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Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals Nicolas Kern, Mateusz P. Plesniak, Joseph J. W. McDouall and David J. Procter* Abstract The rapid generation of molecular complexity from simple starting materials is a key challenge in synthetic science. Enantioselective radical cyclization cascades have the potential to deliver complex, densely-packed, polycyclic architectures, with control of three dimensional shape, in one-step. Unfortunately, carrying out reactions with radicals in an enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals generated using the classical reagent, SmI 2 . Here, we demonstrate that the first enantioselective SmI 2 - mediated radical cyclizations and cascades can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocenters with high enantio- and diastereocontrol, and exploit a simple, recyclable chiral ligand. The first computational study of a SmI 2 -mediated carbon-carbon bond-forming process has been used to probe the origin of the selectivity. Our studies suggest that many processes that rely on SmI 2 can be rendered enantioselective by the design of suitable ligands. Introduction The enantioselective construction of all-carbon cyclic and polycyclic arrays is of great importance due to the ubiquity of such motifs in bioactive natural products and the role that these three-dimensional scaffolds play in inspiring modern drug design and the provision of molecular probes for biology. 1,2,3 Due to the difficulty of forming C-C bonds between sterically crowded reacting sites and the need to control the stereochemical outcome of such processes, accessing densely functionalized all-carbon molecular architectures is a major challenge in synthetic science. As reactions of open-shell reactive intermediates are often exothermic and proceed through early

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Enantioselective cyclizations and cyclization cascades of samarium ketyl radicals

Nicolas Kern, Mateusz P. Plesniak, Joseph J. W. McDouall and David J. Procter*

Abstract

The rapid generation of molecular complexity from simple starting materials is a key challenge in synthetic science.

Enantioselective radical cyclization cascades have the potential to deliver complex, densely-packed, polycyclic architectures,

with control of three dimensional shape, in one-step. Unfortunately, carrying out reactions with radicals in an

enantiocontrolled fashion remains challenging due to their high reactivity. This is particularly the case for reactions of radicals

generated using the classical reagent, SmI2. Here, we demonstrate that the first enantioselective SmI2-mediated radical

cyclizations and cascades can convert symmetrical ketoesters to complex carbocyclic products bearing multiple stereocenters

with high enantio- and diastereocontrol, and exploit a simple, recyclable chiral ligand. The first computational study of a SmI2-

mediated carbon-carbon bond-forming process has been used to probe the origin of the selectivity. Our studies suggest that

many processes that rely on SmI2 can be rendered enantioselective by the design of suitable ligands.

Introduction

The enantioselective construction of all-carbon cyclic and polycyclic arrays is of great importance due to the ubiquity of

such motifs in bioactive natural products and the role that these three-dimensional scaffolds play in inspiring modern drug

design and the provision of molecular probes for biology.1,2,3 Due to the difficulty of forming C-C bonds between sterically

crowded reacting sites and the need to control the stereochemical outcome of such processes, accessing densely functionalized

all-carbon molecular architectures is a major challenge in synthetic science. As reactions of open-shell reactive intermediates

are often exothermic and proceed through early transition states, long incipient C-C bonds can mean steric impedance can be

overcome in difficult C-C couplings and methods involving radicals have thus emerged for the construction of targets bearing

contiguous stereocenters in crowded acyclic and cyclic settings.4,5,6 On the other hand, this high reactivity makes the

development of enantioselective radical reactions difficult and creative attempts to surmount this challenge have led to key

breakthroughs in synthesis.7,8 For example, the use of chiral Lewis acids was established in seminal studies by Porter and Sibi and

constitutes a robust strategy for selective radical conjugate additions and atom transfer reactions involving two-point-binding

substrates.9,10,11 More recently, enantioselective radical approaches exploiting various ingenious reactivity manifolds have been

devised, including the synergistic combination of Lewis acid catalysis12 or organocatalytic methods13,14,15 with photoinduced

electron transfer, the use of chiral thiols as radical16 or hydrogen atom-donating17 catalysts, and transition metal-catalyzed

electron transfer processes.18,19,20,21 In particular, Yoon,22 Streuff,23 and Knowles24 have recently described reductive ketyl

generation and enantioselective C–C bond formation.

Despite these exciting advances, multiple-ring-forming, enantioselective cascade reactions triggered by radical

generation remain rare. To our knowledge, the only three examples were reported in 2006 by Yang and involve atom transfer,

radical-radical cyclization cascades initiated by Et3B/O2 (Fig. 1a).25 Related to the chiral Lewis acid approach of Porter and Sibi, the

method grants access to all-carbon bicyclic scaffolds from organoselenium precursors with moderate to high enantioselectivity.

In Yang’s seminal study a stoichiometric amount of chiral reagent was found to deliver optimal enantioselectivities. Thus, the

great synthetic potential of enantioselective radical cyclization cascades remains largely unexplored. The exploitation of new

activation modes in the development of enantioselective radical cyclization cascades is therefore an important and timely goal

that promises to greatly expand the palette of synthetic methods available for the streamlined preparation of complex

molecules.

A mild and widely used method for radical initiation relies on the use of single electron transfer (SET) reductants to

generate nucleophilic ketyl radical anions from carbonyl compounds, thus allowing a formal umpolung (polarity reversal) of the

carbonyl.26,27 Of particular note, such ketyls readily add to olefins,28 forging new C–C bonds and delivering cycloalkanols rich in

stereochemistry. The commercially available reagent samarium diiodide (SmI2, Kagan's reagent29) is arguably the most efficient

promoter of such reductive C–C couplings, as evidenced by its pivotal use in numerous high profile total syntheses.30,31 The many

outstanding features of SmI2 include its high reducing ability, allowing many classes of carbonyl substrate to be converted to

ketyls, its high oxophilicity, often leading to exquisite control of relative stereochemistry via chelated transition states, and the

potential to fine-tune reactivity and selectivity using various additives.25,32 Unfortunately, in the four decades since its

introduction to organic synthesis, attempts to use SmI2 in reagent-controlled enantioselective radical C-C couplings have met

with little success. In fact, only one isolated study by Mikami describes the enantioselective intermolecular C-C coupling of

samarium ketyls, derived from aryl ketones, with acrylates using SmI2 and the ligand (R)-BINAPO.33,34 Unfortunately, the process

was limited in scope and gave low diastereoselectivities and yields. Examples of enantioselective intramolecular C-C coupling are

even more elusive; for example, an attempted samarium ketyl cyclization by Skrydstrup using an enantiopure bisphosphoramide

ligand proceeded with little enantiocontrol (Fig. 1b).35 No examples of enantioselective C–C bond-forming cascade cyclizations

using SmI2 have been described.

Herein, we describe enantioselective desymmetrizing ketyl-alkene radical cyclizations and cyclization cascades of dienyl

-ketoesters mediated by an in situ generated chiral Sm(II) reagent. Key to the success of this process is the use of a readily

available and recyclable, enantiopure tripodant aminodiol, and an achiral alcohol additive, in conjunction with SmI2 (Fig. 1c). The

resulting samarium(II) reagent effectively triggers radical cyclizations via chelated Sm(III) ketyl intermediates I, desymmetrizing

simple starting materials and delivering complex mono- and polycyclic all-carbon scaffolds containing up to five stereocenters

and versatile alkenyl units for further elaboration, with high enantio- and diastereocontrol. The first computational study on a

SmI2-mediated radical C–C bond forming process has been used to explore the origin of enantioselectivity.

Results & discussion

Reagent design. Given the lack of precedent for enantioselective SmI2-mediated transformations, several factors guided our

reaction design. First, drawing on the seminal work of Molander,36 a neighboring Lewis basic ester group was used to coordinate

to Sm(II) thus facilitating reduction and helping to control the stereochemical course of samarium(III) ketyl cyclizations through

the provision of chelated transition states. Thus, readily available dienyl -ketoesters, such as 1a, were selected as benchmark

two-point binding substrates for the development of enantioselective desymmetrizing ketyl radical cyclizations. Attractively,

desymmetrization of dienyl -ketoesters 1 allows complex products, bearing multiple stereocenters and an alkenyl unit for

further functionalization, to be assembled rapidly. Second, and with regard to the choice of chiral ligand, to maximise the

interaction of the substrate with the chiral Sm(III) species we chose to avoid the use of Lewis basic phosphoramide-type chiral

ligands (cf. Fig. 1b) as Flowers has suggested that the cyclization of HMPA-bound samarium ketyls takes place via a solvent-

separated ion pair.37 Third, protonation of both a Sm(III)–O and a Sm(III)–C bond in the intermediate III, formed after cyclization

and further SET reduction of II, is required (cf. Fig 1c). Protonation of the Sm(III)–O bond prevents detrimental retro-aldol

pathways of the product, but should be sufficiently slow as to not compromise the transfer of stereochemical information from

the Sm(III)-ligand moiety in I in the desymmetrization step. We proposed that either a chiral or achiral protic additive could

affect this task. The affinity of ethyleneglycol for SmI2 is well known38 and chiral C2-symmetrical diols have been employed

successfully for the enantioselective protonation of Sm(III) enolates.39 Thus, we hypothesized that a flexible multidentate chiral

diol would bind Sm(II), accommodate the change in ionic radius from Sm(II) to Sm(III) following SET to the substrate, potentially

control asymmetry during the cyclization of the Sm(III) ketyl radical, and act as a proton source in quenching the anions formed

during the process.

The feasibility of the enantioselective samarium ketyl cyclization of 1a was assessed through the extensive screening of

chiral diols 3 in conjunction with a slight excess of SmI2 in THF (2.2 equiv), as summarized in Table 1 (see e.r.s associated with

structures and entries 1-4). Early studies suggested that a 1:1 ratio between the chiral ligand and SmI2 gave the best

enantioselectivities. From the outset, the crucial influence of temperature was clear and significant enantioselectivity (up to

65:35 e.r. with 3f) was only obtained when the reaction was conducted at ─40 °C (entry 2). At this temperature, acceptable

conversion to 2a (≥ 70% in most cases) was also observed. Evans et al. have shown that the samarium(III) bis-alkoxide derived

from 3f is a highly efficient catalyst for the enantioselective Meerwein-Ponndorf-Verley reduction of aryl ketones,40 but there are

no reported applications of the neutral form of the aminodiol in synthesis. Employing its dimethyl ether analog 3g afforded

racemic 2a, confirming the expected higher affinity of SmI2 for free hydroxyl-containing chiral ligands (entry 3). Similarly,

replacing the N-benzyl moiety in the aminodiol with a neopentyl unit (ligand 3h, entry 4) resulted in a low-yielding cyclization

with no asymmetric induction, thus underlining the importance of sterics in ligand binding to Sm(II).

We next investigated the impact of small amounts of achiral protic additives on the samarium ketyl cyclization of 1a.

We reasoned that the additive would act as a proton source, in place of the chiral aminodiol, in the quenching of anionic

intermediates, thus leaving the crucial chiral ligand and its coordination chemistry unaltered. While adding non-coordinating

alcohol additives was inefficient (entries 5 and 6), addition of MeOH (equimolar to SmI2) resulted in an enhancement of

enantioselectivity and efficiency in the formation of 2a (entry 7). An erosion of asymmetric induction was observed when excess

MeOH was present (entry 8), while the use of H2O as an additive resulted in near racemic 2a (entry 9). The negative impact of

H2O likely arises from displacement of the chiral ligand from Sm(III) or fast protonation41 of the Sm(III) ketyl species involved in

the enantiodetermining step. It is known that H2O exhibits high affinity for SmI2 even at low concentrations.42 Similarly,

coordination of MeOH to Sm(III) ketyls has been used to rationalise the outcome of several reactions requiring fast proton

transfer.43,44 On the basis of these results, it is unlikely that the achiral additive acts solely as a proton source, and may act as an

additional ligand for samarium. Thus, the role of MeOH in improving enantioinduction in the ketyl cyclization is likely twofold: (i)

the achiral alcohol acts as a sacrificial proton donor, thus preserving the integrity of the chiral aminodiol ligand; (ii) MeOH binds

to Sm(II) and/or Sm(III) effecting the coordination chemistry and the environment around the metal and producing a species that

gives rise to higher enantioinduction.

A second round of ligand optimization was undertaken. Most analogs of 3f (readily prepared by epoxide aminolysis)

displayed lower efficiency in the reaction (for example, entry 10), with the exception of 3j bearing bulkier 3,5-dimethylphenyl

substituents in place of the phenyl groups in 3f (entry 11). However, the use of 3j was detrimental to the diastereoselectivity of

the cyclization. Focusing on the use of 3f, subtle adjustments to the protocol (e.g. adding SmI2 then MeOH to the chiral ligand

before slow cooling) prevented precipitation and resulted in improved yield and enantioselectivity (89:11 e.r.) (entry 12).

Attempts to use cosolvents in conjunction with THF typically led to lower enantiocontrol; for example, performing the reaction

in THF/toluene resulted in the efficient formation of 2a but with significantly lower enantio- and diastereocontrol. Crucially,

ligand 3f is easy to prepare in one step on a multigram scale (65% yield) from inexpensive (R)-styrene oxide and benzylamine

and can be readily isolated after use and recycled (>90% recovery). In contrast to Evans’ use of the aminodiolate derived from 3f

in a Sm(III)-catalyzed asymmetric hydride transfer process, our studies employ 3f in its diol form in a Sm(II)/Sm(III)-mediated

radical, carbon–carbon bond-forming process.

Enantioselective radical cyclizations. Having identified optimal conditions for the enantioselective samarium ketyl cyclization

using ligand 3f, we set out to assess the scope of the process using a range of bis-homoallylic ketoester derivatives (Table 2).

Pleasingly, enantioselective cyclization of disubstituted diene E–1b at –45 °C afforded cyclopentanol E–2b in 75% yield and 91:9

e.r. Interestingly, analogous diene Z–1b only underwent cyclization at ─40 °C giving Z–2b in 72% yield but with significantly lower

selectivity (90:10 d.r., 87:13 e.r.). This likely arises from unfavorable steric interactions in the transition state of the cyclization

(vide infra). Pleasingly, trisubstituted diene 1c underwent cyclization to give 2c with high enantioselectivity (91:9 e.r.) and as a

single diastereoisomer. bis-Allenyl substrates 1d and 1f delivered vinyl substituted cyclopentane 2d (78:22 e.r.) and methylene

cyclopentane 2f (e.r. 65:35, 2:1 mixture of exo and endo alkene regioisomers) in good yield but with modest enantiocontrol. A

successful alternative approach for the formation of a vinyl substituted cyclopentane product employed bis-allylic acetate 1e

and a process terminated by anionic elimination; 2e was formed in 80% yield with high enantiocontrol (92:8 e.r.) and complete

diastereocontrol. Surprisingly, switching from the methyl ester group in 1a (2a obtained in 89:11 e.r.) to the larger isopropyl

ester group (in 1g) resulted in a significant drop in enantiocontrol (2g obtained in 79:21 e.r.): the large isopropyl group likely

disrupts the all-important binding of the ester group and the chiral ligand to Sm(III). Furthermore, the attempted use of a more

Lewis basic amide moiety in 1h resulted in the formation of racemic product 2h. The amide has a higher affinity for Sm(III) than

the corresponding ester and its presence may also prevent or alter the coordination of the chiral aminodiol to Sm(III).32 We next

examined the feasibility of an enantioselective transannular cyclization of cycloheptenyl methyl ketoester 1i. Pleasingly,

bicyclo[3.2.1]octane 2i was obtained in 80% yield, high enantiocontrol (93:7 e.r.) and as a single diastereoisomer. To our

knowledge, this reaction constitutes the first example of an enantioselective transannular radical reaction proceeding under

reagent control. X-ray crystallographic analysis of a derivative allowed the absolute and relative stereochemistry of 2a to be

assigned. X-ray crystallographic analysis of the 4-bromobenzoate benzoate 4 allowed the absolute and relative stereochemistry

of 4 and 2i to be assigned. The absolute stereochemistry of 2a–h (and 2j–r, vide infra) was inferred based on the assignment of

2a and 2i.

Model for stereoinduction. A model for the enantio– and diastereocontrol observed in the desymmetrizing samarium-ketyl

cyclizations is shown in (Fig. 2a). SmI2, aminodiol 3f and the substrate 1a form a 1:1:1 complex giving model 5a. SET from Sm(II)

in 5a gives a Sm(III)-ketyl (cf. I in Fig. 1c) that can react via its Re face (transition structure anti-6a) or its Si face (transition

structure anti-6a’). It is well-established that anti modes of addition are typically favored in ketyl-alkene cyclizations.25 We

propose that transition structure anti-6a’ is disfavored due to steric interactions between the alkenyl side chain and the phenyl

ring of the aminodiol ligand and also between the methyl group at the radical center and the proximal hydroxyl of the aminodiol

ligand (See Supplementary Figure 6). Ketyl-alkene cyclization therefore proceeds through anti–transition state 6a to give 2a with

high control. Computational studies have been used to probe the enantioselective process and to validate the proposed model.

To our knowledge, the study of Sm(II)-mediated carbon-carbon bond formation using computational chemistry has not

previously been reported (see Supplementary Information page 70-74). Focusing on the enantioselective cyclizations of 1a, and

using 3f’ (N-Me) as a simplified model for ligand 3f (N-Bn), density functional calculations were performed to elucidate the

nature of the electronic and geometric transformations involved in the cyclization process. The optimized structure of the

Sm(III)-ketyl radical, 1a-rad, and the transition structures for the cyclizations anti-6a and anti-6a’, denoted as anti-[6a]‡ and anti-

[6a’]‡, are shown in Figure 2b. As expected, the anti-modes of cyclization (alkene orientated anti to the C–O bond of the ketyl)

are favoured; for example, compare the energy of anti-[6a]‡ (22.2 kJmol-1) to that of syn-[6a’]‡ (31.2 kJmol-1). As can be seen from

the reaction profile for the cyclization of 1a-rad, there is a significant energetic preference for the formation of 2a (rather than

ent-2a) via the transition structure anti-[6a]‡. Having shown the feasibility of modelling complex samarium-bound radicals and

predicting the absolute stereochemistry of the products arising from enantioselective cyclization, future studies will develop

new computational models that probe the important role of MeOH in the process and predict enantioselectivities in line with

those observed experimentally. Crucially, these computational models will facilitate the rational design of new enantioselective

processes involving low valent lanthanides.

Enantioselective radical cascade cyclizations. We next sought to develop enantioselective desymmetrizing samarium-ketyl

cyclization cascades that would deliver higher returns in terms of molecular complexity. Thus, allyl ketones 1j–r were prepared

and exposed to SmI2, ligand 3f, and MeOH in THF. In the case of 1j, cis-octahydropentalene 2j bearing four stereocenters was

formed in 75% yield. No monocyclization product was detected. Complete control of relative stereochemistry was observed in

the first radical cyclization of the cascade, while the second radical ring closure proceeded with good selectivity (80:20 d.r.,

major diastereoisomer shown). Running the reaction at ─50 °C resulted in full conversion of 1j and 2j was obtained with

enhanced enantioselectivity (93:7 e.r.) when compared to the related monocyclization (conversion of 1a to 2a). Radical

cyclization of prenyl-substituted analog 1k was next examined and was found to afford byproducts arising from bimolecular

disproportionation of the tertiary radical formed upon cascade cyclization.45 Addition of excess 1,4-cyclohexadiene as a

hydrogen atom source completely suppressed this unwanted pathway and isopropyl-substituted 2k was isolated in 73% yield

with excellent diastereo- and enantiocontrol (92:8 d.r. and 98:2 e.r.). ((E)-5-Phenylpent-2-enyl) precursor 1l gave 2l with similarly

high control (94:6 d.r. and 95:5 e.r.), while efficient control over the formation of five contiguous stereocenters was achieved in

the cascade cyclization of 1m (the major diastereoisomeric product 2m was obtained with 97:3 e.r.). The generation of a third

fully-substituted center in the cascade proved more challenging and higher temperature was required (–25 °C) for the

transformation of ketoester 1n: gem-dimethyl product 2n was obtained in good yield but with moderate enantioselectivity

(82:18 e.r.). Finally, 1o bearing an allylic leaving group gave vinyl-substituted product 2o after a highly selective cascade

terminated by acetate elimination (94:6 d.r. and 93:7 e.r.). It should be noted that high sequence integrity was observed in all

the radical cascade cyclizations, with only minor amounts of monocyclization byproducts (<5%) detected by 1H NMR analysis of

some crude product mixtures. Finally, an even higher degree of molecular complexity can be accessed from cycloheptene

substrates 1p-r. For these substrates, tricyclic products 2p-2r were obtained in good yields and uniformly high enantioselectivity

(94:6 e.r.) albeit with moderate control of relative stereochemistry in the second cyclization event in the cascade.

Conclusion

We have developed the first enantioselective SmI2-mediated radical cyclizations. The combination of SmI2 with a simple

and inexpensive, recyclable chiral aminodiol promotes the enantioselective desymmetrizing 5-exo ketyl-alkene cyclization of

unsaturated ketoesters. Cyclizations typically proceed with high enantioselectivity (up to 92:8 e.r.) and diastereoselectivity (up

to >99:1 d.r.). An analogous transannular variant delivers enantiomerically enriched bicyclic tertiary alcohol 2i (93:7 e.r. and

>99:1 d.r.). Enantioselective, desymmetrizing cascade cyclizations mediated by SmI2 proceed with high sequence integrity and

deliver even more complex molecular architectures: two carbocyclic rings and up to five contiguous stereocenters are formed

with high enantiocontrol (>98:2 e.r.). The first computational study of a Sm(II)-mediated carbon-carbon bond-forming process

has been used to probe the origin of enantioselectivity in the cyclizations.

Data availability

The X-ray crystallographic coordinates for a derivative of 2a (2a’’) and 4 have been deposited at the Cambridge Crystallographic

Data Centre (CCDC) under deposition number CCDC 1511568. This data can be obtained free of charge from the CCDC via

www.ccdc.cam.ac.uk/data_request/cif. The authors declare that all other data supporting the findings of this study are available

within the article and its Supplementary Information file.

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Acknowledgements

This work was partially supported by The Leverhulme Trust (Postdoctoral Fellowship to N.K.) and the EPSRC (DTA Studentship to M.P.; Established Career Fellowship to D.J.P.).

Author contributions

N.K. and D.J.P. conceived the study and co-wrote the manuscript. N.K. designed and performed experiments and M.P. performed experiments. J.J.W.M. performed the computational study.

Additional information

Supplementary information and chemical compound information are available in the online version of the paper. Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to D.J.P.

Competing financial interests

The authors declare no competing financial interests.

Figure Captions

Figure 1 | Reagent-controlled enantioselective radical carbon-carbon bond-forming cyclizations. The Figure shows an example of an enantioselective radical cascade reaction, an attempt to control the enantioselectivity of a SmI 2-mediated intramolecular carbon-carbon bond-forming reaction, and our strategy to achieve enantiocontrol in both radical cyclization and cyclization cascade processes mediated by SmI2. a, Enantioselective group transfer radical carbon-carbon bond-forming cyclization cascades of phenylselenyl ketoesters mediated by a chiral Lewis acid (Yang). b, An attempted enantioselective radical carbon-carbon bond-forming pinacol-type cyclization mediated by SmI2 (Skrydstrup). c, This work involves the SmI2-mediated enantioselective

desymmetrizing radical carbon-carbon bond-forming cyclizations and cyclization cascades of unsaturated ketoesters using a readily available and recyclable chiral ligand. The two-electron processes convert readily-accessible substrates to complex products containing up to two new rings and five new stereocenters. Computational studies have been used to probe the origin of the selectivity observed.

Figure 2 | Origin of enantioselectivity in the cyclizations. The Figure shows a working model for the active Sm(III)-ligand-substrate complex and the origin of asymmetric induction. a, the model suggests that anti-transition structure 6a is favored over anti-transition structure 6a’ due to steric interactions between the alkenyl side chain and the phenyl ring of the aminodiol ligand and also between the methyl group at the radical center and the proximal hydroxyl of the aminodiol ligand in the later transition structure. b, density functional calculations exploring the nature of the electronic and geometric transformations involved in the enantioselective cyclization of 1a and supporting the proposed model for the origin of selectivity. Activation barriers (kJ mol –1) are given for two anti-transition structures and one syn-transition structure formed from 1a-rad. c Optimised structures obtained at the PBE0/Def2-SVP level for 1a-rad, anti-[6a]‡, anti-[6a’]‡, and syn-[6a’]‡. Hydrogen atoms have been omitted in all structures for clarity.

Table 1 | Optimisation of the enantioselective, SmI2-mediated desymmetrizing ketyl cyclization of 1aa

Entry Ligand Additive (equiv) Yield (%)b e.r.c

1 3e - 60 63:372 3f - 54 65:353 3g - 52 50:504 3h - 13 50:505 3f tBuOH (2.2) 47 67:336 3f CF3CH2OH (2.2) 40 59:417 3f MeOH (2.2) 74 85:158 3f MeOH (8.8) 77 77:239 3f H2O (2.2) 81 52:4810 3i MeOH (2.2) 75 76:2411 3j MeOH (2.2) 68 (12:1 d.r.) 84:1612d 3f MeOH (2.2) 82 89:11

a Unless otherwise stated; ROH premixed with substrate in THF (0.1 M) before addition to Sm(II)/ligand solution. b d.r. > 30:1 unless noted (determined by 1H NMR and chiral GC analysis); yield of isolated product after ageing at –40 °C until discoloration of the mixture (full consumption of Sm(II) species). Mass balance consists of unreacted starting material. c Determined by chiral GC analysis. d MeOH added to Sm(II)/ligand solution before cooling to ─70 °C at which temperature the substrate was added before warming to ─50 °C.

Table 2 | Scope of the enantioselective, SmI2-mediated desymmetrizing ketyl olefin cyclizationa

a Isolated yields. d.r. determined by 1H NMR analysis of the crude reaction mixture; e.r. determined by chiral GC analysis. Substrate 1 (in THF) added dropwise 20 °C below the described temperature followed by slow warming (e.g. –65 °C for E–1b; range ± 2 °C). Ligand 3f recycled by column chromatography following elution of product (typical recovery yield >90%). b Ligand recovered following acidification of the crude mixture dissolved in Et2O with aq. 1N HCl followed by basification of the aqueous layer with aq. 2N NaOH and extraction with EtOAc. c

Reaction time: 90 min. * denotes a center at which control is not complete and mixtures of diastereoisomers result.

Table 3| Scope of the enantioselective, SmI2-mediated desymmetrizing ketyl-olefin cyclization cascadea

a Isolated yields (inseparable mixtures of diastereomers). d.r. determined by 1H NMR analysis; e.r. determined by chiral GC or HPLC analysis. Substrate 1 (in THF) added dropwise 20 °C below the described temperature followed by slow warming. Ligand 3f recycled by column chromatography following elution of product (typical recovery yield >90%). * denotes a center at which control is not complete and mixtures of diastereoisomers result. b 12 equiv. of 1,4-cyclohexadiene added prior to substrate 1.