Practical, scalable, high-throughput approaches to η3- pyranyl and η3-pyridinyl organometallic enantiomeric scaffolds using the achmatowicz reaction

Article abstract of DOI:10.1021/jo702006z

(Figure Presented) A unified strategy for the high-throughput synthesis of multigram quantities of the η³-oxopyranyl- and η³-oxopyridinylmolybdenum complexes TpMo(CO)₂(η ³-oxopyranyl) and TpMo(CO)₂(η³- oxopyridinyl) is described (Tp = hydridotrispyrazolylborato). The strategy uses the oxa- and aza-Achmatowicz reaction for the preparation of these organometallic enantiomeric scaffolds, in both racemic and high enantiopurity versions.

Full text of DOI:10.1021/jo702006z

Practical, Scalable, High-Throughput Approaches to η3-Pyranyl and
η3-Pyridinyl Organometallic Enantiomeric Scaffolds Using the
Achmatowicz Reaction
Thomas C. Coombs, Maurice D. Lee, IV, Heilam Wong,† Matthew Armstrong, Bo Cheng,
Wenyong Chen, Alessandro F. Moretto,‡ and Lanny S. Liebeskind*
Department of Chemistry, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
lanny.liebeskind@emory.edu
ReceiVed September 13, 2007
A unified strategy for the high-throughput synthesis of multigram quantities of the η3-oxopyranyl- and
η3-oxopyridinylmolybdenum complexes TpMo(CO)2(η3-oxopyranyl) and TpMo(CO)2(η3-oxopyridinyl)
is described (Tp ) hydridotrispyrazolylborato). The strategy uses the oxa- and aza-Achmatowicz reaction
for the preparation of these organometallic enantiomeric scaffolds, in both racemic and high enantiopurity
versions.
Introduction
the promise of “atom economy”13-15 and environmental sus-
tainability.16,17
One of the major challenges in contemporary organic
chemistry is the design and execution of concise approaches to
complex molecular targets; enantiocontrolled bond construction
represents a key element of this challenge. Three fundamentally
different methodologies have been widely used to address the
requirement for control of absolute stereochemistry: (1) syn-
theses that use materials originating from the “chiral pool” as
“chirons”,1-3 as auxiliaries,4,5 or for classical resolutions, (2)
enzymatic transformations,6-8 and (3) metallo-9 or organo-
catalytic10-12 asymmetric transformations. In recent decades
catalytic approaches to enantiocontrolled bond construction have
dominated the literature of new synthetic methods because of
Enantiomeric scaffolding provides an alternative strategic and
structured approach to enantiocontrolled bond construction in
complex organic systems. In the scaffolding strategy, a con-
ceptually simple core molecule of high enantiopurity that bears
tactically versatile functionality is constructed. The resident
functionality enables the general elaboration of the core molecule
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† Current Address: Lonza Guangzhou R&D Center, Nansha Development
Zone, Guangzhou 511455, P. R. China.
‡ Current Address: Wyeth Research, Chemical Sciences, 200 Cambridge Park
Drive, Cambridge, MA 02140.
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10.1021/jo702006z CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/03/2008
882
J. Org. Chem. 2008, 73, 882-888

Organometallic Enantiomeric Scaffolds
in ways that allow access to diverse families of important
molecules. The principal examples of organic enantiomeric
scaffolding for the enantiocontrolled synthesis of complex
molecules have come from the laboratories of Comins,18-24
Marazano,25-29 Husson/Royer,30-34 and Bosch,35-44 among
others (Figure 1).45,46
Although less well-studied, organometallic enantiomeric
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readily available, single enantiomers of air-stable organometallic
π-complexes of key unsaturated ligands from which diVerse
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FIGURE 1. Enantiomeric scaffolds.
high enantiopurity. The metal and its auxiliary ligands provide
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Coombs et al.
FIGURE 2. Organometallic enantiomeric scaffolding. Dashed arrows represent currently unpublished work.
SCHEME 1. Generalized Achmatowicz-Based Scaffold
Synthesisa
High enantiopurity TpMo(CO)2(η3-pyranyl) and TpMo(CO)2-
(η3-pyridinyl) complexes have proven to be versatile organo-
metallic enantiomeric scaffolds.48-66 Taking advantage of novel
trends in reactivity and selectivity, single enantiomers of these
air- and moisture-stable pyranyl and pyridinyl organometallic
scaffolds have been used in the enantiocontrolled construction
of a diverse set of heterocyclic organic systems exemplified in
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a Reagents: (i) m-CPBA, CH2Cl2; (ii) Ac2O, Et3N, cat. DMAP; (iii)
Mo(CO)3(DMF)3 then KTp.
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Figure 2. Of strategic interest in organic synthesis, the principles
of organometallic enantiomeric scaffolding allow the develop-
ment of parallel reaction profiles applicable to both pyran- and
piperidine-derived systems, an option not available with tradi-
tional organic enantiomeric scaffolds.
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The practical utility of these molybdenum-based scaffolds
in organic synthesis warrants their simple construction on
multigram scale. Herein we report a unified stategy for the
practical, scalable, and high-throughput synthesis of both TpMo-
(CO)2(η3-pyranyl) and TpMo(CO)2(η3-pyridinyl) organometallic
enantiomeric complexes that is based on the oxo-67 and aza-
Achmatowicz68-71 oxidative rearrangements. Scheme 1 high-
lights the generic reaction sequence whereby furfuryl alcohols
and N-protected furfuryl amines A are oxidatively rearranged
to hydroxypyranones and hydroxypyridinones B, respectively.
These intermediates undergo oxidative addition to Mo(DMF)3-
(CO)3, either after or without acetylation of the allylic alcohol.
Subsequent ligand exchange with potassium tris(pyrazolyl)-
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Organometallic Enantiomeric Scaffolds
SCHEME 2. Synthesis of Racemic Oxopyranyl Scaffolda
SCHEME 4. Four-Step Synthesis of Chiral, Nonracemic
Oxopyranyl Scaffolds
a Reagents: (i) m-CPBA, CH2Cl2; (ii) Ac2O, Et3N, cat. DMAP; (iii)
Mo(CO)3(DMF)3 then KTp.
SCHEME 3. Synthesis of the Racemic Oxopyridinyl
Scaffolda
a Reagents: (i) Mo(CO)3(DMF)3 then KTp.
containing the aza-Achmatowicz rearrangement product is
filtered, washed, and degassed before solid Mo(DMF)3(CO)3
is added. After ligand exchange with KTp, chromatographic
purification delivers the pyridinyl scaffold (()-7.
The Chiral, Nonracemic Series Scaffolds. (a) The Oxopy-
ranyl Scaffold. Both antipodes of the chiral, nonracemic
oxopyranyl scaffold 4 can be accessed from racemic 6-acetoxy-
pyranone 3 by ZnCl2-mediated diastereomer formation and
separation with commercially available chiral, nonracemic
alcohols. In a previous report we demonstrated that diastereo-
merically pure (R)-pantolactone-derived pyranones underwent
oxidative addition to Mo(CO)3(DMF)3, predominantly with
inversion of configuration.60 In the present study the use of (S)-
1-phenylbutanol produced diastereomeric 6-alkoxypyranones 8
and 9 that consistently and reproducibly provided the oxopyranyl
scaffolds in higher enantiopurities (before recrystallization)
compared to the previous method with pantolactone (Scheme
4). The use of the benzyl alcohol-derived chiral auxiliary
probably minimizes the coordination-induced retention pathway
that leads to lower enantioselectivities, as is observed with the
pantolactone-derived pyranone.62 Thus, both antipodes of ox-
opyranyl scaffold 4 are available in high enantiopurity in four
operations from commercially available furfuryl alcohol.
The stereochemistry at the acetal carbon of the 6-alkoxy-
pyranones 8 and 9 is not known. However, the fast eluting
diastereomer 8 provides (+)-4 while the slower eluting diaste-
reomer 9 leads to the antipodal scaffold, (-)-4. The absolute
configurations shown for (+)-4 and (-)-4 are deduced from
earlier studies utilizing X-ray crystallographic analysis and Flack
parameters.60
a Reagents: (i) NaOH, CbzCl; (ii) m-CPBA, CH2Cl2; (iii) Mo(CO)3(DMF)3
then KTp.
borohydride (KTp) provides the air-stable and easily handled
TpMo(CO)2-based 5-oxopyranyl and pyridinyl complexes C.
Results and Discussion
The Racemic Series Scaffolds. (a) The Oxopyranyl Scaf-
fold. The racemic parent oxopyranyl scaffold 4 is prepared from
furfuryl alcohol 1 by using a simple three-operation sequence
(Scheme 2): (1) Achmatowicz reaction, (2) acetylation of the
hydroxypyranone 2 to give 3, and (3) one-pot transformation
of the acetoxypyranone directly into the oxopyranyl scaffold 4.
The synthesis of (()-4 was described previously by using this
reaction sequence, but as a three-pot transformation that required
isolation and purification of intermediates.60 In this improved
version the sequence has been streamlined to permit the high-
throughput preparation of racemic oxopyranyl scaffold without
chromatographic purification of intermediates (i.e., 18 g of
product generated with 500 mL glassware). The reaction
sequence proceeds in good yield over the three operations (59%)
and requires only one aqueous wash, and only one chromato-
graphic separation of the final product. Attempts to shorten
the reaction sequence further by direct metalation of the
6-hydroxypyranone 2 led to lower yields of the scaffold.
(b) The Oxopyridinyl Scaffold. A similar Achmatowicz
approach can be used to generate the analogous racemic
oxopyridinyl scaffold (()-7 (Scheme 3). This scaffold can be
trivially prepared in only three steps from furfuryl amine 5: (1)
N-protection as the Cbz urethane and (2) treatment with
m-CPBA followed by metalation with Mo(DMF)3(CO)3 and
KTp. This sequence can be conducted without rigorous purifica-
tion of intermediates and reproducibly provides 45% isolated
yields of oxopyridinyl scaffold (()-7. The key difference
between the oxa- and the aza-Achmatowicz-based scaffold
preparations is the direct use of the non-acetylated aza-
Achmatowicz rearrangement product 6 in the oxidation addition
to Mo(DMF)3(CO)3. This tactic was taken because of the
tendency of the aza-Achmatowicz intermediates to rearrange
to the corresponding aromatic pyridines72-76 by transfer of the
protecting group from N to O.77 In practice, the reaction mixture
(b) The Oxopyridinyl Scaffold. To access the chiral,
nonracemic oxopyridinyl scaffold 12, furfuryl amine was
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(77) This undesired aromatization can be suppressed by using an electron-
withdrawing p-toluenesulfonyl nitrogen protecting group and by exchanging
the anomeric hydroxyl group for an isopropyloxy group, according to
Speckamp’s protocol (Hopman, J. C. P.; van den Berg, E.; Ollero, L. O.;
Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1995, 36, 4315-4318).
This intermediate can be metalated under standard conditions {Mo(CO)3-
(DMF)3 then KTP} in 44% yield. Unfortunately, all attempts to remove
the sulfonamide protecting group from the 5-oxopyridinyl metal complex
led only to decomposition.
J. Org. Chem, Vol. 73, No. 3, 2008 885

Coombs et al.
SCHEME 5. Two-Step Synthesis of Chiral, Nonracemic
Oxopyridinyl Scaffolds
SCHEME 7. Unanticipated Racemization
TABLE 1. Other Substitution Patterns
SCHEME 6. Correlation of Absolute Stereochemistry
entry
Z
R1
R2
R3
% overall yield
1
2
3
4
O
O
NCbz
O
CH3
H
H
H
H
H
H
CH3
32
41
54
CH3
CH3
H
H
57 (1:2, anti:syn)
Other auxiliaries were explored but were less effective than
the -CO2CH(R)Ph derivatives. For example, the diastereomers
resulting from the use of mandelic acid methyl ester could be
easily separated (>99.5% de) by either chromatography or
recrystallization, but removal of the protecting group from 17
by either Pd-catalyzed hydrogenolysis or BBr3-mediated de-
benzylation resulted in degradation of enantiopurity as judged
by determination of the ee of the free amine scaffold 15 (Scheme
7, 67-82% ee). In contrast, as reported above, the chiral,
nonracemic auxiliary (S)-1-phenylbutanol provided easily sepa-
rable diastereomers (>99.8% de), and Pd-catalyzed hydro-
genolysis of the (S)-1-phenylbutanol protecting group of (+)-
14 and reprotection with CbzCl provided the desired metal
complex (+)-7 in 98.5% ee. The (S)-1-phenylethanol auxiliary
provided similar results. The different behavior of these two
auxiliary systems is not well-understood at this writing.
Other Scaffolds. The experiments depicted in Table 1 were
carried out to probe the use of oxo- and aza-Achmatowicz
reactions in the synthesis of TpMo(CO)2 pyranyl and pyridinyl
scaffolds of various substitution patterns. Methyl groups were
chosen to generically represent other substituents. Entries 1-3
highlight the ease with which 2- and 4-methyl-substituted
pyranyl (18, 19) and 4-methyl-substituted pyridinyl (20) com-
plexes may be synthesized starting from appropriately substi-
tuted furans. The synthetic protocol to prepare the methyl-
substituted pyranyl scaffolds 18 and 19 shown in Table 1 is
analogous to that used to prepare the unsubstituted parent
oxopyranyl complex: (1) Achmatowicz oxidative rearrangement
of the appropriate methyl-substituted furfuryl alcohol, (2)
acetylation of the intermediate hydroxypyranone, and (3) one-
pot transformation into the substituted oxopyranyl scaffold with
N-protected as a -CO2CH(R)Ph urethane 11 by using the
imidazolyl urethane 10, which was derived from commercially
available (S)-1-phenylethanol (R ) Me) or (S)-1-phenylbutanol
(R ) n-Pr). Sequential treatment of these N-protected furfuryl
amines in one pot without purification of intermediates with
m-CPBA followed by metalation with Mo(DMF)3(CO)3 and
KTp reproducibly provided 36-39% isolated yields of a
diastereomeric mixture of N-protected oxopyridinyl scaffold 12
(Scheme 5). The oxopyridinyl π-facial enantiomers (-)-13 and
(+)-14 were then easily obtained in excellent stereochemical
purity on large scale by simple chromatographic separation of
diastereomers on silica gel eluting with 15:1 toluene/EtOAc.
Oxopyridinyl scaffolds bearing NCbz and NCO2CH(R)Ph (R
) Me, n-Pr) urethane protecting groups display identical reaction
profiles in all synthetic manipulations explored to date, thus
allowing the chiral nonracemic urethanes to be retained and used
as simple Cbz equivalents.
Absolute configurations of the pyridinyl metal complexes
depicted in Scheme 5 were determined by preparing the free
amine (+)-15, of known absolute configuration, from the η3-
pyridinyl complex 1678 by hydrolysis and hydrogenolytic
removal of the Cbz protecting group (Scheme 6). The same
free-base oxopyridinyl complex of identical optical rotation was
obtained upon hydrogenolytic removal of the -CO2CH(n-Pr)-
Ph urethane protecting group from (+)-14 thus allowing
assignment of the absolute stereochemistries depicted in Scheme
5.
(78) Wong, H. Design, Synthesis and Resolution of a Chiral, Non-racemic
Organometallic Chiron: Asymmetric Total Syntheses of Tetrahydropyridine-
based Alkaloids. Ph.D. Dissertation, Emory University, Atlanta, 2006.
886 J. Org. Chem., Vol. 73, No. 3, 2008

Organometallic Enantiomeric Scaffolds
SCHEME 8. Synthesis of Enantiopure syn- and anti-21:
and aza-Achmatowicz reactions of furfuryl alcohols and N-
protected furfuryl amines, respectively.81 These new protocols
supersede earlier lengthier and less efficient synthetic methods
for construction of molybdenum-based organometallic enantio-
meric scaffolds.57,59,60,78 It should be noted that both starting
materials, KTp and Mo(DMF)3(CO)3, are easily prepared on
large scale (multi-100 g lots) in one step from commercially
available materials. KTp is prepared from KBH4 and pyrazole
upon heating without solvent,82,83 while Mo(DMF)3(CO)3 is
trivially generated upon heating Mo(CO)6 in DMF.84 From a
synthetic perspective the TpMo(CO)2 moiety functions as a non-
traditional protecting group/auxiliary that can be carried through
multistep sequences, and whose overall expense and scalability
do not differ significantly from those of some more traditional
systems. Recovery of the molybdenum complexes after de-
metalation, an option in large-scale operations, has not yet been
investigated.
Confirmation of Relative Stereochemistrya
a Reagents: (i) m-CPBA, CH2Cl2; (ii) Ac2O, Et3N, cat. DMAP; (iii)
Mo(CO)3(DMF)3 then KTp.
Mo(DMF)3(CO)3 and KTp. The 4-methyl-substituted pyridinyl
complex 20 listed in entry 3 of the table was made by analogy
to the parent, unsubstituted pyridinyl complex, whereby oxida-
tive rearrangement of the Cbz-protected furfuryl amine deriva-
tive was followed by direct metalation without acetylation of
the intermediate hydroxypyridinone. In all cases, a single
chromatographic purification was required at the end of the
sequence to obtain the desired metal complexes in high purity.
Although not explored in this current study, the use of
commercially available chiral, nonracemic alcohols to prepare
and resolve diastereomeric substituted 6-alkoxypranones is
expected to provide the desired substituted TpMo(CO)2-
(oxopyranyl) scaffolds (18, 19) in high enantiopurity as observed
in the asymmetric preparation of the parent, unsubstituted
pyranyl scaffolds. Similarly, the use of chiral, nonracemic
urethane protecting groups derived from appropriate com-
mercially available chiral, nonracemic alcohols is expected to
allow straightforward resolution of diastereomeric substituted
oxopyridinyl complexes (like 20) after metalation.
The 6-methyl-substituted scaffolds 21 and 22 shown in entry
4 of Table 1 represent a special case. The oxopyranyl scaffold
is obtained as a 1:2 mixture of diastereomers (anti:syn), which
may be separated by flash chromatography.79 The formation of
these diastereomers affords the opportunity to produce high-
enantiopurity 6-methyl-substituted TpMo(CO)2(oxopyranyl) scaf-
folds from high-enantiopurity 1-furan-2-yl-ethanol (Scheme 8),
which is available via the asymmetric reduction of acetylfuran
by using Noyori’s protocol.80 (R)-1-Furan-2-yl-ethanol (R)-(+)-
23 (98% ee) underwent Achmatowicz rearrangement and
acetylation to produce a mixture of the diastereomeric 6-ac-
etoxypyranones. This mixture was treated without separation
with Mo(CO)3(DMF)3 followed by KTp to produce a 1:2 (anti:
syn) mixture of the diastereomers of 21 and 22 in 98% and
97% ee, respectively. The relative and absolute configuration
of the slower eluting (-)-syn diastereomer 22 was confirmed
by X-ray crystallography. The enantiopurity of the diastereo-
meric scaffolds was determined by chiral HPLC by comparison
to racemic mixtures.
Experimental Section
Representative Experimental Procedure. (S)-1-Phenylbutyl
1H-imidazole-1-carboxylate, 10 (R ) n-Pr): To a Schlenk flask
charged with (S)-(-)-1-phenyl-1-butanol (98% ee, 10.7 g, 71.5
mmol, 1.00 equiv, purchased from Fluka), 1,1′-carbonyldiimidazole
(12.8 g, 78.7 mmol, 1.10 equiv), and 4-(dimethylamino)pyridine
(28.3 mg, 0.232 mmol, 0.3 mol %) was added CH2Cl2 (180 mL).
The solution was stirred at room temperature for 1.75 h, washed
with water (3 × 150 mL), dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography (SiO2, 5.0 cm × 32.0 cm, hexanes:EtOAc )1:1)
to afford a yellow oil 10, R ) n-Pr (16.9 g, 97%), which solidified
at low temperature.
10 (R ) n-Pr): TLC Rf 0.47 (50% EtOAc in hexanes). [R]20
D
+3.25 (c 1.23, CH2Cl2). IR (cm-1) 2960 (w), 1752 (s), 1389 (s),
1
1279 (s), 1236 (s), 997 (s), 698 (s). H NMR (400 MHz, CDCl3)
δ 8.15 (s, 1 H), 7.43-7.32 (m, 6 H), 7.05 (s, 1 H), 5.90 (dd, J )
7.6, 6.5 Hz, 1 H), 2.09 (m, 1 H), 1.90 (m, 1 H), 1.38 (m, 2 H),
0.96 (t, J ) 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3) δ 148.2,
138.9, 137.2, 130.7, 128.8, 126.7, 117.2, 80.9, 38.1, 18.8, 13.8.
HRMS (ESI) calcd for C14H17N2O2 [M + H]+ 245.1290, found
245.1285.
(S)-1-Phenylbutyl (2-furylmethyl)carbamate, 11 (R ) n-Pr):
To a solution of (S)-1-phenylbutyl 1H-imidazole-1-carboxylate 10,
R ) n-Pr (5.59 g, 22.9 mmol, 1.10 equiv), in CH2Cl2 (24 mL)
were added 4-(dimethylamino)pyridine (28.3 mg, 0.232 mmol, 1.1
mol %) and Et3N (4.36 mL, 31.2 mmol, 1.50 equiv). While
monitoring the temperature inside the reaction flask, furfuryl amine
5 (1.84 mL, 20.8 mmol, 1.00 equiv) was added dropwise to the
solution at 0 °C. The solution was stirred at room temperature for
20.5 h, washed with water (3 × 80 mL), dried over MgSO4, and
concentrated under reduced pressure. The crude product was
purified by flash chromatography (SiO2, 5.5 cm × 39.0 cm, 33%
EtOAc in hexanes) to afford a yellow oil 11 (5.63 g, 99%).
11 (R ) n-Pr): TLC Rf 0.62 (50% EtOAc in hexanes). IR (cm-1
)
3330 (w), 2958 (w), 1697 (s), 1506 (m), 1241 (s), 698 (s). 1H NMR
(400 MHz, CDCl3) δ 7.35-7.26 (m, 6 H), 6.31 (s, 1 H), 6.19 (d,
J ) 3.2 Hz, 1 H), 5.69 (t, J ) 7.0 Hz, 1 H), 5.18 (br s, 1 H), 4.37
(dd, J ) 15.3, 6.0 Hz, 1 H), 4.28 (dd, J ) 15.6, 5.5 Hz, 1 H), 1.89
(m, 1 H), 1.75 (m, 1 H), 1.33 (m, 2 H), 0.93 (t, J ) 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3) δ 156.0, 151.8, 142.1, 141.3, 128.4,
Conclusions
Synthetically versatile oxopyranyl and oxopyridinyl organo-
metallic enantiomeric scaffolds are easily prepared on multigram
scale by using high-throughput sequences based on the oxa-
(79) Examples of related transformations with substituted furfuryl amines
leading to 6-substituted-5-oxopyridinyl complexes can be found in Moretto,
A. F. The Utilization of Stoichiometric Molybdenum π-Complexes for the
Synthesis of Substituted Piperidines. Ph.D. Dissertation, Emory University,
Atlanta, 1999.
(80) Fujii, A.; Hashigucki, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522.
(81) Oxopyranyl and oxopyridinyl enantiomeric scaffolds will be avail-
able from Synthonix, Ltd (www.synthonix.com).
(82) Trofimenko, S. Chem. ReV. 1993, 93, 943-980.
(83) Trofimenko, S. J. Am. Chem. Soc. 1967, 89, 3170.
(84) Pasquali, M.; Leoni, P.; Sabatino, P.; Braga, D. Gazz. Chim. Ital.
1992, 122, 275-277.
J. Org. Chem, Vol. 73, No. 3, 2008 887

Coombs et al.
127.7, 126.5, 110.4, 107.2, 76.7, 38.7, 38.1, 18.8, 13.9. HRMS (ESI)
calcd for C16H20NO3 [M + H]+ 274.1443, found 274.1440.
(+)-Dicarbonyl[hydridotris(1-pyrazolyl)borato]{(2R)-(η3-2,3,4)-
5-oxo-1-[(1S)-phenylbutoxycarbonyl]-5,6-dihydro-2H-pyridin-
2-yl}molybdenum, (+)-14, and (-)-Dicarbonyl[hydridotris(1-
pyrazolyl)borato]{(2S)-(η3-2,3,4)-5-oxo-1-[(1S)-phenyl-
butoxycarbonyl]-5,6-dihydro-2H-pyridin-2-yl}molybdenum, (-)-
13. A solution of (S)-1-phenylbutyl (2-furylmethyl)carbamate 11
(R ) n-Pr) (11.47 g, 42.0 mmol, 1.0 equiv) in CH2Cl2 (190 mL)
was cooled to 0 °C. To the stirring solution was added m-CPBA
(∼77% purity, 14.11 g, 62.9 mmol, 1.5 equiv) portionwise, and
the reaction was stirred for 5.0 h at 0 °C. The white solids were
removed by vacuum filtration, and the filtrate was washed with
water (2 × 100 mL). The organic phase was dried over MgSO4
and filtered, and the filtrate was degassed with argon for 15 min.
To the degassed solution at 0 °C was quickly added solid Mo-
(DMF)3(CO)3 (23.65 g, 59.2 mmol, 1.41 equiv). After stirring for
5 min at 0 °C, the reaction was warmed to room temperature and
stirred for 23 h. To the reaction mixture at 0 °C was added
potassium hydridotris(1-pyrazolyl)borate (KTp) (14.9 g, 59.2 mmol,
1.41 equiv). The reaction mixture was stirred at room temperature
for 1.5 h, filtered through a pad of Celite, and concentrated under
reduced pressure. The crude product was subjected to short filter
chromatography (SiO2, 9.0 cm × 6.0 cm, hexanes:EtOAc ) 9:1
ramping gradually to 100% EtOAc). Fractions overlapping with
impurities were subjected to chromatography (gravity flow, SiO2,
7.5 cm × 35.0 cm, toluene:EtOAc ) 15:1) to afford a mixture of
diastereomers. Chromatography (gravity flow, SiO2, 7.5 cm × 42.0
cm, toluene:EtOAc ) 15:1) afforded (+)-14 (4.75 g, 17.8%) and
(-)-13 (4.05 g, 15.2%) each as orange solids with complete
diastereoseparation (>99.9% de for each isomer).
193.4, 193.1, 154.2, 153.4, 147.3, 144.7, 143.4, 141.5, 141.2, 140.6,
139.8, 139.4, 136.4, 136.2, 134.8, 134.4, 128.7, 128.4, 128.2, 127.9,
127.1, 126.2, 106.2, 106.1, 106.0, 105.8, 103.5, 94.7, 92.7, 79.2,
78.5, 64.3, 63.74, 63.70, 63.0, 48.0, 47.8, 38.4, 37.7, 18.8, 18.5,
13.8, 13.6. HRMS (ESI) calcd for C27H29BMoN7O5 [M + H]+
640.1377, found 640.1392. HPLC: Zorbax Eclipse C8, CH3CN:
H2O (with 0.1% CF3CO2H) ) 55:45, 0.85 mL/min, λ ) 254 nm,
tR ) 25.01 min, >99.9% de.
(-)-13: TLC Rf 0.13 (toluene:EtOAc ) 15:1). [R]20 -466 (c
D
0.190, CH2Cl2). IR (cm-1) 1960 (s), 1865 (s), 1703 (m), 1662 (m),
1278 (s), 1049 (s). 1H NMR (a mixture of two rotamerss400 MHz,
CDCl3) δ 8.49 (d, J ) 2.0 Hz, 0.4 H), 8.37 (d, J ) 1.9 Hz, 0.6 H),
8.21 (d, J ) 2.1 Hz, 0.6 H), 8.13 (d, J ) 2.0 Hz, 0.4 H), 7.80 (d,
J ) 2.1 Hz, 0.4 H), 7.74 (d, J ) 1.7 Hz, 0.6 H), 7.70 (d, J ) 2.4
Hz, 0.4 H), 7.63 (d, J ) 2.4 Hz, 0.4 H), 7.61 (d, J ) 2.1 Hz, 1.2
H), 7.55 (d, J ) 2.1 Hz, 0.4 H), 7.49 (d, J ) 1.9 Hz, 0.6 H), 7.48-
7.25 (m, 6 H), 6.35 (t, J ) 2.4 Hz, 0.4 H), 6.31 (t, J ) 2.0 Hz, 0.4
H), 6.23 (m, 2.2 H), 5.81 (t, J ) 6.8 Hz, 0.4 H), 5.75 (dd, J ) 7.6,
6.0 Hz, 0.6 H), 4.76 (m, 1 H), 4.07 (t, J ) 6.4 Hz, 0.6 H), 4.02 (t,
J ) 6.4 Hz, 0.4 H), 3.60 (AB quartet, J ) 19.6 Hz, 0.6 H), 3.39
(AB quartet, J ) 20.0 Hz, 0.4 H), 3.31 (AB quartet, J ) 19.2 Hz,
0.6 H), 3.27 (AB quartet, J ) 20.0 Hz, 0.4 H), 2.13 (m, 0.4 H),
1.94 (m, 1 H), 1.81 (m, 0.6 H), 1.35 (m, 2 H), 0.95 (t, J ) 7.6 Hz,
1.2 H), 0.92 (t, J ) 7.2 Hz, 1.8 H). 13C NMR (100 MHz, CDCl3)
δ 225.1, 224.3, 222.8, 221.4, 193.4, 193.0, 154.1, 153.2, 147.5,
147.3, 144.5, 142.8, 141.9, 141.4, 140.3, 140.0, 136.6, 136.4, 136.3,
136.2, 134.8, 134.7, 128.6, 128.2, 127.7, 126.6, 126.1, 106.3,
106.11, 106.07, 106.0, 105.8, 105.8, 93.5, 91.6, 78.8, 78.4, 64.8,
64.2, 64.1, 63.5, 48.0, 47.8, 38.7, 38.1, 18.6, 13.8. HRMS (ESI)
calcd for C27H29BMoN7O5 [M + H]+ 640.1377, found 640.1388.
HPLC: Zorbax Eclipse C8, CH3CN:H2O (with 0.1% CF3CO2H)
) 55:45, 0.85 mL/min, λ ) 254 nm, tR ) 23.00 min, >99.9% de.
(+)-14: TLC Rf 0.23 (toluene:EtOAc ) 15:1). [R]20 +566 (c
D
0.080, CH2Cl2). IR (cm-1) 1958 (s), 1863 (s), 1702 (m), 1660 (m),
1280 (s), 1049 (s). 1H NMR (a mixture of two rotamerss400 MHz,
CDCl3) δ 8.42 (d, J ) 1.6 Hz, 0.8 H), 8.37 (s, 0.2 H), 8.29 (d, J
) 1.6 Hz, 0.8 H), 7.73 (s, 0.2 H), 7.71 (app d, 0.8 H), 7.63
(overlapped, 0.2 H), 7.62 (d, J ) 2.4 Hz, 0.8 H), 7.61 (d, J ) 2.0
Hz, 0.8 H), 7.52 (d, J ) 2.0 Hz, 0.8 H), 7.48 (d, J ) 2.0 Hz, 0.2
H), 7.45 (s, 0.2 H), 7.43 (s, 0.2 H), 7.41-7.24 (m, 6 H), 6.30 (t, J
) 2.1 Hz, 0.8 H), 6.25 (t, J ) 2.1 Hz, 0.8 H), 6.23 (t, J ) 2.1 Hz,
1 H), 6.12 (t, J ) 2.1 Hz, 0.2 H), 6.09 (t, J ) 2.1 Hz, 0.2 H), 5.75
(m, 1 H), 4.75 (dd, J ) 6.2, 1.4 Hz, 1 H), 4.01 (t, J ) 6.2 Hz, 0.8
H), 3.97 (t, J ) 6.2 Hz, 0.2 H), 3.55 (AB quartet, J ) 20.0 Hz, 0.8
H), 3.46 (AB quartet, J ) 20.0 Hz, 0.2 H), 3.36 (AB quartet, J )
20.0 Hz, 0.8 H), 3.23 (AB quartet, J ) 20.0 Hz, 0.2 H), 2.18 (m,
0.2 H), 1.97 (m, overlapped, 0.2 H), 1.92 (m, 0.8 H), 1.73 (m, 0.8
H), 1.44-1.20 (m, 2.0 H), 0.97 (t, J ) 7.2 Hz, 0.6 H), 0.90 (t, J )
7.2 Hz, 2.4 H). 13C NMR (100 MHz, CDCl3) δ 225.2, 224.7, 221.9,
Acknowledgment. This work was support by grant No.
GM043107, awarded by the National Institute of General
Medical Sciences, DHHS. We are most grateful to Dr. Kenneth
Hardcastle for his skilled and efficient assistance with X-ray
crystallography. Dr. Gary Allred of Synthonix is acknowledged
for his interest in and contributions to our chemistry.
Supporting Information Available: Full experimental details
and characterization data for all compounds and X-ray crystal-
lography data for compound (-)-syn-22 and copies of proton and
carbon NMR spectra of all new compounds prepared in this study.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO702006Z
888 J. Org. Chem., Vol. 73, No. 3, 2008