Article

Lactonization as a general route to

β-C(sp3)–H functionalization

https://doi.org/10.1038/s41586-019-1859-y Zhe Zhuang1 & Jin-Quan Yu1*

Received: 16 July 2019

Accepted: 26 November 2019 Functionalization of the β-C–H bonds of aliphatic acids is emerging as a valuable
Published online: 11 December 2019 synthetic disconnection that complements a wide range of conjugate addition
reactions1–5. Despite efforts for β-C–H functionalization in carbon–carbon and
carbon–heteroatom bond-forming reactions, these have numerous crucial
limitations, especially for industrial-scale applications, including lack of mono-
selectivity, use of expensive oxidants and limited scope6–13. Notably, the majority of
these reactions are incompatible with free aliphatic acids without exogenous
directing groups. Considering the challenge of developing C–H activation reactions,
it is not surprising that achieving different transformations requires independent
catalyst design and directing group optimizations in each case. Here we report a Pd-
catalysed β-C(sp3)–H lactonization of aliphatic acids enabled by a mono-N-protected
β-amino acid ligand. The highly strained and reactive β-lactone products are versatile
linchpins for the mono-selective installation of diverse alkyl, alkenyl, aryl, alkynyl,
fluoro, hydroxyl and amino groups at the β position of the parent acid, thus providing
a route to many carboxylic acids. The use of inexpensive tert-butyl hydrogen peroxide
as the oxidant to promote the desired selective reductive elimination from the Pd(iv)
centre, as well as the ease of product purification without column chromatography,
render this reaction amenable to tonne-scale manufacturing.

Alkyl carboxylic acids are ubiquitous and inexpensive reagents in by 2% β-lactone17,18. γ-Lactonization of benzylic C–H bonds has also been
organic chemistry; as such, they are favourable substrates for C–H reported using Pd and Pt catalysts19,20. These observations indicate that
activation reactions4,5. The scope of such transformations is often β-lactonization is a highly disfavoured process. Guided by previous
limited by the incompatibility of certain reaction partners. Indeed, work using a bystanding oxidant to promote C–H activation/cycliza-
for C–C bond formations, alkylation reactions are limited to primary tion reactions21,22, we investigated catalysts and conditions to achieve a
alkyl iodide or alkyl boron coupling partners6–8; olefination reactions β-C–H lactonization reaction. Compared to β-lactam formation, where
are applicable only to electron-deficient olefins9,10; alkynylation reac- a nucleophilic directing group can be employed to form a strong C–N
tions are limited to silyl acetylene bromide11; and arylation reactions bond23,24, β-C–H lactonization poses an additional challenge because
are compatible only with aryl iodides, but not with the more practical of the low nucleophilicity of the carboxylic acid, the strain generated
aryl bromides and chlorides12,13, despite the design of various directing in forming a four-membered ring and the facile ring opening under
groups. Most importantly, carbon–heteroatom (C–Y) bond-forming C–H activation conditions. Most problematically, Pd(iv) intermediates
reactions (such as fluorination, hydroxylation and amination) based could readily undergo conventionally favoured reductive elimina-
on β-C–H activation of free aliphatic acids have not yet been realized. tion to produce non-cyclic C–O bond-formation products, such as the
Considering these persistent limitations of the conventional β-C–H most common competing pathways acetoxylation and alkoxylation
activation approach, we turned to a one-for-all β-lactonization strategy (Fig. 1b). We selected 2,2-dimethylbutyric acid 1a as a model substrate
(Fig. 1a). β-Lactones are strained heterocycles that have received consid- in our search for reactivity with a wide range of oxidants and catalysts.
erable attention as valuable synthetic intermediates in the syntheses of Exploratory studies using various common oxidants for Pd(ii)/Pd(iv)
natural and unnatural products14,15. Owing to their inherent ring strain, chemistry—such as PhI(OAc)2, K2S2O8 and F+ reagents—consistently
they readily react with a wide range of nucleophiles by either acyl C–O gave undesired non-cyclic oxidation products (see Supplementary
or alkyl C–O bond cleavage. The lack of precedent of this reaction is Information Table 3 and section ‘Mechanistic studies’ for details).
probably due to the highly unfavoured four-membered lactonization To avoid the undesired reductive-elimination pathway, we tested the
transition state15. Notably, this β-lactonization could provide a strategy sterically bulky oxidant tert-butyl hydrogen peroxide (TBHP)4, as well as
to synthesize carboxylic acids containing α-quaternary centres that are PdCl2-derived catalysts, because the tBuO and Cl anions are less prone
inaccessible by conjugate addition chemistry, and difficult to prepare to reductive elimination due to sterics and electronics. The desired
via α-substitution16. β-lactone 2a was formed in 15% 1H NMR (nuclear magnetic resonance)
A mixture of K2PtCl4, (17 mol%) and K2PtC16 (33 mol%) can promote the yield using a combination of Pd(CH3CN)2Cl2, TBHP oxidant, CsHCO3
formation of γ-lactones from aliphatic acids in 16% yield, accompanied and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solvent. Encouragingly,

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. *e-mail: [email protected]
1

656 | Nature | Vol 577 | 30 January 2020

 a O O O Cs+ Me
R1 O
R1 Cat. Pd/L11 (≥1 mol%) Nu– R1 R1
OH OH O CO2H
Base, TBHP R2
R2 R2 R2
HFIP, 60 °C, 12 h O NHAc L11
H Nu H PdIIL11
1 2
Nu = C(sp3), C(sp2), C(sp), CN,
Up to 94% yield
No column F, Br, N3, NHNs, OH, SPh

b OH
O Cs+ O O O
O L Reductive R1
R1 PdII L elimination O R1 R1 R1
O PdIV
OH + OH + OH + OH
TBHP L R2
R2 R2 R2 R2
O
H R1 OtBu OH OtBu Nu
1 R2
Pd(IV) intermediate

3
Fig. 1 | β-C(sp )–H functionalization. a, Lactonization as a general and scalable route to β-C(sp3)–H functionalization. b, Challenges: multiple reductive-
elimination pathways of Pd(iv) centres. Nu, nucleophile (acid, solvent); L, ligand.

no γ-lactone or β-, γ-hydroxylated products were observed during the In light of the recent advances in ligand-accelerated Pd(ii)-catalysed
reaction. The unique role of TBHP in favouring β-lactone formation C–H activation26, we next searched for ligands that could substantially
can be rationalized on the basis of studies on the oxidation of Pd(ii) improve the reactivity of the catalyst. It is also possible that an appropri-
to Pd(iv) by benzoyl peroxide25 and TBHP4. Following the oxidation of ate ligand could enhance the otherwise unfavoured β-lactonization.
Pd(ii) to Pd(iv) by TBHP, tBuO− and HO− bound to a Pd(iv) centre are less Using the mono-N-protected α-amino acid (MPAA) ligand N-acetyl
likely to undergo rapid reductive elimination due to the strong Pd–OtBu glycine L1, the yield was improved to 36%. Modification of the backbone
(OH) bond. According to the principle of organometallic chemistry, the of the α-amino acid ligand led only to minor improvements (L2 to L5).
steric hindrance of tBuO− could also enhance the reductive elimination Considering the challenging reductive elimination of a strained four-
of the carboxylate from the substrate to generate β-lactone product. membered ring from Pd(iv), we reasoned that switching the ligand

O
Pd(CH3CN) 2Cl2 (10 mol%) R1 Me
R1 L11 (20 mol%) O
OH
CsHCO3 (0.5 equiv.) R2 CO2H
R2
TBHP (~5.5 M in decane) (2.0 equiv.) O
H HFIP, 60 °C, 12 h NHAc L11
1 2

Me Me
O Me O O 3 O O O
Me Me ( )

Me Me Me Me Me Me Me
O O O O O O
2a, 73% 2b, 50% 2c, 71% 2d, 74% 2e, 73% 2f, 45%

O O

)4 O )5 O )4 O Me O P O O
F ( Cl ( CF 3 ( EtO
OEt BocN
Me Me Me Me Me Me
O O O O O O
2g, 72% 2h, 47% 2i, 67% 2j, 74% 2k, 38% 2l, 51%

3 4
O MeO ( ) O BnO ( ) O MOMO O ( )3 O ( )3 O
O Cl
Me Me Me Me Me Me
O O O O O O
2m, 71% 2n, 81% 2o, 46% 2p, 56% 2q, 60% 2r, 46%

NO2 Me
Me Me
O n O 3 O O 4 O 3 O
O PhO ( ) O () F () MeO ( )

Me Me Me Me Et Et Et
O O O O O O
2s, 41% n = 2, 2t, 86% 2v, 93% 2w, 62% 2x, 52% 2y, 62%
n = 3, 2u, 94% from gemfibrozil
Br

n n
( )3 O PhO ( ) O O MeO ( )
4 O PhO ( ) O O ()
4 O

Et Et
O O O O O O
2z, 59% n = 2, 2aa, 68% 2ac, 51% 2ad, 82% n = 3, 2ae, 69% 2ag, 40%
n = 3, 2ab, 90% n = 4, 2af, 32%

Fig. 2 | Aliphatic acid scope for β-C(sp3)–H lactonization. Conditions for 2a 60 °C, 12 h. Conditions for 2t to 2v and 2aa to 2ag: 1 (0.1 mmol), Pd(OAc)2
to 2s and 2w to 2z: 1 (0.1 mmol), Pd(CH3CN)2Cl2 (10 mol%), L11 (20 mol%), (10 mol%), L11 (20 mol%), NaOAc (1.0 equiv.), TBHP (about 5.5 M in decane)
CsHCO3 (0.5 equiv.), TBHP (about 5.5 M in decane) (2.0 equiv.), HFIP (1.0 mL), (2.0 equiv.),

Nature | Vol 577 | 30 January 2020 | 657

Article
Me Me Me
O Pd (1 mol%) O
Standard conditions Me Nu –
( )3 3 O ( )3
Me O OH Aqueous wash O () Me O OH
Me Me
H Me Nu
O
Gemfibrozil (1v), 1.0 g 2v, 92%

Me Me
O Me O
Me O
O ( )3 ( )3
Me O OH ( )3 Me O OH
Me O OH
( )3 Me Me
Me O OH Me Me
Me
R Me
R = Et, 3a, 93% 3c, 79% 3d, 76% 3e, 66%
R = Bn, 3b, 82%
Me Me
O O
Me Me ( )3
O Me O OH ( )3
O Me O OH
Me Me
( )3 ( )3 Me
Me O OH Me O OH
Me Me NH
R Me

H H Me
R = H, 3f, 91% 3h, 61% 3i, 68% 3j, 32%
R = Me, 3g, 81%
Me
O
Me Me Me
( )3 O O O
Me O OH
Me ( )3 ( )3 ( )3
Me O OH Me O OH Me O OH
Me Me Me
Ph CN F Br
3k, 70% 3l, 98% 3m, 50% 3n, 92%

Me Me Me Me
O O O O
( )3 ( )3 ( )3 ( )3
Me O OH Me O OH Me O OH Me O OH
Me Me Me Me
N3 NHNs OH SPh
3o, 86% 3p, 73% 3q, 95% 3r, 92%

Fig. 3 | Gram-scale β-C(sp3)–H lactonization of Gemfibrozil with 1 mol% CuBr⋅SMe2 (20 mol%), Me2S (1.0 equiv.), Nu (3.0 equiv.), THF (1.0 mL), 0 °C, 1 h.
Pd and diverse transformations. Nu, Grignard reagents (3a to 3j), Conditions for 3k to 3r: 2v (0.1 mmol), Nu (2.0 or 3.0 equiv.), 1–12 h.
alkynylaluminum reagent (3k), TBACN (3l), TBAF (3m), MgBr2 (3n), NaN3 (3o), See Supplementary Information for details.
NaNHNs (3p), KOH (3q), PhSNa (3r). Conditions for 3a to 3j: 2v (0.1 mmol),

binding mode from five- to six-membered chelation will increase (2o), and methoxymethyl (MOM) (2p) were also well tolerated. Phenyl
the bite angle, thereby favouring the desired reductive elimination. (2q to 2r) and phenyl ether (2s to 2v) groups were compatible with the
The β-amino acid-derived ligand N-acetyl β-alanine L6 under the same TBHP system, and remained intact despite the potentially reactive aryl
conditions improved the yield to 48%. Building on this promising find- or benzylic C–H bonds. A range of substituents on the aryl ring from
ing, we then investigated the influence of substituents on the ligand’s electron-donating (Me and O-alkyl) to electron-withdrawing (chloro,
side chain. Substituents at the β position slightly reduced the reactivity bromo and nitro) groups were all well tolerated. Gemfibrozil (1v), an
(L7 to L10), suggesting that steric hindrance around the NHAc moiety oral drug used to lower lipid levels27, was converted to the correspond-
was detrimental to reactivity. Moreover, substitution at the α position ing β-lactone 2v in high yield. This lactone could serve as a versatile
proved beneficial (L11 to L13), with methyl-substituted L11 giving 65% intermediate for library construction in medicinal chemistry (see
yield. The isolated yield of β-lactone could be further improved to below). Notably, the remaining α-methyl group from the above cases
73% when using TBHP in decane (see Supplementary Information for could then undergo further C–H functionalizations to afford greater
further optimization). structural diversity. Tertiary aliphatic acids containing a single α-methyl
After determining the optimized ligand and conditions, we explored group (2w to 2ab) consistently afforded useful yields, in addition to
the scope of this methodology (Fig. 2). Aliphatic acids containing those substrates containing α-hydrogens (2ac to 2ag).
α-gem-dimethyl groups with various aliphatic chains including cyclobu- To demonstrate the scalability and practicality of this transforma-
tanes (2f) were all compatible, affording the β-lactones (2a to 2f) in tion, we conducted a gram-scale β-lactonization of Gemfibrozil (1v)
high yields. A range of functionalities—such as fluoro (2g), chloro (2h), with 1 mol% Pd (Fig. 3). Pure product was obtained by a simple aqueous
trifluoromethyl (2i), ketone (2j) and phosphoric ester (2k)—were toler- wash without chromatography. 1.0 g gemfibrozil (1v) in HFIP, Pd(OAc)2
ated, with halogen (2h), ketone (2j) and phosphoric ester (2k) moieties (1.0 mol%), commercially available MPAA ligand L6 (2.0 mol%) and
serving as useful synthetic handles for subsequent derivatization. The NaOAc (1.0 equiv.) were added to a reaction tube, followed by TBHP
lactone products containing a piperidine (2l) or a tetrahydropyran (70% in water) (2.0 equiv.). After stirring at 60 °C for 24 h, the HFIP
(2m) motif are especially valuable. Different protecting groups on solvent was removed by evaporation, followed by dissolution with
the hydroxyl group including simple methyl (Me) (2n), benzyl (Bn) ethyl acetate and washing with saturated NaHCO3 solution to remove

658 | Nature | Vol 577 | 30 January 2020

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Article
Methods Acknowledgements We acknowledge The Scripps Research Institute and the NIH (NIGMS,
R01GM084019) for financial support.

General procedure for β-C(sp3)–H lactonization Author contributions J.-Q.Y. conceived the concept. Z.Z. developed the lactonization reaction.
Pd(CH3CN)2Cl2 (10 mol%, 2.6 mg), ligand L11 (20 mol%, 2.9 mg), CsHCO3 J.-Q.Y. directed the project.

(0.5 equiv., 9.7 mg) and carboxylic acid 1 (0.1 mmol), in that order, were
Competing interests The authors declare no competing interests.
weighed in air and placed in a culture tube with a magnetic stir bar.
Then HFIP (1.0 mL) and TBHP (about 5.5 M in decane) (2.0 equiv., 36 μL) Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41586-019-
were added. The reaction mixture was stirred at room temperature
1859-y.
for 3 min and then heated to 60 °C for 12 h (600 rpm). After cooling to Correspondence and requests for materials should be addressed to J.-Q.Y.
room temperature, the mixture was concentrated in vacuo, and the Peer review information Nature thanks Michael Doyle and the other, anonymous, reviewer(s)
for their contribution to the peer review of this work.
resulting mixture was purified by preparative thin-layer chromatog-
Reprints and permissions information is available at http://www.nature.com/reprints.
raphy or diluted with ethyl acetate and washed with saturated NaHCO3
solution. The full experimental details and characterization of the new
compounds can be found in Supplementary Information.

Data availability
The data supporting the findings of this study are available within the
article and its Supplementary Information files.