Synthesis of chiral 13C,77Se-labeled selones.

Article abstract of DOI:10.1021/jo049747o

Stable isotope-labeled N-acyl selones have been constructed in fewer than four steps from readily available starting materials. Site-specific labeling was achieved using the following synthons: bromo[2-(13)C]acetic acid, [(13)C]formic acid, and elemental (77)Se. These labeled selones have been found to provide unique insights into enolate structure and may be useful in the detection and quantitation of remotely disposed chiral centers in compounds in short supply.

Full text of DOI:10.1021/jo049747o

Syn th esis of Ch ir a l 13C,77Se-La beled
Selon es
SCHEME 1
Morgane Ollivault-Shiflett, David B. Kimball and
L. A. “Pete” Silks*
Los Alamos National Laboratory, Bioscience Division,
the Biotechnology, Spectroscopy, and Isotope Chemistry
group (B-SIC), NIH National Stable Isotope Resource,
MS E529, Los Alamos, New Mexico 87545
pete-silks@lanl.gov
Received February 12, 2004
Abstr a ct: Stable isotope-labeled N-acyl selones have been
constructed in fewer than four steps from readily available
starting materials. Site-specific labeling was achieved using
the following synthons: bromo[2-13C]acetic acid, [13C]formic
acid, and elemental 77Se. These labeled selones have been
found to provide unique insights into enolate structure and
may be useful in the detection and quantitation of remotely
disposed chiral centers in compounds in short supply.
F IGURE 1. 77Se NMR 1D proton-decoupled spectrum of
oxazolidine selone 7.
paper, we describe the synthesis of stable isotope-labeled
selones and N-acyl selones. These may provide important
details on aldol reactions using NMR spectroscopy and
could prove useful in the detection and quantitation of
chiral centers of natural products in limited supply.
During the past several decades, we have been inter-
ested not only in developing the unique chemistry as-
sociated with the selenocarbonyl but also in applying the
extreme chemical shift sensitivity of the selenium nucleus
in these systems to a wide variety of inorganic, organic,
and biological systems.1 This chemical shift sensitivity
(CSS) has been harnessed for the detection and quanti-
tation of remotely disposed chiral centers.2 In that initial
report, the method proved to be useful in detecting chiral
centers seven bonds removed from the observing sele-
nium nucleus. In addition, in a series of studies it was
demonstrated that a particularly useful structural motif
to have optimal sensitivity for the selenium nucleus is
the selenocarbonyl (Figure 1).3 More recently, the ap-
plication of the CSS was demonstrated for a variety of
carboxylic esters that were subjected to enzymatic (hy-
drolysis) resolution.4 This study also served to reveal the
limits of detection of the chiral center by the observed
selenium nucleus. If a chiral center was more than eight
bonds removed from the selenium atom the method failed
to detect the diastereomers, and only a singlet was
observed in the 1D 77Se NMR spectrum. More recently,
these chiral selone systems were found to provide a
unique platform for aldol reactions.5 In-depth studies
using stable isotope labeling with 77Se and 13C NMR
spectroscopy and molecular modeling have provided
unique mechanistic insights into aldol reactions that
involve discrete monomeric titanium complexes.6 In this
Key to gaining insights into the structure of titanium-
based enolates by NMR spectroscopy is the ability to
incorporate strategic stable isotope labeling. Because
these chiral selones provide a platform for aldol reactions
and, in addition, a rare example of a chiral auxiliary
promoted anti-aldol process, one of the more important
atoms to label is selenium. In addition, changes in the
selenocarbonyl bond length could be monitored by mea-
suring the coupling constant of the directly bonded carbon
and selenium atoms.7 Due to the instability of the Ti
complexes and enolates for long periods, dual labeling
13C-77Se
was required to allow measurement of the J
in a
reasonable amount of time. In an effort to monitor the
side-chain dynamics and local environment the R-carbon
also required labeling. A reporter at this position may
also allow better understanding of the unique couplings
which occur in these systems.
Starting with commercial L-valinol 2 and formic acid
1, chiral oxazolines are formed in enantiomerically pure
form using the modified method of Meyers et al.8 (Scheme
1). In the case of the oxazoline 3, the 13C formic acid 1
was synthesized from the reaction of sodium [13C]formate
and 85% phosphoric acid followed by distillation. If
sulfuric acid is used instead, the formic acid decomposes
giving rise to carbon monoxide.9 Interestingly, the solu-
* To whom correspondence should be addressed. Tel: 01-505-667-
0151.
(1) Wu, R.; Hernandez, G.; Dunlap, R. B.; Odom, J . D.; Martinez,
R. A.; Silks, L. A. Trends Org. Chem. 1998, 7, 105.
(2) Silks, L. A.; Dunlap, R. B.; Odom, J . D J . Am. Chem. Soc. 1990,
112, 4979.
(3) Wu, R.; Odom, J . D.; Dunlap, R. B.; Silks, L. A. Tetrahedron:
Asymmetry 1999, 10, 1465.
(4) Hedenstrom, E.; Nguyen, B. V.; Silks, L. A. Tetrahedron:
Asymmetry 2002, 13, 835.
(6) Kimball, D. B.; Michalczyk, R.; Moody, E.; Ollivault-Shiflett, M.;
De J esus, K.; Silks, L. A. P. J . Am. Chem. Soc. 2003, 125, 14666.
(7) Typical J Se-C for selenocarbonyls range from 220 to 242 Hz. The
decrease in the value of the coupling constant indicates less s character
in the bonding system, which results in a longer bond.
(8) For the construction of the valinol-derived oxazoline: Meyers,
A. I.; Collington, E. W. J . Am. Chem. Soc. 1970, 92, 6676. Also see:
Leonard, W. R.; Romine, J . L.; Meyers, A. I. J . Org. Chem. 1991, 56,
1961.
(5) Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J . D.; Silks,
L. A. P. J . Am. Chem. Soc. 2000, 122, 386.
(9) (a) Meyer, J . Z. Elektrochem. Angew. Phys. Chem. 1909, 15, 506.
(b) Schierz, E. R. J . Am. Chem. Soc. 1923, 45, 447.
10.1021/jo049747o CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/16/2004
5150
J . Org. Chem. 2004, 69, 5150-5152

SCHEME 2
SCHEME 3
SCHEME 4
tion of the formic acid and valinol requires high temper-
atures before the mixture of oxazoline and water co-
distill. Temperatures more than 200 °C evidently cause
a “cracking” event to occur. The mixture is then distilled
into a diethyl ether sodium sulfate suspension. In addi-
tion, isolation of 3 is complicated by the relatively low
boiling point and high volatility of the oxazoline. Despite
these limitations, the process is straightforward if per-
formed on the 10-20 g scale. In addition, for long-term
storage it was found that efficient drying was required.
Metalation of oxazoline 3 was carried out with lithium
bis(trimethylsilyl)amide (LHMDS) in THF (Scheme 2).10
LHMDS was first generated at 0 °C, after which the pale
yellow solution was chilled to -78 °C and the oxazoline
was added dropwise as a THF solution. In a separate
flask, the grey 77Se was sublimed to red selenium with
heat under a vacuum. The sublimation was complete
when a ring of red selenium deposited just above the
heating mantle and no grey selenium was observed
remaining in the bottom of the flask. This sublimation
was found to be essential for the following reaction to
proceed. The flask was cooled, THF was added, and the
contents were chilled to -78 °C. The metalated oxazoline
solution was then cannula transferred into this flask. The
solution was swirled to bring the red selenium into
contact with the carbanion solution. After warming and
stirring, the mixture was quenched with 0.1 M citric acid
and an extraction/aqueous workup was performed. Un-
reacted selenium (39%) was recovered from the flask. The
crude selone was purified by flash chromatography.
Examination of the 77Se NMR spectrum revealed a
doublet at 112 ppm with a coupling constant of 233 Hz.
Optical purity was verified via derivitization with Mosh-
er’s acid chloride.10,11
(Figure 1) could arise from a through-bond coupling or
through-space. This seemingly simple question has been
investigated on both sides and has so far eluded explana-
tion. For example, the R methylene protons are not
coupled to the Se through-space, but through-bond
coupling of the CdO to Se was not observed when it was
13C labeled. Efforts are currently underway to help reveal
the nature of this coupling system and will be reported
in due course.
Selone 4 was also acetylated with propionyl chloride
and benzyloxy[2-13C]acetyl chloride 6 to form, respec-
tively, amide 8 and 9 (Scheme 4).
These compounds may provide additional insight into
the structural complexities of metal complexes and
enolates by NMR spectroscopy. In addition to the use of
77Se-labeled selones for the detection and quantitation
of chirality for materials in short supply, these systems
may also prove to be of some value for the synthesis of
stable isotope-labeled ribonucleic acids and carbohy-
drates.
Alkylation of benzyl alcohol by ethyl bromo[2-13C]-
acetate with sodium hydride in THF gave the benzyloxy-
[2-13C]acetate. Reaction with freshly distilled oxalyl
chloride at rt provided benzyloxy[2-13C]acetyl chloride 6
in 60% yield for the three-step process.12
Exp er im en ta l Section
(S )-(-)-4-(1-Me t h yle t h yl)-[2-13C]-oxa zolin e -[77Se ]-se -
lon e (5). In a flamed three-neck flask cooled under argon, HMDS
(0.222 g, 1.37 mmol) and THF (6 mL) were cooled to 0 °C and
nBuLi (2.5 M in hexanes, 1.44 mmol) was added. The reaction
was allowed to stir at 0 °C for 30 min. 77Selenium (0.074 g, 0.96
mmol) was placed in another three-neck flask without a stir bar
and was sublimed using a heating mantle under high vacuum
until the selenium became red. The deprotonation reaction was
cooled to -78 °C, and the oxazoline 3 (0.142 g, 1.25 mmol) in
THF (1 mL) was slowly added. The reaction was stirred for 2 h
at -78 °C. A stir bar and 3 mL of THF were added to the
activated selenium, and the mixture was cooled to -78 °C. The
LHMDS-oxazoline solution was transferred via cannula to the
activated selenium mixture. After addition, the cooling bath was
removed and the reaction was stirred for 2 h at rt. The reaction
was quenched by addition of a 0.1 M solution of citric acid. The
The triply labeled amide 7 was synthesized from [77Se-
13C]selone 5 and the [2-13C]acyl chloride 6 in CH2Cl2 at
0 °C with an excess of triethylamine (Scheme 3). Filtra-
tion over a pad of silica gel and flash chromatography
offered the desired product.13 The 77Se NMR spectrum
exhibiteda resonance at 447 ppm (dd, J ) 16, 241 Hz).
Interestingly, the presence of a doublet of doublets
(10) Peng, J .; Barr, M. E.; Ashburn, D. A.; Odom, J . D.; Dunlap, R.
B.; Silks, L. A. J . Org. Chem. 1994, 59, 4977.
(11) For 1H, 77Se, and 13C NMR spectra of this adduct, see the
Supporting Information (S5-7). The 77Se NMR shows a single doublet
at 550.2 ppm (the apparent minor doublet at 680 ppm has J ) 140 Hz
and cannot be from a selenocarbonyl). Dale, J . A.; Dull, D. L.; Mosher,
H. S. J . Org. Chem. 1969, 34, 2543.
(12) (a) Gravestock, M. B.; Knight, D. W.; Lovell, J . S.; Thornton,
S. R. J . Chem. Soc., Perkin Trans. 1 1999, 3143. (b) Miller, R. D.; Theis,
W.; Heilig, G.; Kirchmeyer, S. J . Org. Chem. 1991, 56, 1453.
(13) Peng, J .; Barr, M. E.; Ashburn, D. A.; Lebioda, L.; Garber, A.
R.; Martinez, R. A.; Odom, J . D.; Dunlap, R. B.; Silks, L. A. J . Org.
Chem. 1995, 60, 5540.
J . Org. Chem, Vol. 69, No. 15, 2004 5151

product was extracted with CH2Cl2 and dried over Na2SO4.
Evaporation of the solvent offered 0.170 g of the crude product.
Unreacted selenium (29 mg, 39%) was recovered. Silica gel flash
chromatography with first CH2Cl2 and then 10% EtOAc/CH2-
Cl2 gave 100 mg (84% based on recovered Se) of 5 as a colorless
oil: 1H NMR (CDCl3) δ 9.60 (s, br, 1H), 4.73 (td, J ) 9.3,
2.6[J H-C] Hz, 1H), 4.42 (ddd, J ) 9.3, 6.5, 3.4[J H-C] Hz, 1H),
3.93-3.85 (m, J ) 13.4, 9.3, 6.5, 3.2[J H-C] Hz, 1H), 1.92-1.81
(m, J ) 13.4, 6.7 Hz, 1H), 0.98 (d, J ) 6.7 Hz, 3H), 0.94 (d, J )
6.8 Hz, 3H); 13C NMR (CDCl3) δ 187.1 (d, J ) 232 Hz), 74.7,
63.5, 31.9, 16.6 (2C); 77Se NMR (CDCl3) δ 112 (d, J ) 233 Hz);
4-(S)-(-)-(1-Meth yleth yl)-3-[(ph en ylm eth oxy)-[2-13C]-ace-
tyl]-[2-13C]-oxa zolid in e[77Se]-selon e (7). To the previous se-
leno compound 5 (44.7 mg, 0.234 mmol) in 2.5 mL of CH2Cl2, in
an ice bath, was added acetyl chloride 6 (52.2 mg, 0.281 mmol)
in 0.5 mL of CH2Cl2 and triethylamine (0.742 g, 0.304 mmol).
The bright yellow reaction was stirred for 15 min at 0 °C and
then 1 h at rt. When TLC showed disappearance of the starting
material, the reaction was filtered over a pad of silica gel and
rinsed with CH2Cl2. After solvent evaporation in vacuo, the
yellow oil was purified by flash chromatography with 15% ethyl
acetate/hexanes to offer 64 mg (80%) of 7: 1H NMR (CDCl3) δ
7.48-7.32 (m, 5H), 5.26 (d, J ) 147.8 Hz, 2H), 4.82-4.76 (m,
1H), 4.72 (d, J ) 4.1 Hz, 2H), 4.54-4.42 (m, 2H), 2.48-2.38 (m,
1H), 0.99 (d, J ) 7 Hz, 3H), 0.93 (d, J ) 7 Hz, 3H); 13C NMR
(CDCl3) δ 188.5 (d, J ) 241.2 Hz), 72.3 (d, J ) 16.3 Hz)
[unlabeled 7: δ 188.5, 170.9, 137.0, 128.5, 128.2, 128.0, 73.6,
72.2, 70.3, 64.3, 28.8, 18.1, 14.9]; 77Se NMR (CDCl3) δ 447.35
(dd, J ) 16.3, 241.2 Hz); MS + 1 341.1, MS2 + 1 282.1
4-(S)-(-)-(1-Meth yleth yl)-3-(1-oxop r op yl)-[2-13C]-oxa zo-
lid in eselon e (8): 70%; 1H NMR (CDCl3) δ 4.72-4.65 (m, 1H),
4.41-4.29 (m, 2H), 3.53-3.26 (ABX3, J ) 17.9, 7.3 Hz, 2H),
2.33-2.21 (m, 1H), 1.14 (t, J ) 7.2 Hz, 3H), 0.88 (d, J ) 7.0 Hz,
3H), 0.82 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3) δ 189.3 (apparent
doublet, J ) 242 Hz, is from 7% 77Se natural abundance), 154.4,
69.4, 64.1, 32.2, 28.8, 18.1, 14.9, 8.6.
MS + 1 192.1, MS2 + 1 86.1, 69.0; HRMS calcd for C513CH11
-
NO77Se 191.0073, obsd 191.0069.
P h en ylm eth oxy-[2-13C]-a cetyl Ch lor id e (6). Phenylmeth-
oxy-[2-13C]-acetic acid was first synthesized using a procedure
modified from Gravestock et al.11a A typical example is as follows.
To a suspension of NaH (1 g, 60% dispersion in mineral oil, 25.0
mmol) in dry THF (35 mL) under Ar at 0 °C was added a solution
of benzyl alcohol (1.17 mL, 11.3 mmol) in THF (5 mL). After the
mixture was stirred for 1 h, a solution of bromo-[2-13C]-acetic
acid (1.0 g, 7.1 mmol) in THF (20 mL) was added and the mixture
was refluxed overnight. The mixture was quenched with metha-
nol (20 mL), diluted with water, and washed with ether. The
aqueous layer was then acidified with concd HCl to pH 4 and
extracted with ethyl acetate. The combined ethyl acetate extracts
were dried (Na2SO4) and filtered, and the solvent was evaporated
to give 1.14 g (96% yield) of crude product as a slightly yellow
oil. NMR spectra were analogous to unlabeled commercial
samples and showed sufficient purity for subsequent reactions:
1H NMR (CDCl3) δ 7.44-7.37 (m, 5H), 4.70 (d, J ) 4.3 Hz, 2H),
4.20 (d, J ) 144.2 Hz, 2H); 13C NMR (CDCl3) δ 175.5 (d, J ) 61
Hz), 136.6, 128.6, 128.2, 128.1, 127.7, 127.1, 73.4, 66.5; MS + 1
166.5, 148.3.
4-(S)-(-)-(1-m eth yleth yl)-3-[(ph en ylm eth oxy)-[2-13C]-ace-
tyl]-[2-13C]-oxa zolid in eselon e (9): 72%; 1H NMR (CDCl3) δ
7.48-7.32 (m, 5H), 5.26 (d, J ) 147.8 Hz, 2H), 4.82-4.76 (m,
1H), 4.72 (d, J ) 4.1 Hz, 2H), 4.54-4.42 (m, 2H), 2.48-2.38 (m,
1H), 0.99 (d, J ) 7 Hz, 3H), 0.93 (d, J ) 7 Hz, 3H); 13C NMR
(CDCl3) δ 188.6, 72.2.
Ack n ow led gm en t. We gratefully acknowledge par-
tial financial support from the National Stable Isotopes
Program, NIH NIBIB Institute (RR 02231), and the Los
Alamos National Laboratory Laboratory Directed Re-
search and Development (LDRD) fund X1CG and XAB2.
Work done at Los Alamos National Laboratory was
performed under the auspices of the U.S. Department
of Energy.
The acid chloride was obtained using the procedure of Miller
et al.11b The acid (8.0 g, 48.0 mmol) was dissolved in dry CH2Cl2
(150 mL) and chilled to 0 °C under Ar. A solution of (COCl)2
(50.0 mL, 2 M in CH2Cl2, 100.0 mmol) was added, and the
solution was stirred 4 h and then allowed to gradually warm to
ambient overnight. The solvent was coevaporated with toluene,
and the product was distilled under reduced pressure (0.65
mmHg, bp14 88-90 °C) to give 5.65 g (63%) of acid chloride 6 as
a clear oil: 1H NMR (CDCl3) δ 7.48-7.38 (m, 5H), 4.72 (d, J )
4.0 Hz, 2H), 4.50 (d, J ) 148.5 Hz, 2H); 13C NMR (CDCl3) δ 171.9
(d, J ) 57 Hz), 136.1, 134.0, 130.1, 128.7, 128.5, 128.2, 74.8, 73.6;
MS 184.5.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds 5-9, R-13C benzyloxyacetic acid, and R-13C ben-
zyloxyacetyl chloride. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) For the unlabeled compound, lit. bp 81-83 °C, 0.6 mm:
Bennington, F.; Morin, R. D. J . Org. Chem. 1961, 26, 194.
J O049747O
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