-Yielding Palladium-Catalyzed Intramolecular
Alkane Arylation:ꢀ Reaction Development and Mechanistic
Studies. Journal of the American Chemical Society 2007, 129,
14570–14571; (c) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G.
Highly Efficient Syntheses of Azetidines, Pyrrolidines, and
Indolines via Palladium Catalyzed Intramolecular Amination of
C(sp3)–H and C(sp2)–H Bonds at γ and δ Positions. Journal of the
American Chemical Society 2012, 134, 3–6; (d) Nadres, E. T.;
Daugulis, O. Heterocycle Synthesis via Direct C–H/N–H Coupling.
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G.; Zhang, S.-Y.; Nack, W. A.; Li, Q.; Chen, G. Use of a Readily
Removable Auxiliary Group for the Synthesis of Pyrrolidones by
the Palladium-Catalyzed Intramolecular Amination of Unactivated
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Journal of the American Chemical Society
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Me
O
Me
Me
CO2Me
10 steps
(LLS)
1
O
O
2
Me
N
3
4
5
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8
HO
HO
OH
OH
<$1/g
HO2C
Me
Me
(–)-maximiscin
• convergent
pyridone synthesis
OH
Me
HO2C
• Desymmetrizing C–H activation
defines 4 stereocenters
• Radical cascade
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