Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery

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Perspective

Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery Joel Smith, Janice Dixon, Justine Nicole deGruyter, and Phil S. Baran J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b01303 • Publication Date (Web): 01 Oct 2018 Downloaded from http://pubs.acs.org on October 6, 2018

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Journal of Medicinal Chemistry

Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery Joel M. Smith†, Janice A. Dixon†, Justine N. deGruyter, and Phil S. Baran* Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 93037. Abstract: The modern constraints of drug discovery demand a rigorous validation process of all new reactions prior to widespread implementation. To this end, sulfinates (now marketed as Diversinates) have seen alacritous adoption by the medicinal chemistry community, as evidenced by the recent outpour of both patent and primary reports. Featuring more than 50 examples, this Perspective seeks to highlight those particularly compelling cases published in the last five years, with an eye toward the identification of robust and predictable trends in reactivity. The discovery of new therapeutics for the amelioration of human disease is inextricably linked to organic synthesis. Indeed, the evolution of medical treatment is intimately tied to our 1

growing chemical proficiency and, with that, the ability to access intricate molecular architectures with relative ease. More than 100 years ago, the demand for atropine during WWI inspired Robinson’s legendary one-step synthesis of tropinone; today, the challenges facing 2

medicinal chemists are of an entirely different sort, marked by increasing chemical complexity and the need for broadly applicable reactions. As such, the modern pharmaceutical industry 3

ACS Paragon Plus Environment

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relies on the sustained invention of chemical tools with which to create new bonds with exacting precision.

4

B. Borono-Minisci Arylation

A. Inspiration: C–H Oxidation H 2N

HN

HN

Cl

H

N3

AgIIpicolinate

NH 3

Cl

10% TFA/H2O 69% [C–H oxidation]

O N3

R

NH

1

NH OH

HN

NH 3

N

AgNO3 K 2S 2O8, TFA

1-electron reactivity

N3

2

R

PhB(OH) 2

[C–H alkylation]

AgNO3 K 2S 2O8, TFA 62% [C–H arylation]

Minisci (1971)

Baran (2010)

R1

O N3

R

R1 CO2H

H

N

Ph

N

R

C. Early Precedent Cu(OTf)2 NaSO 2CF 3 TBHP

MeO 2C

MeO 2C

strong oxidant,

ubiquitous

designed

heat, or light

HO 2C R C–C BDE ≈ 91 kcal mole -1

R SO2M

R

OH MeCN, H 2O 21% Langlois (1991) [No patents prior to 2012]

OH CF 3

Het

TBHP

C–S BDE ≈ 20 kcal mole -1

R

R

rt

Het

[C–H alkylation]

“Provided…[substitution]…by mesomeric electron-releasing groups, trifluoromethyl aromatics were obtained.” [B. Langlois]

D. Commercial Sulfinates

F 3C

O

O

S

S

O

Zn 2 771406 [TFMS] NaO 2S

F

HF 2C

O

NaO 2S

R

SO2Na

SO2Na

O

R = Et, ALD00294 = Pr, ALD00432

SO2Na

SO2Na

SO2Na

ALD00442

SO2Na

F

F N3

N Cbz ALD00456

900630

746118 [DAAS-Na] O

O Cl

S

O

Zn 2

PhO 2S

791105 [MCMS] NaO 2S

O

SO2Na

6 O

S

O O

S

2 F F 792446 [Shabat Sulfinate]

iPr

O S

Zn 2

ALD00442

809063

O O

790788 [MCES]

SO2Na

SO2Na

X = H, 790796 = Cl, ALD00468 = Br, ALD00476 = Me, 809101 SO2Na = OMe, ALD00438

SO2Na

Me

Cl O

Zn 2

790796 [BNS] X

O

792187 [PSMS]

Me

ALD00442

809098

ALD00466 SO2Na

Me

ALD00434 nBu

ALD00238 [TFPS]

O

Cl

ALD00462

SO2Na

SO2Na

CF 3

SO2Na NaO 2S

ALD00484

790184 [TFCS-Na]

Ph

ALD00458

BocN ALD00236 O ALD00234 [AZS-Na] [THFS-Na]

Zn 2 745480 [IPS]

iPr

ALD00230 [DFHS]

F F

O S

6

F

Cl

SO2Na

Br

Br

ALD00232 [THPS-Na]

F

F Cl

F

Br

O

SO2Na F 3C

Zn F

O

O

F

SO2Na

SO2Na

Zn F F CF 3 2 2 767840 [DFMS] 745405 [DFES-Na] 745499 [TFES]

F

ALD00460

S

SO2Na

Me

Zn 2

nPr

S

O

Zn 2

791040 [NPS]

fluoroalkyl

heterocyclic

aromatic

linker-type

tBu

SO2Na

SO2Na

tBu

ALD00288 [TBS-Na]

ALD00290 [DMPS-Na]

alkyl [40 distinct sulfinates]

Figure 1. (A) Inspiration from C–H oxidation. (B) Expansion of Minisci reaction. (C) Precedent from Langlois and (D) Commercial sulfinates.

Our own scholastic studies on pyrrole-imidazole alkaloids (including the iconic palau’amine structure) led to a radical-based oxidant singularly capable of a chemo- and regioselective C–H oxidation (1 to 2) in water. Though the product appeared susceptible to 5


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oxidation, the key spirocyclic guanidine still gave way late in the sequence with the redoxcontrolled installation of a crucial C–O bond (Figure 1A). Concurrently, regular consulting sessions with various pharmaceutical companies inspired the pursuit of similarly curious radicalbased transformations; might they, too, operate under the nitrogen-rich constraints of modern medicine? Here, the pioneering work of the late Francesco Minisci proved most instructive—his eponymous reaction, of course, relies on the unique affinity of radicals for charged heterocycles.

6

Although Minisci was able to harness alkyl carboxylic acids for the direct C–H alkylation of heterocycles, aryl systems were found lacking. To satisfy the growing call from the medicinal chemistry community, we accepted this decades-old challenge and began to explore boronic acids as aryl radical precursors. Development by us and others saw further expansion to alkyl 7

8

9

boronic acids, reactions that have now been employed across a range of both academic and industrial settings. The progress of this work effected a thought that would map our studies for years to come—the molecules most useful in medicinal chemistry (nitrogen-rich heterocycles) are often the least compliant with two-electron functionalization methods. Indeed, a hallmark question asked by a medicinal chemist in the face of a new reaction is, “Does it work on an unsubstituted pyridine?” In this regard, radicals offer a privileged scaffold with a distinct preference for these errant systems, performing well even in the presence of air and water. This 10

innate chemoselectivity roused a rich research program within our laboratory, much of it beginning with an interest in the radical decomposition pathway of the sulfinate functional group. This Perspective will highlight the industrial impact of sulfinates as appraised by a survey of recent patent literature (2012–2018). Similar to the oxidative homolysis of carboxylic and boronic acids, the oxidative decomposition pathway of the sufinate group was described by Langlois as early as the 1990s.



The

potential

of

this

reaction—

Page 4 of 26

A. Sulfinate Regioselectivity Guidelines nucleophilic radical selectivity

exemplified by the trifluoromethylation of phenols and anilines using sodium

CN

CN

OMe

N

N

N

electrophilic radical selectivity

H C2 >> C3

trifluoromethylsulfinate (Na-TFMS), a

C3 >> C2

C2 = C3 [unreactive]

CN

CN

OMe

N

N

N

H C2 > C3

C3 > C2

C2 = C3

B. Reactivity Flowchart: Methyl 3-methylpicolinate

copper

(II)

salt,

butylhydroperoxide

and

tert-

(TBHP)—went

STEP ONE: Identify innate reactivity sites. Me N

STEP TWO: Identify conjugate reactivity sites. Me

CO2Me

largely unnoticed at the time, likely due

N

to Langlois’ claim that the chemistry

stifled

industrial interest for more than two decades (Figure 1C); in fact, prior to

the

patent

Me N

deactivating influence

CO2Me

mixed influence

C. Sufinates and Radical Retrosynthesis

Br

CN 1 e –

2 e–

N

CF3 N

CN

Shortly before that first report came our

6

Trt N N

Cl

range of electron-rich and -deficient

N Me

heterocycles can be engaged by a

I

N 9

Bpin N 7, TBHP; 4, [Pd]

1 e–

1.[Pd], Mo(CO) 6, MeOH 3. [O] 4. DAST 2. DIBAL-H

7 SO2Na CF3

• Single step • Innate selectivity

8

H N

Cl

N

N Me

CN 4

Trt N N

Cl 2 e–

N

3

• Uses strong base and CH2N 2 • 3% overall yield

Br

Br

N

4 CF 3CO2Et 5 1. nBuLi; 5 Br 2. Tebbe 4. heat 3. CH 2N 2 5. [Pd],B 2pin 2; 4 N

literature.

own observation that an impressive

CO2Me

STEP FOUR: Combine factors and choose conditions.

enhances innate reactivity (C3 preferred)

activating influence

2012, his sulfinate reagent was entirely from

N

CO2Me

acidic conditions (H+, solvent)

CO2Me

11

absent

N

N CO2Me R = CF 3 R Me neutral conditions (DMSO) N

specificity

CO2Me

enhances innate reactivity (C4 preferred)

was limited to electron-rich arenes. presumed

Me

Me

R Me

This

STEP THREE: Consider factors that modify reactivity.

CF2H

Me

1. DFMS, TFA, TBHP 2.TrtCl

[redox fluctuation] Merck Sharp & Dohme [direct] [ideal]

simple oxidant, presumably due to the relatively low homolytic barrier of the sulfinate

C–S

bond.

In

Figure 2. (A) Regioselectivity guidelines. (B) Reactivity flowchart of sulfinates. (C) Radical retrosynthesis with sulfinates.

commercial

partnership with MilliporeSigma, we have since developed 40 sulfinates (Figure 1D) for use in both early- and late-stage arene modification. These sulfinates are now available as fluoroalkyl


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(pink), alkyl (green), heterocyclic (blue), aromatic (orange), and linker-type (manila), each of which has seen near-immediate adoption by the medicinal chemistry community, and has helped to expand the accessible molecular space for both industrial and academic laboratories.

12

Though occasionally capricious, the behavior of nitrogenous heterocycles in the presence of radical intermediates is not without guiding principles. With few exceptions, the addition of an oxidant (typically TBHP) to a sulfinate salt results in the formation of a carbon-centered radical. The nature of the radical generated—as well as the reaction conditions, be they acidic or neutral—dictates the regioselectivity of the innate radical addition event (see Figure 2A). In the case of nucleophilic radicals (e.g., alkyl, aryl, CF H): When the arene substrate is adorned with 2

one or more electron-withdrawing substituents, acidic conditions result in selective functionalization adjacent to the N atom (C2). However, in a neutral reaction environment, the regioselectivity favors that of a radical conjugate addition (C3). By contrast, electron-donating substituents can hamper, or even preclude, heterocycle reactivity with nucleophilic radicals under the right circumstances. For electrophilic radicals (e.g., CF ): The same regioselectivity is 3

observed for electron-deficient heteroarenes, regardless of medium pH, though the effects are less pronounced. The true divergence is seen in the reactivity of electron-poor radicals with a heteroarene-bearing donor group—here, the regioselectivity typical of electrophilic aromatic substitution prevails. An abbreviated reactivity flowchart (Figure 2B, adapted from ref. 13) 13

depicts the impact of engineered reaction parameters on substitution outcome, even within the confines of a single sulfinate salt. An early example of this simplifying strategy is illustrated by the radical-based retrosynthetic analysis in Figure 2C. The existing synthesis of bipyridine 3 hinged on a polar two-electron approach in which the requisite trifluoromethylcyclopropyl group was installed over several steps from dibromopyridine 6. Following borylation and cross14



Page 6 of 26

Early-Stage Monocyclic Intermediates (Patent Literature 2013–2018) O

Me

O

OEt

N

N

N 10 CF2H

Me

O

N

N

[DFMS, TBHP] 14% [2 analogues] Nimbus Lakshmi, Inc. (Ref. 21)

No yield reported

CF2H

CF2H

N

N

N

N

HF2C

O

N N

NC

N

N

O

15

O

16

Cl

Cl

Cl

F

OMe

(Ref. 18a)

H. Lundbeck A/S

HN O

Me CF3 HN N

CO2H [TFMS, TBHP] 7%

Boehringer Ingelheim (Ref. 23)

N

HN

O

F

N

Plexxikon inc. (Ref. 24)

CF3

CF3

MeN

F

[DFMS, TFA, TBHP] 35% [7 analogues]

(Ref. 18a)

(Ref. 18b)

O

N Me

O

[TFMS, TBHP] 50% W. China Sichuan (Ref. 19)

H. Lundbeck A/S

NH2

N

CF2H


Cl

[TFMS, TFA, TBHP] 19% [2 analogues] Bayer Pharma (Ref. 22)

[Na-TFMS, TBHP] 55%

NC HN

N H

O

N N

CN Me


CF3

HN

N

S

Me

N

12

CF2H

NH2

HF2C

Novartis AG (Ref. 17b)

CF2H

14

N

O

CF2H

N H

S

No yield reported

HF2C

13

N

O N

Cl

O

O

[DFMS, TFA, TBHP] 100% (Ref .17a), 95% (Ref. 17b) [40 analogues] Domain Terapeutics, Novartis AG (Refs. 17a and 17b)

N

N

CF2H

N H

11

Me

O

O

Cl

N

[Na-TFMS, TBHP] 57% [2 analogues] Hoffmann-La Roche, Inc. (Ref. 20)

Figure 3. Examples of early-stage sulfinate products from the patent literature.

coupling, the target molecule was obtained after multiple chromatographic purifications in relatively low (3%) yield. In our hands, treatment of pyridine 7 with sulfinate 8 enabled a onepot trifluoromethylcyclopropantion/Suzuki-Miyaura coupling sequence, providing direct access to 3 after a single purification step.

15

Shortly thereafter, Merck & Co. disclosed two routes to difluoromethylated pyrazolopyridine 9, the most expeditious of which relied on zinc difluoromethanesulfinate (DFMS), while the contrasting polar approach required a number of nonstrategic redox manipulations. Step-count metrics aside, it is worth emphasizing just how simplifying the 16

experimental protocol is: The setup requires no rigor with regard to reaction isolation (open flask is fine), solvent purification (provided radical inhibitors are not present), or purity of starting materials (one-pot sequences are well tolerated). The procedure calls only for the substrate, oxidant (TBHP), solvent, and desired sulfinate; though not necessary, a Brønsted and/or Lewis acid (vide infra) may be added to improve yields or influence selectivity.

12


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In the context of medicinal chemistry, the typical sulfinate reactions can be categorized as either early- or late-stage functionalization. Ten early-stage examples are shown in Figure 3, including the reactive intermediate, general conditions, isolated yields, and patented utility in library development; in each case, the bond highlighted in red was forged using the requisite sulfinate in an oxidative C–H functionalization event. Note that the observed regioselectivities are in complete agreement with the trends parameterized in previous reports from our lab.

13

Importantly, these are not esoteric models—difluoromethylated pyridine 10, for example, is the primary building block of

40 analogues, including both 11 and 12.

17

The same

difluoromethylaltion reaction was exploited by H. Lundbeck A/S to efficiently access to 13, the precursor to medicinal leads 14–16. For a complete list of early-stage sulfinate modification 18

products and their patented derivatives, see the Supporting Information. With the synthesis of each compound in Figure 3, even in unoptimized form, SAR space was undeniably expanded. Indeed, without the innate C–H functionalization behavior predicated by this type of radical reaction, a “total synthesis” of each analogue would have been required; in the midst of a discovery campaign, it is entirely possible that they would not have been pursued at all. As exemplified by the compounds in Figures 4 and 5, the foremost advantage of these reagents is not the capacity for modification of complex drug targets, but the ability to do so with such reliable predictability. Figure 4A, for instance, describes the trifluoromethylation of an advanced intermediate recently reported by Gilead Sciences (17–18). Here, basic C NMR 25

13

predictions performed in ChemDraw accurately detect the most probable site of functionalization; the most electron-rich site occupies the position furthest upfield—one can 26

now confidently forecast the intrinsic preference of the electrophilic trifluoromethyl radical.



Cases of imperfect selectivity are often

Page 8 of 26

Late-Stage Diversification of Medicinal Leads A. Reactivity Site Prediction 134.8

used to the advantage of the practitioner, allowing access to several derivatives in a single bid. In one fortuitous example,

H 2N

efficient

N

Cl N

N

NH 72.0

compound 19, developed by Actelion underwent

128.6

Me

N

Pharmaceuticals,

124.8

NH2

N

Me H 2N

91.5

HN

N

N

N

CF3 NH2

Gilead Sciences Inc. (Ref. 25)

O

NH

N

132.0

17

Cl

N

Na-TFMS TBHP

O

NH

18

B. Late-Stage Patented Examples Et

Br HF2C

difluoromethylation at the expected C2

Et

N

O

H N

Me Me

N

NH

N O

CF3

position and C4 of the cyanopyridine; both products proved critical in establishing

[TFMS, TBHP] 30% Peleton Therapeutics (Ref. 30)

SAR space about the target lead.

F3C

[DFMS, TFA, TBHP] 52% Astellas Pharma, Inc. (Ref. 31)

CF2H

Br

O

O

[DFMS, TFA, TBHP] 42% Bayer Pharma Aktiengesellschaft (Ref. 32)

Me 27

N NH

O

Electronic considerations are not, of

Cl

Me

S

course, the sole influencing factor—the

O

N

HN

Me

resulting product, per the trends delineated

N

N H

NH

4

CN

N

F

N3

[NaSO2CF2(CH2)6N3, TFA, TBHP] Konica Minolta (Ref. 29) iPr

O

N 2 CF2H

N HN

S Me

[Na-TFMS, TFA, TBHP] 14% Janssen Sciences Ireland (Ref. 33)

choice of sulfinate may also dictate the

F

F

O N

in the guidelines above. Researchers at

F

O

O

CF3

N NMe2

N NMe2

O

Kyungpook National University (KNU)

19

20 iPr

[DFMS, TFA, TBHP]

capitalized on this trait in the study of

Hofmann-La Roche Inc. (Ref. 27)

estrogen-related receptor gamma (ERRγ) inverse agonists: Under otherwise identical

21 HO

MeO

HO

MeO

[IPS, TFA, TBHP] [TFMS, TFA, TBHP] 4% 7% Kyungpook National University (Ref. 28)

Figure 4. (A) NMR prediction for late-stage diversification. (B) Late-stage use of sulfinates.

conditions, trifluoromethylation with TFMS (an electrophilic radical source) was shown to proceed on the electron-rich substituted phenol ring (21), while substitution with sodium isopropylsulfinate (IPS, a nucleophilic radical source) occurred exclusively at C2 of the embedded pyridine (20). Much like the KNU examples, most of the Figure 4 examples were 28


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Additional Mono- and Bicyclic Heteroarenes A. Early-Stage Intermediates NH 2 O F 3C

NH 2

HF 2C

N

N

N

CF 3

CF2H N N

Br

O

Me

S

iPr

O

O

Br

CN

N

N

OH

CF2H

[Na-TFMS, TBHP] [2 analogues]

[TFMS, TFA, TBHP] 10% [3 analogues]


[TFMS, TBHP] 44% [2 analogues]

[DFMS, TBHP] 17% [2 analogues]

[DFMS, TFA, TBHP] [3 analogues]

Takeda (Ref. 39)

Merck (Ref. 40)

Allergan, Inc. (Ref. 41)

Bristol-Myers Squibb (Ref. 42)

Janssen Pharma (Ref. 43)

Merck Sharp & Dohme (Ref. 44)

B. Late-Stage Products

Cl

H N

CF 3

Cl

N

N N H

N

MeO

F 3C

F 3C

N

Northwestern U. Bayer Pharma AG (Ref. 46)

O 22

F

N

N

O

S N

N

N O

N Me

N

F 3C

Cl

N

N

[Na-TFMS, TBHP] 12% Ono Pharmaceutical Co. (Ref. 38)

S

N

TFA

N

N

NH

N

Me

Me

O

N

CF 3

Me I

Cl

25

Ph N

N

N

HN

N

Me N

Me

N

H 2N O

O S

N

NH 2

24

[Na-TFMS, TBHP] 33%

CF 3

N

23

O H N

Me iPr

N Me

tBu

Grunenthal (Ref. 36)

N N

Cl

[Na-TFMS, TBHP] 30%

Merck Sharp & Dohme (Refs. 16 and 45)

Me

N O

N

F

R = F, [Na-TFMS, TBHP], 13% R = H, [DFMS, TFA, TBHP] [6 analogues]

NH 2

N

N

N

N

Me

N

Me

RF 2C


CF 3

[IPS, TFA, TBHP] 30%

[Na-TFMS, TBHP]

[TFMS, TBHP] 10%

[TFMS, TBHP] 5%

Shanghai Inst. of Material Medica CAS (Ref. 37)

Euroscreen SA (Ref. 47)

Incyte (Ref. 48)

Plexxicon Inc. (Ref. 49)

O N Me

Cl

CO2Me

N

N

Cl

CF2H

N

N

O N

NH

N

O NH

F 3C N

N Me

F 3C

Cl

S

CO2Et

N

F

NH

N

N

OH Me Me

N

CF 3

CF2R

CF 3

H N N

N

H N

H N O

OMe

CF2H

Ph

N

N

Me Br

HN

F N

Me

N

H 2N [Na-TFMS, TBHP] 68%

[Na-TFMS, TBHP] 76%

[Na-TFMS, TBHP] 16%

R = H, [DFMS, TBHP] R = F, [TFMS, TBHP]

[Na-TFMS, TBHP]

[DFMS, TFA, TBHP] 24%

Active Biotech (Ref. 51)

Merck & Co. (Ref. 52)

Merck Sharp & Dohme (Ref. 53)

Janssen Pharmaceutica (Ref. 54)

Almac Discovery (Ref. 50) N

Me HN F 3C

N

TFA

HF 2C

N

O

N

CF2H

N N

N S

NH 2 HN

HN N

O N H

S

N

S O

CF2H

CF2H

N

Me MeN

N

O CO2Et Me

O Me

[DFMS, TBHP]

[DFMS, TFA, TBHP] 14%

Gllead Sciences, Inc. (Ref. 55)

Janssen Pharmaceutica (Ref. 56)

Syros Pharmaceuticals (Ref. 57)

S N

N NH

O

NH

[TFMS, TFA, TBHP]

N

N

[DFMS, FeCl 2, TFA, TBHP] 32%

OH

[Na-DFMS, FeSO 4, TFA, TBHP] 15% Pfizer, Inc. (Ref. 58)

Figure 5. Further examples of (A) early-stage and (B) late-stage sulfinate products from the patent literature.

eventually integrated into late-stage libraries for lead optimization. This is not to say, however, that application is limited to drug discovery; Konica Minolta, for example, found great utility in



Page 10 of 26

the use of sulfinates as conjugation handles (e.g., via an appended azido group) for use in chemical biology studies.

29

It would be incorrect to interpret the role of pyridine as the medicinal chemists’ flagship as all-encompassing; though undeniably important, this group occupies but a fraction of druglead space. Figure 5 describes a large selection of both (relatively) electron-rich azoles and 34

bicyclic heteroarenes, all of which undergo predictable early- (highlighted in blue) or late-stage (highlighted in gray) (fluoro)alkylation reactions. If alternative routes for the preparation of these compounds indeed exist, the multistep sequence required would almost certainly discourage immediate pursuit. Of particular note are the di- and trifluoromethylation of pyrazole and pyrrole-type heterocycles—while circuitous two-electron cross-coupling and electrophilic aromatic substitution transforms dominate conventional retrosynthetic analyses, a sulfinate35

based radical disconnection enables the direct functionalization of these densely-substituted heterocycles (e.g., 22–23 from Grunenthal). The innate selectivity of these reactions, even when 36

faced with complex leads, is quite remarkable, as in the case of sterically-encumbered products 24 (Ono Pharmaceutical Co.) and 25 (Shanghai Inst. of Material Medica CAS) . Despite the 37,38

modest unoptimized yields, the true value of this technology is on clear display: rapid, predictable expansion of developing pharmaceutical libraries. In yet another impressive display of divergence, Boehringer Ingelheim described an interest in expanding the SAR space about the pyrimidine ring of 28 (Figure 6A). The authors reported the productive coupling of four distinct sulfinates, each of which demonstrated preference for the most electrophilic position. Sulfinates have also found use in the study of fundamental chemical reactivity. Recently, Kuttruff and coworkers (Figure 6A) evaluated the late-stage selectivity of sulfinates in the presence of various drug candidates (e.g., 26). While the 59


Page 11 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Late-Stage Diversification and Natural Products Modification A. Late-Stage Functionalization F

F NH 2

OH sulfinate, TBHP N

26

F F

N


HO H

N

OH

Me

NH 2

CN

N

N

Me

CF2CH 3

O


N

N

CN

N

Me

N

R CN

NH 2 N

N O

N

N

N

NH 2 N

O

N N

N

N

28

N

N

iPr

N

R

R1

R1 N

N

O

HO H

NH 2

sulfinate, TBHP additive

N

N

N

Me

CF2R O

N

N

CN

O

N

N N

Me

N

CN

RF 2C

[IPS], 26%

R = F, [TFMS], 17% R = H, [DFMS], 21%

[DFES, TFA], 36%

R = H, [DFMS, TFA], 12% R = F, [TFMS, TFA], 45%

[THFS], 25%

B. Effects of Fe Additives Me

Me N

O

S

O

O

N

NH F

sulfinate, TBHP additive

N

S

O

NH

N F

N

iPr

H H

Me HO N

O X

TFMS or DFMS TBHP

NH H

X = CF 3, Y = H, 49% X = Y = CF 3, 25% X = H, Y = CF 3, 13% X = CF2H, Y = H, 29%

NH

O agelastatin

H N

Y

H

O Het

O

NaO 2S

Me F

F

O

O

N

cinchona alkaloid dervative O

F

O

Het

O

N N

MeN O Et

Me

N

Me

F

F N

CO2H H N

N

N

OH O

RNHNH 2 R = peptide

OMe Y cinchona alkaloid analogues

Me

F

O

Het N

N N

O

Me Me

X

F

O

RHN

X = CF 3, Y = H, 11% X = H, Y = CF 3, 19% X = iPr, Y = H, 44% X = Bn, Y = H, 29%

OMe

agelastatin analogues

F

Me TFMS, IPS or NaSO 2Bn TFA, TBHP

N

O

F

[TFMS], 11% [TFMS, TFA, Fe], 23%

O

NH

D. Bioconjugation Handles

N

Me

NH H

N N N

[IPS], 22% [IPS, TFA, Fe], 30%

C. Natural Product Modification Me HO N

CF 3

R1

N

N N

N R

N N

F

27

N

N

N N

N N

N

N R1

F

N

N

78%

O 28%

NH 2

F N Me

N

NH 2

N N

N

NH 2

CO2H O 35%

Figure 6. (A) Late-stage modification of drugs with the sulfinates platform. (B) Effect of Fe additive. (C) Use of sulfinates with natural products. (D) Use of sulfinates in bioconjugation of drug molecules.

general trends were unremarkable, the scientists did discover that Fe(III) salts, usually Fe(acac) , 3

can be used to improve yields (Figure 6B). In the case of pyridine 27, though all substitutions occur at the electrophilic C2 position, isolated yields saw significant improvement in the presence of Fe(III) as compared to that of the parent reaction. Alternatively, more exotic modes of initiation, including electro- and photochemical, can be useful specific instances. 60

61



Page 12 of 26

Returning again to academic studies, the influence of heteroaromatic-containing natural products in drug discovery was established long before the modernization of medicinal chemistry. Even those timeworn compounds may reveal behaviors hitherto undetected, as in the preparation of quinine and agelastatin analogues by the Waldmann and Molinski groups, 63

respectively (Figure 6C). Following sulfinate functionalization, Waldmann and coworkers 64

discovered that three of the obtained cinchona alkaloid derivatives exhibited enhanced selectivity in autophagy inhibition. In addition to the observed SAR improvements about the cited compounds, the Molinski team specifically noted the value of mild TBHP conditions as compared to PET-based initiation protocols. Finally, Shabat and coworkers exploited the masked methyl ketone of their namesake sulfinate for heterocyclic tagging and peptide bioconjugation (Figure 6D).

65

In an age of increasingly complex biological targets and narrowing IP space, the import of efficiency in complex molecule synthesis cannot be discounted. Sulfinates offer medicinal chemists an opportunistic retrosynthetic approach—disconnection priority can be placed on the parent scaffold, while peripheral substituents are duly treated as an afterthought rather than a primary consideration. Though unanticipated on initial development, the broad industrial adoption of the commercial sulfinate platform further validates the need for the continued study of fundamental organic chemistry by academic and medicinal chemists alike. Corresponding Author *Email: [email protected] Funding Sources


Page 13 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The authors thank the Arnold and Mabel Beckman Foundation for a Postdoctoral Fellowship (J.M.S.), the NSF GRFP for graduate support (J. N. D.), as well as Bristol-Myers Squibb, Pfizer Inc., and LEO Pharma for financial support of the described research. Notes †These

authors contributed equally.

The authors declare no competing financial interest. Biographies Dr. Joel M. Smith was born in Raleigh, North Carolina in 1987, received his B.S. in Chemistry and music at Furman University in 2010, and his Ph.D. at UCLA in 2015. Since then, he has been an Arnold O. Beckman Postdoctoral Fellow with Professor Phil S. Baran at TSRI and has since begun his independent academic career at Florida State University.

Janice Dixon was born in Honolulu, Hawaii and received her B.S. in Chemistry at the University of Hawai‘i at Mānoa in 2004 and continued her work there until 2010. She joined the Baran lab in 2011 as a research associate and has since worked on The Portable Chemist’s Consultant iBook while serving as an editorial assistant for the Journal of the American Chemical Society for Professor Baran.

Justine N. deGruyter is a New Mexico native and received her B. S. in Chemistry from New Mexico State University, where she graduated in 2014 with highest honors. Currently, Justine is a graduate student at The Scripps Research Institute, working in the laboratory of Professor Phil S. Baran.



Page 14 of 26

Prof. Phil S. Baran was born in New Jersey in 1977 and received his undergraduate, graduate, and postdoctoral education from New York University, The Scripps Research Institute, and Harvard, respectively. Since returning to TSRI in 2003, his laboratory has been dedicated to the study of fundamental organic chemistry. ACKNOWLEDGMENTS The authors thank the Arnold and Mabel Beckman Foundation (J.M.S.) and NSF Graduate Research Fellowship Program for financial support (J. N. D.). We are especially grateful to the co-workers that made much of this work possible (names listed in references) and our many industrial collaborators from Bristol-Myers Squibb and Pfizer, Inc. ABBREVIATIONS

Na-TFMS, sodium trifluoromethanesulfinate; TFMS, Zinc bis(trifluoromethanesulfinate); DFMS, Zinc bis(difluoromethanesulfinate); DFES, Sodium difluoroethanesufinate; IPS, sodium 2-propylssulfinate;

TFCS,

Sodium

Trifluorocyclopropanesulfinate;

TFES,

Zinc

bis(trifluoroethanesulfinate); TFPS, Sodium trifluoropropanesulfinate; DFES, Sodium 1,1difluoroethanesulfinate; bis(propanesulfinate);

TFPS-Na. MCES,

Sodium Zinc

3,3,3-trifluoropropanesulfinate;

bis(monochloroetanesulfinate);

NPS,

MCMS,

Zinc Zinc

bis(monochloromethanesulfinate); PSMS, Zinc bis(phenylsulfonylmethanesulfinate); TBS-Na, Sodium tert-butylsufinate; DMPS-Na, Sodium 2,2-dimethylpropylsulfinate; BNS, Zinc bis(benzylsulfinate);

DFHS, Sodium 4,4-difluorocyclohexanesulfinate; THPS, Sodium


Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


tetrohydropyranylsulfinate;

THFS,

Sodium

tetrohydrofuranylsulfinate;

AZS,

Sodium

azetidinylsulfinate; DAAS-Na, Sodium (difluoroalkylazido)sulfinate. REFERENCES 1. (a) Corey, E. J.; Czakó, B.; Kürti L. Molecules and Medicine; Wiley: Hoboken, 2007. (b) Nicolaou, K. C.; Montagnon T. Molecules That Changed the World; Wiley-VCH: Weinheim, 2008. (c) Lowe, D. The Chemistry Book: From Gunpowder to Graphene, 250 Milestones in the History of Chemistry; Sterling: New York, 2016. 2. Robinson, R. LXIII. A synthesis of tropinone. J. Chem. Soc., Trans. 1917, 111, 762–768. 3. Li, J.; Eastgate, M. D. Current complexity: a tool for assessing the complexity of organic molecules. Org. Biomol. Chem. 2015, 13, 7164–7176. 4. (a) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 2016, 45, 546–576. (b) Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 2018, 10, 383–394. 5. Seiple, I. B.; Su, S.; Young, I. S.; Nakamura, A.; Yamaguchi, J.; Jørgensen, L.; Rodriguez, R. A.; O’Malley, D. P.; Gaich, T.; Köck, M.; Baran, P. S. Enantioselective total syntheses of (–)palau’amine, (–)-axinellamines, and (–)-massadines. J. Am. Chem. Soc. 2011, 133, 14710– 14726. 6. For review on the Minisci reaction, see: (a) Minisci, F.; Vismara, E.; Fontana, F. Recent developments of free-radical substitutions of heteroaromatic bases. Heterocycles 1989, 28, 489– 519. (b) Minisci, F.; Fontana, F.; Vismara, E. Substitutions by nucleophilic free radicals: a new



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Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery

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