Haochuan Lu
email: haochuanlu@gmail.com

Jonathan Dumon
email: jonathan.dumon@gipsa-lab.inpg.fr

Carlos Canudas
email: carlos.canudas-de-wit@gipsa-lab.inpg.fr

Experimental study of the D-OSKIL mechanism for controlling the stick-slip oscillations in a drilling laboratory testbed

The presence of harmful stick-slip oscillations in oil well drillstrings has attracted the attention of the control community in recent years. The control law named D-OSKIL mechanism which uses the weight on the bit (WoB) force as an additional control variable to extinguish limit cycles has been investigated [1]. This paper reports experimental implementation of such a mechanism, in a laboratory testbed. We also provide details of the experimental process and the obtained drilling performance. Results show that the stick-slip oscillations can be effectively suppressed by this mechanism.

I. INTRODUCTION

Deep wells for exploration of oil are drilled with a rotary drillstring system. Different drillstring oscillations are an important cause for premature failure of drillstring components and drilling inefficiency. The occurrence of stick-slip oscillation as a common and damaging phenomena given at the bottom-hole assembly (BHA), i.e., the top of the drillstring rotates with constant rotary speed whereas the bit (cutting tool) rotary speed varies between zero and up to six times the rotary speed measured at the surface, has attracted attention of control community in the last decade.

There are several feasible alternatives to suppress stickslip oscillations. This project adopted the mechanism named drilling oscillation killer (D-OSKIL) that is proposed in the paper [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF]. We implemented it on an experimental setup that emulates a real oil drilling platform. The mechanism mainly utilizes the weight on the bit (WoB) force as an additional control variable to eliminate stick-slip oscillations. An important property of D-OSKIL is that it allows recovering the nominal operation condition (the WoB recovers its nominal drilling value) while oscillations are suppressed.

The next section describes the testbed assembled in this project. Then we reviews the system model and the D-OSKIL mechanism. Subsequent section are devoted to the experimental validation of the D-OSKIL mechanism, and the last part gives the conclusion. II. TESTBED DESCRIPTION An experimental setup which emulates the oil drilling system in the field was constructed to investigate the performance of D-OSKIL mechanism on a real platform. It can reproduces similar stick-slip oscillations as the ones reported in field tests. The experimental setup as illustrated in Fig. 1 and in Fig. 2

consists of following parts:

ROTARY SYSTEM is composed of: • DC motor (M2) provides necessary mechanical energy to make the system rotate. A rotary speed sensor is built. • Quadrature encoder. measures the rotary angle of the bit. This rotary angle is then used to compute the rotary speed at the bit. • Bit is the cutting tool used to drill. SUPPORT PLATFORM platform consists of:

• DC motor (M3) is employed to move the rotary system vertically and vary the weight applied to the bit during the drilling process (WoB). A rotary speed sensor and a quadrature encoder are built in. • Specimen holder fixes the specimen below the drill bit.

• Support structure is used to support other physical parts and provide necessary safety mechanism. Suitable combinations of drill bit and specimen were selected to meet the criterion that the oscillation must be able to be removed when the applied WoB is small. An oil drilling system in the field usually has a circulation system to lubricate and refrigerate the contact between the rock and the bit.As we do not have such facility in the setup, the swarf removal ability of the bit is vital. If the swarf is not removed as fast as it is produced, the flutes will clog and prevent the tool drilling efficiently, causing vibration, tool wear and overheating. Thus we chose the milling cutter shown in Fig. 4 as the drill bit which satisfies our criterion. Cedar wood blocks (Fig. 4) were used as the specimens in our test. As depicted in Fig. 5, the drillstring was used in this experimental setup. An experiment was carried out to determine the rotational stiffness of the drillstring. A rotational torque (τ ) in the step of 0.1 from 0 to 3 N•M was applied to the rotary table with the bit fixed. Corresponding rotational angles (θ) of the rotary table was plotted with respect to the torque. Fig. 6 shows the relation is approximately linear within the range. Then rotational stiffness was determined through linear regression.

C. Drillstring Characteristic Measurement

τ = τ 0 + k • θ (1) k = 0.6706 N•m/rad τ 0 =0.7069N•m,
where k is the rotational stiffness of the drillstring and τ 0 is the static friction torque without causing rotation.

III. MODEL AND PARAMETER IDENTIFICATION

A. Drillsting Model

Various kind of models have been used in literature to describe drillstring systems (for example [START_REF] Leine | Stick-slip whirl interaction in drillstring dynamics[END_REF] and [START_REF] Spanos | Oil well drilling: A vibrations perspective[END_REF]). The lumped model used in the study of the D-OSKIL mechanism is a two-degree-of-freedom model with two inertial masses J r and J b , locally damped by d r and d b . The inertias are coupled with each other by an elastic shaft of stiffness k and damping c. The variables ϕ r and ϕ b stand for the rotary and the bit angle. The rotary torque control signal v is used to regulate the rotary angular velocity φr . The T oB (Torque on Bit) represents the total friction torque over the drill bit. The model equations are as follows:

J r φr + c( φr -φb ) + k(ϕ r -ϕ b ) + d r φr = υ J b φb + c( φb -φr ) + k(ϕ b -ϕ r ) + d b φb = -T oB
In constants above, the sub-script 'r' and 'b' stands for rotary table and bit, respectively.

The T oB is given by the product of μ( φb ), which describes the normalized (dimensionless) torsional bit-rock friction (different bit-rock friction models are presented in [START_REF] Navarro-Lopez | Modelling and analysis of stick-slip behaviour in a drillstring under dry friction[END_REF]), and the normal force u (WoB), i.e.

T oB = μ( φb ) • u, u = u 0 + ũ
The effective value of T oB can be modified by controlling the tension force, ũ, of the drillstring. We assume that a counterweight force ũ, ũ ∈ [-u 0 , 0], can be applied to counteract the gravitational nominal force u 0 = Mg (M is the total drillstring mass and g is the gravity). This lumped model has the following state-space representation:

ẋ = Ax + Bν + Hμ(x 3 )u (2)
with

A = ⎛ ⎝ 0 1 -1 -k Jr -dr+c Jr c Jr k J b c J b -c+d b J b ⎞ ⎠ B = ⎛ ⎝ 0 1 Jr 0 ⎞ ⎠ , H = ⎛ ⎝ 0 0 -1 J b ⎞ ⎠
where the state x = [x 1 , x 2 , x 3 ] T is defined as follows:

x 1 = ϕ r -ϕ b x 2 = φr x 3 = φb
Realistic values for the parameters which were identified from our experimental setup are given in Table .

B. Parameter Identification

In the real drilling system in the field, there exists significant friction between drillstring and the surrounding, e.g., borehole wall and the drilling mud, which is reflected by the damping coefficient c in the model shown in Section III-A. In our test, as the drillstring is directly exposed to the air, such friction is negligible, i.e. c = 0.

Except the stiffness k which has been calculated in Section II-C, the other four parameters of the system model were identified as follows.

Firstly, the drillstring linked between the rotary table and the bit was removed to identify J r and d r . Then step torque produced by the DC motor (M2) was applied on the rotary table periodically, and the rotary speed ( φr ) response of the rotary table was recorded. The step value of the applied torque was determined to keep the rotary table speed close to the speed used in the drilling ( φr ≈ w d = 5rad/s). The system can be represented by Equation [START_REF] Spanos | Oil well drilling: A vibrations perspective[END_REF].

J r φr + d r φr = τ r (3)
Secondly, for J b and d b , we used such a steel pole of high stiffness as the drillstring that the rotation difference between the rotary table and the bit is zero, i.e. φrφb = 0. The system can be represented by Equation ( 4). Then we obtained the step response of the rotary speed ( φr+b ).

(J r + J b ) φr+b + (d r + d b ) φr+b = τ r+b (4)
By processing the step response results, we can calculate the parameters of the first order model as follows.

In s-domain:

φr (s) τ r (s) = 1 J r s + d r = 24.60 s + 6.172 φr+b (s) τ r+b (s) = 1 (J r + J b )s + (d r + d b ) = 21.81 s + 5.63 Giving: J r = 0.04065Kg • m, d r = 0.25088 s -1 J b = 0.0052Kg • m, d b = 0.00726 s -1
Steps for experimental validations, not reported here for lack of space, were performed on the setup.

IV. CONTROL ARCHITECTURE

A. Rotary table speed control loop

A speed control loop is designed to regulate the output rotary table speed φr to a desired value ω d (typical value for ω d is 5rad/s).

Though many advanced speed control law, (i.e. H ∞ ), are available in the literature, oil well drilling often operates with reduced-order simple control laws. We adopted the control structure proposed in [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF]:

υ = k 1 + k 2 s (ω d -φr ) -k 3 ( φr -φb ) (5)
which can also be written as:

υ = k 1 (ω d -x 2 ) + k 2 x 4 -k 3 (x 2 -x 3 ), ẋ4 = ω d -x 2
then the closed-loop equation take the form,

ẋ = A cl x + B cl ω d + H cl μ(x)u (6)
with the state of dimension four, i.e.x = [x 1 , x 2 , x 3 , x 4 ], and with the A cl , B cl , H cl given as follows:

A cl = ⎛ ⎜ ⎜ ⎝ 0 1 -1 0 -k Jr -dr+c+k1+k3 Jr c+k3 Jr k2 Jr k J b c J b -c+d b J b 0 0 -1 0 0 ⎞ ⎟ ⎟ ⎠ B cl = ⎛ ⎜ ⎜ ⎝ 0 k1 Jr 0 1 ⎞ ⎟ ⎟ ⎠ , H cl = ⎛ ⎜ ⎜ ⎝ 0 0 -1 J b 0 ⎞ ⎟ ⎟ ⎠
The gains values can be designed using pole placement for the closed loop system. The details about the speed controller gain tuning in our case is presented in later section. The oscillation pattern shown by Fig. 7 is generated with our testbed setup. They reflect the main characteristic of the drill oscillations: first oscillations will present a bias term, and second they are dominated by a main harmonic with a relatively well-defined period. Thus, the SBDF (Sinusoid plus bias describing function) method can be used as a first approximation to predict possible limit cycle and to study its stability. The detail analysis given in [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF] demonstrates the relationships among system bandwidth (ω n ), WoB, and the possibility to enter into oscillation. On the basis of this analysis, oscillation may be eliminated either by changing ω n , and/or by reducing the WoB magnitude.

B. Oscillation characteristics

Keeping WoB low will be a too conservative strategy. High-performance drilling operation usually takes place in a region in the plane (WoB -ω n ), where potential oscillations may occur. Typical values of ω n are in the range [20,30]rad/s. So in the design of the control law we account for this particularity assuming that the nominal system operation parameters are taken within this zone.

C. D-OSKIL Mechanism

The D-OSKIL mechanism to be implemented is thus built under the following base-lines:

• nominal values for (WoB -ω n ) are in the potential stable limit cycle zone but the system trajectories are at their equilibrium, i.e. u = u 0 and φb = ω d . Then, stick-slip limit cycles are possible under a substantial perturbation. As it is often the case during the real drill operation, variation on the rock friction characteristics may bring the closed-loop system trajectories outside the local stable zone producing stick-slip cycles.

[1] • the oscillation is suppressed by reducing the WoB,i.e.

adjusting the control signa ũ, so that the local attraction domain is enlarged about the equilibrium points until system trajectories are attracted to them. • after that, the WoB will have to be recovered to its nominal value to continue with the proper drilling task, i.e. u → u 0 . This is possible as long as the system trajectories are kept within the local attraction domain, by a slow variation of the WoB, see [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF].

One possible variation for the D-OSKIL mechanism is the following one (the superscript * indicates steady-state values):

y = Ce = φb -ω d , (7) y f = F (s)y (8) 1 σ u = -ũ -sat 0 -u0 {Φ(y f )} (9) Φ(y f ) = λ • y • sgn(μ(y f )), λ ≥ 0 (10) u = u 0 + ũ ( 11
)
where e = xx * , ũ(0) = 0, σ > 0 and the assumption of the possibility to measure or estimate φb is made. Remarks Equation (7) selects a suitable output reflecting the stickslip oscillations. This choice is not unique, and it may depend on the signal-to-noise ratio of the considered output. To simplify matters, the selected output is y = φbω d .

Equation ( 8) defines a band-pass filter F(s) used to extract the main oscillatory component. A filter of the following form can be used.

F (s) = K f s (s + ω 1 )(s + ω 2 )
with ω 1 = ω 0 -Δω > 0, and ω 2 = ω 0 + Δω > 0 (ω 0 is the frequency of the main oscillation component). The value of K f and Δω are designed such that |F (jω 0 )| ≈ 1, and frequencies away from ω 0 are filtered out. ω 0 can be obtained from a frequency estimator. In this test run, and for simplicity it was approximately identified from the experimental data.

Equation ( 9) describes the control law, with output saturation. It forces ũ ∈ (-u 0 , 0], ∀t ≥ 0. Thus, in Equation (11) u is bounded in (0, u 0 ]. 1 σ can be understood as a time constant of the controller.

In Equation ( 10) Φ(y f ) is a nonlinear function which must be designed to ensure system stability, i.e. As φb → ω d , ũ → 0. The paper [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF] shows relevant stability analysis and presents the criteria to select proper values of σ and λ. Details about tuning of the two DOSKIL control parameters σ and λ on the experimental setup will be demonstrated in later section.

V. EXPERIMENTAL VALIDATION

A. Weight on Bit force Regulation

A PI controller with following structure is used to regulate the WoB during the drilling process.

C 3 = c 0 -(W oB d -W oB)( K i3 s + 1) K p3
C 3 is the output torque of the controller (input of the DC motor M3) and c 0 is the offset torque corresponding to the total weight of the rotary system. W oB and W oB d are respectively weight on bit measured and desired. The ability of the PI controller directly affects the performance of the D-OSKIL mechanism. For instances, larger overshoot may significantly disturb the torque on the bit and potentially cause some oscillations. The performance of the closed-loop controller which operated while drilling was checked. The step responses obtained with our settings, K i3 = 5.9504, and K p3 = 2.3, shows that the rise time is less than 0.2 second, overshoot is less than 35%, and steadystate error is less than 0.5%. The performance is satisfactory in our test.

B. D-OSKIL

The D-OSKIL mechanism shown by the equation 9-13 contains two main control parameters σ and λ. The other two parameters (ω 0 and Δω) for the bandpass filter were determined by identifying the oscillation frequency in the experimental result. In our case, the main oscillation frequency is around 3.2Hz. Thus we chose ω 0 = 20rad/s and Δω = 0.5. 1 σ can be understood as a time constant which controls the speed of transition from oscillation regime to stabilization period and the stabilization time for the Wob, i.e. how fast the WoB recovers to its nominal value. Together with σ, λ determines the magnitude of the output control signal ũ. It have to be tuned properly to make the output signal reflect the magnitude of the oscillation. The effects of these two parameters on the control performance are discussed in [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF].

It must be noted that the remaining oscillations (e.g. high frequency torsional vibrations) always exists and our goal is to eliminate the stick-slip oscillations. From a practical point of view, above factors must be balanced and the parameters values with σ=0.15 and λ=5 has been proved to be valid in our experiment. The result are shown in Fig. 10. positions on the wood specimens were different for each test and the wood is heterogeneous mixture, we have to assume that the condition is approximately same for each test.

C. Experimental results

In these figures, the typical profiles of both the bit and the rotary table rotary speed, system Wob, and drilling depth (x 3 ) are shown. As it can be observed in Fig. 9, without D-OSKIL mechanism, the system is under a stickslip oscillation regime. The sustained stick-slip phenomenon is significant from 78 seconds to 84 seconds.

In Fig. 10, the D-OSKIL mechanism is able to suppress the stick-slip oscillation. The WoB recovers after the stick-slip oscillation has been eliminated. The remaining oscillations always exist due to the nature of the closed-loop system, and some other factors (e.g. vertical vibrations). Compared with Fig. 9, the penetration rate (gradient of the plot of x 3 ) of the drilling with D-OSKIL mechanism is smaller than that without D-OSKIL mechanism.

In addition to the simple visual evaluation of the OSKIL mechanism, we used some analytical methods to analyze the experiment data. Following analysis results are obtained by processing the experiment data from 40s to 100s in Fig. 9 and the data from 40s to 300s in Fig. 10. One major feature of harmful stick-slip phenomenons is that the bit stops rotating regularly. We propose to use the proportion of stick time for the bit in the whole drilling process as an evaluation factor. Due to the inaccuracy in the measurement, the moment when the rotary speed at the bit is below a certain small value (ω cutof f ) is considered as bit sticking.

Another analysis is performed in frequency domain. We got the power spectrum of the bit speed using Fast Fourier Transform (FFT). For clearer comparison between these two, the two spectrums are plotted in Fig. 12. It is observed that the stick-slip components with frequency around 3.3Hz have been suppressed to 12 percent of the original value, because the bandpass frequency of the filter in D-OSKIL mechanism was set to around 20 rad/s. It is obvious that the stick-slip oscillation can be suppressed effectively.

VI. CONCLUSION

This paper presents the implementation of the D-OSKIL mechanism proposed in [START_REF] Canudas-De Wit | D-oskil: A new mechanism for controlling stick-slip oscillations in oil well drillstrings[END_REF] to suppress stick-slip oscillations in a oil well drilling system. We have constructed a test platform to emulate the oil well drillstring system in the field, and implemented the D-OSKIL mechanism on the setup.

Several tests have been conducted to investigate the performance of the D-OSKIL mechanism in our circumstance. The test scenario and results have been illustrated in this paper. The results show that this mechanism is able to effectively suppress stick-slip oscillations occurred during drilling process.

APPENDIX

Fig. 1 .Fig. 2 .

 12 Fig. 1. Experimental setup and the schematic of the rotary system

Fig. 3 .Fig. 4 .

 34 Fig. 3. Function blocks of the platform

Fig. 5 .

 5 Fig. 5. The drillstring

Fig. 6 .

 6 Fig. 6. The torque vs. rotational angle characteristics of the drillstring

Fig. 7 .

 7 Fig. 7. Stick-slip measured in our experimental drilling system

Fig. 8 .

 8 Fig. 8. Block scheme of the D-OSKIL mechanism

Fig. 9 .

 9 Fig. 9. Experiment result without D-OSKIL scheme: Overall view (Upper) and detailed (Bottom) view

Fig. 10 .Fig. 11 .Fig. 12 .

 101112 Fig. 10. Experiment result with D-OSKIL scheme: Overall view (Upper) and detailed (Bottom) view scheme

•

  Tension force sensor is used to measure the vertical force applied on the rotary system. POWER SYSTEM: power supply and peripheral circuits. It provides electrical energy for other parts of the experiment setup.

	A. Software
	D-OSKIL
	User
	Interface
	ωd	Rotary Speed Controller	Hardware
		Drilling	Motors
	u0	Operation and
	Control parameters	Data Acquisition
	Operating
	commands	Management Unit	Sensors

COMPUTER BASED CONTROL SYSTEM: Host PC and xPC Target • Host PC It is used to create applications using Matlab, Simulink. It serves as an interface to command the target PC. • Target PC It is xPC Target real-time platform used for controlling the whole setup . The target PC downloads executable code created using Matlab, Simulink and Stateflow software from the host PC and interacts with the host PC and hardware system to perform tasks.

TABLE I TABLE OF PARAMETER

 IOF VALUES USED IN THE TEST

	Jr	0.04065	[Kg • m 2 ]
	J b	0.0052	Kg • m 2
	k	0.67	[Nm/rad]
	c	0	[1/s 2 ]
	dr	0.25088	[1/s]
	d b	0.00726	[1/s]
	μc	0.015	[-]
	μs	0.025	[-]
	νs	0.01	[rad/s]
	σ 0	25	[rad/s]
	σ 1 u 0	0.05 180	[rad/s] Kg • m/s 2
	ω d	5	rad/s
	k 1	2 [N m/rad/s]
	k 2	1.8	[Nm/rad]
	k 3	0.034 [N m/rad/s]
	ω 0	20	rad/s
	Δω	0.5	rad/s


Xin Chu

Linhua Shen

Bo Li

Peng Yang

Chengzhuo Du

Xiaoye Wang

Gang He

Samir Messaoudi

Gong Chen

Construction of Peptide Macrocycles via Palladium-Catalyzed Multiple S-Arylation: An Effective Strategy to Expand the Structural Diversity of Crosslinkers

ABSTRACT: While the chemistry for peptide macrocyclization has been greatly advanced, methods capable of introducing crosslinker motifs with large structural diversity are still limited. Herein, we report a simple and versatile method to staple unprotected native peptides with a wide range of easily accessible diiodo and triiodoarene reagents via palladium-catalyzed multiple S-arylation of cysteine residues. Iodoarenes with different arene and heteroarene cores can be incorporated into peptide macrocycles of varied ring size and amino acid composition in high efficiency and selectivity under mild conditions. Synthetic peptide macrocycles are becoming an increasingly valuable source for hit identification in drug discovery. 1 Stapling linear peptide precursors with crosslinking molecules is commonly used to generate the peptide macrocycles. 2 While the crosslinkers were mainly used to constrain the peptide conformation in the early developments of peptide stapling, recent studies showed that linker motifs can play more active roles in constructing sophisticated three-dimensional structures, modulating physiochemical properties or directly engaging with the targets. [START_REF] Fujimoto | Development of a series of cross-linking agents that effectively stabilize α-helical structures in various short peptides[END_REF] By far, methods for stapling peptide via crosslinking the side chain of cysteine (Cys) residues have enjoyed the most success due to the high reactivity and selectivity of Cys under biocompatible conditions. [START_REF] Chalker | Chemical modification of proteins at cysteine: opportunities in chemistry and biology[END_REF][START_REF] Kumita | For selected reports on SN2-mediated peptide macrocyclization[END_REF][START_REF] Kohn | Single-step formation of structurally defined bicyclic peptides via SNAr cyclization[END_REF][START_REF] Renault | Covalent modification of biomolecules through maleimide-based labeling strategies[END_REF][START_REF] Rojas | Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation[END_REF][START_REF] Triola | Racemization-free synthesis of S-alkylated cysteines via thiol-ene reaction[END_REF] Among the crosslinking chemistry, substitution reactions with reagents bearing multiple halide handles such as benzyl halides and halo acetamides for SN2 substitution and electron-deficient haloarenes for SNAr reaction have been widely employed. [START_REF] Kumita | For selected reports on SN2-mediated peptide macrocyclization[END_REF][START_REF] Kohn | Single-step formation of structurally defined bicyclic peptides via SNAr cyclization[END_REF] Nucleophilic addition reactions with strong electrophiles such as maleimides provide another common tactic. [START_REF] Renault | Covalent modification of biomolecules through maleimide-based labeling strategies[END_REF] Recently, the chemoselective arylation of cysteine and lysine side chains with organometallic complexes has also been successfully utilized. [START_REF] Rojas | Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation[END_REF] Despite these significant Scheme 1. Construction of complex peptide macrocycles via crosslinking cysteines with multi-armed linkers. advances, the existing methods are not particularly well suited to incorporate linkers with complex structures or to expand the structural diversity of linkers due to the associated synthetic difficulties. Herein, we report a new method to construct peptide macrocycles via palladium-catalyzed multiple Sarylation of cysteine residues of native peptides with diiodo and triiodoarene reagents. A large number of easily accessible iodoarenes with different arene and heteroarene cores can be incorporated into peptide macrocycles of varied ring size and amino acid (AA) composition in high efficiency and selectivity under mild conditions.

Metal-catalyzed arylation reactions of thiols have recently emerged as a viable strategy for selective modification of peptides in unprotected form and proteins under mild conditions. [START_REF] Gasser | For selected reviews on metal-catalyzed modification of peptides[END_REF][START_REF] Kung | Cyclometalated gold (III) complexes for chemoselective cysteine modification via ligand controlled C-S bond-forming reductive elimination[END_REF][START_REF] Migita | The palladium catalyzed nucleophilic substitution of aryl halides by thiolate anions[END_REF][13][14] Notably, Pentelute and Buchwald reported the use of stoichiometric aryl-palladium complexes for chemoselective S-arylation of Cys residue of unprotected peptides at room temperature (rt). 13 Messaoudi and co-worckers developed a more practical protocol for S-arylation of peptides with various aryl iodides using the Xantphos-Pd-G3 catalyst. 14 Recently, we applied Messaoudi's protocol in an intramolecular fashion to construct aryl thioether-bridged peptide macrocycles. [START_REF] Yang | Streamlined construction of peptide macrocycles via palladium-catalyzed intramolecular S-arylation in solution and on DNA[END_REF] This method has also been successfully adapted to make DNA-encoded library of peptide macrocycles. While this intramolecular reaction provides a useful method to generate aryl thioether-bridged peptide macrocycles, it requires the use of peptide precursors carrying a preinstalled iodo handle. To overcome such limitation, we set out to investigate whether two Cys residues of unprotected native peptides can be crosslinked by bis S-arylation with diiodoarene reagents under similar Pd-catalyzed conditions.

As shown in Scheme 2, we were pleased to find the reaction of linear peptide PA-Leu-Cys-Ala-Val-Ala-Cys-NH2 a bearing two Cys residues separated by three spacing AA units reacted with 2.0 equiv of 1,4-diidobenzene 1 to give the desired cyclic product a-1 in 66% isolated yield under the conditions of 10 mol% of Xantphos-Pd-G3 catalyst and 4.0 equiv of diisopropyl ethylamine (DIPEA) base in the mixed solvents of THF and H2O (4/1) at a concentration of 10 mM at rt for 30 minutes. The N-terminus of substrate a was capped with a picolinamide (PA) group to enhance the UV absorption in LC analysis. Besides a-1, small amounts of disulfide-linked cyclic side product SP1 and acyclic side product SP2 with both Cys residues arylated with a 4-iodo-phenyl group were also formed (~15% combined yield based on LC analysis). The yield of product a-1 slightly dropped when THF was replaced with CH3CN. EtOH and MeOH co-solvent gave comparable results, while dioxane and hexafluoroisopropanol (HFIP) co-solvents gave considerably lower yield (see supporting information (SI) for details). The peptide substrate a was prepared using the standard solid phase peptide synthesis (SPPS) procedure and obtained as a trifluoracetic acid (TFA) salt following the cleavage and deprotection with TFA. The reaction of crude TFA-containing peptide substrate without the addition of base proceeded slowly and completed in about 4 hours under the otherwise identical conditions. The addition of DIPEA greatly accelerated the reaction, allowing the reaction to complete in 10 minutes. The use of other bases such as Et3N and K2CO3 gave similar results (see SI for detailed reaction optimization). Reaction at 1.0 mM concentration of a gave similar results. However, significant amount of side product SP2 was formed (57% LC-estimated yield) when the reaction was carried out at a 50 mM concentration of a.

This macrocyclization strategy was then applied to a wide range of peptide substrates and iodoarene reagents. The majority of iodoarenes are commercially available at relatively low costs. Most of these reagents can be prepared from readily available precursors in short steps. As seen in the previous studies, all unprotected proteinogenic amino acid residues such as Asp (b-1), Gln (j-20), Lys (k-20), Ser (i-20), Thr (l-20), Met (j-20), His (j-20), Trp (k-20), and Arg (j-20) were tolerated. A variety of other functional groups such benzaldehyde (a-29), boronic acid (c-11), nitro (d-2), nitrile (a-10), azo (n-35), and ketone (i-31) were well tolerated. Aryl bromides (e.g. f-21) were unreactive. Both para-and meta-diiodo substituted monoarenes and monoheteroarenes can react well. In contrast, macrocyclization with ortho-diiodo arenes were much less effective (e.g. c-19). A series of heteroarene motifs such as pyridine (e-5), pyridazine (a-6), pyrimidine (c-15, h-16), and thiophene (e-17) can be incorporated. Product d-18 bearing an azulene linker was obtained in good yield. It should be noted that the reactions with asymmetrical diiodides gave the macrocyclic products as a mixture of regioisomers (e.g. e-5, c-14).

Polyarene linkers of large spans and sizes can also be incorporated into the macrocyclic peptide scaffolds in high efficiency. For example, peptide drugs Octreotide bearing 4 spacing AA units (l-20) and Somatostatin bearing 10 spacing AA units (k-20) between the two Cys residues were stapled with the 4,4'-biphenyl linker in 48% and 38% isolated yield respectively. Symmetrical linkers such as dibenzothiophene (a-22), carbazole (a-23, a-24), fluorene (d-25, a-26), diphenyl ether (m-27), diphenylamine (m-28), bithiophene (d-30), bisthiophenylmethanone (i-31), pyrene (d-33), and anthracene (e-37) showed similar reactivities. Product a-32 featuring an indazole linker was formed in low yield. Incorporation of longer linkers such as stilbene (n-34), azobenzene (n-35), and terphenyl (n-36) worked well for peptide substrates bearing more than 5 spacing AA units between the two Cys residues.

As shown in Scheme 3, peptide substrates bearing three Cys residues can undergo tri S-arylation with symmetrical triiodoarene reagents to give the corresponding bicyclic products under the same Pd-catalyzed conditions. For example, reaction of linear peptide PA-Val-Cys-Gly-Leu-Cys-Gly-Pro-Gly-Cys-Gly-NH2 p with 1,3,5-triiodobenzene 38 gave product p-38 in 45% isolated yield. Monocyclic side products SP3 and SP4 were formed in small quantities (~30% combined yield based on LC analysis of the reaction Scheme 2. Construction of monocyclic peptides via Pd-catalyzed bis-S-arylation of cysteine with diiodoarenes. a) Reaction was performed with a 10 mM concentration of peptide substrate on a 0.05 mmol scale. LC yields were based on UV absorption of peptides. HPLC isolated yields are shown in parenthesis. The number of spacing AA units between the two Cys residues is shown in parentheses next to Cys side chain. b) Product was obtained as a mixture of regioisomers. c) Catalyst-related species came out during the HPLC column washing period which is not shown here. For more nonpolar peptide substrates, the catalyst-related species could come out during the gradient separation period. See SI for details. Thr(ol): L-threoninol. PA: picolinic acid. mixture, see Scheme 3 and SI for their structures). Reactions with tri(4-iodophenyl)amine 39 and 1,3,5-tris(4iodophenyl)benzene 40 gave the corresponding tricyclic products in moderate yields. Reagents 38-40 are commercially available and relatively inexpensive. Scheme 3. Construction of bicyclic peptides via Pd-catalyzed tri-S-arylation of cysteine with triiodoarenes. a) Reaction was performed with a 10 mM concentration of peptide substrate at a 0.05 mmol scale. LC yields were based on UV absorption of peptides. HPLC isolated yields were shown in parenthesis. The number of spacing AA units between the two Cys residues is shown in parentheses next to Cys side chains. b) Catalyst-related species came during the column washing period which is not shown here. For nonpolar peptide substrates, the catalyst-related species could come out during the separation period. See SI for details. c) Schematic structures of SP3 and SP4 based on molecular weight (See SI for details).

In summary, we have developed a practical and versatile method to construct complex peptide macrocycles via palladium-catalyzed multiple S-arylation of cysteine residues of unprotected native peptides with diiodo and triiodoarene reagents. A wide range of arene and heteroarene linkers can be incorporated into peptide macrocycles in high efficiency under mild conditions. This method provides a powerful tool to introduce large structural diversity to the crosslinker motifs of peptide macrocycles using readily accessible peptide precursors and linker reagents.

[1] For selected reviews on peptide macrocycles in drug discovery:

  (hetero)aryl halides (S N Ar) A) Commonly used linkers with high reactivity B) Macrocyclization via Pd-catalyzed multiple S-arylation with aryl iodides (this work) XantPhos-Pd-G3 (cat) DIPEA (base), THF/H 2 O (4/1) rt,

  (a) Driggers, E. M.; Hale, S. P.; Lee, J.; Terrett, N. K. The exploration of macrocycles for drug discovery-an underexploited structural class. Nat. Rev. Drug Discov. 2008, 7, 608-624. (b) Marsault, E.; Peterson, M. L. Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. J. Med. Chem. 2011, 54, 1961-2004. (c) Bockus, A. T.; McEwen, C. M.; Lokey, R. S. Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr. Top. Med. Chem. 2013, 13, 821-836. (d) Giordanetto, F.; Kihlberg, J. Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties? J. Med. Chem. 2014, 57, 278-295. (e) Hill, T. A.; Shepherd, N. E.; Diness, F.; Fairlie, D. P. Constraining cyclic peptides to mimic protein structure motifs. Angew. Chem., Int. Ed. 2014, 53, 13020-13041. (f) Vinogradov, A. A.; Yin, Y.; Suga, H. Macrocyclic peptides as drug candidates: recent progress and remaining challenges. J. Am. Chem. Soc. 2019, 141, 4167-4181. [2] For selected reviews on methods for peptide macrocyclization and stapling: (a) White, C. J.; Yudin, A. K. Contemporary strategies for

ACKNOWLEDGMENT

We gratefully thank NSFC-21725204, NSFC-22071119, and NCC2020FH02 (Nankai University) for financial support of this work. Authors acknowledge also support of this project by CNRS, University Paris-Saclay, and the China Scholarship Council for a fellowship (CSC) to Linhua Shen.

ASSOCIATED CONTENT Supporting Information.

Additional experimental procedures, LC analysis traces, and NMR spectra for selected compounds are provided. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author

*Email: samir.messaoudi@universite-paris-saclay.fr *Email: gongchen@nankai.edu.cn ORCID Gong Chen: 0000-0002-5067-9889 Samir Messaoudi: 0000-0002-4994-9001

Notes

The authors declare no competing financial interest.