Samarium iodide-mediated Reformatsky reactions for the stereoselective preparation of β-hydroxy-γ-amino acids: Synthesis of isostatine and dolaisoleucine

Article abstract of DOI:10.1021/jo202091r

The synthesis of β-hydroxy-γ-amino acids via SmI ₂-mediated Reformatsky reactions of α- chloroacetyloxazolidinones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of the Evans chiral auxiliary employed in the reaction, allowing erythro or threo products to be obtained selectively. The potential utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c). This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.

Full text of DOI:10.1021/jo202091r

Note
pubs.acs.org/joc
Samarium Iodide-Mediated Reformatsky Reactions for the
Stereoselective Preparation of β-Hydroxy-γ-amino Acids: Synthesis of
Isostatine and Dolaisoleucine
Christopher G. Nelson and Terrence R. Burke, Jr.*
Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute,
National Institutes of Health, Frederick, Maryland 21702, United States
S
* Supporting Information
ABSTRACT: The synthesis of β-hydroxy-γ-amino acids via SmI2-mediated Reformatsky reactions of α-chloroacetyloxazolidi-
nones with aminoaldehydes is reported. Diastereoselective coupling is demonstrated to depend on the absolute configuration of
the Evans chiral auxiliary employed in the reaction, allowing erythro or threo products to be obtained selectively. The potential
utility of the methodology is exemplified by the facile synthesis of biologically relevant N-Boc-isostatine (2b) and N-Boc-
dolaisoleucine (3c).
onproteinogenic amino acids containing β-hydroxy-γ-
amino acid motifs comprise a biologically important class
in ref 5). Of particular note for the preparation of analogues
such as 46 and 57 that contain substituents at the α-position are
“double stereo-differentiating”8 aldol reactions of amino
aldehydes with chiral acyloxazolidinones, where nascent α-
functionality within the auxiliary facilitates chirality transfer.
As shown in Scheme 1 (eq 1), the aldol addition of pro-
panoyloxazolidinone 7a to N-Boc-(S)-prolinal 6 provides the
Dap precursor 8 as a single diastereomer. In contrast, similar
chemistry applied to the preparation of products that lack α-
substituents can result in significantly less effective stereo-
induction. This is exemplified by the synthesis of N-Cbz Dil
(3b) through the reaction of N-Cbz-N-methyl (S)-isoleucinal
(9) with the boron enolate of acetyloxazolidinone 7b, where a
near complete lack of stereocontrol is observed at the β-
hydroxyl center of the resulting product 10a (Scheme 1, eq 2).9
In this latter example, limitations imposed by the absence of an
α-substitutent can be overcome through a two-step process
involving the aldol reaction of a methylthio-containing
acyloxazolidinone (7c), which yields a thiomethyl group at
the α-position (10b) that facilitates chirality transfer to the β-
hydroxyl center. Once the stereodirecting role of the
thiomethyl group has been achieved, it can be removed
reductively to provide the desired final product, N-Cbz Dil
(3b).9
N
of agents that includes (3S,4S)-4-amino-3-hydroxy-6-methyl-
heptanoic acid (statine, 1), a component of aspartic protease
inhibitors such as peptstatine1 and (3S,4R,5S)-4-amino-3-
hydroxy-5-methylheptanoic acid (isostatine, 2a), found in the
cytotoxic didemnin cyclodepsipeptides.2 Additional examples
are (3S,4R,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoic
acid (dolaisoleucine or “Dil”, 3a) and (2R,3R)-3-methoxy-2-
methyl-3-((S)-pyrrolidin-2-yl)propanoic acid (dolaproine or
“Dap”, 4), both of which are key constituents of cytotoxic
peptides, including dolastatin 10,3 as well as (2S,3S,4R)-4-
amino-3-hydroxy-2-methylpentanoic acid (5), a component of
the antineoplastic glycopeptide, bleomycin B2 (Figure 1).4
Metal-catalyzed Reformatsky reactions between aldehydes or
ketones and compounds containing α-halo carbonyls can
provide an alternate approach to the synthesis of β-hydroxy
Figure 1. Structures of β-hydroxy-γ-amino acids discussed in the text.
Several synthetic methodologies have been reported for the
stereoselective syntheses of β-hydroxy-γ-amino acids (reviewed
Received: October 12, 2011
Published: December 2, 2011
This article not subject to U.S. Copyright.
Published 2011 by the American Chemical
Society
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Note
The differentiation of conformers vs stereoisomers was made
using NMR. COSY analysis displayed two distinct CHγ−NH
correlations and NOESY analysis revealed a same-phase
(relative to the diagonal) crosspeak between the two NH
signals.15 This same-phase crosspeak arises from the conforma-
tional exchange of a single diastereomer. The presence of two
diastereomers would not display such a NH−NH crosspeak.
The synthesis of N-Boc-Dil (3c) started with N-Boc-N-
methylisoleucinal 14. This was obtained from commercially
available N-Boc-N-methylisoleucine9 in a manner analogous to
that used to convert N-Boc-D-allo-isoleucine to N-Boc-D-
allo-isoleucinal (13). As noted above, while isostatine and Dil
share the same relative β,γ-erythro stereochemistry, they are
enantiomeric. Accordingly, α-chloroloacetyloxazolidinone (S)-
1212 was used in the Sm-mediated Reformatsky coupling with
aldehyde 14. Under similar reaction conditions as above,
successful coupling was again realized to provide the secondary
alcohol 15 as a single diastereomer in good yield (Scheme 3).
Scheme 1. Aldol Reaction Strategies for the Construction of
Dap Precursor 8 (eq 1)6 and Dil Precursors 10a,b (eq 2)9
Employing Chiral Auxiliaries in the Presence (7a and 7c)
and Absence (7b) of α-Functionality
Scheme 3. Synthesis of N-Boc-Dil (3c)
derivatives.10 However, literature pertaining to the synthesis of
β-hydroxy-γ-amino acids by asymmetric Reformatsky reactions
employing oxazolidinone chiral uxiliaries is significantly less
extensive than for asymmetric aldol reactions. These protocols
often involve substituents at the α-position, as exemplified by
the synthesis of Dap (4) via a cobalt−phosphine complex-
directed Reformatsky reaction.11 Therefore, we noted with
interest the ability of SmI2 to mediate Reformatsky reactions of
haloacetyloxazolidinones with aldehydes to form β-hydroxy
adducts in high stereoselectivity without the necessity of α-
substituents (for example, see ref 12). As reported herein, in
order to examine the potential utility of this chemistry for the
preparation of β-hydroxy-γ-amino acids lacking α-substituents,
we applied SmI2-catalyzed Reformatsky chemistry to the
synthesis of N-Boc-protected isostatine (2b) and Dil (3c).
The synthesis of 2b began with the known aldehyde 11,
which was obtained from commercially available N-Boc-D-allo-
isoleucine.2,13 We were pleased to observe that the addition of a
mixed solution of aldehyde 11 and α-chloroacetyloxazolidinone
Subsequent O-methylation using trimethyloxonium tetrafluoro-
roborate2 and oxidative removal of the chiral auxiliary yielded
N-Boc-Dil (3c), having spectral and optical properties matching
literature values.3
The stereochemical outcome of the SmII-mediated formation
of Reformatsky products 13 and 15 presumably depends highly
on the nature of the chiral auxiliary Sm-enolate complex.
However additions of achiral lithium enolates to (S)-prolinal
derivatives have also been shown to be highly diastereo-
selective.16 To determine whether the selectivities observed
with the SmII-mediated Reformatsky reactions to form products
13 and 15 are derived from the chirality of the SmIII enolate (ie.
auxiliary control) or from preferential approach of a SmIII
enolate to a low energy conformation of the aldehyde (i.e.,
Felkin addition),16 we coupled N-Boc-(S)-prolinal (6) to both
α-chloroacetyloxazolidinones (R)-12 and (S)-12 using the
above reaction conditions (Scheme 4).
14
(R)-1212 to an excess (3 equiv) of SmI2 resulted in the
formation of the secondary alcohol 13 as a single diastereomer
(Scheme 2). Removal of the chiral auxiliary under oxidative
d
Scheme 2. Synthesis of N-Boc-isostatine (2b)
Treatment of 6 with oxazolidinones (R)-12 and (S)-12 pro-
vided the alcohols 17 and 19, respectively (Scheme 4).
Oxidative removal of the chiral auxiliaries gave the correspond-
ing diastereomeric β-hydroxyacids 18 and 20, respectively.
Spectral analysis confirmed that the stereochemical outcome of
the SmII-mediated Reformatsky coupling was indeed controlled
by the chirality of the auxiliary employed in the reaction,
allowing threo (17; dr 5:1) or erythro (19; dr 14:1) products to
be obtained selectively. It should be noted that chiral induction
by α-amino aldehydes generally favors the erythro products.16
This preference accounts for the difference in selectivity
observed in the formation of threo product 17 (dr 5:1) vs
conditions11 provided N-Boc-isostatine (2b) as a 3:1 mixture of
conformers, as indicated by NMR. The optical rotation of the
product and the spectral properties of the major conformer
agreed well with literature values.
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Note
All aqueous phases were back extracted with Et2O (1 × 50 mL).
Combined organic fractions were dried (Na2SO4), concentrated in
vacuo and chromatographed over silica gel to afford 11 (706 mg, 3.3
mmol, 76% yield) as a colorless oil. Spectroscopic data for compound
11 matched that previously reported.17
Scheme 4. Stereoselective Synthesis of (R)- and (S)-β-
Hydroxy-γ-amino Acids Derived from N-Boc-(S)-prolinal
(6)
Samarium Iodide (SmI2). Using standard anhydrous techniques,
with careful exclusion of oxygen, to a round-bottomed flask was added
a dry mixture of samarium metal (99.9% purity, 40 mesh, 3.76 g, 25.00
mmol; 1.25 equiv) and diiodine (5.08 g, 20 mmol) under argon. The
flask containing the dry mixture was then quickly evacuated and argon
backfilled (3×), anhydrous THF (200 mL) was added via cannula, the
flask was wrapped in aluminum foil, and the mixture was stirred at
room temperature (4 h). The SmI2 obtained in this fashion is deep
green-blue in color with a nominal concentration of 0.1 M. When
protected from light and stored under argon, this stock solution is
stable over a period of approximately 1 week without any appreciable
loss of activity.
General Procedure (A) for SmI2-mediated Reformatsky
Coupling. To a dry round-bottomed flask, evacuated and backfilled
with argon (3×) at −78 °C, was added freshly prepared SmI2
(3 equiv) followed by a solution of aldehyde (1.2 equiv) and α-
chloroacetyloxazolidinone (1 equiv) in dry THF (0.3 M), dropwise via
syringe. The transfer was quantitated with additional THF, and the
mixture was stirred at −78 °C (5 min). The reaction was terminated
by bubbling O2 through the solution to quench residual SmII
(indicated by a change in color from blue-green SmII to yellow
SmIII). A solution of saturated aqueous NH4Cl was then added at
−78 °C, and the mixture was brought to room temperature and
further diluted with aqueous NH4Cl. The mixture was extracted with
Et2O, and the combined organic phases were washed thoroughly with
15% aqueous Na2S2O3, dried (Na2SO4), and concentrated in vacuo.
The resulting crude residue was purified by silica gel chromatography
to provide the desired coupled products (see below).
erythro product 19 (dr 10:1). Utilizing the appropriate chiral
auxiliary can enhance this preference (erythro/threo = 10:1
vs 4:116a) or reverse it (erythro/threo = 1:5).
In summary, the SmI2-mediated Reformatsky coupling of
amino aldehydes with α-chloroacetyloxazolidinones has been
successfully applied to the synthesis of the β-hydroxy-γ-amino
acids N-Boc-isostatine (2b) and N-Boc-dolaisoleucine (3c). The
stereochemical outcomes of the reactions are controlled by the
absolute configuration of the chiral auxiliaries used, allowing the
selective formation of erythro or threo products. These results
should serve as a general method for the construction of β-
hydroxy-γ-amino acids that enables the synthesis of both natural
and unnatural peptide sequences for biological evaluation.
(3S,4R,5S)-4-tert-Butyl carbamate-3-hydroxy-1-((R)-4-isoprop-
yl-2-oxazolidinone-3-yl)-5-methyl-1-oxoheptanone (13). The
general procedure “A” outlined above was followed using SmI2 (9.29
mL, 0.929 mmol, 3 equiv), N-Boc-D-allo-isoleucinal (11) (80 mg,
0.372 mmol, 1.2 equiv) and α-chloroacetyloxazolidinone (R)-12 (63.7
mg, 0.310 mmol). The product residue was chromatographed over
silica gel to afford alcohol 13 (90.4 mg, 0.234 mmol, 76%) as a
EXPERIMENTAL SECTION
■
General Information. Reactions were stirred magnetically under
an argon atmosphere, unless otherwise noted, and reagents were
purchased from commercial sources and used without further
purification. Solvents were removed by rotary evaporation under
reduced pressure and silica gel chromatography was performed using
flash silica gel (230−400 mesh, 40−60 μm particle size). Anhydrous
solvents were obtained commercially and used without further drying.
Infared (IR) measurements were made using a Fourier transform
infared spectrometer equipped with an ATR probe. NMR measure-
ments were performed at 25 °C (unless otherwise noted) at either 400
or 500 MHz. When required, NMR spectra were acquired at elevated
temperatures, specified within the reported data and in the spectral
parameters.
25
colorless oil: TLC Rf1 = 0.27 (40% EtOAc/hexane); αD (c 2.5,
CHCl3) = (−) 38.27; H NMR (25 °C, 500 MHz, CDCl3) δ 4.49−
4.45 (m, 2H), 4.31 (t, J = 8.6 Hz, 1H), 4.20 (dd, J = 9.0, 2.6 Hz, 1H),
3.95 (bs, 0.1H), 3.86 (ddd, J = 14.9, 8.5, 3.3 Hz, 0.9H), 3.69 (td, J =
9.6, 3.5 Hz, 1H), 3.58 (d, J = 8.1 Hz, 1H), 3.34 (dd, J = 17.4, 6.6 Hz,
1H), 3.04 (dd, J = 17.4, 3.3 Hz, 1H), 2.38−2.31 (m, 1H), 1.97 (ddd,
J = 13.8, 6.9, 3.6 Hz, 1H), 1.44 (s, 1H), 1.41 (s, 8H), 1.38−1.30 (m,
1H), 1.26−1.19 (m, 1H), 0.92 (d, J = 7.0 Hz, 3H), 0.92−0.87 (m,
3H), 0.88 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H); 1H NMR (75
°C, 500 MHz, DMSO-d6) δ 4.59 (bs, 1H), 4.41−4.36 (m, 1H), 4.31 (t,
J = 8.6 Hz, 1H), 4.28−4.27 (m, 1H), 4.25 (dd, J = 8.9, 3.0 Hz, 1H),
3.03 (bs, 1H), 2.92 (dd, J = 15.9, 3.4 Hz, 1H), 2.66 (s, 3H), 2.25−2.18
(m, 1H), 1.89−1.81 (m, 1H), 1.50 (bs, 1H), 1.40 (s, 9H), 1.07−1.00
(m, 1H), 0.96 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.85 (t, J =
7.5 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H); 13C NMR (25 °C, 125 MHz,
CDCl3) δ 173.6, 156.4, 154.04, 79.5, 69.6, 63.8, 58.6, 56.1, 37.7, 33.7,
28.8, 28.3, 27.1, 18.0, 14.9, 13.1, 11.7; IR (neat film, cm−1) 3371, 2963,
1783, 1697, 1236; HRMS (MALDI - TOF) calcd for C19H34N2O6
[M + Na]+ 409.2315, found 409.2327.
N-Boc-D-allo-isoleucinal (11). To a solution of N-Boc-D-allo-
isoleucine (1 g, 4.32 mmol) in THF (4.32 mL), at −10 °C under
argon, was added N-methylmorpholine (0.475 mL, 4.32 mmol),
followed by isobutyl chloroformate (0.568 mL, 4.32 mmol). After
being stirred at −10 °C (10 min), the reaction mixture was filtered
(glass fritted funnel) to remove the precipitate and the filtrate cooled
to −10 °C. A solution of NaBH4 (0.245 g, 6.49 mmol) in H2O (2.2
mL) was then added over 5 min. Upon complete addition, the reaction
was diluted with H2O (5 mL) and extracted with EtOAc (3 × 30 mL).
The organic phase was dried (Na2SO4) and concentrated in vacuo.13
The crude residue was diluted with DMSO (4.3 mL) under argon, and
NEt3 (3.01 mL, 21.60 mmol) was added. The mixture was stirred at
room temperature (15 min) before being cooled to 0 °C. SO3−
pyridine complex (3.438 g, 21.60 mmol) was added, and the mixture
was stirred at 0 °C (45 min). The reaction was halted by the addition
of H2O (30 mL). The mixture was extracted with Et2O (3 × 60 mL),
and the organic phases were washed, successively, with 10% aqueous
citric acid, H2O, saturated aqueous NaHCO3, and brine (20 mL each).
N-Boc-N-methylisoleucinal (14). To a solution of N-Boc-N-Me-
isoleucine (2.94 g, 12 mmol) in dry THF (8.4 mL) at 0 °C was added
BH3−THF complex (1.0 M in THF, 18 mL, 1.5 equiv) dropwise via
syringe. The reaction solution was stirred at 0 °C (2 h) and then room
temperature (1 h). The reaction was halted by the slow addition of
H2O (20 mL), and the mixture was extracted with EtOAc (3 × 50
mL). The organic phase was washed, successively, with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL). Removal of the
solvent in vacuo afforded the crude amino alcohol as a viscous clear oil
which was diluted with DMSO (10.81 mL) and NEt3 (7.53 mL, 54.0
mmol) under argon. The mixture was stirred at room temperature
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The Journal of Organic Chemistry
Note
(15 min) then cooled to 0 °C. SO3−pyridine complex (8.60 g, 54.0
mmol) was added and the mixture was stirred at 0 °C (45 min). The
reaction was halted by the addition of H2O (50 mL). The mixture was
extracted with Et2O (3 × 100 mL), and the organic phase was washed,
successively, with 10% aqueous citric acid, water, saturated aqueous
NaHCO3, and brine (15 mL each). All aqueous phases were
backwashed with Et2O (1 × 40 mL). Combined organic fractions
were dried with Na2SO4 and concentrated in vacuo. The residue was
eluted through a short plug of silica gel to afford 14 (2.061 g, 8.99
mmol, 75% yield) as a colorless oil. Spectroscopic data for compound
14 matched that previously reported.6
(3S,4R,5S)-4-((tert-Butoxycarbonyl)amino)-3-hydroxy-5-
methylheptanoic Acid (N-Boc-isostatine, 2b). To a solution of
amide 13 (50 mg, 0.129 mmol) in 3:1 THF/H2O (0.35 mL) at 0 °C
was added 50% aqueous H2O2 (0.056 mL, 0.776 mmol) followed by
LiOH−H2O (14.13 mg, 0.336 mmol). The mixture was stirred at 0 °C
(3 h), and then excess peroxide was quenched by the addition of 1.5 N
aqueous Na2SO3 (1 mL, 1.5 mmol) at 0 °C, and the mixture was
stirred at room temperature (overnight). The pH was adjusted to ∼9−
10 by the addition of saturated aqueous NaHCO3 and the free
oxazolidinone side product was extracted using DCM. The aqueous
phase was acidified to pH ∼2 using 1 N aqueous HCl and extracted
with EtOAc . The combined EtOAc phases were dried (Na2SO4) and
taken to dryness in vacuo to afford N-Boc-isostatine (2b) (30.3 mg,
0.11 mmol, 85%) as a colorless semisolid: αD25 (c 1.25, CHCl3) = (−)
7.5; 1H NMR (25 °C, 500 MHz, CDCl3, 2 conformers) δ 5.77 (NH, d,
J = 10.6 Hz, 0.36H, minor conformer, exchanges), 4.51 (NH, d, J = 9.6
Hz, 0.64H, major conformer, exchanges), 3.95 (td, J = 8.1, 3.0 Hz,
1H), 3.65 (td, J = 9.7, 3.8 Hz, 0.66H, major), 3.58 (t, J = 8.6 Hz,
0.33H, minor), 2.70−2.62 (m, 1H), 2.57−2.47 (m, 1H), 1.92−1.85
(m, 1H), 1.47 (s, 3H, minor), 1.44 (s, 6H, major), 1.40−1.32 (m, 1H),
1.26−1.19 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H), 0.89−0.85 (m, 3H); 13C
NMR (25 °C, 125 MHz, CDCl3) δ major 176.65, 156.6, 80.0, 69.1,
56.8, 38.3, 33.9, 28.31, 27.0, 13.3, 11.6; minor 176.67, 157.8, 81.4, 68.5,
58.0, 39.2, 34.1, 28.26, 26.8, 12.8, 11.8; LRMS (ESI−negative mode)
m/z 274 [M − H]−, 310 [M + 35Cl]−, 312 [M + 37Cl]−; LRMS (ESI−
positive mode) m/z 298 [M + Na]+; HRMS (MALDI - TOF) calcd
for C13H25NO5 [M + Na]+ 298.1630, found 298.1640.
tetrafluoroborate (281 mg, 1.90 mmol, 2.5 equiv). The mixture was
brought to room temperature, sealed under argon, and stirred (48 h).
The mixture was filtered through Celite and concentrated in vacuo,
and the residue was chromatographed over silica gel to afford methyl
ether 16 (271 mg, 0.66 mmol, 86%) as a colorless oil: TLC Rf = 0.42
20
1
(35% EtOAc/hexane); αD (c 0.9, CHCl3) = (+) 36.0; H NMR
(25 °C, 400 MHz, DMSO-d6, two conformers) δ 4.41−4.36 (m, 1H),
4.34−4.26 (m, 2H), 4.03−3.85 (m, 2H), 3.26 (s, 1.6H), 3.23 (s, 1.4H),
3.08−3.02 (m, 2H), 2.62 (s, 1.7H), 2.60 (s, 1.3H), 2.22−2.13 (m, 1H),
1.84−1.71 (m, 1H), 1.38 (s, 9H), 1.41−1.34 (m, 1H), 1.08−0.95 (m,
1
1H), 0.89 (d, J = 6.6 Hz, 3H), 0.87−0.82 (m, 6H), 0.79 (m, 3H); H
NMR (60 °C, 400 MHz, DMSO) δ 4.42−4.37 (m, 1H), 4.33 (t, J =
8.5 Hz, 1H), 4.27 (dd, J = 8.9, 2.9 Hz, 1H), 4.00−3.93 (m, 1.4H), 3.85
(bs, 0.4H), 3.26 (s, 3H), 3.14−3.00 (m, 2H), 2.64 (s, 3H), 2.26−2.15
(m, 1H), 1.84−1.73 (m, 1H), 1.45−1.38 (m, 1H), 1.39 (s, 9H), 1.04
(m, 1H), 0.92 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.86−0.82
(m, 3H), 0.81 (d, J = 6.9 Hz, 3H); 13C NMR (60 °C, 100 MHz,
DMSO-d6, major conformer) δ 170.4, 153.7, 76.9, 63.3, 57.9, 37.3,
33.2, 27.8, 25.3, 17.2, 15.8, 14.5, 10.4; IR (neat film, cm−1) 2965, 1777,
1688, 1150; HRMS (MALDI - TOF) calcd for C21H38N2O6 [M +
Na]+ 437.2628, found 437.2632.
(3R,4S,5S)-4-((tert-Butoxycarbonyl)(methyl)amino)-3-me-
thoxy-5-methylheptanoic Acid (N-Boc-Dolaisoleucine, 3c). To
a solution of carbamate 16 (261 mg, 0.548 mmol) in a 1:1 mixutre of
THF/H2O (1.26 mL), under argon and at 0 °C, was added 50%
aqueous H2O2 (0.114 mL, 1.972 mmol) over 5 min. The resultant
solution was stirred (5 min), LiOH−H2O (36.8 mg, 0.876 mmol) was
added, and stirring was continued at 0 °C (3 h). The reaction was
quenched by the addition of Na2SO3 (276 mg, 2.191 mmol, 4 equiv)
in H2O (1.5 mL, 1.46 M), and the mixture was stirred at room
temperature (overnight). The mixture was concentrated in vacuo, and
the resulting aqueous slurry was washed with DCM. The aqueous
phase was acidified to pH ∼2 using 37% aqueous HCl and extracted
with EtOAc. The original DCM extracts were again extracted with 5%
NaOH (10 mL), and the aqueous layer was acidified and extracted
(EtOAc) as before. The DCM organic phases were dried (Na2SO4)
and concentrated in vacuo to afford recovered chiral auxiliary (64 mg,
90%). The combined EtOAc organic phases were dried (Na2SO4) and
taken to dryness in vacuo to afford 3c (158 mg, 0.52 mmol, 95%) as a
(3R,4S,5S)-4-(tert-Butoxycarbonyl)(methyl)amino-3-hy-
droxy-1-((S)-4-isopropyl-2-oxazolidinone-3-yl)-5-methyl-1-ox-
oheptanone (15). The general procedure “A” outlined above was
followed using SmI2 (136 mL, 13.60 mmol, 3 equiv), N-Boc-N-Me-
isoleucinal 14 (1.247 g, 5.44 mmol, 1.2 equiv), and α-chloroacetylox-
azolidinone (S)-12 (0.932 g, 4.53 mmol). The product residue was
chromatographed over silica gel to afford alcohol 15 (1.54 g, 3.85
mmol, 86%) as a colorless oil: TLC Rf = 0.22 (35% EtOAc/hexane);
αD25 (c 2.6, CHCl3) = (−) 38.71; 1H NMR (25 °C, 500 MHz, DMSO-
d6) δ 4.84 (dd, J = 7.3, 28.7 Hz, 1H), 4.40−4.35 (m, 1H), 4.32−4.20
(m, 3H), 3.76 (bs, 1H), 2.99−2.85 (m, 1H), 2.91 (d, J = 6.2 Hz, 1H),
2.64 (s, 1.6H), 2.59 (s, 1.3H), 2.22−2.14 (m, 1H), 1.82 (m, 1H),
1.53−1.43 (m, 1H), 1.38 (s, 9H), 1.04−0.95 (m, 1H), 0.94−0.90 (m,
19
1
viscous oil: αD (c 2.5, CHCl3) = (−) 10.9; H NMR (25 °C, 400
MHz, CDCl3) δ 4.02−3.80 (m, 2H), 3.38 (s, 3H), 2.67 (s, 3H), 2.60−
2.43 (m, 2H), 1.82−1.69 (m, 1H), 1.51−1.40 (m, 1H), 1.43 (s, 9H),
1.12−1.02 (m, 1H), 0.94 (d, J = 5.9 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H);
13C NMR (25 °C, 100 MHz, CDCl3) δ 176.5 and 176.4, 156.6, 80.1
and 79.6, 78.3, 60.9 (br), 57.7 and 57.6, 37.1 and 36.9, 34.9 (br) and
34.5, 28.39 and 28.35, 25.9 and 25.7, 16.2 and 16.1, 11.28; HRMS
(MALDI - TOF) calcd for C15H29NO5 [M + Na]+ 326.1943, found
326.1916.
(S)-tert-Butyl 2-((S)-1-Hydroxy-3-((R)-4-isopropyl-2-oxoxazo-
lidin-3-yl)-3-oxopropyl)pyrrolidine-1-carboxylate (17) and (S)-
tert-Butyl 2-((R)-1-Hydroxy-3-((R)-4-isopropyl-2-oxoxazolidin-
3-yl)-3-oxopropyl)pyrrolidine-1-carboxylate (epi-17). The gen-
eral procedure “A” outlined above was followed using SmI2 (29.2 mL,
2.92 mmol, 3.0 equiv), N-Boc-prolinal 6 (233 mg, 1.168 mmol, 1.2
equiv), and (R)-12 (200 mg, 0.973 mmol, 1.0 equiv). The product
residue was chromatographed over silica gel to afford a mixture (310
mg, 0.84 mmol, 86%, dr 5:1) of alcohols 17 and epi-17: TLC Rf = 0.34
1
3H), 0.87−0.78 (m, 9H); H NMR (75 °C, 500 MHz, DMSO-d6) δ
4.61 (bs, 1H), 4.41−4.37 (m, 1H), 4.31 (t, J = 8.6 Hz, 1H), 4.29−4.23
(m, 1H), 4.25 (dd, J = 8.9, 2.8 Hz, 1H), 3.81−3.59 (m, 1H), 3.01 (bs,
1H), 2.92 (dd, J = 15.7, 3.1 Hz, 1H), 2.66 (s, 3H), 2.22 (dtd, J = 13.8,
6.9, 4.0 Hz, 1H), 1.86 (dd, J = 13.4, 6.7 Hz, 1H), 1.55−1.45 (m, 1H),
1.40 (s, 9H), 1.08−0.98 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H), 0.87 (d, J =
7.0 Hz, 3H), 0.88−0.84 (m, 3H), 0.82 (d, J = 6.9 Hz, 3H); 13C NMR
(75 °C, 125 MHz, d6-DMSO) δ 170.7, 153.5, 78.1, 67.1, 63.3, 57.8,
40.6, 34.6, 34.2, 28.1, 27.7, 25.0, 17.1, 16.0, 14.5, 10.9; IR (neat film,
cm−1) 3458, 2964, 1780, 1684; HRMS (MALDI - TOF) calcd for
C20H36N2O6 [M + Na]+ 423.2471, found 423.2477.
23
1
(55% EtOAc/hexane); αD (c 1.4, CHCl3) = (−) 94.5; 17 H NMR
(25 °C, 400 MHz, DMSO-d6) δ 4.90 (s, 0.1H), 4.81 (d, J = 5.9 Hz,
0.9H), 4.39−4.32 (m, 1H), 4.33−4.22 (m, 2.3H), 4.12 (bs, 0.6H),
3.95−3.75 (m, 0.8H), 3.61 (bs, 0.1H), 3.37−3.28 (m, 1H), 3.26−2.99
(m, 1.7H), 2.99−2.60 (m, 1.3H), 2.27−2.12 (m, 1H), 1.94−1.77 (m,
2.8H), 1.75−1.63 (m, 1.2H), 1.40 (s, 1.7H), 1.38 (s, 7.3H), 0.85 (d,
(3R,4S,5S)-4-tert-Butoxycarbonyl)(methyl)amino-1-((S)-4-
isopropyl-2-oxazolidinone-3-yl)-3-methoxy-5-methyl-1-oxo-
heptanone (16). A mixture of alcohol 15 (304 mg, 0.76 mmol) and
molecular sieves (4 Å, oven-dried, 300 mg) was diluted with
anhydrous 1,2-dichloroethane (1.12 mL) under an argon atmosphere
and stirred (20 min). The mixture was cooled to 0 °C prior to the
sequential addition of proton sponge [1,8-bis(dimethylamino)-
naphthalene; 423 mg, 1.97 mmol, 2.6 equiv] and trimethyloxonium
1
J = 7.0 Hz, 3H), 0.82−0.77 (m, 3H); H NMR (60 °C, 400 MHz,
DMSO-d6) δ 4.68 (d, J = 5.2 Hz, 0.86H), 4.39−4.35 (m, 1H), 4.30
(t, J = 8.4 Hz, 1H), 4.25 (dd, J = 8.9, 3.1 Hz, 1H), 4.25−4.17 (m, 1H),
3.88 (bs, 0.86H), 3.42−3.33 (m, 1H), 3.24−3.14 (m, 1.4H), 3.04−
2.82 (m, 1.6H), 2.26−2.17 (m, 1H), 1.90−1.81 (m, 3H), 1.75−1.68
(m, 1H), 1.40 (s, 7.7H), 0.86 (d, J = 7.1 Hz, 3H), 0.83 (d, J = 6.8 Hz,
3H); 13C NMR (60 °C, 100 MHz, DMSO-d6) δ 171.4, 154.3, 78.8,
736
dx.doi.org/10.1021/jo202091r | J. Org. Chem. 2012, 77, 733−738

The Journal of Organic Chemistry
Note
63.8, 58.4, 47.5, 28.8, 28.5, 27.2, 17.9, 15.2; IR (neat film, cm−1) 2972,
2360, 1780, 1685; HRMS (MALDI - TOF) calcd for C18H30N2O6
[M + K]+ 409.1741, found 409.1719. epi-17: diagnostic 1H NMR
peaks (60 °C, 400 MHz, DMSO-d6) δ 4.73 (d, J = 5.7 Hz, 0.14H),
3.65 (bs, 0.14H), 2.73 (dd, J = 15.8, 3.3 Hz, 0.2H), 1.41 (s, 1.3H).
(S)-3-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-3-hydroxy-
propanoic Acid (18). To a solution of carbamate 17 (70 mg, 0.189
mmol) in 4:1 THF/H2O (1.08 mL, 0.175 M), at 0 °C, was added 50%
aqueous H2O2 (39 μL, 0.680 mmol, 3.6 equiv) dropwise via syringe. A
solution of LiOH−H2O (12.70 mg, 0.302 mmol, 1.6 equiv) in H2O
(216 μL) was added, and stirring was continued at 0 °C (3 h). A
solution of Na2SO3 (95 mg, 0.756 mmol, 4 equiv) in H2O (518 μL,
1.46 M) was added, and the mixture was stirred at room temperature
(overnight). The mixture was concentrated in vacuo, and the residue
was diluted with 5% aqueous NaHCO3 (10 mL). The aqueous phase
was washed with DCM (2 × 10 mL, acidified to pH ∼2 with 37%
aqueous HCl and extracted with EtOAc. The original DCM washes
were extracted with 5% aqueous NaHCO3 (10 mL), and the aqueous
layer was acidified and extracted with EtOAc. The DCM phases were
dried (Na2SO4) and concentrated in vacuo to afford recovered chiral
auxiliary (23 mg, 0.178 mmol, 94% recovered). The combined EtOAc
phases were dried (Na2SO4) and taken to dryness in vacuo to afford a
mixture (46.4 mg, 0.179 mmol, 95%, dr = 5:1) of acids 18 and 20 as a
aqueous H2O2 (39 μL, 0.680 mmol, 3.6 equiv) dropwise via syringe. A
solution of LiOH-H2O (12.70 mg, 0.302 mmol, 1.6 equiv) in H2O
(216 μL) was added and the reaction solution was stirred at 0 °C
(3 h). To this solution was added a solution of Na2SO3 (95 mg, 0.756
mmol, 4 equiv) in H2O (518 μL, 1.46 M) and the mixture was stirred
at room temperature (overnight). The mixture was concentrated in
vacuo, and the residue was diluted with 5% aqueous NaHCO3 (10 mL)
and washed with DCM (2 × 10 mL). The resulting aqueous layer was
acidified to pH∼2 using 37% aqueous HCl and extracted with EtOAc.
The original DCM washes were extracted with 5% aqueous NaHCO3
(10 mL), and the resultant aqueous layer was acidified and extracted
with EtOAc. The DCM phases were dried (Na2SO4) and concentrated
in vacuo to afford recovered chiral auxiliary (23 mg, 0.178 mmol, 94%
recovered). The combined EtOAc phases were dried (Na2SO4) and
taken to dryness in vacuo to afford acid 20 (46.8 mg, 0.18 mmol, 96%)
as a pale red oil. αD (c 2.3, CHCl3) = (−) 46.3; H NMR (65 °C,
400 MHz, d6-DMSO) δ 4.14−4.06 (m, 1H), 3.66−3.60 (m, 1H),
3.38−3.29 (m, 1H), 3.20−3.10 (m, 1H), 2.28 (dd, J = 14.9, 4.2 Hz,
1H), 2.18 (dd, J = 14.8, 8.7 Hz, 1H), 1.97−1.81 (m, 2H), 1.77−
1.64 (m, 2H), 1.41 (s, 9H); 13C NMR (65 °C, 100 MHz, d6-DMSO)
δ 172.8, 153.7, 78.0, 67.8, 61.0, 61.0, 46.4, 39.8, 28.0, 25.0, 23.2; IR
(neat film, cm−1) 3397, 2972, 1676, 1401; HRMS (MALDI - TOF)
calcd for C12H21NO5 [M + Na]+: 282.1317, found 282.1318.
20
1
20
1
colorless oil: αD (c 2.3, MeOH) = (−) 47.1; 18 H NMR (25 °C,
400 MHz, DMSO-d6) δ 4.27−4.17 (m, 0.45H), 4.17−4.07 (m,
0.55H), 3.85−3.75 (m, 0.84H), 3.39−3.25 (m, 1H), 3.24−3.11 (m,
1H), 2.32−2.19 (m, 1H), 2.13 (dd, J = 15.0, 9.3 Hz, 1H), 1.91−1.73
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds are provided. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
(m, 3H), 1.73−1.63 (m, 1H), 1.39 (s, 9H); H NMR (65 °C, 400
MHz, DMSO-d6) δ 4.23−4.08 (m, 1H), 3.86−3.79 (m, 0.83H), 3.41−
3.31 (m, 1H), 3.22−3.12 (m, 1H), 2.28 (dd, J = 15.0, 4.0 Hz, 1H),
2.16 (dd, J = 15.1, 9.0 Hz, 1H), 1.89−1.76 (m, 3H), 1.74−1.64 (m,
1H), 1.41 (s, 9H); 13C NMR (65 °C, 100 MHz, DMSO-d6) δ 172.6,
154.2, 78.3, 68.9, 60.3, 46.8, 37.9, 27.9, 26.2, 23.2; IR (neat film, cm−1)
3402, 2930, 2361, 1677, 1394; HRMS (MALDI - TOF) calcd for
AUTHOR INFORMATION
Corresponding Author
*Tel: +1 340 846 5906. Fax: +1 340 846 6033. E-mail: tburke@
helix.nih.gov.
■
1
C12H21NO5 [M + Na]+ 282.1317, found 282.1318. 20: diagnostic H
NMR peak (25 °C, 400 MHz, DMSO-d6) δ 3.62−3.56 (m, 0.16H);
1
diagnostic H NMR peak (65 °C, 400 MHz, DMSO-d6) δ 3.66−3.60
ACKNOWLEDGMENTS
(m, 0.16H).
■
(S)-tert-Butyl 2-((R)-1-Hydroxy-3-((S)-4-isopropyl-2-oxooxa-
zolidin-3-yl)-3-oxopropyl)pyrrolidine-1-carboxylate (19) and
(S)-tert-Butyl 2-((S)-1-Hydroxy-3-((S)-4-isopropyl-2-oxooxazoli-
din-3-yl)-3-oxopropyl)pyrrolidine-1-carboxylate (epi-19). The
general procedure “A” outlined above was followed using SmI2
(29.200 mL, 2.92 mmol), N-Boc-prolinal 6 (233 mg, 1.168 mmol),
and (S)-12 (200 mg, 0.973 mmol). The product residue was
chromatographed over silica gel to afford pure alcohol 19 (272 mg,
0.75 mmol, 74%). An additional amount (71 mg) of 19 and epi-19 was
also obtained as a mixture (ratio 19:epi-19 = 53:47). 19: TLC Rf =
We thank Dr. James Kelley and Christopher Lai (Chemical
Biology Laboratory, NCI) for HRMS data and Dr. Joseph
Barchi (Chemical Biology Laboratory, NCI) for NMR
assistance. This work was supported in part by the Intramural
Research Program of the NIH, Center for Cancer Research,
NCI-Frederick, and the National Cancer Institute, National
Institute of Health. The content of this publication does not
necessarily reflect the views or policies of the Department of
Health and Human Services, nor does mention of trade names,
commercial products, or organizations imply endorsement by
the U.S. Government.
22
0.35 (55% EtOAc/hexane); αD (c 0.79, CHCl3) = (+) 17.1; 1H
NMR (25 °C, 400 MHz, DMSO-d6) δ 4.94−4.83 (m, 1H), 4.42−4.33
(m, 1H), 4.33−4.24 (m, 2H), 4.24−4.14 (m, 1H), 3.69−3.57 (m, 1H),
3.34−3.27 (m, 1H), 3.22−3.08 (m, 1H), 3.07−2.77 (m, 2H), 2.24−
2.12 (m, 1H), 1.99−1.80 (m, 2H), 1.78−1.64 (m, 2H), 1.40 (s, 9H),
REFERENCES
■
1
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400 MHz, DMSO-d6) δ 4.75 (d, J = 5.0 Hz, 1H), 4.41−4.36 (m, 1H),
4.31 (t, J = 8.5 Hz, 1H), 4.26 (dd, J = 9.0, 3.1 Hz, 1H), 4.23−4.18 (m,
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737
dx.doi.org/10.1021/jo202091r | J. Org. Chem. 2012, 77, 733−738

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1
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738
dx.doi.org/10.1021/jo202091r | J. Org. Chem. 2012, 77, 733−738