Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

Article abstract of DOI:10.3762/bjoc.12.110

A full account of our efforts toward an asymmetric redox bicycloisomerization reaction is presented in this article. Cyclopentadienylruthenium (CpRu) complexes containing tethered chiral sulfoxides were synthesized via an oxidative [3 + 2] cycloaddition reaction between an alkyne and an allylruthenium complex. Sulfoxide complex 1 containing a p-anisole moiety on its sulfoxide proved to be the most efficient and selective catalyst for the asymmetric redox bicycloisomerization of 1,6- and 1,7-enynes. This complex was used to synthesize a broad array of [3.1.0] and [4.1.0] bicycles. Sulfonamide- and phosphoramidate-containing products could be deprotected under reducing conditions. Catalysis performed with enantiomerically enriched propargyl alcohols revealed a matched/mismatched effect that was strongly dependent on the nature of the solvent.

Full text of DOI:10.3762/bjoc.12.110

Chiral cyclopentadienylruthenium sulfoxide catalysts for
asymmetric redox bicycloisomerization
Barry M. Trost*, Michael C. Ryan and Meera Rao
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1136–1152.
Department of Chemistry, Stanford University, Stanford, California
94305-5580, USA
doi:10.3762/bjoc.12.110
Received: 16 March 2016
Accepted: 03 May 2016
Published: 07 June 2016
Email:
Barry M. Trost* - bmtrost@stanford.edu
* Corresponding author
This article is part of the Thematic Series "Organometallic chemistry" and
is dedicated to the memory of Prof. Peter Hofmann.
Keywords:
asymmetric catalysis; [3.1.0] bicycles; [4.1.0] bicycles;
cycloisomerization; 1,6-enyne; 1,7-enyne; ruthenium catalysis;
sulfoxide
Guest Editor: L. Gade
© 2016 Trost et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A full account of our efforts toward an asymmetric redox bicycloisomerization reaction is presented in this article. Cyclopentadi-
enylruthenium (CpRu) complexes containing tethered chiral sulfoxides were synthesized via an oxidative [3 + 2] cycloaddition
reaction between an alkyne and an allylruthenium complex. Sulfoxide complex 1 containing a p-anisole moiety on its sulfoxide
proved to be the most efficient and selective catalyst for the asymmetric redox bicycloisomerization of 1,6- and 1,7-enynes. This
complex was used to synthesize a broad array of [3.1.0] and [4.1.0] bicycles. Sulfonamide- and phosphoramidate-containing prod-
ucts could be deprotected under reducing conditions. Catalysis performed with enantiomerically enriched propargyl alcohols
revealed a matched/mismatched effect that was strongly dependent on the nature of the solvent.
Introduction
Due to their prevalence in natural products [1], medicinal strates intended for thermal Alder–ene reactions [8]. They
targets [2], and materials [3], organic chemists have made the serendipitously discovered that palladium(II) salts catalyzed the
construction of cyclic, organic molecules one of the most im- cyclization of 1,6-enynes at much lower temperatures com-
portant areas of research in their discipline. Of the available pared to the thermal process [9], which normally requires tem-
methods to affect cyclization, transition metal-catalyzed enyne peratures in excess of 200 °C (Scheme 1, path a).
cycloisomerizations [4] have been recognized as an atom- [5],
step- [6], and redox-economical [7] class of reactions that are More recently, the same research group disclosed a
able to stitch together cyclic molecules quickly and efficiently. CpRu(MeCN)3PF6-catalyzed variant of the same reaction that
proceeds even at room temperature [10]. The ruthenium process
The very first enyne cycloisomerization reactions were re- differs from the initially-discovered palladium reaction in that it
ported by the Trost group while they were synthesizing sub- produces cyclic 1,4-dienes exclusively; no olefin isomerization
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Scheme 1: Divergent behavior of the palladium and ruthenium-catalyzed Alder–ene reaction.
is detected (Scheme 1, path b). Moreover, ruthenium can reaction is rather limited, as this is the only example presented
tolerate many sensitive functional groups, such as free alcohols, in the paper. Mechanistic studies performed by the same group
silyl enol ethers, and ketones, which makes it an attractive metal on this system support a hydropalladation/cyclization/β-hydride
for late stage functionalization and elaboration of complex mol- elimination mechanism. Rhodium catalysis of simple 1,6-
ecules. It is thought that the origin of ruthenium’s divergent be- enynes displayed a broader scope than Mikami’s palladium
havior stems from a difference in reaction mechanism. Where- system, although none of the examples contained a quaternary
as the palladium-catalyzed Alder–ene reaction proceeds through stereocenter [25].
an initial hydrometallation of a palladium hydride intermediate,
ruthenium is speculated to first form a ruthenacyclopentene Asymmetric enyne cycloisomerization reactions can be extend-
prior to β-hydride elimination. Since the hydrogen leading to ed beyond the construction of 1,4-dienes, depending on the
the 1,3-diene is inaccessible to the ruthenacyclopentene, it must transition metal used and the adjacent functionality on the sub-
exclusively abstract the exocyclic hydrogen, which results in strate in question. For example, Hayashi has shown that a
1,4-diene formation. Palladium, which is not restricted to a rhodium/phosphoramidite catalysis is particularly effective for
metallacycle, is free to choose either hydrogen, and therefore asymmetric [5 + 2] cycloaddition reactions (Scheme 2b). The
performs β-hydride elimination on the allylic hydrogen.
(S,R,R)-diastereomer of the Feringa-style phosphoramidite
ligand proved to be crucial to both the yield and enantioselectiv-
Recognizing that enantioenriched, cyclic molecular architec- ity of this reaction, as there was a severe matched/mismatched
tures hold a particular interest to the chemical community, espe- effect observed with another diastereomer. In contrast to the ru-
cially in the fields of natural product synthesis and drug design, thenium-catalyzed [5 + 2] cycloaddition of enynes, which is
researchers have made a significant effort to discover asym- thought to proceed through a ruthenacyclopentene intermediate
metric variations of enyne cycloisomerization reactions [11,12]. [26], it has been proposed that rhodium first undergoes oxida-
Researchers have used a variety of transition metals to affect tive cyclization with the vinylcyclopropane prior to alkyne
asymmetric enyne cycloisomerization [13-23]..In particular, insertion.
Mikami has disclosed a palladium-catalyzed asymmetric enyne
cycloisomerization where a tetrahydrofuran containing a quater- The asymmetric enyne cycloisomerization reaction has been
nary, all-carbon stereocenter is created in excellent yield and shown to be instrumental in the construction of medicinal
selectivity [24] (Scheme 2a). Unfortunately, the scope of this chemistry targets. For example, the Fürstner group realized that
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Scheme 2: Some asymmetric enyne cycloisomerization reactions.
gold catalysis would be particularly suited for the construction lyzed redox bicycloisomerization of 1,6- and 1,7-enynes to
of the [4.1.0] bicyclic piperidine core of GSK1360707 [27], a construct structurally complex [3.1.0] and [4.1.0] bicycles con-
triple-uptake inhibitor developed by GlaxoSmithKline [28,29] taining vicinal, quaternary all-carbon stereocenters [41]
(Scheme 2c). The construction of this interesting molecular (Figure 1a). The proposed mechanism of this fascinating reac-
scaffold was a motivator of much of our early work on the ru- tion involves chloride abstraction of the ruthenium catalyst by
thenium-catalyzed redox bicycloisomerization reaction (vide indium(III) triflate and phosphine ligand dissociation. The
infra). Unlike ruthenium and palladium enyne cycloisomeriza- propargyl alcohol then coordinates to the now coordinatively
tion, which operate via metallacycle formation or hydrometalla- unsaturated cyclopentadienylruthenium (CpRu) fragment in a
tion, gold acts as a π-acid, increasing the electrophilicity of the bidentate fashion and undergoes a redox isomerization reaction
alkyne by η2 coordination. The pendant alkene cyclizes on the wherein the carbinol proton performs a 1,2-hydride shift. The
alkyne, and the resulting tertiary carbocation is trapped by a resulting vinylruthenium intermediate can be seen as a reso-
gold carbenoid intermediate to form the fused cyclopropane. nance structure of a ruthenium carbene, which coordinates to a
pendant alkene, performs a [2 + 2] cycloaddition to form a
While there had been reports of utilizing chiral ruthenium com- ruthenacyclobutane, and reductively eliminates to generate the
plexes for asymmetric catalysis prior to our studies [30-40], bicyclic product.
there had previously been no reported examples of asymmetric
ruthenium-catalyzed cycloisomerization reactions in the litera- Intrigued by the possibility of rendering this reaction asym-
ture. In 2011, our research group disclosed the ruthenium-cata- metric, we wondered if an appropriate choice of catalyst,
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Figure 1: (a) Mechanism for the redox biscycloisomerization reaction. (b) Ruthenium catalyst containing a tethered chiral sulfoxide. (c) Possible dia-
stereomeric complexes formed from alcohol coordination.
namely the chiral CpRu-sulfoxide catalysts 1 our group de- our search for an asymmetric ruthenium-catalyzed redox bicy-
veloped for asymmetric allylic substitution reactions [42] cloisomerization reaction [43].
(Figure 1b), would be able to impart sufficiently useful enantio-
Results and Discussion
selectivities on these complex, drug-like molecules. While the
idea certainly was appealing at first glance, this reaction is Catalyst synthesis
complicated by the fact that the 1,6- and 1,7-enyne substrates Synthesis of CpRu-sulfoxide complexes requires a six-step se-
contain a stereogenic center that, upon coordination to rutheni- quence that was developed in our group [44]. Scheme 3 outlines
um, create diastereomeric, chiral-at-ruthenium complexes the synthetic sequence of p-anisyl catalyst 1. In situ reduction of
(Figure 1c). It was unclear a priori whether this transfer of 4-methoxysulfonyl chloride by triphenylphosphine and trap-
stereochemical information would have an adventitious, negli- ping with (−)-menthol affords diastereomerically pure sulfinate
gible, or detrimental impact on the enantioselectivity of the ester 2 after enrichment by recrystallization [45]. Grignard addi-
reaction. With this important consideration in mind, we began tion attaches a TMS-protected alkyne of appropriate tether
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Scheme 3: Synthesis of p-anisyl catalyst 1.
length via stereospecific nucleophilic displacement of the chiral While certainly attractive, the main limitation to this synthetic
auxiliary with complete inversion of configuration at the sulfur route is that the diastereomeric mixture of sulfinate esters made
center [46,47]. Sulfoxide 3 is incorporated into the catalyst via a in the first step is required to either be a solid that can be recrys-
[3 + 2] oxidative cycloaddition with allylruthenium complex 4. tallized to diastereomeric purity or be separable by column
Desilylation of cationic complex 5, ion exchange, and photoly- chromatography. Figure 2 contains the attempted sulfinate
sis of 6 completes the synthesis of catalyst 1. Using this ester syntheses that failed using the method described in
strategy, a variety of catalysts including p-tolyl, 2-naphthyl, Scheme 3. An alternate method to synthesize these chiral
1-naphthyl, and tert-butyl sulfoxide complexes were all synthe- sulfoxides needed to be explored, preferably one that did not
sized in an analogous fashion. This method has a distinct advan- rely on crystallization.
tage over a traditional CpRu catalyst synthesis in that the com-
plexes can be made quickly and efficiently without relying on In 2005, the Senanayake group described a process in which
toxic thallium salts to transfer substitutionally complex cyclo- (+)-norephedrine-derived oxathiazolidine 2-oxides are used as
pentadienyl ligands to ruthenium.
sulfinyl transfer agents in the synthesis of optically pure sulfox-
Figure 2: Failed sulfinate ester syntheses.
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ides and sulfinamides [48]. The application of this method to Substrate synthesis
the synthesis of our chiral sulfoxide tethers is presented in The substrates for the enyne bicycloisomerization reaction can
Scheme 4. Tosyl protection of the primary amine of (+)-nor- be readily accessed in two steps. Alkylation of a secondary
ephedrine and treatment with thionyl chloride furnishes chiral propargylamide can be achieved by sodium hydride deproton-
oxathiazolidine 2-oxide 7 as a single diastereomer in 87% yield ation of its acidic proton and SN2 substitution of a substituted
over two steps. Heterocycle 7 is a bench stable white powder propargyl bromide (Scheme 5a). Alternatively, the same
that can be stored indefinitely in a dessicator without any propargylamide can be alkylated under Mitsunobu conditions
noticeable decomposition. The sulfonamide moiety activates with a desired primary alcohol. One such alcohol, 2-cyclo-
sulfur towards nucleophilic addition, making the first addition propylprop-2-en-1-ol, can be synthesized using a modified
of an organometallic reagent faster than the second. By per- Suzuki coupling procedure developed by Soderquist [49]
forming two successive organometallic additions to 7, one (Scheme 5b). A cyclopropyl boronate can be generated from
could in principle obtain any desired chiral sulfoxide. Addition propargyl bromide, 9-BBN, and aqueous sodium hydroxide.
of a slight excess of (5-trimethylsilyl)-4-pentynylmagnesium This reactive intermediate can be used in situ for the subse-
iodide to the auxiliary at −78 °C affords sulfinate ester 8 in a quent coupling reaction, which constructs the desired allyl
66% yield and as a single diastereomer. Organocuprate addi- alcohol after deprotection in a 52% yield over two steps. After
tion to 8 completes the synthesis of tether precursors 9 and 10. alkylation, the newly-formed enynes can then be deprotonated
The use of an organocuprate is essential in order to obtain good with either n-BuLi or LiHMDS and trapped with an aldehyde to
yields of the desired sulfoxides; the enantiospecificity of this form a substituted propargyl alcohol. With a convenient route
organocuprate addition was checked by comparison of the towards these enyne substrates in hand, we set our sights on op-
optical rotation of 3 synthesized by this method with 3 synthe- timizing the asymmetric enyne bicycloisomerization reaction.
sized by the menthyl sulfinate ester method used in Scheme 3.
The o-anisyl sulfoxide 12 had to be synthesized in a slightly dif- Initial experiments and reaction optimization
ferent manner because the organocuprate addition to 8 failed, Due to the similarity of 14 to the triple-uptake inhibitor
most likely due to deactivation of the organometallic by the GSK1360707 (see Scheme 2), we decided to initiate our efforts
proximal methoxy group. Instead, sulfinate ester 11 was synthe- on 1,7-enyne sulfonamide 13 for reaction optimization. Table 1
sized and subjected to alkylation with (5-trimethylsilyl)-4- showcases our initial experiments. With 3 mol % of CpRu-sulf-
pentynylmagnesium iodide. Because the order of addition was oxide catalyst 1 in THF at 40 °C, 14 could be obtained in a 69%
reversed, it is important to note that 12 has the opposite absolute yield and a promising 26.5:73.5 er (Table 1, entry 1). This im-
configuration. In this way, sulfoxides containing m-xylyl, portant first experiment establishes that 1 not only efficiently
o-methoxyphenyl, and cyclohexyl groups have been made and catalyzes redox bicycloisomerization, but also that the ligated
carried through the remainder of the standard catalyst synthesis chiral sulfoxide can induce asymmetry in the [4.1.0] bicyclic
as outlined in Scheme 3. None of the catalysts made through product. Indeed, we have shown through control experiments
this method could be synthesized through separation of sulfi- that CpRu(MeCN)3PF6 does not catalyze this reaction without
nate ester diastereomers.
added ligands, implying that the sulfoxide must be bound to the
Scheme 4: Using norephedrine-based oxathiazolidine-2-oxide 7 for chiral sulfoxide synthesis.
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Scheme 5: (a) General synthetic sequence to access enyne bicycloisomerization substrates (b) Synthesis of 2-cyclopropylprop-2-en-1-ol using a
modified Suzuki coupling reaction developed by Soderquist.
Table 1: Initial result for the asymmetric redox bicycloisomerization of 1,7-enyne 13 with chiral CpRu-sulfoxide complex 1 and the effect of added
ligands.
entry
ligand
temp. (°C)
conversion (%)a
yield (%)
erb
1
2
3
4
5
6
7
8
none
none
40
60
60
60
60
40
40
40
100
100
0
69
89
26.5:73.5
26.0:74.0
–
PPh3
n.r.
n.r.
74
P(OPh)3
0
–
(+)-(R)-methyl p-tolyl sulfoxide
(+)-(R)-methyl p-tolyl sulfoxide
(−)-(S)-methyl p-tolyl sulfoxide
(±)-N-(p-tosyl) methyl p-tolyl sulfimide
100
50
0
28.0:72.0
41.5:58.5
–
22
N.R.
22
50
50.0:50.0
aDetermined by NMR integration. bDetermined by chiral HPLC.
metal in order for the reaction to proceed. Raising the tempera- phine ligand before catalysis can occur (vide supra). In other
ture to 60 °C had a negligible impact on enantioselectivity words, ruthenium must have two open coordination sites in
(Table 1, entry 2).
order to bind the substrate. To test if there is a similar require-
ment for 1, we decided to add one catalyst equivalent of an
Our proposed mechanism of the racemic redox bicycloisomer- auxiliary ligand to test its impact on reaction rate, conversion,
ization reaction necessitates the decomplexation of one phos- and enantioselectivity. Added phosphorous-based ligands only
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served to completely shut down all reactivity (Table 1, entries 3 Initially, we thought that this difference in selectivity between
and 4). At 60 °C, 3 mol % of chiral (+)-(R)-methyl p-tolyl sulf- acetone and THF was due to their drastically different steric
oxide had no impact on the reaction, indicating negligible profiles, so we tested bulkier analogues of these solvents, 2,5-
binding of the ligand to the metal (Table 1, entry 5). In general, dimethyl THF (mixture of cis and trans, entry 5) and 3-methyl-
untethered, exogenous sulfoxides are poorer ligands to rutheni- 2-butanone (Table 2, entry 6). Complex 1 catalyzed the redox
um than phosphines or phosphites. As the reaction temperature bicycloisomerization reaction less efficiently in both solvents.
is lowered to 40 °C, however, one begins to see a significant de- Chlorinated (Table 2, entry 7), aromatic (entry 8), ester (entry
crease in reaction rate and conversion (Table 1, entry 6). The 9), and alcohol (entry 10) solvents were all tried, with inferior
enantioselectivity of the reaction also drops to 41.5:58.5 er results to acetone and THF and without any obvious trends in
Interestingly, (−)-(S)-methyl p-tolyl sulfoxide completely inhib- selectivity apparent. Finally, alternative ethereal solvents like
ited any reaction at 40 °C (Table 1, entry 7). Finally, the more 1,4-dioxane (Table 2, entry 11) and DME (entry 12) were
electron-withdrawing (±)-N-p-tosyl methyl p-tolyl sulfimide checked, as well as the effect of adding a small volume percent-
(p-CH3Ph(S=NTs)CH3) also reduced both conversion and er. age of N,N-dimethylformamide (Table 2, entries 13 and 14). No
improvement in enantioselectivity was observed.
As seen in Table 2, the redox bicycloisomerization reaction is
compatible with a number of solvents that have vastly different The effect of catalyst structure on the selectivity of the redox
steric profiles and dielectric constants. The nature of the bicycloisomerization reaction was explored in both acetone and
solvent also had a significant impact on the enantiomeric ratios. THF, due to the differential nature of both of these solvents
Switching from THF to acetone, we observed a dramatic (Table 3). p-Tolyl and 2-naphthyl sulfoxide complexes 15 and
reversal in enantioselectivity, going from 26.5:73.5 to 16 were both able to catalyze the reaction to complete conver-
67.0:33.0, respectively (Table 2, entry 2). Changing the reac- sion, although the enantiomeric ratios of 14 were lower than in
tion temperature had no impact on the er, similar to the temper- the p-anisyl case. Curiously, the bulkier 1-naphthyl sulfoxide
ature studies done in THF (Table 2, entries 3 and 4).
complex 17 was completely ineffective, most likely due to deli-
Table 2: Solvent effects on asymmetric redox bicycloisomerization reaction as described in [43].
entry
solvent
conversion (%)a
yield (%)
erb
1
2
THF
acetone
acetone
acetone
2,5-Me2THFf
iPr Me ketone
DCE
100
100
100
91
69
72
26.5:73.5
67.0:33.0
67.0:33.0
66.0:34.0
26.5:73.5
57.5:42.5
60.5:39.5
31.5:68.5
37.0:63.0
45.0:55.0
32.0:68.0
27.0:73.0
41.0:59.0
61.0:39.0
3c
4d
5c
6c
7
69
n.d.e
17
50
70
47
100
59
66
8
toluene
n.d.e
65
9
EtOAc
100
100
100
100
62
10
11
12
13
14
MeOH
80
1,4-dioxane
DME
59
56
THFg
13
acetoneg
88
56
aDetermined by NMR integration. bDetermined by chiral HPLC. cReaction performed at 60 degrees. dReaction performed at room temperature. eNot
determined due to inseparability from starting substrate. fMixture of cis and trans. g2 vol % DMF added.
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Table 3: Effect of the catalyst structure on the redox bicycloisomerization as described in [43].
entry
1
R
solvent
conversion (%)a
yield (%)
erb
acetone
THF
100
100
72
69
67.0:33.0
26.5:73.5
1
acetone
THF
100
100
72
53
64.5:35.5
41.0:59.0
2
3
15
16
acetone
THF
100
100
72
58
60.5:39.5
31.5:68.5
acetone
THF
0
0
n.r.
n.r.
–
–
4
5
6
17
18
acetone
THF
100
93
69
44
40.5:59.5
43.5:56.5
acetone
THF
50
82
11
36
52.0:48.0
54.0:46.0
19
acetone
THF
100
63
50
30
27.5:72.5
22.0:78.0
7c
8
20
21
acetone
THF
100
100
70
57
73.5:26.5
47.5:52.5
aDetermined by NMR integration. bDetermined by chiral HPLC. cCatalyst enantiomer opposite to the one shown.
gation of the sulfoxide prior to coordination of the substrate THF and acetone and with the same absolute configuration
(Table 3, entry 4). The more electron-rich, bulky t-butyl sulf- (Table 3, entry 7). This could possibly be due to a chelation
oxide catalyst 18, was able to maintain coordination to rutheni- effect wherein the o-methoxy group acts as a hemilabile ligand,
um, though the enantiomeric ratios obtained were unsatisfac- changing the steric and electronic environment around the metal
tory (Table 3, entry 5). m-Xylyl 19 was similarly disappointing center. Since 20 displayed inferior conversions and yields, how-
(Table 3, entry 6). However, o-anisyl 20 was interesting in that ever, it was eschewed in favor of complex 1. Cyclohexyl 21
it was able to maintain high enantiomeric ratios of 14 in both was also an excellent catalyst in terms of reactivity, but again
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Beilstein J. Org. Chem. 2016, 12, 1136–1152.
this system did not prove to be differential towards the enan- Since subtle changes in the structure of the enyne substrate
tiomeric ratio of 14.
could have a significant impact on enantioselectivity, variations
of the substituent on nitrogen were examined (Table 5). These
Before moving forward with complex 1, we wondered how reactions were conducted in THF, as this solvent provided the
these complexes compare to other catalyst/ligand systems in highest enantioselectivities in the [4.1.0] system. Incorporating
terms of reactivity (Table 4). After all, complexing an achiral, electron rich or electron poor aromatics on the sulfonamide
commercially available catalyst CpRu(MeCN)3PF6 with a chiral resulted in diminished reactivities and selectivities, as seen in
ligand would constitute a much simpler solution to the develop- the cases of entries 2 and 3 (Table 5). Surprisingly, 2-biphenyl
ment of an asymmetric redox bicycloisomerization reaction. To sulfonamide 26 gave an unimproved 26.0:74.0 er, despite the
compare the efficiency of each catalyst system, we decided to increased steric bulk on the substrate (Table 5, entry 4). Further
run the reaction for a shorter period of time, stop the reaction, increasing the Lewis basicity of the nitrogen completely shuts
and check the conversion by proton NMR.
down catalyst activity, as can be seen in the case of the
benzhydryl tertiary amine 28 (Table 5, entry 5). Phosphor-
As seen in Table 4, when this experiment is performed with amidate 31 could be obtained in good yield and with an in-
3 mol % complex 1, a 54% conversion is observed after creased enantioselectivity when compared to the parent sulfon-
1.5 hours (entry 1). When the same experiment is conducted amide (Table 5, entry 6). Amide 32 also reacted, but with a
with 3 mol % of CpRu(MeCN)3PF6 and 3 mol % triphenyl- lower conversion and yield, possibly due to increased coordina-
phosphine, the reaction only proceeds to 15% conversion, indi- tion of the amide to the Lewis acidic ruthenium center (Table 5,
cating that the tethered sulfoxide complex is much more effi- entry 7). Gratifyingly, utilizing the bulkier 2,4,6-triisopropyl-
cient at catalyzing redox bicycloisomerization (Table 4, entry benzenesulfonyl group (Tris) significantly improved the er of
2). As one would expect from the lessons learned in the protected piperidine 35 to 15.0:85.0. Because of its differential
previous studies, chiral bidentate (R)-BINAP completely impact on selectivity, this protecting group was pursued more
inhibits any reactivity (Table 4, entry 3). Surprisingly, broadly in the substrate scope.
monodentate (S,S,R)-Feringa was also an ineffective ligand for
this process, which underscores the stringent electronic require- Substrate scope
ments a ligand must have in order to promote redox bicycloiso- Unfortunately, the conditions developed for the Tris-protected
merization (Table 4, entry 4). To date, the only effective ligands [4.1.0] bicycle 35 did not extend to other similarly protected
for redox bicycloisomerization have been triaryl phosphines, 1,7-enynes [43]. We decided to shift our focus from 1,7- to 1,6-
biaryl sulfoxides, or monoaryl monoalkyl sulfoxides. After enynes to determine if bicyclic [3.1.0] pyrrolidines are more
1.5 hours, (S)-methyl p-tolyl sulfoxide also showed no conver- broadly accessible to our synthetic method (Table 6). While the
sion (Table 4, entry 5).
1,6-enyne substrates 36 and 38 exhibited the desired reactivity
Table 4: Comparison of complex 1 to other catalyst systems as described in [43].
entry
[Ru]
ligand
conversion (%)a
1
2
3
4
5
1
none
PPh3
54
15
0
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
CpRu(MeCN)3PF6
(R)-BINAP
(S,S,R)-Feringa
(S)-methyl p-tolyl sulfoxide
0
0
aDetermined by 1H NMR.
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Table 5: Effect of the nitrogen protecting group on reactivity and enantioselectivity as described in [43].
entry
1
R
substrate
product
yield (%)
69
era,b
13
14
26.5:73.5
2
22
23
21
31.5:68.5
3
4
24
26
25
27
n.d.c
59
43.5:56.5
26.0:74.0
5
6
7
28
30
32
29
31
33
n.r.d
52
–
21.0:79.0
26.5:73.5
45e
8
34
35
56
15.0:85.0
aDetermined by chiral HPLC. b(Enantiomer A:Enantiomer B). Absolute configuration not determined. Bold indicates major enantiomer. cn.d.= not de-
termined. Conversion ~30%. dn.r. = no reaction. eConversion ~50%.
in THF, the enantioselectivities for the process were poor. internal position of the pendant olefin, as polycyclic 46 and 48
Considering how impactful a judicious choice of solvent had on displayed excellent enantiomeric ratios. It is also important to
the enantioselectivity of the [4.1.0] bicycles, we decided to try point out that no ring opening of either 49 or its vinylcyclo-
the same reactions in acetone. Pleasingly, exceptional yields propane precursor 48 was observed. Finally, styrenyl substrates
and enantioselectivities of 37 and 39 were obtained in this sol- like 50 can be used for redox bicycloisomerization, but
vent, surpassing those obtained for 35. Catalyst 1 exhibits their pyrrolidine products are isolated in somewhat diminished
excellent functional group compatibility. Substrates containing enantioselectivities.
remote electron-neutral aromatic rings 40, alkenes 42, and
alkynes 44 are all tolerated and remain intact under the reaction After examining the scope of the redox bicycloisomerization
conditions. The reaction can also tolerate branching at the reaction for the synthesis of Tris-protected [3.1.0] pyrrolidines,
1146

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Table 6: Tris-protected [3.1.0] bicyclic pyrrolidines made by redox bicycloisomerizationa.
entry
R
R’
Me
iPr
enyne
36
product
37
Yield (%)
er
1
2
Me
Me
78
85
56.0:44.0b
90.5:9.5
38
39
47
75
64.0:36.0b
98.5:1.5
3c
4
Me
Me
Bn
-(CH2)8CH=CH2
-(CH2)4C≡CH3
iPr
40
42
44
46
48
50
41
43
45
47
49
51
88
57
48
42
75
50
92.0:8.0
93.0:7.0
90.0:10.0
94.0:6.0
90.0:10.0
82.5:17.5
5d
6
Me
cyclopentyl
cyclopropyl
p-tolyl
7
cyclohexyl
Me
8
aTris = 2,4,6-triisopropylbenzenesulfonyl. bReaction conducted in THF. c5 mol % of catalyst used. d8.5 mol % of catalyst used.
it occurred to us that protecting groups other than Tris may be Indeed, when tosyl- or phosphoramidate-protected 1,6-enynes
equally effective for the [3.1.0] system. The Tris group was were tested, excellent yields and enantioselectivities were ob-
chosen during our optimization of the six-membered ring served (Table 7). Like the Tris substrates, branching at the
system (Table 5), which may have significantly different propargylic and alkenyl positions were well tolerated. Carbo-
requirements necessary to achieve high enantioselectivity. cyclic 69 could also be isolated with similar results, although
Table 7: Other substrate tethers for redox bicycloisomerization.
entry
X
R
R’
enyne
product
yield (%)
er
1
2
-NTs
Me
Me
Me
Bn
52
54
56
58
60
62
64
66
68
53
55
57
59
61
63
65
67
69
81
84
56
84
61
64
51
69
49
94.0:6.0
95.0:5.0
91.0:9.0
98.0:2.0
97.0:3.0
96.0:4.0
96.0:4.0
88.0:12.0
92.0:8.0
-NTs
3
-NTs
cyclopentyl
Me
iPr
4
-NP(O)(OPh)2
-NP(O)(OPh)2
-NP(O)(OPh)2
-NP(O)(OPh)2
-NP(O)(OPh)2
-C(CO2Bn)2
Me
5a
6
Me
Bn
cyclopentyl
Me
iPr
7
cyclohexyl
Me
8
Ph
9b
Me
iPr
a5 mol % of catalyst used. b7.5 mol % of catalyst used.
1147

Beilstein J. Org. Chem. 2016, 12, 1136–1152.
the catalyst loading for this substrate had to be increased to
7.5 mol %. This is most likely due to the tendency of rutheni-
um to coordinate to certain aromatic rings in a η6 fashion.
There were a few substrate classes that were not amenable to
redox bicycloisomerization (Figure 3). For example, we thought
that by increasing the steric bulk on styrenyl-substituted com-
pound 50, either on the aromatic ring or at the propargylic posi-
tion, the enantioselectivity would also increase. On the contrary,
neither substrate 70 or 71 reacted at all, which indicated to us
that this substrate class is very sensitive to steric substitution
and where it is placed on the enyne. In other words, while both
phenyl substitution and branching at the propargylic position
are tolerated on separate enyne substrates (see for example 48
and 50), putting both moieties on the same substrate results in
no reaction. Increasing steric congestion near the sulfonamide
(substrate 72) also inhibits enyne bicycloisomerization, as does
placing an additional alkyne in conjugation with the pendant
alkene (substrate 73). Both cis- and trans-1,2-disubstituted
alkenes 74 and 75 were observed to decompose under the stan-
dard reaction conditions.
Figure 3: Failed bicycloisomerization substrates. Reactions per-
formed at 40 °C for 16 hours with 3 mol % of catalyst 1 in acetone at a
0.25 M concentration relative to substrate.
The tosyl and 2,4,6-triisopropylbenzenesulfonyl groups on be removed with lithium aluminum hydride in excellent yield.
nitrogen can be removed after protection of the ketone as the The absolute configuration of the [3.1.0] pyrrolidines was
cyclic acetal by using sodium naphthalide in THF (Scheme 6). assigned by analogy to 76, which was determined to be (R,R) by
After protection, the diphenylphosphoramidate group can also single crystal X-ray crystallography.
Scheme 6: Deprotection of [3.1.0] bicycles and X-ray crystal structure of 76.
1148

Beilstein J. Org. Chem. 2016, 12, 1136–1152.
Mechanistic studies
provided drastically different results. While redox bicycloiso-
After having successfully developed this synthetic methodolo- merization of (R)-52 was very enantioselective, affording 53 in
gy, a few questions still remained pertaining to the mechanism a 92.0 to 8.0 enantiomeric ratio, (S)-52 performed much worse.
of the reaction. First, does the propargylic stereocenter on the Product 53 was isolated in a 68.0 to 32.0 enantiomeric ratio in
enyne substrate have a significant impact on the enantioselectiv- this case. The same matched/mismatched effect was observed
ity of the reaction, despite it being destroyed during redox isom- for chiral 1,7-enynes in THF [44]. Based on these results, it is
erization? Second, what role does the nature of the solvent play clear that the high enantioselectivity of the redox bicycloiso-
in determining enantioselectivity? To answer these questions, merization reaction of 1,6-enynes is due to acetone’s ability to
we synthesized a 1,6-enyne containing an enantioenriched override any impact the propargylic stereocenter has on the
propargyl alcohol using our group’s zinc ProPhenol chemistry course of the reaction.
(Scheme 7). By employing the opposite enantiomers of the
ProPhenol catalyst, either enantiomer of propargyl alcohol can Considering the data presented in Table 8, we now propose a
be accessed with this methodology. Additionally, no other working mechanism for the origin of enantioselectivity in the
attempted synthetic strategy was able to provide (R)-52, includ- redox bicycloisomerization reaction. There are two important
ing Noyori and CBS reduction, which highlights the utility of factors to consider when putting together such a mechanism:
this asymmetric transformation.
coordination of the propargyl alcohol on the metal center and
facial selectivity for the [2 + 2] cycloaddition. We will look at
In acetone, the nature of this stereocenter had very little impact each in turn. First, coordination by the propargyl alcohol creates
on the enantiomeric ratio of the final product, as both (R)- and four possible diastereomeric, chiral-at-ruthenium intermediates
(S)-52 gave results that were almost identical to the racemic (Figure 4). As long as the metal does not epimerize over the
substrate (Table 8). Interestingly, however, switching to THF course of the reaction, this transfer of stereochemical informa-
Scheme 7: ProPhenol-catalyzed addition of zinc acetylide to acetaldehyde for the synthesis of a chiral 1,6-enyne substrate.
Table 8: Effect of propargylic stereocenter on enantioselectivity.
entry
solvent
alcohol configuration
yield (%)
er
1
2
3
4
5
6
acetone
acetone
acetone
THF
rac
(R)a
(S)a
rac
81
84
81
52
61
52
94.0:6.0
93.5:6.5
96.5:3.5
80.0:20.0
92.0:8.0
68.0:32.0
THF
(R)a
(S)a
THF
aStarting alcohol has a 97.0:3.0 er.
1149

Beilstein J. Org. Chem. 2016, 12, 1136–1152.
Scheme 8: Curtin–Hammitt scenario of redox bicycloisomerization in
acetone.
Figure 4: Diastereomeric metal complexes formed after alcohol coor-
dination.
Conclusion
In conclusion, we have developed a ruthenium-catalyzed asym-
metric redox bicycloisomerization utilizing a chiral CpRu–sulf-
oxide complex 1. This constitutes the first example of an asym-
metric ruthenium-catalyzed redox isomerization known to date.
We were able to demonstrate that the nitrogen protecting group
on the 1,7-enynes had a significant impact on the enantioselec-
tivity of the redox bicycloisomerization as did the choice of sol-
vent. Extending the chemistry to the 1,6-enynes, we showed
that these substrates were much more amenable to a wider range
of groups on nitrogen, though a significant solvent effect was
still observed in these cases. The mechanism of the reaction was
then probed by performing the redox isomerization reaction on
enantioenriched propargyl alcohols. While a significant
matched/mismatched effect was observed in THF, no such
effect was seen in acetone. We postulate that there are two dif-
ferent enantiodetermining steps that center around a chosen
tion can then be transferred back to the substrate following
redox isomerization, influencing the overall enantioselectivity
of the process. For both the (R)- and the (S)-propargyl alcohols,
the CpRu-sulfoxide catalyst prefers to place the stereocenter
away from the steric bulk of the sulfoxide (anti configuration).
Both syn configurations are disfavored, but the syn-(R)-configu-
ration is energetically more taxing than the syn-(S)-configura-
tion, creating a larger energy difference between syn-(R) and
anti-(R). This larger energy difference is reflected in the higher
enantioselectivities obtained for the (R) enantiomer in THF
(Table 8, entry 5). The smaller energetic difference between
syn-(S) and anti-(S) means that there is less of a preference for
either coordination mode, which leads to poorer enantioselectiv-
ities in THF (Table 8, entry 6).
We propose that acetone, being more Lewis basic than THF, solvent’s ability to epimerize a metal center following redox
has the effect of epimerizing the chiral-at-ruthenium intermedi- isomerization.
ates formed prior to [2 + 2] cycloaddition. The rate of epimeri-
zation is much faster than the [2 + 2] cycloaddition, creating a
Supporting Information
classic Curtin–Hammitt scenario wherein all of the substrate is
funneled into the observed enantiomer of product (Scheme 8).
Supporting Information File 1
Rate k1 is much slower than k2 due to the severe steric hin-
drance imposed by the ligated chiral sulfoxide, which block
alkene coordination. The pendant olefin prefers to approach the
carbene anti to the aforementioned sulfoxide, resulting in the
observed enantiomer of 53. In THF, the rate of epimerization is
significantly slower than the [2 + 2] cycloaddition, which means
that the enantiomeric ratios observed in the products are
affected more by the initial coordination of the propargyl
alcohol.
Experimental details and NMR data of new catalysts.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-110-S1.pdf]
Supporting Information File 2
X-ray crystallography data for 76.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-110-S2.cif]
1150

Beilstein J. Org. Chem. 2016, 12, 1136–1152.
24.Hatano, M.; Terada, M.; Mikami, K. Angew. Chem., Int. Ed. 2001, 40,
249.
Acknowledgements
We would like to thank the NSF for their generous support
doi:10.1002/1521-3773(20010105)40:1<249::AID-ANIE249>3.0.CO;2-
X
(NSF-CHE-1360634).
25.Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104.
doi:10.1002/1521-3773(20001117)39:22<4104::AID-ANIE4104>3.0.CO
;2-X
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