Homo-Roche ester derivatives by asymmetric hydrogenation and organocatalysis

Article abstract of DOI:10.1021/jo401996m

Asymmetric hydrogenation routes to homologues of The Roche ester tend to be restricted to hydrogenations of itaconic acid derivatives, that is, substrates that contain a relatively unhindered, 1,1-disubstituted alkene. This is because in hydrogenations mediated by RhP₂ complexes, the typical catalysts, it is difficult to obtain high conversions using the alternative substrate for the same product, the isomeric trisubstituted alkenes (D in the text). However, chemoselective modification of the identical functional groups in itaconic acid derivatives are difficult; hence, it would be favorable to use the trisubstituted alkene. Trisubstituted alkene substrates can be hydrogenated with high conversions using chiral analogs of Crabtree's catalyst of the type IrN(carbene). This paper demonstrates that such reactions are scalable (tens of grams) and can be manipulated to give optically pure homo-Roche ester chirons. Organocatalytic fluorination, chlorination, and amination of the homo-Roche building blocks was performed to demonstrate that they could easily be transformed into functionalized materials with two chiral centers and α,ω-groups that provide extensive scope for modifications. A synthesis of (S,S)- and (R,S)-γ-hydroxyvaline was performed to illustrate one application of the amination product.

Full text of DOI:10.1021/jo401996m

Article
pubs.acs.org/joc
Homo-Roche Ester Derivatives by Asymmetric Hydrogenation and
Organocatalysis
Sakunchai Khumsubdee, Hua Zhou, and Kevin Burgess*
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77841, United States
S
* Supporting Information
ABSTRACT: Asymmetric hydrogenation routes to homologues of
The Roche ester tend to be restricted to hydrogenations of itaconic
acid derivatives, that is, substrates that contain a relatively unhindered,
1,1-disubstituted alkene. This is because in hydrogenations mediated
by RhP2 complexes, the typical catalysts, it is difficult to obtain high
conversions using the alternative substrate for the same product, the
isomeric trisubstituted alkenes (D in the text). However, chemo-
selective modification of the identical functional groups in itaconic acid
derivatives are difficult; hence, it would be favorable to use the trisubstituted alkene. Trisubstituted alkene substrates can be
hydrogenated with high conversions using chiral analogs of Crabtree’s catalyst of the type IrN(carbene). This paper demonstrates
that such reactions are scalable (tens of grams) and can be manipulated to give optically pure homo-Roche ester chirons.
Organocatalytic fluorination, chlorination, and amination of the homo-Roche building blocks was performed to demonstrate that
they could easily be transformed into functionalized materials with two chiral centers and α,ω-groups that provide extensive
scope for modifications. A synthesis of (S,S)- and (R,S)-γ-hydroxyvaline was performed to illustrate one application of the
amination product.
less than the diacid or the diester.6,8 Alternatively, it is possible
to begin the syntheses with monoesters of itaconic acid, and
INTRODUCTION
Roche ester derivatives A are some of the most widely appre-
■
ciated chirons in organic syntheses.1−4 This is because such
indeed some of these are commercially available. However,
these starting materials are expensive, so overall it is better to
compounds have functional groups at both termini enabling
bidirectional modifications and a tremendous scope for in-
corporating methyl-substituted chiral centers. It seems logical
that the homologous chiron B would be similarly useful if it
were more readily available. For the purposes of this study, we
refer to the generic class of fragments B as homo-Roche ester
avoid this strategy. Any pathway that uses hydrogenation of
itaconic acid, in fact, is vulnerable to the types of deactivation
pathways that have been documented previously.9,10 Another
route to chirons B is via asymmetric additions of cuprates to
α,β-unsaturated thioesters.11
derivatives.
Scalable syntheses of chirons B have not attracted much
attention in the literature. Homologation of the parent chiron5
Both the hydrogenation syntheses of chirons B described
above feature bisphosphite complexes formed from Rh-
is probably not the best route to obtain compounds B, even
+
(COD)2 in situ. Hydrogenation of type D trisubstituted
though they only contain one more skeletal carbon than A
alkenes would give products that are chemically related to C,
but these types of transformations tend to be difficult to achieve
because The Roche ester is not a cheap starting material; small
quantities tend to cost more than $1 per gram. Another approach is
using RhP2 complexes because the double bonds are
via asymmetric hydrogenations of itaconic acid or the correspond-
hindered.12 In fact, the preferred catalysts for the trisubstituted
alkenes D tend to be IrN,P complexes, that is, chiral analogs of
Crabtree’s catalyst.12 Consequently, the work described here
was undertaken to use our particular chiral analog of Crabtree’s
ing diesters to give the C5-building blocks C.6,7 Bidirectional
homologation of chirons C requires efficient chemoselective
modification of one of the two esters; we are aware of only one
method for doing this, and it features a relatively expensive
lipase in a chemoenzymatic hydrolysis.6 It is possible to instead
begin with a monoester of itaconic acid and hydrogenate that,
but in fact the enantioselectivities for this process tend to be
Received: September 9, 2013
Published: November 12, 2013
© 2013 American Chemical Society
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catalyst, cat,13,14 to reduce D-type substrates via scalable
transformations. We also set out to establish that all
stereoisomeric forms of the 2-substituted chirons E could be
obtained via organocatalytic modifications of the homo-Roche
ester derivatives B. Similar reactions of achiral substrates are
well-known, but finding appropriate organocatalysts to over-
come the stereochemical bias exerted by the C3 chiral center
was an open issue.
Scheme 2. Asymmetric Transformations of Substrates 6: (a)
Chlorination; (b) Fluorination; and (c) Amination
a
RESULTS AND DISCUSSION
■
There is a literature procedure for conversion of glyoxylic acid
monohydrate into the α,β-unsaturated ester F.15 The first new
step in this work was to chemoselectively reduce the ester
group of F in the presence of its carboxylic acid functionality16
to give the hydroxyacid 1,17,18 which was isolated via acid−base
extraction (in this manuscript, numbers are given to com-
pounds obtained via a new route, even if they are known); this
procedure seems to be superior to both the established routes
to 1.17,18 Subsequently, the hydroxyacid 1 was esterified to give
the known19 hydroxyester 2. None of the steps described in
Scheme 1a involve column chromatography, and the synthesis
can give tens of grams of the product 2.
Scheme 1. (a) Synthesis of the Hydrogenation Substrate 2
and (b) Asymmetric Hydrogenation of Alkene 2
a
Throughout, selectivities were determined via analytical HPLC on a
Chiralcel-OD column.
15 g of the hydroxyester 2 can be hydrogenated with complete
conversion to give 3 (a type B chiron), and the catalysts is
still active at the end of this transformation. High, but not
perfect, enantioselectivities are obtained in this process, and
the acyclic product 3 can be lactonized to 4 then efficiently
recrystallized to give optically pure material. For subsequent
applications of these products (here and perhaps elsewhere),
the lactone 4 was converted to two other potentially useful
acyclic chirons, the alcohol 3 (now as one enantiomer) and
the silyl ether 5.
Hydrogenation of alkene 2 is the key transformation in this
paper. Under the conditions shown in Scheme 1b, approximately
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The next task was to convert ester 5 to the corresponding
aldehyde 6 (reaction 1); Brookhart’s catalytic silylation/hydrolysis
procedure20 was used for this transformation. This reduction
afforded the aldehyde 6 for elaboration via organocatalytic pro-
cesses involving iminium and enamine intermediates.
Finally, derivatives of γ-hydroxyvaline J were prepared to
illustrate how the amination products 9 could be used in a
novel short synthesis. γ-Hydroxyvalines are naturally occurring
amino acids that have been associated with stimulation of
insulin secretion.30 Hydrogenolysis of the benzyl protecting
groups of 9 and simultaneous homolysis of the N−N bond gave
the N-protected amino alcohols 11 after addition of Fmoc
(Scheme 3). Catalytic oxidation of those alcohols gave the
N-Fmoc-γ-silyl protected amino acid 12. All four stereoisomers
of 12 could be obtained by this route, and one enantiomer of
each of the syn- and anti-forms was made to prove this. The
final products 12 are suitably protected for many peptide
synthesis strategies, so no attempt was made to obtain the
corresponding γ-hydroxyvalines since we have no immediate
application for these. The synthesis of the 2S,3S-syn-isomer was
performed on a large enough scale to obtain 0.42 g of product.
Previous syntheses of γ-hydroxyvaline derivatives required
either 12 steps to obtain an enantiomer of the N-BOC-O-
PMB-protected form of the reduced product (i.e., alcohol not
carboxylic acid),31 or via multistep routes to syn,anti-mixtures of
various protected derivatives that were then separated (via
crystallization of diastereomeric copper complexes,32 or via
column chromatography33).
To the best of our knowledge, organocatalytic transfor-
mations of the homo-Roche aldehydes 6 have not been re-
ported before. However, there is precedent for electrophilic
α-substitutions of β-chiral aldehydes,21 and, of course, a great
deal of literature for the parent reactions of acyclic nonchiral
aldehydes.22 Scheme 2 shows the data accumulated for the
organocatalytic transformations of aldehyde 6. Part a refers to
chlorinations performed using MacMillan’s catalyst M•TFA23
(a commercial sample of the hydrochloride catalyst did not
work in this reaction, so it was converted to the trifluoroacetate,
that is, the salt used by MacMillan’s group). It emerged that
the (S)-enantiomer of the catalyst matched24 the substrate bias
and gave an excellent stereoselectivity for the syn-isomer of 7
after borohydride reduction. However, in the mismatched case
(R)-M•TFA overwhelmed the substrate bias hence a 10:1.0
ratio in favor of anti-7 was observed. Similarly, MacMillan’s
Scheme 3. Syntheses of α-N-γ-O-Protected Forms of
γ-Hydroxyvaline
fluorination procedure25 using (R)-M•Cl2HCCO2 gave even
−
better matched and mismatched selectivities in catalyst-
controlled reactions to give the 2-fluoroalcohols 8 after reduc-
tion. For amination reactions it was desirable to use dibenzyl
azocarboxylate rather than other alkyl derivatives for the
reasons indicated below (Scheme 3), so we used List’s pro-
cedure that described application of exactly that electrophile.26
Just as in the chlorination and fluorination reactions, the amin-
ations were catalyst-controlled. These transformations gave
superb selectivity in the matched case for syn-9, and a 13:1.0
ratio for the anti-isomer via the mismatched process.
Reactions 2 and 3 show how the isomeric 2-chloroalcohols 7
were efficiently ring closed to the corresponding epoxides 10.
These reactions were performed because the epoxides 10 are
valuable chirons, but their use has been limited by the fact that
syntheses of these materials require multiple steps and some
routes are only practical for one or two of the four possible
stereoisomers.27−29
CONCLUSIONS
■
The pivotal observation in this paper is that we may use type-D
trisubstituted alkenes, specifically 2, to give the same product
that would be formed from hydrogenation of itaconic acid (or
the diester) and differentiation of the two carboxylate groups
(then reduction). Key to this is the fact that chiral Crabtree’s
analogs like cat can mediate hydrogenations of trisubstituted
alkenes without suitable coordinating functional groups
(CFGs) for binding Rh-centers. Fortunately, the starting
material 2 is also easy to make and this facilitates the whole
process.
Prior to our studies, Alexakis and Mazet elegantly combined
enantioselective iridium-mediated isomerization reactions34−37
with organocatalytic functionalization of aldehydes to form two
chiral centers.21 The work we have performed here is con-
ceptually similar except that it is based on production of a par-
ticularly high-value chiron, the homo-Roche ester, and elab-
oration of that in distinct steps. Moreover, the initial chiral
center is established here via hydrogenation rather than iso-
merization reactions.
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Catalytic Hydrogenation. (E)-Methyl 4-hydroxy-3-methylbut-2-
enoate 2 (120 mmol) and (S)-cat (1 mol %) were dissolved in CH2Cl2
(0.5 M). The resulting mixture was degassed by three cycles of freeze−
pump−thaw and then transferred to a Parr Bomb. The bomb was
pressurized to 50 bar with hydrogen and the mixture was stirred at
300 rpm for 24 h. The bomb was then vented and solvent was
evaporated. The crude product was passed through a short silica plug
using 10−30% EtOAc/hexanes as the eluent. The enantiomeric ratio
was then measured through chiral GC analysis.
EXPERIMENTAL SECTION
■
General Procedures. All reactions were carried out under an air
atmosphere unless it stated. Glassware for anhydrous reactions was dried in
an oven at 140 °C for minimum 6 h prior to use. Dry solvents were
obtained by passing the previously degassed solvents through activated
alumina columns. Reagents were purchased at a high commercial quality
(typically 97% or higher) and used without further purification, unless
otherwise stated. High field NMR spectra were recorded at 400 MHz for
1H, and 100 MHz for 13C. Chemical shifts of H and 13C spectra were
1
Methyl (S)-4-Hydroxy-3-methylbutanoate (3). Colorless oil, 15.2 g
referenced to the NMR solvents. Flash chromatography was performed
using silica gel (230−600 mesh). Thin layer chromatography was
performed using glass plates coated with silica gel 60 F254. The following
abbreviations were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double
doublet, dq = double quartet, m = multiplet, br = broad.
1
(95% isolated yield); H NMR (400 MHz, CDCl3) δ 4.05 (s, 3H),
3.35 (dd, J = 6.6, 12 Hz, 2H), 2.48 (m, 2H), 2.07 (m, 1H), 0.92 (d, J =
6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 68.5, 62,1, 37.8,
32.5, 14.7. HRMS (ESI, TOF): m/z = 133.0864, calcd For C6H13O3
[M+H]+ 133.0865.
Preparation of (S)-4-Methyldihydrofuran-2(3H)-one (4). To a
solution of methyl (S)-4-hydroxy-3-methylbutanoate (12 g, 90 mmol)
Preparation of (E)-Methyl 4-Hydroxy-3-methylbut-2-enoate (2).
in 30 mL of CH2Cl2, TsOH (0.95 equiv) was added at room tem-
perature. The mixture was stirred for 6 h, then the organic layer was
washed with H2O (3 × 30 mL), brine and dried over Na2SO4. Solvent
was removed under reduced pressure to yield product as colorless oil
(9.8 g, 98%).
Procedure for Recrystallization. (S)-4-Methyldihydrofuran-
2(3H)-one 4 was dissolved in EtOAc and hexane and the mixture
was cooled to −20 °C. After getting precipitation, solvent was de-
canted in low temperature and washed with cold hexane.
Preparation of Methyl (S)-4-((tert-Butyldiphenylsilyl)oxy)-3-
methylbutanoate (5). To a solution of methyl (S)-4-hydroxy-3-
(E)-4-Methoxy-3-methyl-4-oxobut-2-enoic Acid (F).15 To a solution
of (1-methoxy-1-oxopropan-2-yl)triphenylphosphonium
bromide (42.9 g, 100 mmol) in dry MeCN (300 mL) was added
triethylamine (13.2 mL, 95 mmol) and glyoxylic acid monohydrate
(8.74 g, 95 mmol) at 0 °C. The solution was further stirred at 0 °C for
2 h and at room temperature overnight. Half of the solvent was removed
under reduced pressure, and ethyl acetate (100 mL) was added. The result-
ing solution was washed with saturated aqueous NaHCO3 (3 × 50 mL).
The combined aqueous layers were extracted with ethyl acetate (2 ×
50 mL), acidified (pH 1 - 2) at 0 °C with concentrated HCl (50 mL) and
extracted with ethyl acetate (3 × 50 mL). The combined organic layers
were evaporated to dryness, yielding a clear oil F (10.5 g, 73%) which was
used for the next reaction without further purification.
(E)-4-Hydroxy-3-methylbut-2-enoic Acid (1).16 LiBH4 (400 mmol)
was added to (E)-4-methoxy-3-methyl-4-oxobut-2-enoic acid F
(200 mmol) in THF (200 mL) at 0 °C. The reaction mixture was
then allowed to ambient temperature and stirred for 12 h. The mixture was
poured into 1N HCl and extracted with ethyl acetate (3 × 50 mL). The
combined organic layers were dried over Na2SO4 and solvent was removed
under reduced pressure to yield the product 1 as a white solid (16 g, 69%),
which was used for the next reaction without further purification.
methylbutanoate 3 (5.5 g, 42 mmol) in 30 mL of DMF, TBDPSCl
(0.95 equiv) was added at room temperature. The mixture was stirred
for 4 h, then solvent was removed under reduced pressure. The residue
was dissolved in CH2Cl2. The organic layer was washed with H2O
(3 × 30 mL), brine and dried over Na2SO4. Solvent was removed
under reduced pressure and the crude was purified by chromatography
using 5% EtOAc/hexane as eluent to obtain product 5 as a clear oil
1
(15 g, 99%). H NMR (400 MHz, CDCl3) δ 7.79−7.30 (m, 10H),
(E)-Methyl 4-Hydroxy-3-methylbut-2-enoate (2). To a solution of
H2SO4 in 50 mL of MeOH, (E)-4-hydroxy-3-methylbut-2-enoic acid 1
(150 mmol) was added at room temperature. The mixture was stirred
and refluxed for 4 h. After cooling to ambient temperature, solvent was
removed under reduced pressure. The residue was dissolved in
CH2Cl2. The organic layer was washed with NaHCO3, brine and dried
over Na2SO4. Solvent was removed under reduced pressure to obtain
3.69 (s, 3H), 3.59 (dd, J = 3.3, 12 Hz, 2H), 2.63−2.60 (m, 2H), 2.32−
2.20 (m, 1H), 1.09 (s, 9H), 1.02 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.5, 137.8, 133.8, 129.7, 126.9, 68.7, 51.9,
38.7, 26.8, 19.7, 16.1. HRMS (ESI, TOF): m/z = 371.0222, calcd For
C22H31O3Si [M+H]+ 371.0242.
Preparation of (S)-4-(tert-Butyldiphenylsilyloxy)-3-methyl-
butanal (6). A modification of reported procedure20 was used.
1
product 2 as a clear oil (12 g, 62%). H NMR (400 MHz, CDCl3)
δ 6.48 (d, J = 4.7 Hz, 1H), 3.96 (s, 2H), 3.63 (s, 3H), 1.89 (d, J =
6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 132.3, 119.7, 67.2,
58.3, 26.2. HRMS (ESI, TOF): m/z = 131.0711, calcd For C6H11O3
[M+H]+ 131.0708.
Under an atmosphere of argon, to an oven-dried flask was added
[Ir(COD)Cl]2 (10.1 mg, 0.015 mmol) and 1.5 mL of CH2Cl2. Then
diethyl silane (529 mg, 6.0 mmol) was added and the resulting mixture
was stirred at 23 °C for 1 min. After addition of methyl (S)-4-((tert-
butyldiphenylsilyl)oxy)-3-methylbutanoate 5 (3.0 mmol), the mixture
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1
was stirred at 23 °C for 1 h. Then add another portion of [Ir(COD)-
Cl]2 (10.1 mg, 0.015 mmol) and diethyl silane (265 mg, 3.0 mmol) to
the mixture and allow it to stir 23 °C for 2 h. The reaction was diluted
with diethyl ether and quenched by 0.1 M HCl. After stirring for
20 min, the layers were separated and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried with MgSO4,
and concentrated under vacuum. Purification of the residue by flash
chromatography on silica gel, eluting with ∼10−15% CH2Cl2/hexanes
yield). H NMR (400 MHz, CDCl3) 7.81−7.75 (m, 4H), 7.54−7.44
(m, 6H), 4.49−4.45 (m, 1H), 3.88−3.86 (m, 2H), 3.71−3.62 (m, 2H),
2.34 (br, 1H), 2.22−2.16 (m, 1H), 1.12 (s, 9H), 1.05 (d, J = 6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 135.6, 135.6, 133.2, 129.8,
127.8, 66.5, 65.7, 65.7, 38.8, 26.9, 19.3, 11.8. IR (CH2Cl2) νcm−1)
3356, 3071, 2932, 2859, 2361, 1470, 1427, 1377, 1111, 822. HRMS
(ESI, TOF): m/z = 377.1718, calcd For C21H30ClO2Si [M+H]+
377.1704. The diastereoselectivity was 18:1.0, determined by 1H
NMR and confirmed by Chiral HPLC (Chiralcel OD, Hex/iPrOH
99:1, 1 mL/min, 25 °C), tr 11.7 min (major diastereomer), tr 12.7 min
(minor diastereomer).
1
gave the desired aldehyde 6 as colorless oil (766 mg, 75%). H NMR
(400 MHz, CDCl3) δ 9.86 (t, J = 2.1 Hz, 1H), 7.81−7.74 (m, 4H),
7.54−7.47 (m, 6H), 3.70 (dd, J = 9.9, 5.1 Hz, 1H), 3.57 (dd, J = 9.9,
6.9 Hz, 1H), 2.69 (ddd, J = 15.9, 5.7, 2.1 Hz, 1H), 2.48−2.39 (m, 1H),
2.35 (ddd, J = 15.9, 7.2, 2.1 Hz, 1H), 1.18 (s, 9H), 1.05 (d, J = 6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 202.5, 135.6, 135.6, 133.6, 133.5
129.8, 127.8, 68.5, 48.2, 31.3, 27.0, 19.3, 16.9. IR (CH2Cl2) νcm−1)
3070, 2931, 2858, 2360, 1724, 1469, 1427, 1111, 806.3, 740.7, 702.1.
HRMS (ESI, TOF): m/z = 347.2021, calcd for C21H28O2SiLi [M+H]+
347.2019.
The product was converted to the epoxide according to the typical
procedure for preparation epoxides. Purification by flash chromatog-
raphy afforded (2R,3R)-4-tert-butyldiphenylsilyloxy-1,3-epoxy-3-meth-
1
ylbutane (anti-10) as a colorless oil (67.5 mg, 95% isolated yield). H
NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 4H), 7.49−7.38 (m, 6H),
3.66 (dd, J = 6.3, 1.6 Hz, 2H), 2.90−2.87 (m, 1H), 2.79 (dd, J = 4.9,
4.1 Hz, 1H), 2.63 (dd, J = 5.0, 2.8 Hz, 1H), 1.65−1.56 (m, 1H), 1.09
(s, 9H), 1.03 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
135.6, 133.6, 129.7, 127.7, 66.4, 55.1, 46.8, 39.1, 26.8, 19.2, 13.3. IR
(CH2Cl2) νcm−1) 3070, 2927, 2859, 2338, 1462, 1427, 1389, 1362,
1111, 933.6, 887.3, 821.7. HRMS (ESI, TOF): m/z = 347.2020, calcd
For C21H28O2SiLi [M+Li]+ 347.2019.
Typical Procedure for α-Chlorination of the Aldehyde. A
modification of reported procedure23 was used. 5-Benzyl-2,2,3,-
(2R,3R)-4-((tert-Butyldiphenylsilyl)oxy)-2-chloro-3-methylbutan-
1-ol (anti-7). The compound was prepared according to the typical
chlorination procedure catalyzed by (R)-5-benzyl-2,2,3,-trimethylimi-
dazolidin-4-one trifluoroacetic acid salt. Purification by flash chro-
matography afforded anti-7 as colorless oil (141 mg, 75% isolated
yield). 1H NMR (400 MHz, CDCl3) δ 7.74−7.68 (m, 4H), 7.51−7.39
(m, 6H), 4.26−4.22 (m, 1H), 3.95 (dd, J = 12.2, 4.5 Hz, 1H), 3.87
(dd, J = 12.2, 6.5 Hz, 1H), 3.78 (dd, J = 10.4, 5.9 Hz, 1H), 3.72 (dd,
J = 10.4, 4.3 Hz, 1H), 2.54 (br, 1H), 2.27−2.16 (m, 1H), 1.10 (s, 2H),
1.06 (d, J = 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.6, 133.1,
129.8, 127.8, 67.4, 65.5, 65.1, 39.4, 26.9, 19.2, 14.6. IR (CH2Cl2)
νcm−1) 3383, 3071, 2932, 2859, 2361, 1470, 1427, 1389, 1111. HRMS
(ESI, TOF): m/z = 377.1710, calcd For C21H30ClO2Si [M+H]+
377.1704. The diastereoselectivity was 1.0:10 determined by 1H
NMR and confirmed by Chiral HPLC (Chiralcel OD, Hex/iPrOH
99:1, 1 mL/min, 25 °C), tr 11.8 min (minor diastereomer), tr 12.8 min
(major diastereomer).
trimethylimidazolidin-4-one trifluoroacetic acid salt (13.5 mg, 0.05 mmol)
in chloroform (1 mL) is cooled to −30 °C for five minutes prior to
addition of 2,3,4,5,6,6-hexachloro-2,4-cyclohexadien-1-one (181 mg,
0.6 mmol). The aldehyde 6 (170 mg, 0.5 mmol) was added to the
yellow mixture. The resulting mixture was stirred at −30 °C for 8 h.
The reaction was then warmed to 0 °C and MeOH (1 mL) was added
to the mixture, followed by NaBH4 (80 mg, 2 mmol). After stirring at
0 °C for 5 min, the reaction was quenched by 1 M KHSO4. The
aqueous solution was extracted with EtOAc three times. The
combined organic layers were dried with MgSO4, and concentrated
in vacuo. Purification of the residue by flash chromatography on silica
gel, eluting with 2.5% ∼ 5.0% EtOAc/hexanes gave the desired alcohol
as colorless oil.
Typical Procedure for Preparation Epoxides. Under Ar, to a
solution of 7 (75.4 mg, 0.2 mmol) in anhydrous THF was added NaH
The product was then converted to the epoxide according to the
typical procedure for preparation epoxides. Purification by flash chro-
matography afforded (2S,3R)-4-tert-butyldiphenylsilyloxy-1,3-epoxy-3-
methylbutane (syn-10) as colorless oil (61.3 mg, 90% isolated yield).
The relative stereochemistry was determined by comparing with a
known epoxide, which was reported previously.29 1H NMR (400 MHz,
CDCl3) δ 7.74−7.66 (m, 4H), 7.48−7.38 (m, 6H), 3.75 (qd, J = 9.9,
5.1 Hz, 2H), 3.02−2.99 (m, 1H), 2.81−2.75 (m, 1H), 2.57 (dd, J =
5.0, 2.8 Hz, 1H), 1.68−1.60 (m, 1H), 1.10 (s, 9H), 1.03 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 135.6, 133.8, 129.6, 127.6, 66.2,
54.0, 45.6, 38.5, 26.9, 19.3, 12.6. IR (CH2Cl2) νcm−1) 3071, 2928,
2859, 1470, 1427, 1389, 1362, 1111, 933.6, 875.7, 821.7. HRMS (ESI,
TOF): m/z = 347.2003, calcd For C21H28O2SiLi [M+Li]+ 347.2019.
(10.0 mg, 0.4 mmol) and the mixture was stirred at 60 °C for 4 h. The
reaction was quenched by 1 M KHSO4. The aqueous solution was
extracted with CH2Cl2 three times. The combined organic layers
were dried with MgSO4, and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel, eluting with CH2Cl2/
hexanes (20%) gave the desired epoxide as a colorless oil.
1
Relative stereochemistry determination of 7: the H NMR data of
syn-10 matched with reported data29 and differs from that of anti-10.
Therefore, the relative stereochemistry assignment was confirmed.
Typical Procedure for α-Fluorination of the Aldehyde. A
modification of reported procedure25 was used. 5-Benzyl-2,2,3,-
trimethylimidazolidin-4-one dichloroacetic acid salt (38.0 mg,
0.1 mmol) and N-fluorobenzenesulfonimide (315 mg, 1.0 mmol)
(2S,3R)-4-((tert-Butyldiphenylsilyl)oxy)-2-chloro-3-methylbutan-
1-ol (syn-7). The compound was prepared according to the typical
α-chlorination procedure catalyzed by (S)-5-benzyl-2,2,3,-trimethyli-
midazolidin-4-one trifluoroacetic acid salt. Purification by flash chro-
matography afforded syn-7 as a colorless oil (147 mg, 78% isolated
i
was dissolved in THF (4.5 mL) and PrOH (0.5 mL). The mixture
was cooled to −10 °C prior to addition of the aldehyde (170 mg,
0.5 mmol). The resulting mixture was stirred at −10 °C for 16 h and
11952
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99:1, 1 mL/min, 25 °C), 3tr 16.05 min (minor diastereomer), tr 23.68
min (major diastereomer).
Relative stereochemistry determination of 8: since both catalyst and
reaction condition are identical to what has been reported, and the re-
action is catalyst controlled; the stereochemistry was assigned ac-
cording to MacMillan’s fluorinated product. The product cannot be
easily converted to any known structure.
Typical Procedure for the α-Amination of the Aldehyde. A
modification of reported procedure38 was used. Dibenzyl azodicarbox-
was then warmed to 0 °C. To the mixture at 0 °C was added 1 mL
MeOH and NaBH4 (200 mg, 5 mmol). After stirring at 0 °C for 5 min,
the reaction was quenched by 1 M KHSO4. The mixture was diluted
with water and the aqueous solution was extracted with EtOAc three
times. The combined organic layers were dried with MgSO4, and
concentrated in vacuo. The residue was redissolved in dichloromethane
and the solid was filtered off on a small silica pad. The mixture was
concentrated again in vacuo. Purification of the residue by flash chro-
matography on silica gel, eluting with ∼5−10% EtOAc/hexanes gave
the desired alcohol as colorless oil.
ylate (90%, 1.29 g, 3.9 mmol) and proline (70 mg, 0.6 mmol) in
MeCN (10 mL) were cooled down to −3 °C. The aldehyde (1.02 g 3.0
mmol) was then added and the mixture was stirred at −3 °C for 2 h.
The reaction was gradually warmed to 20 °C within ca. 1 h. The
mixture was then cooled to 0 °C, treated with MeOH (3 mL) and
NaBH4 (240 mg, 6.0 mmol) and was stirred for 5 min at 0 °C. The
reaction was quenched by 1 M KHSO4. The aqueous solution was
extracted with EtOAc three times. The combined organic layers were
dried with MgSO4, and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel, eluting with 15%
EtOAc/hexanes gave the desired alcohol as white foamy solid.
(2S,3R)-4-((tert-Butyldiphenylsilyl)oxy)-2-fluoro-3-methylbutan-
1-ol (syn-8). The compound was prepared according to the typical
α-fluorination procedure catalyzed by (S)-5-benzyl-2,2,3,-trimethyli-
midazolidin-4-one dichloroacetic acid salt. Purification by flash chro-
matography afforded syn-8 as a colorless oil (162 mg, 90% isolated
yield). 1H NMR (400 MHz, CDCl3) δ 7.72−7.69 (m, 4H), 7.51−7.39
(m, 6H), 4.66 (dtd, J = 48.4, 6.2, 3.0 Hz, 1H), 3.96−3.68 (m, 4H),
2.22−2.01 (m, 2H), 1.11 (s, 9H), 1.04 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 135.6 (d, J = 2.3 Hz), 133.5 (d, J = 3.1 Hz),
129.7 (d, J = 1.3 Hz), 127.7 (s), 95.4 (d, J = 170.3 Hz), 64.5 (d, J =
6.1 Hz), 63.3 (d, J = 22.2 Hz), 37.1 (d, J = 18.9 Hz), 26.9 (s), 19.3 (s),
13.0 (d, J = 6.8 Hz); 19F NMR (282 MHz, CDCl3) δ −194.48 (dtd,
J = 40.0, 25.3, 14.5 Hz). IR (CH2Cl2) νcm−1) 3364, 3071, 2928, 2855,
2361, 1470, 1427, 1393, 1362, 1111, 1049. HRMS (ESI, TOF): m/z =
361.2021, calcd For C21H30FO2Si [M+H]+ 361.1999. The diaster-
eoselectivity was 19F NMR and confirmed by 22:1.0 determined by
Chiral HPLC (Chiralcel OD, Hex/iPrOH 99:1, 1 mL/min, 25 °C), tr
16.05 min (major diastereomer), tr 23.68 min (minor diastereomer).
Dibenzyl 1-((2R,3S)-4-((tert-Butyldiphenylsilyl)oxy)-1-hydroxy-3-
methylbutan-2-yl)hydrazine-1,2-dicarboxylate (anti-9). The com-
pound was prepared according to the typical α-amination proce-
dure catalyzed by (S)-Proline. Purification by flash chromatography
afforded anti-9 as a white foamy solid (1.54 g, 80% isolated yield). 1H
NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 4H), 7.50−7.27 (m, 16H),
6.85 (d, J = 31.1 Hz, 1H), 5.37−5.10 (m, 4H), 4.45−4.12 (m, 2H),
3.80−3.41 (m, 4H), 1.95−1.66 (m, 1H), 1.12−1.09 (m, 9H), 0.99−
0.88 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 157.4, 135.6,
133.3, 133.2, 129.6, 129.8, 128.7, 128.6, 128.2, 127.9, 127.8, 127.7,
68.6, 65.9, 65.6, 60.4, 35.6, 26.9, 19.3, 15.1. IR (CH2Cl2) νcm−1) 3356,
3032, 2928, 1717, 1454, 1408, 1265, 1227, 1111, 1057. HRMS (ESI,
TOF): m/z = 641.3078, calcd For C37H45N2O6Si [M+H]+ 641.3047.
The diastereoselectivity was 1.0:13, determined by Chiral HPLC
(Chiralcel OD, Hex/iPrOH 93:7, 1 mL/min, 25 °C), tr 10.3 min (minor
diastereomer), tr 14.4 min (major diastereomer).
(2R,3R)-4-((tert-Butyldiphenylsilyl)oxy)-2-fluoro-3-methylbutan-
1-ol (anti-8). The compound was prepared according to the typical
α-fluorination procedure catalyzed by (R)-5-benzyl-2,2,3,-trimethyli-
midazolidin-4-one dichloroacetic acid salt. Purification by flash
chromatography afforded anti-8 as a colorless oil (153 mg, 85%
1
isolated yield). H NMR (400 MHz, CDCl3) δ 7.74−7.69 (m, 4H),
7.51−7.41 (m, 6H), 4.72 (dtd, J = 48.8, 6.4, 3.1 Hz, 1H), 3.97−3.75
(m, 2H), 3.67−3.64 (m, 2H), 2.28 (br, 1H), 2.11−2.00 (m, 1H), 1.12
(s, 9H), 0.99 (dd, J = 7.0, 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 135.6 (d, J = 4.5 Hz), 133.3 (d, J = 8.2 Hz), 129.8 (s), 127.8 (d, J =
1.6 Hz), 95.4 (d, J = 171.0 Hz), 65.2 (d, J = 6.0 Hz), 63.7 (d, J = 22.6
Hz), 37.4 (d, J = 19.6 Hz), 26.9 (s), 11.7 (d, J = 5.8 Hz); 19F NMR
(282 MHz, CDCl3) δ −198.46 to −198.93 (m). IR (CH2Cl2) νcm−1)
3356, 3071, 2932, 2859, 2361, 1470, 1427, 1389, 1362, 1111, 1034.
HRMS (ESI, TOF): m/z = 361.2035, calcd For C21H30FO2Si [M+H]+
361.1999. The diastereoselectivity was 1.0:58, determined by 19F
NMR and confirmed by Chiral HPLC (Chiralcel OD, Hex/iPrOH
Dibenzyl 1-((2S,3S)-4-((tert-Butyldiphenylsilyl)oxy)-1-hydroxy-3-
methylbutan-2-yl)hydrazine-1,2-dicarboxylate (syn-9). The com-
pound was prepared according to the typical α-amidation procedure
catalyzed by (R)-Proline. Purification by flash chromatography
afforded syn-9 as a white foamy solid (1.63 g, 85% isolated yield).
1H NMR (400 MHz, CDCl3) δ 7.69−7.62 (m, J = 13.5, 6.6 Hz, 4H),
11953
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7.50−7.24 (m, 16H), 6.96 (s, 1H), 5.30−5.22 (m, 3H), 5.13 (dd, J =
12.1, 9.6 Hz, 1H), 4.36−4.16 (m, 2H), 3.86−3.70 (m, 2H), 3.59−3.44
(m, 2H), 1.80 (br, 1H), 1.11−1.08 (m, 9H), 0.93−0.90 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 158.2, 156.8, 156.5, 135.9, 135.6,
135.5, 135.4, 133.0, 130.1, 129.9, 128.6, 128.5, 128.1, 127.9, 127.8,
68.3, 64.0, 63.2, 60.6, 35.5, 27.0, 19.2, 14.9. IR (CH2Cl2) νcm−1) 3356,
3032, 2959, 1724, 1470, 1408, 1261, 1223, 1111, 1053. HRMS (ESI,
TOF): m/z = 641.3063 calcd For C37H45N2O6Si [M+H]+ 641.3047.
The diastereoselectivity was 62:1.0, determined by Chiral HPLC
(Chiralcel OD, Hex/iPrOH 93:7, 1 mL/min, 25 °C), tr 10.2 min (minor
diastereomer), tr 14.3 min (major diastereomer).
13C NMR (100 MHz, CDCl3) δ 138.5, 135.6, 133.8, 133.7, 129.6,
128.4, 127.7, 127.6, 74.3, 73.2, 66.8, 29.7, 26.9, 19.3, 11.7.
Relative stereochemistry determination of 9: the 13C NMR data of
syn-13 matched with reported data39 and differ from that of anti-13.
Therefore, the relative stereochemistry assignment was confirmed.
Typical Procedure for the Preparation of α-Amino Acid. To
Raney−Nickel (∼1.5 g, prewashed with dry MeOH) in MeOH (10 mL),
Typical Procedure for the Hydrogenolysis and Benzylation
of the Alcohol. To Raney−Nickel (∼0.3 g, prewashed with dry
MeOH) in MeOH (1 mL), was added AcOH (0.3 mL) and a solution
of 9 (64.0 mg, 0.1 mmol) in MeOH (1 mL). The solution was
degassed and stirred under a slightly positive pressure of hydrogen
(balloon) at 23 °C for 16 h. The reaction was then filtered through a
short pad of Celite, and washed with CH2Cl2. The mixture was
concentrated in vacuo and the residue was redissolved in CH2Cl2 and
was neutralized by anhydrous Na2CO3. The solvent was removed by
vacuum and the crude product was subjected to benzyl protection
without further purification. Under Ar atmosphere, to a solution of the
hydrogenated crude product (0.15 mmol) in anhydrous THF was
added NaH (4.8 mg, 0.4 mmol). After stirring for 5 min, BnBr (19 μL,
was added AcOH (3 mL) and a solution of 9 (1.44 g, 2.25 mmol) in
MeOH (10 mL). The solution was degassed and stirred under a
slightly positive pressure of hydrogen (balloon) at 23 °C for 16 h. The
reaction was then filtered through a short pad of Celite, and washed
with CH2Cl2. The mixture was concentrated in vacuo and the residue
was redissolved in CH2Cl2 and was neutralized by anhydrous Na2CO3.
The solvent was removed by vacuum and the crude product was
subjected to Fmoc-protection without further purification. To a solu-
tion of the above crude product in H2O (10 mL) and acetone (10 mL)
was added FmocOSu (830 mg, 2.5 mmol) and Na2CO3 (715 mg,
6.7 mmol). The reaction was stirred at 23 °C for 16 h. The mixture was
extracted with EtOAc three times. The combined organic layers were
dried with MgSO4, and concentrated in vacuo. Purification of the residue
by flash chromatography on silica gel, eluting with 10% ∼ 20% EtOAc/
hexanes gave 11 as a white foamy solid. To a solution of RuCl3 (29 mg,
0.14 mmol) and NaIO4 (2.95 g, 13.8 mmol) in water was added 11
(800 mg, 1.38 mmol). The mixture was stirred at 23 °C for 2 h, and
then added MeOH (2 mL). The reaction was stirred until solid
precipitation occurred. The solid was filtered on Celite and washed it
with EtOAc. One M KHSO4 (3 mL) was added to the filtrate. Then, the
aqueous phase was extracted by EtOAc. The combined organic layers
were dried with MgSO4, and concentrated in vacuo. Purification of the
residue by flash chromatography on silica gel, eluting with ∼15−50%
EtOAc/hexanes gave the desired acid 12 as a white foamy solid.
n
0.15 mmol) and Bu4NI (11.1 mg, 0.03 mmol) was added and the
mixture was stirred at 23 °C for 16 h. The reaction was quenched by
1 M KHSO4. The aqueous solution was extracted with EtOAc (three
times). The combined organic layers were dried with MgSO4, and
concentrated in vacuo. Purification of the residue by flash chroma-
tography on silica gel, eluting with ∼1.0−2.5% MeOH/CH2Cl2 gave
the desired product as a white foamy solid.
(2S,3S)-1-(Benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)-3-methylbu-
tan-2-amine (syn-13). The compound was prepared according to the
typical hydrogenolysis and benzylation procedure. Purification by flash
chromatography afforded syn-13 as a white foamy solid (22.2 mg, 50%
yield in two steps). 1H NMR (400 MHz, CDCl3) δ 7.71−7.65
(m, 4H), 7.48−7.28 (m, 11H), 4.55 (d, J = 4.8 Hz, 2H), 3.77−3.60
(m, 3H), 3.47 (dd, J = 9.3, 7.6 Hz, 1H), 3.18 (td, J = 7.2, 3.4 Hz, 1H),
2.80 (br, 2H), 1.90−1.79 (m, 1H), 1.08 (s, 9H), 0.94 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 138.1, 135.6, 133.4, 133.3,
129.7, 128.4, 127.8, 127.7, 73.3, 72.8, 66.8, 53.9, 38.1, 27.0, 19.2, 13.9.
(9H-Fluoren-9-yl)methyl ((2S,3S)-4-((tert-Butyldiphenylsilyl)oxy)-
1-hydroxy-3-methylbutan-2-yl)carbamate (syn-11). Purification by
flash chromatography afforded syn-11 as a white foamy solid (1.28 g,
98% yield in two steps). H NMR (400 MHz, CDCl3) δ 7.86−7.74
1
(m, 6H), 7.66 (dd, J = 7.3, 3.6 Hz, 2H), 7.55−7.40 (m, 8H), 7.34 (t,
J = 7.4 Hz, 2H), 6.05 (d, J = 6.7 Hz, 1H), 4.50 (d, J = 6.5 Hz, 2H),
4.28 (t, J = 6.8 Hz, 1H), 3.93−3.74 (m, 4H), 3.69 (dd, J = 10.4, 4.5 Hz,
1H), 3.31 (br, 1H), 2.05 (br, 1H), 1.19 (s, 9H), 1.13 (d, J = 6.7 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 157.4, 144.1, 141.4, 135.7,
132.9, 130.0, 127.9, 127.7, 127.1, 125.2, 120.0, 66.9, 66.0, 64.6, 56.7,
47.4, 35.7, 27.0, 19.2, 15.3. IR (CH2Cl2) νcm−1) 3402, 3067, 2928,
1701, 1508, 1450, 1327, 1227, 1111, 1042. HRMS (ESI, TOF): m/z =
580.2874, calcd For C36H42NO4Si [M+H]+ 580.2883.
(2R,3S)-1-(Benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)-3-methyl-
butan-2-amine (anti-13). The compound was prepared according
to the typical hydrogenolysis and benzylation procedure. Purification
by flash chromatography afforded anti-13 as a white foamy solid
(22.3 mg, 50% yield in two steps). 1H NMR (400 MHz, CDCl3) δ 7.70−
7.67 (m, 4H), 7.49−7.28 (m, 11H), 4.54 (s, 2H), 3.68−3.58 (m, 2H),
3.56−3.49 (m, 1H), 3.38 (dd, J = 10.2, 6.5 Hz, 1H), 3.26 (br, 1H),
1.83 (br, 1H), 1.51 (br, 2H), 1.08 (s, 9H), 0.92 (d, J = 6.9 Hz, 3H);
(9H-Fluoren-9-yl)methyl ((2R,3S)-4-((tert-Butyldiphenylsilyl)oxy)-
1-hydroxy-3-methylbutan-2-yl)carbamate (anti-11). Purification by
flash chromatography afforded anti-11 as a white foamy solid (1.24 g,
1
95% yield in two steps). H NMR (500 MHz, CDCl3) δ 7.84−7.77
11954
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Article
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7.55−7.39 (m, 8H), 7.33 (td, J = 7.5, 1.0 Hz, 2H), 5.85 (d, J = 8.3 Hz,
1H), 4.51−4.43 (m, 2H), 4.26 (t, J = 6.9 Hz, 1H), 3.90 (dd, J = 11.2,
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63.0, 56.3, 47.4, 37.2, 27.0, 19.2, 14.1. IR (CH2Cl2) νcm−1) 3368,
3067, 2928, 1701, 1512, 1450, 1242, 1111. HRMS (ESI, TOF): m/z =
580.2865, calcd For C36H42NO4Si [M+H]+ 580.2883.
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(2S,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-
butyldiphenylsilyl)oxy)-3-methylbutanoic acid (syn-12). Purification
by flash chromatography afforded syn-12 as a white foamy solid (0.42 g,
49% yield). 1H NMR (400 MHz, CDCl3) δ 7.89−7.60 (m, 8H), 7.55−
7.29 (m, 10H), 6.41 (d, J = 8.4 Hz, 1H), 4.61−4.51 (m, 7H), 4.34 (t,
J = 6.9 Hz, 1H), 3.88 (d, J = 8.5 Hz, 1H), 3.62 (dd, J = 10.7, 5.1 Hz,
1H), 2.49 (m, 1H), 1.25−1.09 (m, 12H); 13C NMR (100 MHz,
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127.1, 125.3, 120.0, 67.4, 66.1, 58.1, 47.1, 36.4, 26.9, 19.2, 14.7. IR
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(2R,3S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-4-((tert-
butyldiphenylsilyl)oxy)-3-methylbutanoic acid (anti-12). Purification
by flash chromatography afforded anti-12 as a white foamy solid (0.34 g,
40% yield). 1H NMR (400 MHz, CDCl3) δ 7.81−7.56 (m, 8H), 7.49−
7.27 (m, 10H), 5.90 (d, J = 8.2 Hz, 1H), 4.69 (d, J = 6.2 Hz, 2H), 4.51−
4.34 (m, 2H), 4.24 (t, J = 6.5 Hz, 1H), 3.70−3.57 (m, 2H), 2.43 (br,
1H), 1.09 (s, 9H), 0.95 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 156.4, 143.8, 141.3, 135.6, 133.0, 129.8, 127.8, 127.7, 127.1,
125.1, 119.9, 67.3, 66.1, 56.1, 47.2, 37.9, 29.7, 26.8, 19.1. HRMS (ESI,
TOF): m/z = 594.2752, calcd For C36H40NO5Si [M+H]+ 594.2676.
8826.
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Tetrahedron 2010, 66, 5407.
ASSOCIATED CONTENT
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(29) Mori, K.; Kyota, H.; Malosse, C.; Rochat, D. Liebigs Ann. Chem.
1993, 1201.
S
* Supporting Information
1H and 13C NMR spectra of 2, 3, 5−13, and GC traces after
hydrogenation, recrystallization of 3. This material is available
free of charge via the Internet at http://pubs.acs.org.
(30) Broca, C.; Manteghetti, M.; Gross, R.; Baissac, Y.; Jacob, M.;
Petit, P.; Sauvaire, Y.; Ribes, G. Eur. J. Pharmacol. 2000, 390, 339.
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(34) Mantilli, L.; Gerard, D.; Torche, S.; Besnard, C.; Mazet, C.
Angew. Chem., Int. Ed. 2009, 48, 5143.
AUTHOR INFORMATION
Corresponding Author
*E-mail: burgess@tamu.edu.
■
Notes
(35) Mantilli, L.; Mazet, C. Tetrahedron Lett. 2009, 50, 4141.
(36) Mantilli, L.; Gerard, D.; Torche, S.; Besnard, C.; Mazet, C.
Chem.Eur. J. 2010, 16, 12736.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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(37) Mantilli, L.; Mazet, C. Chem. Commun. 2010, 46, 445.
(38) Diez, S.; Navarro, G.; Tros de Ilarduya, C. J. Gene Med. 2009,
11, 38.
We thank The National Institutes of Health (GM087981) and
The Robert A. Welch Foundation (A-1121) for financial
support.
(39) Panek, J. S.; Beresis, R. T. J. Org. Chem. 1996, 61, 6496.
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