SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and...

22
The University of Manchester Research SmI2-catalyzed cyclization cascades by radical relay DOI: 10.1038/s41929-018-0219-x Document Version Accepted author manuscript Link to publication record in Manchester Research Explorer Citation for published version (APA): Huang, H-M., McDouall, J. J. W., & Procter, D. (2019). SmI 2 -catalyzed cyclization cascades by radical relay. Nature Catalysis, 2(3), 211-218. https://doi.org/10.1038/s41929-018-0219-x Published in: Nature Catalysis Citing this paper Please note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscript or Proof version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version. General rights Copyright and moral rights for the publications made accessible in the Research Explorer are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Takedown policy If you believe that this document breaches copyright please refer to the University of Manchester’s Takedown Procedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providing relevant details, so we can investigate your claim. Download date:22. Apr. 2021

Transcript of SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and...

Page 1: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

The University of Manchester Research

SmI2-catalyzed cyclization cascades by radical relay

DOI:10.1038/s41929-018-0219-x

Document VersionAccepted author manuscript

Link to publication record in Manchester Research Explorer

Citation for published version (APA):Huang, H-M., McDouall, J. J. W., & Procter, D. (2019). SmI

2-catalyzed cyclization cascades by radical relay.

Nature Catalysis, 2(3), 211-218. https://doi.org/10.1038/s41929-018-0219-x

Published in:Nature Catalysis

Citing this paperPlease note that where the full-text provided on Manchester Research Explorer is the Author Accepted Manuscriptor Proof version this may differ from the final Published version. If citing, it is advised that you check and use thepublisher's definitive version.

General rightsCopyright and moral rights for the publications made accessible in the Research Explorer are retained by theauthors and/or other copyright owners and it is a condition of accessing publications that users recognise andabide by the legal requirements associated with these rights.

Takedown policyIf you believe that this document breaches copyright please refer to the University of Manchester’s TakedownProcedures [http://man.ac.uk/04Y6Bo] or contact [email protected] providingrelevant details, so we can investigate your claim.

Download date:22. Apr. 2021

Page 2: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

SmI2-catalyzed cyclization cascades by radical relay

Huan-Ming Huang, Joseph J. W. McDouall, David J. Procter*

School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL,

UK.

*Correspondence author. Email: [email protected]

Abstract

Radical cyclization cascades are powerful tools used to construct the complex

three-dimensional structures of some of society’s most prized molecules. Since its

first use forty years ago, SmI2 has been used extensively for reductive radical

cyclizations. Unfortunately, SmI2 must almost always be used in significant excess

thus raising issues of cost and waste. Here we have developed radical cyclization

cascades that are catalyzed by SmI2 and that exploit a radical relay/electron-catalysis

strategy. The approach negates the need for a super-stoichiometric co-reductant and

requires no additives. Complex cyclic products, including products of dearomatization,

containing up to four contiguous stereocenters are obtained in excellent yield.

Mechanistic studies support a single-electron transfer radical mechanism. Our strategy

provides a long-awaited solution to the problem of how to avoid the need for

stoichiometric amounts of SmI2 and establishes a conceptual platform upon which

other catalytic radical processes using the ubiquitous reducing agent can be built.

Introduction

Page 3: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Biologically-active molecules often possess intricate three-dimensional,

ring-containing structures. Classical approaches to these complex polycyclic targets,

involving the use of many reagents and operations over many reaction steps, are being

superseded by strategies employing one-pot sequences, or cascades, of ring-forming

reactions that deliver the target in expedient fashion.1–4 The unique combination of

high reactivity and high selectivity associated with open-shell intermediates makes

radical processes5,6 ideal for cascade reactions in which simple substrates undergo a

series of changes involving bond formation (and bond cleavage) to give complex,

high value products and single electron transfer (SET) is commonly used to generate

the radical character that drives such processes.7–9 The well-known reductant

samarium(II) diiodide (SmI2, Kagan’s reagent)10 is arguably one the most important

and widely used SET reagents11,12 and it has proved adept at unlocking the total

synthesis of numerous high profile and complex natural products (Fig. 1A).13–18 Many

of the most important radical reactions of SmI2 involve SET to ketones and aldehydes

and the generation of ketyl radicals.11 Despite almost 40 years of widespread use, the

reductant is almost invariably used in super-stoichiometric amounts, thus raising

issues of cost and waste. The development of new and sustainable processes catalytic

in SmI2 would be a major advance. Of the few reports of the use of catalytic SmI2, all

require the use of super-stoichiometric amounts of a metal co-reductant to regenerate

Sm(II).19–22 For example, Corey described one of the very few SmI2-catalyzed radical

cyclizations:19 Unfortunately, the catalytic system requires 15 equivalents of Zn/Hg

amalgam (Fig. 1B). Over twenty years later, this system remains the state-of-the-art in

the field.

The development of efficient catalytic variants of important reactions requiring

stoichiometric reagents is key to the future of synthesis.23 In the field of radical

Page 4: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

chemistry involving SET, radical relay/electron-catalysis strategies are highly

attractive and atom economical as radical character is recycled and stoichiometric

oxidants and reductants are not required.24,25 For example, Yoon,26–28 Song,29,30 and

Meggers31 have described elegant examples of this approach in cyclizations and

cyclization cascades involving ketyl radicals. However, even in these systems,

co-reductants and additives are required. For example, in the only reported radical

relay cyclization cascade, stoichiometric La(OTf)3, TMEDA, and MgSO4 are

employed.26 The work we report here was prompted by the desire to address the

longstanding inability to use catalytic amounts of SmI2 and to advance the application

of radical relays in synthesis.

Here we describe radical cyclization cascades mediated solely by a SmI2 catalyst. Our

approach represents the use of the classical SET reagent in a radical relay, converts

simple cyclopropyl ketones 1 to complex cyclic ketones 2 (Fig. 1C), avoids the use of

co-reductants and additives, involves short reaction times (< 20 min), is operationally

straightforward, and exhibits broad scope. Key to the catalytic radical process is the

spring-loaded nature of ketyl radical I which is formed by reversible SET from SmI2

to substrate 1a. Ketyl radical I fragments32,33 to give distal radical II. Cyclization then

generates radical III which rebounds by addition to the Sm(III)-enolate moiety,

regenerating new ketyl radical IV. Back electron transfer to Sm(III) regenerates the

SmI2 catalyst and liberates product 2a (Fig. 1D). The use of substrates bearing alkenes

and alkynes as radical acceptors delivers complex products containing two new rings

and up to four new stereocenters. Furthermore, dearomatizing radical cyclizations

using catalytic SmI2 are also possible using heteroarene substrates (Fig. 1C).

Page 5: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Fig. 1 | Importance of stoichiometric SmI2-mediated cyclizations and the

challenge of catalysis using SmI2. (A) Selected complex bioactive natural products

synthesized using stoichiometric amounts of SmI2. (B) A rare example of a

SmI2-catalyzed radical cyclization requires a large excess of stoichiometric

co-reductant and additives. (C) SmI2-catalyzed cyclization cascades. (D) Proposed

catalytic cycle.

Results

Ph

O Me

Me

Ph O

H

H

EtO2C CO2Et EtO2C CO2Et

O

O OH

HHO OAc

AcO

OO

PhO

O

Ph

HO

NH

Ph

O

EtO2C CO2Et

Ph

O Me

EtO2C CO2Et

Me

O

Ph Me

EtO2C CO2Et

Ph O

H

2a

Me

EtO2C CO2Et

Ph O

H

HI

II

III

IV

1a

(+)-Pleuromutilinn 2.5 equiv. SmI2

Strychninen 2.4 equiv. SmI2

Taxol® (paclitaxel)n 5.2 equiv. SmI2

H

HO

O

OAc

OO

H

(–)-Maoecrystal Zn 3.0 equiv. SmI2

A. Stoichiometric SmI2 required for cyclization cascades B. SmI2-catalyzed radical reactions are rare (Corey, Ref 19)

COOAr

O

O

OSmI2(10 mol%)Zn•Hg (15 equiv.)

LiI (5.2 equiv.)

TMSOTf (3 equiv.)THF, RT, 10 h 78-84%

n Super-stoichiometric co-reductant & additivesn Long reaction times

SmII

D. Proposed catalytic cycle

+

Ar = mesityl

SmIIAr/HetAr

Ar/HetAr

R1

H

C. This work: SmI2-catalyzed cyclization cascade by radical relay

X

O

X

R1

O

H

H21

n Catalytic SmI2 (5 mol%) n No stoichiometric co-reductant n No additives required n Short reaction time (< 20 min)n Operationally simple n Dearomatizing radical cascades

N

O

H

N

O

H

H

HO

OH

O O

OH

SmIII

SmIII

SmIII

SmIII

SmI2-catalysisby radical relay

SmII

Ph O

S

CO2EtEtO2C

H H

H

Representative products

EtO2C CO2Et

Ph O

H

H H

H S

EtO2C CO2Et

Ph O

H

H

O

Ph O

O

H H

H

N

Ph O

H

H

MeMe

EtO2C CO2Et

O

H

H

F

Ts

Page 6: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Optimization studies. To assess the feasibility of the proposed catalytic radical

process, 1a (Ar = Ph, R1 = Me, X = C(CO2Et)2) was treated with 30 mol% SmI2 (Fig.

2). The corresponding bicyclic product 2a was obtained in 68% isolated yield (see

Supplementary Table 1). When the catalyst loading of SmI2 was decreased to 10

mol%, the yield of 2a dropped to 56% with 1a recovered in 31% yield. Pleasingly, the

efficiency of the cyclization cascades increased upon heating; using 5 mol% SmI2 at

65 °C, 2a was obtained in 87% isolated yield and 71:29 dr, with the reaction complete

in <20 min. Formation of 2a was not observed in the absence of the SmI2 catalyst and

only starting material 1a was recovered.

Catalytic radical cyclizations of alkynes. The scope of the SmI2-catalyzed

cyclization cascade was initially assessed using a range of alkyne substrates 1a-1v

(Fig. 2). In almost all cases, products were obtained in good yield and with moderate

diastereocontrol after short reaction times. Furthermore, gram-scale reaction of 1a

gave cascade product 2a in an improved 99% yield (1.10 g) in less than 20 minutes.

The process tolerated various groups on the alkyne unit including alkyl (2a, 2d),

hydrogen (2b), silyl (2c) and aryl (2e-h, 2m, 2n). Furthermore, important functional

groups including various ester (e.g. 2a, 2i, 2j), bromo (2f, 2q), fluoro (2s), protected

amino (2k), methoxy (2h, 2r), naphthyl (2t), cyclopropyl (2v), and 2-thienyl (2u)

were compatible with the catalytic radical process. In addition to a wide range of

carbocyclic products, including less-substituted carbocycle 2n, variation of the tether

allowed valuable heterocyclic products to be obtained (2k-m). SmI2-catalyzed

cyclization of 1v bearing a medicinally-relevant cyclopropyl substituent gave cascade

product 2v in excellent yield and with the strained ring intact. This result suggests that

5-exo-trig cyclization of the alkenyl radical intermediate (cf. III in Fig. 1D) is faster

than radical fragmentation.34 X-ray crystallographic analysis of 2k, 2m and 2o

Page 7: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

confirmed the relative stereochemistry of the major diastereoisomeric cascade

products.

Page 8: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Fig. 2 | Substrate scope for alkynes. Reaction conditions: To a solution of 1 (0.1

mmol) in THF (4 mL, 0.025 M) at 65 °C under N2 was added SmI2 (5 mol%). The

reaction was quenched after 20 minutes by opening to the air. Isolated yields are

given. Dr determined by 1H NMR spectroscopy of crude product mixtures. a 10 mol%

SmI2 required. b 20 mol% SmI2 required. c 40 mol% SmI2 required.

X-ray crystalstructure of 2k

X-ray crystalstructure of 2m

X-ray crystalstructure of 2o

EtO2C CO2Et

O

H

H

2v94%, 70:30 dr

1.10 g, 99%

X

Ar

O R1

X

R1

Ar O

H

H

2a–v1a–v

Me

EtO2C CO2Et

Ph O

H

H

2a87%, 71:29 dr

EtO2C CO2Et

Ph O

H

H

2b80%, 67:33 dra

EtO2C CO2Et

Ph O

H

H

2e X = H, 81%, 75:25 dr2f X = Br, 88%, 75:25 dr

2g X = Me, 86%, 75:25 dr2h X = OMe, 97%, 75:25 dr

EtO2C CO2Et

Ph O

H

H

2d97%, 71:29 dra

Me

EtO2C CO2Et

Ph O

H

H

2c93%, 77:23 dr

TMS

NTs

Ph O

H

H

2k84%, 73:27 drb

X-ray

MeMe

MeO2C CO2Me

Ph O

H

H

2i89%, 71:29 dr

Me

tBuO2C CO2tBu

Ph O

H

H

2j89%, 73:27 dr

O

R

Ph O

H

H

2l R = Me, 86%, 89:11 dr2m R = Ph, 82%, 85:15 dr

X-ray

Me

EtO2C CO2Et

O

H

H

2r X = OMe, 58%, 71:29 drb

2s X = F, 78%, 73:27 dra

X

Me

EtO2C CO2Et

O

H

H

2t60%, 71:29 drb

Me

EtO2C CO2Et

O

H

H

2o74%, 79:21 dra

X-ray

Me

Me

EtO2C CO2Et

O

H

H

2u53%, 65:35 drc

S

Me

EtO2C CO2Et

O

H

H

2p82%, 68:32 dra

OMe

Ph O

H

H

2n73%, 82:18 dr

Me

EtO2C CO2Et

O

H

H

2q64%, 67:33 drb

Br

X

5 mol% SmI2

THF, 65 °C

Page 9: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Catalytic radical cyclizations of alkenes. We next investigated the capacity of alkenes

to participate in the SmI2-catalyzed cyclization cascade (Fig. 3). In almost all cases,

products were obtained in good yield and with good diastereocontrol during the

formation of four stereocenters. Alkene 3a (R1 = Ph, X = C(CO2Et)2) underwent

radical cascade cyclization on gram scale upon treatment with only 5 mol% SmI2 to

give product 4a (0.91g, 83%). The presence of a variety of functional groups was

tolerated, including chloro (4b), fluoro (4c), bromo (4d-e), trifluoromethyl (4f),

methoxy (4g), acetoxy (4h), chloromethyl (4i), naphthyl (4j), benzothienyl (4k and

4m) and benzofuranyl (4l). Again, variation of the tether allowed access to

less-substituted carbocyclic (4n) and heterocyclic products (4o and 4p). The relative

stereochemistry of the cascade products 4n and 4o was confirmed by X-ray

crystallography.

Page 10: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Fig. 3 | Substrate scope for alkenes. Reaction conditions: To a solution of 3 (0.1

mmol) in THF (4 mL, 0.025 M) at 65 °C under N2 was added SmI2 (5 mol%). The

reaction was quenched after 20 minutes by opening to the air. Isolated yields are

given. Dr determined by 1H NMR spectroscopy of crude product mixtures. a10 mol%

SmI2 required. b15 mol% SmI2 required.

4n80%, 67:33 dra

X-ray

EtO2C CO2Et

Ph O

H

H H

4f86%, 80:20 dr

H CF3

4o68%, 86:14 dra

X-ray

EtO2C CO2Et

Ph O

H

H H

H OAc

EtO2C CO2Et

Ph O

H

H H

H S

EtO2C CO2Et

Ph O

H HS

4h82%, 82:18 dr

EtO2C CO2Et

Ph O

H

H H

H

Br

4d69%, 80:20 dra

EtO2C CO2Et

Ph O

H

H H

H

Cl

4i73%, 83:17 dra

4k59%, 84:16 drb

4m76%, 86:14 drb

X-ray crystalstructure of 4o

0.91 g, 83%

H H

X

Ph

O

X

H

Ph O

H

H

4a–x3a–x

R1

H

R1

EtO2C CO2Et

Ph O

H

H H

4a91%, 82:18 dr

H

EtO2C CO2Et

Ph O

H

H H

4e84%, 86:14 dr

H Br

EtO2C CO2Et

Ph O

H

H H

4g77%, 84:16 dr

H OMe

EtO2C CO2Et

Ph O

H

H H

4b X = Cl, 69%, 84:16 dr4c X = F, 94%, 84:16 dr

H

X

EtO2C CO2Et

Ph O

H

H H

H

4j62%, 86:14 dr

O

Ph O

H

H H

H

O

Ph O

H

H H

Ph O

H

H H

H

4p76%, 62:38 dra

5 mol% SmI2

THF, 65 °C

4l73%, 84:16 drb

EtO2C CO2Et

Ph O

H

H H

H O

Page 11: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Catalytic dearomatizing radical cyclizations of heteroarenes. Catalytic

dearomatization is a particularly powerful strategy for the construction of complex

three-dimensional architectures from simple, two-dimensional starting materials.35–37

However, dearomatizing cascades involving radical intermediates are rare and no

SmI2-catalyzed dearomatizing reactions have been reported.38 We have found that

heteroaromatic radical acceptors can also be employed and the SmI2-catalyzed

cyclization cascades generate complex products of dearomatization (Fig. 4). Upon

treatment with 5 mol% SmI2, benzofuran-containing substrate 5a (R1 = H, R2 = H, X

= C(CO2Et)2) gave complex, tetracyclic product 6a in 99% yield with 93:7 dr. A

gram-scale reaction gave 1.31 g of 6a in 97% yield. SmI2-catalyzed dearomatizing

radical cyclization cascades typically proceeded in excellent yield and with high

diastereocontrol (Fig. 4). The presence of a variety of functional groups was tolerated,

including methoxy (6c, 6i, 6o, 6q), bromo (6d, 6j), fluoro (6e, 6m, 6p),

trifluoromethyl (6n) and naphthyl (6h, 6r). Again, variation of the tether allowed

access to less-substituted carbocyclic (6l) and heterocyclic products (6k). The relative

stereochemistry of 6k and 6l was confirmed by X-ray crystallographic analysis.

Notably, the cyclization cascade of 5s, bearing a 3-methylbenzofuran-2-yl moiety,

delivered 6s bearing two adjacent quaternary stereocenters in 70% isolated yield and

with virtually complete diastereocontrol. Finally, benzothiophene-derivative 5t gave

6t in 90% isolated yield and 81:19 dr.

Page 12: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Fig. 4 | SmI2-catalyzed dearomatizing cyclization cascades. Reaction conditions:

To a solution of 5 (0.1 mmol), in THF (4 mL, 0.025 M) at 0 ° C under N2, was added

SmI2 (5 mol%). The reaction was quenched after 20 minutes by opening to the air. All

yields are isolated yields, dr determined from 1H NMR spectroscopy of crude product

mixtures. a 10 mol% SmI2. b Room temperature. c 20 mol% SmI2. d 15 mol% SmI2. e

65 °C.

Discussion

Mechanistic studies. Preliminary studies on the mechanism of the SmI2-catalyzed

cyclization cascade support a radical relay/electron catalysis process (Fig. 5). First, an

6a R = Et, 99%, 93:7 dr

6b R = Me, 84%, 89:11 dr

O

CO2RRO2C

H H

H

6c X = OMe, 77%, 91:9 dr6d X = Br, 89%, 89:11 dr

6ea,b X = F, 97%, 87:13 dr

6rd

79%, 82:18 dr6tb,d

90%, 81:19 dr6sb,c

70%, > 95:5 dr

6j71%, 86:14 dr

6fa,b R = Me, 98%, 87:13 dr6g R = Ph, 75%, 93:7 dr

6h R = 2-Np, 79%, 94:6 dr

6ia,b 95%, 82:18 dr

6kb,c

79%, >95:5 drX-ray

6lc,e

88%, 86:14 drX-ray

6m X = F, 82%, 92:8 dr6na,e X = CF3, 78%, 88:12 dr6oc,b X= OMe, 59%, 76:24 dr

6pa,e X = F, 68%, 86:14 dr6qb,c X = OMe, 63%, 93:7 dr

5 mol% SmI2

THF, 0 °C

1.31 g, 97%

X

Ar

O

X

R1

Ar O

H

H

6a–t5a–t

Y

R1

R2

Y

R2

Ph O

O

CO2EtEtO2C

H H

H

Ph OX

O

CO2EtEtO2C

H H

H

Ph OR

O

CO2EtEtO2C

H H

H

Ph O

OMe

O

CO2EtEtO2C

H H

H

Ph O

Br

O

CO2EtEtO2C

H H

H

Ph O

O

O

H H

H

Ph O

O

H H

H

Ph O

O

CO2EtEtO2C

H H

H

O

X

O

CO2EtEtO2C

H H

H

OX

O

CO2EtEtO2C

H Me

H

Ph O

S

CO2EtEtO2C

H H

H

Ph O

X-ray crystalstructure of 6k

Page 13: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

alternative mechanism involving Lewis acid-activation of the substrates was

investigated; only starting material was recovered when 1a was exposed to a variety

of Lewis acids, including Sm(III)I3 (Fig. 5A).39 Furthermore, when radical inhibitor

TEMPO was present <10% yield of 2a was obtained. Radical clock experiments were

also performed using a cyclopropane-containing substrate and the corresponding ring

opening product was detected and confirmed by high resolution accurate mass

spectrometry (see Supplementary Figures 1 and 2). To probe the importance of radical

addition to the Sm(III)-enolate moiety in III, we treated 1a with 10 mol% SmI2 in the

presence of 200% TMSCl under our otherwise optimized conditions. It is known that

TMSCl promotes cleavage of the SmIII- O bond to give silyl ethers.20 In the presence

of TMSCl, only 10% yield of 2a was formed suggesting that the Sm(III)-enolate is

trapped by TMSCl thus preventing closure of the catalytic cycle (Fig. 5A). We next

sought to rule out a chain-type process initiated by reductive SET6,40 in which the

ketyl radical intermediate IV reduces starting material 1aby an outer sphere process,

to form product 2a and radical intermediate I, rather than regeneration of Sm(II) by

back electron transfer to the metal. Chain-type processes involving SET are often

characterized by promiscuity with regard to the electron-transfer reagents able to

initiate the chain process.6,40 The attempted use of the SET reductant Cp*TiCl3, in

place of SmI2, consistently gave only a low yield of 2a thus suggesting that Sm(II)

and its regeneration plays a key role in the radical cyclization cascade and suggests

that a chain-type process is not in operation (Fig. 5A). It is important to note that the

reaction mixture typically retains the characteristic blue colour of SmI2 long after the

starting material has been converted to product thus clearly indicating that Sm(II) is

regenerated (see Supplementary Figure 3). Finally, an EPR study was performed

using 1a and the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). Pleasingly,

Page 14: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

trapped species 7 was observed by EPR and also by high resolution mass

spectrometry (Fig. 5B). Similar trapped species were also observed using substrates

3a and 5a (see Supplementary Figures 9-18). Thus, our preliminary mechanistic

studies on the cyclization cascades support a radical relay/electron catalysis process

involving the regeneration of Sm(II).

Page 15: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Fig. 5 | Preliminary mechanistic studies. (A) Probing the importance of Sm(II) and

its regeneration. (B) An EPR study using the spin trap DMPO.

Ph

O Me

Me

Ph O

H

H 2a1a

EtO2C CO2Et EtO2C CO2Et

10% Cp*TiCl320% Zn

THF, 65 °C low yield (18%)

10% SmI2200% TMSCl

THF, 65 °C

Lewis acids e.gn SmI3 n SmI2/O2

n Sm(OTf)3 n La(OTf)3n Yb(OTf)3 n Sc(OTf)3

A

low yield (10%)

B

no reaction

MeEtO2C CO2Et

NMe

MeO

1a

Confirmed by EPR &HRMS: 484.2693

15% SmI250% DMPO

THF, 65 °C7

~9.8 GHz2 G

2 mWRoom temperature

20 scans

O

Ph

Page 16: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

Fig. 6 | Computational studies. Computed DFT free energy profile for the

SmI2-catalyzed cyclization cascades (PBE/Def2-SVP level).

To further support the proposed catalytic radical relay/electron-catalysis mechanism,

detailed DFT calculations were performed. Structures corresponding to the key

intermediates in the catalytic cyclic and the barriers for their formation are shown in

the free energy profile in Figure 6. Coordination of the samarium catalyst to the

carbonyl group of 1a provides complex 1a•SmI2(THF)4. SET from Sm(II) then gives

ketyl radical intermediate I (ΔG = +107.7 kJ mol-1). After ring opening (ΔG = +60.2

kJ mol-1), radical II is formed and undergoes 5-exo-dig cyclization (ΔG = +28.2 kJ

mol-1). Vinyl radical III then undergoes a highly-favourable intramolecular addition

EtO2C CO2Et

Ph

O Me

SmII

I

I

THF

THF

THF

THF

EtO2C CO2Et

Ph

O Me

SmIII

I

I

THF

THF

THF

THF

Me

EtO2C CO2Et

Ph O

H

H

THF

SmII

I

I

THF

THF

THF

I

Me

EtO2C CO2Et

Ph O

H

H

SmIII

I

I

THF

THF

THF

THF

IV

Me

EtO2C CO2Et

Ph O

H

SmIII

I

I

THF

THF

THF

THF

III

EtO2C CO2Et

Me

O

Ph

SmIII

I

I

THF

THF

THF

THF

II

[I to II]† [II to III]† [III to IV]†

2a•SmI2(THF)4

1a•SmI2(THF)4

Page 17: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

to the Sm(III)-enolate moiety (ΔG = +6.9 kJ mol-1) to give new Sm(III)-ketyl radical

IV. Finally, product complex 2a•SmI2(THF)4 is generated after back electron-transfer

to Sm(III) to regenerate the Sm(II) catalyst. Calculated transition structures for the

key events in the catalytic cycle – cyclopropane fragmentation ([I to II]†), 5-exo-dig

cyclization ([II to III]†), and 5-exo-trig cyclization ([III to IV]†) – are also shown

(Fig. 6, inset). Alternative Z-enolate intermediates were found to give rise to higher

energy intermediates and transition states than those of the corresponding E-enolates.

Cyclization of III and formation of the major diastereoisomer observed in the

cyclization cascade was calculated to proceed through a significantly lower energy

transition state than that for the formation of the minor diastereoisomer (see

Supplementary Figure 23)

Conclusion

Using a radical relay/electron-catalysis approach we have developed SmI2-catalyzed

radical cyclization cascades that operate without a stoichiometric co-reductant or

additives. SmI2 loadings as low as 5 mol% deliver complex three-dimensional

polycyclic products containing up to four stereocenters, typically in high yields and

with good diastereocontrol. Furthermore, dearomatizing radical cyclizations using

catalytic SmI2 were also successful using the approach. Our strategy provides a

long-awaited solution to the problem of how to avoid the use of SmI2 in

stoichiometric amounts and establishes a conceptual platform upon which other

catalytic radical processes using the ubiquitous reducing agent can be built.

Page 18: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

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Methods

General procedure for the SmI2-catalyzed cyclization cascades of alkynes and

alkenes. An oven-dried vial containing a stirrer bar was charged with the substrate 1

or 3 (0.1 mmol, 1 equiv.) and placed under a positive pressure of nitrogen. THF

(0.025 M, 4.0 mL) was added and the reaction heated to 65 °C. SmI2 (typically 5

mol%, 0.1 M solution in THF, 0.05 mL) was then added. After the specified time

(typically 20 min), the reaction was filtered through a pad of silica gel and washed

with CH2Cl2 (3 × 5 mL). The organic layers were combined and concentrated in

vacuo to give product (4 or 6) typically without the need for further purification. In

some case, the product required purification by column chromatography on silica gel.

General procedure for the SmI2-catalyzed dearomative cascades. An oven-dried

vial containing a stirrer bar was charged with substrate 5 (0.1 mmol, 1 equiv.) and

placed under a positive pressure of nitrogen. THF (0.025 M, 4.0 mL) was added and,

Page 21: SmI2-catalyzed cyclization cascades by radical relay€¦ · and widely used SET reagents11,12 and it has proved adept at unlocking the total synthesis of numerous high profile and

at the correct temperature (typically, 0 °C), SmI2 (typically 5 mol%, 0.1 M solution in

THF, 0.05 mL) was added. After the specified time (typically 20 min), the reaction

was filtered through a pad of silica gel and washed with CH2Cl2 (3 × 5 mL). The

organic layers were then combined and concentrated in vacuo to give the product 6. In

some cases, the product was purified by column chromatography on silica gel.

Data availability

Materials and methods, optimization studies, experimental procedures, mechanistic

studies, EPR spectra, NMR spectra and mass spectrometry data are available in the

Supplementary Information. Crystallographic data for compounds 2k, 2m, 2o, 4n, 4o,

6k and 6l are available free of charge from the Cambridge Crystallographic Data

Centre under references numbers CCDC 1866917-1866923.All other data is available

from the authors upon reasonable request.

Acknowledgments

We thank Mr. Bin Wang, Dr. Amgalanbaatar Baldansuren and Prof. David Collison

for assistance with EPR studies. We gratefully acknowledge funding from the UK

Engineering and Physical Sciences Research Council (EPSRC; EP/M005062/01 –

Postdoctoral Fellowships to H.-M. Huang and EPSRC Established Career Fellowship

to D.J.P.). We also acknowledge the EPSRC UK National EPR Facility and Service at

the University of Manchester (NS/A000055/1)

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Author contributions

H.-M.H. and D.J.P. conceived and directed the project; H.-M.H. and D.J.P. designed

the experiments; H.-M.H. performed and analyzed all the reactions; J.J.W.M.

performed all computational studies; H.-M.H. and D.J.P and wrote the manuscript.

Competing interests The authors declare no conflicts of interest.

Additional information

Correspondence and requests for materials should be addressed to D.J.P

([email protected]).