Expanding the scope of the acyl-type radical addition reactions promoted by SmI2

Article abstract of DOI:10.1021/jo061299s

N-Acyl oxazolidinones of simple carboxylic acids and amino acids were observed to undergo successful SmI₂-promoted couplings with substituted acrylamides and acrylates, affording a variety of functionalized γ-ketoamides and -esters with yields

Full text of DOI:10.1021/jo061299s

Expanding the Scope of the Acyl-Type Radical Addition Reactions
Promoted by SmI2
Jakob Karaffa, Karl B. Lindsay, 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 June 23, 2006
N-Acyl oxazolidinones of simple carboxylic acids and amino acids were observed to undergo successful
SmI2-promoted couplings with substituted acrylamides and acrylates, affording a variety of functionalized
γ-ketoamides and -esters with yields attaining 85%. As many of these reductive couplings were previously
found to be ineffective employing the corresponding 4-pyridylthio esters, the applicability of this
methodology has been substantially improved. The methodology has been adapted to prepare structures
related to two potent aspartate protease inhibitors, the renin inhibitor aliskiren, and the γ-secretase inhibitor
L-685,458. Finally, a convenient two-step procedure for the preparation of N-acyl oxazolidinones of
N-protected amino acids, which provides consistently good yields of the corresponding imide, has been
devised.
Introduction
limited success (Scheme 1).5 A solution to the latter problem
was found when the acyl thioester unit was exchanged with an
N-acyl oxazolidinone, and the SmI2-promoted coupling reactions
were run in the presence of H2O.6,7 In this way, a series of
radical addition reactions were performed successfully with a
wide variety of N-acyl substituents.
In this paper, we report on the use of N-acyl oxazolidinones
as a viable solution for promoting acyl-like radical couplings8
with both problematic amino acids and R-substituted acrylates
and acrylamides. This methodology is applied to prepare
In 2003, we disclosed the ability of thiopyridyl esters of amino
acids to participate in a SmI2-promoted radical addition to
acrylamides and acrylates, providing a convenient route to the
corresponding γ-keto ester/amides.1,2 Some of these structures
revealed a close similarity to a class of important aspartate
protease inhibitors containing a hydroxyethylene dipeptide
isostere.3 Unfortunately, this methodology proved to be quite
sensitive to the substitution pattern of both the radical donor
and the radical acceptor, as attempts to expand this reaction to
either (a) R-substituted acrylates or acrylamides,4 (b) thioesters
of amino acids containing sterically demanding side chains (e.g.,
valine) or an N-Boc protecting group,2b or (c) thiopyridyl esters
of carboxylic acids other than amino acids were all met with
(5) Blakskjær, P.; Høj, B.; Skrydstrup, T. Unpublished results.
(6) (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.
(7) 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.
(1) Blakskjær, P.; Høj, B.; Riber, D.; Skrydstrup, T. J. Am. Chem. Soc.
2003, 125, 4030.
(2) See also: (a) Mikkelsen, L. M.; Jensen, C. M.; Høj, B.; Blakskjær,
P.; Skrydstrup, T. Tetrahedron 2003, 59, 10541. (b) Jensen, C. M.; Lindsay,
K. B.; Andreasen, P.; Skrydstrup, T. J. Org. Chem. 2005, 70, 7512.
(3) (a) Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000,
43, 305. (b) Bursavich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45, 541.
(4) Lindsay, K. B.; Skrydstrup, T. J. Org Chem. 2006, 71, 4766.
(8) For a comprehensive review on acyl radical chemistry, see: Chat-
gilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
10.1021/jo061299s CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/09/2006
J. Org. Chem. 2006, 71, 8219-8226
8219

Karaffa et al.
SCHEME 1. Examples of Successful (a) and Unsuccessful (b) Acyl-like Radical Addition Reactions with Thiopyridyl Esters
structures related to two potent aspartate protease inhibitors,
namely, aliskiren9 and L-685,458,10 as depicted in Figure 1. In
addition, we disclose a convenient two-step procedure for the
preparation of N-acyl oxazolidinones of N-protected amino
acids, which provides consistently good yields of the corre-
sponding imide.
strates.6 Our initial approach to these oxazolidinones encom-
passed the reaction between the pivaloyl-mixed anhydride of
Cbz-protected phenylalanine 8 and the N-lithiated derivative of
2-oxazolidinone as shown in Table 2 (entry 1).13 There were
several major impediments to this reaction that contributed to
the low yields of 17 (20-40%). The lithium salt of 2-oxazo-
lidinone is not soluble in THF at either -78 °C or at room
temperature and, therefore, was only poorly reactive to elec-
trophiles. The anhydride electrophile has two possible sites of
attack, and indeed, both Cbz-Phe-OH and the pivaloyl
derivative of 2-oxazolidinone were detectable in the product
mixture. Alternative methods for activating the carboxylic acid
were also examined, as shown in entries 2 and 3, although
without any progress. A clear improvement was found when
using AlMe3 to activate the 2-oxazolidinone, as the resulting
aluminum salt was highly soluble in organic solvents and
strongly nucleophilic. When this was used with the pivaloyl
mixed anhydride 8, a much cleaner reaction was observed (entry
4); however, the yield remained modest (30%). Other activated
(and one nonactivated) esters were, therefore, tried in order to
Results and Discussion
Table 1 summarizes reactions carried out with simple N-acyl
oxazolidinones in the presence of R- and â-substituted acrylates
and acrylamides.11 When 1 equiv of R-substituted acrylamide
and 1.5 equiv of the N-acyl oxazolidinone were reacted at -78
°C with samarium diiodide (4 equiv) in the presence of water
(8 equiv, entries 1, 3, 5, and 6) for 20 h, good yields of the
γ-keto amides 1, 3, 5, and 6 were obtained. A slight excess of
the oxazolidinone was desirable, as separation of the starting
acrylamide and product was frequently not possible. Particularly
noteworthy is the successful result obtained for the example in
entry 6, as previous attempts to couple the thiopyridyl ester of
Cbz-protected phenylalanine to the same acrylamide were
nonrewarding.4 R-Substituted acrylates (entries 2 and 4) were
also well tolerated by the reaction providing 2 and 4 in
acceptable yields; however, in these cases, excess acrylate was
used (2 equiv), as product separation was not an issue, and the
reaction was run at -40 °C to ensure good conversion. It was
interesting to note that â-methyl acrylates can be applied to these
C-C bond forming reactions, but only in less hindered cases.
For example, the reaction of ethyl crotonate with the N-
phenylacetyl oxazolidinone provided the ketone 7 in satisfactory
yield (entry 7); however, when the N-pivaloyl oxazolidinone
was applied under identical conditions (entry 8), there was no
detectable product formation.
(12) For some examples on the synthesis and application of other
hydroxyethylene isosteres for the inhibition of a variety of proteases, see
ref 19 and: (a) Holladay, M. W.; Rich, D. H. Tetrahedron Lett. 1983, 24,
4401. (b) Evans, B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J. P.;
Hirshfield, J.; Veber, D. F. J. Org. Chem. 1985, 50, 4615. (c) Bradbury, R.
H.; Major, J. S.; Oldham, A. A.; Rivett, J. E.; Roberts, D. A.; Slater, A.
M.; Timms, D.; Waterson, D. J. Med. Chem. 1990, 33, 2335. (d) Poss, M.
A.; Reid, J. A. Tetrahedron Lett. 1992, 33, 1411. (e) Baker, W. R.; Pratt,
J. K. Tetrahedron 1993, 49, 8739. (f) Myers, A. G.; Barbay, J. K.; Zhong,
B. J. Am. Chem. Soc. 2001, 123, 7207. (g) Ghosh, A. K.; Shin, D.; Downs,
D.; Koelsch, G.; Lin, X.; Ermolieff, J.; Tang, J. J. Am. Chem. Soc. 2000,
122, 3522. (h) Brewer M.; Rich, D. H. Org. Lett. 2001, 3, 945. (i) Nadin,
A.; Sa´nchez Lope´z, J. M.; Neduvelil, J. G.; Thomas, S. R. Tetrahedron
2001, 57, 1861. (j) Tossi, A.; Benedetti, F.; Norbedo, S.; Skrbec, D.; Berti,
F.; Romeo, D. Bioorg. Med. Chem. 2003, 11, 4719. (k) Brewer M.; James,
C. A.; Rich, D. H. Org. Lett. 2004, 6, 4779. (l) Haug, B. E.; Rich, D. H.
Org. Lett. 2004, 6, 4783. (m) Hom, R. K.; Gailunas, A. F.; Mamo, S.; Fang,
L. Y.; Tung, J. S.; Walker, D. E.; Davis, D.; Thorsett, E. D.; Jewett, N. E.;
Moon, J. B.; John, V. J. Med. Chem. 2004, 47, 158. (n) Våbenø, J.; Lejon,
T.; Nielsen, C. U.; Steffansen, B.; Chen, W.; Ouyang, H.; Borchardt, R.
T.; Luthman, K. J. Med. Chem. 2004, 47, 1060. (o) Brady, S. F.; Singh, S.;
Crouthamel, M.-C.; Holloway, M. K.; Coburn, C. A.; Garsky, V. M.;
Bogusky, M.; Pennington, M. W.; Vacca, J. P.; Hazuda, D.; Lai, M.-T.
Bioorg. Med. Chem. 2004, 14, 601. (p) Hanessian, S.; Hou, Y.; Bayrak-
darian, M.; Tintelnot-Blomely, M. J. Org. Chem. 2005, 70, 6735. (q)
Hanessian, S.; Yun, H.; Hou, Y.; Tintelnot-Blomely, M. J. Org. Chem.
2005, 70, 6746. (r) Hanessian, S.; Yun, H.; Hou, Y.; Yang, G.; Bayrakdarian,
M.; Therrien, E.; Moitessier, N.; Roggo, S.; Veenstra, S.; Tintelnot-Blomely,
M.; Rondeau, J.-M.; Ostermeier, C.; Strauss, A.; Ramage, P.; Paganetti,
P.; Neumann, U.; Betschart, C. J. Med. Chem. 2005, 48, 5175. (s) Specker,
E.; Bo¨ttcher, J.; Heine, A.; Sotriffer, C. A.; Lilie, H.; Schoop, A.; Mu¨ller,
G.; Griebenow, N.; Klebe, G. J. Med. Chem. 2005, 48, 6607.
With the successful initial results using simple substrates, we
next turned our attention to amino acid substrates, in keeping
with an interest within the group to prepare hydroxyethylene
dipeptide isosteres.2b,4,12 Prior to beginning this study, we
required an efficient method for accessing N-acyl oxazolidinones
directly from N-protected amino acids, as existing methods were
incompatible, such as the use of acid chlorides as earlier
employed for the preparation of simpler oxazolidinone sub-
(9) Rahuel, J.; Rasetti, V.; Maibaum, J.; Rueger, H.; Goschke, R.; Cohen,
N. C.; Stutz, S.; Cumin, F.; Fuhrer, W.; Wood, J. M.; Grutter, M. G. Chem.
Biol. 2000, 7, 493.
(10) Wolfe, M. S. J. Med. Chem. 2001, 44, 2039.
(11) R-Substituted acrylates were prepared according to: Lee, H. S.; Park,
J. S.; Kim, B. M.; Gellman, S. H. J. Org. Chem. 2003, 68, 1575. These
were transformed into the corresponding acrylamides via standard methods.
(13) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737.
8220 J. Org. Chem., Vol. 71, No. 21, 2006

Acyl-Type Addition Reactions
FIGURE 1. Structures of two potent aspartate protease inhibitors.
TABLE 1. SmI2-Promoted Coupling of N-Acyl Oxazolidinones
with r- and â-Substituted Acrylates and Acrylamides
further improve the reaction. While the Weinreb amide 10 (entry
5) and methyl ester 11 (entry 6) were completely unreactive
toward the aluminum salt, both the pentafluorophenol (PFP)
ester 12 (entry 7) and the 4-mercaptopyridine thioester 13 (entry
8) gave smooth (albeit slow) conversions to the desired
oxazolidinone 17 after 2 days (81% yield in both cases).
Subjection of the PFP esters of other amino acids, as illustrated
in entries 9-11, to the same conditions also afforded the desired
oxazolidinones 18-20 of Boc-Phe (83%), Boc-Leu (73%), and
Cbz-Val (62%), respectively. It was noted, however, that
excessively prolonged reaction times can result in carbamate
cleavage when using Cbz-protected amino acids, and we,
therefore, recommend either tracking the reaction closely by
TLC or the use of Boc-protected amino acids.
Further work was then carried out to examine the suitability
of the oxazolidinones derived from amino acids as coupling
partners with the R,â-unsaturated esters and amides. As can be
seen in Table 3, these compounds react in a well-behaved
manner with R-substituted acrylamides (entries 1, 2, and 6) and
acrylates (entries 3, 4, 5, 7, 8, and 9) when using the standard
coupling conditions described above. The olefin substituents
examined were methyl, isopropyl, isobutyl, and benzyl, intended
to mimic the amino acids alanine, valine, leucine, and phenyl-
alanine, respectively. Earlier, we had observed that the 4-thi-
opyridine esters of Boc-protected amino acids were less reactive
in the addition reactions compared to their Cbz-counterparts.1,2
As illustrated in entries 4, 5, and 7, the N-acyl oxazolidinone
derivates of the Boc-protected amino acids were just as effective
as the Cbz-derivatives as coupling partners. The dipeptide mimic
25 prepared by the coupling of the Boc-phenylalanine derivative
17 to ethyl R-benzyl acrylate (entry 5) represents a key fragment
of the potent γ-secretase inhibitor, L-685,458.10
Selectivities in these reactions were nevertheless generally
low (as determined by 1H NMR of the isolated products), with
the exception of entry 2, where a 5:1 ratio of isomers 22 was
observed. The lack of selectivity is not unexpected when
considering the fact that the configuration about this center is
expected to arise upon protonation of the surmised samarium
enolate intermediate with water. Attempts to influence this
selectivity with bulky chiral proton sources complexed to the
divalent lanthanide reagent under anhydrous conditions as
previously reported by Takeuchi and Mikami14 were unsuc-
cessful. Finally, it is interesting to note the good reactivity
exhibited by the Cbz-valine derivative 20 when coupled to two
R-substituted acrylates (entries 8 and 10). In both cases, a 69%
yield of the γ-keto esters 28 and 30 was obtained along with
unreacted starting materials, which could be recovered almost
quantitatively. In contrast, performing a similar reaction with
the corresponding 4-thiopyridyl derivative led to none of the
desired coupling product.2b
a All yields are based on chromatographically pure compounds. b Yield
calculated from 1H NMR of an inseparable mixture of product and starting
oxazolidinone.
Our recent interest in the total synthesis of aliskiren4 prompted
a short study regarding the applicability of the above reactions
to its synthesis. Earlier work in a model study had revealed the
inability of the 4-thiopyridine ester of Cbz-phenylalanine to
couple to ethyl R-isopropyl acrylate, forcing us to choose an
alternative, but longer, route for the introduction of the isopropyl
side chain.4 However, the successful coupling noted between
the N-acyl oxazoldinone 17 and the same acrylate (Table 3,
entry 9) encouraged us to examine this protocol as a more direct
(14) Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Yamaoka, M.; Yoshida, A.;
Mikami, K. Tetrahedron 1999, 55, 4595.
J. Org. Chem, Vol. 71, No. 21, 2006 8221

Karaffa et al.
TABLE 2. N-Acyl Oxazolidinone Synthesis Studies
TABLE 3. SmI2-Promoted Coupling of Amino Acid
Oxazolidinones with Substituted Acrylates and Acrylamidesa
a All yields are based on chromatographically pure compounds.
Conclusions
We have successfully demonstrated the suitability of both
simple N-acyl oxazoldinones and amino acid derivates thereof
to undergo SmI2-promoted additions to substituted acrylates and
acrylamides. These results expand considerably the applicability
of these reactions for the synthesis of functionalized γ-keto
amides and esters. Efforts are underway to improve the
stereochemical issues of these radical coupling reactions with
substituted acrylates and acrylamides by means of functionalized
acrylates possessing chiral auxiliaries. With the known ability
to stereoselectively reduce R-aminoketones to either the syn-
or anti-vicinal amino alcohol in mind,16,17 success in such studies
would provide a rapid and general approach to the important
class of hydroxyethylene dipeptide isosteres.
route to the renin inhibitor. Acid 314,15 was first transformed
into the PFP ester 32 in an excellent yield of 98% via an EDCI-
promoted coupling with pentafluorophenol (Scheme 2). After
purification, 32 was then reacted with 2-oxazolidinone previ-
ously treated with AlMe3. Displacement of pentafluorophenox-
ide was slow at room temperature; however, the desired N-acyl
oxazolidinone 33 could be obtained in good yield after 4 days
without detectable R-epimerization. With the oxazolidinone in
hand, the coupling reaction with ethyl R-isopropyl acrylate was
finally carried out as described for the simple derivative 17
(Table 3, entry 9). To our delight, the radical reaction proceeded,
affording the coupling product 34 in a 52% yield after a reaction
time of 2 days (95% yield based on 43% recovered 33).
Although the diastereomeric ratio in this reaction was merely
5:4 and no attempt was made to assign the two inseparable
diastereomers, this example represents a highly promising and
convergent approach to the basic carbon framework of aliskiren.
Experimental Section
N-tert-Butyl-2,5,5-trimethyl-4-oxohexanamide (1). General
Procedure for Coupling with Acrylamides. To a solution of
3-pivaloyloxazolidin-2-one (96 mg, 0.561 mmol, 1.5 equiv) and
N-tert-butylmethacrylamide (53 mg, 0.375 mmol, 1 equiv) in THF
(5.0 mL) was added H2O (54 µL, 3.00 mmol, 8 equiv), and then
(15) Goeschke, R.; Stutz, S.; Heinzelmann, W.; Maibaum, J. HelV. Chim.
Acta 2003, 86, 2848.
(16) Hoffman, R. V.; Maslouh, N.; Cervantes-Lee, F. J. Org. Chem. 2002,
67, 1045.
(17) Våbenø, J.; Brisander, M.; Lejon, T.; Luthman, K. J. Org. Chem.
2002, 67, 9186.
8222 J. Org. Chem., Vol. 71, No. 21, 2006

Acyl-Type Addition Reactions
SCHEME 2. Potential Application to the Synthesis of Aliskirena
a Reagents and conditions: (a) EDCI, DMAP, pentafluorophenol, 0 °C, CH2Cl2, 98%; (b) 2-oxazolidinone, AlMe3, CH2Cl2, 30 min, then 32, 20 °C, 4
days, 77%; (c) H2CdC(iPr)CO2Et, SmI2, H2O, -78 °C, THF, 52%, dr ) 5:4.
the solution was cooled to -78 °C. To this a solution of SmI2 (0.1
M, 15 mL, 1.5 mmol, 4 equiv), at room temperature (rt), was added
dropwise over 1 h. The solution was left stirring at -78 °C for 24
h. Excess SmI2 was oxidized by flushing the mixture with oxygen
from a balloon. To the resulting yellow solution was added saturated
NH4Cl (4 mL) at -78 °C followed by warming to rt. HCl(aq) (1
M, 5 mL) was added followed by extraction with EtOAc (3 × 10
mL). The combined organic phases were washed with NaS2O3(aq)
(10 mL), dried over MgSO4, and then evaporated in Vacuo. The
pure product was then obtained by gradient flash chromatography
on silica gel using 2-6% acetone in DCM as eluant, which gave
Benzyl (2S)-5-(tert-Butylcarbamoyl)-3-oxo-1-phenylhexan-2-
ylcarbamate (21). This was prepared using the general method
for coupling with acrylamides, with oxazolidinone 17 (206 mg,
0.559 mmol) and N-tert-butylmethacrylamide (53 mg, 0.375 mmol).
EtOAc (10%) in pentane was used as eluant for flash chromatog-
raphy, which gave compound 21 (135 mg, 0.318 mmol, 85%) as a
colorless solid and recovered acrylamide. 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.35-7.10 (m, 10H), 5.50 (br s, 1H), 5.27 (br s,
1H), 5.06-5.00 (m, 2H), 4.57-4.52 (m, 1H), 3.20-2.28 (m, 5H),
1.32 (s, 9H), 1.12 (d, J ) 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 207.8, 174.7, 156.0, 136.0, 136.4, 129.6 (2C), 129.4 (2C),
129.3 (2C), 128.8 (2C), 128.2, 127.2, 68.1, 67.0, 51.1, 44.2, 37.5,
36.8, 28.9 (3C), 18.4. HRMS C25H32N2O4 [M + Na+]: calcd,
447.2260; found, 447.2273.
1
compound 1 (54 mg, 0.238 mmol, 63%) as a colorless solid. H
NMR (400 MHz, CDCl3) δ (ppm) 5.53 (br s, 1H), 2.93 (dd, J )
18.1, 8.7 Hz, 1H), 2.62 (m, 1H), 2.39 (dd, J ) 18.1, 4.5 Hz, 1H),
1.28 (s, 9H), 1.10 (s, 9H), 1.08 (d, J ) 6.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 215.4, 175.2, 51.0, 44.1, 41.5, 36.6,
28.9 (3C), 26.5 (3C), 18.0. HRMS C13H25NO2 [M + Na+]: calcd,
250.1783; found, 250.1779.
Benzyl (2S)-5-(tert-Butylcarbamoyl)-3-oxo-1,6-diphenylhexan-
2-ylcarbamate (22). This was prepared using the general method
for coupling with acrylamides, with oxazolidinone 17 (206 mg,
0.559 mmol) and 2-benzyl-N-tert-butylacrylamide (81 mg, 0.373
mmol). EtOAc (increasing polarity, 10 to 20%) in pentane was used
as eluant for flash chromatography, which gave compound 22 (105
N-tert-Butyl-2-methyl-4-oxo-5-phenylpentanamide (3). This
was prepared using the general method for coupling with acryla-
mides, with 3-(2-phenylacetyl)oxazolidin-2-one (114 mg, 0.555
mmol) and N-tert-butylmethacrylamide (53 mg, 0.375 mmol).
EtOAc (10%) in pentane was used as eluant for flash chromatog-
raphy, which gave an inseparable 1:0.08 mixture of product 3 and
starting oxazolidinone (67 mg) (mass of product 61 mg, 0.232
1
mg, 0.210 mmol, 56%) as a colorless solid. H NMR (400 MHz,
CDCl3) δ (ppm) major isomer 7.36-7.05 (m, 15H), 5.35 (br s,
1H), 5.27 (br s, 1H), 4.58-4.51 (m, 1H), 3.22-2.40 (m, 7H), 1.17
(s, 9H); minor isomer inter alia 2.42 (dd, J ) 17.9, 3.3 Hz, 1H),
1.13 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) major isomer
207.5, 172.8, 156.0, 139.2, 136.4, 135.9, 129.6 (2C), 129.4 (2C),
129.3 (2C), 128.8 (2C), 128.7 (2C), 128.5 (2C), 127.3, 127.2, 126.8,
67.1, 60.5, 51.2, 44.7, 42.8, 39.2, 36.9, 28.7 (3C); minor isomer
inter alia 136.4, 61.1, 45.0. HRMS C31H36N2O4 [M + Na+]: calcd,
523.2573; found, 523.2571.
1
mmol, 62%). The yield has been calculated from the H NMR of
this mixture. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.33-7.18 (m,
5H), 5.62 (br s, 1H), 3.67 (s, 2H), 2.94 (dd, J ) 18.0, 8.8 Hz, 1H),
2.65-2.60 (m, 1H), 2.42 (dd, J ) 18.0, 4.5 Hz, 1H), 1.10 (s, 9H),
1.07 (d, J ) 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm)
207.8, 175.0, 134.1, 129.6 (2C), 128.9 (2C), 127.2, 51.2, 50.5, 46.2,
36.8, 28.9 (3C), 18.0. HRMS C16H23NO2 [M + Na+]: calcd,
284.1626; found, 284.1626.
Benzyl 2-(2-Benzyl-5-(benzyloxycarbonylamino)-4-oxo-6-phe-
nylhexanamido)-4-methylpentanoate (26). This was prepared
using the general method for coupling with acrylamides, with
oxazolidinone 17 (276 mg, 0.75 mmol) and (S)-benzyl 2-(2-
benzylacrylamido)-3-phenylpropanoate (137 mg, 0.375 mmol).
EtOAc (30%) in pentane was used as eluant for column chroma-
tography, which gave compound 26 (126 mg, 0.195 mmol, 52%)
N-tert-Butyl-2-benzyl-4-oxo-5-phenylpentanamide (5). This
was prepared using the general method for coupling with acryla-
mides, with 3-(2-phenylacetyl)oxazolidin-2-one (114 mg, 0.555
mmol) and 2-benzyl-N-tert-butylacrylamide (82 mg, 0.377 mmol).
EtOAc (15%) in pentane was used as eluant for flash chromatog-
raphy, which gave compound 5 (56 mg, 0.166 mmol, 44%) as a
1
1
as a colorless solid. H NMR (400 MHz, CDCl3) δ (ppm) 7.39-
colorless solid. H NMR (400 MHz, CDCl3) δ (ppm) 7.31-7.13
7.05 (m, 21H), 5.96 (d, J ) 7.1 Hz, 1H), 5.12 (s, 2H), 5.03 (s,
2H), 4.62-4.45 (m, 2H), 3.15-2.46 (m, 7H), 1.61-1.15 (m, 3H),
0.90-0.86 (m, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm) major
isomer 203.3, 169.6, 168.6, 151.9, 134.7, 132.4, 132.0, 131.7, 125.5
(2C), 125.2 (2C), 124.9 (2C), 124.8 (2C), 124.6 (2C), 124.5 (2C),
124.4 (2C), 124.3 (2C), 123.2 (2C), 122.9 (2C), 63.2, 63.1 (2C),
55.5, 47.1, 39.6, 37.8, 34.6, 33.3, 20.9, 19.0, 18.2; minor isomer
(m, 5H), 5.09 (br s, 1H), 3.67 (s, 2H), 3.01 (dd, J ) 17.9, 8.6 Hz,
1H), 2.81-2.71 (m, 2H), 2.63 (dd, J ) 11.9, 5.1 Hz, 1H), 2.49
(dd, J ) 17.9, 3.9 Hz, 1H), 1.13 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 207.5, 173.0, 139.4, 134.1, 129.6 (2C), 129.3 (2C),
128.9 (2C), 128.6 (2C), 127.2, 126.6, 51.1, 50.5, 44.9, 44.5, 38.8,
28.7 (3C). HRMS C22H27NO2 [M + Na+]: calcd, 360.1939; found,
360.1938.
J. Org. Chem, Vol. 71, No. 21, 2006 8223

Karaffa et al.
inter alia 203.6, 169.9, 168.8, 152.1, 56.8, 39.8, 38.7, 38.3, 37.7,
34.4, 33.5. HRMS C40H44N2O6 [M + Na+]: calcd, 671.3097; found,
671.3099.
for coupling with acrylates, with oxazolidinone 17 (138 mg, 0.375
mmol) and ethyl 2-benzylacrylate (143 mg, 0.752 mmol). EtOAc
(10%) in pentane was used as eluant for column chromatography,
which gave compound 23 (126 mg, 0.266 mmol, 71%) as a colorless
solid and recovered 17 (37 mg, 0.101 mmol, 27%). 1H NMR (400
MHz, CDCl3) δ (ppm) major isomer 7.35-7.01 (m, 15H), 5.24
(d, J ) 7.2 Hz, 1H), 5.05 (s, 2H), 4.51-4.43 (m, 1H), 4.11 (q, J
) 7.1 Hz, 2H), 3.16-2.32 (m, 7H), 1.18 (t, J ) 7.1 Hz, 3H); minor
isomer inter alia 5.32 (d, J ) 7.5 Hz, 1H), 5.12 (s, 2H). 13C NMR
(100 MHz, CDCl3) δ (ppm) major isomer 207.0, 174.5, 155.9,
138.4, 136.5, 136.1, 129.5 (2C), 129.3 (2C), 129.2 (2C), 128.8 (2C),
128.7 (2C), 128.3 (2C), 128.2, 127.2, 126.9, 67.1, 60.9, 60.6, 42.2,
41.5, 41.3, 37.9, 37.4, 14.3; minor isomer inter alia 206.6, 67.7,
60.5, 41.9, 41.5, 41.3, 37.8. HRMS C29H31NO5 [M + Na+]: calcd,
496.2100; found, 496.2094.
Ethyl (2S)-5-(tert-Butoxycarbonyl)-7-methyl-4-oxooctanoate
(24). This was prepared using the general method for coupling with
acrylates, with oxazolidinone 19 (108 mg, 0.375 mmol) and methyl
acrylate (65 mg, 0.755 mmol). EtOAc (10-50%) in pentane was
used as eluant for column chromatography, which gave compound
24 (68 mg, 0.226 mmol, 60%) as an oil and recovered 19 (51 mg,
0.177 mmol, 35%). 1H NMR (400 MHz, CDCl3) δ (ppm) 4.98 (d,
J ) 8.4 Hz, 1H), 4.29 (ddd, J ) 10.0, 8.0, 4.4 Hz, 1H), 3.64 (s,
3H), 2.88 (dt, J ) 18.8, 6.8 Hz, 1H), 2.77 (dt, J ) 18.4, 6.0 Hz,
1H), 2.52-2.69 (m, 2H), 1.54-1.77 (m, 2H), 1.43 (s, 9H), 1.35
(ddd, J ) 14.4, 10.0, 4.8 Hz, 1H), 0.96 (d, J ) 6.4 Hz, 3H), 0.94
(d, J ) 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 208.6,
177.0, 155.6, 79.7, 57.7, 51.8, 40.4, 34.2, 28.2, 27.4, 24.8, 23.2,
21.6. HRMS C15H27NO5 [M + Na+]: calcd, 324.1786; found,
324.1787.
Ethyl 2-Benzyl-5,5-dimethyl-4-oxohexanoate (2). General
Procedure for Coupling with Acrylates. To a solution of
3-pivaloyloxazolidin-2-one (64 mg, 0.374 mmol, 1 equiv) and ethyl
2-benzylacrylate (143 mg, 0.752 mmol, 2 equiv) in THF (5.0 mL)
was added H2O (54 µL, 3.00 mmol, 8 equiv), and then the solution
was cooled to -40 °C. To this a solution of SmI2 (0.1 M, 15.0
mL, 1.50 mmol, 4 equiv), at rt, was added dropwise over 1 h. The
solution was left stirring at -40 °C for 24 h. Excess SmI2 was
oxidized by flushing the mixture with oxygen from a balloon. To
the resulting yellow solution was added saturated NH4Cl (4 mL)
at -40 °C followed by warming to rt. HCl(aq) (1 M, 5 mL) was
added followed by extraction with EtOAc (3 × 10 mL). The
combined organic phases were washed with NaS2O3(aq) (10 mL),
dried over MgSO4, and then evaporated in Vacuo. The pure product
was then obtained by gradient flash chromatography on silica gel
using 10% EtOAc in pentane as eluant, which gave compound 2
(62 mg, 0.224 mmol, 60%) as an oil. 1H NMR (400 MHz, CDCl3)
δ (ppm) 7.29-7.14 (m, 5H), 4.07 (q, J ) 7.1 Hz, 2H), 3.15-3.09
(m, 1H), 2.99 (dd, J ) 13.5, 6.7 Hz, 1H), 2.92 (dd, J ) 18.1, 8.9
Hz, 1H), 2.72 (dd, J ) 13.5, 8.2 Hz, 1H), 2.51 (dd, J ) 18.1, 4.5
Hz, 1H), 1.15 (t, J ) 7.1 Hz, 3H), 1.09 (s, 9H). 13C NMR (100
MHz, CDCl3) δ (ppm) 214.1, 175.1, 138.9, 129.1 (2C), 128.6 (2C),
126.7, 60.7, 44.1, 42.2, 38.0, 26.6 (3C), 14.2. HRMS C17H24O3 [M
+ Na+]: calcd, 299.1623; found, 299.1631.
Ethyl 2-Benzyl-4-oxo-5-phenylpentanoate (4). This was pre-
pared using the general method for coupling with acrylates, with
3-(2-phenylacetyl)oxazolidin-2-one (77 mg, 0.375 mmol) and ethyl
2-benzylacrylate (143 mg, 0.752 mmol). EtOAc (increasing polarity,
5 to 8%) in pentane was used as eluant for flash chromatography,
tert-Butyl (2S)-5-(Ethoxycarbonyl)-3-oxo-1,6-diphenylhexan-
2-ylcarbamate (25). This was prepared using the general method
for coupling with acrylates, with oxazolidinone 18 (125 mg, 0.374
mmol) and ethyl 2-benzylacrylate (143 mg, 0.752 mmol). EtOAc
(10%) in pentane was used as eluant for column chromatography,
which gave compound 25 (134 mg, 0.305 mmol, 81%) as a colorless
1
which gave compound 4 (76 mg, 0.245 mmol, 65%) as an oil. H
NMR (400 MHz, CDCl3) δ (ppm) 7.34-7.09 (m, 10H), 4.06 (q, J
) 7.1 Hz, 2H), 3.64 (s, 2H), 3.66-3.18 (m, 1H), 2.96 (dd, J )
13.5, 6.5 Hz, 1H), 2.85 (dd, J ) 18.0, 8.8 Hz, 1H), 2.70 (dd, J )
13.5, 8.3 Hz, 1H), 2.48 (dd, J ) 18.0, 4.7 Hz, 1H), 1.14 (t, J ) 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ (ppm) 206.4, 174.7, 138.6,
134.1, 129.6, 129.2 (2C), 128.9 (2C), 128.6 (2C), 127.2 (2C), 126.8,
60.8, 50.2, 42.8, 42.2, 37.8, 14.2. HRMS C20H22O3 [M + Na+]:
calcd, 333.1467; found, 333.1469.
Ethyl 2-Isopropyl-4-oxo-5-phenylpentanoate (6). This was
prepared using the general method for coupling with acrylates, with
3-(2-phenylacetyl)oxazolidin-2-one (77 mg, 0.375 mmol) and ethyl
3-methyl-2-methylenebutanoate (106 mg, 0.745 mmol). EtOAc
(increasing polarity, 5 to 8%) in pentane was used as eluant for
flash chromatography, which gave compound 6 (54 mg, 0.206
mmol, 55%) as an oil. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.34-
7.18 (m, 5H), 4.11 (q, J ) 7.1 Hz, 2H), 3.72 (s, 2H), 2.93 (dd, J
) 17.6, 10.5 Hz, 1H), 2.75 (dd, J ) 5.3, 3.5 Hz, 1H), 2.44 (dd, J
) 17.6, 3.5 Hz, 1H), 1.95-1.91 (m, 1H), 1.22 (t, J ) 7.1 Hz, 3H),
0.87 (dd, J ) 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ (ppm)
207.1, 174.7, 134.3, 129.6 (2C), 128.9 (2C), 127.2, 60.5, 50.3, 46.5,
40.6, 30.1, 20.2, 19.8, 14.4. HRMS C16H22O3 [M + Na+]: calcd,
285.1467; found, 285.1468.
1
solid. H NMR (400 MHz, CDCl3) δ (ppm) major isomer 7.29-
7.04 (m, 10H), 4.95 (d, J ) 6.6 Hz, 1H), 4.48-4.44 (m, 1H), 4.13-
4.05 (m, 2H), 3.18-2.31 (m, 7H), 1.36 (s, 9H), 1.19-1.17 (m,
3H); minor isomer inter alia 5.12 (d, J ) 7.2 Hz, 1H), 2.34 (dd, J
) 18.0, 4.3 Hz, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ
(ppm) major isomer 207.2, 174.6, 155.3, 138.5, 136.5, 129.5 (2C),
129.2 (2C), 128.8 (2C), 128.7 (2C), 127.1 (2C), 126.9, 80.0, 60.9,
41.9, 41.4, 38.0, 28.4 (3C), 14.3; minor isomer inter alia 207.6,
138.4, 136.6, 60.9, 60.5, 42.1, 41.2, 37.9. HRMS C26H33NO5 [M
+ Na+]: calcd, 462.2256; found, 462.2245.
tert-Butyl (2S)-5-(Ethoxycarbonyl)-7-methyl-3-oxo-1-phenyl-
octan-2-ylcarbamate (27). This was prepared using the general
method for coupling with acrylates, with oxazolidinone 18 (125
mg, 0.374 mmol) and ethyl 4-methyl-2-methylenepentanoate (116
mg, 0.743 mmol). EtOAc (10%) in pentane was used as eluant for
column chromatography, which gave compound 27 (103 mg, 0.254
mmol, 68%) as a colorless solid and recovered 18 (24 mg, 0.072
1
mmol, 19%). H NMR (400 MHz, CDCl3) δ (ppm) major isomer
7.30-7.14 (m, 5H), 5.01 (d, J ) 7.7 Hz, 1H), 4.59-4.40 (m, 1H),
4.11 (q, J ) 7.1 Hz, 1H), 3.16-2.30 (m, 5H), 1.58-1.49 (m, 2H),
1.37 (s, 9H), 1.23 (t, J ) 7.0 Hz, 3H), 0.90 (dd, J ) 21.0, 6.3 Hz,
6H); minor isomer inter alia 5.12 (d, J ) 7.6 Hz, 1H), 1.39 (s,
9H). 13C NMR (200 MHz, CDCl3) δ (ppm) major isomer 207.5,
175.8, 155.4, 136.5, 129.5 (2C), 128.9 (2C), 127.2, 80.0, 60.7, 60.1,
42.9, 41.4, 38.2, 37.4, 28.4 (3C), 26.0, 22.5, 14.4; minor isomer
inter alia 208.0, 136.4, 60.4, 60.1, 42.9, 41.3, 38.2, 25.9, 22.6, 22.5.
HRMS C23H35NO5 [M + Na+]: calcd, 428.2413; found, 428.2424.
Benzyl (3S)-6-(Ethoxycarbonyl)-2-methyl-4-oxo-7-phenylhep-
tan-3-ylcarbamate (28). This was prepared using the general
method for coupling with acrylates, with oxazolidinone 20 (120
mg, 0.375 mmol) and ethyl 2-benzylacrylate (143 mg, 0.752 mmol).
EtOAc (10%) in pentane was used as eluant for column chroma-
tography, which gave compound 28 (110 mg, 0.259 mmol, 69%)
Ethyl 3-Methyl-4-oxo-5-phenylpentanoate (7). This was pre-
pared using the general method for coupling with acrylates, with
3-(2-phenylacetyl)oxazolidin-2-one (77 mg, 0.375 mmol) and (E)-
ethyl but-2-enoate (86 mg, 0.753 mmol). EtOAc (10%) in pentane
was used as eluant for column chromatography, which gave
1
compound 7 (53 mg, 0.226 mmol, 60%) as an oil. H NMR (400
MHz, CDCl3) δ (ppm) 7.34-7.18 (m, 5H), 4.10 (q, J ) 7.1 Hz,
2H), 3.70 (s, 2H), 2.92-2.89 (m, 2H), 2.50-2.45 (m, 1H), 1.22 (t,
J ) 7.1 Hz, 3H), 1.12 (d, J ) 6.7 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 206.4, 175.8, 134.2, 129.6 (2C), 128.9 (2C), 127.2,
60.7, 50.4, 45.2, 35.0, 17.2, 14.3. HRMS C14H18O3 [M + Na+]:
calcd, 257.1154; found, 257.1158.
Benzyl (2S)-5-(Ethoxycarbonyl)-3-oxo-1,6-diphenylhexan-2-
ylcarbamate (23). This was prepared using the general method
8224 J. Org. Chem., Vol. 71, No. 21, 2006

Acyl-Type Addition Reactions
as a colorless solid and recovered 20 (24 mg, 0.075 mmol, 20%).
1H NMR (400 MHz, CDCl3) δ (ppm) major isomer 7.35-7.13 (m,
10H), 5.35 (d, J ) 8.2 Hz, 1H), 5.09 (s, 2H), 4.33-4.28 (m, 1H),
4.10-4.04 (m, 2H), 3.15-2.09 (m, 6H), 1.19-1.13 (m, 3H), 0.99
(dd, J ) 20.6, 6.8 Hz, 3H), 0.72 (dd, J ) 15.3, 6.8 Hz, 3H); minor
isomer inter alia 5.06 (s, 2H), 1.39 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ (ppm) major isomer 207.5, 174.6, 155.6, 138.5, 136.5,
129.1 (2C), 128.8 (2C), 128.7 (2C), 128.3 (2C), 128.2, 126.9, 67.2,
64.7, 60.9, 42.2, 41.3, 38.0, 37.4, 28.9, 20.2, 14.2; minor isomer
inter alia 207.0, 174.3, 155.6, 138.4, 136.1, 60.5, 42.2, 41.3, 37.8.
HRMS C25H31NO5 [M + Na+]: calcd, 448.2100; found, 448.2108.
(5S)-Ethyl 5-(Benzyloxycarbonyl)-2-isopropyl-4-oxo-6-phe-
nylhexanoate (29). This was prepared using the general method
for coupling with acrylates, with oxazolidinone 17 (138 mg, 0.375
mmol) and ethyl 3-methyl-2-methylenebutanoate (107 mg, 0.752
mmol). EtOAc (10-80%) in pentane was used as eluant for flash
chromatography, which gave compound 29 (52 mg, 0.122 mmol,
45%) as a colorless gum and recovered 17 (51 mg, 0.138 mmol,
tert-Butyl [(1S)-2-Oxo-2-(2-oxo-3-oxazolidinyl)-1-(phenyl-
methyl)ethyl]carbamate (18). 2-Oxazolidinone (740 mg, 8.46
mmol) was dissolved in dry CH2Cl2 (21 mL) and then cooled to 0
°C before AlMe3 (4.2 mL, 8.40 mmol, 2 M in toluene) was added
dropwise. The mixture was stirred at rt for 30 min and then added
via syringe to a solution of PFP ester 14 (1.60 g, 4.027 mmol) in
CH2Cl2 (21 mL). The mixture was stirred at rt for 20 h and then
poured directly into 1 M HCl (80 mL) and extracted with CH2Cl2
(3 × 30 mL). The combined organic portions were dried (MgSO4),
filtered, and evaporated in Vacuo. The pure product was obtained
by column chromatography (20-70% EtOAc in pentane as eluant),
which gave compound 18 (779 mg, 2.330 mmol, 83%) as a colorless
1
solid. H NMR (400 MHz, CDCl3) δ (ppm) 7.20-7.34 (m, 5H),
5.68 (dt, J ) 8.8, 4.8 Hz, 1H), 5.07 (br d, J ) 7.6 Hz, 1H), 4.32-
4.46 (m, 2H), 4.04 (ddd, J ) 10.8, 9.2, 6.8 Hz, 1H), 3.87-3.97
(m, 1H), 3.18 (br d, J ) 12.8 Hz, 1H), 2.78 (br t, J ) 8.8 Hz, 1H),
1.35 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm) 172.8, 155.0,
153.0, 136.0, 129.5, 128.5 (2C), 127.1 (2C), 80.0, 62.5, 53.9, 42.6,
38.5, 28.2 (3C). HRMS C17H22N2O5 [M + Na+]: calcd, 357.1426;
found, 357.1422.
1
51%). H NMR (400 MHz, CDCl3) δ (ppm) major isomer 7.10-
7.40 (m, 10H), 5.29 (d, J ) 8.0 Hz, 1H), 5.05 (s, 2H), 4.57-4.68
(m, 1H), 4.06-4.18 (m, 2H), 3.19 (dd, J ) 14.0, 6.0 Hz, 1H), 2.74-
3.08 (m, 3H), 2.47 (dd, J ) 17.6, 3.2 Hz, 1H), 1.86-2.03 (m, 1H),
1.26 (t, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H), 0.88 (d, J ) 6.8
Hz, 3H); minor isomer inter alia 5.09 (s, 2H), 2.66 (ddd, J ) 8.4,
5.2, 3.2 Hz, 1H), 2.24 (dd, J ) 17.6, 3.2 Hz, 1H), 1.23 (t, J ) 6.8
Hz, 3H), 0.84 (d, J ) 6.8 Hz, 3H), 0.80 (d, J ) 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 207.0/207.6, 174.3/174.4, 156.0/
155.7, 136.1, 136.1, 129.3 (2C), 129.2 (2C), 128.7 (2C), 128.5/
128.6 (2C), 128.0/128.1, 127.0/127.1, 66.9, 60.4/63.0, 60.4/60.8,
45.8/46.3, 38.9/39.2, 37.2/38.0, 29.8/29.9, 20.7, 14.2/14.2. HRMS
C25H31NO5 [M + Na+]: calcd, 448.2100; found, 448.2098.
Benzyl (3S)-6-(Ethoxycarbonyl)-2,8-dimethyl-4-oxononan-3-
ylcarbamate (30). This was prepared using the general method
for coupling with acrylates, with oxazolidinone 20 (120 mg, 0.375
mmol) and ethyl 4-methyl-2-methylenepentanoate (116 mg, 0.743
mmol). EtOAc (10%) in pentane was used as eluant for column
chromatography, which gave compound 30 (100 mg, 0.255 mmol,
68%) as a colorless solid and recovered 20 (24 mg, 0.075 mmol,
(S)-tert-Butyl 4-Methyl-1-oxo-1-(2-oxooxazolidin-3-yl)pentan-
2-ylcarbamate (19). 2-Oxazolidinone (1.052 g, 12.08 mmol) was
dissolved in dry CH2Cl2 (25 mL) and then cooled to 0 °C before
AlMe3 (6.0 mL, 12.00 mmol, 2 M in toluene) was added dropwise.
The mixture was stirred at rt for 30 min and then added via syringe
to a solution of PFP ester 15 (1.60 g, 4.027 mmol) in CH2Cl2 (10
mL). The mixture was stirred at rt for 18 h and then poured directly
into 1 M HCl (100 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic portions were dried (MgSO4), filtered, and
evaporated in Vacuo. The pure product was obtained by column
chromatography (20-70% EtOAc in pentane as eluant), which gave
compound 19 (847 mg, 2.937 mmol, 73%) as a colorless solid. 1H
NMR (400 MHz, CDCl3) δ (ppm) 5.41 (ddd, J ) 11.2, 8.8, 2.4
Hz, 1H), 5.01 (d, J ) 8.4 Hz, 1H), 4.42 (ddd, J ) 9.2, 7.2, 2.4 Hz,
2H), 4.05 (ddd, 10.8, 8.8, 7.2 Hz, 1H), 3.90-3.98 (m, 1H), 1.72-
1.82 (m, 1H), 1.48-1.59 (m, 1H), 1.41 (s, 9H), 1.32-1.41 (m,
1H), 0.99 (d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ (ppm) 174.3, 155.6, 152.7, 79.7, 62.3, 51.6,
42.5, 41.1, 28.2 (3C), 24.9, 23.4, 20.8. HRMS C14H27N2O5 [M +
Na+]: calcd, 323.1582; found, 323.1581.
1
20%). H NMR (400 MHz, CDCl3) δ (ppm) major isomer 7.37-
7.26 (m, 5H), 5.35 (s, 1H), 5.10 (s, 2H), 4.35 (m, 1H), 4.11 (q, J
) 7.1 Hz, 2H), 3.14-2.22 (m, 4H), 1.59-1.49 (m, 1H), 1.23 (q, J
) 7.1 Hz, 3H), 1.01 (t, J ) 7.0 Hz, 3H), 0.90 (dd, J ) 21.1, 6.3
Hz, 6H), 0.77 (dd, J ) 6.7, 3.8 Hz, 3H); minor isomer inter alia
5.10 (s, 2H), 1.39 (s, 9H). 13C NMR (100 MHz, CDCl3) δ (ppm)
major isomer 207.6, 175.6, 156.6, 136.5, 128.6 (2C), 128.3 (2C),
128.2, 67.1, 64.3, 60.6, 43.2, 41.3, 38.0, 30.3, 25.9, 22.6 (2C), 20.0,
16.2 (2C), 14.2; minor isomer inter alia 207.4, 175.3, 155.5, 136.4,
64.7, 60.6, 42.7, 41.3, 38.5, 26.0, 22.4, 19.9, 16.2, 14.2. HRMS
C22H33NO5 [M + Na+]: calcd, 414.2256; found, 414.2268.
Phenylmethyl [(1S)-2-Oxo-2-(2-oxo-3-oxazolidinyl)-1-(phenyl-
methyl)ethyl]carbamate (17). 2-Oxazolidinone (175 mg, 2.00
mmol) was dissolved in dry CH2Cl2 (5 mL), and then AlMe3 (1.0
mL, 2.00 mmol, 2 M in toluene) was added dropwise. The mixture
was stirred at rt for 30 min and then added via syringe to a solution
of PFP ester 12 (310 mg, 0.666 mmol) in CH2Cl2 (5 mL). The
mixture was stirred at rt for 2 days and then poured directly into 1
M HCl (40 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic portions were dried (MgSO4), filtered, and
evaporated in Vacuo. The pure product was obtained by column
chromatography (40-70% EtOAc in pentane as eluant), which gave
compound 17 (199 mg, 0.540 mmol, 81%) as a colorless solid. 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.17-7.40 (m, 10H), 5.76 (td,
J ) 8.0, 4.8 Hz, 1H), 5.36 (d, J ) 8.0 Hz, 1H), 5.03 (AB system,
J ) 12.0 Hz, 2H), 4.30-4.47 (m, 2H), 4.05 (dd, J ) 16.4, 9.6 Hz,
1H), 3.92 (dd, J ) 16.4, 8.4 Hz, 1H), 3.23 (dd, J ) 13.6, 4.0 Hz,
1H), 2.84 (dd, J ) 13.2, 9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 172.3, 155.8, 152.8, 136.2, 135.6, 129.3 (2C), 128.5 (2C),
128.4 (2C), 128.1, 128.0 (2C), 127.1, 66.9, 62.4, 54.3, 42.5, 38.5.
HRMS C20H20N2O5 [M + Na+]: calcd, 391.1270; found, 391.1271.
(S)-Benzyl 3-Methyl-1-oxo-1-(2-oxooxazolidin-3-yl)butan-2-
ylcarbamate (20). 2-Oxazolidinone (386 mg, 3.90 mmol) was
dissolved in dry CH2Cl2 (10 mL) and then cooled to 0 °C before
AlMe3 (1.95 mL, 3.90 mmol, 2 M in toluene) was added dropwise.
The mixture was stirred at rt for 30 min and then added via syringe
to a solution of PFP ester 16 (540 mg, 1.30 mmol) in CH2Cl2 (3.0
mL). The mixture was stirred at rt for 48 h and then poured directly
into 1 M HCl (100 mL) and extracted with CH2Cl2 (3 × 50 mL).
The combined organic portions were dried (MgSO4), filtered, and
evaporated in Vacuo. The pure product was obtained by column
chromatography (30-50% EtOAc in pentane as eluant), which gave
compound 20 (258 mg, 0.806 mmol, 62%) as a colorless solid. 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.25-7.40 (m, 5H), 5.43-5.50
(m, 2H), 5.08 (AB system, J ) 14.4 Hz, 2H), 4.38 (t, J ) 8.4 Hz,
2H), 3.85-4.07 (m, 2H), 2.10-2.22 (m, 1H), 1.04 (d, J ) 6.8 Hz,
3H), 0.84 (d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
(ppm) 172.6, 156.2, 152.8, 136.2, 128.4 (3C), 128.0 (2C), 66.9,
62.2, 57.5, 42.4, 30.6, 19.6, 16.1. HRMS C16H20N2O5 [M + Na+]:
calcd, 343.1270; found, 343.1267.
(2S,4S)-Perfluorophenyl 4-(4-Methoxy-3-(3-methoxypro-
poxy)benzyl)-2-(benzyloxycarbonylamino)-5-methylhexanoate
(32). Acid 314 (284 mg, 0.582 mmol) was dissolved in CH2Cl2 (5
mL), and then the mixture was cooled to 0 °C. PFP (150 mg, 0.814
mmol), EDCI (191 mg, 1.000 mmol), and DMAP (20 mg, 0.169
mmol) were added, and then the mixture was stirred for 30 min at
0 °C and at rt for a further 30 min. It was then 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
J. Org. Chem, Vol. 71, No. 21, 2006 8225

Karaffa et al.
chromatography (10-25% EtOAc in pentane as eluant), which gave
compound 32 (371 mg, 0.568 mmol, 97%) as a colorless gum. 1H
NMR (400 MHz, CDCl3) δ (ppm) 7.27-7.37 (m, 5H), 6.73-6.80
(m, 2H), 6.68 (d, J ) 8.0 Hz, 1H), 5.19 (d, J ) 8.8 Hz, 1H), 5.14
(s, 2H), 4.68 (br q, J ) 4.8 Hz, 1H), 4.08 (t, J ) 6.0 Hz, 2H), 3.82
(s, 3H), 3.56 (t, J ) 6.0 Hz, 2H), 3.33 (s, 3H), 2.59 (d, J ) 5.6 Hz,
1H), 2.07 (quin, J ) 6.0 Hz, 2H), 1.70-1.88 (m, 4H), 0.91 (d, J )
6.8 Hz, 3H), 0.88 (s, J ) 6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ (ppm) 169.2, 168.0 (br), 155.9, 148.4, 147.8, 142.2 (br), 139.7
(br), 136.7 (br), 136.0 (br), 135.9, 133.0, 128.5 (2C), 128.2, 128.0
(2C), 121.2, 114.3, 111.8, 69.4, 67.3, 65.9, 58.5, 56.0, 52.3, 42.1,
36.3, 33.2, 29.5, 28.2, 19.3, 17.1. HRMS C33H36F5NO7 [M + Na+]:
calcd, 676.2310; found, 676.2253.
Benzyl (2S,4S)-4-(4-Methoxy-3-(3-methoxypropoxy)benzyl)-
5-methyl-1-oxo-1-(2-oxooxazolidin-3-yl)hexan-2-ylcarbamate (33).
2-Oxazolidinone (175 mg, 2.00 mmol) was dissolved in dry CH2-
Cl2 (5 mL), and then AlMe3 (1.0 mL, 2.00 mmol, 2 M in toluene)
was added dropwise. The mixture was stirred at rt for 30 min and
then added via syringe to a solution of PFP ester 32 (370 mg, 0.566
mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt for 4 days
and then poured directly into 1 M HCl (40 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic portions were dried
(MgSO4), filtered, and evaporated in Vacuo. The pure product was
obtained by column chromatography (20-100% EtOAc in pentane
as eluant), which gave compound 33 (242 mg, 0.435 mmol, 77%)
as a colorless gum and recovered 32 (40 mg, 0.061 mmol, 11%).
1H NMR (400 MHz, CDCl3) δ (ppm) 7.26-7.36 (m, 5H), 6.79 (s,
1H), 6.74 (d, J ) 8.0 Hz, 1H), 6.67 (d, J ) 8.0 Hz, 1H), 5.60 (br
t, J ) 8.4 Hz, 1H), 5.40 (br t, J ) 8.8 Hz, 1H), 5.10 (s, 2H), 4.41
(t, J ) 7.6 Hz, 2H), 4.08 (t, J ) 6.0 Hz, 2H), 3.88-4.06 (m, 2H),
3.81 (s, 3H), 3.55 (t, J ) 6.0 Hz, 2H), 3.13 (s, 3H), 2.97 (br d, J
) 11.2 Hz, 1H), 2.37 (dd, J ) 13.6, 10.0 Hz, 1H), 2.06 (quin, J )
6.4 Hz, 2H), 1.45-1.74 (m, 4H), 0.78 (d, J ) 6.8 Hz, 6H). 13C
NMR (100 MHz, CDCl3) δ (ppm) 173.6, 156.0, 152.7, 148.1, 147.4,
136.3, 134.1, 128.4 (2C), 128.0, 127.9 (2C), 121.2, 114.4, 111.6,
69.4, 66.8, 65.9, 62.4, 58.5, 56.0, 51.9, 42.5, 41.9, 36.1, 32.7, 29.6,
27.4, 20.6, 16.1. HRMS C30H40N2O8 [M + Na+]: calcd, 579.2682;
found, 579.2692.
ononanoate (34). Oxazolidinone 33 (37 mg, 0.0664 mmol) was
dissolved in THF (5 mL), and then ethyl R-isopropyl acrylate (150
mg, 1.055 mmol) and water (100 mg, 5.55 mmol) were added. The
mixture was cooled to -78 °C before a 0.1 M solution of SmI2
(15 mL, 1.50 mmol) was added dropwise over 15 min. The mixture
was stirred at -78 °C for 2 days, and then the flask was flushed
with O2. The mixture was poured into 0.5 M HCl (40 mL) and
extracted with EtOAc (5 × 15 mL). The combined organic portions
were washed with saturated Na2S2O3, dried (MgSO4), filtered, and
evaporated. The pure product was obtained by column chromatog-
raphy (10-100% EtOAc in pentane as eluant), which gave
compound 34 (21 mg, 0.0342 mmol, 52%) as a colorless gum and
a 5:4 mixture of isomers and recovered 33 (16 mg, 0.0287 mmol,
1
43%). H NMR (400 MHz, CDCl3) δ (ppm) 7.20-7.30 (m, 5H),
6.60-6.78 (m, 3H), 5.12/5.21 (br d, J ) 8.0 Hz, 1H), 5.03/5.05
(s/AB system, J ) 12.0 Hz, 2H), 4.23/4.32 (br t, J ) 8.0 Hz, 1H),
3.96-4.10 (m, 4H), 3.76 (s, 3H), 3.49 (t, J ) 6.0 Hz, 2H), 3.26 (s,
3H), 2.72-2.90 (m, 1H), 2.56-2.70 (m, 2H), 2.22-2.50 (m, 2H),
2.02 (quin, J ) 6.4 Hz, 2H), 1.84-1.96 (m, 1H), 1.43-1.68 (m,
3H), 1.10-1.27 (m, 4H), 0.68-0.90 (m, 12H). 13C NMR (100 MHz,
CDCl3) δ (ppm) 208.4/208.8, 174.3/174.5, 156.3/156.4, 148.4,
147.7, 133.5, 128.6 (2C), 128.2, 128.0 (2C), 121.3, 114.4, 111.6,
69.6, 66.0/66.9, 60.5/60.6, 58.7, 58.3/58.6, 56.1, 45.8/46.3, 42.1/
42.2, 37.8/38.7, 32.4, 30.0, 29.7, 28.2/28.8, 20.3/20.4, 20.1/20.4,
19.7, 16.9/17.0, 14.3/14.4. HRMS C35H51NO8 [M + Na+]: calcd,
636.3512; found, 636.3510.
Acknowledgment. We are deeply appreciative of the gener-
ous financial support from the Danish National Research
Foundation, the Lundbeck Foundation, and the University of
Aarhus.
Supporting Information Available: Experimental details and
copies of 1H NMR and 13C NMR spectra for compounds 1-7, 17-
30, and 32-34. This material is available free of charge via the
Internet at http://pubs.acs.org.
(5S,7S)-Ethyl 7-(4-Methoxy-3-(3-methoxypropoxy)benzyl)-5-
(benzyloxycarbonylamino)-2-isopropyl-8-methyl-4-ox-
JO061299S
8226 J. Org. Chem., Vol. 71, No. 21, 2006