Stereoselective reactions of N-(9-phenylfluoren-9-yl)-4-oxoproline enolates. An expedient route for the preparation of conformationally restricted amino acid analogues

Article abstract of DOI:10.1021/jo990283h

Methodology for the stereoselective preparation of 3-alkylprolines from N-(9-phenylfluoren-9-yl)4-oxoproline is presented. The enolate of a N-(9- phenylfluoren-9-yl)-4-oxoproline ester was shown to give stereoselective aldol condensations with aromatic and aliphatic aldehydes. The enolate was preferentially approached by the electrophile through the Re face, and high threo selectivity was also observed and provided a route to trans 3- substituted prolines. The reactions are kinetically controlled except for the case of electron-rich or sterically hindered aromatic aldehydes. The ease of the equilibration between the erythro- and threo-aldolates is dictated by the electronic nature of the group at C-4 in substituted benzaldehydes, and the steric compression of the aldehyde group increases the rate of erythro/threo equilibration. Very high stereoselection was also observed in the reductions of the keto group in 3-substituted 4-oxoproline esters. Alkylation or Michael additions of the same enolate were poorly stereoselective, probably due to equilibration of the initially formed products. Kinetic protonation of enolates of 3-alkyl-4-oxoprolines proceeded with high diastereoselection to provide the corresponding cis-3-alkylprolines.

Full text of DOI:10.1021/jo990283h

8786
J . Org. Chem. 1999, 64, 8786-8793
Ster eoselective Rea ction s of N-(9-P h en ylflu or en -9-yl)-4-oxop r olin e
En ola tes. An Exp ed ien t Rou te for th e P r ep a r a tion of
Con for m a tion a lly Restr icted Am in o Acid An a logu es
Mar´ıa-J esu´s Blanco, M. Rita Paleo, Celia Penide, and F. J avier Sardina*
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received February 16, 1999
Methodology for the stereoselective preparation of 3-alkylprolines from N-(9-phenylfluoren-9-yl)-
4-oxoproline is presented. The enolate of a N-(9-phenylfluoren-9-yl)-4-oxoproline ester was shown
to give stereoselective aldol condensations with aromatic and aliphatic aldehydes. The enolate was
preferentially approached by the electrophile through the Re face, and high threo selectivity was
also observed and provided a route to trans 3-substituted prolines. The reactions are kinetically
controlled except for the case of electron-rich or sterically hindered aromatic aldehydes. The ease
of the equilibration between the erythro- and threo-aldolates is dictated by the electronic nature of
the group at C-4 in substituted benzaldehydes, and the steric compression of the aldehyde group
increases the rate of erythro/threo equilibration. Very high stereoselection was also observed in
the reductions of the keto group in 3-substituted 4-oxoproline esters. Alkylation or Michael additions
of the same enolate were poorly stereoselective, probably due to equilibration of the initially formed
products. Kinetic protonation of enolates of 3-alkyl-4-oxoprolines proceeded with high diastereo-
selection to provide the corresponding cis-3-alkylprolines.
Sch em e 1
In tr od u ction
Replacement of natural amino acids in peptides by
proline analogues has been extensively used for the study
of several fundamental biological processes.1a-c Chimeras
possessing the combined characteristics of proline and
another amino acid, in particular, have played a pivotal
role in the establishment of the steric and conformational
constraints for receptor affinity of amino acids and
peptides.1c In this regard, proline analogues that bear
side chains belonging to other amino acids at the 3-posi-
tion of the pyrrolidine ring have been used as probes in
the determination of the active conformations of biologi-
cally active peptides, such as cholecystokinin, angiotensin
II, bradykinin, and the opioid peptides.1c The ability of
3-alkylprolines and related compounds to influence the
cis-trans peptide bond isomerization in proteins, caused
by the interaction of the C-3 substituent with the proline
carboxyl group, has also attracted a good deal of atten-
tion. This conformational influence of 3-alkylprolines is
being used to promote specific types of turns in peptides2
and, in general, for the study of protein folding.3 It must
be pointed out, as well, that the introduction of cis- or
trans 3-alkylprolines in peptides provoke different effects;
thus, for instance, the cis epimer of 3-methylproline
induces a greater proportion of the cis peptide bond
conformation than the trans analogue, or than proline
itself, in dipeptides, which results in a greater distur-
bance of the usual γ-turn conformation of this type of
peptide.2c,d All these facts have contributed to make the
synthesis of 3-alkylprolines a topic of current interest.
Many synthetic methodologies have been developed for
the synthesis of 3-substituted prolines,1c,d but efficient,
versatile approaches that provide enantiomerically pure
3-alkylprolines in a stereoselective fashion are still
lacking. A particularly attractive route, due to its ef-
ficiency and potential for stereocontrol, is depicted in
Scheme 1.
(1) (a) Marshall, G. R. In Chemical Recognition in Biological
Systems; Creighton, A. M.; Turner, S., Eds.; Chemical Society: London,
1982; p 278. (b) Momany, F. A.; Chuman, H. Methods Enzymol. 1986,
124, 3. (c) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 61, 202, and
references therein. (d) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche,
C.; Potier, P. J . Org. Chem. 1997, 62, 765.
(2) (a) Baures, P. W.; Ojala, W. H.; Gleason, W. B.; J ohnson, R. L.
J . Pept. Res. 1997, 50, 1. (b) Holladay, M. W.; Lin, C. W.; May, C. S.;
Garvey, D. S.; Witte, D. G.; Miller, T. R.; Wolfram, C. A. W.; Nadzan,
A. M. J . Med. Chem. 1991, 34, 455. (c) Samanen, J .; Zuber, G.; Bean,
J .; Eggleston, D.; Romoff, T.; Kopple, K.; Saunders: M.; Regoli, D. Int.
J . Pept. Protein Res. 1990, 35, 501. (d) Delaney, N.; Madison, V. J .
Am. Chem. Soc. 1982, 104, 6635.
The use of 4-hydroxyproline (1)4 as starting material
sets the correct configuration needed for the analogues
(3) Beausoleil, E.; Sharma, R.; Michnick, S. W.; Lubell, W. D. J . Org.
Chem. 1998, 63, 6572.
(4) For a review on the use of 4-hydroxyproline in synthesis see:
Remuzon, P. Tetrahedron 1996, 52, 13803.
10.1021/jo990283h CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

Conformationally Restricted Amino Acid Analogues
J . Org. Chem., Vol. 64, No. 24, 1999 8787
Sch em e 2
to show biological activity, while the alkylation of the
4-oxoproline 2 derived enolates should allow for the
introduction of the desired substituents at C-3 in a
manner that could be regio- and stereocontrolled by
judicious choice of the reagents and reaction conditions.
During our studies aimed at the synthesis of poly-
hydroxypyrrolidine glycosidase inhibitors, we developed
a synthetic strategy that exploited the virtues of the
aforementioned approach. We uncovered that the sense
of the stereoinduction of the reaction of the enolates of
prolinones 2 and 3 (R1 ) OMOM, R2 ) H) depended on
the electrophile used: hydroxylation of 2 (LHMDS,
MoOPH) proceeded almost completely through the Si face
of the nucleophile, while protonation and methylation of
the enolate of 3 proceeded almost exclusively through the
Re face.5,6 Lubell and co-workers have studied the
monoalkylation of the enolates of the benzyl ester ana-
logue of ketone 2, and showed that these alkylations
occurred with low stereoselectivity. This behavior starkly
contrasted with the very high stereoselection observed
by us in the reactions of the enolates of prolinones 2 and
3, a discrepancy that could be explained if the initially
formed monoalkylation products could undergo enoliza-
tion and, then, reprotonation or further alkylation. If this
were the case, the degree of stereoselection of the initial
alkylation would be masked by the subsequent reproto-
nation step.1c,3,7,8 To test this hypothesis, and with the
aim of establishing an efficient, versatile route to 3-alky-
lated proline analogues, we decided to revisit the chem-
istry of the enolates of prolinone 2 and of related
compounds in an attempt to develop conditions for their
stereoselective functionalization at C-3.
Resu lts a n d Discu ssion
Ald ol Rea ction s. We decided first to study the aldol
reactions of prolinone 2 with a series of aromatic and
aliphatic aldehydes, with the expectation that the ini-
tially formed, negatively charged aldolate intermediate
would hinder the further enolization of the products, and
thus would preserve the degree of stereoselectivity of the
initial electrophile approach. The results from this study
are shown in Scheme 2.
tion of the aldol products was based on the magnitude of
J
3,1′′, since it has been shown that the coupling constants
in erythro-aldols (2-6 Hz) are smaller than in the threo
isomers (7-10 Hz).10 The major products from all the
reactions showed J 3,1′′ in the range of 6.5-8.1 Hz, while
the minor products exhibited smaller J 3,1′′ (2.7-5.2 Hz).
These observations pointed to the threo-aldols as the
predominant reaction products. The absolute configura-
tion at C-3 could be tentatively established as trans (3S)
by the fact that J 2,3 was in the range of 4.4-6.9 Hz for
all the aldols prepared. It has been shown that in
N-substituted 3-alkylproline esters the cis (3R) isomers
showed larger (8-9 Hz) coupling constants than their
trans (3S) counterparts (2-6 Hz).11,1c
The enolate of 2 was generated with LHMDS or n-BuLi
in THF at -78 or -55 °C and then treated with the
appropriate aldehyde (neat or in THF solution, at -78
°C). The additions proceeded cleanly and usually in high
yields with all the aldehydes tested, with the sole
exception of the highly electron-rich and hindered 2,4,5-
trimethoxybenzaldehyde (entry 10), which was unreac-
tive toward the enolate of ketone 2 even at - 20 °C. Most
of the reactions studied displayed a remarkable stereo-
selectivity since only two, in the worst cases, of the four
possible diastereoisomeric aldol products could be de-
tected in the crude reaction mixtures and, in most cases,
Since the analysis of the 1H NMR spectra of â-hydroxy-
ketones 5 and 6 could not provide a definitive configu-
rational assignment, the preparation of rigid derivatives
of them, in which NOE studies could be safely carried
out, was considered. Reduction of the major benzyl aldol
5a provided exclusively one diol (7a ),12 which gave
one product was clearly predominant or exclusive.9
A
preliminary assignment of the erythro/threo configura-
(5) (a) Blanco, M.-J .; Sardina, F. J . J . Org. Chem. 1996, 61, 4748.
(b) Blanco, M.-J .; Sardina, F. J . Tetrahedron Lett. 1994, 35, 8493.
(6) Blanco, M.-J .; Sardina, F. J . J . Org. Chem. 1998, 63, 3411.
(7) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658.
(8) A closely related approach has been used for the synthesis of
kainic acid analogues: (a) Baldwin, J . E.; Fryer, A. M.; Spyvee, M. R.;
Whitehead, R. C.; Wood, M. E. Tetrahedron Lett. 1996, 37, 6923. (b)
Baldwin, J . E.; Bamford, S. J .; Fryer, A. M.; Wood, M. E. Tetrahedron
Lett. 1995, 36, 4869. (c) Baldwin, J . E.; Rudolph, M. Tetrahedron Lett.
1994, 35, 6163. (d) Gill, P.; Lubell, W. D. J . Org. Chem. 1995, 60, 2658.
(9) Analyses were carried out by inspection of the CO2Me singlets
in the 1H NMR spectra (500 MHz) of the crude reaction mixtures.
Doping experiments using known amounts of various substituted
proline methyl esters showed that the limit of detection was e2%.
(10) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; Vol 3, pp 111-212.
(11) Mauger, A. B.; Irreverre, F.; Witkop, B. J . Am. Chem. Soc. 1966,
88, 2019.
(12) For an explanation of the origin of the stereoselectivity in the
reduction of the C-4 carbonyl group in 4-oxoprolines, see ref 6.

8788 J . Org. Chem., Vol. 64, No. 24, 1999
Blanco et al.
Sch em e 3
of their spectroscopic properties with those of 5a ,k and
6a .
The analysis of the aldol reaction products showed that
the condensation occurred with very high face selectivity
with regard to the enolate component and with a prefer-
ence for threo selectivity with respect to the overall
addition,13,14 but perusal of the data shown in Scheme 2
allowed us to extract some interesting additional conclu-
sions. Aliphatic aldehydes gave highly stereoselective
reactions (entries 12-14), most probably under kinetic
control, but aromatic aldehydes showed a more puzzling
behavior, since an interplay of stereoelectronic effects
influenced both the reaction stereoselectivity and revers-
ibility. Equilibration between threo- and erythro- aldols
5 and 6 was obviously taking place in some of the
reactions studied, most notably in those in which the
substituents on the aromatic ring of the electrophile were
electron-donating or were placed ortho to the aldehyde
group (entries 4-8 and 11), probably through the inter-
vention of a retro-aldol reaction. Our data showed that
the rate of equilibration was a complex function of the
nature and the position of the aromatic ring substituents
in the aldehyde. Interestingly, numerous studies on the
influence of the structure, steric effects, and counterion
of the enolate on the reversibility of the aldol condensa-
tion have been carried out, but to the best of our
knowledge, none have addressed the influence of the
structure of the aldehyde component on the rate of
erythro/threo equilibration.10,15 We observed that the
4-methoxy- (entry 4) and the 3,4-methylenedioxybenzyl
aldols (entry 8) equilibrated significantly faster that their
3-methoxy (entry 6) and 3,4-dimethoxy (entry 7) coun-
terparts. This order of reactivity argued against a simple
explanation in which the electron-richness of the ring
solely influenced the equilibration rate. The fact that the
3,4,5-trimethoxybenzyl aldols (entry 9) showed no signs
of equilibration, even after 5 h at -78 °C, strongly
suggested that the rate of equilibration is strongly
influenced by the substituent at C-4: an electron-
donating substituent increases the rate of equilibration
of the erythro/threo-aldolates, but only if this substituent
can become coplanar with the phenyl ring. If this copla-
narity is prevented by steric factors, as in the 3,4-
dimethoxy or the 3,4,5-trimethoxybenzyl aldols, the
equilibration is retarded (entry 7) or even suppressed
(entry 9). The destabilizing effect of direct electron
donation by the substituent at C-4 on the newly formed
negative charge of the aldolate might be the origin of the
observed trend. Steric effects also play a role in the rate
of equilibration, as can be deduced from entries 5 and
11. The aldol condensation with 2-bromobenzaldehyde
proceeds very rapidly, but equilibration appears to take
place with a high rate as well, giving a poorly stereo-
selective reaction. Equilibration between the 1-naphthyl
acetonide 8a , in excellent overall yield, when reacted with
2,2-dimethoxypropane. The coupling constants J 2,3 (10.7
Hz) and J 3,1′′ (10.2 Hz) indicated a trans-diaxial disposi-
tion for H-3 and H-1′′. NOE studies showed that when
H-4 (δ 3.75 ppm) was irradiated strong enhancements
were experienced by H-2 (δ 2.58 ppm) and H-1′′ (δ 4.40
ppm); when H-1′′ was irradiated enhancements were
experienced by signals corresponding to H-4 and H-2;
irradiation of H-2 led to enhacements of the signals
originated by H-4 and H-1′′. All these facts confirmed the
stereochemical assignment of 8a shown in Scheme 3, and
thus led us to assign a (3S,4S,1′′R) configuration to 5a .
The isopropyl aldol 5k was submitted to the same
protocol as 5a , to yield acetonide 8k , which was shown,
by analysis of J 2,3 (10.7 Hz) and J 3,1′′ (10.2 Hz) and of
NOE enhancements, to have the same stereochemistry
as 8a .
The minor benzyl aldol 6a was reduced with NaBH4
to give diol 9 with very high stereoselectivity. Attempts
to convert diol 9 into the corresponding cyclic acetonide
(as for 5a ) or carbonate (by treatment with COCl2,
diphosgene or triphosgene, and a tertiary amine or NaH)
met with failure, even under forcing conditions (complex
mixtures were obtained). Nevertheless, NOE studies
performed on diol 9 allowed us to assign the (3S,4S,1′′S)
configuration, since when H-4 (δ 3.61 ppm) was irradi-
ated, H-2 (δ 3.29 ppm) and one of the hydrogens at C-5
(H-5b, δ 3.36 ppm) showed intensity enhancements; when
H-1′′ (δ 3.77 ppm) was irradiated a strong enhancement
was experienced by H-2; finally, when H-5b was irradi-
ated, enhancements were seen for the signals of H-4 (3.61
ppm), H-1′′ and H-5a (3.17 ppm). These observations
point to the fact that H-2, H-1′′, and H-4 must be placed
on the same face of the molecule and, thus, that 9 must
be the epimer of 5a at C-1′′ and not at C-3. The failure
of the formation of the acetonide or carbonate of 6a could,
then, be explained since the bulky Ph group of the side
chain would have to occupy an axial position in the
bicyclic product. The structures of the rest of the aromatic
and aliphatic aldol products were assigned by comparison
(13) These results are consistent with a chelated-chair transition
state. Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957, 79,
1920.
(14) Cyclopentanone enolates have been shown to give high threo
selectivity in their reactions with aldehydes and ketones: (a) Fellman,
P.; Dubois, J .-E. Tetrahedron 1978, 34, 1349. (b) Dubois, J . E.; Dubois,
M. J . Chem. Soc. Chem. Commun. 1968, 1567.
(15) (a) Braun, M. In Stereoselective Synthesis; Helmchen, G.,
Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart,
1996; Vol. 3, pp 1603-1607, and references therein. (b) Majewski, M.;
Gleave, D. M. Tetrahedron Lett. 1989, 30, 5681. (c) Noyori, R.; Nishida,
I.; Sakata, J . J . Am. Chem. Soc. 1983, 105, 1598. (d) Heathcock, C. H.;
Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.; Sohn, J . E.; Lampe, J . J .
Org. Chem. 1980, 45, 1066.

Conformationally Restricted Amino Acid Analogues
J . Org. Chem., Vol. 64, No. 24, 1999 8789
Sch em e 4
An important fact that has to be taken into account
when analyzing the stereochemical outcome of these
reactions is that these alkylation or Michael reactions,
unlike the aldol additions, did not take place at -78 °C.
A higher temperature needed to be employed in the C-C
bond forming step (up to -10 °C) due to the lower
reactivity of the electrophiles used compared to the
aldehydes utilized in the aldol condensations. The higher
reaction temperature might be facilitating the deproto-
nation of the initially formed alkylation product, either
by the excess base or by the unreacted starting enolate,
a process that would lead to the erosion of the kinetic
stereoselectivity of the alkylation.17 When the reaction
time was shortened (20 min) or the temperature lowered
somewhat (temperature quench -20 °C), higher diaster-
eomeric ratios (up to 4/1, but with conversions < 40%)
were obtained, a fact that strengthens the deprotona-
tion-reprotonation sequence as the cause for the low
stereoselectivity of these reactions. When an electrophile
that did react at -55 °C with the enolate of 2 was
employed (CD3OD, entry 4) a highly stereoselective
reaction ensued, to give attack through the Re face of
the enolate (85% deuterium incorporation).
In view of this highly stereoselective protonation we
decided to study the protonation of the enolates prepared
from mixtures of epimers of 10a -c and 11a -c (BuLi,
THF, -78 °C) with acetic acid (Scheme 4, entries 5-7).
1
Analysis of the H NMR spectra of the crude protonation
mixtures showed only the presence of the corresponding
cis isomers 11a -c, concurring with the results obtained
in the deuteration of 2 (Scheme 4, entry 4). These results
not only attested the high stereoselectivity of the enolate
protonation process but, by inference, also lent support
to the notion that the initial attack of electrophiles
toward these 4-prolinone enolates proceeded with high
stereoselectivity, and that the low level of stereoselection
displayed by some of these processes is probably caused
by the deprotonation of the initially formed adduct under
the reaction conditions. A corollary of these studies is that
reactions of N-Pf-4-prolinone (Pf ) 9-phenylfluoren-9-yl)
enolates with electrophiles can be expected to proceed
stereoselectively if they can be carried out at low (-78
to -55 °C) temperature.
It is also interesting to note the great tendency of
4-oxoprolines toward enolization, since <2% of nucleo-
philic attack of BuLi on the carbonyl group at C-4 was
detected in the crude reaction mixtures (limit of detection,
1H NMR analysis).6
This alkylation-Michael addition-enolate reprotona-
tion protocol opens a highly stereoselective route for the
preparation of cis 3-alkylprolines, since the 3-alkyl-4-
oxoprolines can be converted into the corresponding
3-substituted prolines in two steps.1c
aldols, in which the steric compression on the alkoxyde
group is less than in the previous case, takes place with
a reduced rate. These results suggest that increasing
steric hindrance in the starting aldehyde (i.e. steric
compression in the alkoxyde group of the aldolate),
increases the rate of the retro-aldol reaction, which is
causing the erythro/threo equilibration.16
In all cases the threo-aldol 5 was the kinetic product,
and most reactions showed good-to-high stereoselectivity.
Even in the cases where the aldol condensation appeared
to be reversible, the 4-oxoproline enolate exclusively
reacted through the Re face, thus opening a highly
stereoselective route toward the trans 3-substituted
prolines, since the 3-alkyl-4-oxoprolines can be converted
into the corresponding 3-substituted prolines in two
steps, without affecting the stereochemistry at C-3.1c
Alk yla tion a n d P r oton a tion Rea ction s. With these
results in hand we undertook the study of other C-C
bond-forming reactions of the enolate of 2, namely
alkylation reactions and Michael additions, to check if
they proceeded with the same degree of stereocontrol.
Our findings are shown in Scheme 4 (entries 1-3).
The best reaction conditions usually involved the use
of n-BuLi (105 mol %) as base, and THF/HMPA as solvent
(reaction time 2 h). Under these conditions, all reactions
proceeded to completion, but in stark contrast with the
aldol condensations, they displayed low levels of stereo-
selection. The configuration at C-3 in each product 10
and 11 was established by the magnitude of the coupling
constant J 2,3, following the precedent of Lubell et al. for
the benzyl ester analogues of 10a -c and 11a -c.1c NOE
experiments were carried out to assign the stereochem-
istry of deuterio ketone 10d .18
Con clu sion
We have developed a methodology for the preparation
of either trans or cis 3-substituted prolines from 4-oxo-
(18) Stereochemical assignment of 10d : The diastereotopic hydro-
gens attached to C-3 in ketone 2 appeared at δ 2.28 (dd, J ) 17.9, 3.1
Hz) and 2.45 ppm (dd, J ) 17.9, 8.5 Hz). The signal at lower field was
assigned to the pro-S H-3 since its irradiation caused enhancement of
H-2 (δ 3.76 ppm) and the other H-3 signal, while irradiation of the
signal at δ 2.28 ppm (pro-R H-3) caused enhancement of only the other
H-3 proton, H-2 being unaffected. In the deuterated ketone 10d , the
signal at δ 2.45 ppm is not present and H-2 has a coupling constant of
2.9 Hz, typical of a trans arrangement, with the residual H-3 hydrogen
(δ 2.20 ppm, bs).
(16) It is known that steric hindrance on the enolate favors the
erythro/threo equilibration, probably due to the release of strain in
the aldolate; see refs 10 and 15a.
(17) Posner, G. H.; Lentz, C. M. J . Am. Chem. Soc. 1979, 101, 934.

8790 J . Org. Chem., Vol. 64, No. 24, 1999
Blanco et al.
with 4-chlorobenzaldehyde (39 mg, 0.275 mmol, 150 mol %)
by following method A described above. Purification by flash
chromatography (EtOAc/hexanes 1/5) gave 74 mg (77%) of 5b
prolines. The aldol and protonation reactions of enolates
of N-Pf-4-oxoprolines were shown to proceed with high
levels of stereoselection. The alkylation and Michael
addition are less stereoselective, probably due to further
deprotonation-reprotonation of the initially formed prod-
uct. The aldol condensations of 2 with aromatic and
aliphatic aldehydes provided trans 3-alkylprolines. The
reactions of the enolate of 2 with alkyl halides or Michael
acceptors proceeded with low stereoselectivity, but eno-
lization-reprotonation of the initially obtained mixtures
of epimers afforded the cis 3-substituted prolinones with
very high stereocontrol.
and 5 mg (5%) of 6b. 5b: [R]20 ) -76.3° (c 1.0, CHCl3); IR
D
(NaCl) 3575, 1751, 1745, 1444 cm-1; H NMR (CDCl3) δ 2.85
1
(s, 3H), 2.88 (dd, J ) 5.5 and 7.7 Hz, 1H), 3.33 (d, J ) 18.2
Hz, 1H), 3.37 (d, J ) 5.4 Hz, 1H), 3.79 (d, J ) 18.2 Hz, 1H),
4.67 (d, J ) 7.8 Hz, 1H), 7.09-7.70 (m, 17H); 13C NMR (CDCl3)
δ 51.4, 56.4, 58.8, 60.7, 72.7, 75.8, 120.1, 120.2, 122.3, 125.8,
126.9, 127.5, 127.8, 128.0, 128.5, 129.0, 129.1, 131.5, 138.9,
140.4, 141.1, 141.2, 144.2, 146.2, 172.6, 213.4. Anal. Calcd for
C
32H26ClNO4: C, 73.3; H, 5.0; N, 2.7. Found: C, 73.2; H, 5.1;
N, 2.6. 6b: [R]22 ) -126.5° (c 1.1, CHCl3); IR (NaCl) 3570,
D
1750, 1745, 1444 cm-1; H NMR (CDCl3) δ 2.77 (s, 3H), 2.90
1
(t, J ) 5.0 Hz, 1H), 3.26 (d, J ) 17.6 Hz, 1H), 3.73 (d, J ) 17.4
Hz, 1H), 3.74 (d, J ) 5.7 Hz, 1H), 5.11 (d, J ) 5.2 Hz, 1H),
7.11-7.72 (m, 17H); 13C NMR (CDCl3) δ 51.3, 56.3, 59.4, 71.4,
75.8, 77.2, 120.1, 120.2, 121.7, 125.8, 127.0, 127.4, 127.5, 127.6,
127.8, 127.9, 128.1, 128.3, 128.5, 128.6, 128.9, 129.0, 131.5,
131.7, 140.0, 140.1, 141.1, 141.5, 143.7, 146.3, 172.6, 211.5.
Anal. Calcd for C32H26ClNO4: C, 73.3; H, 5.0; N, 2.7. Found:
C, 73.1; H, 5.1; N, 2.6.
Exp er im en ta l Section
Gen er a l Meth od s. For general methods, see ref 5a.
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-P h en yl-1′′-h yd r oxy-
methyl]-4-oxo-N-(9′-phenylfluoren-9′-yl)pyrrolidine-2-carboxylic
Acid Meth yl Ester (5a a n d 6a ). Meth od A (En ola te
gen er a tion a t -78 °C). LHMDS (1.01 mL, 1.21 mmol, 260
mol %, 1.2 M in hexane) was added to a precooled (-78 °C)
solution of 2 (179 mg, 0.467 mmol) in THF (1.2 mL). After 1 h
of stirring at -78 °C, benzaldehyde (83 µL, 0.817 mmol, 175
mol %) was added to the reaction mixture. The resulting
solution was stirred for 2.5 h at -78 °C and then it was
quenched with H3PO4 (10%, 0.5 mL). The reaction mixture was
partitioned between H2O (45 mL) and ether (2 × 50 mL). The
combined organic layer was washed with brine, dried with
anhydrous Na2SO4, filtered, and concentrated. The resulting
residue was purified by flash chromatography (EtOAc/hexanes
1/3) and gave 190 mg (85%) of 5a and 32 mg (14%) of 6a (ratio
6:1).
Meth od B (En ola te Gen er a tion a t -55 °C). LHMDS
(0.15 mL, 0.183 mmol, 140 mol %, 1.2 M in hexane) was added
dropwise to a precooled (-58 °C) solution of 2 (50 mg, 0.130
mmol) in THF (0.5 mL). The resulting solution was allowed
to stir at -56/-54 °C for 1 h. Then, the reaction mixture was
cooled (-78 °C) and benzaldehyde (19 µL, 0.183 mmol, 140
mol %) was added. The resulting solution was stirred at -78
°C for 2 h. The procedure described in method A was followed
for the workup. After purification, 58 mg (90%) of 5a and 5
mg (8%) of 6a were obtained (ratio 10:1).
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(4-Br om op h en yl)-1′′-
h yd r oxym eth yl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr r oli-
d in e-2-ca r boxylic Acid Meth yl Ester (5c a n d 6c). A
mixture of compounds 5c and 6c was obtained from the
reaction of the enolate of 2 (prepared from 77 mg, 0.20 mmol)
with 4-bromobenzaldehyde (74 mg, 0.40 mmol, 200 mol %) by
following method A described above. Purification by flash
chromatography (EtOAc/hexanes 1/4) gave 98 mg (86%) of 5c
and 13 mg (11%) of 6c. 5c: [R]23 ) -25.7° (c 0.46, CHCl3); IR
D
(NaCl) 2929, 1746, 1731, 1448 cm-1; H NMR (CDCl3) δ 2.76
1
(s, 3H), 2.90 (t, J ) 4.8 Hz, 1H), 3.06 (d, J ) 5.8 Hz, 1H), 3.25
(d, J ) 17.7 Hz, 1H), 3.73 (d, J ) 17.6 Hz, 1H), 3.74 (d, J )
5.5 Hz, 1H), 5.10 (t, J ) 4.4 Hz, 1H), 7.06-7.72 (m, 17H); 13
C
NMR (CDCl3) δ 51.3, 56.3, 59.4, 71.4, 75.8, 77.2, 120.1, 120.2,
121.7, 125.8, 127.0, 127.4, 127.5, 127.6, 127.8, 127.9, 128.1,
128.3, 128.5, 128.6, 128.9, 129.0, 131.5, 131.7, 140.0, 140.1,
141.1, 141.5, 143.7, 146.3, 172.6, 211.5. Anal. Calcd for C32H26
-
BrNO4: C, 67.6; H, 4.6; N, 2.5. Found: C, 67.8; H, 4.7; N, 2.5.
6c: [R]23D ) -61.4° (c 0.86, CHCl3); IR (NaCl) 3100, 1757, 1452
cm-1; 1H NMR (CDCl3) δ 2.84 (s, 3H), 2.86 (m, 1H), 3.30 (d, J
) 18.1 Hz, 1H), 3.38 (d, J ) 5.3 Hz, 1H), 3.55 (s, 1H), 3.78 (d,
J ) 18.2 Hz), 4.66 (d, J ) 7.6 Hz, 1H), 7.01-7.70 (m, 17H);
13C NMR (CDCl3) δ 51.4, 56.4, 58.8, 60.7, 72.7, 75.8, 120.1,
120.2, 122.3, 125.8, 126.9, 127.5, 127.8, 128.0, 128.5, 129.0,
129.1, 131.5, 138.9, 140.4, 141.1, 141.2, 144.2, 146.2, 172.6,
213.4. Anal. Calcd for C32H26BrNO4: C, 67.6; H, 4.6; N, 2.5.
Found: C, 67.8; H, 4.8; N, 2.6.
Meth od C (En ola te Gen er a tion u sin g n -Bu Li a s Ba se).
n-BuLi (105 mol %, 2.25 M in hexanes) was added to a solution
of 2 in THF at -55 °C. After stirring at -55 to -58 °C for 1 h,
the enolate solution was cooled to -78 °C and treated with
the corresponding aldehyde, and the resulting solution was
stirred at -78 °C for the specified time. The procedure
described in method A was followed for the workup. 5a : [R]25
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(4-Meth oxyp h en yl)-
1′′-h yd r oxym eth yl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in e-2-ca r boxylic Acid Meth yl Ester (5d a n d 6d ). A
mixture of compounds 5d and 6d was obtained from the
reaction of the enolate of 2 (prepared from 78 mg, 0.20 mmol)
with 4-methoxybenzaldehyde (49 µL, 0.41 mmol, 200 mol %)
by following method A described above. Purification by flash
chromatography (EtOAc/hexanes 1/4) gave 37 mg (35%) of 5d
and 21 mg (20%) of 6d . 5d : [R]19D ) -93.4° (c 0.45, CHCl3); IR
(NaCl) 2928, 1755, 1746, 1514, 1450 cm-1; 1H NMR (CDCl3) δ
2.78 (s, 3H), 2.90 (t, J ) 4.6 Hz, 1H), 3.72 (d, J ) 17.4 Hz,
1H), 3.78 (s, 3H), 3.79 (d, J ) 4.8 Hz, 1H), 5.06 (d, J ) 4.1 Hz,
1H), 6.80-7.73 (m, 17H); 13C NMR (CDCl3) δ 51.2, 55.2, 56.2,
59.6, 59.8, 72.0, 77.2, 113.9, 120.1, 120.2, 125.9, 127.0, 127.3,
127.7, 127.9, 128.4, 128.6, 128.9, 133.2, 140.0, 141.3, 141.6,
143.8, 146.5, 159.3, 172.7, 211.9. Anal. Calcd for C33H29NO5:
D
) -94.9° (c 1.25, CHCl3); IR (NaCl) 3060, 1755, 1747, 1452
cm-1; H NMR (CDCl3) δ 2.79 (s, 3H), 2.92 (dd, J ) 7.9 and
1
5.0 Hz, 1H), 3.33 (d, J ) 18.0 Hz, 1H), 3.44 (d, J ) 5.0 Hz,
1H), 3.79 (d, J ) 18.0 Hz, 1H), 4.72 (d, J ) 7.9 Hz, 1H), 7.18-
7.70 (m, 18H); 13C NMR (CDCl3) δ 51.2, 56.1, 58.8, 60.8, 73.4,
75.6, 120.0, 120.1, 125.8, 126.8, 126.9, 127.4, 127.5, 127.7,
127.9, 128.3, 128.4, 128.9, 129.0, 139.8, 140.1, 141.2, 141.3,
144.0, 146.3, 172.4, 213.8. Anal. Calcd for C32H27NO4: C, 78.5;
H, 5.6; N, 2.9. Found: C, 78.2; H, 5.6; N, 2.6. 6a : [R]23
)
D
-132.7° (c 1.03, CHCl3); IR (NaCl) 3594, 1760, 1747, 1447
cm-1; H NMR (CDCl3) δ 2.72 (s, 3H), 2.95 (dd, J ) 5.0 and
1
4.2 Hz, 1H), 3.26 (d, J ) 17.5 Hz, 1H), 3.72 (d, J ) 17.5 Hz,
1H), 3.84 (d, J ) 5.5 Hz, 1H), 5.17 (d, J ) 3.8 Hz, 1H), 7.19-
7.72 (m, 18H); 13C NMR (CDCl3) δ 51.1, 56.2, 59.4, 59.6, 71.9,
76.5, 120.0, 120.1, 125.5, 125.7, 125.9, 126.9, 127.0, 127.3,
127.6, 127.7, 127.8, 127.9, 128.3, 128.4, 128.6, 128.9, 139.9,
140.9, 141.2, 141.6, 143.6, 146.4, 172.7, 211.8. Anal. Calcd for
C, 76.3; H, 5.6; N, 2.7. Found: C, 76.5; H, 5.7; N, 2.7. 6d : [R]24
D
) -71.9° (c 0.54, CHCl3); IR (NaCl) 3664, 1748 cm-1; 1H NMR
(CDCl3) δ 2.83 (s, 3H), 2.89 (dd, J ) 5.4 and 7.9 Hz, 1H), 3.34
(d, J ) 18.0 Hz, 1H), 3.41 (d, J ) 5.0 Hz, 1H), 3.42 (br s, 1H),
3.78 (s, 3H), 3.79 (d, J ) 16.2 Hz, 1H), 4.66 (d, J ) 8.1 Hz,
1H), 6.80-7.71 (m, 17H); 13C NMR (CDCl3) δ 51.3, 55.2, 56.2,
59.0, 61.0, 73.1, 75.6, 113.8, 120.0, 120.1, 125.8, 126.9, 127.3,
127.5, 127.7, 127.8, 127.9, 128.0, 128.4, 128.5, 128.9, 129.0,
132.0, 140.1, 141.1, 141.2, 144.0, 146.3, 159.6, 172.4, 213.8.
C
32H27NO4: C, 78.5; H, 5.6; N, 2.9. Found: C, 78.4; H, 5.6; N,
2.8.
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(4-Ch lor op h en yl)-1′′-
h yd r oxym eth yl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr r oli-
d in e-2-ca r boxylic Acid Meth yl Ester (5b a n d 6b). A
mixture of compounds 5b and 6b was obtained from the
reaction of the enolate 2 (prepared from 70 mg, 0.183 mmol)

Conformationally Restricted Amino Acid Analogues
J . Org. Chem., Vol. 64, No. 24, 1999 8791
Anal. Calcd for C33H29NO5: C, 76.3; H, 5.6; N, 2.7. Found: C,
76.4; H, 5.7; N, 2.7.
1735, 1751 cm-1. Anal. Calcd for C34H31NO6: C, 74.3; H, 5.7;
N, 2.6. Found: C, 74.0; H, 5.6; N, 2.5. 6g: [R]20D ) -156 (c 1.6,
CH2Cl2); 1H NMR (CDCl3) δ 2.72 (s, 3H), 2.82 (t, J ) 4.2, 1H),
2.93 (bs, 1H), 3.24 (d, J ) 17.6, 1H), 3.69 (d, J ) 17.6, 1H),
3.74 (d, J ) 5.4, 1H), 3.77 (s, 3H), 3.78 (s, 3H), 5.00 (bt, J )
3.7, 1H), 6.68 (m, 3H), 7.10-7.35 (m, 10H), 7.42 (d, J ) 7.5,
1H), 7.62 (t, J ) 8.0, 2H); 13C NMR (CDCl3) δ 51.3, 55.8, 55.9,
56.1, 59.5, 59.6, 72.2, 75.6, 108.7, 110.8, 118.0, 120.0, 120.1,
125.7, 126.9, 127.3, 127.7, 127.8, 128.4, 128.8, 128.9, 133.5,
139.9, 141.0, 141.5, 143.6, 146.2, 148.5, 148.9, 172.6, 212.0;
IR (NaCl) 1736, 1751 cm-1. Anal. Calcd for C34H31NO6: C, 74.3;
H, 5.7; N, 2.6. Found: C, 74.1; H, 5.7; N, 2.3.
(2S,3S,1′′R)- a n d (2S,3S,1′′S)- 3-[1′′-(2-Br om op h en yl)-
1′′-h yd r oxym eth yl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in e-2-ca r boxylic Acid Meth yl Ester (5e a n d 6e). A
mixture of compounds 5e and 6e was obtained from the
reaction of the enolate of 2 (prepared from 60 mg, 0.157 mmol)
with 2-bromobenzaldehyde (56 µL, 0.47 mmol, 300 mol %) by
following method A described above. Purification by flash
chromatography (EtOAc/hexanes 1/5) gave 35 mg (39%) of 5e
and 34 mg (39%) of 6e. 5e: [R]20 ) -118.6° (c 1.1, CHCl3); IR
D
(NaCl) 3590, 1756, 1745, 1444 cm-1; H NMR (CDCl3) δ 2.63
1
(s, 3H), 2.81 (d, J ) 4.6 Hz, 1H), 3.16 (d, J ) 17.4 Hz, 1H),
3.30 (m, 1H), 3.62 (d, J ) 17.4 Hz, 1H), 3.93 (d, J ) 6.4 Hz,
1H), 5.53 (br d, 1H), 7.07-7.74 (m, 17H); 13C NMR (CDCl3) δ
51.2, 56.5, 57.1, 59.1, 70.2, 75.7, 120.0, 120.1, 121.4, 125.7,
127.0, 127.2, 127.3, 127.6, 127.8, 127.9, 128.0, 128.3, 128.8,
128.9, 129.1, 132.5, 139.5, 139.6, 141.0, 141.7, 143.0, 146.7,
172.0, 211.0. Anal. Calcd for C32H26BrNO4: C, 67.6; H, 4.6; N,
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(1,3-Ben zod ioxol-5-
yl)-1′′-h yd r oxym et h yl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)-
p yr r olid in e-2-ca r boxylic Acid Meth yl Ester (5h a n d 6h ).
A mixture of compounds 5h and 6h was obtained from the
reaction of the enolate of 2 (prepared from 67 mg, 0.18 mmol)
with a solution of 3,4-methylenedioxybenzaldehyde (40 mg,
0.26 mmol, 150 mol %) in THF (1 mL) by following method C
described above (reaction time, 5 h). Purification by flash
2.4. Found: C, 67.4; H, 4.7; N, 2.4. 6e: [R]26 ) -85.4° (c 1.0,
D
CHCl3); IR (NaCl) 3580, 1755, 1742, 1444 cm-1
;
1H NMR
chromatography (EtOAc/hexanes 1/4) gave 57 mg (61%) of 5h
1
(CDCl3) δ 2.69 (s, 3H), 3.05 (t, J ) 7.3 Hz, 1H), 3.29 (d, J )
18.0 Hz, 1H), 3.69 (d, J ) 17.2 Hz, 1H), 3.70 (d, J ) 7.0 Hz,
1H), 3.97 (br s, 1H), 5.19 (d, J ) 7.4 Hz, 1H), 7.08-7.73 (m,
17H); 13C NMR (CDCl3) δ 51.5, 56.8, 57.9, 61.7, 71.9, 76.0,
120.1, 120.3, 122.6, 125.7, 127.1, 127.3, 127.6, 127.8, 128.1
(2C), 128.4, 128.9, 129.0, 129.1, 129.6, 132.4, 138.4, 140.0,
and 23 mg (25%) of 6h . 5h : [R]20 ) -119 (c 1.0, CH2Cl2); H
D
NMR (CDCl3) δ 2.75 (dd, J ) 4.7, 8.0, 1H), 2.81 (s, 3H), 3.29
(d, J ) 17.9, 1H), 3.33 (d, J ) 4.7, 1H), 3.74 (d, J ) 17.9, 1H),
4.57 (d, J ) 8.0, 1H), 5.85 (d, J ) 1.4, 1H), 5.86 (d, J ) 1.4,
1H), 6.55 (m, 3H), 7.13-7.36 (m, 11H), 7.61 (m, 2H); 13C NMR
(CDCl3) δ 51.4, 56.1, 59.0, 60.8, 73.2, 75.6, 101.1, 107.1, 107.9,
120.1, 120.2, 120.5, 125.8, 126.8, 127.4, 1127.7, 127.9, 128.4,
128.9, 129.0, 133.8, 140.1, 141.1, 141.2, 144.0, 146.2, 147.8,
172.4, 213.7. IR 1740, 1751 cm-1. Anal. Calcd for C33H27NO6:
140.8, 141.4, 143.1, 146.3, 172.2, 213.2. Anal. Calcd for C32H26
-
BrNO4: C, 67.6; H, 4.6; N, 2.4. Found C, 67.3; H, 4.7; N, 2.4.
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(3-Meth oxyp h en yl)-
1′′-h yd r oxym eth yl]-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in e-2-ca r boxylic Acid Meth yl Ester (5f a n d 6f). A
mixture of compounds 5f and 6f was obtained from the reaction
of the enolate of 2 (prepared from 50 mg, 0.13 mmol) with
3-methoxybenzaldehyde (24 µL, 0.20 mmol, 150 mol %) by
following method C described above (reaction time, 2.5 h).
Purification by flash chromatography (EtOAc/hexanes 1/3)
gave 59 mg (87%) of 5f and 7 mg (10%) of 6f. 5f: [R]20D ) -148
C, 74.3; H, 5.1; N, 2.6. Found: C, 74.2; H, 4.9; N, 2.4. 6h : [R]20
D
1
) -174 (c 1.3, CH2Cl2); H NMR (CDCl3) δ 2.76 (s, 3H), 2.78
(m, 1H), 2.96 (bd, J ) 4.7, 1H), 3.22 (d, J ) 17.3, 1H), 3.75 (d,
J ) 17.3, 1H), 3.71 (d, J ) 5.0, 1H), 4.95 (bt, J ) 3.8, 1H),
5.85 (d, J ) 1.6, 1H), 5.86 (d, J ) 1.6, 1H), 6.62 (m, 3H), 7.12-
7.45 (m, 11H), 7.61 (m, 2H); 13C NMR (CDCl3) δ 51.3, 56.0,
59.5, 59.6, 72.2, 75.5, 101.1, 106.4, 108.1, 119.1, 120.0, 120.1,
125.7, 126.9, 127.3, 127.7, 127.8, 127.9, 128.4, 128.9, 135.0,
139.8, 141.0, 141.5, 143.5, 146.3, 147.1, 147.7, 172.5, 211.7;
IR 1734, 1752 cm-1. Anal. Calcd for C33H27NO6: C, 74.3; H,
5.1; N, 2.6. Found: C, 74.0; H, 5.0; N, 2.3.
1
(c 1.1, CH2Cl2); H NMR (CDCl3) δ 2.78 (s, 3H), 2.86 (dd, J )
4.7, 7.9, 1H), 3.30 (d, J ) 17.8, 1H), 3.43 (d, J ) 4.7, 1H), 3.74
(s, 3H), 3.75 (d, J ) 17.8, 1H), 4.69 (d, J ) 7.9, 1H), 6.74 (m,
3H), 7.13-7.39 (m, 12H), 7.64 (m, 2H); 13C NMR (CDCl3) δ
51.3, 55.2, 56.1, 58.9, 60.7, 73.3, 75.5, 111.9, 114.2, 119.1, 120.0,
125.9, 126.8, 127.3, 127.4, 127.7, 127.9, 128.4, 129.0, 129.4,
140.0, 141.2, 141.3, 141.4, 143.9, 146.2, 159.7, 172.5, 213.6.
IR 1731, 1744 cm-1. Anal. Calcd for C33H29NO5: C, 76.3; H,
(2S,3S,1′′R)- a n d
(2S,3S,1′′S)-3-[1′′′(3,4,5-Tr im et h -
o x y p h e n y l)-1′′-h y d r o x y m e t h y l]-4-o x o -N -(9′-p h e n y l-
flu or en -9′-yl)p yr r olid in e-2-ca r boxylic Acid Meth yl Ester
(5i a n d 6i). A mixture of compounds 5i and 6i was obtained
from the reaction of the enolate of 2 (prepared from 66 mg,
0.17 mmol) with a solution of 3,4,5-trimethoxybenzaldehyde
(51 mg, 0.26 mmol, 150 mol %) in THF (1 mL) by following
method C described above (reaction time, 5 h). Purification
by flash chromatography (EtOAc/hexanes 1/2) gave 70 mg
5.6; N, 2.7. Found: C, 76.2; H, 5.4; N, 2.7. 6f: [R]20 ) -172 (c
D
1.7, CH2Cl2); 1H NMR (CDCl3) δ 2.67 (s, 3H), 2.83 (bt, J ) 4.5,
1H), 2.97 (bs, 1H), 3.20 (d, J ) 17.3, 1H), 3.65 (d, J ) 17.3,
1H), 3.69 (s, 3H), 3.75 (d, J ) 5.6, 1H), 5.05 (bd, J ) 2.7, 1H),
6.71 (m, 3H), 7.10-7.45 (m, 12H), 7.59 (d, J ) 7.4, 1H), 7.63
(70%) of 5i and 10 mg (10%) of 6i. 5i: [R]20 ) -122 (c 1.25,
D
13
1
(d, J ) 7.4, 1H); C NMR (CDCl3) δ 51.2, 55.2, 56.1, 59.4,
CH2Cl2); H NMR (CDCl3) δ 2.78 (s, 3H), 2.87 (m, 1H), 3.25
72.1, 75.5, 111.0, 113.4, 117.9, 120.0, 125.8, 126.7, 126.9, 127.3,
127.6, 127.8, 128.4, 128.8, 128.9, 129.4, 139.7, 141.0, 141.6,
(d, J ) 18.7, 1H), 3.37 (d, J ) 5.5, 1H), 3.43 (bs, 1H), 3.71 (m,
1H), 3.72 (s, 3H), 3.74 (s, 6H), 4.57 (d, J ) 7.6, 1H), 6.30 (s,
2H), 7.10-7.35 (m, 11H), 7.59 (d, J ) 7.7, 2H); 13C NMR
(CDCl3) δ 51.4, 56.0, 56.5, 59.0, 60.5, 60.7, 73.3, 75.8, 119.9,
120.0, 125.7, 126.8, 127.3, 127.4, 127.7, 127.8, 128.4, 128.8,
128.9, 135.5, 137.6, 140.2, 140.9, 141.2, 144.1, 146.1, 153.1,
142.5, 143.4, 146.3, 159.6, 172.5, 211.8. IR 1739, 1755 cm-1
.
Anal. Calcd for C33H29NO5: C, 76.3; H, 5.6; N, 2.7. Found: C,
76.5; H, 5.7; N, 2.5.
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(3,4-Dim et h oxy-
p h en yl)-1′′-h yd r oxym et h yl]-4-oxo-N-(9′-p h en ylflu or en -
9′-yl)p yr r olid in e-2-ca r boxylic Acid Meth yl Ester (5g a n d
6g). A mixture of compounds 5g and 6g was obtained from
the reaction of the enolate of 2 (prepared from 77 mg, 0.20
mmol) with a solution of 3,4-dimethoxybenzaldehyde (50 mg,
0.30 mmol, 150 mol %) in THF (1 mL) by following method C
described above (reaction time, 5 h). Purification by flash
chromatography (EtOAc/hexanes 1/2) gave 44 mg (40%) of 5g
and 11 mg (10%) of 6g; 38 mg of ketone 2 were recovered as
well. 5g: [R]20D ) -119 (c 1.1, CH2Cl2); 1H NMR (CDCl3) δ 2.76
(s, 3H), 2.87 (m, 1H), 3.26 (d, J ) 18.2, 1H), 3.33 (d, J ) 5.3,
1H), 3.40 (bs, 1H), 3.72 (d, J ) 18.2, 1H), 3.76 (s, 3H), 3.78 (s,
3H), 4.57 (d, J ) 7.9, 1H), 6.63 (m, 3H), 7.09-7.37 (m, 11H),
7.60 (d, J ) 7.8, 2H); 13C NMR (CDCl3) δ 51.4, 55.7, 55.8, 56.5,
59.0, 60.9, 73.2, 75.7, 109.4, 110.6, 119.3, 120.0, 120.1, 125.7,
126.8, 127.3, 127.4, 127.7, 127.9, 128.4, 128.9, 129.0, 132.3,
140.2, 141.0, 141.2, 144.0, 146.2, 148.9, 172.6, 213.9; IR (NaCl)
172.8, 213.6; IR (NaCl) 1736, 1751 cm-1. Anal. Calcd for C35H33
-
NO7: C, 72.5; H, 5.7; N, 2.4. Found: C, 72.3; H, 5.7; N, 2.3.
1
6i: [R]20 ) -174 (c 1.4, CH2Cl2); H NMR (CDCl3) δ 2.71 (s,
D
3H), 2.81 (m, 1H), 3.03 (t, J ) 5.2, 1H), 3.26 (d, J ) 17.5, 1H),
3.67 (m, 2H), 3.73 (s, 3H), 3.74 (s, 6H), 5.02 (t, J ) 4.3, 1H),
6.35 (s, 2H), 7.13-7.46 (m, 11H), 7.62 (t, J ) 8.0, 2H); 13C NMR
(CDCl3) δ 51.3, 55.9, 56.0, 56.1, 59.2, 59.4, 60.7, 72.3, 75.6,
120.0, 125.7, 126.8, 127.3, 127.7, 127.8, 128.4, 128.9, 129.0,
136.7, 137.1, 139.9, 141.0, 141.5, 143.5, 146.2, 153.2, 172.6,
211.9; IR (NaCl) 1740, 1751 cm-1. Anal. Calcd for C35H33NO7:
C, 72.5; H, 5.7; N, 2.4. Found: C, 72.2; H, 5.7; N, 2.3.
(2S,3S,1′′R)- a n d (2S,3S,1′′S)-3-[1′′-(1-Na p h th yl)-1′′-h y-
dr oxym eth yl]-4-oxo-N-(9′-ph en ylflu or en -9′-yl)pyr r olidin e-
2-ca r boxylic Acid Meth yl Ester (5j a n d 6j). A mixture of
compounds 5j and 6j was obtained from the reaction of the
enolate of 2 (prepared from 45 mg, 0.12 mmol) with a solution
of 1-naphthaldehyde (24 µL, 0.18 mmol, 150 mol %) in THF

8792 J . Org. Chem., Vol. 64, No. 24, 1999
Blanco et al.
(1 mL) by following method C described above (reaction time,
2.5 h). Purification by flash chromatography (EtOAc/hexanes
Anal. Calcd for C32H33NO4: C, 77.6; H, 6.7; N, 2.8. Found: C,
77.4; H, 7.0; N, 2.8.
1/4) gave 47 mg (75%) of 5j and 11 mg (17%) of 6j. 5j: [R]20
)
D
(2S,3S,4S,1′′R)-3-[1′′-P h en yl-1′′-h yd r oxym et h yl]-4-h y-
d r oxy-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r boxyl-
ic Acid Meth yl Ester (7a ). NaBH4 (27 mg, 0.679 mmol, 250
mol %) was added to a precooled (-78 °C) solution of 5a (133
mg, 0.272 mmol) in MeOH/THF (1/1, 2.2 mL). The resulting
suspension was stirred at -78 °C for 4 h and then H3PO4 (10%,
0.25 mL) was added. The reaction mixture was allowed to
warm to room temperature. The resulting suspension was
partitioned between H2O (20 mL) and CH2Cl2 (25 mL). The
aqueous phase was extracted with CH2Cl2 (2 × 15 mL). The
combined organic layer was washed with brine, dried, and
concentrated. The residue was purified by flash chromatog-
raphy (EtOAc/hexanes 2/3) to give 131 mg (98%) of 7a as a
1
-139 (c 1.0, CH2Cl2); H NMR (CDCl3) δ 2.40 (s, 3H), 3.20 (t,
J ) 6.9, 1H), 3.24 (d, J ) 17.9, 1H), 3.36 (d, J ) 5.8, 1H), 3.67
(d, J ) 17.9, 1H), 3.75 (bs, 1H), 5.31 (d, J ) 7.8, 1H), 7.06-
13
7.44 (m, 15 H), 7.57-7.77 (m, 4H), 7.98 (m, 1H);
C NMR
(CDCl3) δ 51.0, 56.5, 58.1, 61.8, 71.6, 75.8, 120.0, 120.1, 123.3,
125.1, 125.6, 125.7, 125.8, 126.2, 126.8, 127.3, 127.6, 128.0,
128.3, 128.8, 128.9, 129.0, 130.6, 133.8, 134.8, 139.9, 141.0,
141.3, 143.5, 146.4, 171.9, 214.0; IR 1740, 1753 cm-1. Anal.
Calcd for C36H29NO4: C, 80.1; H, 5.4; N, 2.6. Found: C, 79.9;
H, 5.2; N, 2.3. 6j: [R]20 ) -198 (c 0.5, CH2Cl2); 1H NMR
D
(CDCl3) δ 2.36 (s, 3H), 2.93 (d, J ) 4.3, 1H), 3.13 (dd, J ) 3.1,
5.9, 1H), 3.19 (d, J ) 17.3, 1H), 3.63 (d, J ) 17.3, 1H), 3.89 (d,
13
white foam. [R]28 ) 172.5° (c 0.61, CHCl3); IR (NaCl) 3585,
J ) 5.9, 1H), 5.98 (bt, J ) 3.1, 1H), 7.08-7.83 (m, 20H);
C
D
1729, 1452 cm-1; 1H NMR (CDCl3) δ 2.05 (d, J ) 2.9 Hz, 1H),
2.26 (br d, J ) 9.9 Hz, 1H), 2.43 (d, J ) 2.7 Hz, 1H), 2.98 (s,
3H), 3.36 (dd, J ) 3.8 and 10.0 Hz, 1H), 3.51 (d, J ) 10.1 Hz,
1H), 3.79 (br d, J ) 9.9 Hz, 1H), 4.23 (br d, J ) 10.8 Hz, 1H),
4.40 (br d, J ) 8.5 Hz, 1H), 6.61-7.81 (m, 18H); 13C NMR
(CDCl3) δ 51.5, 55.1, 59.2, 61.0, 73.0, 75.0, 75.4, 119.9, 120.3,
126.8, 127.0, 127.2, 127.4, 127.5, 127.8, 128.1, 128.3, 128.5,
128.9, 139.0, 141.3, 141.7, 142.4, 145.4, 147.9, 177.4. Anal.
Calcd for C32H29NO4: C, 78.2; H, 6.0; N, 2.9. Found: C, 78.4;
H, 6.1; N, 2.9.
NMR (CDCl3) δ 51.0, 56.3, 58.3, 59.1, 68.3, 75.8, 120.0, 120.1,
121.9, 123.0, 125.1, 125.7, 126.6, 127.0, 127.3, 127.7, 127.9,
128.0, 128.3, 128.4, 128.8, 129.0, 129.3, 136.2, 139.7, 141.0,
141.8, 143.1, 146.6, 171.8, 211.7; IR 1740, 1753 cm-1. Anal.
Calcd for C36H29NO4: C, 80.1; H, 5.4; N, 2.6. Found: C, 80.8;
H, 5.2; N, 2.5.
(2S,3S,1′′R)-3-[1′′-(Isop r op yl)-1′′-h yd r oxym eth yl]-4-oxo-
N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r boxylic Acid
Meth yl Ester (5k ). Compound 5k was obtained from the
reaction of the enolate of 2 (prepared from 140 mg, 0.365 mmol)
with isobutyraldehyde (54 µL, 0.602 mmol, 165 mol %, freshly
distilled from CaH2) by following method B described above.
Purification by flash chromatography (EtOAc/hexanes 1/5)
(2S,3S,4S,1′′R)-3-[1′′-Isop r op yl-1′′-h yd r oxym et h yl]-4-
h yd r oxy-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r box-
ylic Acid Meth yl Ester (7b). The same procedure as for 5k
was used; 75 mg of 5k (0.165 mmol) afforded 73 mg (98%) of
gave 120 mg (72%) of 5k : [R]20 ) -65° (c 1.72, CHCl3); IR
D
(NaCl) 2960, 1746, 1455, 745, 502 cm-1; H NMR (CDCl3) δ
1
7k as a white foam. 7k : [R]20 ) +205° (c 1.25, CHCl3); IR
D
(NaCl) 3416, 1733, 1459, 749, 664 cm-1; H NMR (CDCl3) δ
1
0.71 (d, J ) 6.5 Hz, 3H), 0.80 (d, J ) 6.5 Hz, 3H), 1.53-1.66
(m, 1H), 2.48 (dd, J 32 ) 4.5 Hz, J 31′ ) 6.5 Hz, 1H), 3.05 (s,
3H), 3.20 (dd, J 1′3 ) 6.7 Hz, J 1′2′ ) 5.9 Hz, 1H), 3.42 (d, J )
4.4 Hz, 1H), 3.45 (d, J ) 18.5 Hz, 1H), 3.78 (d, J ) 17.6 Hz,
1H), 7.16-7.67 (m, 13H), 13C NMR (CDCl3) δ 15.1, 18.6, 30.2,
50.7, 54.1, 55.1, 61.4, 74.8, 75.3, 119.4, 119.6, 124.3, 124.8,
125.7, 126.1, 126.7, 127.0, 127.3, 127.8, 128.2, 139.7, 140.3,
140.7, 143.8, 145.4, 171.8, 213.1. Anal. Calcd for C25H21NO3:
C, 76.5; H, 6.4; N, 3.1. Found: C, 76.3; H, 6.4; N, 3.2.
0.55 (d, J ) 6.9 Hz, 3H), 0.59 (d, J ) 6.9 Hz, 3H), 1.18-1.31
(m, 1H), 1.32-1.60 (br d, 1H), 1.88 (d, J ) 8.5 Hz), 2.52-2.56
(m, 2H), 3.12-3.15 (m, 1H), 3.17 (s, 3H), 3.37 (d, J ) 10.4 Hz,
1H), 3.99 (br s, 1H), 4.23-4.24 (m, 1H), 7.1-7.8 (m, 13H), 13
C
NMR (CDCl3) δ 14.4, 20.0, 29.5, 50.9, 55.1, 55.6, 61.4, 72.9,
75.4, 76.0, 120.1, 120.2, 126.4, 127.2, 127.4, 127.5, 127.6, 128.2,
128.4, 128.8, 139.2, 141.4, 141.8, 143.8, 144.8, 147.8, 177.4.
Anal. Calcd for C25H21NO3: C, 76.1; H, 6.8; N, 3.1. Found: C,
76.0; H, 6.9; N, 3.3.
(2S,3S,1′′R)-3-[1′′-(3-Meth ylbu tyl)-1′′-h yd r oxym eth yl]-
4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r b oxyl-
ic Acid Meth yl Ester (5l). Compound 5l was obtained from
the reaction of the enolate of 2 (prepared from 43 mg, 0.11
mmol) with isovaleraldehyde (18 µL, 0.17 mmol, 150 mol %,
freshly distilled from CaH2) by following method C described
above (reaction time, 5 h). Purification by flash chromatogra-
phy (EtOAc/hexanes 1/4) gave 48 mg (91%) of 5l: [R]20D ) -132
(c 1.35, CH2Cl2); 1H NMR (CDCl3) δ 0.84 (d, J ) 6.6, 3H), 0.86
(d, J ) 6.6, 3H), 1.06 (m, 1H), 1.42 (m, 1H), 1.76 (m, 1H), 2.44
(t, J ) 5.3, 1H), 2.89 (bs, 1H), 3.12 (s, 3H), 3.52 (d, J ) 17.7,
1H), 3.53 (d, J ) 4.4, 1H), 3.73 (m, 1H), 3.86 (d, J ) 17.7, 1H),
7.23-7.32 (m, 5H), 7.40-7.48 (m, 6H), 7.73 (d, J ) 7.5, 2H);
13C NMR (CDCl3) δ 21.4, 23.5, 24.1, 43.8, 51.5, 56.0, 57.6, 61.9,
69.6, 75.6, 120.1, 120.3, 125.6, 126.8, 127.4, 127.5, 127.7, 128.1,
128.6, 129.0, 129.1, 140.3, 141.0, 141.2, 144.4, 145.9, 172.9,
213.1; IR (NaCl) 1740, 1751 cm-1. Anal. Calcd for C30H31NO4:
C, 76.7; H, 6.7; N, 3.0. Found: C, 76.4; H, 6.4; N, 2.9.
(2S,3S,4S,1′′S)-3-[1′′-P h en yl-1′′-h yd r oxym et h yl]-4-h y-
d r oxy-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r boxyl-
ic Acid Meth yl Ester (9). By following the same procedure
described above for 5a , starting from 6a , 65 mg (96%) of 9 was
obtained as a white foam. [R]28 ) 183.0° (c 0.46, CHCl3); IR
D
(NaCl) 3200, 1730, 1715, 1452 cm-1; H NMR (CDCl3) δ 1.83
1
(d, J ) 3.3 Hz, 1H), 2.25 (d, J ) 9.2 Hz, 1H), 3.17 (dd, J ) 3.9
and 10.0 Hz, 1H), 3.29 (d, J ) 2.2 Hz, 1H), 3.30 (s, 3H), 3.36
(d, J ) 10.2 Hz, 1H), 3.61 (br d, J ) 10.3 Hz, 1H), 3.77 (dd, J
) 3.1 and 9.2 Hz, 1H), 4.08 (br d, J ) 11.8 Hz, 1H), 7.09-7.81
(m, 18H); 13C NMR (CDCl3) δ 52.0, 55.5, 59.4, 61.6, 72.8, 74.6,
75.6, 120.2, 120.4, 126.3, 126.5, 127.0, 127.2, 127.4, 127.5,
128.4, 128.5 (2C), 128.7; 128.9, 139.7, 141.6, 141.8, 145.6,
147.7, 177.9. Anal. Calcd for C32H29NO4: C, 78.2; H, 6.0; N,
2.9. Found: C, 78.4; H, 6.1; N, 2.9.
(1S,4S,6R,9S)-8-Aza -9-ca r b oxym et h yl-4,4-d im et h yl-2-
ph en yl-3,5-dioxa-N-(9′-ph en ylflu or en -9′-yl)bicyclo [3.4.01,6]-
n on a n e (8a ). A solution of 7a (62 mg, 0.126 mmol) in DMF/
acetone (3/1, 0.4 mL) and 2.2-dimethoxypropane (40 µL, 0.315
mmol, 250 mol %) was stirred with PPTS (2 mg, 0.001 mmol,
7 mol %) at room temperature for 36 h. The mixture was
partitioned between H2O (5 mL) and ether (2 × 8 mL). The
combined organic layer was washed with brine, dried, and
concentrated. The residue was purified by column chromatog-
raphy (EtOAc/hexanes 1/6) to afford 62 mg (93%) of 8a as a
(2S,3S,1′′R)-3-[1′′-(1-Cycloh exyl)-1′′-h yd r oxym eth yl]-4-
oxo-N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r b oxylic
Acid Meth yl Ester (5m ). Compound 5m was obtained from
the reaction of the enolate of 2 (prepared from 70 mg, 0.18
mmol) with cyclohexanecarboxaldehyde (33 µL, 0.27 mmol, 150
mol %, freshly distilled from CaH2) by following method C
described above (reaction time, 6 h). Purification by flash
chromatography (EtOAc/hexanes 1/4) gave 80 mg (88%) of 5m :
1
[R]20 ) -73 (c 1.0, CH2Cl2); H NMR (CD2Cl2-D2O) δ 0.83-
white foam. [R]24 ) 207.8° (c 0.54, CHCl3); IR (NaCl) 2951,
D
D
1.26 (m, 6H), 1.38-1.61 (m, 5H), 2.51 (dd, J ) 4.7, 4.0, 1H),
2.99 (s, 3H), 3.25 (t, J ) 6.2, 1H), 3.38 (d, J ) 17.6, 1H), 3.40
(d, J ) 4.7, 1H), 3.72 (d, J ) 17.6, 1H), 7.16-7.40 (m, 11H),
7.66 (m, 2H); 13C NMR (CDCl3) δ 26.2, 26.5, 26.6, 27.4, 30.1,
41.0, 52.0, 54.8, 56.7, 62.8, 76.3, 76.4, 120.5, 120.7, 126.1, 127.4,
127.8, 128.1, 128.2, 128.5, 129.0, 129.4, 129.5, 140.8, 141.5,
1748 (CO), 1452 cm-1; 1H NMR (CDCl3) δ 1.41 (s, 3H), 1.44 (s,
3H), 2.31 (c, J ) 10.3 Hz, 1H), 2.43 (s, 3H), 2.58 (d, J ) 10.7
Hz, 1H), 3.47 (m, 2H), 3.75 (dd, J ) 10.2 and 17.5 Hz, 1H),
4.40 (d, J ) 10.2 Hz, 1H), 6.93-7.79 (m, 18H); 13C NMR
(CDCl3) δ 20.0, 29.8, 50.7, 51.8, 53.7, 60.2, 76.7, 77.6, 100.7,
119.8, 120.2, 125.5, 127.1, 127.2, 127.4, 127.5, 128.1, 128.3
(2C), 128.4, 129.0, 138.3, 139.0, 142.5, 143.7, 146.8, 147.5,
141.6, 144.8, 146.4, 173.3, 214.1; IR (NaCl) 1738, 1751 cm-1
.

Conformationally Restricted Amino Acid Analogues
J . Org. Chem., Vol. 64, No. 24, 1999 8793
174.2. Anal. Calcd for C35H33NO4: C, 79.1; H, 6.3; N, 2.6.
Found: C, 79.4; H, 6.3; N, 2.7.
1H NMR (CDCl3) δ 2.17 (t, J ) 7.2 Hz, 3H), 1.83 (dd, J ) 8.5
y 17.6 Hz, 1H), 2.43 (m, 1H), 2.57 (dd, J ) 17.6 y 5.2 Hz, 1H),
3.06 (s, 3H), 3.51 (d, J ) 17.6 Hz, 1H), 3.69 (d, J ) 7.5 Hz,
1H), 3.74 (d, J ) 17.6 Hz, 1H), 4.09 (c, J ) 7.1 Hz, 2H), 7.17-
7.67 (m, 13H); 13C NMR (CDCl3) δ 14.0, 32.7, 51.4, 53.2, 55.9,
60.6, 63.8, 74.6, 120.0, 120.3, 126.1, 127.1, 127.3, 127.8, 127.9,
128.0, 128.5, 129.0, 140.6, 141.1, 141.6, 144.6, 146.1, 170.5,
173.1, 211.8. Anal. Calcd for C29H27NO5: C, 74.2; H, 5.8; N,
3.0. Found: C, 74.4; H, 5.9; N, 3.0.
(1S,4S,6R,9S)-8-Aza -9-ca r b oxym et h yl-4,4-d im et h yl-2-
isop r op yl-3,5-d ioxa -N-(9′-p h e n ylflu or e n -9′-yl)b icyclo-
[3.4.01,6]n on a n e (8k ). The same procedure as for 7a was used;
63 mg of 7k (0.138 mmol) afforded 62 mg (93%) of 8k : [R]21
D
) +215° (c 1.11, CHCl3); IR (NaCl) 1756, 1737, 1602, 661 cm-1
;
1H NMR (CDCl3) δ 0.55 (d, J ) 6.8 Hz, 3H), 0.68 (d, J ) 6.6
Hz, 3H), 1.07-1.38 (m, 1H), 1.17 (s, 3H), 1.26 (s, 3H), 1.91 (c,
J ) 10 Hz, 1H), 2.50 (d, J ) 10.7 Hz, 1H), 3.19 (s, 3H), 3.21-
3.28 (m, 2H), 3.37-3.40 (m, 1H), 3.43-4.47 (m, 1H), 7.01-
7.73 (m, 13H). 1H NMR (C6D6) δ 0.17-0.27 (m, 1H), 0.45 (d, J
) 6.9 Hz), 0.59 (d, J ) 6.9 Hz, 3H), 0.88 (s, 3H), 1.16 (s, 3H),
2.09 (c, J ) 10.2 Hz, 1H), 2.59 (d, J ) 10.7 Hz, 1H), 2.79 (s,
3H), 2.98 (dd, J ) 2.2 Hz, J ) 10.2 Hz, 1H), 3.23-3.30 (m,
2H), 3.32-3.45 (m, 1H), 6.53-7.44 (m, 13H).13C NMR (CDCl3)
δ 13.0, 18.4, 18.8, 28.7, 46.8, 50.4, 52.6, 59.3, 70.6, 76.5, 76.7,
98.6, 118.8, 119.1, 124.5, 126.0, 126.2, 126.3, 127.0, 127.4,
127.8, 138.1, 141.3, 142.6, 145.6, 146.7, 174.3. Anal. Calcd for
(2S,3R)- a n d (2S,3S)-3-[2′′-Ca r boxym eth yleth yl]-4-oxo-
N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r boxylic Acid
Meth yl Ester (10c a n d 11c). The same procedure as for 10a
and 11a was used; 65 mg (0.17 mmol) of 2 gave 44 mg (55%)
of 10c and 21 mg (26%) of 11c as white foams. 10c: [R]19
)
D
-42.6° (c 1.0, CHCl3); IR (NaCl) 2930, 1750, 1740, 1738, 1444
1
cm-1; H NMR (C6D6) δ 1.36 (m, 2H), 1.59 (m, 1H), 1.96 (m,
1H), 2.45 (m, 1H), 2.85 (s, 3H), 3.29 (s, 3H), 3.48 (d, J ) 4.5
Hz, 1H), 3.51 (d, J ) 18.0 Hz, 1H), 3.87 (d, J ) 17.3 Hz, 1H),
6.97-7.57 (m, 13H); 13C NMR (CDCl3) δ 24.4, 31.1, 51.0, 51.4,
51.6, 55.2, 64.0, 75.2, 120.1, 120.3, 125.4, 125.7, 127.3, 127.6,
128.1, 128.9, 129.0, 140.4, 141.2, 141.5, 144.5, 146.3, 171.7,
173.0, 212.9. Anal. Calcd for C29H27NO5: C, 74.2; H, 5.8; N,
C
25H21NO3: C, 77.2; H, 7.0; N, 2.8. Found: C, 77.4; H, 6.8; N,
2.8.
(2S,3R)- a n d (2S,3S)-3-Allyl-4-oxo-N-(9′-p h en ylflu or en -
9′-yl)-p yr r olid in e-2-ca r boxylic Acid Meth yl Ester (10a
a n d 11a ). n-BuLi (0.22 mL, 0.33 mmol, 105 mol %, 1.5 M in
hexanes) was added to a cold (-55 °C) solution of 2 (120 mg,
0.31 mmol) in THF/HMPA (1.2 mL/0.12 mL). The resulting
solution was stirred at -55 °C for 1 h, then allyl iodide (86
µL, 0.94 mmol, 300 mol %) was added. The reaction mixture
was stirred while the temperature was allowed to reach -10
°C (2 h). H3PO4 (10%, 0.3 mL) was added and the reaction
mixture was poured onto ether and washed with H2O, aqueous
saturated sodium thiosulfate, and brine. The organic layer was
dried and concentrated to afford a residue that was purified
by column chromatography (EtOAc/hexanes 1/8) to provide 81
mg of 10a (61%) and 40 mg (30%) of 11a as white foams. 10a :
[R]20D ) 27.8° (c 0.85, CHCl3); IR (NaCl) 2925, 1756, 1730, 1444
3.0. Found: C, 73.9; H, 5.9; N, 2.9. 11c: [R]20 ) -134.3° (c
D
0.9, CHCl3); IR (NaCl) 2932, 1752, 1740, 1735, 1444 cm-1; 1H
NMR (C6D6) δ 2.09 (m, 4H), 2.60 (m, 1H), 2.78 (s, 3H), 3.25 (s,
3H), 3.65 (d, J ) 17.0 Hz, 1H), 3.98 (d, J ) 16.0 Hz, 1H), 4.00
(d, J ) 8.1 Hz, 1H), 6.98-7.49 (m, 13H), 13C NMR (C6D6) δ
20.6, 35.6, 50.5, 50.7, 50.9, 54.2, 62.6, 75.7, 120.2, 120.3, 125.7,
127.1, 128.8, 128.9, 142.3, 171.5, 175.8, 211.7. Anal. Calcd for
C
29H27NO5: C, 74.2; H, 5.8; N, 3.0. Found: C, 73.9; H, 5.9; N,
3.0.
(2S,3R)-3-Deu ter o-4-oxo-N-(9′-p h en ylflu or en -9′-yl)p yr -
r olid in e-2-ca r boxylic Acid Meth yl Ester (10d ). Method C
was used for enolate generation. Quenching the reaction with
CD3OD (excess) at -55 °C afforded 10d (83% yield, 85% D
1
1
incorporation by H NMR). 10d : H NMR (CDCl3) δ 2.20 (bs,
1H), 3.20 (s, 3H), 3.48 (d, J ) 17.9 Hz, 1H), 3.67 (d, J ) 2.9,
1H), 3.77 (d, J ) 17.9 Hz, 1H), 7.23-7.48 (m, 11H), 7.71 (m,
2H).
1
cm-1; H NMR (C6D6) δ 2.07 (m, 1H), 2.33 (m, 1H); 2.47 (m,
1H), 2.84 (s, 3H), 3.53 (d, J ) 17.2 Hz, 1H), 3.60 (d, J ) 4.0
Hz, 1H), 3.94 (d, J ) 17.3 Hz, 1H), 4.86 (m, 2H), 5.49 (m, 1H),
6.96-7.57 (m, 13H); 13C NMR (C6D6) δ 33.9, 50.8, 52.4, 55.4,
63.0, 75.9, 117.4, 120.1, 120.3, 126.1, 126.6, 127.0, 127.2, 128.8,
128.9, 134.8, 140.7, 141.5, 142.4, 145.4, 147.2, 172.9, 211.3.
Anal. Calcd for C28H25NO3: C, 79.4; H, 6.0; N, 3.3. Found: C,
Dep r oton a tion -Rep r oton a tion of a Mixtu r e of 10a /
11a . P r ep a r a tion of 11a . n-BuLi (58 µL, 0.1 mmol, 110 mol
%, 1.8 M in hexanes) was added to a cold (-78 °C) solution of
a 2/1 mixure of 10a and 11a (40 mg, 0.95 mmol) in THF (0.8
mL). The resulting solution was stirred at -78 °C for 90 min.
Then HOAc (0.1 mL) was added. The reaction was poured onto
ether and was washed with water. The organic layer was dried,
filtered, and concentrated. The residue was purified by chro-
matography (EtOAc/hexanes 1/5), to afford pure 11a (34 mg,
85%) as a white foam.
79.1; H, 6.1; N, 3.3. 11a : [R]19 ) 86.1° (c 0.56, CHCl3); IR
D
(NaCl) 2925, 1755, 1725, 1444 cm-1
;
1H NMR (C6D6) δ 2.33
(m, 3H, HC-3), 2.51 (m, 3H), 3.42 (d, J ) 17.0 Hz, 1H), 3.72
(d, J ) 7.6 Hz, 1H), 3.75 (d, J ) 16.9 Hz, 1H), 4.56 (m, 2H),
5.33 (m, 1H), 6.73-7.52 (m, 13H); 13C NMR (C6D6) δ 29.4, 50.3,
51.7, 54.0, 62.2, 75.3, 116.4, 120.0, 120.2, 120.3, 125.3, 125.6,
125.9, 126.7, 127.0, 128.9 (2C), 129.0, 129.5, 133.2, 134.8,
135.5, 140.1, 140.3, 141.6, 142.4, 145.9, 147.5, 151.6, 171.3,
211.1. Anal. Calcd for C28H25NO3: C, 79.4; H, 5.6; N, 3.3.
Found: C, 79.6; H, 6.0; N, 3.3.
Dep r oton a tion -Rep r oton a tion of a Mixtu r e of 10b/
11b. P r ep a r a tion of 11b. The same procedure as for 11a was
used; 40 mg (0.85 mmol) of a 1/1 mixture of 10b and 11b
provided 34 mg (85%) of 11b as a white foam.
(2S,3R)- a n d (2S,3S)-3-[1′′-Ca r boxyeth ylm eth yl]-4-oxo-
N-(9′-p h en ylflu or en -9′-yl)p yr r olid in e-2-ca r boxylic Acid
Meth yl Ester (10b a n d 11b). The same procedure as for 10a
and 11a was used; 59 mg (0.15 mmol) of 2 gave 40 mg (55%)
Dep r oton a tion -Rep r oton a tion of a Mixtu r e of 10c/
11c. P r ep a r a tion of 11c. The same procedure as for 11a was
used; 50 mg (0.106 mmol) of a 1/1 mixture of 10c and 11c
provided 45 mg (90%) of 11b as a white foam.
of 10b and 22 mg (29%) of 11b as white foams. 10b: [R]20
)
D
Ack n ow led gm en t . Financial support from the
CICYT (Spain, grants SAF96-0251 and SAF99-0127)
and the Xunta de Galicia (grant XUGA 20912B96) is
gratefully acknowledged as well as fellowships from the
Xunta de Galicia (to M.J .B. and C.P.) and from Fun-
dacio´n Segundo Gil Da´vila (to C.P.). We also thank Prof.
Rafael Suau (Universidad de Ma´laga, Spain) for the
elemental analyses.
-37.8° (c 0.63, CHCl3); IR (NaCl) 1759, 1735, 1739, 1448 cm-1
;
1H NMR (CDCl3) δ 1.14 (t, J ) 7.2 Hz, 3H), 2.46 (m, 2H), 2.90
(m, 1H), 3.12 (s, 3H), 3.43 (d, J ) 17.7 Hz, 1H), 3.45 (d, J )
6.6 Hz, 1H), 3.78 (d, J ) 17.8 Hz, 1H), 4.01 (c, J ) 7.2 Hz,
2H), 7.25-7.73 (m, 13H); 13C NMR (CDCl3) δ 13.9, 32.9, 49.0,
51.5, 55.9, 60.9, 63.8, 76.0, 120.0, 120.3, 126.1, 127.1, 127.3,
127.8, 127.9, 128.0, 128.5, 129.0, 140.6, 141.1, 141.6, 144.6,
146.1, 170.5, 172.9, 211.5. Anal. Calcd for C29H27NO5: C, 74.2;
H, 5.8; N, 3.0. Found: C, 74.4; H, 5.9; N, 3.1. 11b: [R]21
)
D
-142.6° (c 0.7, CHCl3); IR (NaCl) 1760, 1735, 1740, 1448 cm-1
;
J O990283H