Direct entry to peptidyl ketones via SmI2-mediated C-C bond formation with readily accessible N-peptidyl oxazolidinones

Article abstract of DOI:10.1021/jo702286b

(Chemical Equation Presented) In this work, a new method for the preparation of peptidyl ketones is presented employing a SmI₂/H ₂O-mediated coupling of N-peptidyl oxazolidinones with electron-deficient alkenes. The requisite peptide

Full text of DOI:10.1021/jo702286b

Direct Entry to Peptidyl Ketones via SmI2-Mediated C-C Bond
Formation with Readily Accessible N-Peptidyl Oxazolidinones
Tina Mittag, Kasper L. Christensen, Karl B. Lindsay, Niels Christian Nielsen, and
Troels Skrydstrup*
Center for Insoluble Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience
Center, UniVersity of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
ts@chem.au.dk
ReceiVed October 23, 2007
In this work, a new method for the preparation of peptidyl ketones is presented employing a SmI2/H2O-
mediated coupling of N-peptidyl oxazolidinones with electron-deficient alkenes. The requisite peptide
imides were easily prepared by solution-phase peptide synthesis starting from an N-acyl oxazolidinone
derivative of an amino acid. Importantly, they could be used directly in the C-C bond-forming step
without the need for further functionalization. Coupling of these peptide derivatives with a second peptide
possessing an N-terminal acryloyl group leads to ketomethylene isosteres of glycine-containing peptides.
This method represents an alternative means for ligating two small peptides through a C-C bond-forming
step.
Introduction
Liebeskind and co-workers, this goal was reached by Pd-
mediated cross coupling of peptidyl thioesters with aryl and
alkenyl boronic acids.5,6
Peptidyl ketones represent an important class of nonhydro-
lyzable peptide isosteres, exhibiting a broad range of biological
activities. For example, such peptide mimics have been exploited
as effective inhibitors of numerous metabolic proteases,1 as well
as being stable analogue substrates for the di- and tripeptide
transporters,2 and inhibitors of the peptidylglycine R-amidating
monooxygenase (PAM).3 Synthetic routes to peptidyl ketones
generally involve lengthy syntheses, including installation of
the ketone functionality onto an N-protected amino acid
derivative via the addition of carbon nucleophiles, followed by
N-deprotection and peptide chain construction.4 On the other
hand, the possibility for accessing the peptide mimics directly
from a suitably functionalized peptide would provide access to
numerous ketone derivatives without the need for synthesizing
the peptide strand for each modification. In a recent paper by
Previously, we have demonstrated the capacity of 4-pyridyl
thioester derivatives of amino acids to undergo a samarium
diiodide-mediated coupling with electron-deficient alkenes
generating enantiomerically pure R-amino ketones in good yields
(Scheme 1).7,8 These reactions were also found to be adaptable
to the synthesis of methylene isosteres of small glycine-
containing peptides. However, attempts to expand the methodol-
ogy to the use of 4-pyridyl thioesters of small peptides from
(4) For a few representative examples see: (a) DeGraw, J. I.; Almquist,
R. G.; Hiebert, C. K.; Colwell, W. T.; Crase, J.; Hayano, T.; Judd, A. K.;
Dousman, L.; Smith, R. L.; Waud, W. R.; Uchida, I. J. Med. Chem. 1997,
40, 2386. (b) Eda, M.; Ashimori, A.; Akahoshi, F.; Yoshimura, T.; Inoue,
Y.; Fukaya, C.; Nakajima, M.; Fukuyama, H.; Imada, T.; Nakamura, N.
Bioorg. Med. Chem. Lett. 1998, 8, 913. (c) Dragovich, P. S.; Zhou, R.;
Webber, S. E.; Prins, T. J.; Kwok, A. K.; Okano, K.; Fuhrman, S. A.;
Zalman, L. S.; Maldonado, F. C.; Brown, E. L.; Meador, J. W., III; Patick,
A. K.; Ford, C. E.; Brothers, M. A.; Binford, S. L.; Matthews, D. A.; Ferre,
R. A.; Worland, S. T. Bioorg. Med. Chem. Lett. 2000, 10, 45.
(5) Yang, H.; Li. H.; Wittenberg, R.; Egi. M.; Huang, W.; Liebeskind,
L. J. Am. Chem. Soc. 2007, 129, 1132.
(1) For some recent reviews, see: (a) Leung, D.; Abbenante, G.; Fairlie,
D. P. J. Med. Chem. 2000, 43, 305. (b) Powers, J. C.; Asgian, J. L.; Ekici,
O¨ . D.; James, K. E. Chem. ReV. 2002, 102, 4639.
(2) See: Våbenø, J.; Nielsen, U.; Ingebrigtsten, T.; Lejon, T.; Steffansen,
B.; Luthman, K. J. Med. Chem. 2004, 47, 4755 and references cited therein.
(3) Baratt, B. J. W.; Easton, C. J.; Henry, J. D.; Li, I. H. W.; Random,
L.; Simpson, J. S. J. Am. Chem. Soc. 2004, 126, 13306.
(6) For an interesting partial approach to peptidyl ketones, see: Lin, W.;
Tryder, N.; Su, F.; Zercher, C. K.; Jasinski, J. P.; Butcher, R. J. J. Org.
Chem. 2006, 71, 8140.
10.1021/jo702286b CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/29/2007
1088
J. Org. Chem. 2008, 73, 1088-1092

Preparation of Peptidyl Ketones
SCHEME 1. Examples of the Synthesis of r-Aminoketones
via SmI2-Promoted Coupling of 4-Pyridyl Thioesters and
N-Acyl Oxazolidinones of Amino Acids with
Electron-Deficient Alkenes.
SCHEME 2. Proposed Strategy for the Synthesis of
Peptidyl Ketones Starting from an N-Acyl Oxazolidinone
Derivative of an Amino Acid
the corresponding terminal carboxylic acids were hampered by
the desire of the thioesters to undergo intramolecular cyclization
with the adjacent amide group. In later work, we discovered
the possibility of replacing the thiopyridyl esters of amino acids
with their corresponding N-acyl oxazolidinone derivatives, as
illustrated with the example in Scheme 1.9,10 Although the
mechanisms of the C-C bond-forming step with these two
classes of substrates were found to be different,9b the reactions
performed with the N-acyl oxazolidinone derivatives of amino
acids proved to be less sensitive to steric effects with respect
to the substitution pattern of the amino acid and the acrylate/
acrylamide used. As these N-acyl oxazolidinone derivatives of
amino acids, as represented by structure A, were expected to
display greater stability than the corresponding thioesters, we
speculated whether such compounds could be amenable to a
peptide-coupling sequence (Scheme 2). Indeed peptide-coupling
reactions of this type have been demonstrated previously.11 With
this as the case, then without the need for further transformation,
the treatment of this peptide imide with SmI2 and a suitable
alkene could possibly lead directly to a peptidyl ketone.
SCHEME 3. Synthesis of the Dipeptidyl Oxazolidinone 2
In this paper, we confirm the ability of such N-acyl oxazo-
lidinone derivatives of amino acids to be sufficiently stable and
hence to be suitable substrates for peptide-coupling sequences.
In addition, such peptide derivatives not only allow for a novel
access to peptidyl ketones through their coupling with an
electron-deficient olefin under mild conditions, but also provide
for an alternative means of ligating two small peptides via C-C
bond formation.
(7) For previous work featuring SmI2-promoted coupling reactions of
amino acid thioesters see: (a) Blakskjær, P.; Høj, B.; Riber, D.; Skrydstrup,
T. J. Am. Chem. Soc. 2003, 125, 4030. (b) Mikkelsen, L. M.; Jensen, C.
M.; Høj, B.; Blakskjær, P.; Skrydstrup, T. Tetrahedron 2003, 59, 10541.
(c) Jensen, C. M.; Lindsay, K. B.; Andreasen, P.; Skrydstrup, T. J. Org.
Chem. 2005, 70, 7512. (d) Lindsay, K. B.; Skrydstrup, T. J. Org. Chem.
2006, 71, 4766.
(8) For some recent reviews on the use of SmI2 in organic synthesis,
see: (a) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004,
104, 3371. (b) Kagan, H. B. Tetrahedron 2003, 59, 10351. (c) Steel, P. G.
J. Chem. Soc., Perkin Trans. 1 2001, 2727. (d) Krief, A.; Laval, A.-M.
Chem. ReV. 1999, 99, 745. (e) Molander, G. A.; Harris, C. R. Tetrahedron
1998, 54, 3321. (f) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96,
307.
(9) For development of SmI2-promoted N-acyloxazolidinone coupling
reactions see: (a) Jensen, C. M.; Lindsay, K. B.; Taaning, R. H.; Karaffa,
J.; Hansen, A. M.; Skrydstrup, T. J. Am. Chem. Soc. 2005, 127, 6544. (b)
Hansen, A. M.; Lindsay, K. B.; Sudhadevi Antharjanam, P. K.; Karaffa, J.;
Daasbjerg, K.; Flowers, R. A., II; Skrydstrup, T. J. Am. Chem. Soc. 2006,
128, 9616.
(10) (a) Karaffa, J.; Lindsay, K. B.; Skrydstrup, T. J. Org. Chem. 2006,
71, 8219. (b) Lindsay, B. K.; Ferrando, F.; Christensen, K. L.; Overgaard,
J.; Roca, T.; Bennasar, M.-L.; Skrydstrup, T. J. Org. Chem. 2007, 72, 4181.
(11) (a) Ba¨nteli, R.; Brun, I.; Hall, P.; Metternich, R. Tetrahedron Lett.
1999, 40, 2109-2112. (b) Luppi, G.; Soffre, C.; Tomasini, C. Tetrahedron:
Asymmetry 2004, 15, 1645-1650.
Results and Discussion
To examine the viability of the synthetic strategy as repre-
sented in Scheme 2, we prepared the N-acyl oxazolidinone of
phenylalanine 1 exploiting a modification of our previously
published two-step protocol for accessing these amino acid
derivatives (Scheme 3).10a,12 Gratifyingly, its deprotection and
peptide coupling with the partially protected asparagine provided
in good yields the N-dipeptidyl oxazolidinone 2.
The reactivity of the peptide derivative 2 was investigated in
SmI2-mediated coupling experiments with a variety of electron-
deficient alkenes as illustrated in Table 1. The reactions were
performed by adding a solution of SmI2 (0.1 M in THF) over
a period of 30 min to a cold THF solution (-78 °C) of the
alkene and N-acyl oxazolidinone in the presence of water (SmI2:
H2O ratio, 1:2), followed by stirring for approximately 18 h.13
The C-C bond formation proved to proceed well with the
(12) Cardillo, G.; Gentilucci, L.; De Matteis, V. J. Org. Chem. 2002,
67, 5957.
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Mittag et al.
TABLE 1. Scope of the SmI2-Promoted Radical Addition Reaction
with the N-Dipeptidyl Oxazolidinone 2
TABLE 2. Radical Addition of N-Peptidyl Oxazolidinones to
N-tert-Butyl Acrylamides Promoted by SmI2/H2O.
a Isolated yields after column chromatography. b An approximate 1:1
diastereomeric mixture. c 3:1 diastereomeric mixture.
a Isolated yields after column chromatography.
acrylamide and the three acrylates providing the ketones 3-5
and 7 in good yields (entries 1-3 and 5). Couplings were also
possible with acrylonitrile (entry 4), leading to the nitrile
derivative 6 in a 75% yield.
derivatives of a second peptide, thereby representing a novel
peptide ligating technique via C-C bond formation. As shown
in Table 3, these couplings proved successful with yields ranging
from 20% to 82%. It is important to emphasize that the C-C
bond formation leads directly to a ketomethylene isostere of a
glycine-containing peptide. For example, product 23 (entry 4)
represents a ketomethylene analogue of the fibrillating peptide
NFGAIL.14 Compounds such as this can provide important
information on the role of the individual amide functional groups
in the fibrillation process. Although the coupling yield for the
preparation of the hexapeptide mimic was low, it is important
to note that considerable amounts of the starting acrylamide
were recovered due to its low solubility in the reaction
conditions used. Further work is now in progress to provide
solutions to these solubility issues in order to improve the
coupling yields.
Further examination of this coupling protocol was carried out
with other N-peptidyl oxazolidinones ranging from dipeptides
to a tetrapeptide derivative (Table 2). As with 2, all the
N-peptidyl oxazolidinones were prepared by solution-phase
peptide synthesis starting from the easily accessible amino acid
imide derivatives.10a The SmI2-mediated coupling of 8-13 with
N-tert-butyl acrylamide proved again feasible, where in most
cases the yields were not significantly affected by the size of
the starting peptide as shown by the 45% yield obtained with
the tetrapeptide 12 (entry 5). The valine-containing peptides
were slightly less effective, which was attributed to the greater
sterical bulk at the reacting center.7d,10a Equally interesting was
the observation that both the Fmoc and Boc protecting groups
were compatible for the peptidyl ketone syntheses (entry 6
compared to entry 1 from Table 1).
In conclusion, we have disclosed a novel approach to peptidyl
ketones, which can also be applied to the synthesis of ketom-
ethylene isosteres of peptides. Importantly, the starting N-
peptidyl oxazolidinones are easily prepared by simple solution
peptide synthesis and are directly amenable to the C-C bond-
forming step.
Finally, the methodology was examined for its suitability in
the coupling of N-peptidyl oxazolidinones with N-acryloyl
(13) Flowers and Prasad have demonstrated the ability of water to
increase the reducing powers of samarium diiodide, thus facilitating the
electron-transfer step from the divalent lanthanide to the substrate.
Furthermore, the addition of water can also lead to the formation of a dimer
complex of SmI2 and H2O. Prasad, E.; Flowers, R. A., II. J. Am. Chem.
Soc. 2005, 127, 18093.
(14) Wu, C.; Lei, H.; Duan, Y. J. Am. Chem. Soc. 2005, 127, 13530 and
references cited therein.
1090 J. Org. Chem., Vol. 73, No. 3, 2008

Preparation of Peptidyl Ketones
TABLE 3. Coupling of N-Peptidyl Oxazolidinones and Acrylamides of Amino Acids and Peptides.
a Isolated yields after column chromatography.
(td, J ) 8.8, 4.8 Hz, 1H), 5.08 (br d, J ) 6.4 Hz, 1H), 4.32-4.44
Experimental Section
(m, 2H), 4.04 (dt, J ) 10.8, 6.8 Hz, 1H), 3.92 (dt, J ) 10.0, 7.6
Hz, 1H), 3.18 (dd, J ) 9.6, 4.0 Hz, 1H), 2.78 (dd, J ) 9.2, 3.6 Hz,
1H), 1.35 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.9,
155.3, 153.0, 136.1, 129.5, 128.6 (2C), 127.2 (2C), 80.0, 62.6, 54.0,
42.7, 38.6, 28.4 (3C). HRMS C17H22N2O5 [M + Na+] calcd
357.1426, found 357.1424.
1,1-Dimethylethyl [(1S)-2-Oxo-2-(2-oxo-3-oxazolidinyl)-1-
(phenylmethyl)ethyl]carbamate (1):10a General Procedure for
the Preparation of N-Acyl Oxazolidinone Derivatives of Amino
Acids. 2-Oxazolidinone (393 mg, 4.52 mmol) was dissolved in dry
THF (20 mL) and then the solution was cooled to -10 °C, before
iPrMgCl (2 M in toluene, 2.25 mL, 4.50 mmol) was added
dropwise. The mixture was stirred at -10 °C for 30 min under an
atmosphere of argon. The mixture was then added via syringe to a
solution of N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine pen-
tafluorophenyl ester2 (1.50 g, 3.48 mmol) in THF (25 mL). The
mixture was stirred at -5 °C for 2.5 h under an atmosphere of
argon and then water (20 mL) was added and the solvent was
evaporated in vacuo. The remaining aqueous suspension was then
extracted with CH2Cl2 (3 × 30 mL). The combined organic phases
were dried over MgSO4, filtered, and evaporated in vacuo. The
pure product was obtained by column chromatography (increasing
polarity from 40% to 80% EtOAc in pentane as eluant), which gave
the title compound (1.08 g, 3.22 mmol, 93%) as a colorless solid.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.21-7.30 (m, 5H), 5.68
(9H-Fluoren-9-yl)methyl (S)-1,4-Dioxo-1-[(S)-1-oxo-1-(2-oxo-
3-oxazolidinyl)-3-phenylpropan-2-ylamino]-4-(triphenylmethy-
lamino)butan-2-ylcarbamate (2): General Method for N-Ter-
minal Extension of N-Boc Protected Amino Acid-Oxazolidinones.
Oxazolidinone 1 (300 mg, 0.898 mmol) was dissolved in a 1:1
mixture of CH2Cl2 and TFA (10 mL). The mixture was stirred at
rt for 1 h and then all volatiles were removed in vacuo. The crude
oil was redissolved in CH2Cl2 and the solvent was removed in
vacuo. This step was repeated three times, to give the crude TFA
salt as a pale yellow syrup. This was redissolved in CH2Cl2 (20
mL) and NMM (0.50 mL, 4.49 mmol) was added dropwise. Fmoc-
L-Asn-(Trt)-OH (535 mg, 0.898 mmol), HOBt (281 mg, 1.79
mmol), and EDC‚HCl (344 mg, 1.80 mmol) were added and the
J. Org. Chem, Vol. 73, No. 3, 2008 1091

Mittag et al.
reaction was stirred at rt for 2 d. The mixture was poured into water
(40 mL) and extracted with CH2Cl2 (3 × 20 mL), and then the
combined organic portions were dried (MgSO4), filtered, and
evaporated in vacuo. The pure product was obtained by column
chromatography (increasing polarity from 40% to 90% EtOAc in
pentane as eluant), which gave the title compound (657 mg, 0.809
128.1 (6C), 127.8 (2C), 127.2 (5C), 127.1, 125.2 (2C), 120.1 (2C),
70.9, 67.4, 64.7, 59.8, 51.3, 47.1, 38.2, 36.9, 35.3, 30.7, 27.8, 19.2,
13.8. HRMS C54H53N3O7 [M + Na+] calcd 878.3776, found
878.3703.
(9H-Fluoren-9-yl)methyl (S)-1-[(S)-6-(1,1-Dimethylethan-1-
ylamino)-3,6-dioxo-1-phenylhexan-2-ylamino]-1,4-dioxo-4-(triph-
enylmethylamino)butan-2-ylcarbamate (3): General Method for
the SmI2-Promoted Coupling of N-Peptidyl Oxazolidinones with
Acrylamides. The oxazolidinone 2 (102 mg, 0.125 mmol) and
N-tert-butyl acrylamide (11 mg, 0.083 mmol) were dissolved in
THF (3 mL) and then water (18 µL, 1.00 mmol) was added. The
mixture was cooled to -78 °C under a strict argon atmosphere,
before a solution of SmI2 (0.1 M solution in THF, 5 mL, 0.50
mmol)15 was added dropwise over 30 min. The solution was stirred
at -78 °C for 2 d and then the flask was flushed with O2 to quench
excess SmI2, before sat aq NH4Cl (2.5 mL) was added. The mixture
was allowed to warm to rt and then poured into 0.5 M HCl (20
mL). The mixture was extracted with EtOAc (3 × 15 mL), then
the combined organic portions were washed with sat aq Na2S2O3
(10 mL), dried over MgSO4, filtered, and evaporated in vacuo. The
pure product was obtained by column chromatography (increasing
polarity from 10% to 60% EtOAc in CH2Cl2 as eluant), which gave
the title compound (60 mg, 0.071 mmol, 85%) as a colorless solid.
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J ) 7.2 Hz, 2H), 7.55 (d,
J ) 7.2 Hz, 2H), 7.40 (t, J ) 7.2 Hz, 3H), 7.29-7.06 (m, 22H),
6.95 (br s, 1H), 6.30 (d, J ) 6.4 Hz, 1H), 5.36 (br s, 1H), 4.61 (q,
J ) 6.8 Hz, 1H), 4.53-4.48 (m, 1H), 4.35-4.27 (m, 2H), 4.16 (t,
J ) 7.6 Hz, 1H), 3.06-2.97 (m, 2H), 2.82 (dd, J ) 14.0, 7.6 Hz,
1H), 2.73-2.62 (m, 3H), 2.33-2.24 (m, 2H), 1.30 (s, 9H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 207.5, 170.9, 170.8, 170.5, 156.4,
144.4 (3C), 143.9, 143.8, 141.4 (2C), 136.2, 129.3 (2C), 128.8 (6C),
128.8 (2C), 128.1 (6C), 127.9 (2C), 127.3 (5C), 127.1, 125.3 (2C),
120.1 (2C), 71.0, 67.5, 59.9, 51.3 (2C), 47.2, 38.3, 36.9, 35.7, 30.7,
28.9 (3C). HRMS C54H54N4O6 [M + Na+] calcd 877.3936, found
877.3946.
1
mmol, 90%) as a colorless solid. H NMR (400 MHz, CDCl3) δ
7.76 (d, J ) 7.2 Hz, 2H), 7.57 (d, J ) 7.2 Hz, 2H), 7.50 (d, J )
6.4 Hz, 1H), 7.40 (t, J ) 7.2 Hz, 2H), 7.30-7.12 (m, 23H), 6.37
(d, J ) 8.0 Hz, 1H), 5.74-5.79 (m, 1H), 4.55-4.51 (m, 1H), 4.32-
4.17 (m, 5H), 3.89 (dt, J ) 9.6, 7.2 Hz, 1H), 3.80 (dt, J ) 9.2, 7.6
Hz, 1H), 3.14 (dd, J ) 14.0, 5.6 Hz, 1H), 2.99 (br d, J ) 14.4 Hz,
1H), 2.83 (dd, J ) 13.2, 8.4 Hz, 1H), 2.66 (dd, J ) 15.2, 6.4 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ (ppm) 171.6, 171.0, 170.5,
156.3, 153.1, 144.4 (3C), 143.9 (2C), 141.3 (2C), 135.8, 129.4 (2C),
128.8 (8C), 128.6 (2C), 128.1 (6C), 127.8 (2C), 127.2 (5C), 125.3,
120.1 (2C), 71.0, 67.4, 62.5, 53.6, 51.2, 47.2, 42.6, 38.4, 37.4.
HRMS C50H44N4O7 [M + Na+] calcd 835.3102, found 835.3116.
Butyl (S)-5-[(S)-2-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-4-
oxo-4-(triphenylmethylamino)butanamido]-4-oxo-6-phenylhex-
anoate (4): General Method for the SmI2-Promoted Coupling
of N-Peptidyl Oxazolidinones with Acrylates and Acrylonitrile.
The oxazolidinone 2 (203 mg, 0.25 mmol) and n-butyl acrylate
(128 mg, 1.00 mmol) were dissolved in THF (5 mL) and then water
(36 µL, 2.00 mmol) was added. The mixture was cooled to
-78 °C under a strict argon atmosphere, before a solution of SmI2
(0.1 M in THF, 10 mL, 1.00 mmol)15 was added dropwise over 30
min. The solution was stirred at -78 °C for 18 h, and then the
flask was flushed with O2 to quench excess SmI2. The mixture was
poured into sat aq Na2S2O3 (40 mL) and extracted with EtOAc (3
× 20 mL). The combined organic portions were dried over MgSO4,
filtered, and evaporated in vacuo. The pure product was obtained
by column chromatography (increasing polarity from 10% to 60%
EtOAc in pentane as eluant), which gave the title compound (118
1
mg, 0.138 mmol, 55%) as a colorless solid. H NMR (400 MHz,
CDCl3) δ (ppm) 7.78 (d, J ) 7.6 Hz, 2H), 7.58 (d, J ) 7.6 Hz,
2H), 7.45-7.37 (m, 3H), 7.34-7.10 (m, 22H), 7.06 (br s, 1H),
6.37 (d, J ) 7.6 Hz, 1H), 4.67 (q, J ) 6.8 Hz, 1H), 4.59-4.51 (m,
1H), 4.39-4.28 (m, 2H), 4.18 (t, J ) 6.8 Hz, 1H), 4.06 (t, J ) 6.8
Hz, 2H), 3.10-2.97 (m, 2H), 2.89 (dd, J ) 14.0, 7.2 Hz, 1H),
2.72-2.60 (m, 3H), 2.60-2.48 (m, 2H), 1.60 (quin, J ) 6.8 Hz,
2H), 1.37 (hex, J ) 7.2 Hz, 2H), 0.94 (t, J ) 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 206.6, 172.6, 170.9, 170.4, 156.3,
144.4 (2C), 143.8, 143.8, 141.3, 136.3, 129.2 (2C), 128.8 (10C),
Acknowledgment. We are deeply appreciative of generous
financial support from the Danish National Research Foundation,
the Lundbeck Foundation, the Carlsberg Foundation, the OChem
Graduate School, and the University of Aarhus.
Supporting Information Available: Experimental details and
1
copies of H NMR and 13C NMR spectra for compounds 1-29.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Samarium(II) diiodide was prepared according to a literature
procedure. Girard, P.; Namy, J.-L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693.
JO702286B
1092 J. Org. Chem., Vol. 73, No. 3, 2008