Practical catalytic asymmetric synthesis of diaryl-, aryl heteroaryl-, and diheteroarylmethanols

Article abstract of DOI:10.1021/ja9046747

Enantioenriched diaryl-, aryl heteroaryl-, and diheteroarylmethanols exhibit important biological and medicinal properties. One-pot catalytic asymmetric syntheses of these compounds beginning from readily available aryl bromides are introduced. Thus, lith

Full text of DOI:10.1021/ja9046747

Published on Web 08/04/2009
Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl
Heteroaryl-, and Diheteroarylmethanols
Luca Salvi, Jeung Gon Kim, and Patrick J. Walsh*
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received June 8, 2009; E-mail: pwalsh@sas.upenn.edu
Abstract: Enantioenriched diaryl-, aryl heteroaryl-, and diheteroarylmethanols exhibit important biological
and medicinal properties. One-pot catalytic asymmetric syntheses of these compounds beginning from
readily available aryl bromides are introduced. Thus, lithium-bromide exchange with commercially available
aryl bromides and n-BuLi was followed by salt metathesis with ZnCl2 to generate ArZnCl. A second equivalent
of n-BuLi was added to form the mixed organozinc, ArZnBu. In the presence of enantioenriched amino
alcohol-based catalysts, ArZnBu adds to aldehydes to afford essentially racemic diarylmethanols. The low
enantioselectivities were attributed to a LiCl-promoted background reaction. To inhibit this background
reaction, the chelating diamine TEEDA (tetraethylethylene diamine) was introduced prior to aldehyde
addition. Under these conditions, enantioenriched diarylmethanols were obtained with >90% ee. Arylations
of enals generated allylic alcohols with 81-90% ee. This procedure was unsuccessful, however, when
applied to heteroaryl bromides, which was attributed to decomposition of the heteroaryl lithium under the
salt metathesis conditions. To avoid this problem, the metathesis was conducted with EtZnCl, which enabled
the salt metathesis to proceed at low temperatures. The resulting EtZn(ArHetero) intermediates (ArHetero ) 2-
and 3-thiophenyl, 2-benzothiophenyl, 3-furyl, and 5-indolyl) were successfully added to aldehydes and
heteroaryl aldehydes with enantioselectivities between 81-99%. These are the first examples of catalytic
and highly enantioselective syntheses of diheteroarylmethanols. In a similar fashion, ferrocenyl bromide
was used to generate FcZnEt and the ferrocenyl group added to benzaldehyde and heteroaromatic
aldehydes to form ferrocene-based ligand precursors in 86-95% yield with 96-98% ee. It was also found
that the arylation and heteroarylation of enals could be followed by diastereoselective epoxidations to provide
epoxy alcohols with high enantio- and diastereoselectivities in a one-pot procedure.
1. Introduction
Enantioenriched diaryl-, aryl heteroaryl-, and diheteroaryl-
methanols are important intermediates and structural motifs in
medicinal chemistry. Diarylmethanols form the core of several
biologically active compounds, including (R)-neobenodine, (R)-
orphenadrine, and (S)-cetirizine.1-6 The 1-benzofuran deriva-
tives 1a-c are intermediates in the synthesis of chiral azoles
(2a-c, Figure 1). Compounds 2a-c were initially examined
as antifungal agents7 and have been found to be powerful
nonsteroidal aromatase inhibitors.8-13 They are indicated in the
Figure 1. Biologically active heteroaryl- and diheteroarylmethanols.
treatment of hormone-dependent breast cancer.14 Likewise,
diheteroarylmethanols have received recent attention. For
example, chiral dithienylmethanols have been evaluated as
antiallergic and antiischemic agents (3, Figure 1).15 Furthermore,
enantioenriched diarylmethanols can be converted into diaryl-
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J. AM. CHEM. SOC. 2009, 131, 12483–12493 12483

A R T I C L E S
Salvi et al.
Scheme 1. Asymmetric Arylation of 4-Chlorobenzaldehyde with
Ph2Zn (A) and PhZnEt Generated from Ph2Zn and Et2Zn (B) or
from PhB(OH)2 and Et2Zn (C)
methane derivatives via SN2 substitution at the C-O bond
without loss of ee.1 The diarylmethane motif is found in
antimuscarinics,16 antidepressants,17 and endothelin antago-
nists.18
The catalytic enantioselective synthesis of diarylmethanols
has been the focus of many studies.19 The most efficient
approach to their preparation is the arylation of aromatic
aldehydes to generate a C-C bond and stereocenter in a single
step. Early studies by Seebach and co-workers employed
Ph-Ti(O-iPr)3, generated from Cl-Ti(O-iPr)3 and PhLi, in
combination with TADDOL-based titanium catalysts.20-22 To
achieve high enantioselectivity, it was necessary to remove the
LiCl byproduct formed during salt metathesis by centrifugation.
Pioneering studies by Fu and co-workers23 with a planar-
chiral catalyst, diphenylzinc, and 4-chlorobenzaldehyde fur-
nished the diarylmethanol product with 57% ee. A highly
enantioselective catalyst was reported by Pu shortly thereafter.24
These works inspired many subsequent investigations using
diphenylzinc, as exemplified in Scheme 1A.25-30
Despite the large number of studies with diphenylzinc,
significant drawbacks remained. Diphenylzinc is prohibitively
expensive and limited to phenyl transfer.25,31-34 Furthermore,
unlike dialkylzinc additions to aldehydes, which exhibit slow
background reactions, the uncatalyzed addition of diphenylzinc
to aldehydes is sufficiently rapid to compete with most catalyzed
additions.34-36 The latter problem was addressed by Bolm and
co-workers, who discovered that the mixed reagent EtZnPh33
exhibited a slower background reaction than diphenylzinc.
EtZnPh also resulted in higher enantioselectivities with the same
catalysts (Scheme 1B), in part from the reduced contribution
of the background reaction.37-42 EtZnPh is easily generated by
combining Ph2Zn and Et2Zn (eq 1).
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Ph2Zn + Et2Zn u 2Et - Zn - Ph
(1)
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of substituted aryl groups to aldehydes remained a challenge
for several years. Although diarylzinc reagents can be easily
prepared from ArLi or ArMgX and zinc halides (ZnX2), the
salt byproducts LiX and MgX2 are Lewis acidic and readily
promote the background reaction in the presence of enantioen-
riched catalysts, resulting in diarylmethanols with little or no
ee. To bypass this problem, Bolm and co-workers introduced a
method whereby aryl boronic acid derivatives underwent
transmetalation with dialkylzinc reagents to provide access to
salt-free arylzinc reagents, ArZnEt (Scheme 1C).30,42-48 In this
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Practical Catalytic Asymmetric Synthesis
A R T I C L E S
procedure,44 2.4 equiv of the aryl boronic acid was heated with
7.2 equiv of diethylzinc for 12 h to generate ArZnEt. Dimethyl
(polyethylene glycol) (DiMPEG, 10 mol %, MW ≈ 2000) was
used as an additive to inhibit the background reaction caused
by achiral Lewis acidic ZnPh2 or ZnBr2.43,49,50 Further study
and optimization by the groups of Perica`s and Magnus
significantly reduced the transmetalation time.51,52 Braga dem-
onstrated that the acceleration could be achieved by microwave
irradiation.53 Based on Bolm’s breakthrough, several aryl boron
derivatives, such as triarylboranes42,43,49,54-57 and boroxines,52,58,59
were successfully employed in the asymmetric arylation of
aldehydes. Highly enantioselective late transition metal-based
catalysts can also be employed with boronic acid derivatives.60-62
Main group metals other than zinc have been applied to the
asymmetric arylation of aldehydes. In 2008 Muramatsu and
Harada63 introduced a method wherein Grignard reagents (1.2
equiv) could be added to titanium tetraisopropoxide (3 equiv)
in the presence of 2 mol % 3-(3,5-Ph2-C6H3)-H8-BINOL and
aldehydes to provide diarylmethanols with high ee. In a similar
vein, Gau and co-workers employed salt-free Ar3Al·THF
reagents in combination with titanium tetraisopropoxide and
either H8-BINOL64 or sulfonamide alcohol-based ligands,65
which led to diarylmethanols with high enantioselectivities.
These reactions may proceed via an Ar-Ti intermediate.66
At the outset of our research into the arylation of aldehydes
in 2005, two major limitations existed. The first was the
necessity for salt-free aryl zinc reagents. The second was the
use of costly aryl sources such as Ph2Zn and aryl boronic acids,
which are synthesized from aryl halides. To address these
problems, we deemed the following criteria essential to a
practical, cost-effective and scalable protocol: (1) to use readily
available aryl bromides, and (2) to avoid filtration or centrifuga-
tion20-22,43,67 of metal halide byproducts from the aryl orga-
nometallic reagent. Herein we report the full details of the
successful development of a method that fulfills these criteria.68
Thus, metalation of an aryl bromide with n-BuLi, transmeta-
lation to zinc, and enantioselective addition to aldehydes in the
presence of the MIB-based69,70 catalyst can now be performed
in a one-pot procedure (eq 2).68 To circumvent the need for
tedious sublimation, filtration, or centrifugation of the intermedi-
ate arylzinc reagents, we introduced a method to sequester the
LiCl byproduct, enabling the generation of diarylmethanols with
high levels of enantioselectivity in the presence of lithium
chloride. Unfortunately, this procedure was unsuccessful when
applied to the generation of enantioenriched diheteroarylmetha-
nols. Therefore, an alternative procedure for heteroaryl additions
to aldehydes was developed. To our knowledge, these studies
represent the first highly enantioselective catalytic asymmetric
synthesis of diheteroarylmethanols.
Table 1. Solvent Screen in the Asymmetric Phenyl Addition to
2-Naphthaldehyde
entry
solvent
ee (%)
1
2
3
4
5
6
toluene
Et2O
t-BuOMe
t-BuOMe/Hex (1:3)
t-BuOMe/Hex (1:3)
94
60
88
89
92a
2
(49) Rudolph, J.; Lormann, M.; Bolm, C.; Dahmen, S. AdV. Synth. Catal.
2005, 347, 1361–1368.
(50) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71, 833–
835.
(51) Jimeno, C.; Sayalero, S.; Fjermestad, T.; Colet, G.; Maseras, F.;
Perica`s, M. A. Angew. Chem., Int. Ed. 2008, 47, 1098–1101.
(52) Magnus, N. A.; Anzeveno, P. B.; Coffey, D. S.; Hay, D. A.; Laurila,
M. E.; Schkeryantz, J. M.; Shaw, B. W.; Staszak, M. A. Org. Process
Res. DeV. 2007, 11, 560–567.
2 PhLi + ZnCl2 in t-BuOMe/Hex (1:3)
a Reaction conducted at 0 °C.
(53) Braga, A. L.; Paixao, M. W.; Westermann, B.; Schneider, P. H.;
Wessjohann, L. A. J. Org. Chem. 2008, 73, 2879–2882.
(54) Rudolph, J.; Schmidt, F.; Bolm, C. AdV. Synth. Catal. 2004, 346,
867–872.
2. Results and Discussion
The ultimate goal of these investigations was to develop a
practical method for the addition of aryl and heteroaryl groups
to aldehydes using readily available aryl and heteroaryl bro-
mides. Asymmetric additions with commercial diphenylzinc
were used to evaluate catalyst enantioselectivity and for
comparison with reactions using bromobenzene.
2.1. Phenylation with Ph2Zn and MIB. Our first priority was
to determine the enantioselectivity of the (-)-MIB-based catalyst
in phenyl additions to aldehydes. The substrate selected for these
studies was 2-naphthylaldehyde (Table 1), which was used with
commercial ZnPh2 and 5 mol % (-)-MIB.69,70 The phenyl
addition proceeded with 94% enantioselectivity in toluene and
60% enantioselectivity in diethyl ether (entries 1 and 2). Diethyl
ether most likely binds to the MIB-based zinc catalyst, reducing
(55) Bolm, C.; Zani, L.; Rudolph, J.; Schiffers, I. Synthesis 2004, 2173–
2180.
(56) Bolm, C.; Schmidt, F.; Zani, L. Tetrahedron: Asymmetry 2005, 16,
1367–1376.
(57) Dahmen, S.; Lormann, M. Org. Lett. 2005, 7, 4597–4600.
(58) Wu, X.; Liu, X.; Zhao, G. Tetrahedron: Asymmetry 2005, 16, 2299–
2305.
(59) Liu, X. Y.; Wu, X. Y.; Chai, Z.; Wu, Y.; Zhao, G.; Zhu, S. Z. J.
Org. Chem. 2005, 70, 7432–7435.
(60) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem., Int. Ed. 1998, 37,
3279–3281.
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Lett. 2006, 8, 1479–1481.
(62) Yamamoto, Y.; Kurihara, K.; Miyaura, N. Angew. Chem., Int. Ed.
2009, 48, 4414–4416.
(63) Muramatsu, Y.; Harada, T. Chem.sEur. J. 2008, 14, 10560–10563.
(64) Wu, K. H.; Gau, H. M. J. Am. Chem. Soc. 2006, 128, 14808–14809.
(65) Hsieh, S.-H.; Chen, C.-A.; Chuang, D.-W.; Yang, M.-C.; Yang, H.-
T.; Gau, H.-M. Chirality 2008, 20, 924–929.
(68) For our preliminary communication see: Kim, J. G.; Walsh, P. J.
Angew. Chem., Int. Ed. 2006, 45, 4175–4178.
(66) Balsells, J.; Davis, T. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2002, 124, 10336–10348.
(69) Chen, Y. K.; Jeon, S.-J.; Walsh, P. J.; Nugent, W. A. Org. Synth.
2005, 82, 87–92.
(67) Cote, A.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 2771–2773.
9
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A R T I C L E S
Salvi et al.
Table 2. Examination of Possible LiCl Inhibitors
its activity and, therefore, enantioselectivity. When less coor-
dinating tert-butyl methyl ether (TBME) was used, the diaryl-
methanol was obtained with 88% enantioselectivity (entry 3).
In the mixed solvent composed of 1:3 TBME:hexanes the
enantioselectivity was 89% at rt (entry 4) and 92% at 0 °C (entry
5). Of the solvents examined, only TBME was suitable for the
salt metathesis of PhLi with ZnCl2.
To evaluate the possibility of beginning with aryl bromides,
we next generated ZnPh2 by metalation of 4.5 equiv PhBr with
4 equiv n-BuLi in TBME followed by transmetalation with 2
equiv ZnCl2. After addition of hexanes to precipitate additional
LiCl, the in situ generated Ph2Zn solution was used in place of
the commercial Ph2Zn under otherwise identical conditions
(Table 1, entry 6). The expected alcohol product was isolated,
but the ee was only 2%. We hypothesized that the Lewis acidic
LiCl, generated en route to ZnPh2, promoted the addition to
form the racemate faster than the amino alcohol-based Lewis
acid catalyst promoted the asymmetric addition. Other research-
ers have had varying degrees of success employing either
filtration or centrifugation of LiCl and MgX2 byproducts.20-22,33,67
These salt byproducts are often produced as a fine particulate
and are difficult to remove. Although these procedures are quite
useful on laboratory scale, filtration or centrifugation of highly
air-sensitive materials is less practical on large scale. To
overcome this problem, our strategy was to inhibit the LiCl
byproduct rather than remove it. A similar approach was devised
by Bolm and co-workers involving the addition of Ph2Zn to
aldehydes. These researchers observed a beneficial effect of
dimethoxypoly(ethylene glycol) (DiMPEG) on the catalyst
enantioselectivity43,49 and proposed that DiMPEG suppressed
reactions catalyzed by trace achiral Lewis acids, including ZnBr2
and LiBr, allowing the arylation reaction to proceed via the
ligand-accelerated71 pathway.19 Although enantioselectivities
reached 93%, yields ranged from 8-31% when Ph2Zn was
generated from PhLi and ZnBr2.43 Furthermore, we had dif-
ficulties with reproducibility using DiMPEG in combination with
the MIB-based catalyst for enantioselective vinylation of
aldehydes.72,73
2.2. Development of a Lithium Chloride Selective Inhibitor.
The lack of enantioselectivity with Ph2Zn generated from PhBr
in Table 1 (entry 6) suggested that the achiral LiCl is a more
active Lewis acid than the (-)-MIB-based zinc catalyst. There
are three important differences between the lithium and zinc
Lewis acids: (1) the lithium is more electropositive and probably
the stronger Lewis acid, (2) the lithium center is less sterically
saturated than the zinc center in the MIB-based catalyst and
(3) the lithium chloride has at least two aVailable coordination
sites while the MIB-based zinc catalyst has only one accessible
site. Based on this analysis, our strategy was to employ bidentate
inhibitors that would chelate lithium and bind tightly, but
coordinate in a monodentate fashion to the chiral zinc catalyst.
Support for this approach was gained through structures of
[TMEDA·LiCl]n, which contain four-coordinate lithium centers
with bridging chlorides.74,75
entry
inhibitor
equiv.
ee (%)
1
2
3
4
5
6
7
8
none
-
2
55
76
83
83
77
89
92b
81
81
51
80
71
TEEDA
TEEDA
TEEDA
TEEDA
TEEDA
TEEDA
TEEDA
TMEDA
TMEDA
PMDET
PMDET
PMDET
0.2
0.4
0.8
1.0
1.2
0.8
0.8
0.8
1.0
0.1
0.2
0.4
low conversion
t-BuOMe/Tol ) 1:5
t-BuOMe/Tol ) 1:5
9
10
11
12
13
a Solvent ) t-BuOMe/Hex ) 1:3 unless noted. b Addition conducted
at 0 °C.
phenylation of 2-naphthaldehyde with in situ prepared ZnPh2
(Table 2). N,N,N′,N′-Tetraethylethylene diamine (TEEDA) was
first examined, because the amino groups are slightly larger than
those of the tetramethyl analog TMEDA. Use of 0.2 equiv
TEEDA resulted in an increase in the product ee from 2% in
the absence of diamine to 55% ee (Table 2, entries 1 and 2).
Increasing the amount of TEEDA from 0.2-0.8 and 1.0 equiv
resulted in product ee’s of up to 83%. A further increase in
TEEDA to 1.2 equiv, however, resulted in a slower reaction
and a decrease in the product ee to 77%, probably due to
inhibition of the MIB-based zinc catalyst by the diamine. It was
found that addition of 5 equiv toluene (or hexanes) relative to
TBME after transmetalation led to higher enantioselectivity (up
to 89%, entry 7). When the temperature of the addition was
lowered from rt (entry 7) to 0 °C (entry 8) the enantioselectivity
increased to 92%. The same enantioselectivity was obtained with
commercial Ph2Zn in Table 1 (entry 5), indicating that TEEDA
is an excellent inhibitor of LiCl. For comparison, TMEDA was
examined in Table 2 (entries 9 and 10) and found to be nearly
as effective as TEEDA. Pentamethyldiethylene triamine inhib-
ited LiCl at lower concentrations (0.2 equiv, 80% product ee,
entry 12).
2.3. Generation and Application of Mixed Aryl Alkyl Zinc
Reagents. As outlined in the Introduction, the background
reaction of diarylzinc reagents with aldehydes is often
competitive with, or faster than the ligand accelerated
pathway71 with amino alcohol-based catalysts. On the basis
of the successful application of mixed aryl alkyl zinc reagents
by Bolm and co-workers,33 we desired to develop an in situ
route to these species to increase enantioselectivities in the
On the basis of this proposal, multidentate amines were
screened as LiCl inhibitors in the catalytic enantioselective
(70) Nugent, W. A. Chem. Commun. 1999, 1369–1370.
(71) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1059–1070.
(74) Hoffmann, D.; Dorigo, A.; Schleyer, P. v. R.; Reif, H.; Stalke, D.;
Sheldrick, G. M.; Weiss, E.; Geissler, M. Inorg. Chem. 1995, 34,
262–269.
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P. J. J. Am. Chem. Soc. 2009, 131, 8434–8445.
(73) Salvi, L.; Jeon, S.-J.; Fisher, E. L.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2007, 129, 16119–16125.
(75) Chitsaz, S.; Pauls, J.; Neumuller, B. Z. Naturforsch., B: J. Chem.
Sci. 2001, 56, 245–248.
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A R T I C L E S
Table 3. Catalytic Asymmetric Aryl Additions to Aldehydes with ArZnBu Generated from Aryl Bromides
aldehyde arylations. To determine the benefit of the mixed
organozinc reagents with MIB, our initial experiments
involved conproportionation of a 1:1 ratio of commercial
Ph2Zn and Et2Zn to generate PhZnEt (eq 1) followed by
addition of (-)-MIB and 2-naphthaldehyde at 0 °C. Under
these conditions, the enantioselectivity increased from 92%
with Ph2Zn (entry 5, Table 1 and entry 8, Table 2) to 97%
with the mixed PhZnEt (Table 3, entry 1).
To prepare the mixed aryl alkyl zinc reagents in situ we
chose to avoid the use of dialkylzinc reagents, focusing on
the more readily available alkyllithiums. Thus, metalation
of PhBr with n-BuLi (2 equiv each) and addition of 2.1 equiv
ZnCl2 resulted in the generation of PhZnCl. A second dose
of n-BuLi (2 equiv) was then added to produce PhZnBu,
which was used in combination with 0.8 equiv TEEDA in
the asymmetric addition reaction (Table 3, entry 2). Gratify-
ingly, the enantioselectivity with the in situ generated PhZnBu
(97%) was equal to the salt-free PhZnEt, despite the 4 equiv
of LiCl in the reaction vessel.
To determine the generality of this method, a series of
aryl bromides and aldehydes were employed (Table 3).
Bromobenzene and 4-substituted aryl bromides bearing
-OMe, -F, or -Cl substituents were used in the arylation of
benzaldehyde derivatives with 93-97% enantioselectivity.
2-Bromotoluene and 2-bromonaphthalene were added to
benzaldehydes with g95% enantioselectivity. Aryl additions
to R,ꢀ-unsaturated aldehydes occurred with 81-90% enan-
tioselectivity (entries 3, 4, 8, 11, 12, 14, and 15). The aliphatic
substrate, cyclohexanecarboxaldehyde, underwent aryl ad-
dition with 78-82% enantioselectivity (entries 9 and 18).
The examples in Table 3 are the first examples of aldehyde
arylation beginning with aryl bromides.68
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Scheme 2. Synthesis of Enantioenriched 23, the Key Intermediate in the Synthesis of (S)-BMS 184394
Subsequent to our initial communication,68 a related report
appeared by Pu76 employing aryl iodides, and two examples
were reported by Harada.63,77 Woodward also developed a
method using aryl zinc halides in combination with trimethyl
aluminum based on the Schlenk equilibrium.78
Scheme 3. Metathesis with EtZnCl for the Aryl and Heteroaryl
Additions to Aldehydes
Formal Synthesis of (S)-BMS 184394. One example of a
biologically active diarylmethanol is BMS 184394 (24, Scheme
2), a RAR γ selective retinoid with activity against skin diseases
and cancers, in particular breast cancer and acute promyelocytic
leukemia.79-81 Using conditions outlined in Table 3, 3.0 equiv
aryl bromide 22 (Scheme 2) was employed to generate the
mixed aryl butyl zinc reagent. TEEDA (1.5 equiv) and hexanes
were added followed by (+)-MIB (5 mol %) and aldehyde 21.
The addition product 23 was produced with 87% enantioselec-
tivity in 88% yield (Scheme 2). Conversion to (S)-BMS 184394
can be accomplished by saponification of the ester.80
2.4. Attempted Heteroaryl Additions to Aldehydes. General,
highly enantioselective additions of heteroaryl groups to alde-
hydes have not been developed. To our knowledge, the only
examples of highly enantioselective heteroaryl additions were
published in 2008 by Gau and involved the addition of 2-furyl
aluminum reagents to ketones.82 Heteroaryl groups are among
the most important pharmacaphors in medicinal chemistry and
diheteroarylmethanols have been identified as biologically active
structural motifs.15 Thus, not only would methods for heteroaryl
additions to aldehydes increase the classes of enantioenriched
diarylmethanols accessible, it would enable the catalytic asym-
metric synthesis of diheteroarylmethanols that are currently not
directly accessible.
conditions outlined in Table 3, the salt metathesis was conducted
at room temperature for 4.5 h.68 At this temperature (3-thienyl)Li
readily decomposes.
We hypothesized that the absence of product was due to
decomposition of the heteroaryllithium in the transmetalation
step, which was complicated by the limited solubility of ZnCl2
in TBME at low temperature. To address this problem, we
envisaged a more soluble zinc source might undergo transmeta-
lation at lower temperature. Our choice of EtZnCl was based
on the large reactivity difference of sp2 hybridized Zn-C bonds
over their sp3 counterparts. Another advantage of EtZnCl is that
only a single equivalent of LiCl forms during the metathesis,
whereas ZnCl2 produces two equivalents (Scheme 3). Lower
levels of salt byproduct facilitate inhibition of the LiCl-promoted
background reaction.
The synthesis of EtZnCl was initially performed following
the method of Woodward and co-workers by combination of
ZnCl2 and ZnEt2 in THF followed by removal of the solvent
under reduced pressure.83 Using EtZnCl prepared in this manner,
the transmetalation proceeded at -78 °C and the desired
heteroaryl addition products were obtained. Unfortunately,
product yields and ee’s varied greatly from run to run. Our
unsuccessful attempts to develop asymmetric heteroaryl addi-
tions convinced us to first focus on development of a low
temperature transmetalation and then revisit enantioselective
heteroaryl additions.
With the goal of introducing asymmetric heteroaryl additions
to aldehydes, we applied our arylation procedure to metalation
of 3-bromothiophene followed by addition to benzaldehyde. The
only modification was to maintain the temperature of the
heteroaryllithium at -78 °C. Unfortunately, no addition product
was observed. When the aryl bromides were used under the
(76) DeBerardinis, A. M.; Turlington, M.; Pu, L. Org. Lett. 2008, 10,
2709–2712.
2.5. Development of Low Temperature Transmetalation
Conditions and Synthesis of Biologically Active 2a. Momentarily
stepping away from the more challenging enantioenriched
diheteroarylmethanols, we concentrated on developing low
temperature conditions for lithium to zinc transmetalations. We
attributed the inconsistencies in the previously described het-
eroaryl additions to the presence of residual zinc-bound THF
in the EtZnCl, which was observed by 1H NMR spectroscopy.83
THF is known to inhibit the MIB-based zinc Lewis acid catalyst.
(77) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp,
F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed. 2003,
42, 4302–4320.
(78) Shannon, J.; Bernier, D.; Rawson, D.; Woodward, S. Chem. Commun.
2007, 3945–3947.
(79) Thacher, S. M.; Vasudevan, J.; Chandraratna, R. A. S. Curr. Pharm.
Des. 2000, 6, 25–58.
(80) Yu, K. L.; Spinazze, P.; Ostrowski, J.; Currier, S. J.; Pack, E. J.;
Hammer, L.; Roalsvig, T.; Honeyman, J. A.; Tortolani, D. R.; Reczek,
P. R.; Mansuri, M. M.; Starrett, J. E. J. Med. Chem. 1996, 39, 2411–
2421.
(81) Klaholz, B. P.; Mitschler, A.; Moras, D. J. Mol. Biol. 2000, 302,
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(82) Wu, K.-H.; Chuang, D.-W.; Chen, C.-A.; Gau, H.-M. Chem. Commun.
2008, 2343–2345.
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A R T I C L E S
Table 4. Synthesis of Aryl Heteroaryl- and Diheteroarylmethanols using 5 mol % (-)-MIB (Unless Noted below)
a MIB (10 mol %). See Supporting Information for details.
On the basis of this hypothesis, an alternative synthesis of
EtZnCl was pursued.84-86 Using toluene in place of THF
required heating ZnEt2 and sparingly soluble ZnCl2 at 60 °C
for 72 h, after which the solution was filtered to remove any
unreacted ZnCl2. The volatiles were then removed under reduced
pressure to afford EtZnCl as a white solid that could be stored
under nitrogen for months.
limited methods to synthesize the diarylmethanols enantiose-
lectively, most of the studies employed racemic material.11,93,94
Synthesis of 1a with 90% ee suggests that this procedure can
be used to prepare diarylmethanols and their derivatives with
high ee.
The THF-free EtZnCl was first employed with bromobenzene
(eq 3). The transmetalation was conducted at -78 °C to generate
PhZnEt, and the addition to 2-benzofurancarbaldehyde was
performed at 0 °C. After 12 h, the reaction mixture was
quenched with water, worked up, and purified on deactivated
silica. We were pleased to isolate the desired addition product
1a in 92% yield with 90% ee (eq 3). Compound 1a was
converted to the promising breast cancer treatment candidate
2a (Figure 1), without loss of ee in 41% unoptimized yield (84%
based on recovered 1a of 90% ee) via a Mitsunobu reaction
with imidazole.87 SN2 substitutions of this type are known to
be very difficult.1 Alternative methods for this transformation
also appear potentially useful.89-92
2.6. Enantioselective Addition of Heteroaryl Groups to
Aldehydes. The heteroaryl addition was attempted with 3-bro-
mothiophene under the conditions employed with bromobenzene
to generate 1a in eq 3. Thus, after metalation of 3-bro-
mothiophene with n-BuLi, transmetalation was performed at
-78 °C with THF-free EtZnCl. The resulting solution was then
warmed to 0 °C and TEEDA, (-)-MIB, and benzaldehyde were
added (Table 4). After stirring 12 h, workup, and purification
we were pleased to isolate the desired heteroaryl addition
Recently promising diarylmethanes have been examined as
possible inhibitors and receptor agonist candidates, but due to
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M. Organometallics 2006, 25, 3311–3313.
´
´
(85) Boersma, J.; Noltes, J. G. Tetrahedron Lett. 1966, 1521–1525.
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4023.
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Medarde, M. Bioorg. Med. Chem. 2008, 16, 8999–9008.
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8, 5069–5072.
(87) Mitsunobu, O. Synthesis 1981, 1–28.
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Salvi et al.
Figure 2. Structure of Chan’s ligand (L2).
product in 68% yield with 90% ee (Table 4, entry 1). These
revised conditions led to reproducible product ee’s and yields.
To explore the enantioselective synthesis of diheteroaryl-
methanols, the optimized conditions for addition of (3-thie-
nyl)ZnEt to benzaldehyde were employed with heteroaromatic
aldehydes. Thus, addition to 5-methyl-2-furan carboxaldehyde,
2-thiophenecarboxaldehyde and 3-benzofurancarboxaldehyde
occurred with 92-94% enantioselectivity in 60-83% yield
(Table 4, entries 2-4). The differences in yields in entries 1-4
probably arise from a combination of the instability of the
heteroaryl organometallic reagents and diminished electrophi-
licity of the heteroaromatic aldehydes. To develop practical and
useful methods, scalability must be demonstrated. Thus, for the
synthesis of 27, precursor to potential drug candidate 3 (Figure
1), the asymmetric addition was scaled to produce 820 mg (83%
yield and 93% ee, entry 3).
metal-halogen exchange with the aryl bromide generating
t-BuBr and the second drives the equilibrium by promoting
elimination of the liberated t-BuBr to produce isobutylene and
LiBr. Unfortunately, diamines that inhibit LiCl had little impact
when LiBr was formed. Although we do not understand the
intimate differences between LiCl and LiBr at this time, we
speculate that weaker bridging Li-Br interactions in [(di-
amine)LiBr]n facilitate dissociation of the oligomers, opening
a coordination site on lithium. To avoid production of LiBr, a
1:1 ratio of 4-bromoindole to t-BuLi was employed, furnishing
indole-based diarylmethanols with 90% ee and 60-65% yield
(eq 4).
Other heterocycles such as 3-bromobenzothiophene can also
be used in the addition with very good enantioselectivities
(81-88% ee, entries 5-7). Employing 2-bromothiophene and
benzaldehyde afforded diarylmethanol in 90% ee and 57% yield
(entry 8). In a similar fashion 3-furanyl ethyl zinc can be added
to benzaldehyde (93% ee, 86% yield, entry 9) and heteroaro-
matic aldehydes with excellent enantioselectivities (89-99%
ee, entries 11-13). 5-Methyl-2-furan carboxaldehyde gave
addition product of 80% ee (entry 10). Attempts to add
2-furanylzinc reagents to aldehydes, however, resulted in poor
enantioselectivities, probably due to the presence of the
coordinating oxygen in close proximity to zinc.
Scheme 4. Structure of (-)-Aurantioclavine and Intermediates in
its Synthesis by Stoltz and Coworkers99
To determine if our method for addition of heteroaromatic
groups to aldehydes could be extended to other catalysts, we
examined the use of Chan’s ligand (L2, Figure 2)48,95 with
3-bromothiophene and benzaldehyde under the conditions listed
in Table 4, which led to product of 90% ee and 70% yield.
These results are virtually identical to those in entry 1 (Table
4) with MIB, indicating that our strategy employing TEEDA
to inhibit LiCl is applicable to other amino alcohol-based
catalysts.
Enantioenriched indole 38 is a potential intermediate for the
synthesis of (-)-aurantioclavine, which is illustrated in Scheme
4 along with related intermediates in the elegant synthesis of
this alkaloid by Stoltz and co-workers.99
2.7. Tandem Asymmetric Aryl Addition/Diastereoselective
Epoxidation. We recently developed a series of tandem reactions
involvingtheasymmetricadditionofalkyl,100-102 vinyl,73,100,103,104
Indoles are regarded as privileged structures in medicinal
chemistry and are substructures of an enormous variety of
natural products.96,97 We therefore turned our attention toward
the synthesis of enantioenriched diarylmethanols containing the
indole motif. Metalation of N-silyl-protected 4-bromoindole with
n-BuLi was unsuccessful under a variety of conditions, including
those in Table 4, most likely due to the electron rich nature of
the heterocyclic π-system. More challenging metal-halogen
exchange reactions are generally performed with two equiv
t-BuLi.98 In these reactions, the first equiv undergoes the
(98) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51,
5106–5110.
(99) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.;
Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745–
13754.
(100) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J.
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(101) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544–9545.
(102) Jeon, S.-J.; Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 16416–
16425.
(95) Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2001, 12, 2147–2152.
(103) Lurain, A. E.; Carroll, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70,
1262–1268.
(96) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996.
(97) Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach;
2nd ed.; John Wiley: New York, 2002.
(104) Kelly, R. A.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2005,
127, 14668–14674.
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Scheme 5. Tandem Asymmetric Arylation of Aldehydes/Diastereoselective Epoxidation
or allyl105 groups to aldehydes and ketones followed by
diastereoselective epoxidation to provide epoxy alcohols with
three contiguous stereogenic centers.106 These one-pot proce-
dures rapidly increase molecular complexity in a synthetically
efficient fashion. To explore the possibility of performing
arylation and heteroarylation of enals followed by diastereose-
lective epoxidation, we examined asymmetric phenyl addition/
oxidation with 3-methyl-2-butenal. As shown in Scheme 5A,
using the conditions outlined in Table 4 the catalytic asymmetric
phenyl addition was performed. The resulting enantioenriched
zinc allylic alkoxide was then treated with Et2Zn (1 equiv),
TBHP (tert-butylhydroperoxide, 5 equiv), and 20 mol %
titanium tetraisopropoxide at 0 °C. The epoxidation reached
completion in 3 h, after which the reaction mixture was
quenched, worked up, and the product purified by chromatog-
raphy to afford the epoxy alcohol in 67% yield with 90% ee
and >20:1 dr (as determined by 1H NMR). The heteroarylation/
epoxidation was examined with the TIPS protected 4-bromoin-
dole (Scheme 5B). Metalation with t-BuLi, transmetalation with
EtZnCl, and asymmetric addition as performed in eq 4 was
followed by addition of Et2Zn, TBHP and 20 mol % titanium
tetraisopropoxide at 0 °C. Following workup and purification,
the enantioenriched indole epoxy alcohol was isolated in 65%
yield with 90% ee and >20:1 dr. Interestingly, attempted
epoxidation of the isolated indole allylic alcohol product in
Equation 4 with m-CPBA resulted in formation of the epoxy
alcohol in low yield accompanied by several side products. The
examples in Scheme 5 indicate that the asymmetric arylation
and heteroarylation are compatible with our tandem diastereo-
selective epoxidation conditions and could be used to prepare
an array of functionalized epoxy alcohols.
Related motifs107,108 are precursors to important enantioenriched
ferrocene-based ligands such as BoPhoz,109 Josiphos,110
FERRIPHOS,111,112 Pigiphos,113,114 PPFA,115 Walphos,116 Tania-
phos117 and Trap.109,118,119 The ferrocenyl methanol scaffold
is often synthesized by CBS120-122 or Ru/BINAP reduction of
ferrocenyl ketones.4,119,123 Asymmetric reduction of heteroaro-
matic ketone derivatives, however, resulted in only moderate
enantioselectivity (X ) O, 41% ee; X ) S, 68% ee, eq 5).124
Beginning with ferrocenyl bromide (FcBr) and applying the
conditions used in Table 4 to the generation and addition of
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2.8. Synthesis of Ferrocenylzinc and Applications to Asym-
metric Additions. Having developed successful methods for the
enantioselective addition of aryl and heteroaryl groups to
aldehydes, we focused on the generation of the ferrocenylzinc
reagent, (Fc)ZnEt. Highly enantioselective additions of ferro-
cenylzinc reagents to aromatic and heteroaromatic aldehydes
would provide rapid access to heteroaryl ferrocenyl methanols.
(117) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel, P.
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1991, 2, 593–596.
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Table 5. Asymmetric Addition of (Fc)ZnEt to Aldehydes
use of EtZnCl in the transmetalation step with the heteroaryl-
lithium at -78 °C, at which temperature decomposition of the
heteroaryl organometallic species was minimized. Use of EtZnCl
in place of ZnCl2 also halves the amount of LiCl byproduct,
which was detrimental to the enantioselectivity in the asym-
metric addition and must be inhibited by diamine. This method
was also shown to be applicable to the tandem asymmetric
addition/diastereoselective epoxidation to generate epoxy alco-
hols with two stereogenic centers in high enantio- and diaste-
reoselectivity.
Finally, we also described the first examples of generation
and highly enantioselective addition of ferrocenyl zinc reagents
to aldehydes, opening the door to new enantioenriched fer-
rocene-based ligands. The straightforward methods introduced
herein make possible the synthesis of functionalized, previously
inaccessible enantioenriched diheteroarylmethanols. We antici-
pate that these methods will be useful in medicinal chemistry
and asymmetric catalysis.
4. Experimental Section
General Considerations. All reactions were performed under a
nitrogen atmosphere with oven-dried glassware using standard
Schlenk or vacuum line techniques. The progress of reactions was
monitored by thin-layer chromatography (TLC) performed on
Whatman precoated silica gel 60 Å K6F plates and visualized by
ultraviolet light or by staining with cerium-ammonium-molybdate.
t-BuOMe was distilled from Na/benzophenone and toluene was
dried through alumina columns. TEEDA was distilled and stored
(Fc)ZnEt to benzaldehyde with (-)-MIB provided product with
a disappointing 50% ee (Table 5, entry 1). Inspired by the
importance of functionalized ferrocenyl methanols, we screened
other amino alcohol ligands. Fortunately, use of Chan’s48,95
amino alcohol L2 (Figure 2) with benzaldehyde provided the
desired product in 86% yield with 98% ee (Table 5, entry 2).
Use of 2-thiophenecarboxaldehyde and 2-furfural in combination
with L2 provided the ferrocene-based ligand precursors with
enantioselectivities of 96% and yields of 95% (entries 3 and
4). It is known that substitution of furyl groups for phenyl can
lead to an increase in catalyst enantioselectivity.125
1
under nitrogen. The H NMR and 13C{1H} NMR spectra were
obtained on a Bru¨ker Fourier transform NMR spectrometer at either
1
300 or 500 and 75 or 125 MHz, respectively. H NMR spectra
were referenced to tetramethylsilane in CDCl3 or residual protonated
solvent; 13C{1H} NMR spectra were referenced to residual solvent.
Analysis of enantiomeric excess was performed using a Hewlett-
Packard 1100 Series HPLC and a chiral column. Alternatively, a
Berger SFC PioNTo was employed when the compounds could
not be resolved by HPLC. The optical rotations were recorded using
a JASCO DIP-370. Infrared spectra were obtained using a Perkin-
Elmer Spectrum 100 Series spectrometer. All reagents were
purchased from Aldrich or Acros unless otherwise described.
3-Benzofurancarboxaldehyde was synthesized according to known
procedure starting from commercially available 3-methylbenzofu-
ran.127 Binaphthyl amino alcohol ligand was synthesized according
to Chan’s procedure.48,95 EtZnCl was synthesized following Guer-
rero’s method.84,128 All aldehyde substrates were distilled prior to
use. Silica gel (Silicaflash P60 40-63 µm, Silicycle) was used for
air-flashed chromatography.
The high yields and stereochemical purity of functionalized
ferrocenes make them attractive building blocks for the con-
struction of new ferrocene-based ligands for asymmetric catalysis.
3. Summary and Outlook
Herein we described versatile methods for the generation of
diaryl-, aryl heteroaryl-, and diheteroarylmethanols with high
levels of enantioselectivity. The significance of these methods
is that asymmetric arylation of aldehydes can now be initiated
with aryl bromides, many of which are readily available. Key
to the success of our procedures was introduction of a diamine,
such as TEEDA. In the absence of TEEDA the addition reaction
was promoted by LiCl, generating racemic products. The
TEEDA inhibited the LiCl byproduct, allowing the asymmetric
addition to proceed via the ligand accelerated pathway.71,126
Importantly, in the presence of the diamine it was not necessary
to filter,43 centrifuge,67 or isolate the pyrophoric arylzinc
reagents required with previous procedures, making our method
desirable for large scale applications.
Caution. Dialkylzinc and alkyl lithium reagents are pyrophoric!
Care and appropriate laboratory equipment and attire must be used
when handling these reagents.
Arylation of Aldehydes. Preparation of (4-Fluoro-phenyl)-(4-
methoxy-phenyl)-methanol (10). A nitrogen purged Schlenk flask
was charged with 4-bromoanisole (100.1 µL, 0.8 mmol) and
t-BuOMe (1 mL) and cooled to -78 °C. n-BuLi (0.32 mL, 2.5 M
in hexanes, 0.8 mmol) was added dropwise and the solution was
stirred for 1 h and the temperature raised to 0 °C. ZnCl2 (114.5
mg, 0.84 mmol) was added to the reaction mixture and it was stirred
for 30 min. Additional n-BuLi (0.32 mL, 2.5 M in hexanes, 0.8
mmol) was added to the reaction mixture and the resulting solution
was allowed to warm to rt and stirred 4.5 h. Toluene (5 mL) and
TEEDA (68 µL, 0.32 mmol) were added to the reaction vessel and
the solution was stirred. After 1 h (-)-MIB (4.8 mg, 0.02 mmol)
was added and the reaction vessel was cooled to 0 °C for 30 min.
Finally, 4-fluorobenzaldehyde (43 µL, 0.4 mmol) was added and
reaction mixture was stirred at 0 °C and monitored by TLC. After
completion (12 h), the reaction mixture was quenched with H2O
We also developed the first method for the synthesis of highly
enantioenriched diheteroarylmethanols from readily available
heteroaryl bromides. A crucial feature of this approach was the
(125) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
2458–2460.
(126) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric
Catalysis; University Science Books: Sausalito, 2008.
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12492 J. AM. CHEM. SOC. VOL. 131, NO. 34, 2009

Practical Catalytic Asymmetric Synthesis
A R T I C L E S
(20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic
layer was dried over MgSO4, filtered, and the solvent was removed
under reduced pressure. The crude product was purified by column
chromatography on silica gel (hexanes/EtOAc, 95:5) to give 10
(77.7 mg, 84% yield) as a white crystalline solid (mp ) 52 °C).
The enantiomeric excess was determined by HPLC with a Chiralcel
AS-H column (hexanes/2-propanol ) 95:5, flow rate ) 0.5 mL/
min), tr (1) ) 20.0 min, tr (2) ) 22.1 min, [R]2D0 ) +13.8 (c )
0.195, THF, 93% ee); 1H NMR (C6D6, 300 MHz): δ 2.17 (s, 1H),
3.38 (s, 3H), 5.50 (s, 1H), 6.81-6.95 (m, 4H), 7.17-7.29 (m, 4H);
13C{1H} NMR (C6D6, 75 MHz): δ 55.0, 75.3, 114.3, 115.4 (d, J )
21.2 Hz), 128.4, 128.7 (d, J ) 8.0 Hz), 136.9, 141.0 (d, J ) 3.0
Hz), 159.7, 162.6 (d, J ) 243 Hz); IR (neat): 831, 1033, 1248,
1504, 1609, 2837, 2957, 3422 cm-1; HRMS calcd for C14H13FO2
(M)+: 232.0900, found: 232.0900.
Furan-3-yl(thiophen-2-yl)methanol (35). A nitrogen purged
Schlenk flask was charged with 3-bromofuran (67.0 µL 0.75 mmol)
and t-BuOMe (1 mL) and cooled to -78 °C. n-BuLi (0.3 mL, 2.5
M in hexanes, 0.75 mmol) was then added dropwise and the solution
was stirred for 1 h at this temperature. During this time a white
precipitate formed. Solid EtZnCl (97.0 mg, 0.75 mmol) was added
to the reaction mixture at -78 °C followed by toluene (3 mL).
The heterogeneous solution was stirred at -78 °C for 30 min and
then warmed at 0 °C. TEEDA (64 µL, 0.30 mmol) was added and
the solution stirred for an additional 30 min. (-)-MIB (190 µL,
0.1 M solution in hexanes, 0.019 mmol) was added to the reaction
flask and the solution was stirred for 5 min before 2-thiophenecar-
boxaldehyde (35 µL, 0.37 mmol, dissolved in 1.5 mL of toluene)
was added over 1.5 h by syringe pump. The reaction mixture was
stirred at 0 °C and monitored by TLC until completion (ap-
proximately 10 h). The reaction mixture was diluted with 3 mL
EtOAc and quenched with water (5 mL). The organic layer was
separated and the aqueous solution extracted with EtOAc (3 × 10
mL). The combined organic layer was washed with brine (5 mL),
dried over MgSO4, filtered, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography on deactivated silica gel (hexanes/EtOAc, 95:5)
to give 35 (44.4 mg, 60% yield) as a colorless oil. The enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(hexanes/2-propanol ) 97:3, flow rate ) 0.5 mL/min), tr (1) )
40.4 min, tr (2) ) 47.1 min, [R]2D0 ) +18.2 (c ) 0.032, CHCl3,
99% ee); 1H NMR (CDCl3, 500 MHz): δ 2.27 (d, J ) 5.0 Hz, 1H),
6.04 (d, J ) 5.0 Hz, 1H), 6.44-6.45 (m, 1H), 6.97-6.99 (m, 1H),
7.01-7.02 (m, 1H), 7.30 (dd, J ) 1.5, 5.0 Hz, 1H) 7.41 (t, J ) 1.5
Hz, 1H), 7.45-7.46 (m, 1H); 13C{1H} NMR (CDCl3, 125 MHz):
δ 65.8, 109.3, 125.0, 125.6, 126.9, 128.6, 140.1, 143,7, 147.4; IR
(neat): 3410, 3108, 2924, 2855, 1759, 1672, 1614, 1507, 1416, 1264,
1230, 1156, 1022 cm-1; HRMS calcd for C9H7O2S (M-H)+:
179.0167, found 179.0169.
t-BuOMe (1 mL) and cooled to -78 °C. t-BuLi (0.18 mL, 1.7 M
in pentane, 0.3 mmol) was added dropwise and the solution was
stirred for 1 h. Solid EtZnCl (39.6 mg, 0.3 mmol) was added to
the reaction solution at -78 °C. Toluene (3 mL) was next added
giving a heterogeneous mixture. The solution was warmed at -10
°C and stirred for 3 h. TEEDA (26 µL, 0.12 mmol) was then added
and the solution stirred for an additional 30 min. (-)-MIB (150
µL, 0.1 M solution in hexanes, 0.015 mmol) was added to the
reaction flask, the solution was stirred for 5 min, and 3-methyl-2-
butenal (14.7 µL, 0.15 mmol, dissolved in 1.5 mL of toluene) was
added by syringe pump over 1.5 h. The reaction mixture was stirred
at 0 °C and monitored by TLC until the starting aldehyde had been
consumed. Upon completion of the asymmetric addition, ZnEt2
(0.15 mL, 1 M in hexanes, 0.15 mmol) was added followed by
TBHP (0.14 mL, 5.5 M in decane, 0.77 mmol). After stirring for
5 min Ti(O-iPr)4 (30 µL, 1 M in hexanes, 0.03 mmol) was added
and the reaction mixture stirred until complete by TLC analysis
(approximately 3 h). The reaction mixture was diluted with 3 mL
EtOAc and quenched with water (5 mL). The organic layer was
next separated and the aqueous solution extracted with EtOAc (3
× 10 mL). The combined organic layer was washed with brine (5
mL), dried over MgSO4, filtered, and the volatile materials were
removed under reduced pressure. The crude product was purified
by column chromatography on deactivated silica gel (hexanes/
EtOAc, 90:10) to give 41 (36.6 mg, 64.9% yield) as a clear oil.
1
The diastereomeric ratio was determined by H NMR analysis of
the crude product (dr > 20:1); [R]2D0 ) -6.1 (c ) 0.041, CHCl3,
1
90% ee); H NMR (CDCl3, 500 MHz): δ 1.13 (d, J ) 7.6 Hz,
18H), 1.29 (s, 3H), 1.43 (s, 3H), 1.69 (sept, J ) 7.6 Hz, 3H), 2.48
(d, J ) 3.0 Hz, 1H), 3.31 (d, J ) 8.1 Hz, 1H), 4.89 (dd, J ) 3.0,
8.1 Hz, 1H), 6.80 (d, J ) 3.3 Hz, 1H), 7.10-7.14 (m, 1H), 7.30
(d, J ) 3.3 Hz, 1H), 7.47 (dd, J ) 2.8, 6.9 Hz, 1H); 13C{1H} NMR
(CDCl3, 125 MHz): δ 12.8, 18.0, 19.5, 24.8, 60.1, 67.3, 72.2, 103.3,
113.9, 117.6, 121.1, 129.2, 131.5, 141.3; IR (neat): 3445, 3135,
3081, 3048, 2948, 2892, 2868, 2760, 2729, 2625, 2559, 2361, 2343,
2246, 2150, 2074, 1892, 1824, 1740, 1675, 1599, 1514, 1463, 1428,
1378, 1345, 1323, 1280, 1248, 1209, 1150, 1124, 1096, 1073 cm-1
;
HRMS calcd for C22H35NO2NaSi (M+Na)+: 396.2335, found
396.2321.
Acknowledgment. This paper is dedicated to the memory of
our friend and colleague Prof. Ralph F. Hirshmann (Merck and
the University of Pennsylvania), leader of the team that achieved
the first total synthesis of an enzyme. We are grateful to the National
Institutes of Health, National Institute of General Medical Sciences
(GM58101), and National Science Foundation (CHE-0615210) for
financial support of this work. We thank the NIH (1S10RR23444)
for funds to purchase a Waters LCTOF-Xe Premier MS.
Asymmetric Addition/Diastereoselective Epoxidation Reactions.
Preparation of (3,3-Dimethyloxiran-2-yl)(1-(triisopropylsilyl)-1H-
indol-4-yl)methanol (41). A nitrogen purged Schlenk flask was
charged with 4-bromo-1-TIPS indole (106.5 mg, 0.3 mmol) and
Supporting Information Available: Complete experimental
procedures, product characterization, and full author list for ref
93. This material is available free of charge via the Internet at
http://pubs.acs.org.
(127) Zaidlewicz, M.; Chechlowska, A.; Prewysz-Kwinto, A.; Wojtczak,
A. Heterocycles 2001, 55, 569–577.
(128) Guerrero, A.; Hughes, D. L.; Bochmann, M. Organometallics 2006,
25, 1525–1527.
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