A stereocontrolled synthesis of monofluoro ketomethylene dipeptide isosteres

Article abstract of DOI:10.1021/jo981334y

A simple, stereocontrolled synthesis of monofluoro ketomethylene dipeptide isosteres has been developed. N-Tritylated ketomethylene dipeptide isosteres, prepared from N-tritylated amino acids, are converted to their Z- TMS enol ethers and fluorinated with Selectfluor. There is cooperative stereocontrol between the N-tritylamine group and the alkyl group at C-2. The method is short (six steps), diastereoselective (85 → 95%), and enantioselective (>95%).

Full text of DOI:10.1021/jo981334y

126
J . Org. Chem. 1999, 64, 126-132
A Ster eocon tr olled Syn th esis of Mon oflu or o Ketom eth ylen e
Dip ep tid e Isoster es
Robert V. Hoffman* and J unhua Tao
Department of Chemistry and Biochemistry, New Mexico State University,
Las Cruces, New Mexico 88003-0001
Received J uly 9, 1998
A simple, stereocontrolled synthesis of monofluoro ketomethylene dipeptide isosteres has been
developed. N-Tritylated ketomethylene dipeptide isosteres, prepared from N-tritylated amino acids,
are converted to their Z-TMS enol ethers and fluorinated with Selectfluor. There is cooperative
stereocontrol between the N-tritylamine group and the alkyl group at C-2. The method is short
(six steps), diastereoselective (85 f 95%), and enantioselective (>95%).
In tr od u ction
The incorporation of fluorine into biologically active
molecules can induce unique changes in the physical,
chemical, and biological properties of that compound.1
Fluorinated peptide mimetics are particularly interesting
in this regard.2 They contain fluorine-activated electro-
philic carbonyl groups that react readily with active site
nucleophiles such as hydroxyl groups (serine proteases),
thiol groups (cysteine proteases), or water (aspartate or
metallo proteinases) to produce transition-state ana-
logues in the active site.3
Many examples utilize fluorinated methyl ketones 1
(n ) 3, 2) to provide the electrophilic carbonyl group.3-5
Monofluoromethyl ketone analogues 1 (n ) 1) have the
interesting tendency to exhibit both reversible and ir-
reversible inhibition.3c,6 Because the fluorinated methyl
ketone functionality in 1 defines the carboxyl end of the
chain, the peptide chain can only be extended in the P
direction. A second design used a fluorinated R-ketoester
2 to provide the electrophilic carbonyl group.7 In this case,
the peptide chain can only be extended in the P′-direction.
Incorporating R-fluorinated ketones within the peptide
chain is less common. Difluorostatone analogues 3 have
been studied as difluorinated dipeptide mimetics.8 Few
examples of true difluoroketomethylene dipeptide isos-
teres 4 (n ) 2) are extant,9 and only a single example of
a monofluoroketomethylene dipeptide isostere 4 (n ) 1)
has been reported.10 Monofluoroketomethylene peptide
isosteres 4 (n ) 1) could be very interesting peptide
mimetics since they are true peptide isosteres whose
binding region can be extended in both the P and P′
directions. Moreover, the ketone carbonyl group is only
partially hydrated (∼0-50%) upon treatment with water
so that interaction with several different types of pro-
teases is possible.
The first synthesis of a monofluoro ketomethylene
peptide isostere 5 utilized a homoenolate equivalent to
assemble the isostere skeleton and fluorination of a silyl
enol ether to introduce the C-3 fluorine substituent.10
Overall, this route was long (>10 steps), and the intro-
duction of fluorine was completely nonstereoselective. On
the basis of our chiral alkylation methodology for the
synthesis of ketomethylene peptide isosteres,11 our use
of the trityl group as a powerful stereocontrol element
(1) Hudlicky, M., Pavlath, A. E., Eds. Chemistry of Organic Fluorine
Compounds II; ACS Monograph 187; American Chemical Society:
Washington, DC, 1995. See the following chapters: Filler, R.; Kirk,
K. Biological Properties of Fluorinated Compounds; Elliott, A. J .
Fluorinated Pharmaceuticals; Lang, R. W. Fluorinated Agrochemicals.
(2) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic
Chemistry; J ohn Wiley and Sons: New York, 1991. (b) Rich, D. H. In
Comprehensive Medicinal Chemistry; Sammes, P. G., Ed.; Pergamon
Press: Oxford, U.K. 1990; pp 391-441. (c) Sham, H. L. In Biomedical
Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J . R., Welch, J .
T., Eds.; American Chemical Society: Washington D.C., 1996; pp 184-
195.
(3) (a) Abeles, R. H. Drug Dev. Res. 1987, 10, 221. (b) Rauber, P.;
Angliker, H.; Walker, B.; Shaw, E. Biochem. J . 1986, 239, 633. (c)
Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25, 3760. (d) Gelb, M.
H.; Svaren, J . P.; Abeles, R. H. Biochemistry 1985, 24, 1813.
(4) See, for example: (a) Reference 3d. (b) Patel, D. V.; Rielly-
Gauvin, K.; Ryono, D. E.; Free, C. A.; Smith, S. A.; Petrillo, E. W., J r.
J . Med. Chem. 1993, 36, 2431. (b) Edwards, P. D.; Andisik, D. W.;
Strimpler, A. M.; Gomes, B.; Tuthill, P. A. J . Med. Chem. 1996, 39,
1112 and references therein.
(5) Perfluoroethyl ketones have also been reported: Angelastro, M.
R.; Burkhart, J . P.; Bey, P.; Peet, N. P. Tetrahedron Lett. 1992, 33,
3265 and references therein.
(6) (a) Higuchi, N.; Saitoh, M.; Niwata, S.; Kiso, Y.; Hyashi, Y. EP
578978; Chem. Abstr. 1994, 121, 256335j. (b) Schrevel, J .; Monsigny,
M.; Mayer, R.; Picard, I.; Lawton, P. L. F.; Grelier, P. WO 8808717;
Chem. Abstr. 1989, 111, 33672j. (c) Rasnick, D. EP 130679; Chem.
Abstr. 1985, 103, 22931b. (d) Revesz, L.; Briswalter, C.; Heng, R.;
Leutwiler, A.; Mueller, R.; Wuethrich, H.-J . Tetrahedron Lett. 1994,
35, 9693.
(7) (a) Parisi, M. F.; Abeles, R. H. Biochemistry 1992, 31, 9429. (b)
Bastos, M.; Maeji, N. J .; Abeles, R. H. PNAS 1995, 92, 6738.
(8) (a) Veerapandian, B.; Cooper, J . B.; Sali, A.; Bllundell, T. L.;
Rosati, R. L.; Dominy, B. W.; Damon, D. B.; Hoover, D. J . Protein Sci.
1992, 1, 322. (b) J ames, M. N. G.; Sielecki, A. R.; Hayakawa, K.; Gelb,
M. H. Biochemistry 1992, 31, 3872. (c) Beveridge, A. J .; Dealwis, C.;
Cooper, J . B. THEOCHEM 1995, 333, 87 and references therein. (d)
J ones, D. M.; Atrash, B.; Tegernilsson, A. C.; Gyzander, E.; Deinum,
J .; Szelke, M. Lett. Peptide Sci. 1995, 2, 147.
(9) (a) Damon, D. B.; Hoover, D. J . J . Am. Chem. Soc. 1990, 112,
6439. (b) Hong, W.; Dong, L.; Cai, Z.; Titmas, R. Tetrahedron Lett. 1992,
33, 741.
(10) Garrett, G. S.; Emge, T. J .; Lee, S. C.; Fischer, E. M.; Dyehouse,
K.; McIver, J . M. J . Org. Chem. 1991, 56, 4823.
(11) Hoffman, R. V.; Tao, J .-H. Tetrahedron 1997, 53, 7119.
10.1021/jo981334y CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/16/1998

Synthesis of Monofluoro Ketomethylene Dipeptide Isosteres
J . Org. Chem., Vol. 64, No. 1, 1999 127
Sch em e 1
Sch em e 2
in the synthesis of sphingosines,12 and the use of Select-
fluor ((1-chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate)) for electrophilic fluorination
of silyl enol ethers,13 we envisioned the simple and
stereoselective synthesis of monofluoroketomethylene
peptide isosteres 5 shown retrosynthetically in Scheme
1. While the conversion of tritylated amino acids 9 to
ketomethylene peptide isosteres 6 could follow a known
route,11 the stereoselective fluorination of 6 to monofluoro
isostere 5 depended on the unprecedented allylic stereo-
control by an N-trityl group and/or 1,2 stereocontrol by
the R-group at C-2. (It was claimed in the earlier report
that no stereocontrol of the fluorination was observed.10)
A preliminary report demonstrated that this approach
is feasible.13b The successful reduction of Scheme 1 to
practice and the factors that control the fluorination
stereochemistry is the subject of this report.
Ta ble 1. Yield s a n d Ster eoch em ica l P u r ities of Isoster es
6
entry
product
yielda (%)
deb (%)
eec (%)
1
2
3
4
5
6
7
8
6a a
6a b
6bc
6cd
6d e
6ea
6ff
60
49
43
50
53
40
55
50
>95
85
91
92
92
85
>95
90
>95
>95
>95
>95
>95
>95
>95
>95
Resu lts a n d Discu ssion
Tritylated amino acids 914 containing branched, un-
branched, and heteroatom-containing side chains were
converted to allyl â-ketoesters 815 (55-75%), alkylated
with scalemic triflates 7,11 and decarboxylated to provide
tritylated ketomethylene isosteres 616 in good yields (40-
60%) (Scheme 2). In our previous work, a tert-butyl ester
group was used in the â-ketoester 8.11 Since TFA removal
of the tert-butyl group is incompatible with the trityl
group, allyl esters were utilized instead. Palladium(0) not
only cleaved the allyl group selectively but also catalyzed
the decarboxylation to give 6.12
6gg
a
Isolated yields of chromatographed mixtures of diastereomers.
Determined by 1H NMR for the mixture of diastereomers.
b
c Determined by chiral LIS study using Eu(hfc)3 on the separated
major diastereomer.
Sch em e 3
The (R)-enantiomer of triflate 7 produces the R con-
figuration at C-2 of 6, which has the same stereochemical
sense as a normal dipeptide. The S enantiomer of 7 gives
the unnatural stereochemical analogue at C-2. The
diastereoselectivity of the alkylation-decarboxylation
was quite good, ranging from 85 to 95% de (Table 1). In
each case, the major diastereomer of 6 was separated and
examined using the chiral shift reagent Eu(hfc)3.
Within the limits of NMR detection, only one enanti-
omer was present (>95% ee), indicating that no epimer-
ization at C-5 takes place during the reaction sequence.17
syn-(2R,5S)-Isosteres 6a a , 6a b, 6bc, 6cd , 6d e, and
6ea 16 were converted to the corresponding (Z)-TMS enol
ethers 10 using NaHMDS-TMSCl (Scheme 3). It is
known that bulky nitrogen substituents on amino ke-
tones cause enolate formation to occur regiospecifically
distal from the amino group by removal of the R′-
proton.12,18 Moreover, only one vinyl proton signal was
seen in the olefin region of the NMR spectra of 10,
indicating a single double-bond geometry was produced.
The use of NaHMDS under kinetic conditions19 allows
the Z geometry to be assigned to 10.
(12) Hoffman, R. V.; Tao, J .-H.. J . Org. Chem. 1998, 63, 3979.
(13) (a) Hoffman, R. V.; Saenz, J . E. Tetrahedron Lett. 1997, 38,
8469. (b) Hoffman, R. V.; Tao. J . Tetrahedron Lett., in press. (c) Banks,
R. E. J . Fluorine Chem. 1998, 87, 1.
(14) Barlos, K.; Papaioannou, D.; Theodoropoulos, D. J . Org. Chem.
1982, 47, 1324.
(15) Harris, B. D.; J oullie, M. M. Tetrahedron 1988, 44, 3489.
(16) For the combinations used, the reaction of ketoester 8x (derived
from amino acid 9x) with triflate 7y gives γ-ketoester 6xy.
(17) For calibrating the LIS method to determine enantioselectivity,
racemic 7a a was prepared and subjected to examination by the LIS
reagent.
(18) (a) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1988, 110,
7447. (b) Alexander, C. W.; Liotta, D. C. Tetrahedron Lett. 1996, 37,
1961 and references therein.
(19) (a) House, H. O.; Czuba, L. J .; Gall, M.; Olmstead, H. D. J . Org.
Chem. 1969, 34, 2324. (b) Xie, L.; Isenberger, K. M.; Held, G.; Dahl,
L. M. J . Org. Chem. 1997, 62, 7516.

128 J . Org. Chem., Vol. 64, No. 1, 1999
Hoffman and Tao
bonds were evaluated by the AM-1 method.22 For 11S,S,S
there were three low energy conformations that were
1.7-3.0 kcal/mol more stable than the next lowest energy
conformer, and they all had a dihedral angle of 179.5°
between the C-2 and C-3 protons. For 11S,R,S the
conformation of lowest energy was also 2.5 kcal more
stable than the next lowest energy conformation, but it
had a dihedral angle of only 83.2° between the C-2 and
C-3 protons. The substantial coupling constant of J H-H
) 7-8 Hz found in the product is consistent the 179.5°
dihedral angle found for the major conformers of the
11S,S,S diastereomer. (Similar calculational results were
found for R1 ) i-Pr, R2 ) Me.)
Ta ble 2. Ster eoch em ica l Resu lts of th e P r ep a r a tion of
Mon oflu or o Ketom eth ylen e Dip ep tid e Isoster es 9
entry
product
yielda (%)
deb (%)
1
2
3
4
5
6
7
8
9a a
9a b
9bc
9cd
9d e
9ea
9ff
76
73
65
75
68
>95
>95
>95
>95
>95
>95
1.2:1
1.5:1
∼15
71
9gg
74
a
Isolated yields of chromatographed mixtures of diastereomers.
Determined by 1H NMR of the mixture of diastereomers.
b
Sch em e 4
The same conformational analysis was carried out on
the diastereomers of 13. Again, each diastereomer was
found to have one conformation preferred by about 2.5
kcal/mol over the next lowest ones. The most stable
conformer of 13R,R,S was found to have a dihedral angle
between the C-2 and C-3 protons of 170°, and the most
stable conformer of 13R,S,S was found to have a dihedral
angle of 77° between these protons. Thus, the major
isomer, which has J H-H ) 7.8-8.7 Hz, can be assigned
as the 13R,R,S isomer, and the minor diastereomer,
which has J H-H ) 4.6-4.8 Hz, can be assigned as the
13R,S,S isomer.
From these results, it is seen that for the syn-2R,5S
isomers of 6 (i.e., 6a a , a b, bc, cd , d e, ea ) the chiralities
at C-2 and C-5 are complementary in dictating the
S-configuration at C-3, and thus, high diastereoselectivity
is observed. In the anti-2S,5S diastereomers of 6 (i.e.,
6ff and 6gg), the 1,3-allylic stereocontrol afforded by the
N-tritylamine group is opposed by the 1,2 stereocontrol
of the chiral center at C-2, and diastereomeric mixtures
are obtained.
Conformational analysis of the TMS-enol ethers 10 and
12 provides an explanation for this stereoselection, at
least in a simplistic manner (Figure 1). Again using R1,
R2 ) Me for calculational simplicity, the preferred
conformation of 10, which lies 3 kcal/mol lower than the
next lowest energy conformer, minimizes A1,2 interactions
and has both the N-trityl group at C-5 and the methyl
group at C-2 above one face of the enol double bond.
Approach of the fluorinating agent from the face opposite
these groups leads to the observed stereochemistry.
The preferred conformation of 12, which also lies 3
kcal/mol below the next lowest conformer, has the N-trityl
group at C-5 and the methyl group at C-2 on opposite
faces of the double bond (Figure 1). The 1,2 stereocontrol
of the methyl group must be comparable to 1,3-allylic
Direct fluorination of either 10a a or 10a b with Select-
fluor in DMF or MeCN was very sluggish, the major
process being cleavage of the trityl group. In contrast,
treatment of 10 with Selectfluor in the presence of TBAF
led to smooth R′-fluorination to produce monofluoro
ketomethylene dipeptide isosters 11 in generally good
yields (65-76%) (Scheme 3). Proline derivative 10ea gave
a low yield (15%) presumably due to steric hindrance. It
is noteworthy that the methionine derivative 10bc also
gave a good yield since it is known that sulfides can be
oxidized by Selectfluor under similar conditions.20 Even
more noteworthy is that only a single diastereomer was
evident in the NMR spectrum of the monofluorinated
products 11. Thus, the N-tritylamino group and/or the
C-alkyl group (or both) exert significant stereocontrol in
the electrophilic fluorination of 10 (Table 2).
When anti-(2S,5S)-isosteres 6ff and 6gg were con-
verted to (Z)-TMS enol ethers 12 and fluorinated by the
same protocol, mixtures of diastereomers 13 were pro-
duced (Scheme 4, Table 2). Since the configuration at C-5
remained the same, this result suggests that there is a
cooperative effect of the N-tritylamino group and the C-2
alkyl group in determining the stereoselectivity of fluo-
rination.
The NMR signal of the C-3 proton was used to assign
the stereochemistry of the products. The fluorination of
10 produced single diastereomers of 11 whose C-3 proton
signal appeared at δ ∼4.4-4.9 with J H-H ) 7-8 Hz. The
major diastereomer produced by the fluorination of 12
also had δ ∼4.4-4.6 and J H-H ) 7.8-8.7 Hz. The minor
diastereomer formed in the fluorination of 12 had the
same chemical shift for C-3 proton but had J H-H ) 4.6-
4.8 Hz.
The two possible diastereomers of 11 are shown below.
Since the absolute configurations at C-2 and C-5 are
known, only the configuration of the fluorine atom at C-3
is variable.21 Using R1 ) R2 ) CH3 for calculational
simplicity, conformations about the 2-3, 3-4, and 4-5
(22) The semiempirical AM1 calculations were performed on
a
Silicon Graphics workstation (Indigo 2) using the MOPAC program in
Insight II (4.0.0) from MSI. The input geometries for the AM1
calculations were obtained by using the Discover force field (Steepest
first 1000 steps and then Newton; Derivative ) 0.001) within Insight
II (4.0.0).
(20) Lal, G. S. J . Org. Chem. 1993, 58, 2791.
(21) This is based on the very reasonable assumption that epimer-
ization at C-2 or C-5 does not occur during the fluorination.

Synthesis of Monofluoro Ketomethylene Dipeptide Isosteres
J . Org. Chem., Vol. 64, No. 1, 1999 129
Sch em e 6
C-3 shows the that same facial bias by the fluorinating
agent toward the double bond is operative; the problem
in diastereoselection lies in forming the (E)-enolate
cleanly in these very bulky aminoketones.
Asymmetric synthesis of R-fluoroketones has been the
object of several recent studies.23 In general, asymmetric
fluorinating agents derived from camphor are used to
fluorinate ketone enolates.24 This approach, however,
generally gives modest enantioselectivity (<75% ee).
Enders recently described the electrophilic fluorination
of chiral R-silyl ketone enolates.23 In this case, the R-silyl
group provides stereocontrol for fluorination at the R′-
position and is subsequently removed (Scheme 6). High
de’s are found for cyclic ketones. Lower de’s (67-89%)
are found for acyclic ketones, but both enantiomers can
be produced by choosing either the (Z)- or (E)-enolate
geometry.
F igu r e 1.
Sch em e 5
The present work has similar elements in that a bulky
N-trityl group exerts stereocontrol from the R′- position
and the stereochemistry can be varied by choice of enol
geometry. The results have also allowed a working model
to be generated to rationalize the stereoselection. How-
ever, the complex functional and chiral environment
found in the densely functionalized substrates employed
requires further work to fully understand the structural
factors that control diastereoselection.
In summary, a simple, stereocontrolled synthesis of
monofluoro ketomethylene dipeptide isosteres has been
developed. The method is short (six steps), diastereose-
lective (85 f 95%), and enantioselective (>95%).
stereocontrol by the N-trityl group, and a mixture of
diastereomers is produced. This rationale is consistent
with the observation that replacement of the C-2 methyl
group of 12ff with a slightly larger C-2 isobutyl group in
12gg leads to an increase in the diastereoselectivity as
well (Scheme 4). More work is needed to confirm the
validity of these models, but they do provide a paradigm
for understanding the stereocontrol that is observed.
On the basis of the stereoselectivity observed in the
fluorination of the (Z)-enol ether 10, we thought it might
be possible to reverse the diastereoselectivity by using
the corresponding (E)-enol ether 14 as the fluorination
substrate. Thus, 6a a was converted to the (E)-TMS enol
ether 14a a by using LDA as the base (Scheme 5).19 Two
isomeric TMS enol ethers were produced in a 2:1 ratio.
The minor isomer was the (Z)-TMS enol ether 10a a as
indicated by its vinyl proton signal. The major isomer
was assigned as 14a a . Apparently, the bulk of the C-5
carbon and the secondary C-2 carbon make formation of
the (E)-enolate difficult; thus, an E,Z-mixture is produced
under conditions that normally give predominantly the
(E)-enolate.19
Fluorination of this mixture gave a 2:1 mixture of
monofluoro ketomethylene peptide isosteres. The major
diastereomer had the C-3 proton signal at δ 4.61 with
J H-H ) 5.4 Hz. The reduced coupling constant is consis-
tent with 11a a (S,R,S) as described above. The minor
diastereomer had J H-H ) 7 Hz for the C-3 proton signal
at δ 4.84 and was thus 11a a (S,S,S), which comes from
the diastereospecific fluorination of 10a a in the mixture.
Since the fluorination of 10a a was shown to be ste-
reospecific (see above), and since the ratio of fluorinated
diastereomeric products (2:1) is the same as the ratio of
(E)- and (Z)-enol ethers 14a a and 10a a , it is reasonable
to conclude that the fluorination of (E)-enol ether 14a a
is also diastereospecific. The stereochemical reversal at
Exp er im en ta l Section
Infrared spectra were recorded either on neat liquids or KBr
1
pellets. H NMR and 13C NMR spectra were recorded at 200
and 50 MHz, respectively, in CDCl3. Thin-layer chromatogra-
phy was performed on silica gel 60 F254 plates from EM
reagents and visualized by UV irridiation and/or iodine.
Analytical HPLC was performed with the indicated solvent
systems and flow rates on 8 mm × 25 mm cm silica gel
columns using UV detection. Preparative thin-layer chroma-
tography was performed on silica gel 60 F254 plates from EM
reagents and visualized by UV irradiation. Flash chromatog-
raphy was performed using silica gel 60 (230-400 mesh).
Optical rotations were determined on a Perkin-Elmer 241
polarimeter. Tetrahydrofuran was distilled from benzophenone
ketyl. Other solvents were HPLC grade and were used without
further purification. Starting materials were purchased from
Aldrich, Sigma, or Novabiochem and used as received. El-
emental analyses were carried out by M-H-W laboratories,
Phoenix, AZ.
Allyl 4-Tr itylam in o-3-oxo-6-m eth ylh eptan oate, 8a. Gen -
er a l P r oced u r e. To a stirred solution of N-tritylleucine (1.05
g, 2.81 mmol) in THF (20 mL) was added CDI (carbonyl
(23) For an excellent literature survey, see: Enders, D.; Potthoff,
M.; Raabe, G.; Runsink, J . Angew. Chem., Int. Ed. Engl. 1997, 36, 2362.
(24) For a nucleophilic alternative, see: Kabat, M. M. Tetrahedron:
Asymmetry 1993, 4, 1417.

130 J . Org. Chem., Vol. 64, No. 1, 1999
Hoffman and Tao
diimidazole, 503 mg, 2.81 mmol) at room temperature under
a N2 atmosphere. The resulting solution was stirred for 5 h at
the same temperature and used for the next reaction without
further purification. Meanwhile, a solution of lithium tert-
butoxycarbonylmethanide was made from BuLi (2.50 M, 3.54
mL, 8.85 mmol), diisopropylamine (1.63 mL, 8.85 mmol), and
allyl acetate (0.69 mL, 6.40 mmol). The above imidazole
solution was added dropwise to this pale yellow solution of
lithium enloate at -78 °C under a N2 atmosphere. The
resulting mixture was warmed to room temperature 60 min,
quenched with H2O (50 mL), and extracted with ether (3 × 50
mL). The organic extracts were combined, washed with brine
100 mL), dried (MgSO4), passed through a short pad of silica
gel, and concentrated to provide 8a as a a colorless oil: yield
709 cm-1. Anal. Calcd for C29H31O3N: C, 78.88; H, 7.08; N,
3.17. Found: C, 78.63; H, 6.84; N, 2.96.
Allyl 4-tr ityla m in o-3-oxo-5-ben zyloxyp en ta n oa te, 8g:
74% of a white solid, which was obtained by trituration. After
concentration, the yellow residue was dissolved in hexanes
(100 mL) and filtered, and the solid was washed with cold Et2O
(50 mL): mp 106-108 °C; [R]25D +45.0 (c 1.29, CHCl3); 1H NMR
δ 2.75 (d, 1H, J ) 16.6 Hz), 3.11 (m, 2H), 3.43 (d, 1H, J ) 16.6
Hz), 3.69 (m, 2H), 4.38 (s, 2H), 4.51 (d, 2H, J ) 5.6 Hz), 5.22
(m, 2H), 5.82 (m, 1H), 7.21-7.41 (m, 20H); 13C NMR δ 47.9,
61.8, 65.5, 72.5, 73.0, 73.4, 118.2, 126.7, 128.0, 128.8, 132.0,
146.0, 166.6, 206.4; FTIR (neat) 3027, 1750, 1720, 1452, 1098,
749, 709 cm-1. Anal. Calcd for C34H33O4N: C, 78.59; H, 6.40;
N, 2.70. Found: C, 78.70; H, 6.36; N, 2.86.
71% after purification by flash chromatography (hexane/ether
(2R,5S)-Tr ityl-Leu Ψ[COCH2]Ala-OMe, 6aa. Gen er al P r o-
ced u r e. A solution of 3-oxo ester 8a (940 mg, 2.27 mmol) in
THF (10 mL) was added dropwise to a stirred suspension of
NaH (101 mg of 60% in oil, 2.52 mmol) in dry THF (30 mL) at
0 °C under nitrogen. The mixture was stirred for 10 min. Then
a solution of triflate 7a (590 mg, 2.50 mmol) in dichlo-
romethane (10 mL) was added dropwise to this gray suspen-
sion of the 3-oxo ester enolate. The resulting mixture was
stirred at room temperature for 36 h, quenched with cold citric
acid (5%, 50 mL), and extracted with ether (2 × 100 mL). The
organic extracts were combined, washed with brine (100 mL),
dried (MgSO4), passed through a short pad of silica gel, and
concentrated to provide a pale yellow oil. Without further
purification, the above oil was dissolved into THF (18 mL)
under nitrogen and treated with Pd(PPh3)4 (264 mg, 0.232
mmol) followed by morpholine (2.02 mL, 23.2 mmol). After 3
h, the solvent was evaporated, and the residue was taken into
ether (100 mL) and filtered. The filtrate was washed with 5%
citric acid (50 mL), H2O (20 mL), dried (MgSO4), and passed
through a short pad of silica gel to afford a white solid 6a a
(623 mg, 1.36 mmol, 60%) after purification by flash chroma-
tography (hexane/ether ) 85:5): de >95% based on 1H NMR
of the crude; ee >95% by a chiral LIS study using Eu(hfc)3 in
1
) 75:20); [R]25 +37.4 (c 1.04, CHCl3); H NMR(keto form) δ
D
0.83 (d, 3H, J ) 7.0 Hz), 0.86 (d, 3H, J ) 6.8 Hz), 1.28 (m,
1H), 1.44 (m, 1H), 1.74 (m, 1H), 2.85 (d, 1H, J ) 16.1 Hz),
3.02 (d, 1H, J ) 16.1 Hz), 3.47 (m, 1H), 4.52 (d, 2H, J ) 5.6
Hz), 5.22 (m, 2H), 5.81 (m, 1H), 7.21-7.46 (two set of m, 15H);
13C NMR δ 22.6, 23.3, 24.5, 43.7, 45.6, 61.3, 65.5, 71.4, 89.6,
118.4, 126.7, 128.0, 129.0, 131.8, 146.0, 166.7, 205.9; FTIR
(neat) 2947, 1745, 1177, 1148, 918, 734 cm-1. Anal. Calcd for
C
30H33O3N: C, 79.09; H, 7.30; N, 3.07. Found: C, 78.98; H,
7.23; N, 3.13.
Allyl 4-tr itylam in o-3-oxo-6-S-m eth ylh exan oate, 8b: 50%
of a colorless oil after purification by flash chromatography
(hexane/ether ) 85:10); [R]25D +78.8 (c 0.914, CHCl3); 1H NMR
δ 1.28 (m, 1H), 1.90 (m, 1H), 2.07 (s, 3H), 2.43 (m, 1H), 2.62
(d, 1H, J ) 16.1 Hz), 3.08 (d, 1H, J ) 16.1 Hz), 3.66 (m, 1H),
4.52 (m, 2H), 5.23 (m, 2H), 5.81 (m, 1H), 7.24-7.55 (m, 15H);
13C NMR δ 15.6, 29.4, 33.1, 45.2, 61.5, 65.7, 71.4, 118.6, 126.8,
128.0, 128.9, 132.2, 146.1, 166.3, 177.5, 204.8; FTIR (neat)
2937, 1745, 1716, 709 cm-1. Anal. Calcd for C29H31O3NS: C,
73.54; H, 6.60; N, 2.96. Found: C, 73.36; H, 6.45; N, 2.89.
Allyl 4-tr ityla m in o-3-oxo-p en ta n oa te, 8c: 70% of a color-
less oil after purification by flash chromatography (hexane/
1
ether ) 85:10); [R]25 +40.8 (c 0.897, CHCl3); H NMR δ 1.25
comparison with a racemic sample; mp 114.5-116.5 °C; [R]25
D
D
1
(d, 6H, J ) 7.0 Hz), 2.66 (d, 1H, J ) 16.1 Hz), 2.96 (d, 1H, J
) 16.1 Hz), 3.06 (d, 1H, J ) 8.6 Hz), 3.50 (m, 1H), 4.50 (m,
2H), 5.30 (m, 2H), 5.75 (m, 1H), 7.21-7.46 (m, 15H); 13C NMR
δ 20.0, 45.7, 58.2, 65.6, 71.4, 118.5, 127.2, 128.5, 129.3, 132.1,
+73.2 (c 0.343, CHCl3); H NMR δ 0.90 (d, 3H, J ) 6.2 Hz),
0.93 (d, 6H, J ) 6.6 Hz), 1.44 (m, 3H), 1.83 (m, 1H), 2.40 (m,
1H), 2.55 (m, 2H), 3.00 (br, 1H), 3.41 (m, 1H), 3.58 (s, 3H),
7.24-7.44 (two set of m, 15H); 13C NMR δ 17.2, 22.9, 23.4,
24.5, 33.9, 44.1, 44.7, 51.7, 59.6, 71.2, 126.4, 127.7, 129.1, 146.6,
176.4, 212.2; FTIR (neat) 2927, 1735, 1720 cm-1. Anal. Calcd
for C30H35O3N: C, 78.78; H, 7.71; N, 3.06. Found: C, 78.60;
H, 7.53; N, 2.98.
146.7, 166.9, 206.7; FTIR (neat) 2967, 1745, 1716, 709 cm-1
.
Anal. Calcd for C27H27O3N‚0.5H2O: C, 76.75; H, 6.68; N, 3.32.
Found: C, 77.15; H, 6.30; N, 2.97.
Allyl 4-tr ityla m in o-3-oxo-5-p h en ylp en ta n oa te, 8d : 70%
of a colorless oil after purification by flash chromatography
(hexane/ether ) 75:20); [R]25D +53.7 (c 0.659, CHCl3); 1H NMR
(keto form) δ 2.49 (d, 1H, J ) 16.3 Hz), 2.61 (d, 1H, J ) 16.3
Hz), 2.87 (m, 2H), 3.70 (m, 1H), 4.48 (m, 2H), 5.21 (m, 2H),
5.79 (m, 1H), 7.31 (m, 20H); 13C NMR (mixture of keto and
enol) δ 39.8, 45.9, 62.9, 64.6, 70.4, 117.7, 125.8, 127.1, 127.7,
128.2, 128.8, 129.2, 129.9, 130.9, 136.0, 143.7, 145.2, 163.8,
165.6, 204.8; FTIR (neat) 3057, 1750, 1715, 1492, 1158, 704
cm-1. Anal. Calcd for C33H31O3N: C, 80.95; H, 6.38; N, 2.86.
Found: C, 80.76; H, 6.46; N, 2.76.
(2R,5S)-Tr ityl-Leu Ψ[COCH2]Ch a -OMe, 6a b: yield 49%
of a colorless oil after purification by flash chromatography
(hexane/ether ) 85:5); de 85% based on 1H NMR; the major
1
diastereomer had ee >95%; [R]25 +29.1 (c 2.39, CHCl3); H
D
NMR δ 0.80 (d, 3H, J ) 6.6 Hz), 0.84 (d, 3H, J ) 8.8 Hz),
1.11-1.75 (set of m, 16H), 2.14 (d, 2H, J ) 6.8 Hz), 2.55 (m,
1H), 2.73 (br, 1H), 3.38 (m, 1H), 3.61 (s, 3H), 7.20-7.39 (two
set of m, 15H); 13C NMR δ 22.9, 23.9, 24.9, 26.5, 33.2, 33.8,
35.7, 37.4, 40.2, 41.7, 44.7, 51.8, 61.2, 71.8, 127.0, 128.3, 129.5,
146.6, 176.8, 212.5; FTIR (neat) 2927, 1735, 1720, 709 cm-1
.
Allyl 4-[(N-tr ityl)p yr r olid in e-2]-3-oxo-p r op a n oa te, 8e:
Anal. Calcd for C36H45O3N‚H2O: C, 77.52; H, 8.49; N, 2.51.
45% of a colorless oil after purification by flash chromatogra-
Found: C, 77.53; H, 8.24; N, 2.30.
1
phy (hexane/ether ) 85:10); [R]25 -33.1 (c 2.31, CHCl3); H
(2R,5S)-Tr ityl-MetΨ[COCH2]P h e-OMe, 6bc: yield 43%
of a white solid after purification by flash chromatography
(hexane/ether ) 85:5); de 91% based on 1H NMR; the major
D
NMR δ 1.17-1.45 (set of m, 4H), 2.93 (m, 2H), 3.43 (d, 1H, J
) 15.5 Hz), 3.72 (d, 1H, J ) 15.5 Hz), 4.08 (dd, 1H, J ) 2.9,
9.5 Hz), 4.63 (m, 2H), 5.30 (m, 2H), 5.85 (m, 1H), 7.19-7.53
(m, 15H); 13C NMR δ 24.2, 29.7, 46.2, 50.8, 65.8, 69.5, 87.7,
118.6, 126.3, 127.8, 129.2, 131.8, 144.8, 167.0, 206.1; FTIR
2947, 1745, 1716, 709 cm-1. Anal. Calcd for C29H29O3N: C,
79.24; H, 6.65; N, 3.19. Found: C, 79.22; H, 6.44; N, 3.03.
Allyl 4-tr ityla m in o-3-oxo-5-m eth ylh exa n oa te, 8f: 64%
of a colorless oil after purification by flash chromatography
diastereomer had ee >95%; mp 120-121 °C; [R]25 +70.0 (c
D
2.56, CHCl3); 1H NMR δ 1.99 (m, 2H), 2.11 (s, 3H), 2.29-2.53
(set of m, 5H), 2.80 (m, 2H), 3.12 (d, 1H, J ) 9.6 Hz), 3.50 (m,
1H), 3.56 (s, 3H), 7.05-7.41 (two set of m, 20H); 13C NMR δ
15.4, 29.2, 33.6, 37.8, 41.0, 41.4, 51.6, 59.9, 71.2, 16.4, 127.8,
128.5, 128.8, 138.3, 146.2, 174.9, 210.1; FTIR (neat) 2947, 1735,
1716, 709 cm-1. Anal. Calcd for C35H37O3NS: C, 76.19; H, 6.76;
N, 2.54. Found: C, 76.05; H, 6.68; N, 2.52.
(hexane/ether ) 85:10); [R]25 +67.9 (c 2.36, CHCl3); 1H NMR
D
δ 0.93 (d, 3H, J ) 7.0 Hz), 1.10 (d, 3H, J ) 7.0 Hz), 2.10 (m,
1H), 2.40 (d, 1H, J ) 16.5 Hz), 3.00 (d, 1H, J ) 16.5 Hz), 3.04
(d, 1H, J ) 9.8 Hz), 3.45 (dd, 1H, J ) 3.7, 9.8 Hz), 4.50 (m,
2H), 5.20 (m, 2H), 5.79 (m, 1H), 7.21-7.46 (m, 15H); 13C NMR
δ 18.9, 19.5, 32.5, 48.1, 65.8, 66.6, 71.4, 118.7, 127.0, 128.3,
129.5, 132.2, 146.8, 166.9, 205.5; FTIR (neat) 2967, 1745, 1716,
(2R,5S)-Tr ityl-Ala Ψ[COCH2]Leu -OMe, 6cd : yield 50%
of a colorless oil after purification by flash chromatography
(hexane/ether ) 85:5); de 90% based on 1H NMR; the major
1
diastereomer had ee >95%; [R]25 +40.0 (c 1.33, CHCl3); H
D
NMR δ 0.80 (d, 3H, J ) 10.6 Hz), 0.83 (d, 3H, J ) 10.7 Hz),
0.95 (m, 2H), 1.16 (d, 3H, J ) 7.0 Hz), 1.32 (m, 1H), 1.93 (dd,

Synthesis of Monofluoro Ketomethylene Dipeptide Isosteres
J . Org. Chem., Vol. 64, No. 1, 1999 131
1H, J ) 6.6, 17.9 Hz), 2.17 (dd, 1H, J ) 6.6, 17.9 Hz), 2.53 (m,
1H), 3.42 (m, 1H), 3.60 (s, 3H), 7.20-7.44 (two set o m, 15H);
13C NMR δ 19.3, 20.8, 21.7, 24.9, 25.5, 36.7, 40.2, 56.8, 70.3,
125.4, 127.9, 28.8, 145.2, 175.0, 211.0; FTIR (neat) 2957, 1735,
1720, 709 cm-1. Anal. Calcd for C30H35O3N‚0.5H2O: C, 77.22;
H, 7.78; N, 3.01. Found: C, 77.78; H, 7.36; N, 2.56.
ether ) 85:2.5): de >95% based on 1H NMR of the crude
product; [R]25 +65.2 (c 0.940, CHCl3); 1H NMR δ 0.84 (d, 3H,
D
J ) 6.6 Hz), 0.90 (d, 3H, J ) 6.5 Hz), 0.99 (d, 3H, J ) 5.7 Hz),
1.43 (m, 2H), 1.78 (m, 1H), 2.42 (m, 1H), 2.97 (d, 1H, J ) 8.0
Hz), 3.65 (s, 3H), 3.90 (m, 1H), 4.84 (dd, 1H, J ) 6.9, 46.6 Hz),
7.46-7.51 (two set of m, 15H); 13C NMR δ 11.7, 22.9, 23.3,
24.6, 40.2 (d, 2J ) 21.9 Hz), 43.4, 52.0, 71.2, 94.2 (d, 1J ) 187.7
(2R,5S)-Tr ityl-P h eΨ[COCH2]Nva -OMe, 6d e: yield 53%
2
of a colorless oil after purification by flash chromatography
Hz), 126.4, 127.8, 128.9, 146.2, 173.4, 209.5 (d, J ) 23.5 Hz);
(hexane/ether ) 85:10); de 92% based on 1H NMR; the major
FTIR (neat) 2947, 1740, 1726, 709 cm-1. Anal. Calcd for
1
diastereomer had ee >95%; [R]25 +52.2 (c 1.15, CHCl3); H
C30H34O3NF: C, 75.76; H, 7.21; N, 2.95. Found: C, 75.60; H,
D
NMR δ 0.77 (t, 3H, J ) 6.2 Hz), 1.04 (m, 4H), 1.68 (m, 2H),
2.25 (m, 1H), 2.77 (m, 2H), 3.60 (s, 3H), 3.56 (m, 1H), 7.17-
7.33 (m, 20H); 13C NMR δ 13.8, 20.1, 34.1, 39.0, 41.7, 43.0,
51.4, 63.5, 71.2, 126.6, 127.9, 128.0, 129.6, 146.2, 175.8, 212.2;
FTIR (neat) 2957, 1735, 1720, 709 cm-1. Anal. Calcd for
7.47; N, 2.76.
(2S,3S,5S)-Tr ityl-Leu Ψ[COCF H]Ch a -OMe, 11a b. The 1H
NMR of the intermediate TMS-enol ether shows only one
doublet in the vinyl region and one methoxy singlet: yield 73%
of a colorless oil together with about 27% recovered starting
material after flash chromatography (hexane/ether ) 85:2.5);
C
35H37O3N: C, 80.89; H, 7.18; N, 2.70. Found: C, 81.07; H,
7.15; N, 2.60.
de >95% based on 1H NMR of the crude product; [R]25 +51.3
D
1
(2R,5S)-Tr ityl-P r oΨ[COCH2]Ala -OMe, 6ea : yield 40% of
(c 2.52, CHCl3); H NMR δ 0.83 (d, 3H, J ) 6.6 Hz), 0.87 (d,
a colorless oil after purification by flash chromatography
3H, J ) 6.5 Hz), 0.92-1.80 (set of m, 16H), 2.57 (m, 1H), 2.93
(br, 1H), 3.64 (s, 3H), 3.84 (m, 1H), 4.41 (dd, 1H, J ) 7.7, 45.8
Hz), 7.26-7.49 (two set of m, 15H); 13C NMR δ 23.0, 26.2, 32.5,
(hexane/ether ) 85:10); de 85% based on 1H NMR; the major
1
diastereomer had ee >95%; [R]25 -18.8 (c 0.554, CHCl3); H
D
2
NMR δ 0.84-1.43 (set of m, 4H), 1.18 (d, 3H, J ) 6.8 Hz),
2.04 (m, 2H), 2.87-3.05 (two set of m, 3H), 3.34 (m, 1H), 3.68
(s, 3H), 7.24-7.52 (two set of m, 15H); 13C NMR δ 17.6, 24.6,
29.9, 34.5, 43.7, 50.8, 52.3, 69.0, 74.4, 126.6, 128.2, 128.7, 145.4,
176.8, 212.4; FTIR (neat) 2967, 1735, 1720, 714 cm-1. Anal.
Calcd for C29H31O3N‚0.5H2O: C, 77.30; H, 7.16; N, 3.11.
Found: C, 77.05; H, 7.34; N, 3.32.
33.5, 35.4, 43.6, 44.8 (d, J ) 20.2 Hz), 51.8, 56.5, 59.3, 71.2,
93.7 (d, 1J ) 187.7 Hz), 126.6, 128.0, 129.0, 146.3, 172.6, 209.1
(d, 2J ) 24.6 Hz); FTIR (neat) 2927, 1740, 1726, 704 cm-1
.
Anal. Calcd for C36H44O3NF‚0.5H2O: C, 75.99; H, 7.88; N, 2.36.
Found: C, 76.29; H, 8.00; N, 2.47.
(2S,3S,5S)-Tr ityl-MetΨ[COCF H]P h e-OMe, 11bc. The 1H
NMR of the intermediate TMS-enol ether shows only one
doublet in the vinyl region and one methoxy singlet: yield 65%
of a white solid together with about 30% recovered starting
material after flash chromatography (hexane/ethyl acetate )
85:2.5); de >95% based on 1H NMR of the crude product; mp
(2S,5S)-Tr ityl-Va lΨ[COCH2]Ala -OMe, 6ff: yield 55% of
a colorless oil after purification by flash chromatography
(hexane/ethyl acetate ) 85:2.5); de > 95% based on 1H NMR;
the major diastereomer had ee >95%; [R]25 +159.1 (c 0.933,
D
CHCl3); H NMR δ 0.90 (d, 3H, J ) 6.5 Hz), 0.93 (d, 3H, J )
124-126 °C; [R]25 +96.1 (c 1.68, CHCl3); 1H NMR δ 1.97-
1
D
6.8 Hz), 1.06 (d, 3H, J ) 6.9 Hz), 1.82 (dd, 1H, J ) 4.0, 17.8
Hz), 2.02 (m, 1H), 2.18 (dd, 1H, J ) 8.4, 17.8 Hz), 2.40 (m,
1H), 3.36 (m, 1H), 3.61 (s, 3H), 7.20-7.46 (two set of m, 15H);
13C NMR δ 15.7, 17.9, 31.4, 32.9, 43.7, 50.5, 64.4, 69.9, 125.4,
126.7, 128.1, 145.5, 175.0, 209.4; FTIR (neat) 2967, 1735, 1716,
709 cm-1. Anal. Calcd for C29H33O3N: C, 78.52; H, 7.50; N,
3.16. Found: C, 78.75; H, 7.34; N, 3.05.
2.28 (m, 2H), 2.18 (s, 3H), 2.47 (m, 1H), 2.67-2.92 (m, 2H),
3.01-3.13 (m, 2H), 3.59 (s, 3H), 4.02 (m, 1H), 4.92 (dd, 1H, J
) 9.0, 47.1 Hz), 7.08-7.42 (set of m, 20H); 13C NMR δ 15.4,
2
28.8, 32.3, 33.2, 47.6 (d, J ) 14.6 Hz), 52.0, 56.7, 71.1, 92.1
(d, 1J ) 185.3 Hz), 126.4, 127.0, 127.7, 128.8, 137.5, 146.1,
2
170.8, 210.1 (d, J ) 21.0 Hz); FTIR (neat) 2967, 1740, 1726,
709 cm-1. Anal. Calcd for C35H36O3NSF: C, 73.79; H, 6.37; N,
2.46. Found: C, 73.64; H, 6.48; N, 2.35.
(2S,5S)-Tr ityl-Ser (OBn )Ψ[COCH2]Leu -OMe, 6gg: yield
50% of a colorless oil after purification by flash chromatogra-
(2S,3S,5S)-Tr ityl-Ala Ψ[COCF H]Leu -OMe, 11cd . The 1H
NMR of the intermediate TMS-enol ether shows only one
doublet in the vinyl region and one methoxy singlet: yield 75%
of a colorless oil together with about 25% recovered starting
1
phy (hexane/ethyl acetate ) 85:15); de 90% based on H NMR;
the major diastereomer had ee >95%; [R]25 +60.5 (c 0.887,
D
1
CHCl3); H NMR δ 0.76 (d, 6H, J ) 6.2 Hz), 0.82 (d, 3H, J )
6.4 Hz), 0.95 (m, 2H), 1.33 (m, 1H), 1.92 (dd, 1H, J ) 6.2, 17.9
Hz), 2.48 (dd, 1H, J ) 6.2, 17.9 Hz), 2.59 (m, 1H), 3.20 (m,
1H), 3.57 (m, 2H), 3.62 (s, 1H), 4.38 (s, 2H), 7.20-7.44 (two
set of m, 20H); 13C NMR δ 20.8, 21.8, 24.9, 36.8, 40.2, 42.8,
50.4, 60.4, 70.0, 71.8, 72.4, 125.5, 126.8, 127.9, 145.2, 175.2,
210.8; FTIR (neat) 2957, 1735, 1716, 730 cm-1. Anal. Calcd
for C37H41O3N: C, 78.83; H, 7.33; N, 2.48. Found: C, 78.73;
H, 7.09; N, 2.45.
material after flash chromatography (hexane/ethyl acetate )
1
85:2.5); de >95% based on H NMR of the crude product; [R]25
D
+39.6 (c 1.88, CHCl3); 1H NMR δ 0.84 (d, 6H, J ) 4.8 Hz),
1.20 (d, 3H, J ) 7.0 Hz), 1.11-1.56 (m, 3H), 2.51 (m, 1H), 3.06
(br, 1H), 3.64 (s, 3H), 3.90 (m, 1H), 4.54 (dd, 1H, J ) 7.8, 46.0),
7.23-7.50 (two set of m, 15H); 13C NMR δ 21.9, 25.0, 28.7,
2
1
30.1, 35.7, 44.4 (d, J ) 16.2 Hz), 50.7, 56.9, 70.2, 91.9 (d, J
2
) 189.3 Hz), 125.4, 126.0, 127.7, 145.2, 171.2, 208.8 (d, J )
(2S,3S,5S)-Tr ityl-Leu Ψ[COCF H]Ala -OMe, 11a a . Gen -
er a l P r oced u r e. At -78 °C, NaHMDS (2.0 M in THF, 0.27
mL, 0.54 mmol) was added to a solution of 6a a (190 mg, 0.41
mmol) in THF (20 mL). After 3.5 h at the same temperature,
TMSCl (0.1 mL, 0.51 mmol) in THF (10 mL) was added. The
resulting solution was warmed to rt for 1 h and then taken
up into hexanes (150 mL), washed with ice-cold saturated
aqueous sodium bicarbonate (20 mL), dried (Na2SO4), filtered,
and concentrated to provide a residue. The 1H NMR of the
yellow residue showed only one doublet in the vinyl region and
one methoxy singlet. This indicated that only a single enol
ether isomer was formed. Under nitrogen, the residue was
suspended into DMF (3 mL), cooled to -50 °C, and treated
with Selectfluor (150 mg, 0.42 mmol) in DMF (3 mL). After
15 min, the solution was reacted with TBAF ((Bu)4N+F-) (1.0
M in THF, 0.42 mL, 0.42 mmol). The resulting mixture was
warmed to rt for 45 min, treated with cold aqueous NaHCO3
(0.5 M, 10 mL), extracted with ether (50 mL × 2), dried
(MgSO4), and concentrated to provide 11a a as a colorless oil
(157 mg, 0.33 mmol, 76%) and a second component shown to
be diastereomerically pure starting material 6a a (about 24%)
after a careful separation by flash chromatography (hexane/
25.0 Hz); FTIR (neat) 2967, 1740, 1730, 704 cm-1. Anal. Calcd
for C30H34O3NF: C, 75.76; H, 7.21; N, 2.95. Found: C, 75.61;
H, 7.40; N, 2.76.
(2S,3S,5S)-Tr ityl-P h eΨ[COCF H]Nva -OMe, 11d e. The 1H
NMR of the intermediate TMS-enol ether shows only one
doublet in the vinyl region and one methoxy singlet. Yield 68%
of a colorless oil together with about 32% recovered starting
material after flash chromatography (hexane/ethyl acetate )
1
85:2.5); de >95% based on H NMR of the crude product; [R]25
D
+86.0 (c 3.36, CHCl3); 1H NMR δ 0.88 (t, 3H, J ) 7.4 Hz),
1.23 (m, 2H), 1.52 (m, 2H), 2.44-2.74 (two set of m, 2H), 3.07
(m, 2H), 3.59 (s, 3H), 4.20 (m, 1H), 4.65 (dd, 1H, J ) 8.9, 50.0
Hz), 7.11-7.40 (set of m, 20H); 13C NMR δ 12.6, 19.1, 28.5,
38.1, 45.0 (d, 2J ) 19.4 Hz), 50.7, 58.2, 69.6, 92.7 (d, 1J ) 183.7
Hz), 125.3, 125.7, 126.7, 127.3, 128.0, 129.6, 137.2, 145.2,
2
170.7, 209.6 (d, J ) 26.7 Hz); FTIR (neat) 2957, 1740, 1726,
709 cm-1. Anal. Calcd for C35H36O3NF‚0.5H2O: C, 76.90; H,
6.82; N, 2.56. Found: C, 76.52; H, 6.53; N, 2.48.
1
(2R,3R,5S)-Tr ityl-Va lΨ[COCF H]Ala -OMe, 13ff. The H
NMR of the intermediate TMS-enol ether shows only one
doublet in the vinyl region and one methoxy singlet: yield 71%
of a colorless oil together with about 29% recovered starting

132 J . Org. Chem., Vol. 64, No. 1, 1999
Hoffman and Tao
material after flash chromatography (hexane/ethyl acetate )
0.76 (d, 3H, J ) 6.4 Hz),1.29-1.56 (m, 3H), 2.81 (m, 1H), 3.68
(m, 2H), 3.63 (S, 3H), 4.20 (m, 1H), 4.48 (d, 1H, J ) 3.3 Hz),
4.53 (d, 1H, J ) 3.3 Hz), 4.56 (dd, 1H, J ) 4.8, 46.0 Hz), 7.26-
7.55 (two set of m, 20H); 13C NMR δ 20.0, 22.3, 24.7, 35.1, 44.0
(d, 2J ) 20.2 Hz), 50.7, 56.0, 69.8, 71.1, 72.2, 93.9 (d, 1J ) 188.9
Hz), 125.5, 126.5, 127.8, 136.7, 145.1, 171.4, 205.7 (d, 2J ) 28.8
1
85:2.5); de 1.2:1.0 based on H NMR of the crude product. The
major diastereomer (2R,3R,5S) has the following character-
1
istics: [R]25 +51.6 (c 1.23, CHCl3); H NMR δ 0.93 (d, 3H, J
D
) 7.0 Hz), 1.00 (d, 3H, J ) 7.3 Hz), 1.04 (d, 3H, J ) 6.9 Hz),
1.94 (m, 1H), 2.40 (m, 1H), 3.68 (s, 3H), 4.04 (m, 1H), 4.58
(dd, 1H, J ) 8.7, 46.0 Hz), 7.26-7.55 (two set of m, 15H); 13
C
Hz); FTIR (neat) 2957, 1735 (br), 704 cm-1
.
NMR δ 12.2, 16.2, 19.1, 31.0, 40.6 (d, 2J ) 19.4 Hz), 50.9, 61.5,
69.6, 93.1 (d, 1J ) 182.0 Hz), 125.4, 126.7, 128.1, 145.3, 171.8,
207.2 (d, 2J ) 27.4 Hz); FTIR (neat) 2967, 1740, 1726, 704
cm-1. Anal. Calcd for C29H32O3NF: C, 75.46; H, 6.99; N, 3.03.
Found: C, 75.66; H, 7.17; N, 2.98. The minor (2R,3S,5S)
diastereomer has the following characteristics: 1H NMR δ 0.86
(d, 3H, J ) 7.0 Hz), 0.97 (d, 3H, J ) 6.6 Hz), 1.24 (d, 3H, J )
6.9 Hz), 1.96 (m, 1H), 2.71 (m, 1H), 3.66 (S, 3H), 3.95 (m, 1H),
3.96 (dd, 1H, J ) 4.6, 46.3 Hz), 7.26-7.55 (two set of m, 15H);
(2S,3R,5S)-Tr ityl-Leu Ψ[COCF H]Ala -OMe, 11a a . Gen -
er a l P r oced u r e. The same procedure was used with 6a a
except that the base was changed to LDA and the enolate was
1
generated at 0 °C. The H NMR of the intermediate TMS-enol
ether shows two pairs of doublets in the vinylic region and
two methoxy singlets. The ratio is 2.0:1.0, and the signals of
the minor isomer are identical to those of (Z)-TMS-enol ether
10a a . The major isomer was assigned as (E)-TMS enol ether
14a a . Fluorination of the mixture was carried out as described
above: yield 60% of a colorless oil together with about 40%
recovered starting material after flash chromatography (hex-
ane/ethyl ether ) 85:2.5); de 2.0:1.0 base on 1H NMR of the
crude product. The major diastereomer (2S,3R,5S) has the
2
13C NMR δ 9.87, 14.8, 20.2, 28.5, 39.8 (d, J ) 21.0 Hz), 51.0,
1
59.9, 69.3, 93.8 (d, J ) 182.9 Hz), 125.4, 126.7, 128.2, 145.4,
2
171.7, 208.9 (d, J ) 26.3 Hz); FTIR (neat) 2967, 1740, 1726,
704 cm-1
.
(2R,3R,5S)-Tr ityl-Ser (OBn )Ψ[COCF H]Leu -OMe, 11gg.
following characteristics: [R]25 +59.9 (c 0.546, CHCl3); 1H
D
1
The H NMR of the intermediate TMS-enol ether shows only
NMR δ 0.84 (d, 3H, J ) 4.0 Hz), 0.90 (d, 3H, J ) 4.5 Hz), 0.97
(d, 3H, J ) 6.2 Hz), 1.52 (m, 2H), 1.78 (m, 1H), 2.53 (m, 1H),
2.93 (br, 1H), 3.65 (s, 3H), 3.87 (m, 1H), 4.61 (dd, 1H, J ) 5.4,
45.0 Hz), 7.21-7.50 (two set of m, 15H); 13C NMR δ 17.0, 27.6,
one doublet in the vinyl region and one methoxy singlet: yield
74% of a colorless oil together with about 26% recovered
starting material after flash chromatography (hexane/ethyl
acetate ) 85:5); de 1.8:1.0 based on 1H NMR of the crude
2
27.8, 29.1, 46.0 (d, J ) 20.2 Hz), 47.8, 56.4, 63.7, 75.7, 98.9
product. The major diastereomer (2R,3R,5S) has the following
1
(d, J ) 186.7 Hz), 130.9, 132.4, 133.4, 150.7, 176.6, 202.8 (d,
1
characteristics: [R]25 +46.1 (c 1.04, CHCl3); H NMR δ 0.84
D
2J ) 22.4 Hz); FTIR (neat) 2947, 1740, 1726, 709 cm-1. Anal.
Calcd for C30H34O3NF‚0.5H2O: C, 71.69; H, 7.42; N, 2.79.
Found: C, 71.67; H, 7.27; N, 2.66.
(d, 6H, J ) 5.9 Hz), 1.27-1.47 (m, 3H), 2.62 (m, 1H), 3.24 (m,
2H), 3.64 (s, 3H), 4.17 (m, 1H), 4.41 (d, 1H, J ) 3.1 Hz), 4.44
(d, 1H, J ) 3.1 Hz), 4.63 (dd, 1H, J ) 7.8, 45.8 Hz), 7.25-7.49
(two set of m, 20H); 13C NMR δ 20.6, 22.0, 25.0, 35.8, 44.3 (d,
1
2J ) 20.2 Hz), 50.7, 58.4, 69.9, 70.6, 72.1, 92.6 (d, J ) 186.3
Ack n ow led gm en t. The authors would like to thank
the National Science Foundation for support of this
work (CHE 9520431) and Air Products and Chemicals
for the Selectfluor used in this work.
Hz), 125.6, 127.0, 127.7, 136.8, 145.0, 171.3, 205.6 (d, 2J ) 27.4
Hz); FTIR (neat) 2957, 1735 (br), 704 cm-1. Anal. Calcd for
C
37H40O4NF: C, 76.39; H, 6.93; N, 2.41. Found: C, 76.19; H,
7.05; N, 2.42. The minor (2R,3S,5S) diastereomer has the
following characteristics: 1H NMR δ 0.65 (d, 3H, J ) 6.4 Hz),
J O981334Y