Enantiomerically Pure Highly Functionalized α-Amino Ketones from the Reaction of Chiral Cyclic N-(9-Phenylfluoren-9-yl) α-Amido Esters with Organolithium Reagents

Article abstract of DOI:10.1021/jo970277q

The reaction of methyl N-(9-phenylfluoren-9-yl)pyroglutamate with several organolithium reagents afforded the corresponding ketones in excellent yields and with complete retention of enantiomeric purity. The success of this transformation is due to the unusual stability of the tetrahedral intermediates 5, which stems from two factors: the electron-withdrawing effect of the amide nitrogen and the lithium complexing ability of the fluorenyl ring of the 9-phenylfluoren-9-yl group. This ester-to-ketone transformation was also successfully applied to oxazolidinone 9 and imidazolidinone 20 and provided a ketone (21b) that was ultimately transformed into the urea-lactam 26 which incorporates the bicyclic core of streptolidine lactam, a component of the streptrothricin antibiotics.

Full text of DOI:10.1021/jo970277q

4770
J . Org. Chem. 1997, 62, 4770-4779
En a n tiom er ica lly P u r e High ly F u n ction a lized r-Am in o Keton es
fr om th e Rea ction of Ch ir a l Cyclic N-(9-P h en ylflu or en -9-yl)
r-Am id o Ester s w ith Or ga n olith iu m Rea gen ts
Eduardo Ferna´ndez-Meg´ıa, J ose´ M. Iglesias-Pintos, and F. J avier Sardina*,†
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received February 14, 1997X
The reaction of methyl N-(9-phenylfluoren-9-yl)pyroglutamate with several organolithium reagents
afforded the corresponding ketones in excellent yields and with complete retention of enantiomeric
purity. The success of this transformation is due to the unusual stability of the tetrahedral
intermediates 5, which stems from two factors: the electron-withdrawing effect of the amide nitrogen
and the lithium complexing ability of the fluorenyl ring of the 9-phenylfluoren-9-yl group. This
ester-to-ketone transformation was also successfully applied to oxazolidinone 9 and imidazolidinone
20 and provided a ketone (21b) that was ultimately transformed into the urea-lactam 26 which
incorporates the bicyclic core of streptolidine lactam, a component of the streptrothricin antibiotics.
In tr od u ction
N-Pf-glutamate system we treated dimethyl N-Pf-
glutamate (1)7 with n-BuLi under a variety of conditions.
When 100 mol % of n-BuLi was used (THF, -78 °C, 2 h),
methyl N-Pf-pyroglutamate 3a was obtained as the major
product (57%) along with recovered 1 (30%). Under more
drastic conditions [n-BuLi (200 mol %), THF, -78 °C, 24
h], pyroglutamate 3a (28%) and ketone 4d (53%) were
obtained as major products. Therefore, the abstraction
of the NH in 1 was followed by amide attack to the
ω-ester to give 3a , which then would react through its
remaining ester group with the excess organolithium
reagent to give ketone 4d . No traces of the corresponding
tertiary alcohol were detected in the crude reaction
product. Due to the surprising chemoselectivity of this
process, we decided to study further the transformation
of pyroglutamate 3a into ketones 4.
With this idea in mind, a more convenient method for
furnishing the methyl N-Pf-pyroglutamate (3a ) was
explored. Thus, 3a was readily prepared from 1 by
selective hydrolysis of the ω-ester (LiOH, dioxane-H2O,
0 °C) and cyclization of the resulting amino acid (2) with
TsCl in pyridine (91% overall yield).8 When 3a was
treated with several organolithium reagents (THF, -78
°C),9 ketones 4a -c were obtained in excellent yields;
traces of the corresponding tertiary alcohols were isolated
only from the reaction of 3a with MeLi (Scheme 1).
The success of this transformation is due to the
unusual stability of the tetrahedral intermediates 5,
which we attribute to two factors: the electron-with-
drawing effect of the amide nitrogen and the lithium
complexing ability of the fluorenyl ring of the 9-phen-
ylfluoren-9-yl group.10 Thus, when we studied the re-
actions of N-benzylpyroglutamate 3b (poorer Li+ coor-
dinating ability) and N-Pf-proline methyl ester (lower
electron-withdrawing effect) with MeLi, substantial
It is well-known that the reactions of organolithium
and organomagnesium reagents with carboxylic acid
esters initially lead to ketones which, being more elec-
trophilic than the starting esters, undergo a second
nucleophilic addition to give tertiary alcohols. In most
cases it is not possible to stop these reactions at the
ketone stage due to the instability of the tetrahedral
intermediates resulting from the addition of the organo-
metallic reagent to the carboxyl group.1 In those in-
stances where the tetrahedral alkoxide intermediate is
stabilized by intramolecular complexation of the metal
counterion (N-alkoxyamides),2 or by the use of very poor
leaving groups attached to the carbonyl group (lithium
carboxylates),3 or by electron-withdrawal from the car-
bonyl carbon (R-diesters4 or R-polyhalo esters),4,5 acyla-
tions of organolithium nucleophiles to give ketones can
be carried out successfully. We report herein our seren-
dipitous discovery that certain chiral cyclic N-(9-phen-
ylfluoren-9-yl)-R-amido esters react with organolithium
reagents to give the corresponding enantiomerically pure
ketones in excellent yields.
Resu lts a n d Discu ssion
We have recently reported that dimethyl N-(9-phen-
ylfluoren-9-yl)aspartate can be selectively N-deproto-
nated with n-BuLi (100 mol %, THF, -78 °C) and that
advantage could be taken of this behavior to stereose-
lectively prepare 3-hydroxyaspartate derivatives.6 In an
attempt to extend this methodology to the closely related
† Fax: +34-81-595012. e-mail: qojskd@usc.es.
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) O’Neill, B. T. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 398-399.
(2) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(3) (a) Masamune, S.; Choy, W.; Kerdesky, F. A. J .; Imperiali, B. J .
Am. Chem. Soc. 1981, 103, 1566. (b) Rubottom, G. M.; Kim, C. J . Org.
Chem. 1983, 48, 1550. (c) Buckley, T. F., III; Rapoport, H. J . Am.
Chem. Soc. 1981, 103, 6157. (d) Knudsen, C. G.; Rapoport, H. J . Org.
Chem. 1983, 48, 2260.
(7) (a) Koskinen, A. M. P.; Rapoport, H. J . Org. Chem. 1989, 54,
1859. (b) Wolf, J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164.
(8) Brewster, J . H.; Ciotti, C. J ., J r. J . Am. Chem. Soc. 1955, 77,
6214.
(9) (Chloromethyl)lithium was prepared in situ by following a
literature procedure.5
(4) Creary, X. J . Org. Chem. 1987, 52, 5026.
(10) (a) Posner, G. H.; Lentz, C. M. J . Am. Chem. Soc. 1979, 101,
934. (b) Brooks, J . J .; Rhine, W.; Stucky, G. D. J . Am. Chem. Soc.
1972, 94, 7339. (c) Taft, R. W.; Anvia, F.; Gal, J .-F.; Walsh, S.; Capon,
M.; Holmes, M. C.; Hosn, K.; Oloumi, G.; Vasanwala, R.; Yazdani, S.
Pure Appl. Chem. 1990, 62, 17. (d) Staley, R. H.; Beauchamp, J . L. J .
Am. Chem. Soc. 1975, 97, 5920.
(5) (a) Barluenga, J .; Llavona, L.; Concello´n, J . M.; Yus, M. J . Chem.
Soc., Perkin Trans. 1 1991, 297. (b) Barluenga, J .; Baragan˜a, B.;
Concello´n, J . M. J . Org. Chem. 1995, 60, 6696 and references therein.
(6) Fernandez-Meg´ıa, E.; Paz, M. M.; Sardina, F. J . J . Org. Chem.
1994, 59, 7643.
S0022-3263(97)00277-6 CCC: $14.00 © 1997 American Chemical Society

Enantiomerically Pure Highly Functionalized R-Amino Ketones
J . Org. Chem., Vol. 62, No. 14, 1997 4771
Sch em e 1
Sch em e 2
behavior of more complex systems, such as oxazolidinone
9 and imidazolidinone 16.6 In these systems the electron-
withdrawing X-CO (X ) O, NR) group is R to the
electrophile but, since we expected that the most exposed
carboxylate (at C-5) would be preferentially attacked by
the organolithium reagent, the N-Pf group would be â to
the electrophile. Molecular models as well as semiem-
pirical (MNDO) calculations on model systems showed
that intramolecular Pf‚‚‚Li complexation would still be
possible in the tetrahedral adducts obtained from 9 and
16. Thus, when oxazolidinone 9 was treated with several
organolithium reagents15,16 (THF, -78 °C), ketones 10a-d
were obtained in good to excellent yields. The corre-
sponding tertiary alcohols were not detected in the crude
products of these reactions; however it was very difficult
to avoid the formation of small amounts of diketones 11,
resulting from the addition of the RLi to both ester groups
of 9. For example, when 9 was treated with an excess of
PhLi (325 mol %), diketone 11 (R ) Ph) was obtained as
the major product in a 11 (R ) Ph):10c, ratio of 4.5:1.
Even in this instance no traces of the corresponding
tertiary alcohols were detected in the crude product. The
intermediate resulting from the addition of the organo-
lithium reagent to the carboxylate at C-5 of 9 is appar-
ently stable in the reaction medium, which allows the
formation of the corresponding ketone as the only product
even in this system where the reacting ester is â to the
NPf group.
amounts (>20% yields at incomplete conversions) of the
corresponding tertiary alcohols were isolated in both
cases.11
A key point in the preparation of ketones 4a -c is the
question of the enantiomeric purity of the products. This
question was addressed by stereoselective reduction of
ketone 4a with L-selectride (150 mol %, THF, -78 to -25
°C, quantitative)12 and coupling of the resulting alcohol
(6, only one stereoisomer detected) with both L- and D,L-
N-benzenesulfonylproline (DCC, DMAP, CH2Cl2, 95%) to
give esters 7a and 7b (mixture of diatereoisomers). 1H
NMR analysis of mixtures of 7a and 7b of known
composition showed that 6, and therefore 4a , had a ratio
of enantiomers (er) >99.5/0.5. The configuration of the
newly created stereocenter in 6 was established by
acylation of the OH group with both (R)- and (S)-
methoxyphenylacetic acids. The diastereomeric esters 8a
and 8b were obtained in 98% and 93% yields, respectively
(Scheme 2). The application of the Trost-Mosher method
for the determination of the absolute configuration of
secondary alcohols to esters 8a and 8b led us to assign
the S configuration to C1′′ in 6.13,14
In order to further study the generality of the above
observations, and to provide access to heavily function-
alized amino acid derivatives, we decided to study the
The chemoselectivity of the formation of ketones 10
was established by reduction of ketone 10d with LiBH4
(150 mol %, THF-i-PrOH, -78 to -30 °C) and analysis
1
of the H-5 signal in the H NMR spectra of the resulting
pure alcohols, which is always at lower field than that
of H-4. 1H NMR (δ, mult, J ) major isomer, H-5 (4.33,
dd, J ) 3.4 and 5.2 Hz), H-4 (3.90, d, J ) 3.4 Hz); minor
isomer, H-5 (4.35, t, J ) 3.6 Hz), H-4 (4.10, d, J ) 3.8
Hz).17
The higher electron-withdrawing effect of O vs N in 9
than in 3a , or a possible intramolecular complexation
Li‚‚‚O (at C-5), is not responsible for the success of this
(11) Correa, J . F.; Ferna´ndez-Meg´ıa, E.; Sardina, F. J . Unpublished
results.
(12) Other reducing agents tested were (diastereomeric ratio, reac-
tion conversion in percent): NaBH4 (80:20, 100), DIBAL-H (91:9, 70),
K-Selectride (>99:1, 45), Super-Hydride (>99:1, 100), where 6 was
always the major product.
(13) (a) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;
Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,
S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370. (b) Seco, J . M.;
Latypov, Sh.; Quin˜oa´, E.; Riguera, R. Tetrahedron Lett. 1994, 35, 2921.
(c) Seco, J . M.; Latypov, Sh.; Quin˜oa´, E.; Riguera, R. Tetrahedron:
Asymmetry 1995, 6, 107. (d) Latypov, Sh. K.; Seco, J . M.; Quin˜oa´, E.;
Riguera, R. J . Org. Chem. 1995, 60, 504. (e) Latypov, Sh. K.; Seco, J .
M.; Quin˜oa´, E.; Riguera, R. J . Org. Chem. 1996, 61, 8569.
(14) The observed stereoselection is consistent with the Felkin-Anh
rule for reductions occurring through a nonchelated transition state:
Seyden-Penne, J . Reductions by the Alumino- and Borohydrides in
Organic Synthesis; VCH: New York; 1991; pp 47-52.
(15) [(Methoxymethoxy)methyl]lithium was prepared by following
a literature procedure: J ohnson, C. R.; Medich, J . R. J . Org. Chem.
1988, 53, 4131.
(16) [p-[(tert-Butyldimethylsilyl)oxy]phenyl]lithium was prepared
following a literature procedure: Kurokawa, N.; Ohfune, Y. Tetrahe-
dron 1993, 49, 6195.

4772 J . Org. Chem., Vol. 62, No. 14, 1997
Ferna´ndez-Megia et al.
Sch em e 3
Sch em e 4
Sch em e 5
of the desired ketone 17 and the tertiary alcohol 18 was
always obtained. We thought that 18 could result from
either incomplete NH deprotonation prior to the addition
of the organolithium reagent to the C-5 ester (resulting
in the protonation of the intermediate by the residual
NH) or to the instability of a doubly (N-Li and O-Li)
lithiated intermediate.
reaction, since when carbonate (12) or dimethyl acetal
(13) derivatives (Scheme 3) were treated under similar
conditions, the corresponding tertiary alcohols were
detected along with other products.18
To avoid this undesired side reaction we proceeded to
synthesize the N-benzylimidazolidinone 20. Due to the
low yields of the direct benzylation of 16 (base, BnBr),
we decided to prepare 20 by benzylation of the 3-ami-
noaspartate synthetic precursor of 16.22 Mild hydrogena-
tion of 19 [H2 (1 atm), Pd/BaCO3], followed by N-monoben-
zylation (BnBr, Na2CO3, CH2Cl2-H2O, reflux)23 and
cyclization of the resulting diamine with Cl2CO (DMAP,
pyridine, 70 °C),6 provided 20 in 83% overall yield
(Scheme 5).
When 20 was treated with several organolithium
reagents9,24 (THF, -78 °C), ketones 21a -e were obtained
in good to excellent yields. In no instances the corre-
sponding tertiary alcohols were detected in the crude
reaction products.22 Therefore the protection of the NH
had resulted in a stabilization of the intermediate result-
ing from the addition of the organolithium to the C-5
carboxylate of 20, which allowed the formation of the
corresponding ketone as the only product, as in the
previous cases.
Dialkoxy ketone 10b is an advanced intermediate in
the synthesis of polioxamic acid (14), present as 5-O-
carbamoylpolioxamic acid in the polioxins, a family of
antifungal antibiotics widely used in agriculture;19 while
phenoxy ketone 10d is a precursor of (2S,3S,4R)-3,4-
dihydroxyhomotyrosine (15), a component of the cyclic
hexapeptidic antibiotic Echinocandin B20 and other re-
lated natural products,16 which present a great activity
against Candida albicans.16,21
Imidazolidinone 16 proved to be a more demanding
system due to the presence of the acidic NH proton. We
tried to optimize the formation of ketone 17 by using
MeLi (THF, -78 °C) as the nucleophile (Scheme 4).
Under all the reaction conditions tried, a ∼1:1 mixture
(17) The chemical shift of the CO2Me group R to the N-Pf always
appears at higher field (∼0.4 ppm) than the one at position â in N-Pf
aspartic acid diesters, due to the shielding effect of the fluorenyl ring:
Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M. Y.; Rapoport, H. J . Org.
Chem. 1990, 55, 3068 and ref 6. The disappearance of the lower field
methoxyl singlet when 9 (δ 3.72 and 3.29 ppm) and 20 (δ 3.54 and
3.18 ppm) are transformed into the corresponding ketones [i.e., 10a , δ
3.28 ppm; 10c, δ 3.19 ppm; 21a , δ 3.28 ppm; 21d , δ 3.16 ppm) provides
further proof of the regiochemistry of the reaction.
The highly functionalized ketone 21b is an atractive
advanced intermediate in the synthesis of the bicycle
streptolidine lactam (27), a guanidinelactam which forms
the core of the streptothricin antibiotics, a family of
potent antibiotics isolated from microbial sources.25-29
(18) Correa, J . F.; Sardina, F. J . Unpublished results.
(19) (a) Isono, K.; Suzuki, S. Heterocycles 1979, 13, 333. (b) Saksena,
A. K.; Lovey, R. G.; Girijavallabhan, V. M.; Ganguly, A. K. J . Org.
Chem. 1986, 51, 5024 and references therein.
(20) (a) Benz, F.; Knu¨sel, F.; Nu¨esch, J .; Treichler, H.; Voser, W.;
Nyfeler, R.; Keller-Schierlein, W. Helv. Chim. Acta 1974, 57, 2459. (b)
Traber, R.; Keller-J usle´n, C.; Loosli, H.-R.; Kuhn, M.; von Wartburg,
A. Helv. Chim. Acta 1979, 62, 1252.
(22) Ferna´ndez-Meg´ıa, E.; Sardina, F. J . Tetrahedron Lett. 1997,
38, 673.
(21) (a) Balkovec, J . M.; Black, R. M.; Hammond, M. L.; Heck, J .
V.; Zambias, R. A.; Abruzzo, G.; Bartizal, K.; Kropp, H.; Trainor, C.;
Schwartz, R. E.; McFadden, D. C.; Nollstadt, K. H.; Pittarelli, L. A.;
Powles, M. A.; Schmatz, D. M. J . Med. Chem. 1992, 35, 194. (b)
Bouffard, F. A.; Zambias, R. A.; Dropinski, J . F.; Balkovec, J . M.;
Hammond, M. L.; Abruzzo, G. K.; Bartizal, K. F.; Marrinan, J . A.;
Kurtz, M. B.; McFadden, D. C.; Nollstadt, K. H.; Powles, M. A.;
Schmatz, D. M. J . Med. Chem. 1994, 37, 222. (c) Debono, M.; Turner,
W. W.; LaGrandeur, L.; Burkhardt, F. J .; Nissen, J . S.; Nichols, K. K.;
Rodriguez, M. J .; Zweifel, M. J .; Zeckner, D. J .; Gordee, R. S.; Tang,
J .; Parr, T. R., J r. J . Med. Chem. 1995, 38, 3271 and references therein.
(23) Yamazaki, N.; Kibayashi, C. J . Am. Chem. Soc. 1989, 111, 1396.
(24) 1-Ethoxy-1-lithioethene was prepared by following a literature
procedure: (a) Angelastro, M. R.; Peet, N. P.; Bey, P. J . Org. Chem.
1989, 54, 3913. (b) Soderquist, J . A.; Hsu, G. J .-H. Organometallics
1982, 1, 830.
(25) Carter, H. E.; Clark, R. K., J r.; Kohn, P.; Rothrock, J . W.; Taylor,
W. R.; West, C. A.; Whitfield, G. B.; J ackson, W. G. J . Am. Chem. Soc.
1954, 76, 566.
(26) Nakanishi, K.; Ito, T.; Hirata, Y. J . Am. Chem. Soc. 1954, 76,
2845.
(27) Brockmann, H.; Musso, H. Chem. Ber. 1955, 88, 648.

Enantiomerically Pure Highly Functionalized R-Amino Ketones
J . Org. Chem., Vol. 62, No. 14, 1997 4773
Sch em e 6
dioxane-H2O) followed by azide reduction (H2, Pd/C,
p-TsOH‚H2O) and cyclization of the resulting amino acid
with diphenyl phosphoryl azide (Et3N, DMF, 0 °C to rt,
56% yield from 22).34,35 Treatment of 25 with TFA
(CH2Cl2, rt)36 led to the monoprotected urea-lactam 26
in a 84% yield. Studies to complete the synthesis of
streptolidine lactam (27) and its epimer in the C-7
position (from alcohol 23) are in progress.
Con clu sion
We have described that certain N-Pf-R (or â)-amino
esters react with organolithium reagents leading to the
corresponding ketones in good to excellent yields. The
resulting highly functionalized ketones are attractive
synthetic precursors of interesting natural products; thus,
ketone 19b has been transfomed into the urealactam 26
which posesses the bicyclic structure present in strepto-
lidine lactam (27). Studies to extend this methodology
to other related cyclic and acyclic N-Pf-amino esters are
in progress.
Exp er im en ta l Section
Gen er a l. All the reactions were carried out under an
atmosphere of dry argon, unless otherwise noted. Tetrahy-
drofuran (THF) was distilled from sodium/benzophenone im-
mediately before use; methylene chloride, triethylamine,
CH3CN, pyridine, DMF, and HCO2Et were distilled from CaH2;
methanol was distilled from magnesium; and acetone was
distilled from CaCO3. Column chromatography was performed
with 230-400 (low-pressure chromatography) mesh silica gel
unless otherwise noted. Thin-layer chromatography (TLC)
was done on silica 60/F-254 aluminum-backed plates (E.
Merck). Melting points are uncorrected. 1H NMR spectra
were recorded on a Bruker WM-250 MHz or Bruker AMX-500
MHz spectrometer in CDCl3 unless otherwise noted. Chemical
shifts are reported in ppm (δ units) downfield from internal
tetramethylsilane or the appropriate solvent signal [CD2Cl2,
CD3OD, or (CD3)2CO].
(2S)-5-Oxo-1-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r -
boxylic Acid Meth yl ester (3a ): LiOH‚H2O (4881 mg,
116.32 mmol) was added to a solution of 1 (3448 mg, 8.31
mmol) in dioxane (96 mL)/H2O (70 mL, deoxygenated with Ar)
at 0 °C. The resulting solution was stirred at 0 °C for 2 h 30
min and then acidified to pH ) 2 with HCl (5%) and allowed
to reach room temperature. The aqueous phase was extracted
with EtOAc (2 × 250 mL), and the combined organic phase
was washed with brine (250 mL), dried, and concentrated to
give a residue that was dissolved (MeOH, 15 mL) and
evaporated. This operation was repeated three times to
remove traces of dioxane.
Several syntheses of 27 have been reported; all of them
use carbohydrates as starting materials.30-32 Thus, crude
21b was directly reduced with LiEt3BH (THF, 3 Å
molecular sieves, -78 °C)33 to give a mixture of alcohols
22/23 in a 7:1 ratio (77% combined yield from 20).
Furthermore, alcohol 23 could be obtained as the major
diastereoisomer by treatment with DIBAL-H (CH2Cl2-
hexane, -78 °C) in a 22/23, ratio of 1:10 (71% combined
yield from 20). The configuration of the newly created
stereocenter in 22 was established, as above, by reaction
with both (R)- and (S)-methoxyphenylacetic acids. The
diastereomeric esters 28a and 28b were obtained quan-
titatively. The application of the Trost-Mosher method
to esters 28a and 28b led us to assign the S configuration
to C1IV in 22.13
Chloride displacement by NaN3 (DMF, 110 °C) con-
verted 22 into azido alcohol 24. The chemoselectivity of
the formation of ketones 21 was established at this stage,
since a strong NOE was observed between H1IV and the
1
N-benzylic CH2 group in the H NMR spectrum of 24.17
Urea-lactam 25, which contains the bicyclic system
required for the synthesis of streptolidine lactam 27, was
prepared from crude 24 by ester hydrolysis (LiOH‚H2O,
(34) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc.
1972, 94, 6203. (b) Brady, S. F.; Varga, S. L.; Freidinger, R. M.;
Schwenk, D. A.; Mendlowski, M.; Holly, F. W.; Veber, D. F. J . Org.
Chem. 1979, 44, 3101. (c) Brady, S. F.; Freidinger, R. M.; Paleveda,
W. J .; Colton, C. D.; Homnick, C. F.; Whitter, W. L.; Curley, P.; Nutt,
R. F.; Veber, D. F. J . Org. Chem. 1987, 52, 764.
(35) The use of NaHCO3 as base instead of Et3N lead to the
formation of several byproducts.
(36) Dunn, P. J .; Ha¨ner, R.; Rapoport, H. J . Org. Chem. 1990, 55,
5017.
(28) (a) Borders, D. B.; Hausmann, W. K.; Wetzel, E. R.; Patterson,
E. L. Tetrahedron Lett. 1967, 4187. (b) Borders, D. B.; Sax, K. J .;
Lancaster, J . E.; Hausmann, W. K.; Mitscher, L. A.; Wetzel, E. R.;
Patterson, E. L. Tetrahedron 1970, 26, 3123. (c) Kawakami, Y.;
Yamasaki, K.; Nakamura, S. J . Antibiot. 1981, 34, 921.
(29) Kido, Y.; Furuie, T.; Suzuki, K.; Sakamoto, K.; Yokoyama, Y.;
Uyeda, M.; Kinjyo, J .; Yahara, S.; Nohara, T.; Shibata, M. J . Antibiot.
1987, 40, 1698.
(30) (a) Goto, T.; Ohgi, T. Tetrahedron Lett. 1974, 1413. (b)
Kusumoto, S.; Tsuji, S.; Shiba, T. Tetrahedron Lett. 1974, 1417. (c)
Kusumoto, S.; Tsuji, S.; Shiba, T. Bull. Chem. Soc. J pn. 1974, 47, 2690.
(d) Kusumoto, S.; Tsuji, S.; Shima, K.; Shiba, T. Bull. Chem. Soc. J pn.
1976, 49, 3611.
(31) Kinoshita, M.; Suzuki, Y. Bull. Chem. Soc. J pn. 1977, 50, 2375.
(32) Kusumoto, S.; Imaoka, S.; Kambayashi, Y.; Shiba, T. Tetrahe-
dron Lett. 1982, 23, 2961.
(33) The use of 3-Å molecular sieves was necessary to avoid the
presence of around 10-30% of recovered ketone (21b) in the crude
reaction product, probably due to the formation, in part, of the
corresponding hydrate.
(37) Improved procedure for the preparation of 9: dimethyl N-Pf-
glutamate (3123 mg, 7.79 mmol) was treated with LHMDS (120 mol
%, THF-HMPA, -50/-55 °C, 1 h). Then MoOPH was added (135 mol
%, 1 h at -78 °C and 2 h from -78 to -62 °C) and the reaction was
quenched, worked up, and purified as in ref 6. An 11:1 mixture of
(3S)- and (3R)-dimethyl N-Pf-3-hydroxyaspartes was obtained (62%,
76% based on recovered starting material). A sample of this mixture
(3302 mg, 7.92 mmol) was treated with Cl2CO (500 mol %, DMAP,
pyridine, 70 °C, 15 min) and then quenched and worked up as in ref
6. Recrystallization of the crude product (CH2Cl2/hexane) and purifica-
tion of the mother liquors by column cromatography (conditions in ref
6) afforded 9 (93% combined yield) in a ratio of diastereomers 20:1.

4774 J . Org. Chem., Vol. 62, No. 14, 1997
Ferna´ndez-Megia et al.
(2S)-R-Meth yl N-(9′-p h en ylflu or en -9′-yl)glu ta m a te (2)
was obtained pure as a white foam. (Recrystallization of the
crude product from Et2O/hexane afforded pure white crystals.)
TsCl (2376 mg, 12.46 mmol) was added to a solution of the
above residue in pyridine (28 mL) at room temperature. The
resulting solution was stirred for 10 h and then partitioned
between EtOAc (350 mL) and HCl (5%, 250 mL). The organic
layer was washed with HCl (5%, 200 mL), saturated NaHCO3
(150 mL), and brine (150 mL), dried, and concentrated to give
a solid residue that was purified by short column chromatog-
raphy (silica gel 70-230 mesh, 2/1 hexane/EtOAc with 0.2%
pyridine) to afford 3a (2895 mg, 91%) as a white crystalline
solid. An analytical sample, as white crystals, was obtained
by recrystallization from EtOAc/hexane.
4b (78 mg, 100%) as a white crystalline solid. An analytical
sample, as white microcrystals, was obtained by recrystalli-
zation from EtOAc/hexane: mp 170 °C dec; [R]20 +42.8° (c
D
2.85, CHCl3); IR (NaCl) 1696 cm-1; H NMR δ 7.84 (dd, J )
1
1.6 Hz, J ) 6.3 Hz, 1H), 7.58-7.09 (m, 16H), 6.84 (dt, J ) 0.8
Hz, J ) 8.4 Hz, 1H), 4.79 (d, J ) 8.9 Hz, 1H), 2.72 (ddd, J )
9.0 Hz, J ) 11.9 Hz, J ) 16.2 Hz, 1H), 2.35-2.05 (m, 2H),
1.72 (dd, J ) 9.2 Hz, J ) 12.6 Hz, 1H); 13C NMR δ 199.0, 176.8,
148.2, 147.1, 140.8, 140.3, 139.6, 134.5, 133.3, 129.0, 128.7,
128.5, 128.4, 128.3, 128.1, 128.0, 127.7, 127.2, 126.9, 125.6,
119.8, 119.6, 73.3, 61.3, 30.7, 24.5. Anal. Calcd for C30H23NO2‚
0.25H2O: C, 83.0; H, 5.5; N, 3.2. Found: C, 82.9; H, 5.5; N,
3.2.
(5S)-5-(2′′-Ch lor oa cetyl)-1-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in -2-on e (4c). MeLi (0.714 mL, 1.149 mmol, 200 mol
%, 1.61 M in Et2O) was added dropwise to a stirred solution
of 3a (220 mg, 0.574 mmol), chloroiodomethane (0.091 mL,
1.246 mmol, 217 mol %), and LiBr (75 mg, 0.862 mmol, 150
mol %) in THF (5.6 mL) at -78 °C. The resulting yellow
2: mp 148 °C; [R]20D -274.4° (c 1.04, CHCl3); IR (KBr) 1737,
1710 cm-1; 1H NMR δ 7.68 (t, J ) 7.9 Hz, 2H), 7.41-7.14 (m,
11H), 3.28 (s, 3H), 2.63 (dd, J ) 4.6 Hz, J ) 8.9 Hz, 1H), 2.42
(t, J ) 6.9 Hz, 2H), 1.87-1.63 (m, 2H); 13C NMR δ 178.3, 175.9,
148.5, 148.0, 143.8, 141.3, 140.1, 128.6, 128.5, 128.4, 128.2,
127.4, 126.3, 126.0, 125.4, 120.1, 120.0, 72.9, 55.0, 51.7, 31.0,
29.1. Anal. Calcd for C25H23NO4: C, 74.8; H, 5.8; N, 3.5.
Found: C, 74.6; H, 5.7; N, 3.4.
solution was stirred at -78 °C for 70 min, then HCO2
Et (0.232
mL, 2.872 mmol) was added, and after 5 min at -78 °C the
reaction was quenched with MeOH (1 mL). The reaction
mixture was allowed to reach room temperature and was
partitioned between CH2Cl2 (75 mL) and H3PO4 (1 M, 50 mL).
The aqueous layer was washed with CH2Cl2 (50 mL), and the
combined organic layer was washed with brine (75 mL), dried,
and concentrated to give a residue that was purified by
short column chromatography (silica gel 70-230 mesh, 1.3/1
hexane/EtOAc) to give 4c (222 mg, 96%) as a white crystalline
solid. An analytical sample, as white crystals, was obtained
by recrystallization from EtOAc/hexane: mp 170 °C dec;
3a : mp 200-202 °C; [R]20D -91.9° (c 0.57, CHCl3); IR (KBr)
1
1740, 1690, 1207 cm-1; H NMR δ 7.65 (d, J ) 7.4 Hz, 3H),
7.60 (d, J ) 7.7 Hz, 1H), 7.41-7.19 (m, 9H), 3.93 (d, J ) 9.2
Hz, 1H), 3.28 (s, 3H), 2.69 (ddd, J ) 9.3 Hz, J ) 11.0 Hz, J )
16.0 Hz, 1H), 2.41-2.12 (m, 2H), 1.91-1.82 (m, 1H); 13C NMR
δ 176.5, 173.0, 147.0, 146.8, 141.0, 140.1, 129.1, 129.0, 128.3,
128.0, 127.9, 127.0, 126.8, 125.1, 119.8, 119.6, 73.2, 60.5, 51.8,
30.8, 24.3. Anal. Calcd for C25H21NO3: C, 78.3; H, 5.5; N,
3.7. Found: C, 78.6; H, 5.6; N, 3.5.
[R]20 +71.8° (c 2.72, CHCl3); IR (KBr) 1740, 1690 cm-1 1H
;
(5S)-5-Acet yl-1-(9′-p h en ylflu or en -9′-yl)p yr r olid in -2-
on e (4a ). MeLi (0.509 mL, 0.836 mmol, 160 mol %, 1.64 M in
Et2O) was added dropwise to a stirred solution of 3a (200 mg,
0.522 mmol) in THF (5.3 mL) at -78 °C. The resulting orange
solution was stirred for 1 h at -78 °C, then HCO2Et (0.211
mL, 2.611 mmol) was added and after 5 min the reaction was
quenched with MeOH (1.5 mL). The reaction mixture was
allowed to reach room temperature and was partitioned
between CH2Cl2 (100 mL) and H3PO4 (1 M, 100 mL). The
aqueous layer was washed with CH2Cl2 (100 mL), and the
combined organic phase was washed with brine (100 mL),
dried, and concentrated to give a residue that was purified by
column chromatography (silica gel 70-230 mesh, hexane/
EtOAc, 1.05/1) to give 4a (167 mg, 87%) as a white crystalline
solid. An analytical sample, as white crystals, was obtained
D
NMR δ 7.66 (c, J ) 7.7 Hz, 3H), 7.44-7.17 (m, 10H), 4.22 (d,
J ) 8.6 Hz, 1H), 3.41 (d, J ) 16.1 Hz, 1H), 3.17 (d, J ) 16.1
Hz, 1H), 2.70-2.55 (m, 1H), 2.36-2.26 (m, 1H), 2.21-2.06 (m,
1H), 1.78-1.69 (m, 1H); 13C NMR δ 201.3, 176.2, 147.5, 147.2,
140.4, 140.3, 139.9, 129.4, 129.2, 128.6, 128.4, 128.2, 127.3,
127.1, 125.4, 120.0, 73.2, 62.7, 45.8, 30.5, 23.6. Anal. Calcd
for C25H20NO2Cl: C, 74.7; H, 5.0; N, 3.5. Found: C, 74.4; H,
5.0; N, 3.3.
(5S ,1′′S )-5-(1-H yd r oxye t h yl)-1-(9′-p h e n ylflu or e n -9′-
yl)p yr r olid in -2-on e (6). L-Selectride (0.331 mL, 0.331 mmol,
150 mol %, 1 M in THF) was added dropwise to a stirred
solution of 4a (81 mg, 0.221 mmol) in THF (4.25 mL) at -78
°C. The resulting solution was stirred from -78 °C to -25 °C
for 2 h and then quenched with AcOH (0.038 mL, 0.662 mmol).
After 5 min of stirring at -25 °C the reaction was allowed to
reach room temperature. LiOH‚H2O (46 mg, 1.104 mmol) and
H2O2 (30%, 1 mL) were added, and the resulting mixture was
by recrystallization from CH2Cl2/hexane: mp 258-260 °C;
1
[R]20 +71.6° (c 0.55, CHCl3); IR (NaCl) 1720, 1689 cm-1; H
D
NMR δ 7.70 (d, J ) 7.6 Hz, 1H), 7.66 (d, J ) 7.6 Hz, 1H), 7.63
(d, J ) 7.5 Hz, 1H), 7.47 (d, 7.6 Hz, 1H), 7.41-7.37 (m, 3H),
7.34 (t, J ) 7.5 Hz, 1H), 7.30-7.24 (m, 3H), 7.21-7.17 (m, 2H),
3.99 (dd, J ) 1.5 Hz, J ) 9.9 Hz, 1H), 2.59 (ddd, J ) 9.1 Hz,
J ) 11.6 Hz, J ) 16.5 Hz, 1H), 2.30 (ddd, J ) 1.7 Hz, J )
9.3 Hz, J ) 16.5 Hz, 1H), 2.15-2.06 (m, 1H), 1.71-1.66 (m,
1H), 1.55 (s, 3H); 13C NMR δ 207.0, 176.3, 147.7, 147.3, 140.8,
140.3, 139.9, 129.2, 129.0, 128.5, 128.4, 128.1, 127.3, 127.0,
125.4, 119.9, 119.8, 73.2, 65.7, 30.6, 26.2, 23.1. Anal. Calcd
for C25H21NO2: C, 81.7; H, 5.8; N, 3.8. Found: C, 81.6; H,
5.7; N, 3.8.
stirred for 30 min and then partitioned between CH2
Cl2 (35
mL) and H3PO4 (1 M, 40 mL). The aqueous phase was washed
with CH2Cl2 (35 mL), and the combined organic phase was
washed with brine (40 mL), dried, and concentrated to give a
residue that was purified by short column chromatography
(silica gel 70-230 mesh, 1/1.5 hexane/EtOAc) to give 6 (81 mg,
100%) as a white crystalline solid. An analytical sample, as
white microcrystals, was obtained by recrystallization from
CH2
Cl2/hexane: mp 216-218 °C; [R]20 -576.3° (c 1.12,
D
CHCl3); IR (KBr) 3377, 1686, 1664 cm-1; 1H NMR δ 8.17 (d, J
) 7.5 Hz, 1H), 7.69 (d, J ) 7.5 Hz, 1H), 7.62 (d, J ) 7.4 Hz,
1H), 7.44 (t, J ) 7.2 Hz, 1H), 7.35-7.10 (m, 9H), 3.95 (dd, J )
3.4 Hz, J ) 7.7 Hz, 1H), 2.98 (dc, J ) 3.8 Hz, J ) 6.3 Hz, 1H),
2.41-2.28 (m, 2H), 2.20-1.95 (m, 2H), 1.74 (bs, 1H), 0.42 (d,
J ) 6.4 Hz, 3H); 13C NMR δ 176.2, 148.6, 145.6, 142.3, 140.0,
139.4, 129.1, 128.7, 128.4, 128.3, 127.5, 126.9, 126.7, 124.4,
120.1, 119.7, 72.6, 66.8, 63.5, 31.7, 18.0, 15.1. Anal. Calcd
for C25H23NO2: C, 81.3; H, 6.3; N, 3.8. Found: C, 81.2; H,
6.3; N, 3.6.
(5S)-5-Ben zoyl-1-(9′-p h en ylflu or en -9′-yl)p yr r olid in -2-
on e (4b). nBuLi (0.156 mL, 0.256 mmol, 140 mol %, 1.64 M
in hexane) was added dropwise to a stirred solution of PhBr
(0.029 mL, 0.274 mmol, 150 mol %) in THF (0.65 mL) at -78
°C. The resulting solution was stirred at -78 °C for 20 min
and then cannulated dropwise at -78 °C to a precooled (-78
°C) solution of 3a (70 mg, 0.183 mmol, 100 mol %) in THF
(1.2 mL). The resulting orange solution was stirred for 1 h at
-78 °C, then HCO2Et (0.074 mL, 0.914 mmol) was added, and
after 5 min the reaction was quenched with MeOH (1 mL).
The reaction mixture was allowed to reach room temperature
and was partitioned between CH2Cl2 (70 mL) and H3PO4 (1
M, 70 mL). The aqueous phase was washed with CH2Cl2 (50
mL), and the combined organic phase was washed with brine
(100 mL), dried, and concentrated to give a residue that was
purified by short column chromatography (silica gel 70-230
mesh, 1.65/1 hexane/EtOAc, with 0.2% of pyridine) to afford
(2S,1′′S,2′′′S)-1′-[5′′′-Oxo-1′′′-(9IV-ph en ylflu or en -9IV-yl)pyr -
r olid in -2′′′-yl]et h yl 1-(Ben zen esu lfon yl)p yr r olid in e-2-
ca r boxyla te (7a ). L-N-(Benzenesulfonyl)proline (26 mg,
0.101 mmol), DMAP (1 mg, 0.008 mmol), and DCC (21 mg,
0.101 mmol) were added to a solution of 6 (25 mg, 0.068 mmol)
in CH2Cl2 (0.7 mL). The resulting cloudy solution was stirred
at room temperature for 1 h. HCl (5%, 1 mL) was then added,
and after 10 min of stirring, the mixture was partitioned

Enantiomerically Pure Highly Functionalized R-Amino Ketones
J . Org. Chem., Vol. 62, No. 14, 1997 4775
between CH2Cl2 (30 mL) and HCl (5%, 30 mL). The aqueous
phase was washed with CH2Cl2 (20 mL), and the combined
organic phase was washed with saturated NaHCO3 (30 mL)
and brine (30 mL), dried, and concentrated to give a residue
that was filtered (through a cotton plug) and purified by
column chromatography (1/1 hexane/EtOAc) to give 7a (39 mg,
95%) as a white crystalline solid. An analytical sample, as
white crystals, was obtained by recrystallization from CH2Cl2/
allowed to reach room temperature. The resulting mixture
was partitioned between CH2Cl2 (20 mL) and H3PO4 (1 M, 20
mL). The aqueous phase was washed with CH2Cl2 (15 mL),
and the combined organic phase was washed with brine (20
mL), dried, and concentrated to give a residue that was
purified by short column chromatography (70-230 mesh, 2.2/1
hexane/EtOAc) to give 10a [39 mg, 99% yield, in a 35:1 ratio
with the diketone 11 (R ) Me)] as a white crystalline solid
that could be recrystallized from EtOAc/hexane: mp 168-170
hexane: mp 218-220 °C; [R]20 -490.9° (c 0.5, CHCl3); IR
D
(NaCl) 1753, 1691 cm-1; H NMR δ 8.22 (d, J ) 7.6 Hz, 1H),
°C; [R]20 -90.3° (c 0.66, CHCl3); IR (KBr) 1770, 1741, 1734
1
D
7.79-7.69 (m, 4H), 7.61-7.43 (m, 4H), 7.37-7.31 (m, 3H),
7.25-7.15 (m, 6H), 4.17-4.04 (m, 2H), 3.94 (dd, J ) 3.8 Hz, J
) 8.0 Hz, 1H), 3.48-3.40 (m, 1H), 3.18-3.09 (m, 1H), 2.54-
2.47 (m, 2H), 2.39-2.26 (m, 1H), 2.22-2.10 (m, 1H), 1.86-
1.55 (m, 4H), 0.58 (d, J ) 6.4 Hz, 3H); 13C NMR (CD2Cl2) δ
176.4, 170.5, 148.9, 145.8, 143.2, 140.9, 139.9, 138.6, 133.2,
129.7, 129.5, 129.3, 129.1, 128.7, 128.6, 128.1, 127.6, 127.2,
127.1, 125.1, 121.0, 120.5, 73.0, 70.8, 60.9, 60.8, 48.8, 32.0, 31.2,
24.7, 19.2, 12.4. Anal. Calcd for C36H34N2O5S: C, 71.3; H,
5.7; N, 4.6. Found: C, 71.0; H, 5.6; N, 4.5.
cm-1; 1H NMR δ 7.66 (d, J ) 7.2 Hz, 3H), 7.54 (d, J ) 7.4 Hz,
1H), 7.41-7.24 (m, 9H), 4.45 (d, J ) 2.9 Hz, 1H), 4.20 (d, J )
2.9 Hz, 1H), 3.28 (s, 3H), 2.21 (s, 3H); 13C NMR δ 203.1, 169.8,
155.8, 145.8, 145.6, 140.1 (2 × C), 140.0, 129.8, 129.4, 128.6,
128.5, 128.1, 127.8, 127.6, 126.2, 125.4, 120.2, 120.0, 78.4, 72.8,
59,2, 52.5, 26.1. Anal. Calcd for C26H21NO5‚0.5H2O: C, 71.5;
H, 5.1; N, 3.2. Found: C, 71.3; H, 5.0; N, 3.3.
(4S ,5S )-5-(2′′′-(Me t h oxym e t h oxy)a ce t yl)-2-oxo-3-(9′-
p h en ylflu or en -9′-yl)oxa zolid in e-4-ca r boxylic Acid Meth -
yl Ester (10b). nBuLi (0.655 mL, 0.865 mmol, 140 mol %,
1.32 M in hexane) was added dropwise to a solution of
((methoxymethoxy)methyl)tributylstannane (315 mg, 0.865
mmol, 140 mol %) in THF (2.6 mL) at -78 °C. The resulting
solution was stirred at -78 °C for 9 min and then was
cannulated at -78 °C dropwise for 5 min to a solution of 937
(274 mg, 0.618 mmol, 100 mol %) in THF (6 mL) at -78 °C.
The resulting yellow solution was stirred at -78 °C for 30 min,
then acetone (0.091 mL, 1.236 mmol) was added, and stirring
was continued for 3 min at -78 °C. Saturated NH4Cl (4 mL)
was added. The resulting mixture was allowed to reach room
temperature and was partitioned between EtOAc (140 mL) and
saturated NH4Cl (140 mL). The aqueous phase was washed
with EtOAc (100 mL), and the combined organic phase was
washed with H2O (100 mL) and brine (100 mL), dried, and
concentrated to give a residue that was purified by column
chromatography (70-230 mesh, 1/1.35 hexane/EtOAc) to give
10b (198 mg, 66%) as a white foam and the diketone 11 (R )
CH2OMOM) in a 6% yield. An analytical sample of 10b as
white crystals was obtained by recrystallization from Et2O/
(2R,1′S,2′′S)-1′-[5′′-Oxo-1′′-(9′′′-ph en ylflu or en -9′′′-yl)-pyr -
r olid in -2′′-yl]eth yl Meth oxyp h en yla ceta te (8a ). DMAP (1
mg, 0.009 mmol), (R)-methoxyphenylacetic acid (31 mg, 0.187
mmol), and DCC (39 mg, 0.187 mmol) were added to a solution
of 6 (46 mg, 0.124 mmol) in CH2Cl2 (1.2 mL). The resulting
cloudy solution was stirred for 2 h at room temperature. Then
HCl (5%, 1 mL) was added, and after 10 min of stirring, the
mixture was filtered (through a cotton plug) and partitioned
between EtOAc (20 mL) and HCl (5%, 15 mL). The aqueous
phase was washed with EtOAc (15 mL), and the combined
organic phase was washed with HCl (5%, 15 mL), saturated
NaHCO3 (15 mL), and brine (20 mL), dried, and concentrated
to give a residue that was dissolved in CH2Cl2, filtered (through
a cotton plug), and purified by column chromatography (1.5/1
hexane/EtOAc) to give 8a (63 mg, 98%) as a white crystalline
solid. An analytical sample, as white crystals, was obtained
by recrystallization from CH2Cl2/hexane: mp 220-230 °C
1
sublimes; [R]20 -253.2° (c 0.43, CHCl3); H NMR (CD2Cl2) δ
D
8.09 (d, J ) 7.4 Hz, 1H), 7.77 (d, J ) 7.2 Hz, 1H), 7.71 (d, J )
7.5 Hz, 1H), 7.46 (t, J ) 7.2 Hz, 1H), 7.35-7.12 (m, 14H), 4.47
(s, 1H), 4.01 (d, J ) 6.4 Hz, 2H), 3.20 (s, 3H), 2.43-2.36 (m,
2H), 2.29-2.15 (m, 1H), 2.01-1.93 (m,1H), 0.40 (d, J ) 5.0
Hz, 3H); 13C NMR (CD2Cl2) δ 176.3, 169.1, 148.8, 145.8, 143.1,
140.9, 139.9, 136.8, 129.7, 129.4, 129.1, 128.9, 128.8, 128.7,
128.6, 128.1, 127.3, 127.2, 127.0, 125.1, 121.1, 120.5, 82.6, 73.1,
70.5, 61.1, 57.4, 31.9, 19.2, 12.1. Anal. Calcd for C34H31NO4‚
0.5H2O: C, 77.5; H, 6.1; N, 2.7. Found: C, 77.7; H, 5.8; N,
2.6.
EtOAc/hexane: mp 59 °C dec; [R]20 -161° (c 1.52, CHCl3);
D
1
IR (KBr) 2951, 1746, 1450, 1383 cm-1; H NMR δ 7.79-7.20
(m, 13H), 4.77 (d, J ) 2.7 Hz, 1H), 4.64 (d, J ) 1.6 Hz, 2H),
4.41 (d, J ) 5.9 Hz, 2H), 4.32 (d, J ) 2.7 Hz, 1H), 3.36 (s, 3H),
3.24 (s, 3H); 13C NMR δ 201.4, 169.2, 155.6, 145.8, 145.2, 140.1,
140.0, 139.9, 129.7, 129.4, 128.5, 128.2, 127.8, 127.6, 126.1,
125.3, 120.2, 119.8, 96.6, 76.4, 72.6, 69.9, 59.0, 55.8, 52.4.
Anal. Calcd for C28H25NO7‚0.5H2O: C, 67.7; H, 5.3; N, 2.8.
Found: C, 67.5; H, 5.3; N, 2.7.
(2S,1′S,2′′S)-1′-[5′′-Oxo-1′′-(9′′′-p h en ylflu or en -9′′′-yl)p yr -
r olid in -2′′-yl]eth yl Meth oxyp h en yla ceta te (8b). Same
procedure as above. From 6 (46 mg, 0.124 mmol), DMAP (1
mg, 0.009 mmol), (S)-methoxyphenylacetic acid (31 mg, 0.187
mmol), and DCC (39 mg, 0.187 mmol), after purification by
column chromatography in the same conditions as above, was
obtained 8b (60 mg, 93%) as a white crystalline solid. An
analytical sample, as white crystals, was obtained by recrys-
tallization from EtOAc/hexane: mp 180-182 °C; [R]20D -507.2°
(c 0.86, CHCl3); IR (NaCl) 1746, 1690 cm-1; 1H NMR (CD2Cl2)
δ 8.13 (d, J ) 7.6 Hz, 1H), 7.81 (d, J ) 7.5 Hz, 1H), 7.73 (d, J
) 7.6 Hz, 1H), 7.50 (t, J ) 7.0 Hz, 1H), 7.39-7.32 (m, 6H),
7.20-7.09 (m, 8H), 4.49 (s, 1H), 4.03 (dc, J ) 3.7 Hz, J ) 6.5
Hz, 1H), 3.75 (dd, J ) 3.6 Hz, J ) 7.6 Hz, 1H), 3.23 (s, 3H),
2.40-2.34 (m, 2H), 1.95-1.72,(m, 2H), 0.55 (d, J ) 6.6 Hz,
3H); 13C NMR (CD2Cl2) δ 176.2, 169.1, 148.8, 145.6, 143.0,
140.9, 139.8, 137.0, 129.7, 129.4, 129.1, 129.0, 128.9, 128.7,
128.6, 128.1, 127.5, 127.1, 126.9, 125.0, 121.0, 120.5, 82.5, 72.9,
70.3 , 60.7, 57.4, 31.8, 18.7, 12.3. Anal. Calcd for C34H31NO4:
C, 78.9; H, 6.0; N, 2.7. Found: C, 79.0; H, 5.9; N, 2.6.
(4S,5S)-5-Acetyl-2-oxo-3-(9′-p h en ylflu or en -9′-yl)oxa zo-
lid in e-4-ca r boxylic Acid Meth yl Ester (10a ). MeLi (0.040
mL, 0.111 mmol, 120 mol %, 2.78 M in Et2O) was added
dropwise to a solution of 9 (41 mg, 0.092 mmol, 100 mol %) in
THF (1 mL) at -78 °C. The resulting colorless solution was
stirred at -78 °C for 30 min, then acetone (0.068 mL, 0.924
mmol) was added, and stirring was continued for 3 min at -78
°C. H3PO4 (1 M, 1 mL) was added, and the reaction was
(4S,5S)-5-Ben zoyl-2-oxo-3-(9′-p h en ylflu or en -9′-yl)ox-
a zolid in e-4-ca r boxylic Acid Meth yl Ester (10c). nBuLi
(0.215 mL, 0.271 mmol, 150 mol %, 1.26 M in hexane) was
added dropwise to a stirred solution of PhBr (0.031 mL, 0.298
mmol, 165 mol %) in THF (0.75 mL) at -78 °C. The resulting
solution was stirred at -78 °C for 20 min and then cannulated
dropwise at -78 °C to a precooled (-78 °C) solution of 937 (80
mg, 0.180 mmol, 100 mol %) in THF (1.8 mL). The resulting
colorless solution was stirred for 30 min at -78 °C, then
acetone (0.150 mL) was added, and, after 2 min the reaction
was quenched with H3PO4 (1 M, 1 mL). The reaction mixture
was allowed to reach room temperature and was partitioned
between CH2Cl2 (70 mL) and H3PO4 (1 M, 50 mL). The
aqueous phase was washed with CH2Cl2 (40 mL), and the
combined organic phase was washed with brine (70 mL), dried,
and concentrated to give a residue [ratio 10c:diketone 11 (R
) Ph) 15:1] that was purified by column chromatography (2.8/1
hexane/EtOAc) to afford pure 10c (74 mg, 84%) as a white
foam and 11 (R ) Ph) (6 mg, 6%) as a white foam. Both 10c
and 11 (R ) Ph) partially epimerize after 1 day in CDCl3.
10c: [R]20 -158.0° (c 0.89, CHCl3); IR (NaCl) 1774, 1693
D
cm-1; 1H NMR δ 8.00 (d, J ) 7.4 Hz, 2H), 7.94 (d, J ) 7.6 Hz,
1H), 7.70-7.22 (m, 15H), 5.43 (d, J ) 2.3 Hz, 1H), 4.76 (d, J
) 2.3 Hz, 1H), 3.19 (s, 3H); 13C NMR δ 191.3, 169.8, 155.6,
146.6, 145.2, 140.4, 140.3, 139.8, 134.6, 133.1, 129.5, 129.4,
129.2, 129.0, 128.5, 128.3, 128.0, 127.5, 126.5, 125.3, 120.1,
119.6, 75.4, 72.5, 59.0, 52.4. Anal. Calcd for C31H23NO5‚0.5
H2O: C, 74.7; H, 4.9; N, 2.8. Found: C, 74.3; H, 4.7; N, 2.8.

4776 J . Org. Chem., Vol. 62, No. 14, 1997
Ferna´ndez-Megia et al.
11 (R ) P h ): [R]20D -24.6° (c 1.45, CH2Cl2); IR (NaCl) 1774,
1735, 1690 cm-1; 1H NMR (CD2Cl2) δ 7.90-7.87 (m, 2H), 7.71-
7.13 (m, 21H), 5.76 (d, J ) 2.6 Hz, 1H), 5.22 (d, J ) 2.5 Hz,
1H); 13C NMR (CD2Cl2) δ 195.6, 192.6, 156.5, 147.1, 146.4,
141.1, 140.7, 140.4, 135.1, 134.5, 134.1, 133.8, 130.0, 129.9,
129.7, 129.4, 129.1, 128.9, 128.8, 128.5, 128.4, 127.9, 126.8,
126.1, 120.8, 120.3, 76.4, 72.9, 59.3. Anal. Calcd for C36H25NO4‚
0.75H2O: C, 78.7; H, 4.9; N, 2.6. Found: C, 78.8; H, 4.8; N,
2.6.
(Celite), the filter cake was washed with 1/1 CH2Cl2/MeOH,
and the combined filtrate was concentrated to give a white
foam that was dissolved in CH2Cl2 (4 mL). A solution of
Na2CO3 (503 mg, 4.746 mmol) in H2O (1.7 mL, deoxygenated
with Ar) and BrBn (0.310 mL, 2.610 mmol) were added to the
above solution. The resulting mixture was heated at reflux
for 54 h and then partitioned between Et2O (150 mL) and H2O
(150 mL). The aqueous phase was washed with Et2O (2 × 80
mL), and the combined organic phase was washed with brine
(150 mL), dried, and concentrated to give d im eth yl (2S,3S)-
N-(9′-p h en ylflu or en -9′-yl)-3-(ben zyla m in o)a sp a r ta te as a
white foam. [Purification of the crude product by column
chromatography (6.5/1 hexane/EtOAc) led to the pure com-
pound that could be recrystallized from hexane to give white
crystals.] Cl2CO (4.3 mL, 8.3 mmol, 1.93 M in toluene) was
slowly added to a stirred solution of the above foam and DMAP
(29 mg, 0.237 mmol) in pyridine (14 mL) at 70 °C. After 20
min of stirring the brown mixture was cooled in an ice-water
bath and MeOH (4 mL) was added. The resulting mixture
was partitioned between CH2Cl2 (150 mL) and H3PO4 (1 M,
150 mL), the aqueous phase was washed with CH2Cl2 (2 ×
100 mL), and the combined organic phase was washed with
H3PO4 (1 M, 3 × 100 mL) and brine (100 mL), dried, and
concentrated to give a residue that was triturated in hot
hexane (2 × 30 mL) and Et2O (20 mL) to give 20 (1003 mg,
79%) as a white crystalline solid that was recrystallized from
EtOAc/hexane to give white microcrystals. Purification of the
mother liquors by short column chromatography (70-230
mesh, 3.25/1 hexane/EtOAc) afforded 20 (45 mg, 83% combined
yield).
(4S,5S)-5-(4IV-((ter t-Bu tyld im eth ylsilyl)oxy)ben zoyl)-2-
oxo-3-(9′-p h en ylflu or en -9′-yl)oxa zolid in e-4-ca r b oxylic
Acid Meth yl Ester (10d ). nBuLi (1.39 mL, 1.475 mmol, 105
mol %, 1.06 M in hexane) was added dropwise to a solution of
O-(tert-butyldimethylsilyl)-4-bromophenol (444 mg, 1.545 mmol,
110 mol %) in THF (7.5 mL) at -78 °C. The resulting solution
was stirred for 90 min at -78 °C and then cannulated at -78
°C, dropwise for 15 min, over a solution of 937 (623 mg, 1.405
mmol, 100 mol %, ratio of stereoisomers 20:1) in THF (11.5
mL) at -78 °C. The resulting yellow solution was stirred for
90 min at -78 °C, then acetone (0.619 mL, 8.428 mmol) was
added, and stirring was continued for 3 min at -78 °C. HCl
(5%, 2 mL) was added, and the mixture was allowed to reach
room temperature and partitioned between CH2Cl2 (200 mL)
and HCl (5%, 150 mL). The aqueous phase was washed with
CH2Cl2 (150 mL), and the combined organic phase was washed
with brine (200 mL), dried, and evaporated to give a residue
that was purified by column chromatography (70-230 mesh,
4.75/1 hexane/EtOAc) to give 10d (609 mg, 70%) as a white
foam and the diketone 11 (R ) p-PhOTBS) in 6% yield. An
analytical sample of 10d as white crystals was obtained by
recrystallization from Et2O/hexane: mp 85 °C dec; [R]20D -90°
(c 1,86, CHCl3); IR (KBr) 2953, 2929, 2857, 1775, 1682, 1596
cm-1; 1H NMR δ 7.96 (d, J ) 7.0 Hz, 1H), 7.94 (d, J ) 8.4 Hz,
2H), 7.69 (d, J ) 7.6 Hz, 1H), 7.64 (d, J ) 7.4 Hz, 1H), 7.54 (d,
J ) 7.5 Hz, 1H), 7.46-7.20 (m, 9H), 6.90 (d, J ) 8.6 Hz, 2H),
5.37 (d, J ) 1.7 Hz, 1H), 4.82 (d, J ) 1.7 Hz, 1H), 3.19 (s,
3H), 0.99 (s, 9H), 0.25 (s, 6H); 13C NMR δ 189.6, 169.9, 161.7,
155.7, 146.7, 145.2, 140.5, 140.3, 139.8, 131.8, 129.5, 129.2,
128.5, 128.3, 128.0, 127.5, 126.6, 126.5, 125.3, 120.4, 120.0,
119.6, 75.4, 72.5, 59.1, 52.3, 25.4, 18.1, -4.5. Anal. Calcd for
C37H37NO6Si‚H2O: C, 69.7; H, 6.2; N, 2.2. Found: C, 69.8; H,
6.0; N, 2.1.
Dim et h yl (2S,3S)-N-(9′-p h en ylflu or en -9′-yl)-3-(b en z-
yla m in o)a sp a r ta te: mp 91 °C; [R]20D -268.4° (c 2.12, CHCl3);
IR (KBr) 3349, 1740 cm-1; 1H NMR δ 7.64 (t, J ) 6.6 Hz, 2H),
7.38-7.21 (m, 16H), 3.91 (d, J ) 13.6 Hz, 1H), 3.49 (d, J )
14.0 Hz, 1H), 3.43 (s, 3H), 3.28 (s, 3H), 3.23 (bs, 1H), 2.99 (bs,
1H), 2.40 (bs, 1H); 13C NMR δ 173.5, 172.4, 148.9, 147.8, 144.4,
141.0, 140.0, 139.8, 128.4, 128.3, 128.2, 127.8, 127.3, 127.2,
127.0, 126.9, 126.1, 125.7, 119.8, 119.7, 72.6, 62.6, 57.9, 51.9,
51.7 (2 × C). Anal. Calcd for C32H30N2O4‚0.5H2O: C, 74.5;
H, 6.1; N, 5.4. Found: C, 74.3; H, 5.8; N, 5.3.
20: mp 194 °C; [R]20D -45.7° (c 1.15, CHCl3); IR (KBr) 1737,
1
1710 cm-1; H NMR δ 7.78 (d, J ) 7.6 Hz, 1H), 7.64 (d, J )
(4S,5S)-5-Acetyl-2-oxo-3-(9′-p h en ylflu or en -9′-yl)im id a -
zolid in e-4-ca r boxylic Acid Meth yl Ester (17). When 16
was treated with MeLi (200-1000 mol %) in THF at -78 °C
under different reaction conditions, approximately 1:1 mix-
tures of ketone 17 and tertiary alcohol (4S,5S)-5-(1-h yd r oxy-
1-m et h ylet h yl)-2-oxo-3-(9′-p h en ylflu or en -9′-yl)im id a zo-
lid in e-4-ca r boxylic a cid m eth yl ester (18) were always
obtained. 17 and 18 were easily separated by column chro-
matography (1/1.8 hexane/EtOAc).
7.2 Hz, 2H), 7.57 (d, J ) 7.6 Hz, 1H), 7.46-7.18 (m, 14H), 4.88
(d, J ) 15.2 Hz, 1H), 4.08 (d, J ) 15.2 Hz, 1H), 3.93 (d, J )
2.8 Hz, 1H), 3.68 (d, J ) 2.8 Hz, 1H), 3.54 (s, 3H), 3.18 (s,
3H); 13C NMR δ 170.4, 169.7, 158.8, 146.9, 146.1, 141.8, 140.2,
140.0, 136.1, 129.1, 128.9, 128.5, 128.3, 128.2, 128.0, 127.9,
127.6, 127.1, 126.6, 125.5, 119.9, 119.7, 72.9, 58.4, 57.8, 52.5,
52.0, 46.5. Anal. Calcd for C33H28N2O5: C, 74.4; H, 5.3; N,
5.3. Found: C, 74.3; H, 5.3; N, 5.1.
(4S,5S)-5-Acetyl-1-ben zyl-2-oxo-3-(9′-p h en ylflu or en -9′-
yl)im id a zolid in e-4-ca r boxylic Acid Meth yl Ester (21a ).
MeLi (1.41 mL, 1.972 mmol, 105 mol %, 1.4 M in Et2O) was
added dropwise to a stirred solution of 20 (1000 mg, 1.878
mmol, 100 mol %) in THF (19.5 mL) at -78 °C. The resulting
orange solution was stirred at -78 °C for 45 min, then acetone
(0.55 mL, 7.512 mmol) was added, and after 5 min of stirring
at -78 °C the reaction was quenched with HCl (5%, 3 mL).
The resulting mixture was allowed to warm to room temper-
ature and was partitioned between CH2Cl2 (100 mL) and HCl
(5%, 80 mL). The aqueous phase was washed with CH2Cl2 (2
× 70 mL), and the combined organic phase was washed with
brine (100 mL), dried, and concentrated to give a residue that
was purified by short column chromatography (70-230 mesh,
3/1 hexane/EtOAc) to give 21a (892 mg, 92%) as a white
crystalline solid that was recrystallized from EtOAc/hex-
17: white foam that was recrystallized from EtOAc/hexane
to give white crystals: mp 94 °C dec; [R]20 -15.2° (c 1.57,
D
CHCl3); IR (KBr) 1708, 1454, 1407, 1210 cm-1; 1H NMR δ 7.64
(d, J ) 6.7 Hz, 3H), 7.55 (d, J ) 7.5 Hz, 1H), 7.38-7.19 (m,
9H), 6.56 (s, 1H), 3.99 (d, J ) 2.6 Hz, 1H), 3.79 (s, 1H), 3.30
(s, 3H), 1.97 (s, 3H); 13C NMR δ 204.6, 171.0, 161.1, 146.8,
146.1, 141.7, 140.2, 139.9, 129.3, 129.0, 128.5, 128.2, 128.0,
127.9, 127.1, 126.5, 125.4, 120.0, 119.8, 72.7, 61.2, 59.4, 52.3,
25.4.
18: white foam that was recrystallized from Et2O/hexane
to give white crystals: mp 114 °C dec; [R]20 +48.9° (c 0.65,
D
CHCl3); IR (KBr) 3397, 1745, 1703, 1444, 1205 cm-1; 1H NMR
δ 7.70-7.63 (m, 3H), 7.55 (d, J ) 7.6 Hz, 1H), 7.46-7.16 (m,
9H), 6.01 (s, 1H), 3.73 (d, J ) 3.7 Hz, 1H), 3.32 (s, 3H), 3.17
(d, J ) 3.3 Hz, 1H), 2.41 (s, 1H), 0.90 (s, 3H), 0.85 (s, 3H); 13
C
ane to give white microcrystals: mp 188 °C; [R]20 +93.5° (c
NMR δ 172.4, 161.6, 147.0, 146.4, 142.0, 140.5, 140.0, 129.2,
128.9, 128.4, 128.2, 128.0, 127.7, 126.9, 125.6, 119.8 (2 × C),
72.8, 71.2, 62.0, 59.8, 52.0, 25.0, 23.4. Anal. Calcd for
C27H26N2O4: C, 73.3; H, 5.9; N, 6.3. Found: C, 73.3; H, 6.1;
N, 6.0.
D
1.57, CHCl3); IR (KBr) 1746, 1717 cm-1; 1H NMR δ 7.68-7.58
(m, 4H), 7.48-7.16 (m, 14H), 4.80 (d, J ) 15.1 Hz, 1H), 4.03
(d, J ) 15.1 Hz, 1H), 3.55 (d, J ) 3.9 Hz, 1H), 3.50 (d, J ) 3.9
Hz, 1H), 3.28 (s, 3H), 1.64 (s, 3H); 13C NMR δ 204.2, 170.9,
159.5, 146.4, 146.2, 141.4, 140.5, 139.9, 135.9, 129.5, 129.1,
128.7, 128.6, 128.4, 128.3, 128.1, 127.9, 127.3, 126.6, 125.7,
120.0, 119.9, 73.3, 63.9, 57.3, 52.3, 47.0, 24.7. Anal. Calcd
for C33H28N2O4: C, 76.7; H, 5.5; N, 5.4. Found: C, 76.6; H,
5.6; N, 5.2.
(4S,5S)-1-Ben zyl-2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)im i-
d a zolid in e-4,5-d ica r boxylic Acid Dim eth yl Ester (20). A
suspension of 19 (1050 mg, 2.373 mmol) and Pd/BaCO3 (210
mg, 5%) in MeOH (30 mL, deoxygenated with Ar) was stirred
under 1 atm of H2 for 3 h. The reaction mixture was filtered

Enantiomerically Pure Highly Functionalized R-Amino Ketones
J . Org. Chem., Vol. 62, No. 14, 1997 4777
(4S,5S)-1-Ben zyl-2-oxo-5-pen tan oyl-3-(9′′-ph en ylflu or en -
9′′-yl)im id a zolid in e-4-ca r boxylic Acid Meth yl Ester (21c).
nBuLi (0.255 mL, 0.293 mmol, 125 mol %, 1.15 M in hexane)
was added dropwise to a stirred solution of 20 (125 mg, 0.235
mmol) in THF (2.3 mL) at -78 °C. The resulting orange
solution was stirred at -78 °C for 45 min, then HCO2Et (0.038
mL, 0.469 mmol) was added, and after 3 min of stirring at
-78 °C the reaction was quenched with H3PO4 (1 M, 1 mL).
The resulting mixture was allowed to warm to room temper-
ature and was partitioned between CH2Cl2 (50 mL) and H3PO4
(1 M, 40 mL). The aqueous phase was washed with CH2Cl2
(40 mL), and the combined organic phase was washed with
brine (50 mL), dried, and concentrated to give a residue that
was purified by column chromatography (6/1 hexane/EtOAc)
to afford 23 mg (18%) of recovered 20 and 70 mg of a white
crystalline solid, unseparable mixture of 21c (50%, 61% based
on recovered 20) and a product of unknown structure in a ratio
of 14:1. Pure 21c as white crystals was obtained by recrys-
was allowed to reach room temperature and was distributed
between CH2Cl2 (20 mL) and H3PO4 (1 M, 15 mL). The
aqueous phase was washed with CH2Cl2 (2 × 20 mL), and the
combined organic phase was washed with brine (40 mL), dried,
and concentrated to give a residue that was purified by short
column chromatography (70-230 mesh, 3.7/1 hexane/EtOAc
with 0.2% of Et3N) to give 21e (84 mg, 78%) as a white
crystalline solid that was recrystallized from EtOAc/hexane
to give white crystals: mp 152-157 °C; [R]20D -202.4° (c 0.99,
1
CHCl3); IR (KBr) 1709 cm-1; H NMR δ 8.00 (dd, J ) 1.4 Hz,
J ) 6.3 Hz, 1H), 7.62 (t, J ) 8.6 Hz, 2H), 7.42-7.16 (m, 15H),
5.23 (d, J ) 2.7 Hz, 1H), 5.06 (d, J ) 15.6 Hz, 1H), 4.44 (d, J
) 2.7 Hz, 1H), 4.36 (d, J ) 2.1 Hz, 1H), 3.92-3.86 (m, 2H),
3.66 (c, J ) 7.0 Hz, 2H), 3.06 (s, 3H), 1.11 (t, J ) 7.0 Hz, 3H);
13C NMR δ 192.1, 169.9, 159.1, 155.5, 147.5, 145.9, 142.2,
140.3, 139.9, 136.9, 129.0, 128.8, 128.4, 128.3, 128.0, 127.3,
127.1, 126.4, 125.3, 120.0, 119.4, 93.0, 72.5, 63.9, 59.1, 58.1,
51.7, 46.1, 13.6. Anal. Calcd for C36H32N2O5: C, 75.5; H, 5.6;
N, 4.9. Found: C, 75.5; H, 5.7; N, 4.7.
tallization from EtOAc/hexane: mp 139 °C; [R]20 +73.1° (c
D
1.02, CHCl3); IR (KBr) 1751, 1705 cm-1; 1H NMR δ 7.67-7.15
(m, 18H), 4.82 (d, J ) 15.1 Hz, 1H), 3.99 (d, J ) 15.1 Hz, 1H),
3.57 (d, J ) 3.5 Hz, 1H), 3.49 (d, J ) 3.5 Hz, 1H), 3.28 (s, 3H),
2.02 (dt, J ) 7.4 Hz, J ) 17.7 Hz, 1H), 1.81 (dt, J ) 6.9 Hz, J
) 17.6 Hz, 1H), 1.24 (quint, J ) 6.9 Hz, 2H), 1.03 (sext, J )
7.3 Hz, 2H), 0.78 (t, J ) 7.04 Hz, 3H); 13C NMR δ 206.2, 171.0,
159.5, 146.6, 146.2, 141.5, 140.4, 139.9, 136.0, 129.4, 129.0,
128.7, 128.6, 128.4, 128.3, 128.0, 127.9, 127.8, 127.2, 126.7,
125.7, 119.9, 119.8, 73.2, 63.4, 57.4, 52.3, 47.0, 37.4, 25.0, 21.9,
13.6. Anal. Calcd for C36H34N2O4‚0.75 H2O: C, 75.6; H, 6.3;
N, 4.9. Found: C, 75.6; H, 6.1; N, 5.1.
(4S,5S,1IVS)-1-Ben zyl-5-(1IV-h yd r oxy-2IV-ch lor oet h yl)-
2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)im id a zolid in e-4-ca r boxy-
lic Acid Meth yl Ester (22). MeLi (1.88 mL, 3.756 mmol, 200
mol %, 2.0 M in Et2O) was added dropwise to a stirred solution
of 20 (1000 mg, 1.878 mmol), chloroiodomethane (0.297 mL,
4.075 mmol, 217 mol %), and LiBr (245 mg, 2.817 mmol, 150
mol %) in THF (19 mL) at -78 °C. The resulting yellow
solution was stirred at -78 °C for 75 min, then HCO2Et (0.607
mL, 7.512 mmol) was added, and after 3 min of stirring, the
reaction was quenched with H3PO4 (1 M, 2 mL). The resulting
mixture was allowed to warm to room temperature and was
partitioned between CH2Cl2 (100 mL) and H3PO4 (1 M, 75 mL).
The aqueous phase was washed with CH2Cl2 (75 mL), and the
combined organic phase was washed with saturated Na2S2O3
(100 mL) and brine (100 mL), dried, and concentrated to give
(4S,5S)-5-Ben zoyl-1-ben zyl-2-oxo-3-(9′′-p h en ylflu or en -
9′′-yl)im idazolidin e-4-car boxylic Acid Meth yl Ester (21d).
nBuLi (0.255 mL, 0.293 mmol, 125 mol %, 1.15 M in hexane)
was added dropwise to a stirred solution of PhBr (0.035 mL,
pure
(4S,5S)-1-b en zyl-5-(2IV-ch lor oa cet yl)-2-oxo-3-(9′′-
ph en ylflu or en -9′′-yl)im idazolidin e-4-car boxylic acid m eth -
yl ester (21b) as a white foam (recrystallization of the crude
product from EtOAc/hexane led to white crystals). The above
crude was divided in four flasks which were dried under
vacuum for 16 h at 65 °C; then aliquots of THF (16.4 mL in
total) were added and the solutions were stirred in the
presence of 3 Å molecular sieves for 2 h 15 min at room
temperature. After each solution was cooled at -78 °C,
aliquots of LiEt3BH (4.42 mL in total, 3.756 mmol, 200 mol
%, 0.85 M in THF) were added dropwise. The resulting yellow
solutions were stirred at -78 °C for 2 h and then were
quenched with AcOH (0.376 mL in total, 6.573 mmol, deoxy-
genated with Ar), stirred for 3 min at -78 °C, and warmed to
-15 °C. LiOH‚H2O (473 mg in total, 11.268 mmol) and H2O2
(30%, deoxygenated with Ar, 2 mL in total) were added, and
after 20 min of stirring at -15 °C H3PO4 (1 M, 4 mL in total)
was added. The resulting mixtures were allowed to warm to
room temperature, combined, and partitioned between CH2Cl2
(125 mL) and H3PO4 (1 M, 75 mL). The aqueous phase was
washed with CH2Cl2 (100 mL) and the combined organic phase
was washed with brine (75 mL), dried, and concentrated to
give a residue (ratio of isomers 7:1) that was recrystallized
twice from EtOAc/hexane to give a first (484 mg, 47%) and a
second crop (102 mg, 10%) of pure 22 as white crystals. The
mother liquours were purified by column chromatography
(2.2/1 hexane/EtOAc) to give a mixture of isomers 22:23, 1:1
(210 mg, 20%), as a white crystalline solid, that could be
recrystallized twice from EtOAc/hexane to give pure 22.
21b: mp 174-176 °C; [R]20D +34.6° (c 2.84, CHCl3); IR (KBr)
1744, 1708 cm-1; 1H NMR δ 7.67 (d, J ) 6.3 Hz, 2H), 7.61 (d,
J ) 7.9 Hz, 2H), 7.47-7.16 (m, 14H), 4.74 (d, J ) 15.1 Hz,
1H), 4.07 (d, J ) 15.0 Hz, 1H), 3.85 (d, J ) 3.6 Hz, 1H), 3.63
(d, J ) 16.1 Hz, 1H), 3.58 (d, J ) 3.6 Hz, 1H), 3.50 (d, J )
16.0 Hz, 1H), 3.26 (s, 3H); 13C NMR δ 197.9, 170.4, 159.2,
146.6, 146.0, 141.3, 140.4, 140.0, 135.7, 129.6, 129.1, 128.9,
128.6, 128.5, 128.4, 128.1, 128.0, 127.3, 126.5, 125.7, 120.1,
119.9, 73.4, 61.7, 57.6, 52.3, 47.4, 44.5. Anal. Calcd for
C33H27N2O4Cl‚0.25 H2O: C, 71.3; H, 5.0; N, 5.0. Found: C,
71.4; H, 4.9; N, 5.1.
0.329 mmol, 140 mol %) in THF (1 mL) at -78 °C. The
resulting solution was stirred at -78 °C for 22 min and then
cannulated dropwise at -78 °C to a precooled (-78 °C) solution
of 20 (125 mg, 0.235 mmol, 100 mol %) in THF (1.3 mL). The
resulting pale orange solution was stirred at -78 °C for 45
min, then HCO2Et (0.038 mL, 0.469 mmol) was added, and
after 3 min the reaction was quenched with H3PO4 (1 M, 1
mL). The reaction mixture was allowed to reach room tem-
perature and was partitioned between CH2Cl2 (50 mL) and
H3PO4 (1 M, 50 mL). The aqueous phase was washed with
CH2Cl2 (50 mL), and the combined organic phase was washed
with brine (50 mL), dried, and concentrated to give a residue
that was purified by column chromatography (3.7/1 hexane/
EtOAc) to afford 124 mg of a white foam, unseparable mixture
of 21d (85%) and a product of unknown structure in a ratio of
14:1. Pure 21d (85 mg, 63%) as white crystals was obtained
by recrystallization from Et2O/hexane: mp 189-191 °C; [R]20
D
1
-145.6° (c 1.08, CHCl3); IR (KBr) 1750, 1718, 1683 cm-1; H
NMR δ 7.95 (d, J ) 6.9 Hz, 1H), 7.71-7.51 (m, 5H), 7.44-
7.12 (m, 17H), 5.07 (d, J ) 15.4 Hz, 1H), 4.57 (d, J ) 2.4
Hz, 1H), 3.95 (d, J ) 2.5 Hz, 1H), 3.85 (d, J ) 15.4 Hz,
1H), 3.16 (s, 3H); 13C NMR δ 194.6, 170.6, 159.2, 147.4, 145.9,
142.1, 140.1, 139.9, 136.4, 134.1, 133.8, 129.1, 128.9, 128.7,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.5, 127.1, 126.6,
125.4, 119.9, 119.4, 72.7, 59.6, 58.9, 52.1, 46.3. Anal. Calcd
for C38H30N2O4: C, 78.9; H, 5.2; N, 4.8. Found: C, 78.8; H,
5.2; N, 4.7.
(4S ,5S )-5-(2IV-E t h oxya cr yloyl)-1-b e n zyl-2-oxo-3-(9′′-
p h en ylflu or en -9′′-yl)im id a zolid in e-4-ca r b oxylic Acid
Meth yl Ester (21e). Ethyl vinyl ether (0.054 mL, 0.563
mmol, 300 mol %) was added to THF (0.65 mL) at -78 °C.
Then t-BuLi (0.226 mL, 0.469 mmol, 250 mol %, 2.08 M in
pentane) was added dropwise, and the resulting yellow solu-
tion was allowed to reach 0 °C for 2 h 5 min and then was
stirred at this temperature for an additional 45 min. The
1-ethoxy-1-lithioethene colorless solution was cooled to -78
°C and then cannulated dropwise at -78 °C over a solution of
20 (100 mg, 0.188 mmol) in THF (1.4 mL) at -78 °C. The
resulting yellow solution was stirred from -78 to -55 °C for
45 min and then at -55 °C for 35 min. The reaction was
quenched with HCO2Et (0.076 mL, 0.939 mmol), and after 3
min at -55 °C, H3PO4 (1 M, 1 mL) was added and the reaction
22: mp 210 °C; [R]20D +39.2° (c 1.17, CHCl3); IR (KBr) 3392,
1737, 1690, 1450 cm-1; 1H NMR δ 7.71-7.61 (m, 4H), 7.49 (d,

4778 J . Org. Chem., Vol. 62, No. 14, 1997
Ferna´ndez-Megia et al.
J ) 7.0 Hz, 2H), 7.43-7.18 (m, 12H), 4.65 (d, J ) 15.3 Hz,
1H), 4.20 (d, J ) 15.4 Hz, 1H), 3.68-3.63 (m, 2H), 3.38 (t, J )
2.1 Hz, 1H), 3.26 (dd, J ) 7.2 Hz, J ) 11.5 Hz, 1H), 3.21 (s,
and H2O (65 mL). The organic phase was washed with H2O
(65 mL) and the combined aqueous phase with EtOAc (65 mL).
The combined organic phase was washed with brine (100 mL),
dried, and concentrated to give a residue that was purified by
column cromatography [70-230 mesh, CH2Cl2/MeOH (2%)/
Et3N (0.1%)] to give pure 25 (77 mg, 56% overall yield) as a
white crystalline solid that could be recrystallized from EtOAc/
hexane to give white crystals (25 after 1 day in CDCl3 partially
descomposes to give another product, probably the cis-fused
bicycle).
3H), 3.07 (dd, J ) 6.0 Hz, J ) 11.4 Hz, 1H), 2,11 (bs, 1H); 13
C
NMR δ 172.0, 160.1, 146.8, 146.2, 141.9, 140.6, 140.0, 137.0,
129.4, 128.9, 128.8, 128.4, 128.3, 128.0, 127.8, 127.7, 127.1,
126.5, 125.6, 120.0, 119.9, 73.4, 70.1, 58.3, 55.7, 52.1, 46.7, 43.7.
(4S,5S,1IVR)-1-Ben zyl-5-(1IV-h yd r oxy-2IV-ch lor oeth yl)-
2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)im id a zolid in e-4-ca r boxy-
lic Acid Meth yl Ester (23). Same procedure as above. From
20 (205 mg, 0.385 mmol), chloroiodomethane (0.061 mL, 0.835
mmol, 217 mol %), LiBr (50 mg, 0.577 mmol, 150 mol %), and
MeLi (0.467 mL, 0.770 mmol, 200 mol %, 1.65 M in Et2O), a
residue of pure 21b was obtained as a foam. DIBAL-H (0.577
mL, 0.577 mmol, 1 M in hexane) was added dropwise to a
solution of the above crude in CH2Cl2 (4.9 mL) at -78 °C. The
mixture was stirred for 70 min at -78 °C and then was
quenched with EtOAc (1 mL). The resulting mixture was
stirred for 3 min at -78 °C and then was allowed to reach
room temperature and was concentrated to give a residue that
was dissolved in CHCl3 (4 mL). Saturated K2CO3 (3 drops)
was added, and the residue was stirred until turbidness was
seen. Then, KH2PO4 (500 mg) and Na2SO4 were added and
after 3 min of stirring the residue was filtered and concen-
trated to give a crude product (ratio of isomers 22:23 ) 1:5.4)
that was purified by column chromatography (70-230 mesh,
2.5/1 hexane/EtOAc) to give 23 (152 mg; ratio of isomers 22:
23 ) 1:10; 71% overall yield) as a white foam. An analytical
sample of pure 23 (ratio of isomers ) 1:40), as white crystals,
was obtained by recystallizing twice from EtOAc/hexane; this
mixture was used for the caracterization of 23 (23 partially
24: mp 155-158 °C; [R]20D +44.9° (c 0.94, CHCl3); IR (KBr)
1
3391, 2101, 1744, 1688 cm-1; H NMR δ 7.73 (d, J ) 7.6 Hz,
1H), 7.69 (d, J ) 7.6 Hz, 1H), 7.66 (d, J ) 7.6 Hz, 1H), 7.57 (d,
J ) 7.6 Hz, 1H), 7.50 (d, J ) 7.6 Hz, 2H), 7.44-7.19 (m, 12H),
4.60 (d, J ) 15.4 Hz, 1H), 4.26 (d, J ) 15.4 Hz, 1H), 3.63 (d,
J ) 4.6 Hz, 1H), 3.56-3.53 (m, 1H), 3.26 (s, 3H), 3.23 (dd, J )
1.9 Hz, J ) 4.5 Hz, 1H), 3.13 (dd, J ) 7.8 Hz, J ) 12.5 Hz,
1H), 2.78 (dd, J ) 5.1 Hz, J ) 12.6 Hz, 1H), 1.69 (d, J ) 3.2
Hz, 1H); 13C NMR δ 172.0, 160.1, 146.8, 146.2, 141.8, 140.6,
139.9, 137.0, 129.4, 128.9, 128.8, 128.4, 128.3, 127.9, 127.8,
127.1, 126.6, 125.6, 120.0, 119.9, 73.4, 68.8, 58.6, 55.8, 52.1,
51.4, 46.6. Anal. Calcd for C33H29N5O4: C, 70.8; H, 5.2; N,
12.5. Found: C, 70.6; H, 5.2; N, 12.4.
(4S,5S,1IVR)-1-Ben zyl-5-(1IV-h yd r oxy-2IV-a zid oeth yl)-2-
oxo-3-(9′′-p h en ylflu or en -9′′-yl)im id a zolid in e-4-ca r boxy-
lic a cid : mp 230-231 °C dec; [R]20 +38.4° (c 0.75, CH3OH);
D
1
IR (KBr) 3503, 2115, 1735, 1685 cm-1; H NMR [(CD3)2CO] δ
7.79-7.70 (m, 4H), 7.52-7.48 (m, 2H), 7.43-7.11 (m, 12H),
4.83 (d, J ) 15.7 Hz, 1H), 4.14 (d, J ) 15.7 Hz, 1H), 3.92-
3.86 (m, 2H), 3.37 (dd, J ) 1.9 Hz, J ) 4.1 Hz, 1H), 3.19 (dd,
J ) 8.0 Hz, J ) 12.8 Hz, 1H), 2.87 (dd, J ) 4.6 Hz, J ) 12.8
Hz, 1H); 13C NMR [(CD3)2CO] δ 173.5, 160.5, 148.7, 148.0,
144.5, 141.7, 141.1, 138.5, 129.9, 129.6, 129.4, 129.1, 128.8,
128.7, 128.6, 128.1, 127.4, 126.7, 120.8, 120.6, 74.1, 69.9, 60.0,
56.8, 52.9, 46.2. Anal. Calcd for C32H27N5O4‚0.25 H2O: C,
69.9; H, 5.0; N, 12.7. Found: C, 69.9; H, 5.0; N, 12.9.
epimerizes in CDCl3 after 1 day): mp 200-205 °C; [R]20
D
1
+90.2° (c 0.59, CHCl3); H NMR δ 7.73-7.63 (m, 4H), 7.54-
7.16 (m, 14H), 4.80 (d, J ) 15.3 Hz, 1H), 4.08 (d, J ) 15.3 Hz,
1H), 3.60-3.55 (m, 1H), 3.51 (d, J ) 3.7 Hz, 1H), 3.38 (t, J )
4.0 Hz, 1H), 3.24 (s, 3H), 3.16 (dd, J ) 3.8 Hz, J ) 11.4 Hz,
1H), 2.82 (dd, J ) 8.7 Hz, J ) 11.3 Hz, 1H), 2.24 (d, J ) 5.3
Hz, 1H); 13C NMR δ 171.8, 160.2, 146.52, 146.49, 141.5, 140.5,
139.8, 136.5, 129.4, 129.1, 128.7, 128.3, 128.2, 127.8, 127.7,
127.2, 126.4, 125.6, 120.0, 73.4, 72.2, 57.7, 57.0, 52.1, 47.8, 44.8.
Anal. Calcd for C33H29N2O4Cl: C, 71.7; H, 5.3; N, 5.1.
Found: C, 71.6; H, 5.3; N, 5.1.
25: mp ≈240-260 °C dec; [R]20 -109.4° (c 1.42, Cl3CH);
D
IR (KBr) 3377, 1700 cm-1; 1H NMR δ 7.98 (d, J ) 7.5 Hz, 1H),
7.66 (d, J ) 7.5 Hz, 1H), 7.62 (d, J ) 7.5 Hz, 1H), 7.55 (d, J )
7.7 Hz, 1H), 7.35-7.17 (m, 14H), 4.99 (d, J ) 4.9 Hz, 1H), 4.78
(d, J ) 14.7 Hz, 1H), 4.09 (d, J ) 12.2 Hz, 1H), 3.95-3.84, m,
2H), 3.45-3.34 (m, 1H), 3.05 (dd, J ) 3.0 Hz, J ) 12.0 Hz,
1H), 2.90 (d, J ) 13.4 Hz, 1H), 1.22 (s, 1H); 13C NMR δ 170.4,
163.3, 147.4, 145.9, 143.2, 141.7, 139.9, 137.1, 129.7, 129.3,
128.8, 128.6, 128.3, 128.2, 127.5, 127.4, 126.8, 126.5, 125.3,
119.7, 119.1, 74.2, 61.8, 60.9, 54.5, 48.4, 47.0. Anal. Calcd
for C32H27N3O3: C, 76.6; H, 5.4; N, 8.4. Found: C, 76.5; H,
5.4; N, 8.2.
La cta m 25. A solution of 22 (152 mg, 0.275 mmol) and
NaN3 (54 mg, 0.825 mmol) in DMF (1.1 mL) was heated at
110 °C for 6 h 30 min, then allowed to reach room temperature,
and partitioned between EtOAc (40 mL) and H2O (30 mL). The
organic phase was washed with H2O (30 mL) and the combined
aqueous phase, with EtOAc (40 mL). The combined organic
phase was washed with brine (50 mL), dried, and concentrated
to give a residue of (4S,5S,1IVR)-1-ben zyl-5-(1IV-h yd r oxy-
2IV-a zid oeth yl)-2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)im id a zo-
lid in e-4-ca r boxylic a cid m eth yl ester (24) [purification of
the crude product by short column chromatography (70-230
mesh, 2.5/1 hexane/EtOAc) afforded pure 24 (90%) as a white
crystalline solid that could be recrystallized from EtOAc/
hexane to give white crystals]. A solution of the above crude
24 and LiOH‚H2O (161 mg, 3.848 mmol) in dioxane (1.5 mL)-
H2O (0.75 mL) was stirred at room temperature for 14 h. Then
HCl (5%) was added until pH ) 2 and the mixture was
extracted with EtOAc (2 × 65 mL). The combined organic
phase was washed with brine (80 mL), dried, and concentrated
to give (4S,5S,1IVR)-1-b en zyl-5-(1IV-h yd r oxy-2IV-a zid o-
et h yl)-2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)im id a zolid in e-4-
ca r boxylic a cid as a white solid (an analytical sample, as
white crystals, was obtained by recrystallization of the crude
product from EtOAc/hexane). A mixture of the above crude
product, p-TsOH‚H2O (57 mg, 0.302 mmol, 110 mol %), and
Pd/C (10%, 34 mg) in MeOH (deoxygenated with Ar, 3.1 mL)
was hydrogenated (1 atm) for 75 min and then filtered (Celite)
and concentrated to give a residue that was dissolved in DMF
(6.0 mL). Et3N (0.096 mL, 0.687 mmol, 250 mol %) was added,
and the resulting solution was cooled to 0 °C. DPPA (0.080
mL, 0.371 mmol, 135 mol %) was added, and stirring was
continued at 0 °C for 5.5 h; then the reaction was allowed to
reach room temperature. After 22 h of total reaction time,
the reaction mixture was partitioned between EtOAc (65 mL)
La cta m 26. TFA (0.070 mL) was added to a solution of 25
(16 mg, 0.032 mmol) in CH2Cl2 (0.350 mL). The resulting red
solution was stirred at room temperature for 90 min and then
concentrated. The residue was washed with Et2O (4 × 7 mL)
to give pure 26 (7 mg, 84%) as a white crystalline solid
that could be recrystallized from CH2Cl2/MeOH/Et2O to give
white crystals: mp ≈ 226-260 °C dec; [R]20 -87.6° (c 0.29,
D
CH3OH); IR (KBr) 3370, 3328, 3298, 3250, 1710, 1683, 1668
cm-1 1H NMR (CD3OD) δ 7.34 (s, 5H), 4.78 (d, J ) 15.2
;
Hz, 1H), 4.37-4.34 (m, 1H), 4.30 (d, J ) 13.3 Hz, 1H), 4.17
(d, J ) 15.2 Hz, 1H), 3.53 (dd, J ) 5.3 Hz, J ) 14.1 Hz, 1H),
3.28 -3.17 (m, 2H); 13C NMR (CD3OD) δ 172.1, 166.0, 137.5,
129.9, 129.6, 128.9, 61.8, 61.5, 51.3, 50.5, 47.0. Anal. Calcd
for C13H15N3O3: C, 59.7; H, 5.8; N, 16.1. Found: C, 59.3; H,
5.8; N, 16.5.
(4S,5S,1IVS,2VR)-1-Ben zyl-5-[2IV-ch lor o-1IV-(m et h oxy-
p h en yla cet oxy)et h yl]-2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)-
im id a zolid in e-4-ca r boxylic Acid Meth yl Ester (28a ). A
solution of 22 (37 mg, 0.067 mmol), (R)-methoxyphenylacetic
acid (17 mg, 0.100 mmol), DCC (21 mg, 0.100 mmol), and
DMAP (1 mg, 0.008 mmol) in CH2Cl2 (0.7 mL) was stirred at
room temperature for 90 min. H3PO4 (1 M, 1 mL) was then
added, and after 10 min of stirring, the mixture was parti-
tioned between Et2O (20 mL) and H3PO4 (1 M, 20 mL). The
organic phase was washed with H3PO4 (1 M, 20 mL), saturated
NaHCO3 (20 mL), and brine (20 mL), filtered (through a cotton
plug), dried, and concentrated to give a residue that was
purified by short column chromatography (5/1 hexane/EtOAc)

Enantiomerically Pure Highly Functionalized R-Amino Ketones
J . Org. Chem., Vol. 62, No. 14, 1997 4779
to give 28a (47 mg, 100%) as a white crystalline solid. An
[R]20 +181.1° (c 1.05, CHCl3); 1H NMR δ 7.78 (d, J ) 7.6 Hz,
D
analytical sample, as white crystals, was obtained by recrys-
1H), 7.75 (d, J ) 7.6 Hz, 1H), 7.69 (d, J ) 7.5 Hz, 1H), 7.50-
7.43 (m, 5H), 7.36-7.23 (m, 14H), 7.19 (t, J ) 7.6 Hz, 1H),
5.06 (dt, J ) 1.2 Hz, J ) 6.8 Hz, 1H), 4.93 (d, J ) 15.5 Hz,
1H), 4.35 (s, 1H), 3.98 (d, J ) 15.4 Hz, 1H), 3.56 (d, J ) 5.1
Hz, 1H), 3.51-3.49 (m, 1H), 3.37 (s, 3H), 3.23 (s, 3H), 3.00
(dd, J ) 6.4 Hz, J ) 11.8 Hz, 1H), 2.91 (dd, J ) 6.8 Hz, J )
11.7 Hz, 1H); 13C NMR δ 171.7, 169.6, 159.7, 146.6, 146.4,
141.7, 140.9, 139.9, 135.8, 135.5, 129.4, 129.1, 129.0, 128.73,
128.70, 128.3, 128.2, 127.8, 127.7, 127.2, 125.5, 120.02, 119.96,
81.4, 73.3, 70.6, 57.1, 56.3, 55.7, 52.3, 46.2, 39.7. Anal. Calcd
for C42H37N2O6Cl: C, 71.9; H, 5.3; N, 4.0. Found: C, 71.6; H,
5.3; N, 4.1.
tallization from EtOAc/hexane: mp 165 °C; [R]20 +45.0° (c
D
1.0, CHCl3); IR (KBr) 1766, 1751, 1705 cm-1; 1H NMR δ 7.71-
7.70 (m, 1H), 7.68 (d, J ) 7.6 Hz, 1H), 7.64 (d, J ) 7.5 Hz,
1H), 7.60 (d, J ) 7.8 Hz, 1H), 7.47-7.45 (m, 2H), 7.41-7.19
(m, 15H), 7.10-7.08 (m, 2H), 4.89 (dt, J ) 3.5 Hz, J ) 5.7 Hz,
1H), 4.77 (d, J ) 15.3 Hz, 1H), 4.68 (s, 1H), 3.73 (d, J ) 15.3
Hz, 1H), 3.54 (d J ) 4.5 Hz, 1H), 3.44 (t, J ) 3.9 Hz, 1H), 3.36
(s, 3H), 3.34 (dd, J ) 6.2 Hz, J ) 11.9 Hz, 1H), 3.08 (s, 3H),
3.10-3.07 (m, 1H); 13C NMR δ 171.0, 170.0, 159.7, 146.6, 146.2,
141.6, 140.4, 140.0, 136.0, 135.4, 129.4, 129.1, 128.9, 128.6,
128.5, 128.3, 127.8, 127.7, 127.2, 127.1, 126.7, 125.6, 120.0,
119.9, 82.4, 73.1, 73.0, 57.3, 57.2, 55.9, 52.1, 46.7, 40.3. Anal.
Calcd for C42H37N2O6Cl: C, 71.9; H, 5.3; N, 4.0. Found: C,
71.9; H, 5.3; N, 4.2.
Ack n ow led gm en t. We thank the CICYT (Spain,
Grant SAF96-0251) and the Xunta de Galicia (grant
XUGA 20912B96) for financial support. E.F.-M. thanks
the Xunta de Galicia and the Universidad de Santiago
de Compostela for fellowships. We thank J uan F.
Correa for the experiments with N-Pf-proline methyl
ester and compounds 12 and 13 and Prof. Rafael Suau
(Universidad de Ma´laga, Spain) for the elemental
analyses.
(4S,5S,1IVS,2VS)-1-Ben zyl-5-[2IV-ch lor o-1IV-(m et h oxy-
p h en yla cet oxy)et h yl]-2-oxo-3-(9′′-p h en ylflu or en -9′′-yl)-
im id a zolid in e-4-ca r b oxylic Acid Met h yl E st er (28b ).
Same procedure as above. From 22 (33 mg, 0.060 mmol), (S)-
methoxyphenylacetic acid (15 mg, 0.090 mmol), DCC (18 mg,
0.090 mmol), and DMAP (1 mg, 0.008 mmol) was obtained a
residue that was purified by short column chromatography
(4/1 hexane/EtOAc) to give 28b (42 mg, 100%) as a white
foam. An analytical sample, as white crystals, was obtained
by recrystallization from Et2O/hexane: mp 146-149 °C;
J O970277Q