Enantioselective synthesis of α-phenyl- and α-(dimethylphenylsilyl)alkylboronic esters by ligand mediated stereoinductive reagent-controlled homologation using configurationally labile carbenoids

Article abstract of DOI:10.1039/c5ob00159e

Chain extension of boronic esters by the action of configurationally labile racemic lithium carbenoids in the presence of scalemic bisoxazoline ligands was explored for the enantioselective synthesis of the two title product classes. Enantioenriched 2° carbinols generated by oxidative work-up (NaOOH) of initial α-phenylalkylboronate products were obtained in 35-83% yield and 70-96% ee by reaction of B-alkyl and B-aryl neopentyl glycol boronates with a combination of O-(α-lithiobenzyl)-N,N-diisopropylcarbamate and ligand 3,3-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl] pentane in toluene solvent (-78 °C to rt) with MgBr₂·OEt₂ additive. Enantioenriched α-(dimethylsilylphenylsilyl)alkylboronates were obtained in 35-69% yield and 9-57% ee by reaction of B-alkyl pinacol boronates with a combination of lithio(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate and ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl]propane in cumene solvent (-45 °C to -95 °C to rt). The stereochemical outcome of the second type of reaction depended on the temperature history of the organolithium·ligand complex indicating that the stereoinduction mechanism in this case involves some aspect of dynamic thermodynamic resolution. This journal is

Full text of DOI:10.1039/c5ob00159e

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Enantioselective synthesis of α-phenyl- and
α-(dimethylphenylsilyl)alkylboronic esters by
ligand mediated stereoinductive reagent-
controlled homologation using configurationally
labile carbenoids†
Cite this: Org. Biomol. Chem., 2015,
13, 3781
Adam L. Barsamian, Zhenhua Wu and Paul R. Blakemore*
Chain extension of boronic esters by the action of configurationally labile racemic lithium carbenoids in
the presence of scalemic bisoxazoline ligands was explored for the enantioselective synthesis of the two
title product classes. Enantioenriched 2° carbinols generated by oxidative work-up (NaOOH) of initial
α-phenylalkylboronate products were obtained in 35–83% yield and 70–96% ee by reaction of B-alkyl
and B-aryl neopentyl glycol boronates with a combination of O-(α-lithiobenzyl)-N,N-diisopropylcarba-
mate and ligand 3,3-bis[(4S)-4,5-dihydro-4-isopropyloxazol-2-yl] pentane in toluene solvent (−78 °C to
rt) with MgBr2·OEt2 additive. Enantioenriched α-(dimethylsilylphenylsilyl)alkylboronates were obtained in
35–69% yield and 9–57% ee by reaction of B-alkyl pinacol boronates with a combination of lithio
(dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate and ligand 2,2-bis[(4S)-4,5-dihydro-4-isopropyl-
oxazol-2-yl]propane in cumene solvent (−45 °C to −95 °C to rt). The stereochemical outcome of the
second type of reaction depended on the temperature history of the organolithium·ligand complex indi-
cating that the stereoinduction mechanism in this case involves some aspect of dynamic thermodynamic
resolution.
Received 27th January 2015,
Accepted 12th February 2015
DOI: 10.1039/c5ob00159e
www.rsc.org/obc
form and which exhibit configurational stability on the time-
scale of ate-complex formation. Carbenoids that have been suc-
Introduction
The asymmetric chain extension of boronic esters provides a cessfully used in StReCH include α-chloroalkyllithiums (gener-
versatile and systematic approach to organic synthesis that ated by sulfoxide-lithium exchange),5 and lithiated carbamates
complements more traditional methods for carbon–carbon (typically generated by kinetic enantioselective lithiation),6
bond formation.1 Among the strategies that are conceivable for among others.7
the stereoselective homologation of boronates,2 only two have
To broaden the scope of asymmetric chain extension, and
risen to prominence: the stereoinductive substrate-controlled taking our inspiration from the seminal work of Beak,8
process of Matteson et al.3 and stereospecific reagent- Hoppe,9 and Toru,10 a subtle but significant variation on the
controlled homologation (StReCH).4 The first process leads to ‘lithiation/borylation’ StReCH strategy of Aggarwal and co-
stereoregular arrays upon direct iteration while StReCH offers workers6h was envisioned involving chiral ligand mediated
true stereochemical programming because the chain elongated dynamic kinetic (or thermodynamic) resolution of a configura-
adduct (4) arises via rearrangement of an intermediate ate- tionally labile racemic carbenoid 5 (Fig. 1). In this type of
complex (3) formed by stereospecific trapping of a stereo- stereoinductive reagent-controlled homologation (i-StReCH)
defined carbenoid reagent (2) by a boronate substrate (1) (Fig. 1). process, substituents R1 may be introduced that would be pro-
StReCH is a powerful technique but limited in scope to those hibited in normal StReCH due to configurational instability
carbenoid species that can be accessed in an enantioenriched issues; furthermore, since carbenoid generation is decoupled
from the stereodetermining event, various lithiation tactics
will be compatible with the technique (e.g., deprotonation,
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331, USA.
metal exchange phenomena, reductive lithiation etc.). Here we
report successful realization of ligand mediated i-StReCH
using two types of configurationally labile carbenoid, one a
benzyllithium and the other an α-silylmethyllithium, and so
achieve the enantioselective synthesis of α-phenyl- and
E-mail: paul.blakemore@science.oregonstate.edu
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra for all compounds;
CSP HPLC chromatograms for %ee determinations. See DOI: 10.1039/
c5ob00159e
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Table 1 Exploration of bisoxazoline (8) mediated stereoinductive
reagent-controlled homologation of phenethylboronates 9 using four
types of benzylic lithium carbenoids 7 (X = SPh, S-2Py, OCb, OTIB)
Entry
X
R1/R2
B(OR)2 T (°C) Add.
Yield (%) %ee
1a
2b
3
4
5
SPh
i-Pr/Me Bpin
−78
−78
−78
−78
−40
−40
−78
−78
−78
−78
HgCl2
HgCl2
None
None
None
None
None
None
0
0
na
na
15
45
39
−17
33
74
83
S-2Py i-Pr/Me Bpin
OCb
OCb
OCb
OCb
i-Pr/Me Bpin
44
43
67
68
74
54
Fig. 1 Stereospecific reagent-controlled homologation (StReCH) of a
boronic ester 1 requires a stereodefined, configurationally stable carbe-
noid 2 while ligand mediated stereoinductive reagent-controlled homo-
logation (i-StReCH) relies on dynamic kinetic resolution (DKR, as
illustrated above) or dynamic thermodynamic resolution (DTR, not illus-
trated above) of a configurationally labile racemic carbenoid 5 in the
presence of a chiral ligand (L*); M = electrofugal substituent, X = nucleo-
fugal substituent.
i-Pr/Et
i-Pr/Et
Bpin
Bpin
6
t-Bu/Et Bpin
7a
8
OTIB i-Pr/Et
Bpin
Bneo
Bneo
Bneo
OCb
OCb
OCb
i-Pr/Et
i-Pr/Et
i-Pr/Et
d
9
MgBr2d 61
10c
MgBr2 66
81
a Lithiation conducted with t-BuLi. b Lithiation conducted with n-BuLi.
c Et2O as solvent (reaction conditions duplicated from Crudden
et al.12). d MgBr2·OEt2 (3 eq.) in Et2O. 2Py = 2-pyridyl; Cb = i-Pr2NC
(vO); TIB = 2,4,6-i-Pr3C6H2C(vO); Bpin = B[O(CMe2)2O]; Bneo =
B[OCH2CMe2CH2O].
α-(dimethylphenylsilyl)alkylboronates.11 During the course of
our studies, Crudden and coworkers disclosed essentially
identical independent results for the same benzylic carbenoid
as applied to the i-StReCH of arylboronates (2014)12 and, in an
isolated example, a vinylboronate (late 2013).13
with CD3OD), they proved incapable of chain extending
BnCH2Bpin either by thermolysis of the putative ate-complex
or (as illustrated) by activation with a thiophile (entries 1
and 2). The difficulty of homologating boronic esters with
α-(thioaryl)alkyllithiums has been previously documented,14
although it is interesting to note that such reactions can be
successfully accomplished with α-alkoxy-α-(thioaryl)-alkyl-
Results and discussion
Studies with benzyllithium based carbenoids: enantioselective
synthesis of α-phenylalkylboronates
Racemization of benzylic organolithiums 5 (R1 = aryl, M = Li, lithiums (e.g., PhSCH(Li)OMe).14b,15 Carbenoids 7 bearing
X = heteroatom) is generally facile9 making these species ideal carboxylate-type nucleofuges (X = OCb, OTIB) were studied
candidates for the exploration of i-StReCH. Of note, Toru et al. next (entries 3–10). Given the widespread use of lithiated car-
reported highly enantioselective trapping of configurationally bamates6 and TIB esters7d,e in conventional StReCH reactions,
labile α-phenyl-α-(thioaryl)methyllithiums with simple probe the fact that chain extension occurred with these benzyl-
electrophiles in the presence of scalemic bisoxazoline ligands lithiums was not at all surprising; however, it was gratifying to
(in PhMe or cumene, ≤−50 °C),10 while Hoppe et al. achieved realize meaningful enantioselectivity via i-StReCH upon evalu-
comparable results by applying similar reaction conditions to ation of only a handful of standard bisoxazolines 8. The ligand
the lithiate of O-benzyl N,N-diisopropyl carbamate.9 On the previously identified as optimal for asymmetric trapping of 7
basis of this precedent, enantioselective synthesis of an α-phe- (X = OCb) with electrophiles by Hoppe and coworkers (8, R1/R2
nylalkylboronate from B-phenethylboronates
9
via chiral = i-Pr/Et),9a proved to be superior (cf. entries 3, 4, and 6). The
ligand mediated i-StReCH was evaluated using benzylic carbe- sense of stereoinduction was curiously dependent on the steric
noids generated from four potentially suitable precursors 6 demand of the R1 bisoxazoline substituent (entries 5 vs. 6),
(X = SPh, S-2-Py, OCb, and OTIB) under Toru/Hoppe reaction and the lithiated carbamate 7 (X = OCb) offered higher
conditions (Table 1). The chain extended adduct was isolated enantioselectivity than the lithiated ester 7 (X = OTIB) (entries
as its carbinol derivative 10 following oxidative work-up with 4 vs. 7). A significant boost in %ee was realized by using a neo-
aq. NaOOH.
pentyl glycol boronic ester starting material (BnCH2Bneo) in
Carbenoids 7 possessing thiolate nucleofuges (X = SPh, place of the less reactive pinacol boronate employed earlier,
S-2Py) were evaluated first; however, although these benzyl- and an additional gain in efficacy was obtained by using a
lithiums could be generated efficiently from precursors 6 Lewis acid additive (MgBr2·OEt2) to promote ate-complex
using either t-BuLi or n-BuLi (as established by quenching 7 rearrangement (cf. entries 4, 8, and 9). We have previously
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taken advantage of both of these last two variable changes to Studies with α-silylmethyllithium based carbenoids:
optimize conventional StReCH reactions,5a and in their inde- enantioselective synthesis of α-silylalkylboronates
pendent efforts, Crudden et al. likewise found that employ-
In common with most benzyllithiums, α-silylmethyllithiums 5
ment of neopentyl glycol boronates is essential for the
(R1 = SiR3, M = Li, X = OCb/O2CR) are configurationally labile
obtainment of high ee when using benzylic carbenoid 7 (X =
and so their use in conventional StReCH is precluded. For
example, Aggarwal et al. observed the formation of a racemic
chain-extended boronate when the carbenoid generated by
OCb).12,13 Direct comparison of the near identical Crudden
protocol (conducted in Et2O solvent and also using MgBr2)12 to
our own (in PhMe solvent) revealed no significant difference
enantioselective lithiation of TMSCH2OCb with (−)-sparteine/
for the homologation of a B-phenethyl substrate (entries 9
s-BuLi was used as an homologation agent (at −78 °C).16
vs. 10).
A related silylmethyllithium (PhMe2SiCHLiO2CTr) was found
To evaluate scope, the optimized i-StReCH protocol (as in
Table 1, entry 9) was applied to a range of B-alkyl and B-aryl
neopentyl glycol boronic esters and the homologated adducts
were isolated as their carbinol derivatives following work-up
to rapidly enantiomerize at −95 °C.17 Given that low configura-
tional stability is desired in ligand mediated i-StReCH, and
considering that the direct introduction of heteroatom-bearing
stereogenic centers via reagent-controlled homologation is a
with aq. NaOOH (Fig. 2). Moderate yields of the expected alkyl/
largely unsolved problem,15,18 we elected to investigate boronic
aryl 2° alcohols 11–14 were obtained from B-alkyl boronates
ester chain extension using the organolithium derived from
possessing varying degrees of chain branching. Good enantio-
selectivity was observed throughout and both 1° and 2° B-alkyl
boronates were successfully chain extended. Pleasingly, when
( )-s-BuBneo was used as substrate, the product (14) was
obtained in low dr but with at least the usual level of ee for
each diastereoisomer (N.B., a dr of 50 : 50 is the desired
outcome from this experiment). This result is noteworthy
because it reveals that preexisting stereochemistry in the sub-
silylmethyl benzoate 19 (Table 2). Ester 19 was obtained from
methyl 2,4,6-triisopropylbenzoate (MeOTIB) by lithiation19
followed by silylation (see ESI†).
Evaluated reaction conditions paralleled those pioneered by
Toru et al. for their work with lithiated benzylic thioethers,10
and we found that carbenoid 20 (generated in racemic form
from 19 by addition of t-BuLi at −78 °C) combined with ligand
8 (R1/R2 = i-Pr/Me) in cumene solvent gave the best results for
strate (albeit for a stereocenter bearing geminal Me & Et
the enantioselective generation of α-silylalkylboronate 21 from
groups) did not influence stereoselectivity; i.e., reagent-control
B-phenethyl boronic ester precursors 9. An alternate BOX
dominated and matching/mismatching effects are potentially
ligand 8 with R1 = Ph decomposed in the presence of s-BuLi
of limited importance. The synthesis of diaryl 2° carbinols
(presumably via a ring-opening β-elimination pathway), while
15–18 from B-aryl boronates was consistent with the recently
a bulky ligand 8 with R1 = t-Bu gave the product 21 in superior
published findings of Crudden et al.12 Gentle heating was
yield but with low enantiomeric purity (entries 1 and 2 vs.
required to obtain a reasonable yield of carbinol 16 from the
corresponding boronic ester possessing an electron deficient
Table 2 Exploration of bisoxazoline (8) mediated stereoinductive
3,5-bis(trifluoromethyl)phenyl substituent.
reagent-controlled homologation of phenethylboronates
9
using
α-lithio (dimethylphenylsilyl)methyl 2,4,6-triisopropylbenzoate 20
Entry
R1/R2
B(OR)2
T1 (°C)
T2 (°C)
Yield (%)
%eea
1b
2
3
4
5
6
7
8
9
Ph/Me
t-Bu/Me
i-Pr/Me
i-Pr/Me
i-Pr/Me
i-Pr/Me
i-Pr/Et
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bneo
Bneo
−78
−78
−78
−95
−45
−45
−45
−45
−45
−78
−78
−78
−95
−45
−95
−95
−95
−95
0
92
78
75
68
69
66
58
13
na
14
21
41
23
57
−47
54
Fig. 2 Enantioenriched 2° alcohols RPhCHOH obtained by BOX ligand
mediated i-StReCH of boronates RBneo by 7 (X = OCb) using reaction
conditions as in Table 1, entry 9. Chain extended adducts RCHPhBneo
were oxidized to the illustrated carbinols 11–18 with aq. NaOOH prior to
isolation and yield/%ee determination. Where indicated, absolute
configuration determined by correlation to literature data. a Reaction
mixture heated to 40 °C for 16 h following addition of MgBr2·OEt2.
i-Pr/Me
i-Pr/Et
−42
a %ee determined by CSP-HPLC analysis of the carbinol generated by
aq. NaOOH oxidation of the boronate. b s-BuLi added to mixture of
ester 19 and ligand 8. TIB = 2,4,6-i-Pr3C6H2C(vO); Bpin = B[O-
(CMe2)2O]; Bneo = B[OCH2CMe2CH2O].
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entry 3). The effect of varying the temperature profile of the bearing on stereochemical outcome since the diastereomers of
reaction was investigated using the initial ligand of choice 24 were not generated in equal quantity (cf. 14 above).
(entries 3–6). The operation of a purely DKR mechanism is
revealed if product ee is independent of conversion and depen-
dent on the temperature at which the electrophile is intro-
Conclusions
duced (T2) but not on the temperature history profile of the
organolithium–ligand complex 20·8.8b Sensitivity of product ee In summary, it has been established that the enantioselective
to conversion and to the temperature history profile (−78 °C to chain extension of various types of boronic esters can be
T1 to T2) of complex 20·8 indicates that DTR factors into the effected with configurationally labile carbenoid species by
stereodetermining mechanism.8b,10 In the event, for four reac- employing the principle of ligand mediated stereoinductive
tions at comparable conversion, it was found that isothermal reagent-controlled homologation (i-StReCH). This technique is
incubation of 20·8 at −95 °C (following its generation at potentially very versatile because it obviates the more stringent
−78 °C) prior to the introduction of the boronate electrophile demands of conventional StReCH which requires both a con-
gave a higher level of product ee than related reactions held at figurationally stable carbenoid and a means to access it in an
either −78 °C or −45 °C (entry 4 vs. entries 3 and 5); however, highly enantioenriched form. The method was successfully
initial warming of 20·8 to −45 °C and an aging period of demonstrated for the synthesis of α-phenylalkylboronates and
30 minutes before cooling to −95 °C and then addition of the α-silylalkylboronates but the generation of other types of pro-
electrophile gave a better result still (entry 6). Taken in sum, ducts previously inaccessible via reagent-controlled homologa-
these data indicate that the origin of enantioselectivity cannot tion is readily envisioned. Installation of heteroatom-bearing
be solely DKR, nor solely a simple resolution, but that stereocenters is of particular value and in this regard the
dynamic thermodynamic equilibration of diastereomeric organo- ability to control the configuration of a dimethylphenylsilyl
lithium–ligand complexes factors into the process in combi- substituted carbon atom within a growing chain is significant
nation with kinetic effects influencing stereodetermination at because this silane moiety is a surrogate for an oxygen atom
the point of electrophile addition. Applying the optimal temp- via the Fleming oxidation.20 Efforts to improve on the
erature history profile to the gem diethyl BOX ligand 8 (R1/R2 = efficiency of ligand mediated i-StReCH and to widen its scope
i-Pr/Et) gave an inferior result to 8 (R1/R2 = i-Pr/Me), but inter- to encompass carbenoids bearing yet other types of useful sub-
estingly the more elaborate ligand favored the opposite enan- stituents, including further heteroatoms, are in progress and
tiomer of 21 (entry 6 vs. entry 7). Evaluation of a neopentyl will be reported in due course.
glycol boronic ester substrate likewise did not result in a better
outcome, but again gem dimethyl and gem diethyl type BOX
ligands each favored a different major enantiomer of the
chain-extension product (entry 8 vs. entry 9). The potential
Experimental section
scope of the α-silylalkylboronate synthesis was briefly exam- All reactions requiring anhydrous/anaerobic conditions were
ined by application of the optimized reaction conditions to conducted in flame-dried glassware under an atmosphere of
three additional boronic ester substrates (Fig. 3). An attempt to Ar gas. Anhydrous THF and toluene were dispensed from a
prepare α-silylboronate 22 from B-phenyl pinacol boronate commercially available solvent purification system employing
failed but chain extension of two 2° alkyl pinacol boronates activated Al2O3 drying columns.21 Anhydrous cumene (i-PrPh)
was successful, albeit with modest efficiency. Thus, B-cyclo- was obtained by distillation from CaH2 under Ar. Preparative
hexyl pinacol boronate afforded the sterically congested homo- chromatographic separations were performed on silica gel 60
logation adduct 23 in 35% yield and 9% ee, while racemic (35–75 μm) and reactions followed by TLC analysis using silica
B-sec-butyl pinacol boronate gave as expected a pair of diaster- gel 60 plates (2–25 μm) with fluorescent indicator (254 nm)
eomeric products 24 each in enantioenriched form. In this and visualized with UV or phosphomolybdic acid. Commer-
case, the preexisting stereocenter within the substrate had a cially available reagents were used as received. Melting points
were determined from open capillary tubes on a melting point
apparatus and are uncorrected. Infra-red (IR) spectra were
recorded in Fourier transform mode using KBr disks for
solids, while oils were supported between NaCl plates (“neat”).
1H and 13C NMR spectra were recorded in Fourier transform
mode at the field strength specified and from the indicated
deuterated solvents in standard 5 mm diameter tubes. Chemi-
cal shift in ppm is quoted relative to residual solvent signals
calibrated as follows: CDCl3 δH (CHCl3) = 7.26 ppm, δC
=
Fig. 3 Enantioenriched
α-silylalkylboronates
R(Me2PhSi)CHBpin
1
77.2 ppm. Multiplicities in the H NMR spectra are described
as: s = singlet, d = doublet, t = triplet, q = quartet, m = multi-
plet, br = broad. Numbers in parentheses following carbon
atom chemical shifts refer to the number of attached hydrogen
obtained by BOX ligand mediated i-StReCH of boronates RBpin by 20
using reaction conditions as in Table 2, entry 6. %ee determined by
CSP-HPLC analysis of the derived carbinols generated by aq. NaOOH
oxidation of the illustrated boronates. Bpin = B[O(CMe2)2O].
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atoms as revealed by the DEPT spectral editing technique. Low cumene (0.40 mL) and the mixture incubated for 10 min at
(MS) and high resolution (HRMS) mass spectra were obtained −78 °C. After this time, the reaction vessel was transferred to
using either electron impact (EI) or electrospray (ES) ionization another cold bath held at −45 °C, stirred for 30 min, then
techniques. Ion mass/charge (m/z) ratios are reported as values transferred to a third cold bath held at −95 °C and stirred for
in atomic mass units.
an additional 10 min. A solution of B-phenethyl pinacol boro-
nate 9 (58.0 mg, 0.250 mmol) in anhydrous cumene (0.40 mL)
was then added dropwise during 3 min and the mixture
allowed to stir for a further 1 h at −95 °C before the cold bath
Representative procedure for ligand mediated i-StReCH to
α-phenylalkylboronates (Table 1, entry 9)
(−)-(S)-1,3-Diphenyl-propan-1-ol (10). A stirred solution of was removed and the vessel allowed to warm to rt during 24 h.
O-benzyl-N,N-diisopropylcarbamate (6, OCb, 26 mg, Sat. aq. NH4Cl (4.0 mL) was added and the mixture partitioned
X
=
0.110 mmol)22 and (S,S)-bisoxazoline ligand 8 (R1/R2 = i-Pr/Et, between EtOAc (15 mL) and H2O (6 mL). The layers were separ-
37 mg, 0.126 mmol)23 in anhydrous toluene (0.8 mL) at −78 °C ated and the aqueous phase was extracted with EtOAc (2 ×
under Ar was treated with s-BuLi (0.10 mL, 1.20 M in cyclo- 7 mL). The combined organic phases were washed with brine
hexane, 0.12 mmol). After stirring at −78 °C for 2.5 h, a solu- (2 mL), dried (Na2SO4), and concentrated in vacuo. The residue
tion of neopentyl glycol boronate 9 (22 mg, 0.101 mmol) in (396 mg) was purified by column chromatography (SiO2,
anhydrous toluene (0.2 mL) was added dropwise during 3 min. eluting with 0–5% Et2O in hexanes) to afford (S)-21 (65.8 mg,
The resulting mixture was stirred at −78 °C for 1 h and then a 0.173 mmol, 69%, 57% ee) as a colorless oil: [α]2D0 = −11.8 (c =
freshly prepared ethereal solution of MgBr2·OEt2 (0.30 mmol 1.00, CHCl3, at 57% ee) [lit.16 for (R)-21 [α]D20 = +24 (c = 1.0,
in ≤1.0 mL Et2O, see ESI† for details of preparation) was CHCl3 at %ee ≥94%]; IR (neat) 2977, 1353, 1308, 1249, 1145,
added dropwise during 3 min. The reaction mixture was 1112, 995, 847, 815 cm−1 1H NMR (400 MHz, CDCl3) δ
;
allowed to stir for a further 30 min at −78 °C, allowed to warm 7.52–7.48 (2H, m), 7.35–7.32 (3H, m), 7.28–7.25 (1H, m), 7.24
to rt during 3 h, and then stirred for 16 h at rt. After this time, (1H, dm, J = 7.5 Hz), 7.16 (1H, tt, J = 7.4, 2.2 Hz), 7.12 (2H, dm,
the reaction mixture was cooled to 0 °C and treated with 10 wt J = 6.9 Hz), 2.71 (1H, ddd, J = 13.8, 9.8, 4.9 Hz), 2.47 (1H, ddd,
% aq. NaOH (0.2 mL) followed by 30 wt% aq. H2O2 (0.08 mL). J = 13.4, 9.7, 6.8 Hz), 1.90 (1H, dddd, J = 13.6, 11.5, 9.8, 5.0),
The biphasic mixture was then allowed to warm to rt and 1.65 (1H, dddd, J = 13.0, 9.9, 6.9, 3.1 Hz), 1.24 (6H, s), 1.21
stirred vigorously for 2 h. EtOAc (5 mL) and H2O (3 mL) were (6H, s), 0.72 (1H, dd, J = 12.0, 3.0 Hz), 0.33 (3H, s), 0.31 (3H, s)
added and the layers shaken and separated. The aqueous ppm; 13C NMR (100 MHz, CDCl3) δ = 142.8 (0), 139.0 (0), 134.0
phase was extracted with EtOAc (3 × 5 mL) and the combined (2C, 1), 129.0 (1), 128.7 (2C, 1), 128.4 (2C, 1), 127.8 (2C, 1),
organic phases washed with brine (5 mL), dried (Na2SO4), and 125.8 (1), 83.0 (2C, 0), 39.6 (2), 28.2 (2), 25.4 (2C, 3), 24.9 (2C,
concentrated in vacuo. The residue was purified by column 3), 13.8 (1, br RCHBpin), −2.1 (3), −3.2 (3) ppm. 1H and 13C
chromatography (SiO2, eluting with 6–12% EtOAc in hexanes) NMR spectral data in agreement with those previously
to afford (S)-10 (13 mg, 0.061 mmol, 61%, 83% ee) as a color- reported by Aggarwal and coworkers.16 %ee determined by
less oil: [α]2D0 = −22.9 (c = 1.30, CHCl3, at 83% ee); IR (neat) chiral stationary phase HPLC analysis of the derived NaOOH
1
3370, 3027, 2924, 1603, 1495, 1454, 1059, 1029, 914 cm−1; H oxidation product (see ESI† for details).
NMR (400 MHz, CDCl3) δ 7.37–7.35 (4H, m), 7.31–7.26 (3H, m),
7.22–7.18 (3H, m), 4.70 (1H, t, J = 6.0 Hz), 2.77 (1H, ddd, J =
14.0, 9.8, 5.9 Hz), 2.68 (1H, ddd, J = 13.9, 9.3, 6.6 Hz),
Acknowledgements
2.20–1.99 (2H, m), 1.88 (1H, br s) ppm; 13C NMR (100 MHz,
CDCl3) δ = 144.7 (0), 142.0 (0), 128.7 (2C, 1), 128.62 (2C, 1), Financial support from the US National Science Foundation
128.57 (2C, 1), 127.8 (1), 126.1 (2C, 1), 126.0 (1), 74.1 (1), 40.6 (grant CHE-0906409) is gratefully acknowledged.
1
(2), 32.2 (2) ppm. H and 13C NMR spectral data in agreement
with those previously reported.24 %ee and absolute configur-
ation determined by chiral stationary phase HPLC analysis fol-
Notes and references
lowing the method previously described by Liu and coworkers
(see ESI† for details).24
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