Diastereoselective Radical Hydrogen Transfer Reactions using N-Heterocyclic Carbene Boranes

Article abstract of DOI:10.1021/acs.joc.6b02066

Reported herein are the first diastereoselective and Lewis acid-mediated radical reactions of N-heterocyclic carbene (NHC) boranes. We applied these reactions to the synthesis of four propionate diastereoisomers combining an aldol reaction, followed by a stereoselective radical-based reduction in which the NHC borane serves as the hydrogen donor, thus obviating the use of tin-based reagents. The 2,3-syn isomer is obtained by combining an NHC-borane and a Lewis acid (MgBr₂·OEt₂), while using a reverse polarity strategy provides the 2,3-anti isomer.

Full text of DOI:10.1021/acs.joc.6b02066

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Note
Diastereoselective Radical Hydrogen Transfer
Reactions using N-Heterocyclic Carbene Boranes
Guillaume Tambutet, and Yvan Guindon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02066 • Publication Date (Web): 06 Oct 2016
Downloaded from http://pubs.acs.org on October 8, 2016
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Diastereoselective Radical Hydrogen Transfer Reactions using N-
Heterocyclic Carbene Boranes
Guillaume Tambutet,†,‡ and Yvan Guindon*,†,‡,§
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† Bio-Organic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM), Montréal,
Québec H2W 1R7, Canada
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‡ Département de Chimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada
§ Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec H3A
2K6, Canada
yvan.guindon@ircm.qc.ca
Abstract: Reported herein are the first diastereoselective and Lewis acid mediated radical reactions of N-
heterocyclic carbene (NHC) boranes. We applied these reactions to the synthesis of four propionate
diastereoisomers combining an aldol reaction followed by a stereoselective radical based reduction in
which the NHC borane serves as the hydrogen donor, thus obviating the use of tin-based reagents. The
2,3-syn isomer is obtained by combining an NHC-borane and a Lewis acid (MgBr2·OEt2), while using a
reverse polarity strategy provides the 2,3-anti isomer.
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Despite recent advances in diastereoselective and enantioselective free radical-based processes,1
their usefulness and practicability continue to be plagued by the necessity of tin reagents, such as
Bu3SnH, to achieve an effective hydrogen transfer. Aside from the biological and environmental
toxicities of tin reagents,2 the removal of residual tin hydrides and corresponding tin halides have
proven difficult and time consuming. Not surprisingly, finding an alternative to tin-based reagents
has been the focus of several research groups. Seminal contributions by Curran, Malacria and
colleagues have shown the recent emergence of NHC-boranes as hydrogen transfer agents in free-
radical reactions.3
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NHC-boranes, such as 1,3-dimethylimidazole-3-ylidene borane (1), are easy to access,4 bench
stable, and reduce xanthates, bromides, iodides and ketones through a radical chain reaction.3a,5 In
addition, secondary alkyl halides possessing an adjacent electron withdrawing group can be
efficiently reduced.6 Due to the lower reactivity of NHC-boranes, as compared to Bu3SnH, these
reactions are typically performed at room temperature or higher3d,5a potentially diminishing the
diastereoselective control of reactions occurring under kinetic conditions. No precedent exists for
the creation of stereogenic centers using a radical based approach with NHC-boranes. Due to our
interest in the synthesis of polypropionates7 and the desire to form these motifs in the absence of
tin, we investigated if NHC-boranes could be employed as effective hydrogen transfer reagents at
low reaction temperatures in the presence of a Lewis acid.
Our group has previously reported a combined aldol and hydrogen transfer reaction using Bu3SnH
to synthesize all possible polypropionate stereopentads starting from a single stereogenic
center.7a,7b As illustrated in Figure 1, pre-complexing the β-hydroxy ester with Me3Al (TS A)
followed by addition of Et3B, as the initiator, and tributyltin hydride provides the 2,3-syn-3,4-anti
isomer (3a) at 78 °C. The 2,3-anti-3,4-anti isomer (3b) is obtained using dibutylboron triflate to
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initially form the corresponding C3-borinate (TS B). Reduction at 78 °C using tributyltin hydride
and Et3B generates the 2,3-anti isomer with high diastereoselectivity (dr >20:1).
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Figure 1. Radical Reduction and Transition States for the Synthesis of 2,3-syn and 2,3-anti
Polypropionate Motifs.
The selectivity of such hydrogen transfer reactions as well as their mechanisms have been
extensively studied both experimentally and theoretically.7c,8 The presence of Lewis acids, such as
Me3Al, also increases the rate of radical reactivity toward allylation using allyltrimethylsilane or
allyltributylstannane.9 This improved reactivity is attributed to a decrease in the SOMO energy of
the radical embedded in the cyclic chelate (ground state C, Figure 2). DFT calculations confirmed
that the SOMO energy of the chelate radical (ground state C) is 239.1 kcal/mol while the C3
aluminate (ground state D) is 146.7 kcal/mol, thereby predicting an enhanced reactivity for the
chelated substrate.8a,10
Figure 2. Ground State SOMO Energies of Sluminate Radical Intermediates C and D.
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The radical reduction precursors (2a,b) with an α-tertiary bromide were prepared as previously
described.7a An aldol reaction using TiCl4 or BF3·OEt2 provided the 3,4-anti (2a,b, Table 1) and
3,4-syn isomers (4a,b, Table 3), respectively, which were used to investigate the hydrogen transfer
reaction with NHC-boranes.11 The 3,4-anti substrate (2a,b) was reacted with NHC-borane 1 and
Et3B in CH2Cl2 at 78 °C in the absence of a Lewis acid (Table 1, entry 1). Preferential formation
of the desired 2,3-syn isomer 3a (dr 5:1) was observed, however, only in a modest 30% yield. The
low diastereselectivity could be attributed to a competition between TS A and TS B (Figure 1).
Hydrogen bonding between the free hydroxyl group at C3 and the ester would allow the endocyclic
pathway (TS A) to be competitive with the acyclic pathway (TS B). Upon addition of Me3Al (entry
2), the 2,3-syn isomer was formed with a >20:1 diastereoselectivity, albeit still in low yield (40%).
Upon increasing the reaction temperature to 40 °C, only a trace amount of product was observed
suggesting that the Me3Al reacts with the NHC-borane (a mild Lewis base).12 The complete
decomposition of 1 by Me3Al was in fact observed by 1H NMR in 10 minutes in the presence of
the Lewis acid at room temperature in deuterated dichloromethane. A milder Lewis acid,
MgBr2·OEt2, was next considered. At 78 °C, an excellent ratio (>20:1) and yield (81%) were
obtained for the formation of the 2,3-syn diastereomer 3a (entry 4). This high diastereoselectivty
and yield was maintained when the reaction was done at 10 °C (entry 5).13
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Table 1. Diastereoselective Hydrogen Atom Transfer for the Synthesis of the 2,3-syn-3,4-anti
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Diastereomer 3a.
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ratioa
time
(h)
yieldb
(%)
entry
Lewis acid
temp
(3a : 3b)
1
2
-
24
24
5:1
30
40
78 °C
78 °C
Me3Al
>20:1
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4
5
Me3Al
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3
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traces
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40 °C
78 °C
10 °C
MgBr2·OEt2
>20:1
>20:1
∙
2
85
MgBr2 OEt2
aProduct ratios were determined by 1H NMR analysis of the
crude reaction mixtures. bIsolated yields. Equivalents of
reagents used can be found in the experimental section.
The possible reaction pathway for the synthesis of the 2,3-syn isomer 3a is illustated in Scheme 1.
Initiation involves reaction of dioxygen with Et3B to generate the ethyl radical (Et•).14 Abstraction
of the bromide from the Lewis acid complexed radical precursor (RX-LA) furnishes radical LA-
R•. This radical reacts with the NHC-borane, resulting in a hydrogen atom transfer to form the 2,3-
•
•
syn product (RH) and NHC-BH2 . The NHC-BH2 species propagates the chain through further
reaction with RX-LA. 1,4-Dinitrobenzene is added as the chain terminator prior to reaction
workup.
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Scheme 1. Possible Reaction Pathway for the Formation of the 2,3-syn Diastereomer 3a.
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Reduction of tertiary bromide 2a,b was further investigated to access the 2,3-anti isomer 3b. To
generate this anti selectivity, the β-hydroxyl group needs to be protected to prevent chelate
formation with the ester. As previously demonstrated,7c,15 this can be achieved by installing a C3-
borinate as a temporary protecting group. Addition of NHC-borane 1 to the C3-borinate, prepared
in situ from reaction of the β-hydroxy ester with dibutylboron triflate and diisopropylamine,
provided an 8:1 mixture in favor of the desired 2,3-anti product 3b at 78 °C (Table 2, entry 1).
In an effort to lower the energy of the SOMO and thus enhance reactivity, MgBr2·OEt2 was added
(entries 2 and 3). The yields of the reduction were significantly improved, but the
diastereoselectivity was lost. This implied that the two reaction pathways leading to the syn and
anti isomers were activated, indicating that the C3-borinate was partly cleaved under these
conditions.
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Table 2. Diastereoselective Hydrogen Atom Transfer for the Synthesis of the 2,3-anti Diastereomer
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3b.
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ratioa
Lewis acid or
thiol (eq)
entry
temp
yieldb (%)
(3a:3b)
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1:8
30
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78 °C
78 °C
0 °C
MgBr2·OEt2
MgBr2·OEt2
1:1
1:2
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BF3·OEt2
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78 °C
78 °C
78 °C
78 °C
10 °C
MAD
1:8
30
50
75
91
SMBP (0.2)
SMBP (0.8)
SMBP (0.8)
1:12
1:>20
1:15
aProduct ratios were determined by 1H NMR analysis of
the crude reaction mixture. bIsolated yield. cReaction was
stirred for 24 h opposed to 2-3 h.
MAD: methylaluminum bis(2,6-di-tert-butyl-4-
methylphenoxide) SMBP: Methyl-5-tert-butylthiophenol.
Equivalents of reagents used can be found in the
experimental section.
Other Lewis acids were next considered. As seen in entry 4, no reactivity was observed with
monodentate Lewis acid BF3·OEt2, only starting material 2a,b was recovered. It is possible that the
NHC-borane reacts with BF3·OEt2 providing NHC-BF3.16 This may be the reason that the reaction
does not work with this Lewis acid. A sterically encumbered Lewis acid, methylaluminum bis(2,6-
di-tert-butyl-4-methylphenoxide) (MAD), which has been employed in free radical reactions,17 did
not improve the yields (entry 5). It is assumed that competitive decomposition of the NHC-borane
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was again at play. To increase the yields and diastereoselectivity of the halide reduction using
NHC-boranes with our borinates, we examined the use of polar reversal catalysis. Curran and
colleagues reported that unproductive radical reductions of alkyl and aryl halides with NHC-
boranes could be overcome by addition of a thiol.5a,18
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•
The reverse polarity catalysis approach is based on the fact that the NHC-BH2 radical reacts
quickly with the alkyl halide, while NHC-BH3 is a relatively poor hydrogen donor when the
carbon-centered radical is unactivated. Thiyl radicals have been recognized as compatible
hydrogen transfer agents and react well with NHC-BH3 to propagate the radical chain.18a,19 Methyl-
5-tert-butylthiophenol (SMBP), a commercially available and odorless thiol, was considered. The
borinates were prepared at 40 °C and upon lowering the reaction temperature to 78 °C, SMBP
(0.2 equiv), Et3B and NHC-borane 1 were added. As seen in entry 6 (Table 2), the increase in yield
and ratio was only marginal. However, by increasing the amount of SMBP (0.8 equiv), the yield
and ratio were significantly enhanced (entry 7). An excellent yield (91%) and ratio (1:15) were
obtained when the reaction was performed at 10 °C. We have thus developed a tin free protocol
to access one of the most challenging 2,3-anti-3,4-anti propionate motifs.
A possible reaction pathway leading to the 2,3-anti diastereomer 3b is illustrated in Scheme 2. The
first initiation step involving Et3B and RX proceeds as described above to generate the radical R•.
Transfer of a hydrogen atom to R• from R1SH, which has a higher polarity affinity than NHC-BH3,
results in the formation of the desired product (RH). The generated R1S• reacts with NHC-BH3
•
(nucleophilic) to form R1SH and also propagates the chain through generation of NHC-BH2 .
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Scheme 2. Possible Reaction Pathway for the Formation of the 2,3-anti Diastereomer 3b.
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The optimized conditions for generation of the 2,3-syn-3,4-anti (3a) and 2,3-anti-3,4-anti (3b)
scaffolds (Table 3, entries 1 and 2), were tested for the 3,4-syn diastereoisomers (entries 3 and 4).
The synthesis of 2,3-syn-3,4-syn (5a) (entry 3) and 2,3-anti-3,4-syn (5b) (entry 4) occurred with
excellent yields and selectivity.
Table 3. Diastereoselective Hydrogen Transfer Reactions with 3,4-anti and 3,4-syn α-Bromoesters.
Yieldb
dr
entry
additive
solvent
(a:b)a
(%)
1
2
∙
CH2Cl2 >20:1
81
75
MgBr2 OEt2
DIEA/Bu2BOTf/SMBP toluene 1:>20
∙
3
CH2Cl2 >20:1
75
MgBr2 OEt2
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DIEA/Bu2BOTf/SMBP toluene 1:>20
81
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1
aProduct ratios were determined by H NMR analysis of the
crude reaction mixture. bIsolated yields. Reactions were
performed at 78 °C. Equivalents of reagents used can be
found in the experimental section.
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As summarized in Table 3, this strategy provides access to four different propionate motifs. These
reactions also worked well using other thiols, such as tert-dodecylmercaptan and different NHC-
boranes, such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, attesting to the general nature
of our findings.4
Conclusions
We have demonstrated that the use of mild Lewis acids can expand the scope of NHC-boranes in
hydrogen transfer radical reductions providing excellent 2,3-syn selectivity. A diastereoselective
radical based reduction, leading to the 2,3-anti isomer, can be achieved by combining the efficacy
of NHC-boranes as a chain propagator with that of thiol derivatives. This work demonstrates that
the four possible propionate derivatives can be synthesized using tin-free radical based reactions.
A new synthetic method for stereoselective radical reductions without the use of tin hydride has
thus been developed.
Experimental Section
General Comments. All reactions requiring anhydrous conditions were carried out under an
atmosphere of nitrogen or argon in flame dried glassware using standard syringe techniques.
Dichloromethane, THF and toluene were dried with 4 Å molecular sieves prior to use. The 4 Å
molecular sieves (1−2 mm beads) were activated by heating at 180 °C for 48 h under a vacuum
prior to adding to new bottles of solvent purged with argon. Commercially available reagents were
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used as received. Flash chromatography was performed on silica gel 60 (0.040−0.063 mm) using
forced flow flash chromatography or an automated flash purification system. Analytical thin-layer
chromatography (TLC) was carried out on precoated (0.25 mm) silica gel aluminum plates.
Visualization was performed with UV short wavelength and/or revealed with ammonium
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molybdate or potassium permanganate solutions. H NMR spectra were recorded at room
temperature on 500 MHz NMR spectrometers. The data are reported as follows: chemical shift in
ppm referenced to residual solvent (CDCl3 δ 7.26 ppm), multiplicity (s = singlet, bs = broad singlet,
d = doublet, dd = doublet of doublets, m = multiplet, q= quartet), coupling constants (Hz), and
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integration. C NMR spectra were recorded at room temperature using 125 MHz. The data are
reported as follows: chemical shift in ppm referenced to residual solvent (CDCl3 δ 77.16 ppm).
Infrared spectra were recorded using a FTIR spectrophotometer on a NaCl support, and signals are
reported in cm−1. Mass spectra were recorded either through electrospray ionization (ESI) positive
ion mode. A Q exactive mass analyzer was used for HRMS measurements. Optical rotations were
measured at room temperature from the sodium D line (589 nm) using CH2Cl2 as solvent unless
otherwise noted and calculated using the formula αD = (100)αobs/(l · (c)), where c = (g of
substrate/100 mL of solvent) and l = 1 dm.
Synthesis of NHC-Borane
1,2-Dimethyl-1,2,4-triazol-3-ylidene borane (1)
Following a modified Curran’s protocol,6a a solution of 1-methyl-1H-imidazole (10 mL, 100
mmol) and iodomethane (2 equiv., 15 mL) in dry toluene (1.0 M, 100 mL) was stirred at reflux for
16 h. The reaction was cooled to 25 oC with vigorous stirring to break aggregates. After stirring
for 1 h at 25 oC, the solid was filtered and washed with toluene (2 x 50 mL). Solid was dried under
vacuum for 3 h and was used as a crude for the next step. To a solution of the crude (24 g, 100
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mmol) in dry THF (0.5 M, 200 mL) at 78 °C, was added NaHMDS (1.2 equiv., 120 mL). The
reaction mixture was stirred at 78 °C for 1 h before slow addition of BH3·NEt3 (1.1 equiv., 16.4
mL). The mixture was then warmed to 25 oC and refluxed for 16 h. After evaporation of volatiles
in vacuo., a saturated solution of NH4Cl (50 mL) and CH2Cl2 (50 mL) were added and the aqueous
layer was extracted with CH2Cl2 (3 x 50 mL). The combined organic fractions were washed with
brine (50 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The resulting solid was
filtered and washed (3 x 50 ml) with cold Hexane/Et2O (1:1) and dried under vacuum to afford 1
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as a white powder (11 g, quantitative yield). H and C NMR spectra correspond with those
reported.6a
1: 1H NMR (CDCl3, 500 MHz): δ 6.79 (s, 2H), 3.73 (s, 6H), 1.01 (q, J = 86.3 Hz, 3H); 13C NMR
(CDCl3, 125 MHz): δ 119.9, 35.9.
Synthesis of tertiary bromides (2a,b) and (4a,b)
Preparation and characterization of 2a,b7a and 4a,b7b have been previously reported by our
laboratory. The synthesis was done starting with racemic compounds.
Synthesis of polypropionate (3a, 3b, 5a and 5b)
General Procedure A: Diastereoselective Hydrogen Atom Transfer for the Synthesis of the
2,3-syn Diastereomer (Endocyclic Effect)
To a stirred solution of the appropriate α-bromoesters (1.0 equiv.) in dry CH2Cl2 (0.1 M) at the
corresponding temperature (See Table 1) was added the corresponding Lewis acid (3.5 equiv. for
Me3Al and 5 equiv. for MgBr2•OEt2). The reaction mixture was stirred for 1 h at the same
temperature before adding NHC-borane 1 (1.2 equiv.), Et3B (0.4 equiv. of a 1.0 M solution in
hexanes) and air (for 100 µL of Et3B, 1 ml of air was added in the solution via syringe). The
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resulting suspension was stirred at the corresponding temperature, then 0.2 equiv. of Et3B followed
by air was added every 45 minutes until the reaction was judged complete by TLC (around 2-3 h).
1,4-Dinitrobenzene (0.2 equiv.) was then added to the solution, and the mixture was stirred for an
additional 15 minutes. A saturated soluiton of NH4Cl was added to the reaction mixture followed
by evaporation of CH2Cl2 in vacuo. The aqueous layer was extracted with Et2O (3x). The organic
layer was successively washed with NaHCO3 sat. solution and brine, dried over anhydrous MgSO4
and concentrated in vacuo. The residue was purified by flash chromatography (Hexanes:Et2O
70:30) to afford the desired compound.
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Note: Radical propagation is more efficient in toluene, but due to the low solubility of MgBr2•OEt2
in toluene at low temperatures, the synthesis of the 2,3-syn diastereomers were done in CH2Cl2.
(±)Methyl (2R,3S,4S)-5-(benzyloxy)-3-hydroxy-2,4-dimethylpentanoate (3a)
General Procedure A was followed using 1.18 g of 2a,b. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a >20:1 mixture in favor of 3a (entry 5, Table 1).
Purification by flash chromatography (Hexanes:Et2O 70:30) provided 3a in 85% yield (700 mg).
The 1H and 13C NMR for compound 3a correspond to those previously reported by our lab.7a
3a: 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.29 (m, 5H), 4.53 (s, 2H), 3.95 – 3.88 (m, 1H), 3.71 (s,
3H), 3.69 – 3.64 (m, 1H), 3.58 – 3.54 (m, 2H), 2.66 – 2.60 (m, 1H), 1.95 – 1.87 (m, 1H), 1.21 (d,
13
J = 7.0 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H). C NMR (125 MHz, CDCl3) δ 176.1, 137.8, 128.4,
127.74, 127.65, 75.9, 74.7, 73.5, 51.8, 42.5, 35.8, 13.9, 9.8.
(±)Methyl
(2S,3S,4S)-5-(benzyloxy)-3-hydroxy-2,4-dimethylpentanoate
(5a)General
Procedure A was followed using 82 mg of 4a,b. 1H NMR spectroscopic analysis of the unpurified
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product indicated the formation of a >20:1 mixture in favor of 5a (entry 3, Table 3). Purification
by flash chromatography (Hexanes:Et2O 70:30) provided 5a in 75% yield (47 mg).
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5a: Rf = 0.37 (Hexanes:Et2O, 80:20); Formula C15H22O4; MW 266.33 g/mol; IR (neat) υmax
=
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-1
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3529, 2950, 1734, 1452, 1262 cm ; H NMR (500 MHz, CDCl3) δ 7.41 – 7.27 (m, 5H), 4.55 –
4.48 (m, 2H), 3.94 (dd, J = 7.4, 3.9 Hz, 1H), 3.69 (s, 3H), 3.57 – 3.46 (m, 2H), 2.94 (bs, 1H) 2.68
(m, 1H), 1.90 – 1.80 (m, 1H), 1.27 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 7.1 Hz, 3H).13C NMR (125
MHz, CDCl3) δ 176.2, 138.0, 128.4, 127.7, 127.6, 76.8, 74.7, 73.4, 51.7, 43.1, 36.1, 13.3, 11.3;
HRMS calcd for C15H23O4 [M+H]+ : 267.1591, found: 267.1588 (-1.1 ppm).
General Procedure B: Diastereoselective Hydrogen Atom Transfer for the Synthesis of the
2,3-anti Diastereomer (Acyclic Effect)
To a stirred solution of the appropriate α-bromoesters (1.0 equiv.) in dry toluene (0.1 M) at 40
°C were added iPr2NEt (1.5 equiv.) and Bu2BOTf (1.3 equiv.). The reaction mixture was stirred
for 1 h at 40 °C before adjusting to the corresponding temperature (See Table 2). Addition of
SMBP (0.8 equiv.), NHC borane 1 (1.5 equiv.), Et3B (0.4 equiv. of a 1.0 M solution in hexanes)
and air (for 100 µL of Et3B, 1 ml of air was added in the solution via syringe). The resulting
suspension was stirred at the corresponding temperature, then 0.2 equiv. of Et3B with air was added
every 45 minutes until the reaction was judged complete by TLC (around 1-3 hours). 1,4-
Dinitrobenzene (0.2 equiv.) was then added to the solution, and the mixture was stirred for an
additional 15 minutes. The reaction mixture was brought to 40 °C, and MeOH (0.1 M) was added
slowly keeping the internal temperature below 35 °C. After stirring 5 minutes, H2O2 (30%, 1.5
mL/mmol of starting material) was added very slowly, again keeping the internal temperature
below 35 °C. The solution was stirred at 40 °C for 45 minutes then warmed to 0 °C.H2O was
poured into the reaction mixture. The aqueous layer was extracted with ether (3 x) and the organic
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layer was successively washed with NaHCO3 sat. solution and brine. The organic layer was dried
over MgSO4, and concentrated. The residue was purified by flash chromatography (Hexanes:Et2O
70:30) to afford the desired compound.
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(±)Methyl (2S,3S,4S)-5-(benzyloxy)-3-hydroxy-2,4-dimethylpentanoate (3b)
1
General Procedure B was followed using 76 mg of 2a,b. H NMR spectroscopic analysis of the
unpurified product indicated the formation of a >20:1 mixture in favor of 3b (entry 7, Table 2).
Purification by flash chromatography (Hexanes:Et2O 70:30) provided 3b in 75% yield (43 mg).
The 1H and 13C NMR for compound 3b correspond to those previously reported by our lab.7a
3b: 1H NMR (500 MHz, CDCl3) δ 7.23-7.39 (m, 5H), 4.52 (s, 2H), 3.70 (s, 3H), 3.61- 3.68 (m,
2H), 3.52-3.61 (m, 1H), 3.41 (d, J= 7.0 Hz, 1H), 2.70- 2.79 (m, 1H), 1.84-2.00 (m, 1H), 1.22 (d, J
= 7.5 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 176.1, 138.0, 128.5, 128.4,
127.6, 73.6, 73.5, 73.3, 51.7, 43.1, 36.2, 14.9, 14.6.
(±)Methyl (2R,3R,4S)-5-(benzyloxy)-3-hydroxy-2,4-dimethylpentanoate (5b)
General Procedure B was followed using 195 mg of 4a,b. 1H NMR spectroscopic analysis of the
unpurified product indicated the formation of a >20:1 mixture in favor of 5b (entry 4, Table 3).
Purification by flash chromatography (Hexanes:Et2O 70:30) provided 5b in 81% yield (120 mg).
The 1H and 13C NMR for compound 5b correspond to those previously reported by our lab.7b
5b: Rf = 0.17 (Hexanes:Et2O, 70:30); Formula C15H22O4; MW 366.33 g/mol; IR (neat) υmax
=
3504, 3063, 2973, 1736, 1456 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.35-7.24 (m, 5H), 4.51 (d, J
= 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 3.93 (dd, J = 2.8, 8.8 Hz, 1H), 3.69 (s, 3H), 3.53 (m,
2H), 3.04 (bs, 1H), 2.62 (qd, J = 8.8, 7.1 Hz, 1H), 1.95-1.87 (m, 1H), 1.12 (d, J = 7.1 Hz, 3H),
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0.95 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 177.0, 138.3, 128.6, 127.9, 127.8, 74.9,
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74.7, 73.6, 52.0, 43.5, 35.2, 14.4, 10.0.
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ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra are available for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Y.G.:yvan.guindon@ircm.qc.ca
Acknowledgment
The authors thank the Natural Sciences and Engineering Research Council of Canada (NSERC)
for financial support.
References
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