Enantioselective ring opening of epoxides with silicon tetrachloride in the presence of a chiral lewis base: Mechanism studies

Article abstract of DOI:10.1002/adsc.200600551

The enantioselective ring opening of meso-epoxides (from both cyclic and acyclic olefins) with silicon tetrachloride under catalysis by chiral phosphoramides affords enantiomerically enriched chlorohydrins in excellent yields. Experiments designed to eluc

Full text of DOI:10.1002/adsc.200600551

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DOI: 10.1002/adsc.200600551
Enantioselective Ring Opening of Epoxides with Silicon
Tetrachloride in the Presence of a Chiral Lewis Base: Mechanism
Studies
Scott E. Denmark,a,* Paul A. Barsanti,a Gregory L. Beutner,a and Tyler W. Wilsona
a
245Roger Adams Laboratory, Box 18, Department of Chemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL
61801, USA
Fax : (+1)-217-333-3984; phone: (+1)-217-333-0066; e-mail: denmark@scs.uiuc.edu
Received: October 24, 2006
This paper is dedicated to Professor Masakatsu Shibasaki in recognition of his pioneering and creative contri-
butions to the field of asymmetric catalysis.
Abstract: The enantioselective ring opening of meso- reactive species does not change over the course of
epoxides (from both cyclic and acyclic olefins) with the reaction. Kinetic studies together with asymmet-
silicon tetrachloride under catalysis by chiral phos- ric amplification experiments have suggested that
phoramides affords enantiomerically enriched chloro- more than one catalyst molecule may be bound to
hydrins in excellent yields. Experiments designed to SiCl4 in the stereochemistry-determining transition
elucidate the mechanistic foundation and origins of structure.
enantioselectivity are described. From studies on the
loading and stoichiometry of the reagent (SiCl4) and Keywords: asymmetric catalysis; C C bond forma-
the catalyst [(R)-1] it was established that only one tion; cross-coupling; enzyme catalysis; homogeneous
À
chloride per SiCl4 is delivered and that the nature of catalysis
Introduction
Background
The desymmetrization of meso-compounds is an intri- Despite extensive studies on site and stereochemical
guing strategy for asymmetric synthesis.[1] Whereas selectivity in epoxide opening reactions,[4] an enantio-
asymmetric transformations often involve enantiotop- selective variant did not appear until Yamashitaꢀs
ic face selection with compounds that contain no ste- seminal report on the first asymmetric ring opening of
[7]
reogenic centers, these reactions involve enantiotopic a meso-epoxide in 1985(Scheme 1). In the presence
group selection with Cs symmetric compounds that of either zinc or copper tartrate complexes, TMSN3
may contain a number of stereogenic centers. There- reacted with a variety of epoxides in good yields but
fore, in a maneuver termed by Fischli the “meso-
trick”, a number of stereogenic centers can be un-
veiled at once by a single transformation with high di-
astereo- and enantioselectivity.[2] Epoxides are a read-
ily available class of meso-compounds that have been
the focus of continuing interest.[3] The myriad ring
opening reactions of epoxides with many different nu-
cleophiles makes them extremely versatile synthetic
intermediates for organic synthesis.[4] Therefore it is
not surprising that the enantioselective syntheses[5]
and transformations[6] of epoxides remain active re-
search endeavors.
Scheme 1.
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Scott E. Denmark et al.
Scheme 2.
Scheme 4.
Scheme 5.
Scheme 3.
with only moderate levels of enantioselectivity. Sinou
and co-workers extended this method to the use of a a variety of epoxides with TMSN3 (Scheme 3).[12] The
titanium tartrate complex to provide similarly modest versatility of this method was demonstrated by
levels of enantioselectivity.[8] The first highly-selective Ganem and co-workers in the synthesis of allosami-
method for epoxide desymmetrization, published by din.[13] Mechanistic studies on this and related systems
Nugent in 1992, involves a zirconium(IV) trialkanol- have demonstrated that the reaction is second order
amine complex which catalyzes a highly enantioselec- in catalyst.[14] The cooperativity of the catalyst mole-
tive addition of i-PrMe2SiN3 to a variety of meso-epox- cules in the transition structure led to the develop-
ides, (Scheme 2).[9]
These pioneering studies on the desymmetrization dendridic catalysts.[15]
ment of a variety of highly selective oligomeric and
of meso-epoxides were only capable of delivering ni-
The use of this chromium-(salen) complex is not
trogen centered nucleophiles.[10] Although chiral limited to the addition of nitrogen-centered nucleo-
amino alcohols are an important class of compounds, philes. The complex is the sole effective agent for the
a more general method that would allow access to a asymmetric synthesis of vicinal fluorohydrins albeit
wider variety of products derived from the additions with a stoichiometric loading of the complex shown in
of oxygen-, sulfur- and even carbon-centered nucleo- Scheme 4.[16] Further extensions of the scope of this
philes would be a great advance. Jacobsen proposed catalyst system for the additions of thiols to meso-ep-
that the manganese-(salen) complex that provides oxides employ the titanium-(salen) complex as also
high enantioselectivity in the epoxidation of cis-ole- shown in Scheme 4.[17] Finally, a cobalt-(salen) com-
fins might also effect a highly enantioselective epox- plex catalyzes the highly selective addition of carbox-
ide opening of meso-epoxides. This chiral metallo- ylic acids.[18,19]
(salen) complex developed by Jacobsen and co-work-
As part of their pioneering studies on the use of
ers for asymmetric epoxidations does allow for de- heterobimetallic complexes as catalysts for asymmet-
symmetrization of meso-epoxides with a wide range ric synthesis, Shibasaki and co-workers reported the
of nucleophiles.[11] A thorough survey of transition application of gallium-lithium bis(binaphthoxide)
metals revealed that chromium
ACHTRE(UGN III) uniquely led to complexes for the enantioselective opening of meso-
high yields and enantioselectivities in the opening of epoxides with thiols and phenols (Scheme 5).[6c-e]
568
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Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
Scheme 8.
Scheme 6.
Scheme 7.
Scheme 9.
The addition of carbon-centered nucleophiles to
Curiously, less attention has been directed toward
meso-epoxides in a selective manner remains a syn- the asymmetric opening of meso-epoxides to afford
thetic challenge. In one of the first reports on the ad- the corresponding vicinal halohydrins. Halohydrins
dition of a carbon nucleophile, Tomioka and co-work- serve as important synthetic intermediates in their
ers described the enantioselective addition of phenyl- own right,[25] in addition to being key intermediates in
lithium to cyclohexene oxide in the presence of a stoi- the synthesis of halogenated natural products.[26] The
chiometric amount of a chiral ligand.[20] The develop- classical reagents for halohydrin synthesis are strong
ment of a catalytic method was reported by Crotti Lewis[25] or hydrohalic acids[27] that provide powerful
and co-workers who showed that the chromium- electrophilic activation. The asymmetric synthesis of
(salen) complex can promote the enantioselective ad- chlorohydrins by enantioselective ring opening of ep-
dition of lithium enolates to meso-epoxides oxides relies on the use of stoichiometric amounts of
(Scheme 6).[21] Another method, developed by Oguni chiral, Lewis acid halides (Scheme 8).[28] Alternatively,
and co-workers, involves the addition of phenyllithi- cis-halohydrins can be obtained by enantioselective a-
um catalyzed by the chiral Schiff base complex B chlorination of ketones followed by reduction
(Scheme 6).[22]
(Scheme 9).[29]
The opening of cyclohexene oxide with cyanide can
At the time our work was initiated, no catalytic
be performed using either a polypeptide-based cata- procedure for desymmetrization of meso-epoxides
lyst developed by Oguni, Snapper and Hoveyda[23] with halide nucleophiles had been developed. Howev-
(Scheme7) or a ytterbium-pybox catalyst developed er, subsequently, Nugent reported a catalytic, enantio-
by Jacobsen and co-workers (Scheme 6).[24]
selective ring opening of meso-epoxides to afford the
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could be very efficiently catalyzed with as little as 0.4
mol% of Ph3P, Scheme 11.[32]
The use of a more reactive silicon species, SiCl4,[33]
allows for a similar reaction to proceed under milder
conditions and opens the possibility for the introduc-
tion of an asymmetric environment during the enan-
tiodetermining event. The Lewis base-catalyzed for-
mation of chlorohydrins mediated by SiCl4 has been
studied in several laboratories and a wide variety of
chiral Lewis bases have proven successful in providing
high selectivities. In 1998, the first example of catalyt-
ic, enantioselective opening of epoxides with chlorosi-
lanes to afford the corresponding chlorohydrins was
reported from these laboratories.[34] The use of the
chiral phosphoramide (R)-1 in combination with SiCl4
led to the enantioselective synthesis of chlorohydrins,
Scheme 12. Following our initial report, other groups
described the use of N-oxides,[35,36] phosphines,[37] and
phosphine oxides[38] (Scheme 13).
Scheme 10.
Scheme 11.
As part of an ongoing program in these laborato-
corresponding halohydrins, again employing the chiral ries on Lewis base-catalyzed reactions of silicon tetra-
zirconium catalyst, Scheme 10.[30]
chloride, we sought to investigate a number of prepa-
A conceptually distinct approach for halide opening rative and mechanistic features of the epoxide ring
of an epoxide involves activation of Lewis acids (e.g., opening reaction to garner a clearer understanding of
TMSCl) by Lewis bases. This method offers unique the role of each of the reaction components and po-
opportunities for asymmetric catalysis by disconnect- tentially the origin of enantioselectivity.
ing the roles of activator and nucleophile.[31] In one of
the few examples in the literature, Andrews and co-
workers found that epoxide ring opening with TMSCl Results
Chlorosilane Sources
The first phase of these studies probed the influence
of chlorosilane structure on the rate and selectivity of
the epoxide opening. For these studies, cyclohexene
oxide was chosen as the test substrate under the stan-
dard reaction conditions [0.1 equiv. of (R)-1, 0.1M cy-
clohexene oxide in CH2Cl2 at À788C for 2 h, then
pouring into saturated aqueous KF/KH2PO4]. All of
the following chlorosilanes afforded trans-2-chlorocy-
clohexanol: SiCl4, HSiCl3, PhSiCl3, CH3SiCl3,
(CH3)2SiCl2, (CH2)3SiCl2, (CH2)3SiCH3Cl, (CH3)3SiCl,
Scheme 12.
PhCO2SiCl3, t-BuCO2SiCl3. However, only SiCl4 and
Scheme 13.
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Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
Table 1. Survey of chlorosilane sources.
Entry
Chlorosilane
(R)-1 [mol%]
Time [h]
Temperature [8C]
er[a]
Conversion [%][b]
1
2
3
4
SiCl4
HSiCl3
HSiCl3
10
10
100
10
10
10
3
3
3
17
3
À78
À78
À78
À78
24
93.5/6.5
76.0/24.0
76.0/24.0
-
0
0
100
68
100
42
100
70
[c]
AcOSiCl3
5MeSiCl
6
3
A
6
24
[a]
Determined by CSP-SFC analysis.
Conversion determined by H NMR analysis.
0.1 equiv. of HMPA employed as catalyst.
[b]
[c]
1
HSiCl3 afforded the chlorohydrin product in an enan- Internal Quench
tiomerically enriched form; all the other chlorosilanes
gave rise to racemic trans-2-chlorocyclohexanol.
During the course of these investigations, it was
The formation of racemic products from all other found that if the reactions had not proceeded to com-
chlorosilane sources was extremely puzzling, but pletion, then quenching under the standard conditions
closer consideration of the process revealed several (pouring the reaction mixture into a 1/1 mixture of sa-
factors that could explain this outcome. Hydrogen turated aqueous KF/KH2PO4 solution at 08C) gener-
chloride is a potential contaminant in all of these ated HCl which rapidly opened the unreacted epoxide
chlorosilanes and because the corresponding back- to the chlorohydrin. The racemate thus formed then
ground reactions were not examined in this initial led to erroneous conversions and enantiomerically di-
screening, it was possible that the products could be luted products. Therefore, it was critical to establish a
formed as an artifact of opening with HCl (and are highly reproducible, internal quench that avoided the
therefore racemic). After establishing that HCl could problem of generating HCl. The results of the
be removed by continuously refluxing the chlorosi- quenching study are compiled in Table 2.
lanes in a still, a few of the other chlorosilanes were
Two epoxides were chosen for study: cis-stilbene
reinvestigated.[39] Because cis-stilbene oxide 2 led to oxide 2 and 1,2-epoxydodecane 3. These two epoxides
the most enantioselective opening, and is also one of behave very differently toward opening and would
the least acid-sensitive, a number of chlorosilanes represent a spectrum of reactivities for subsequent
were reinvestigated with this epoxide, and the results studies. Initial experiments with 3 employed hindered
are compiled in Table 1.
amines 4 and 5, and various fluoride sources as bases.
Entries 2 and 3 show that HSiCl3 afforded the cor- Entries 1–3 show that quenching the reactions with al-
responding chlorohydrin with 76:24 er when either 10 cohols in the presence of either of these amines or
mol% or 100 mol% of (R)-1 was employed as the CsF led rapidly to the formation of HCl which
catalyst. However, there was a significant decrease in opened 3 to the corresponding chlorohydrin. The use
rate and selectivity upon switching from SiCl4 to of TASF was ineffective for the faster reacting epox-
HSiCl3 (entries 1 and 2). Acetoxytrichlorosilane react- ide 3 (entry 4) leading to 43% of the chlorohydrin, al-
ed even slower, affording a 42% conversion after 17 h though this quench method proved more effective for
at À788C when 10 mol% HMPA was employed as the slower reacting epoxide 2 (entry 5).
the catalyst (entry 4).
These results showed that epoxide 3 was more ef-
Surprisingly, MeSiCl3 failed to induce any reaction fective at scavenging the HCl than a hindered, terti-
at À788C after 24 h with either 10 or 100 mol% of ary amine base. Logically therefore, a faster-reacting
(R)-1 whilst (CH2)3SiCH3Cl provided a mere 17% epoxide (e.g., propylene oxide) would serve as a suit-
conversion after 4 d at À788C with 100 mol% of (R)- able HCl scavenger for quenching with MeOH.
1. However, at room temperature, full conversion was Indeed, entries 6 and 7 show that a pre-mixed solu-
observed with MeSiCl3 after 3 h with 10 mol% of tion of propylene oxide and MeOH led to only 7%
(R)-1. Unfortunately, the product was racemic conversion of 3 after the quench. Even better results
(entry 5). Use of (CH2)3SiCH3Cl with 10 mol% of were obtained by adding propylene oxide rapidly
(R)-1 led to 70% conversion after 6 h, and again, the before the dropwise addition of MeOH. These condi-
product was racemic (entry 6).
tions reproducibly led to only 3% conversion. In ad-
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Table 2. Internal quench of reaction mixtures.[a]
Entry
Epoxide
Quench conditions
Ring opening [%][b]
1
2
3
4
5
6
7
3
3
3
3
2
2
2
2
2
8 equivs. 4, 50 equivs. MeOH, À788C
100
100
89
43
12
7
7
3
5
10 equivs. 5, 10 equivs. i-PrOH, À788C
10 equivs. CsF, 37 equivs. MeOH, À788C
5equivs. TASF, À788C
10 equivs. TASF, À788C
10 equivs. propylene oxide pre-mixed with 10 equivs. MeOH, À788C
15equivs. propylene oxide pre-mixed with 10 equivs. MeOH, À788C
10 equivs. propylene oxide, À788C, 30 s, then 5 equivs. MeOH, À788C
15equivs. propylene oxide, À788C, then 5equivs. MeOH, À788C
8
9[c]
[a]
1.0 equiv of SiCl4 in CH2Cl2.
Determined by H NMR analysis.
Contained 10 mol% HMPA prior to quench.
[b]
[c]
1
dition to this, it was important to establish that the hydrin to the starting epoxide). Development of the
quench was instantaneous. Entry 9 shows that when internal quench allowed for reproducible conversions
10 mol% of HMPA was added to a mixture of cis-stil- to be obtained at any time point throughout the
bene oxide and SiCl4 at À788C, followed immediately course of the reaction. This tactic proved to be instru-
by the addition of propylene oxide, and then MeOH, mental in validating and interpreting the data and
only 5% of the chlorohydrin was formed. Thus, the
quench was indeed rapid.
also enabled the following investigation on the stoi-
chiometry requirements of SiCl4.
By use of this quenching protocol for a reaction
either in progress or at completion leads to the isola-
tion of the corresponding silyloxy chlorohydrin 6 Stoichiometry of SiCl4
(Scheme 14). In this product, both MeOH and the
chlorohydrin derived from the HCl opening of propyl- Although SiCl4 was not the only chlorosilane source
ene oxide have exchanged the chloride ligands at the that afforded enantiomerically enriched products, it
silicon center. Therefore, conversions could be ob- did prove superior to all others both in terms of rates
tained, but desilylation of 6 was required to isolate and selectivity. Therefore SiCl4 was employed for all
the pure chlorohydrins for determination of enantio- subsequent mechanistic studies.
meric composition. This maneuver was conveniently
The mechanistic inquiry began by establishing the
achieved by treatment of the silyloxychlorohydrin stoichiometry of the reaction, i.e., to determine how
with TBAF buffered with AcOH (since TBAF alone many of the chlorines in SiCl4 are transferrable. It is
was basic enough to effect ring closure of the chloro- conceivable that the initial product, a trichlorosilylox-
ychlorohydrin, could also be susceptible to the same
Lewis base promotion, leading to a dialkoxydichloro-
silane, etc. If this were the case, then the reaction
would not require a full equivalent of SiCl4 for full
conversion. To test this hypothesis, the loading of
SiCl4 was varied in the reaction of cis-stilbene oxide
2, employing HMPA as the catalyst. The reactions
were then quenched internally and the conversion ex-
1
amined by H NMR analysis. The standard conditions
involved stirring a solution of 2 (0.1M in CH2Cl2)
with SiCl4 and 0.1 equiv. of HMPA at À788C for 3 h,
then quenching with 15equivs. of propylene oxide at
À788C, followed by 5equivs. of MeOH at À788C.
Surprisingly, the use of 0.52 equiv of SiCl4 reprodu-
Scheme 14.
cibly led to 55% conversion, suggesting that only one
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Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
Scheme 15. Sccheme 16
chlorine per SiCl4 is delivered under these conditions.
Moreover, 0.25equivs. of SiCl 4 led to 29% conver-
sion, which upon desilylation afforded a 22% yield of
pure chlorohydrin. Likewise, 0.75equivs. of SiCl 4 led
to 76% conversion, affording a 64% yield of the iso-
lated chlorohydrin after desilylation.
Even though only one chlorine per SiCl4 is active, it
is still possible that the nature of the reactive species
changes as a function of conversion. To test this sce-
nario, 10 mol% of (R)-1 was combined with
Figure 1. Loading study with SiCl4 and (R)-1.
1.1 equivs. of SiCl4 and cis-stilbene oxide 2, then the tionalize because the rates and selectivities should fall
reaction was quenched internally after 5min. This ex- off proportionally. Clearly, this is not the case, and
periment provided a 20% conversion of 2, which currently, no explanation is available. That not with-
upon desilylation afforded a 15% yield of the chloro- standing, at catalyst loadings from 100 mol% to 4
hydrin in a 90:10 er, along with 74% of recovered 2, mol%, primarily one catalytic pathway is operative.
Scheme 15. Because essentially the same enantiomer-
ic composition was observed at early conversion or
full conversion, the ring opening species would Investigation of the Order in Catalyst
appear to be consistent throughout the course of the
reaction.
Kinetic Studies
To determine the order in the catalyst, the rapid injec-
tion NMR (RINMR) technique was employed be-
cause of the high rates and the sensitivity of the reac-
Catalyst Loading
The enantiomeric composition of the chlorohydrin tion to adventitious moisture. This technique has
from the reactions of 2 and SiCl4 was determined as a proven applicable to the study of a number of reac-
function of catalyst loading with (R)-1 and the results tions employing highly reactive species and therefore
are depicted in Figure 1. As the graph clearly shows, seemed the method of choice for study of this Lewis
only a slight erosion in enantioselectivity is observed base-catalyzed reaction process.[40]
from 100 mol% to 4 mol% of (R)-1. However, the
The kinetic experiments were performed using
enantioselectivity is greatly eroded at catalyst load- 1.1 equiv of SiCl4, epoxide 2 and HMPA as the cata-
ings less than 4 mol%. Although the rates were great- lyst in dichloromethane-d2 at À788C and an overall
ly reduced at these lower loadings, control experi- concentration 0.2M.[41] First, the order of each re-
ments established that the low selectivity observed was agent was determined using the method of initial
not due to a background reaction. Experiments using rates. Data from the 15% conversion run were em-
2 mol% of (R)-1 were repeated many times and the ployed to assess changes in initial rate as the concen-
results were highly variable until the internal quench tration of a particular reagent was varied.[42] Each ex-
method was developed. Once the internal quench had periment was performed in triplicate to assure that
been established, the 2 mol% loading experiment led the results were reproducible. However, despite ex-
to a 71% conversion (after 40 h), which afforded the tensive optimization, the extreme sensitivity of the re-
chlorohydrin 7 in 63% yield and with 34% ee. The action to traces of acid led to a degree of irreproduci-
background for this reaction was 3.5% after 40 h.
bility in the results. Although this problem hampered
The reason for this precipitous drop in selectivity the collection of data, a number of conclusions can
from 4 mol% to 2 mol% of (R)-1 is difficult to ra- still be drawn.
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Figure 2. Kinetic analysis of the HMPA-catalyzed opening of 2.
Examination of the reaction using the integral tains synthetically relevant catalyst loadings. Plotting
method revealed that the reaction exhibited good, lnACHTER[UNG HMPA] against lnCAHRTEU(NG kobs) revealed that the order in
overall 1st order behavior (Figure 2). The possibility HMPA was between 1.95and 2.2, depending on
of overall 2nd order behavior was ruled out by com- whether the analysis was performed on the basis of
parison of graphs of ln(2t) and 1/(2t) versus time out the disappearance of 2 or the appearance of the tri-
to 70% conversion [R2(ln(2t))=0.9977 vs. R2(1/(2t)= chlorosilyl ether trichlorosiloxychlorohydrin, respec-
0.9421]. The linearity of the ln(2) vs. time plot was tively (0.9769<R2 <0.9786). On the basis of these re-
clearly higher than that of the 1/(2) vs. time plot. A sults, the following rate equation for the epoxide
similar conclusion could be drawn from plots of ln- opening is proposed: Àd(2)/dt=k
[HMPA]2[SiCl4]0[2]1.
ACHRTEUNG ACHTREUGN
G
N
ploying the method of initial rates, the order in SiCl4 their studies of the N-oxide-catalyzed opening of
was determined to be zero. From 1.0 to 10 equivs. of meso-epoxides with SiCl4.[35b]
SiCl4, only small changes in initial rate were observed
These results suggest the intriguing possibility that
and overall 1st order behavior was maintained the Lewis base catalyst is saturated with SiCl4 and
throughout [vi(1 equiv. SiCl4)=(1.3Æ0.1)”10À6 sÀ1 vs. that a 2:1 complex between the phosphoramide and
vi(10 equivs. SiCl4)=(3.5Æ0.3)”10À6 sÀ1]. To deter- SiCl4 may be the catalyst resting state. Binding of the
mine the order in HMPA, changes in the first order epoxide to this intermediate complex or attack of
rate constant (kobs) were examined within the range chloride on complex of HMPA, SiCl4 and 2 is the
of 10–20 mol% catalyst. This narrow range of catalyst rate-determining step, although no further conclusions
concentrations was employed because of changes in can be drawn at this point.
the rate of these reactions and the unexpected prob-
The observed zero order rate dependence on the
lems associated with lower catalyst loadings. Despite concentration of SiCl4 also implies that under the
these limitations, this concentration range still con- standard reaction conditions, the majority of the cata-
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Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
lyst exists as a complex with SiCl4 rather than as free
catalyst. Therefore, it may be possible to observe the
Lewis base-Lewis acid adduct spectroscopically.
Indeed, 29Si NMR spectroscopy is a powerful and
well-understood technique that has proven to be the
tool of choice in the search for silyl cations.[43] This
Scheme 16.
nucleus has an extremely large dynamic range
(~600 ppm) and the chemical shift is strongly effected
by the coordination number of the silicon species applies to the latter. Although kinetic studies of the
under observation. The identity of the peripheral li- epoxide opening of 2 with (R)-1 would directly ad-
gands has a smaller, albeit predictable effect on chem- dress this question, problems of irreproducibility pre-
ical shift. One factor that has almost no effect on the cluded any analysis of the reaction order in (R)-1. In
value of the chemical shift for a particular silicon spe- the absence of such data, we resorted to the use of
cies is charge. A chemical shift that can be predicted enantiomeric composition experiments to provide in-
on the basis of coordination number rather than over- sight into the molecularity of the chiral catalyst.
all charge or consideration of the identity of the pe-
ripheral ligands is extremely useful. Interestingly, few
29Si NMR chemical shifts have been reported for Non-Linear Effect Studies
Lewis base complexes of a trichlorosilyl species. Ko-
bayashi and co-workers, during their investigation of Following Kagan,[47] a series of experiments was per-
allylations with allyltrichlorosilane catalyzed by for- formed to establish the relationship of ee product as a
mamides, reported observation of a new signal at function of ee catalyst, employing 10 mol% of (R)-1.
À170 ppm, assigned as the hexacoordinate complex, Varying amounts of accurately weighed (S)-1 and (R)-
allylSiCl3ACHTREUNG
(DMF)2.[44] A closer analogy to systems rele- 1 were mixed but in addition, the ee of the catalyst
vant to this work is provided by the pentacoordinate was accurately assayed using CSP-SFC.[48] This analy-
trichlorosilylamidinate complexes reported by Karsch sis was conveniently carried out by sampling 50 mL of
and co-workers (À89<d<À99 ppm).[45]
the pre-mixed catalyst directly from the reaction
Initial studies with SiCl4 and HMPA confirmed the flask, prior to adding SiCl4. The results are depicted
results of the kinetic analysis. At À608C in CDCl3 so- in Figure 3.
lution, (conditions intended to approximate those
All experiments were duplicated with good repro-
used in the preparative reactions) an equimolar mix- ducibility. The graph clearly demonstrates a weak
ture of SiCl4 and HMPA showed three majors signals “negative non-linear effect,” which supports the hy-
(Scheme 16).[31a] The signal appearing at À19 ppm was pothesis that more than one phosphoramide is in-
assigned as free SiCl4 while other signals appeared far volved in the stereodetermining transition structure.
upfield at À110 and À206 ppm. The signal at However, there are two other mechanistic scenarios
À110 ppm was a triplet with a coupling constant of
9 Hz, consistent with those spectra observed by
Cremer and Bassindale for HMPA complexes of trial-
kylsilyl cations.[46] The signal at À110 ppm was tenta-
tively assigned as the bis-HMPA complex of a tri-
chlorosilyl cation i, with its chemical shift falling
squarely in the middle of the range for a pentacoordi-
nate silicon species (À5 0 toÀ150 ppm).[43a] The signal
at À206 ppm can then be assigned as the dianion hex-
achlorosilicate (SiCl62À).[47] These results indicate the
presence of
[SiCl3HMPA2 ]
a
fairly complex ion in solution:
+
2À
[SiCl6
]
(i). Inspection of the
31P NMR spectrum of this mixture in CDCl3 revealed
that the signal corresponding to free HMPA (27 ppm)
had completely disappeared, only to be replaced by a
single, new signal at 19 ppm.
Although these results suggest that a 2:1 complex
between SiCl4 and a Lewis basic phosphoramide is
the active catalytic intermediate in these epoxide
openings, the significant structural and catalytic effi-
ciency differences between HMPA and (R)-1 still
leave open the question of whether a similar analysis Figure 3. Non-linear effect study with (R)-1.
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Scott E. Denmark et al.
that can lead to a non-linear effect that do not involve both the rate and stereochemistry determining steps
a higher order in the molecularity of the catalyst.[48]
of the epoxide opening. Therefore, it was hoped that
The first of the alternative scenarios is referred to the use of a chiral, dimeric phosphoramide catalyst
as the reservoir effect. This phenomenon can give rise would lead to improvements in enantioselectivity. In
to a non-linear effect if the catalyst molecules are ag- all of the other reactions that employ the combination
gregated in the resting state, but not in the transition of silicon tetrachloride and a chiral Lewis base for
structure. If a reservoir effect were responsible for the enantioselective addition reactions, dimeric ligands
observed non-linear effect, then its magnitude should deliver higher selectivities when compared to the re-
be catalyst concentration-dependent. To test for this lated monomers.[31] Accordingly, dimeric bisphosphor-
eventuality, an experiment employing 100 mol% of amides of the general structure (R,R)-8 were pre-
(R)-1 of 42.0% ee afforded the product in 94% yield pared and assayed in the opening of 2 under the opti-
and with a 30.9% ee. Thus, the deviation from lineari- mized reaction conditions. The results collected in
ty is the same at 100 mol% loading as for 10 mol% Table 3 show that none of these structures gave re-
loading, and therefore the eeprod is independent of cat- sults superior to those from (R)-1. Although this does
alyst concentration over a 10-fold range. Therefore, not eliminate the possibility that two catalyst mole-
the observed non-linear behavior is not a result of the cules are involved in the transition structure, it does
reservoir effect.
suggest that the two are not in close proximity to
The other mechanistic scenario is referred to as each other (vide infra).
product inhibition. In this case, a non-linear effect
arises because one enantiomer of the catalyst binds
selectively with the chiral, non-racemic product. If Discussion
this were the case, then one would expect the extent
of the non-linear deviation to change as a function of Chlorosilane Source
conversion. Thus, an experiment using 100 mol%
(R)-1 with 52.4% ee was quenched after 7 min to In the survey of chlorosilane structure, the three
afford the chlorohydrin in 28% yield and 39.6% ee. agents, SiCl4, HSiCl3 and AcOSiCl3 all induced the
Thus, quenching the reaction at low conversion af- opening of 2 with 10 mol% of (R)-1 at À788C. With
fords the chlorohydrin with the same ee as for the re- SiCl4 the reaction was complete after 3 h, however,
action at full conversion. Therefore, the non-linear HSiCl3 afforded only 68% conversion over the same
behavior is not the result of product inhibition.
time. Although AcOSiCl3 did react at À788C, this
silane required 17 h to reach 42% conversion. An
even greater difference in reactivity was observed in
with the alkylchlorosilanes. For example, neither
MeSiCl3 nor (CH2)3SiCH3Cl reacted at À788C, even
Catalyst Structure Survey
The combination of kinetic and non-linear effect stud- with a full equivalent of (R)-1. However, both these
ies suggests that two phosphoramides are involved in chlorosilanes did react at room temperature with 10
mol% of (R)-1; full conversion was observed for
Table 3. Survey of dimeric catalysts.
MeSiCl3 after 3 h and 70% conversion for
(CH2)3SiCH3Cl after 6 h. These results lead to the fol-
lowing reactivity trend: SiCl4 >HSiCl3 >MeSiCl3 >
(CH2)3SiCH3Cl, where substitution of a chloride by H
or AcO still allows the reaction to take place (albeit
slower) at À788C, but substitution for an alkyl group
shuts down the reaction at À788C. It would appear
that replacement of a chloride with an alkyl substitu-
ent disfavors ionization. In addition, it was established
that the lack of selectivity observed in the reactions
with alkyl-substituted chlorosilanes was not due to a
competing background reaction.
Catalyst
Yield [%][a]
er[b]
A
ACHTREUNG
ACHTREUNG
ACHTREUNG
93
93
98
68
69.3/30.7
47.4/52.6
53.5/46.5
31.0/69.0
Stoichiometry of SiCl4
From the loading study, it was clearly established that
only one chlorine per SiCl4 is available, which in turn
implies that the product, a trichlorosilyloxychlorohy-
drin, is not capable of delivering a chloride under the
[a]
[b]
Yield of isolated, purified product.
Determined by CSP-SFC analysis.
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Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
same conditions. This result is consistent with the con- 1:1 complex. This hypothesis is supported by the cata-
clusions of the chlorosilane survey which demonstrat- lyst loading study which showed decreasing enantiose-
ed that other reagents, particularly AcOSiCl3 are less lectivity at relatively low catalyst loading. At higher
active than SiCl4.
catalyst concentrations the more selective 2:1 path-
Furthermore, the enantioselectivity of the opening way should be favored and conversely, the less selec-
does not change as a function of conversion. This out- tive 1:1 pathway should only intervene at low catalyst
come further substantiates the conclusion that the concentrations (Scheme 17).
product alkoxytrichlorosilane does not materially con-
The results of the loading study establish that little
tribute to the reaction pathway. The stoichiometry erosion is observed for catalyst concentrations down
study rules out the involvement of such intermediates, to 4 mol% of (R)-1, but that a precipitous drop off is
and shows that the nature of the reactive species does observed below 4 mol%. It is difficult to explain the
not change throughout the course of the reaction.
dramatic change observed in both the rates and enan-
tioselectivities. Catalyst turnover, although slow, is
still sufficient to afford 71% conversion after 40 h at
À788C. In addition, the product is obtained with 34%
ee, and the fact that any level of stereoinduction is ob-
Catalyst Loading Studies
From the survey of chlorosilane structure, both SiCl4 served is clearly indicative of a phosphoramide-pro-
and HSiCl3 were found to be the only enantioselec- moted pathway. However, even if this is the result of
tive reagents. This outcome leads to the hypothesis a 1:1 pathway, it still does not explain why there is
that these agents are unique in their ability to be ion- such a sharp change in going from 4 mol% to 2
ized by the catalysts at low temperature and perhaps mol% of (R)-1. Nevertheless, in conjunction with the
even bind two phosphoramides. This pentacoordinate results of the kinetic studies, it is clear that at catalyst
or hexacoordinate silicon species, now possessing a concentrations down to 4 mol% catalyst, a singular
more crafted chiral environment, gives rise to enan- pathway is operative.
tioenriched products. By contrast, the other chlorosi-
lanes were not sufficiently Lewis acidic and hence
bind only one phosphoramide, leading to an unselec- Kinetic and Non-Linear Effect Studies
tive reaction. However, even if this proposition were
true, we were still concerned that a competitive path- The results of the kinetic studies combined with the
way may be operative with SiCl4 that also involves a non-linear effects studies indicate that two phosphor-
Scheme 17.
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Scheme 18.
amides are likely involved in both the rate and stereo- complex to form the silicate species iii, which serves
chemistry determining steps of the epoxide opening. to activate the chloride to nucleophilic attack.[49] In
The observation of the siliconium ion [SiCl3HMPA2]+ this scenario, with the chiral phosphoramide now inti-
by 29Si NMR supports the observed saturation kinetics mately involved with the nucleophile, it is somewhat
in SiCl4, but also provides insights into the true easier to rationalize the observed asymmetric induc-
nature of the active, catalytic intermediate in these re- tion. In the initial hypothesis, it is hard to envisage
actions.
how the chloride is able to distinguish between the
Although the kinetic studies with HMPA helped to two enantiotopic centers of the epoxide when the
clarify the role of the catalyst, the questions regarding chiral phosphoramide is distal to the approaching nu-
the role of the chiral catalyst (R)-1 remain open. The cleophile.[51] The current kinetic studies are unable to
results of the non-linear effect experiments demon- differentiate between these two mechanistic scenarios
strate a weak, negative deviation from linearity which due to the observed, zeroth order behavior in SiCl4.
suggests that subtle interactions are involved, possibly However, the failure of bisphosphoramide to improve
with participation from a higher order species. A the enantioselectivity of the opening also supports the
weak negative deviation indicates that the heterochi- notion that, if two phosphoramides are involved, then
ral complex is more kinetically competent than the they are not acting on the same silicon atom.
homochiral complex.
The two other mechanistic interpretations of the
data that could explain this effect, namely a reservoir Conclusions
effect and product inhibition, were ruled out by ap-
propriate control experiments and assured the conclu- A number of key mechanistic insights into the enan-
sion that more than one phosphoramide molecule is tioselective opening of meso epoxides with silicon tet-
likely involved in the stereodetermining transition rachloride have been identified. First, silicon tetra-
structure.
chloride is unique in its ability to give highly enantio-
In spite of these two pieces of information regard- merically enriched chlorohydrins. Second, only one of
ing the role of the catalyst, it is still not possible to the four chlorines in SiCl4 is active. Third, a single
state whether the two phosphoramides are bound to mechanistic pathway is operative between 4 and 100
the same silicon atom. It is possible that there are two mol% catalyst [(R)-1], but the selectivity drops off
silicon species, each with one phosphoramide bound significantly at 2 mol% of (R)-1. Fourth, kinetic stud-
to them that would also give the same molecularity in ies suggest that the reaction is second order in
phosphoramide, such as shown in Scheme 18. A cat- HMPA. Finally, a weak, negative non-linear effect has
ionic silicon species such as ii would serve to activate been demonstrated, again suggesting that more than
the epoxide, whilst the chloride that dissociates in the one catalyst molecule is involved in the stereochemis-
ionization combines with the SiCl4/phosphoramide try determining transition structure. Unlike many
578
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Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
other reactions promoted[52] by SiCl4, dimeric phos-
phoramide catalysts did not improve the enantioselec-
tivity of the epoxide opening, suggesting that if two
catalyst molecules are involved, they may not be
bound to the same silicon atom.
Further mechanistic investigations, including kinetic
analysis with (R)-1 and the identification of reaction
parameters that will allow addition of other nucleo-
philes are currently underway, as are continuing stud-
ies to expand the preparative scope of the reaction.
with Et2O (40 mL) and was allowed to warm to room tem-
perature. The organic layer was separated, and the aqueous
layer extracted with Et2O (3”20 mL). The combined organ-
ic extracts were dried (Na2SO4), filtered, and evaporated
under reduced pressure. The resulting pale-yellow liquid
was analyzed by 1H NMR spectroscopy (for conversion),
prior to desilylation as follows: to a solution of the crude si-
lyloxy chlorohydrin in THF (5mL) was added a premixed
solution of TBAF (1M in THF, 1.2 mL, 1.2 mmol,
1.2 equivs.) and AcOH (0.15mL). After 15min, the reaction
was poured onto saturated aqueous NaHCO3 solution
(10 mL). The organic layer was separated, and the aqueous
layer extracted with CH2Cl2 (4”25mL). The combined or-
ganic extracts were dried (Na2SO4), filtered, and evaporated
under reduced pressure. The resulting pale-yellow liquid
was purified by silica gel chromatography (hexane/Et2O, 9/
1) to afford (S,S)-2-chloro-1,2-diphenyl-1-ethanol. Spectro-
scopic data matched those from the literature.[34] 1H NMR
(400 MHz): d=7.25–7.13 (m, 8H), 7.13–7.07 (m, 2H), 5.01
(d, J=8.3 Hz, 1H), 4.95(dd, J=8.3 Hz, 2.7, 1H), 3.02 (d,
J=2.7 Hz, 1H).
Experimental Section
General Experimental Methods
1H NMR spectra were recorded on a Varian Unity 400
(400 MHz) spectrometer. Spectra are referenced to residual
1
chloroform (d=7.26 ppm, H) in CDCl3. Chemical shifts are
reported in ppm (d); multiplicities are indicated by s (sin-
glet), d (doublet), t (triplet), q (quartet), quint (quintet), m
(multiplet) and br (broad). Coupling constants, J, are report-
ed in Hertz.
Representative Procedure for Stoichiometry Studies
using the Internal Quench
All reactions were performed in oven and/or flame-dried
glassware under an atmosphere of dry nitrogen. Dichloro-
methane (CH2Cl2) was distilled from P2O5, SiCl4, HSiCl3 and
MeSiCl3 were heated to reflux overnight then distilled im-
mediately before use from a still. (CH2)3SiCH3Cl and AcO-
SiCl3 were distilled immediately before use. Diethyl ether
(Et2O) was of reagent grade and used as received; other sol-
vents for chromatography and extraction were technical
grade and distilled from the indicated drying agents:
hexane, and dichloromethane (CaCl2); ethyl acetate
(K2CO3). Analytical thin-layer chromatography was per-
formed on Merck silica gel plates with QF-254 indicator.
Column chromatography was performed using EM Science
230–400 mesh silica gel by the method of Still. Analytical su-
percritical fluid chromatography (SFC) was performed on a
Berger Instruments packed-column SFC with built-in photo-
metric detector (l=220 nm) using Daicel Chiralpak AD
and AS columns. Retention times (tR) and peak ratios were
determined with a Hewlett Packard 3396 Series II integra-
tor. cis-Stilbene oxide 2 was prepared by epoxidation of the
corresponding alkenes with mCPBA. (R)-4 and (R)-1 were
prepared as previously reported.[52]
To a cooled (À788C), stirred solution of cis-stilbene oxide
(2) (196 mg, 1.0 mmol) and HMPA (20 mL, 0.11 mmol,
0.11 equivs.) in CH2Cl2 (10.0 mL) was added SiCl4 (86 mL,
0.75mmol, 0.75equivs.) dropwise over 1 min. After the ad-
dition was complete, the mixture was stirred at À788C for
3 h and then was quenched by the rapid addition of propyl-
ene oxide (680 mL, 11.25mmol, 15equivs. with respect to
SiCl4). After 1 min, MeOH (152 mL, 3.75mmol, 5equivs.
with respect to SiCl4) was added. After 30 min at À788C,
the mixture was poured into cold (08C), rapidly stirring sa-
turated aqueous KF/KH2PO4 solution (1/1, 20 mL), then was
diluted with Et2O (40 mL) and was allowed to warm to
room temperature. The organic layer was separated, and the
aqueous layer extracted with Et2O (3”20 mL). The com-
bined organic extracts were dried (Na2SO4), filtered, and
evaporated under reduced pressure. The resulting pale-
1
yellow liquid was analyzed by H NMR spectroscopy (which
showed 76% conversion), prior to desilylation as follows: to
a solution of the crude silyloxychlorohydrin in THF (5mL)
was added a premixed solution of TBAF (1M in THF,
0.9 mL, 0.90 mmol, 1.2 equivs.) and AcOH (0.1 mL). After
15min, the reaction was poured onto saturated aqueous
NaHCO3 solution (10 mL). The organic layer was separated,
and the aqueous layer extracted with CH2Cl2 (4”25mL).
The combined organic extracts were dried (Na2SO4), fil-
tered, and evaporated under reduced pressure. The resulting
pale-yellow liquid was purified by silica gel chromatography
(hexane/Et2O, 9/1) to afford (S,S)-2-chloro-1,2-diphenyl-1-
ethanol; yield: 0.148 g (64%). Spectroscopic data matched
those from the literature.[34]
General Procedure for Ring-Opening of cis-Stilbene
Oxide with Chlorosilanes
To a cooled (À788C), stirred solution of cis-stilbene oxide
(2) (196 mg, 1.0 mmol) and promoter [either (R)-1 or
HMPA] (0.10 mmol, 0.10 equiv.) in CH2Cl2 (10.0 mL) was
added chlorosilane (1.1 mmol, 1.1 equivs.) dropwise over
1 min. After the addition was complete, the mixture was stir-
red at À788C (for time see Table 1) and then was quenched
by the rapid addition of propylene oxide (1.0 mL,
16.5mmol, 15equivs. with respect to chlorosilane). After
1 min, MeOH (222 mL, 5.5 mmol, 5 equivs. with respect to
chlorosilane) was added. After 30 min at À788C, the mix-
ture was poured into cold (08C), rapidly stirring saturated
aqueous KF/KH2PO4 solution (1/1, 20 mL), then was diluted
Representative Procedure for Loading Studies with
(R)-1
To a cooled (À788C), stirred solution of cis-stilbene oxide
(2) (392 mg, 2.0 mmol) and catalyst (R)-1 (44 mg, 0.1 mmol,
0.1 equiv.) in CH2Cl2 (20.0 mL) was added SiCl4 (250 mL,
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Scott E. Denmark et al.
2.2 mmol, 1.1 equivs.) dropwise over 1 min. After the addi- References
tion was complete, the mixture was stirred at À788C for
19 h and then was quenched by pouring into cold (08C),
rapidly stirring saturated aqueous KF/KH2PO4 solution (1/1,
30 mL), then was diluted with Et2O (50 mL), and was al-
lowed to stir for 15min. The organic layer was separated,
and the aqueous layer extracted with Et2O (3”25mL). The
combined organic extracts were washed with brine (25mL)
and the brine wash was back extracted with Et2O (15mL).
The combined organic extracts were dried (Na2SO4), fil-
tered, and evaporated under reduced pressure. The resulting
pale-yellow liquid was purified by silica gel chromatography
(hexane/Et2O, 86/14) to afford (+)-(S,S)-2-chloro-1,2-di-
phenyl-1-ethanol [(+)-(7)]; yield: 0.437 g (94%). Spectro-
scopic data matched those from the literature.[34] SFC: tR
(S,S)-7, 3.34 min (87.3%); tR (R,R)-7 3.88 min (12.7%)
(Chiralpak AS, 150 bar, 308C, 10% CH3OH in CO2,
2.5mLmin À1).
[1] a) R. W. Hoffmann, Angew. Chem. Int. Ed. 2003, 42,
1096; b) M. C. Willis, J. Chem. Soc., Perkin Trans. 1
1999, 1765; c) C. S. Poss, Acc. Chem. Res. 1994, 27, 9.
[2] A. Fischli, M. Klaus, H. Mayer, P. Schoenholzer, R.
Ruegg, Helv. Chim. Acta 1975, 58, 564.
[3] a) E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421;
b) E. N. Jacobsen, M. H. Wu, in: Comprehensive Asym-
metric Catalysis, (Eds.: E. N. Jacobsen, A. Pfaltz, H. Ya-
mamoto), Springer Verlag, Heidelberg, 1999, Vol. III,
Chapter 35.1.
[4] a) I. Erden, in: Comprehensive Heterocyclic Chemistry,
2nd edn, (Ed.: A. Padwa), Pergamon Press, Oxford,
1996, Vol. 1 A, Chapt. 1.03; b) M. Bartok, K. L. Lang,
in: The Chemistry of Heterocyclic Compounds, (Eds.:
A. Weissberger, T. C. Taylor), Wiley, New York, 1985,
Vol. 42, Part 3, p 1; c) A. S. Rao, S. K. Paknikar, J. G.
Kirtane, Tetrahedron 1983, 39, 2323.
[5] a) R. A. Johnson, K. B. Sharpless, in: Comprehensive
Organic Synthesis, Vol. 7, Oxidation, (Ed.: S. V. Ley),
Pergamon Press, Oxford, 1991, Chapt. 3.2; b) R. A.
Johnson, K. B. Sharpless, in: Catalytic Asymmetric Syn-
thesis, (Ed.: I. Ojima), VCH, Weinheim, 1993, Chapt.
4.1; c) E. N. Jacobsen, in: Catalytic Asymmetric Synthe-
sis, (Ed.: I. Ojima), VCH, Weinheim, 1993, Chapt. 4.2.
[6] For leading references of enantioselective ring opening
of epoxides, see: a) L. E. Martinez, J. L. Leighton,
D. H. Carsten, E. N. Jacobsen, J. Am. Chem. Soc. 1995,
117, 5897; b) D. M. Hodgson, A. R. Gibbs, G. P. Lee,
Tetrahedron 1996, 52, 14361; c) T. Iida, N. Yamamoto,
H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1997. 119,
4783; d) T. Iida, N. Yamamoto, S. Matsunaga, H.-G.
Woo, M. Shibasaki, Angew. Chem. Int. Ed. 1998, 37,
2223; e) S. Matsunaga, J. Das, J. Roels, E. M. Vogl, N.
Yamamoto, T. Iida, K. Yamaguchi, M. Shibasaki, J.
Am. Chem. Soc. 2000, 122, 2252, and references cited
therein.
Representative Procedure for Non-Linear Effect
Studies with Promoter 1
A mixture of promoter (R)-1 (35.3 mg) and (S)-1 (8.9 mg)
[total of 44.2 mg (to make 60% ee), 0.1 mmol, 0.1 equiv.]
were added to a Schlenk flask, followed by cis-stilbene
oxide (2) (196 mg, 1.0 mmol). To this was added CH2Cl2
(10.0 mL), and then a 50 mL aliquot was removed via a gas-
tight syringe (SFC analysis of 1 shows 60.8% ee R). The stir-
red solution was cooled to À788C before the addition of
SiCl4 (125 mL, 1.1 mmol, 1.1 equivs.) dropwise over 1 min.
After the addition was completed, the mixture was stirred at
À788C for 3.25h and then was quenched by pouring into
cold (08C), rapidly stirring, saturated aqueous KF/KH2PO4
solution (1/1, 20 mL), diluted with Et2O (30 mL), and al-
lowed to stir for 10 min. The organic layer was separated,
and the aqueous layer extracted with Et2O (3”25mL). The
combined organic extracts were washed with brine (15mL)
and the brine wash was back extracted with Et2O (15mL).
The combined organic extracts were dried (Na2SO4), fil-
tered, and evaporated under reduced pressure. The resulting
pale-yellow liquid was purified by silica gel chromatography
(hexane/Et2O, 9/1) to afford (+)-(S,S)-2-chloro-1,2-diphenyl-
1-ethanol [(+)-7]; yield: 0.217 g (93%). SFC: tR (R)-1,
2.59 min (80.4%); tR (S)-1, 3.48 min (19.6%) (Chiralpak
AD, 150 bar, 308C, 25% CH3OH in CO2, 3.5mLmin À1).
SFC: tR (S,S)-7, 3.34 min (87.3%); tR (R,R)-7, 3.88 min
(12.7%) (Chiralpak AS, 150 bar, 308C, 10% CH3OH in
CO2, 2.5mLmin À1).
[7] a) H. Yamashita, Chem. Lett. 1987, 525; b) H. Yamashi-
ta, T. Mukaiyama, Chem. Lett. 1985, 1643.
[8] M. Emzaine, K. I. Sutowardoyo, D. Sinou, J. Organo-
met. Chem. 1988, 346, C7.
[9] W. A. Nugent, J. Am. Chem. Soc. 1992, 114, 2768.
[10] For a lanthanide-catalyzed addition of anilines to meso
epoxides see: F. CarrØe, R. Gil, J. Collin, Org. Lett.
2005, 7, 1023–1026.
[11] J. F. Larrow, E. N. Jacobsen, Top. Organomet. Chem.
2004, 6, 123.
[12] a) S. E. Schaus, J. F. Larrow, E. N. Jacobsen, J. Org.
Chem. 1997, 62, 4197; b) M. H. Wu, E. N. Jacobsen, Tet-
rahedron Lett. 1997, 38, 1693; c) L. E. Martinez, W. A.
Nugent, E. N. Jacobsen, J. Org. Chem. 1996, 61, 7963;
d) J. L. Leighton, E. N. Jacobsen, J. Org. Chem. 1996,
61, 389; e) L. E. Martinez, J. L. Leighton, D. H.
Carsten, E. N. Jacobsen, J. Am. Chem. Soc. 1995, 117,
5897.
Acknowledgements
We are grateful to the National Science Foundation for gener-
ous financial support (CHE 0105205 and 0414440). G.L.B.
thanks Boehringer Ingelheim Pharmaceuticals, Inc., and the
Johnson and Johnson Pharmaceutical Research Institute for
graduate fellowships.
[13] D. J. Kassab, B. Ganem, J. Org. Chem. 1999, 64, 1782.
[14] a) L. P. C. Nielsen, C. P. Stevenson, D. G. Blackmond,
E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 1360;
b) K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J. Am.
Chem. Soc. 1996, 118, 10924.
580
www.asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 567 – 582

DEDICATED CLUSTER
FULL PAPERS
Enantioselective Ring Opening of Epoxides with Silicon Tetrachloride
[15] a) J. M. Ready, E. N. Jacobsen, J. Am. Chem. Soc. 2001,
123, 2687; b) R. Breinbauer, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2000, 39, 3604.
Denmark, S. Fujimori, in: Modern Aldol Reactions,
(Ed.: R. Mahrwald), Wiley-VCH, Weinheim, 2004, Vol.
2. Chap. 7.
[16] a) G. Haufe, S. Bruns, Adv. Synth. Catal. 2002, 344, 165;
b) G. Haufe, S. Bruns, M. Runge, J. Flourine Chem.
2001, 112, 55; c) S. Bruns, G. Haufe, J. Fluorine Chem.
2000, 104, 247; d) S. Bruns, G. Haufe, Tetrahedron:
Asymmetry 1999, 10, 1563.
[32] G. C. Andrews, T. C. Crawford, L. G. Contillo, Tetrahe-
dron Lett. 1981, 22, 3803.
[33] Silicon tetrafluoride has been used together with Hꢂnig
base to open epoxides: M. Shimizu, H. Yoshioka Tetra-
hedron Lett. 1988, 29, 4101.
[17] a) J. Wu, X.-L. Hou, L.-X. Dai, L.-J. Xia, M.-H. Tang,
Tetrahedron: Asymmetry 1998, 9, 3431; b) M. H. Wu,
E. N. Jacobsen, J. Org. Chem. 1998, 63, 5252.
[34] S. E. Denmark, P. A. Barsanti, K.-T. Wong, R. A.
Stavenger, J. Org. Chem. 1998, 63, 2428; for a correc-
tion of several erroneous reports in the literature, see;
S. E. Denmark, T. Wynn, B. Jellerichs, Angew. Chem.
Int. Ed. 2001, 40, 2255.
[35] a) G. E. Garrett, G. C. Fu, J. Org. Chem. 1997, 62,
4534; b) B. Tao, M.-C. Lo, G. Fu, J. Am. Chem. Soc.
2001, 123, 353–354.
[18] E. N. Jacobsen, F. Kakiuchi, R. G. Konsler, J. F. Larrow,
M. Tokunaga, Tetrahedron Lett. 1997, 38, 773.
[19] The utility of this transformation, however, pales in
comparison to the impact of the hydrolytic kinetic reso-
lution of racemic epoxides which uses the cobalt salen
catalyst or oligomeric/polymeric versions thereof in
conjunction with water; a) M. Tokunaga, J. F. Larrow,
F. Kakiuchi, E. N. Jacobsen, Science 1997, 277, 936;
b) J. M. Keith, J. F. Larrow, E. N. Jacobsen, Adv. Synth.
Cat. 2001, 343, 5–26; c) S. E. Schaus, B. D. Brandes,
J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould,
M. Furrow, E. N. Jacobsen, J. Am. Chem. Soc. 2002,
124, 1307.
[20] a) M. Mizuno, M. Kanai, A. Iida, K. Tomioka, Tetrahe-
dron: Asymmetry 1996, 7, 2483; b) M. Mizuno, M.
Kanai, A. Iida, K. Tomioka, Tetrahedron 1997, 53,
10699.
[21] P. Crotti, V. Di Bussolo, L. Favero, F. Macchia, M.
Pineschi, Gazz. Chim. Ital. 1997, 127, 273.
[36] M. Nakajima, M. Saito, M. Uemura, S. Hashimoto, Tet-
rahedron Lett. 2002, 43, 8827.
[37] S. H. Paek, S. C. Shim, C. S. Cho, T.-J. Kim, Synlett
2003, 849.
[38] E. Tokuoka, S. Kotani, H. Matsunaga, T. Ishizuka, S.
Hashimoto, M. Nakajima, Tetrahedron: Asymmetry
2005, 16, 2391.
[39] Background reactions were performed with freshly dis-
tilled chlorosilanes and only when<5% conversion
was detected at room temperature was the chlorosilane
used for catalyzed reactions.
[40] a) S. E. Denmark, S. M. Pham, Helv. Chim. Acta 2000,
83, 1846–1853; b) S. E. Denmark, S. M. Pham, R. A.
Stavenger, X. Su, K.-T. Wong, Y. Nishigaichi, J. Org.
Chem. 2006, 71, 3904.
[41] Unfortunately, all attempts to study the kinetic behav-
ior of the epoxide opening reaction of 2 in the presence
of the chiral catalyst (R)-1 were thwarted by irreprodu-
cibility, most likely from the extreme water sensitivity
of the reaction.
[42] R. Schmid, V. N. Sapunov, Non-Formal Kinetics; Verlag
Chemie, Weinheim, 1982.
[43] a) J. D. Kennedy, W. McFarlane, in: Multinuclear NMR,
(Ed.: J. Mason), Plenum Press, New York, 1987, Chap.
11; b) L. Olsson, C. H. Ottosson, D. Cremer, J. Am.
Chem. Soc. 1995, 117, 7460.
[22] N. Oguni, Y. Miyagi, K. Itoh, Tetrahedron Lett. 1998,
39, 9023.
[23] a) K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W.
Kuntz, M. L. Snapper, A. H. Hoveyda, Angew. Chem.
Int. Ed. Engl. 1997, 36, 1704–1707; b) B. M. Cole, K. D.
Shimizu, C. A. Krueger, J. P. A. Harrity, M. L. Snapper,
A. H. Hoveyda, Angew. Chem. Int. Ed. Engl. 1996, 35,
1668; c) M. Hayashi, M. Tamura, N. Oguni, Synlett
1992, 663.
[24] S. E. Schaus, E. N. Jacobsen, Org. Lett. 2000, 2, 1001.
[25] C. Bonini, G. Righi, Synthesis 1994, 225.
[26] For reviews see; a) R. E. Moore, in: Marine Natural
Products, (Ed.: P. J. Scheuer), Academic Press, New
York, 1978, Vol. 1, Chap. 2; b) W. Fenical, in: Marine
Natural Products, (Ed.: P. J. Scheuer), Academic Press,
New York, 1980, Vol. 2, 174; c) D. J. Faulkner, Nat.
Prod. Rep. 1984, 251; d) D. J. Faulkner, Nat. Prod. Rep.
1986, 1.
[27] A. D. Cross, Quart. Rev. Chem. Soc. 1960, 14, 317.
[28] a) N. N. Joshi, M. Srebnik, H. C. Brown, J. Am. Chem.
Soc. 1988, 110, 6246; b) Y. Naruse, T. Esaki, H.
Yamamoto, Tetrahedron 1988, 44, 4747.
[29] a) M. Marigo, S. Bachmann, N. Halland, A. Braunton,
K. A. Jørgensen, Angew. Chem. Int. Ed. 2004, 43, 5507;
b) S. Bertelsen, N. Halland, S. Bachmann, M. Marigo,
A. Braunton, K. A. Jørgensen, Chem. Commun. 2005,
4821.
[30] B. W. McCleland, W. A. Nugent, M. G. Finn, J. Org.
Chem. 1998, 63, 665 6.
[44] S. Kobayashi, K. Nishio, Tetrahedron Lett. 1993, 34,
3453.
[45] H. H. Karsch, T. Segmueller, in: Organosilicon Chemis-
try V. From Molecules to Materials, (Ed.: N. Auner, J.
Weis), Wiley-VCH, Weinheim, 2003, p 270.
[46] a) M. Arshadi, D. Johnels, U. Edlund, C.-H. Ottoson,
D. Cremer, J. Am. Chem. Soc. 1996, 118, 5 120; b) A. R.
Bassindale, J. Jiang, J. Organomet. Chem. 1993, 446,
C3.
[47] H. Marsmann, in: NMR Basic Principles and Progress,
Vol. 17, (Eds: P. Diehl, E. Fluck, R. Kosfeld), Springer
Verlag, Berlin, 1981, p 65.
[48] a) D. R. Fenwick, H. B. Kagan, Top. Stereochem. 1999,
22, 257; b) C. Girard, H. B. Kagan, Angew. Chem. Int.
Ed. Engl. 1998, 37, 2922; c) M. Avalos, R. Babiano, P.
Cintas, J. L. Jimenez, J. C. Palacios, Tetrahedron: Asym-
metry 1997, 8, 2997.
[31] For a thorough analysis of this concept, see: a) S. E.
Denmark, G. L. Beutner, T. Wynn, M. D. Eastgate, J.
Am. Chem. Soc. 2005, 127, 3774–3789; b) S. E.
[49] For discussion of non-linear effects, the use of enantio-
meric excess (ee) is preferred. For a discussion of the
relative merits of er vs. ee, see: a) H. B. Kagan, Recl.
Adv. Synth. Catal. 2007, 349, 567 – 582
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
581

DEDICATED CLUSTER
FULL PAPERS
Scott E. Denmark et al.
Trav. Chem. Pays-Bas 1995, 114, 203; b) V. Schurig, En-
antiomer 1996, 1, 139; c) R. E. Gawley, J. Org. Chem.
2006, 71, 2411.
[51] This hypothesis finds analogy in the dual role played
by the chromium-salen complexes in Jacobsenꢀs epox-
ide ring opening reactions, Ref.[15]
[52] S. E. Denmark, X. Su, Y. Nishigaichi, K.-T. Wong,
D. M. Coe, S. B. D. Winter, J. Y. Choi, J. Org. Chem.
1999, 64, 1958.
[50] For spectroscopic evidence for such a silicate species
see Refs.[31a,][40]
582
www.asc.wiley-vch.de
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 567 – 582