Conformational analysis of 4-amido-2,4-dimethylbutyric acid derivatives

Article abstract of DOI:10.1039/a910179i

Both syn- and anti-4-amido-2,4-dimethylbutyric acid derivatives 5 and 6 were found to populate a conformation in which the amido group is gauche to the main chain of the molecule. In the anti series (6) a single conformation predominates, in which the acid carbonyl group is also gauche to the main chain. In the syn series (5) two local conformers prevail about the C-2-C-3 bond.

Full text of DOI:10.1039/a910179i

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Conformational analysis of 4-amido-2,4-dimethylbutyric acid
derivatives
Reinhard W. Ho†mann,*a Francisco Caturla,a Miguel A. Lazaro,a Eric Framery,a M. Carmen
Bernabeu,a Ingrid Valancogneb and Christian A. G. N. Montalbettib
a Fachbereich Chemie der Philipps-Universitat Marburg, D-35032 Marburg, Germany.
E-mail: rwho=mail.chemie.uni-marburg.de
b Department of Chemistry, University of Newcastle-upon-T yne, Bedson Building,
Newcastle-upon-T yne, UK NE1 7RU
Received (in Montpellier, France) 20th December 1999, Accepted 14th January 2000
Both syn- and anti-4-amido-2,4-dimethylbutyric acid derivatives 5 and 6 were found to populate a conformation in
which the amido group is gauche to the main chain of the molecule. In the anti series (6) a single conformation
predominates, in which the acid carbonyl group is also gauche to the main chain. In the syn series (5) two local
conformers prevail about the C-2ÈC-3 bond.
In certain natural products such as bleomycin A 1 or calycu-
2
lin C,2 nature connects two e†ector domains of a molecule by
a short linker chain, cf. 1 and 2. In both cases the linker is a
derivative of a c-aminobutyric acid, which carries methyl
groups in the 2- and 4-positions. It can be envisaged that
these methyl groups serve to give the linker unit a preferred
conformation,3 while maintaining full conformational Ñex-
Results and discussion
ibility.
Synthesis
Compounds of both the syn and anti series 5 and 6 have been
synthesized in enantiomerically pure form from alanine by
Koskinen and Pihko.6,7 Since racemic material suffices for our
study we explored a shorter route to the (2R*,4S*) series 5
starting from the meso-anhydride 78 (Scheme 1).
Thus, opening of 7 with methanol led to the half ester 8,
which may be resolved if optically pure material is desired.9
Curtius degradation of the acid 8, in the presence of benzyl
alcohol led us to the Cbz-protected ester 9. The Boc- and
Fmoc-protected derivatives 10 and 11 were obtained in a like
manner.
In fact, for both 12 and 24 NMR coupling constants indi-
cate the predominance of a single conformation of the linker
region in solution. The importance of this conformational pre-
organization for its biological activity has been probed for
bleomycin
A
by synthesizing analogs containing, for
2
example, the linker units 3 and 4. The observed decrease in
biological activity has been attributed4 to a lower conforma-
tional preorganization in the molecules containing the linkers
3 and 4.
These phenomena were of interest to us in the context of
learning more about Ñexible molecular backbones with a pre-
ferred conformation.3 In particular, we were interested to
learn whether the conformational preferences observed in 1
and 2 are an inherent property of the dimethylated c-
amidobutyric acid derivatives 5 and 6, or whether they are
mainly a consequence of the Ñanking groups present in calyc-
Scheme 1
ulin C or bleomycin A . For this reason we prepared a series
In order to prepare dipeptides containing the (2R*,4S*)-4-
amino-2,4-dimethylbutyric acid (cf. 5) the Boc group was
cleaved with triÑuoroacetic acid to form the ester 12.
However, any attempts to couple activated amino acids to the
2
of compounds having the structural units 5 or 6 and studied
their conformational behaviour.5 We report here our results
in detail.
DOI: 10.1039/a910179i
New J. Chem., 2000, 24, 187È194
187
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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basis of 3J
H,H
coupling constants the signals of the individual
diastereotopic protons at C-3 needed to be assigned. This was
done for compounds 33 and 34 by stereospeciÐc deuterium
labelling. To this end, the pyrrolinone 316,7 was reduced
(Scheme 6) with a ““copper deuterideÏÏ reagent.13 This produc-
ed a 1 : 1.5 mixture of the C-2 epimeric pyrrolidinones 32, the
spectral data of which corresponded to those given by Pihko
and Koskinen.7
We presume that the deuterium was incorporated into com-
pound 31 trans to the C-4 methyl group. The pyrrolidinones
32 were then converted into the esters 33 and 34 by hydrolysis
with aqueous lithium hydroxide, followed by a diazomethane
treatment. The esters 33 and 34 were separated by preparative
HPLC. The 1H-NMR spectrum of 33 allowed signal assign-
ments to the individual diastereotopic C-3 protons in 10.
Likewise, the spectrum of 34 suggested an assignment of the
diastereotopic protons in the corresponding acid 29.
Scheme 2
resulting amino ester 12 led only to the formation of the c-
lactam 13 (Scheme 2).
Conformational analysis
This necessitated a more circuituous route, in which the
ester 9 was Ðrst saponiÐed with aqueous lithium hydroxide to
give the acid 14 (Scheme 3). The protecting group in 14 was
changed to Fmoc (viz. 15). Next, the acid 15 was attached to
chlorotrityl resin. It could then be successfully coupled
with the N-protected amino acids 16 and 17 using
O-benzotriazolyl-N,N,N@,N@-tetramethyluronium tetraÑuoro-
borate as coupling reagent. Apparently, the undesired closure
to the lactam 13 is sufficiently slower in the chlorotrityl ester
to allow dipeptide formation to proceed. The dipeptides 18
and 19 were eventually cleaved from the resin using standard
techniques.
In the (2R*,4S*) series 5 MM3* calculations suggest a prefer-
ence to populate the conformation 5a, which corresponds to
the one found in solution for calyculin C2 and the one sug-
gested for desoxybleomycin A .4
2
In order to gain information on the conformational behav-
iour of more extended systems, the heptenoic acid derivatives
25 and 27 (Scheme 4) were required. Thus, the enantio-
merically pure half-ester ent-8 was converted to the aldehyde
21.10 Wittig reaction with the phosphorane 2211 furnished the
a,b-unsaturated ester 23. Hydrolysis of the methyl ester with
aqueous lithium hydroxide and Curtius rearrangement gener-
ated the desired heptenoate 25.
The stereoisomeric heptenoate 27 was synthesized in an
analogous manner from the (R*,R*) half-ester 26.12
Two additional compounds of interest, 29 and 30 (Scheme
5), were prepared following the route described by Koskinen
and Pihko.6,7 The former compound was converted via the
c-amino acid to the Fmoc-protected derivative 30 in 89%
overall yield.
According to the calculations, conformation 5b should also
be easily accessible, whereas conformation 5c should be sub-
stantially higher in energy (]7 kJ mol~1 relative to 5a). It
should be noted that the acylamido group is gauche to the
main chain of the molecule in all of the conformers 5a to 5c.
Any conformational preference, such as this feature, should be
manifest from the vicinal 1H-NMR coupling constants
between C-2-H, the diastereotopic C-3-H protons and C-4-H.
Determination of the coupling constants from the 1H-NMR
In order to identify the preferred conformation of the 4-
amido-2,4-dimethylbutyric acid derivatives 5 and 6 on the
Scheme 3
188
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Scheme 4
C-4 is arranged predominantly gauche to the main chain. The
““averageÏÏ coupling constant between C-3-H to C-2-H
spectra was limited in several cases by signal overlap and line
broadening due to the presence of amide rotamers. Neverthe-
less, the coupling constants could be derived for a representa-
tive set of compounds, cf. Table 1.
provR
indicates that more than one conformation around the
C-2ÈC-3 bond is populated. This is in line with the few values
More insight into the nature of the preferred conformation
recorded for the coupling constants between C-3-H
and
provS
can be gained when the 3J
coupling constants can be
C-2-H. We interpret this as indicating that both conformers 5a
and 5b contribute signiÐcantly to the conformer equilibrium.
This contrasts with the situation found in calyculin C,
where the coupling constants indicate that a single conformer
5a dominates the conformer equilibrium. This Ðnding cannot
simply be ascribed to the presence of a Ñanking group on the
N-terminus of 5, as the dipeptides 18 and 19 show the same
behaviour as the model compound 11. An extension at the
C-terminus of 5, viz. the a,b-unsaturated ester 25, did not alter
the conformational preferences either. This suggests that there
is an inherent preference in structures of the type 5 to have a
single conformation about the C-3ÈC-4 bond, whereas the
molecules remain biconformational with regard to the
C-2ÈC-3 bond. This may hold as well for the linker unit in
H,H
related to the individual diastereotopic protons at C-3. In all
compounds of type 5 the two C-3-H protons give rise to a
high-Ðeld signal around d 1.4 and a low-Ðeld signal around d
1.9 ppm. StereospeciÐc deuterium labelling of 33 as outlined
above, allowed the assignment of the d \ 1.4 signal to H
provS
and the d \ 1.7 signal to H
, deÐned in the table.14 This
provR
assignment of the signals of the diastereotopic protons at C-3
is consistent with that made for the linker unit in calyculin C,2
the data of which are also included in the table. In view of this
consistency we assume that the same assignment holds for all
of the compounds corresponding to 5 listed in the table.
The coupling constants refer to a weighted average of the
values of the individual conformers contributing to the con-
former equilibrium. The high (ca. 10 Hz) coupling constant for
deoxybleomycin A . In calyculin C, however, there is an
2
C-3-H
to C-4-H indicates that indeed the amido group at
additionalÈas yet undeterminedÈe†ect, which renders the
provR
linker unit monoconformational also about the C-2ÈC-3
bond.
In the (2R*,4R*) series 6, deuterium labelling of 34 allowed
the assignment of the high-Ðeld and low-Ðeld C-3-H signals to
the individual diastereotopic hydrogen atoms. It is assumed
that this assignment holds also for compounds 27, 29, and 30.
The coupling constants listed in the table for 29 and 30 are
large, both for the coupling between C-3-H
provR
to C-4-H. This indicates that a single conformer
to C-2-H and
of C-3-H
provS
6a predominates substantially in the conformer equilibrium, a
conformation identical to the conformation found for 29 in
the crystalline state.7,15
The conformation 6a corresponds to the arrangement
deduced for the helical structure of c-peptides16 derived from
4-substituted c-aminobutyric acids of the type 35. It may be
Scheme 5
Scheme 6
New J. Chem., 2000, 24, 187È194
189

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Table 1 Characteristic 3J
coupling constants for 4-amido-2,4-dimethylbutyric acid derivatives
H, H
C-3-H
C-3-H
(provR)
3J to H-2
(provS)
3J to H-2
Solvent
T /K
d
3J to H-4
d
3J to H-4
1a
C D
298
298
2.18
1.94
1.5
6.2
13.0
9.6
1.84
1.68
12.5
6.7
1.5
6
6
b
CDCl
n.d.
3
10
9
CDCl
CDCl
CDCl
298
333
333
1.7
7
10
1.4
7c
n.d.
4.8
3
3
3
1.85
1.87
7.2
7.2
9.6
9.8
1.48
1.48
6.7c
n.d.
15
n.d.
18
CDCl
298
1.89
8.0
9.9
1.49
n.d.
n.d.
3
19
25
CDCl
C D
328
298
1.86
1.11
7.6
6.6
10.3
8.7
1.49
1.01
6.5
7.7
3.9
3
n.d.
6
6
27
29
30
CDCl
CDCl
CDCl
298
253
298
1.48
1.75
1.80
9.4c
10.7
9.6
n.d.
3.3
4.5
1.48
1.4
5.4c
n.d.
4.5
n.d.
n.d.
9.5
3
3
3
1.43
a Values from ref. 2. b Values from ref. 7. c Taken from the coupling pattern of the C-2-H signal. n.d. \ not determined.
anticipated that the conformational preference, and hence, the
helix-forming and helix-stabilizing abilities will be even more
marked in c-peptides derived from the conformationally pre-
organized amino acids 6. This is indeed borne out by a recent
study17 in which an octapeptide derived from c-amino acids
of the type 6 had a helical secondary structure, whereas the
analogous octapeptide from c-amino acids corresponding to
the biconformational amino acid 5 did not adopt a helical
arrangement.17
1. Methyl (2S*,4R*)-4-(benzyloxycarbonylamino)-2-methyl-
pentanoate(9)
Triethylamine (0.7 ml, 5 mmol) was added to a solution of
(2R*,4S*)-2,4-dimethylpentanedioic acid monomethyl ester (8,
870 mg, 5.0 mmol) in toluene (3.3 ml). After establishing a
nitrogen atmosphere diphenylphosphoryl azide (1.4 g, 5
mmol) was added and the solution was heated to 80 ¡C. After
nitrogen evolution had ceased benzyl alcohol (595 mg, 5.5
mmol) was added and stirring was continued for 6 h at 80 ¡C.
The solvent was removed under reduced pressure, the residue
was taken up in diethyl ether (25 ml) and the solution was
washed with water (3 ] 15 ml). The organic phase was dried
We conclude that the (R*,R*)-4-amido-2,4-dialkylbutyric
acid derivatives 6 have a strong tendency to populate a con-
formation shown as 6a. In the (R*,S*) series, cf. 5, the com-
pounds have
a
biconformational behaviour. In both
(MgSO ) and concentrated. 3,4-Dihydro-2H-pyran (220 mg,
conformers, however, the amido substituent is gauche to the
main chain. This information is valuable for the design of con-
formationally preorganized linker units for novel functional
molecules.
4
2.5 mmol) and a solution of p-toluenesulfonic acid (1 mg,
0.005 mmol) in CH Cl (5 ml) was added at 0 ¡C to the
2
2
residue. After stirring for 10 min at 0 ¡C and 2.5 h at room
temperature brine (15 ml), saturated aqueous NaHCO solu-
3
tion (15 ml) and water (30 ml) were added and the mixture
was extracted with diethyl ether (3 ] 20 ml). The combined
Experimental
organic layers were dried (MgSO ) and concentrated. Flash
4
All temperatures quoted are not corrected. Reactions were
carried out under dry nitrogen or argon. Boiling range of the
petroleum ether used is 40È60 ¡C. 1H- and 13C-NMR spectra
were recorded on Bruker ARX-200, AC-300 and AMX-500
spectrometers. Spectra were recorded for ca. 0.2 mM solutions
chromatography of the residue with pentaneÈdiethyl ether
(65 : 35) yielded 1.09 g (78%) of the product 9 as a colourless
liquid. 1H NMR (500 MHz, CDCl ): d \ 1.18 (d, J \ 6.8 Hz,
3
3 H), 1.20 (d, J \ 6.6 Hz, 3 H), 1.52 (m, 1 H), 1.86 (ddd,
J \ 14.0, 9.9 and 7.5 Hz, 1 H), 2.54 (sextet, J \ 6.8 Hz, 1 H),
3.61 (s, 3 H), 3.81 (m, 1 H), 4.61 (br d, J \ 7.4 Hz, 1 H), 5.08 (s,
in CDCl (99% d), which was also used as an internal stan-
3
dard. Flash chromatography was run using silica gel Si 60
2 H), 7.29È7.35 (m, 5 H). 13C NMR (50 MHz, CDCl ):
3
(40È63 lm, E. Merck AG, Darmstadt).
d \ 17.8, 22.5, 37.3, 41.2, 46.1, 52.1, 66.9, 128.5, 128.9, 137.0,
190
New J. Chem., 2000, 24, 187È194

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156.2, 177.7. HR-MS: C
279.1476.
H
NO ` requires 279.1471; found
1 M HCl. The resulting precipitate was dissolved by extrac-
tion with ethyl acetate (3 ] 30 mL). The organic solution was
concentrated and the residue was crystallized from ethyl
acetateÈpentane (1 : 3) to give 3.24 g (97%) of the product 15
of mp 132È133 ¡C. [a]20 \ [0.98 (c \ 10.2, CHCl ). 1H
15 21
4
2. Methyl (2S,4R)-4-(tert-butoxycarbonylamino)-2-methyl-
pentanoate (10)
D
3
NMR (500 MHz, CDCl , 333 K): d \ 1.16 (m, 6 H), 1.48 (m,
This compound was prepared as described for 9 using tert-
butanol as the alcohol component. The product was puriÐed
by Ñash chromatography with pentaneÈethyl acetate (4 : 1) to
give 43% of 10 as a colourless oil. 1H NMR (500 MHz,
3
1 H), 1.87 (ddd, J \ 14.1, 9.8, and 7.8 Hz, 1 H), 2.49 (m, 1 H),
3.80 (m, 1 H), 4.22 (br t, J \ 6.6 Hz, 1 H), 4.44 (br d, J \ 6.6
Hz, 2 H), 4.59 (m, 1 H), 7.31 (m, 2 H), 7.39 (t, J \ 7.5 Hz, 2 H),
7.58 (d, J \ 7.5 Hz, 2 H), 7.75 (d, J \ 7.5 Hz, 2 H), 9.96 (br s, 1
CDCl ): d \ 1.06 (d, J \ 6.6 Hz, 3 H), 1.11 (d, J \ 7.0 Hz, 3
H). 13C NMR (75 MHz, CDCl ): d \ 16.9, 21.9, 36.6, 40.4,
3
H), 1.35 (s, 9 H), 1.40 (m, 1 H), 1.73 (ddd, J \ 14.0, 10.0, and
3
45.3, 47.2, 66.4, 119.9, 125.0, 127.0, 127.6, 141.2, 143.9, 155.9,
7.0 Hz, 1 H), 2.44 (sextet, J \ 7.0 Hz, 1 H), 3.60 (s, 3 H), 3.67
182.3. C
71.11, H 6.50, N 3.91%.
H
NO requires C 71.37, H 6.56, N 3.96; found C
(m, 1 H), 4.3 (m, 1 H). 13C NMR (50 MHz, CDCl ): d \ 17.3,
21 23
4
3
22.1, 28.3, 36.9, 40.9, 44.9, 51.7, 79.0, 155.3, 177.4. C
H
NO
12 23
4
requires C 58.75, H 9.45, N 5.71; found C 57.99, H 9.08, N
6.36%.
6. tert-Butyl (2S)-2-(Ñuorenylmethoxycarbonylamino)-4-oxo-
4-[(2S)-1-triÑuoroacetylpyrrolidin-2-yl]butyrate
3. Methyl (2R*,4S*)-4-(Ñuorenylmethoxycarbonylamino)-
To a solution of (S)-N-triÑuoroacetyl proline (0.249 g, 1.125
mmol) in dry toluene (1 mL) was added freshly distilled oxalyl
chloride (0.202 mL, 2.25 mmol) at 0 ¡C under nitrogen. Adding
one drop of dry dimethylformamide started the reaction. After
20 min stirring at 0 ¡C the gas evolution stopped. Solvents
were removed using a rotary evaporator and the resulting
solid was redissolved in dry toluene. This operation was
repeated twice and the crude (S)-N-triÑuoroacetylproline acid
chloride19 was used directly in the next step.
A solution of b-iodo-N-Fmoc-L-alanine tert-butyl ester20
(0.370 g, 0.75 mmol) in dry toluene (3 mL) and dry DMF (0.20
mL) was added to a dry nitrogen purged Ñask charged with
zincÈcopper couple21 (0.090 g). The resulting mixture was
stirred at 50 ¡C under nitrogen for 25 min until no starting
material remained (as judged by TLC visualized with
KagiÈMosher solution). Bis(triphenylphosphine)palladium
dichloride (0.028 g, 0.04 mmol) was added, followed by the
freshly prepared N-triÑuoroacetylproline acid chloride solu-
tion (1.125 mmol) in toluene (1 mL) and the mixture was
stirred at 50 ¡C under nitrogen for a further 90 min. Ethyl
acetate (50 mL) was added to the cooled reaction mixture,
2-methylpentanoate (11)
This compound was prepared as described for 9 using Ñuo-
renylmethanol as the alcohol component. The product was
puriÐed by Ñash chromatography with pentaneÈethyl acetate
(4 : 1) to give 87% of the product 11. 1H NMR (300 MHz,
CDCl ): d \ 1.14È1.19 (m, 6 H), 1.50 (m, 1 H), 1.84 (m, 1 H),
3
2.49 (sextet, J \ 6.9 Hz, 1 H), 3.62 (s, 3 H), 3.79 (m, 1 H), 4.18
(m, 1 H), 4.39 (m, 2 H), 4.64 (br d, J \ 8.1 Hz, 1 H), 7.13È7.40
(m, 4 H), 7.58 (d, J \ 7.4 Hz, 2 H), 7.74 (d, J \ 7.3 Hz, 4 H).
13C NMR (75 MHz, CDCl ): d \ 17.3, 22.0, 36.9, 40.7, 45.6,
3
47.3, 51.6, 66.3, 119.9, 124.9, 127.0, 127.6, 141.3, 144.0, 155.8,
177.2. C
71.91, H 6.86, N 3.81%.
H
NO requires C 71.83, H 6.71, N 3.75; found C
14 19
4
4. (2S,4R)-4-(Benzyloxycarbonylamino)-2-methylpentanoic
acid (14)
Aqueous LiOH solution (5 M, 5 mL) was added to a solution
of 9 (ca. 4 mmol) in dimethoxyethane (16 mL) and water
(10 mL). After stirring for 30 min water (200 mL) was added
and the mixture was extracted with ether (3 ] 25 mL). The
aqueous layer was acidiÐed with hydrochloric acid (1 M) and
extracted with dichloromethane (3 ] 25 mL). The combined
organic phases were washed with water (3 ] 20 mL), dried
which was Ðltered into
a separating funnel. Sequential
washing with brine (25 mL) and extraction with ethyl acetate
(50 mL), followed by drying over anhydrous sodium sulfate,
Ðltration and concentration under reduced pressure gave a
crude product. Flash chromatography over silica gel (light
petroleumÈethyl acetate 9 : 1) gave N-Fmoc-L-alanine tert-
butyl ester (150 mg, 55%) and the title compound (196 mg,
46%). The resulting solid was recrystallized from dichloro-
methane by addition of warm n-hexane until turbidity was
reached to a†ord 162 mg of Ðne needles of mp 155È157 ¡C;
[a]25 \ [26.3, (c \ 1.09, CH Cl ). 1H NMR (500 MHz,
(MgSO ) and concentrated to give 0.95 g of the acid 14.
4
[a]20 \ ]6.3 (c \ 20.19, CHCl ). 1H NMR (200 MHz,
D
3
CDCl ): d \ 1.14È1.25 (m, 6 H), 1.49 (m, 1 H), 1.85 (m, 1 H),
3
2.51 (m, 1 H), 3.84 (m, 1 H), 4.83 (br d, J \ 6.6 Hz, 1 H), 5.07
(m, 2 H), 7.33 (br s, 5 H). 13C NMR (50 MHz, CDCl ):
3
d \ 17.5, 22.4, 37.1, 41.0, 45.9, 67.0, 128.4, 128.5, 128.9, 136.9,
156.4, 182.4. HR-MS: C
265.1310.
H
NO ` requires 265.1314; found
14 19
4
D
2 2
CDCl ): d \ 1.45 (s, 9 H), 1.94È2.05 (m, 3 H), 2.16È2.23 (m, 1
3
H), 3.07 (dd, J \ 18.3 and 3.7 Hz, 1 H), 3.29 (dd, J \ 18.3 and
5. (2S,4R)-4-(Fluorenylmethoxcarbonylamino)-2-methyl-
pentanoic acid (15)
4.6 Hz, 1 H), 3.71È3.76 (m, 1 H), 3.79È3.84 (m, 1 H), 4.24 (t,
J \ 7.3 Hz, 1 H), 4.31È4.38 (m, 2 H), 4.53È4.57 (m, 1 H), 4.61È
4.64 (m, 1 H), 5.87 (d, J \ 8.5 Hz, 1 H), 7.29È7.33 (m, 2 H),
7.40 (t, J \ 7.3 Hz, 2 H), 7.62 (d, J \ 7.7 Hz, 2 H), 7.76 (d,
10% Pd on charcoal (92 mg) was added to a solution of 14
(920 mg, 3.5 mmol) in methanol (25 mL). The suspension was
stirred 15 h under an atmosphere of hydrogen. The mixture
was Ðltered through a pad of Celite and the Ðltrate was con-
centrated. The residue was taken up in water (14 mL);
Na CO (1.84 g, 17.4 mmol) was added and the solution
J \ 7.3 Hz, 2 H). 13C NMR (125 MHz, CDCl ): d \ 24.9,
3
27.1, 27.8, 30.0, 42.0, 47.5, 50.4, 65.6, 67.3, 82.5, 116.2 (q,
J \ 285 Hz), 120.0, 125.3, 127.0, 127.7, 141.3, 143.8, 143.9,
155.8 (q, J \ 38 Hz), 156.2, 169.8, 205.0. IR (Ðlm, cm~1): 3362,
1728,
1689,
1152.
MS
(electrospray):
m/z \ 459.
2
3
was
cooled
to
0 ¡C.
A
solution
of
N-
C
H F N O requires C 62.14, H 5.57, N 5.00; found: C
Ñuorenylmethoxycarbonyloxysuccinimide (Fmoc-OSu,18 1.75
g, 5.2 mmol) in dioxane (28 mL) was added in increments over
5 min. The pH of the solution was adjusted to 9 by adding
10% aqueous Na CO solution. After stirring for 1 h at 0 ¡C
29 31 3
2 6
61.40, H 5.58, N 4.83%.
7. 2-(Fluorenylmethoxycarbonylamino)-4-oxo-4-[(2S)-1-
(2,2,2-triÑuoroacetyl)pyrrolidin-2-yl]butanoic acid (16)
2
3
and 2 h at room temperature the mixture was diluted with
water (100 mL) and was washed with diethyl etherÈethyl
acetate (1 : 1, 3 ] 50 mL). The combined organic layers were
extracted with aqueous Na CO (2%, 2 ] 30 mL) and the
The tert-butyl ester described in section 6 (150 mg, 0.27 mmol)
was dissolved in a 1 : 1 mixture of dry dichloromethane and
triÑuoroacetic acid (2 mL). The mixture was stirred at room
temperature for 3 h, and then the volatiles were removed to
2
3
combined aqueous layers were brought to pH 1 with aqueous
New J. Chem., 2000, 24, 187È194
191

View Article Online
a†ord the crude acid (ca. 130 mg), which was used in the
coupling step without further puriÐcation. 1H NMR (300
to stir for
a
further 30 min. Methyl (2S)-2-(Ñuo-
renylmethoxycarbonylamino)-3-iodopropionate20 (0.31 g, 0.7
mmol) was dissolved in dry DMF (0.9 mL), and transferred
via syringe to the reaction mixture, which was then heated to
35 ¡C. Monitoring the reaction by TLC, using petroleum
etherÈethyl acetate (2 : 1), showed complete consumption of
starting material after 1 h. 2,5-Dibromopyridine (0.22 g, 0.93
mmol) was added, followed by bis(triphenylphosphine)-
palladium(II) chloride (0.026 g, 0.037 mmol). The reaction was
heated at 50 ¡C for 3 h and then allowed to cool to room
temperature. The mixture was diluted with EtOAc (50 mL),
washed with water (30 mL) and with brine (30 mL), dried with
MHz, CDCl ): d \ 1.95, 2.12 (2 m, 4 H), 3.06 (dd, J \ 15.5
3
and 4.0 Hz, 1 H), 3.26 (dd, J \ 15.5 and 3.8 Hz, 1 H), 3.68 (m,
2 H), 4.16 (t, J \ 7.2 Hz, 1 H), 4.30 (d, J \ 7.2 Hz, 2 H), 4.58È
4.64 (m, 2 H), 5.88 (d, J \ 8.6 Hz, 1 H), 6.21 (br s, 1 H), 7.19È
7.34 (m, 4 H), 7.53 (d, J \ 7.2 Hz, 2 H), 7.68 (d, J \ 7.5 Hz, 2
H). 13C NMR [50 MHz, (CD ) CO]: d \ 25.0, 27.0, 41.5,
3 2
47.4, 47.8, 49.7, 66.3, 66.8, 116.5 (q, J \ 150.0 Hz), 120.2, 125.6,
127.4, 128.0, 141.5, 144.4, 154.5 (q, J \ 55.0 Hz), 156.3, 172.2,
204.1. 19F NMR (188 MHz, CDCl ): d \ 73.0.
3
8. (2S,4R)-4-[(1S)-1-(Fluorenylmethoxcarbonylamino)-
3-oxo-3-[(2S)-1-(2,2,2-triÑuoroacetyl)pyrrolidine-2-yl]propyl-
carboxamido]-2-methylpentanoic acid (18)
MgSO and Ðltered through a Celite layer. Flash column
chromatography over silica gel, with an appropriate pet-
roleum etherÈethyl acetate gradient, furnished the title com-
4
pound (0.20 g, 60%), mp 99È101 ¡C. [a]20 ] 22.5 (c \ 1,
To a suspension of 2-chlorotrityl chloride resin (200È400
mesh, 1% divinylbenzene crosslinked, 219 mg, ca. 0.3 mmol) in
dry dichloromethane (1.1 ml) was added diisopropylethyl-
amine (131 ll, 0.75 mmol) and 15 (110 mg, 0.31 mmol). The
mixture was stirred over 19 h at room temperature. Methanol
(38 ll) and diisopropylethylamine (39 ll) were added and the
resin was stirred for an additional 15 min. The resin was
washed with dichloromethane (3 ] 5 ml) and methanol (3 ] 5
ml) and dried in vacuo over KOH. For Fmoc deprotection
the resin was treated with a 10% piperidine solution in
dichloromethane (3 ] 3 ml, 10 min each) and subsequently
washed with dimethylformamide (3 ] 5 ml), dichloromethane
(3 ] 5 ml), methanol (3 ] 5 ml), and dichloromethane (3 ] 5
ml). After drying in vacuo 260 mg of the loaded resin was
obtained.
D
CH Cl ) IR (cap. Ðlm, cm~1): 3333 (NÈH), 3064 (ArÈH), 2951
2
2
(Me), 1721 (C2O), 1516 (NH), 1450 (2CÈH), 759 (3H adj), 739
(4H adj). 1H NMR (500 MHz, CDCl ): d \ 3.29 (dd, J \ 4.5
3
and 15.0 Hz, 1 H), 3.34 (dd, J \ 5.5 and 15.0 Hz, 1 H), 3.72 (s,
3 H), 4.22 (t, J \ 7.0 Hz, 1 H), 4.37 (d, J \ 7.0 Hz, 2 H), 4.78È
4.74 (m, 1 H), 6.04 (d, J \ 7.6 Hz, 1 H), 7.03 (d, J \ 8.2 Hz, 1
H), 7.30 (t, J \ 7.6 Hz, 2 H), 7.40 (t, J \ 7.6 Hz, 2 H), 7.57 (t,
J \ 7.6 Hz, 2 H), 7.76È7.73 (m, 3 H), 8.58 (s, 1 H). 13C NMR
(125 MHz, CDCl ): d \ 172.1, 155.7, 155.0, 150.2, 143.9, 141.3,
3
139.4, 127.7, 127.0, 125.1, 125.1, 119.9, 118.6, 67.1, 53.2, 52.5,
47.2, 38.4. MS (EI): m/z \ 482 (M`, 20%), 480 (M`, 19), 421
(M` [ CO Me, 12), 423 (M` [ CO Me, 12), 284È286
2
2
(M` [ Ñuorenylmethyloxy, 80È82), 257È259 (M` [ Fmoc,
32), 178 (FmocCH , 100), 165 (Ñuorene`, 62). C
requires C 59.9, H 4.4, N 5.8; found: C 60.1, H 4.1, N 5.8%.
H
N O Br
2
24 21
2
4
A portion of the above resin (105 mg, ca. 0.1 mmol) was
suspended in a solution of 16 (126 mg, 0.25 mmol) in
dimethylformamide (1 ml). Diisopropylethylamine (88 ll, 0.5
mmol) was added and O-benzotriazolyl-N,N,N@,N@-tetra-
methyluronium tetraÑuoroborate (161 mg, 0.5 mmol) in DMF
(1 ml) was added. After stirring for 1 day the resin was washed
with dimethylformamide (3 ] 5 ml), dichloromethane (3 ] 5
ml), methanol (3 ] 5 ml), and dichloromethane (3 ] 5 ml).
The resin was dried in vacuo and suspended in a 1 : 1 : 3
mixture of triÑuoroethanolÈacetic acidÈdichloromethane (2
ml) for 1 h at room temperature. The resin was washed with
the same mixture (2 ] 1 ml) and the Ðltrates were concen-
trated in vacuo to give crude 18, which was puriÐed by Ñash
chromatography over silica gel with pentaneÈethyl acetateÈ
acetic acid (4 : 6 : 0.5) to give 25 mg (41%) of compound 18,
mp 119È120 ¡C. [a]20 \ [14.8 (c \ 0.27, CHCl ). 1H NMR
10. (2S)-2-(Fluorenylmethoxycarbonylamino)-3-(5º-bromo-2º-
pyridyl)propionic acid (17)
The methyl ester obtained in section 9 (0.57 g, 1.19 mmol) was
dissolved in THF (12 mL) and aqueous LiOH (0.2 N, 12 mL,
2.4 mmol) was added. The reaction was stirred at room tem-
perature and monitored by TLC. After complete consumption
of the starting material, the solvent was removed under
reduced pressure. The residue was dissolved in a minimum of
water (10 mL) and then washed with EtOAc (5 mL). The
aqueous phase was acidiÐed to pH 3.8 with AcOH. The
product was extracted with EtOAc (2 ] 10 mL). The com-
bined extracts were dried with MgSO and concentrated by
4
rotary evaporation, yielding the carboxylic acid 17 (0.49 g,
90%) as a white solid, mp 219È221 ¡C. IR (KBr disc, cm~1):
D
3
(500 MHz, CDCl ): d \ 1.12 (d, J \ 6.5 Hz, 3 H), 1.18 (d,
3321 (NÈH and OÈH), 3037 (ArÈH), 1695 (C2O), 1421 (2CÈH),
3
J \ 6.8 Hz, 3 H), 1.49 (m, 1 H), 1.89 (ddd, J \ 14.2, 9.9, and
838 (2H adj), 757 (4H adj). 1H NMR (500 MHz, CDCl ):
8.0 Hz, 1 H), 2.00È2.23 (m, 4 H), 2.46 (m, 1 H), 2.87 (dd,
J \ 18.1 and 4.8 Hz, 1 H), 3.35 (m, 1 H), 3.72 (m, 2 H), 4.00 (m,
1 H), 4.23 (t, J \ 7.0 Hz, 1 H), 4.40 (m, 2 H), 4.57 (m, 1 H), 4.62
(dd, J \ 8.4 and 4.6 Hz, 1 H), 6.24 (d, J \ 9.0 Hz, 1 H), 6.45 (d,
J \ 8.2 Hz, 1 H), 7.31 and 7.39 (2t, J \ 7.5 Hz, 4 H), 7.61 (m, 2
H), 7.76 (d, J \ 7.5 Hz, 2 H), 7.76 (d, J \ 7.5 Hz, 2 H), 7.96 (br
3
d \ 3.40È3.34 (m, 2 H), 4.23 (t, J \ 7.0 Hz, 1 H), 4.41 (dd,
J \ 10.5 and 6.5 Hz, 1 H), 4.48 (dd, J \ 10.5 and 7.0 Hz, 1 H),
4.62È4.56 (m, 1 H), 5.97È5.90 (br s, 1 H), 7.09 (d, J \ 8.0 Hz, 1
H), 7.33 (t, J \ 7.5 Hz, 2 H), 7.42 (d, J \ 7.5 Hz, 2 H), 7.59 (d,
J \ 7.5 Hz, 2 H), 7.78 (d, J \ 7.5 Hz, 2 H), 7.85 (d, J \ 8.0 Hz,
1 H), 8.65 (s, 1 H). 13C NMR (125 MHz, CDCl ): d \ 175.5,
s, 1 H). 13C NMR (125 MHz, CDCl ): d \ 17.4, 20.8, 24.8,
3
172.7, 155.6, 146.2, 143.7, 141.3, 139.3, 127.7, 127.1, 125.7,
3
27.0, 37.1, 40.1, 41.7, 44.5, 47.0, 47.5, 51.0, 65.8, 67.5, 115.2 (q,
125.1, 123.0, 119.9, 66.8, 52.3, 47.2, 38.1. MS (EI): m/z \ 468È
J \ 285.0 Hz), 120.0, 125.2, 127.1, 127.8, 141.3, 143.7, 155.8 (q,
466 (M`, 13%), 450È448 (M` [ H O, 63), 244È242
J \ 37.5), 156.5, 170.0, 181.5, 206.3. C
H
N O F requires
2
(M` [ Fmoc, 25), 229È227 (M` [ NHFmoc, 80), 196
31 34
3 7 3
C 60.29, H 5.55, N 6.80; found C 60.10, H 5.33, N 6.67%.
(Ñuorenylmethyloxy`, 17), 178 (FmocCH , 100), 165
2
(Ñuorene`, 80). HR-MS: C
found 466.0497.
H
N O Br` requires 466.0528;
9. Methyl (2S)-2-(Ñuorenylmethoxycarbonylamino)-
3-(5º-bromo-2º-pyridyl)propionate
23 19
2 4
Zinc dust (0.27 g, 4.2 mmol) was heated to ca. 100 ¡C in a 50
mL Ñask with side arm, then evacuated and Ñushed with
nitrogen 3 times. Dry DMF (0.5 mL) and 1,2-dibromoethane
(18 lL, 0.21 mmol) were added and the mixture was heated in
a hot water bath (90 ¡C) with vigorous stirring for 30 min. The
reaction mixture was allowed to cool. Trimethylsilyl chloride
(5 lL, 0.042 mmol) was added and the mixture was allowed
11. (2S,4R)-4-[(1S)-1-(Fluorenylmethoxycarbonylamino)-
2-(5-bromo-2-pyridyl)ethylcarboxamidol-2-methylpentanoic
acid (19)
This material was prepared from another portion of the resin
obtained in section 6 by coupling with the acid 17 (117 mg,
0.25 mmol) to give 21 mg (37%) of compound 19, mp 80È
192
New J. Chem., 2000, 24, 187È194

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81 ¡C. [a]20 \ ]6.3 (c \ 0.48, CHCl ). 1H NMR (500 MHz,
raphy with pentaneÈethyl acetate (4 : 1) a†orded 683 mg (75%)
D
3
CDCl , 328 K): d \ 1.06 (d, J \ 6.5 Hz, 3 H), 1.15 (d, J \ 6.8
of the ester 25 as colourless crystals, mp 63È64 ¡C. [a]22 \
3
D
Hz, 3 H), 1.49 (ddd, J \ 14.0, 6.5, and 3.9 Hz, 1 H), 1.86 (ddd,
]27.1 (c \ 3.06, CHCl ). 1H NMR (300 MHz, CDCl ):
3
3
J \ 14.0, 10.3 and 7.6 Hz, 1 H), 2.38 (m, 1 H), 3.17 (dd,
J \ 14.3 and 6.9 Hz, 1 H), 3.23 (dd, J \ 14.3 and 5.4 Hz, 1 H),
4.04 (m, 1 H), 4.10 (t, J \ 6.7 Hz, 1 H), 4.32 (d, J \ 6.7 Hz, 2
H), 4.59 (m, 1 H), 5.96 (br s, 1 H), 6.39 (d, J \ 7.1 Hz, 1 H),
6.61 (d, J \ 8.2 Hz, 1 H), 7.26È7.75 (m, 1 H), 8.53 (s, 1 H). 13C
d \ 0.95 (d, J \ 6.5 Hz, 3 H), 1.06 (d, J \ 6.3 Hz, 3 H), 1.30È
1.40 (m, 2 H), 1.40 (s, 9 H), 1.71 (d, J \ 1.4 Hz, 3 H), 2.40 (m, 1
H), 3.60 (m, 1 H), 4.14 (t, J \ 6.6 Hz, 1 H), 4.33 (d, J \ 6.8 Hz,
2 H), 4.40 (m, 1 H), 6.38 (d, J \ 9.9 Hz, 3 H), 7.20 (dt, J \ 7.4
and 1 Hz, 2 H), 7.30 (t, J \ 7.4 Hz, 2 H), 7.50 (d, J \ 7.4 Hz, 2
NMR (125 MHz, CDCl ): d \ 17.7, 20.6, 22.0, 25.4, 29.7, 44.4,
H), 7.70 (d, J \ 7.4 Hz, 2 H). 13C NMR (75 MHz, CDCl ):
3
3
47.0, 66.5, 67.3, 140.3, 141.3, 149.4, 156.1, 156.4, 170.3, 180.6.
d \ 12.7, 19.9, 21.9, 28.3, 30.4, 44.2, 47.5, 66.5, 80.2, 120.1,
C
H
N O Br requires C 60.01, H 5.21, N 7.24; found C
125.1, 127.1, 127.8, 141.5, 144.2, 145.8, 155.2, 165.6. HR-MS:
29 30
3 5
59.89, H 5.15, N 7.17%.
C
H
NO ` requires 449.2566; found 449.2562.
28 35
4
12. tert-Butyl (2E,4S,6R)-6-methoxycarbonyl-2,4-dimethyl-2-
tert-Butyl (2E,4S,6S)-6-(Ñuorenylmethoxycarbonylamino)-
heptenoate (23)
2,4-dimethyl-2-heptenoate (27). This compound was prepared
in an analogous manner from the corresponding tert-butyl
To a solution of the phosphorane 2211 (1.95 g, 5.0 mmol) in
CH Cl (9 mL) was added a solution of the aldehyde 2110
(2E,4S,6S)-6-methoxycarbonyl-2,4-dimethylheptenoate.
Mp
94È95 ¡C. [a]20 \ ]16.3 (c \ 1.53, CHCl ). 1H NMR (300
2
2
D
3
(668 mg, 4.2 mmol) in CH Cl (4 mL). After heating at reÑux
MHz, CDCl ): d \ 0.99 (d, J \ 6.3 Hz, 3 H), 1.12 (d, J \ 6.3
2
2
3
for 19 h the solvents were removed and the residue was trit-
urated with pentane (50 mL). Triphenylphosphine oxide was
removed by Ðltration and the Ðltrate was concentrated in
vacuo. Flash chromatography of the residue with pentaneÈ
ethyl acetate (9 : 1) furnished 870 mg (76%) of 23 as a colour-
less oil. [a]22 \ ]5.1 (c \ 2.4, CHCl ). 1H NMR (200 MHz,
Hz, 3 H), 1.48 (m, 11 H), 1.75 (d, J \ 1.3 Hz, 3 H), 2.57 (m, 1
H), 3.60 (m, 1 H), 4.19 (t, J \ 6.7 Hz, 1 H), 4.39 (d, J \ 6.9 Hz,
2 H), 4.67 (m, 1 H), 6.40 (d, J \ 10.0 Hz, 1 H), 7.29 (dt, J \ 7.4
and 1.1 Hz, 2 H), 7.38 (t, J \ 7.2 Hz, 2 H), 7.58 (t, J \ 7.3 Hz,
2 H), 7.74 (d, J \ 7.4 Hz, 2 H). 13C NMR (75 MHz, CDCl ):
3
d \ 12.4, 20.0, 21.5, 28.0 30.2, 43.8, 47.3, 66.2, 79.9, 119.8,
D
3
CDCl ): d \ 0.96 (d, J \ 6.6 Hz, 3 H), 1.08 (d, J \ 6.9 Hz, 3
124.9, 126.9, 127.5, 128.4, 141.2, 143.9, 145.4, 155.5, 167.4.
3
H), 1.60 (m, 1 H), 1.44 (s, 9 H), 1.70 (m, 1 H), 1.74 (d, J \ 1.1
HR-MS: C
H
NO requires 449.2566; found 449.2560.
28 35
4
Hz, 3 H), 2.40 (m, 1 H), 2.50 (m, 1 H), 3.60 (s, 3 H), 6.33 (d,
J \ 10.1 Hz, 1 H). 13C NMR (50 MHz, CDCl ): d \ 12.5,
14. (2S,4S)-4-(Fluorenylmethoxycarbonylamino)-2-methyl-
pentanoic acid (30)
3
17.4, 20.1, 28.1, 31.2, 37.6, 40.5, 51.5, 80.0, 128.4, 145.5, 167.6,
177.0. HR-MS:
270.1819.
C
H
NO ` requires 270.1831; found
15 26
4
To
a
solution of (2S,4S)-4-tert-butoxycarbonylamino-2-
methyl-2-pentanoic acid (29)7 (1.16 g, 5.0 mmol) in CH Cl
2
2
tert-Butyl
(2E,4S,6S)-6-(methoxycarbonyl-2,4-dimethyl-2-
(25 mL) was added dropwise at 0 ¡C triÑuoroacetic acid (4.59
mL, 60 mmol). After stirring for 1 h at room temperature the
solution was concentrated, diethyl ether (15 mL) was added
and the solution was concentrated again. The residue was
taken up in water (20 mL), Na CO (2.65 g, 25 mmol) was
heptenoate. The half-ester 26 was converted to the correspond-
ing aldehyde12 and subjected to the Wittig reaction as above
to give 58% of the title compound. 1H NMR (300 MHz,
CDCl ): d \ 0.99 (d, J \ 6.7 Hz, 3 H), 1.14 (d, J \ 7.0 Hz, 3
3
2
3
H), 1.35 (m, 1 H), 1.49 (s, 9 H), 1.75 (d, J \ 1.3 Hz, 3 H), 1.82
added and the mixture was cooled to 0 ¡C. A solution of
Fmoc-OSu18 (2.53 g, 7.5 mmol) in dioxane (35 mL) was added
in several increments over 5 min. The pH of the solution was
adjusted to 9 by adding 10% aqueous Na CO solution. The
(m, 1 H), 2.39 (m, 1 H), 2.52 (m, 1 H), 3.67 (s, 3 H), 6.37 (d,
J \ 10.2 Hz, 1 H). 13C NMR (75 MHz, CDCl ): d \ 12.4,
17.9, 20.2, 28.1, 31.3, 37.5, 40.9, 51.4, 79.9, 128.5, 145.5, 167.5,
177.0.
3
2
3
mixture was stirred at 0 ¡C for 1 h and at room temperature
for 2 h. Water (130 mL) was added and the aqueous solution
was extracted with diethyl etherÈethyl acetate (1 : 1, 250 mL).
The combined organic extracts were washed with 2% aqueous
Na CO solution (125 mL) and the aqueous layers were acid-
13. tert-Butyl (2E,4S,6R)-6-(Ñuorenylmethoxycarbonyl-
amino)-2,4-dimethyl-2-heptenoate (25)
Aqueous lithium hydroxide (5 M, 2.8 mL, 14 mmol) was
added to a solution of the diester 23 (592 mg, 2.2 mmol) in
dimethoxyethane (9 mL) and water (5.6 mL). After stirring for
17 h the mixture was diluted with water (10 mL) and extracted
with diethyl ether (3 ] 10 mL). The aqueous layer was acid-
iÐed at 0 ¡C with aqueous hydrochloric acid and extracted
with ethyl acetate (3 ] 10 mL). The combined organic extracts
2
3
iÐed to pH 1 with 1 M aqueous hydrochloric acid. The pre-
cipitated white solid was extracted with ethyl acetate (2 ] 250
mL), the extracts were concentrated and the residue was crys-
tallized from ethyl acetateÈhexane (1 : 3, 60 mL) to give 1.57 g
(89%) of the desired acid, mp \ 102 ¡C. [a]20 \ ]18.9
D
(c \ 1.5, CH OH). 1H NMR (300 MHz, CDCl ): d \ 1.15 (d,
3
3
J \ 6.6 Hz, 3 H), 1.18 (d, J \ 7.6 Hz, 3 H), 1.40È1.58 (m, 1 H),
1.80 (ddd, J \ 13.9, 9.1 and 4.8 Hz, 1 H), 2.40È2.60 (m, 1 H),
3.50È3.88 (m, 1 H), 4.21 (br t, J \ 6.1 Hz, 1 H), 4.43 (br d,
J \ 6.0 Hz, 2 H), 4.73 (br d, J \ 7.8 Hz, 1 H), 7.28 (t, J \ 7.4
Hz, 2 H), 7.39 (t, J \ 7.3 Hz, 2 H), 7.58 (d, J \ 7.4 Hz, 2 H),
7.75 (d, J \ 7.4 Hz, 2 H), 10.2 (br s, 1 H). Irradiation at
d \ 3.8 collapses the 4.8 Hz coupling at d \ 1.80. Irradiation
at d \ 2.4 collapses the 4.5 Hz coupling at d \ 1.43, 13C
were washed with brine (3 ] 5 mL), dried (MgSO ) and con-
centrated to leave 518 mg (92%) of the carboxylic acid as a
4
colourless oil. [a]22 \ ]7.8 (c \ 2.56, CHCl ). 1H NMR (300
D
3
MHz, CDCl ): d \ 0.99 (d, J \ 6.6 Hz, 3 H), 1.14 (d, J \ 7.0
3
Hz, 3 H), 1.30È1.40 (m, 1 H), 1.45 (s, 9 H), 1.70È1.80 (m, 1 H),
1.77 (d, J \ 1.4 Hz, 3 H), 2.40 (m, 1 H), 2.50 (m, 1 H), 6.36 (d,
J \ 10.1 Hz, 1 H). 13C NMR (75 MHz, CDCl ): d \ 12.5,
3
17.0, 20.0, 28.1, 30.9, 37.3, 40.0, 80.1, 128.6, 145.2, 167.6, 182.8.
NMR (75 MHz, CDCl ): d \ 17.4, 21.3, 36.4, 41.0, 45.6, 47.3,
66.5, 119.8, 125.0, 127.1, 127.7, 141.3, 143.1, 156.3, 180.7.
The acid obtained was dissolved in toluene (1.3 mL). Tri-
ethylamine (0.3 mL, 2.0 mmol) and diphenylphosphorylazide
(0.43 mL, 2.0 mmol) were added. The mixture was heated to
80 ¡C and after 2 h, when nitrogen evolution had ceased, Ñuo-
renylmethanol (784 mg, 4.0 mmol) was added. After 6 h at
80 ¡C the solvents were removed under reduced pressure and
the residue was taken up in diethyl ether (20 mL). The solu-
3
C
H
NO (353.4) requires C 71.37, H 6.56, N 3.96; found C
21 23
4
70.73, H 6.76, N 3.89%.
15. (3R/S,4S,5R)-1-(tert-Butoxycarbonyl)-4-deutero-3,5-
dimethylpyrolidine-2-one (32)
tion was washed with water (3 ] 5 mL), dried (MgSO ) and
Methanol-OD (0.24 mL, 6 mmol) was added to a solution of
lithium aluminium deuteride (84 mg, 2 mmol) in THF (2 mL).
4
concentrated. PuriÐcation of the residue by Ñash chromatog-
New J. Chem., 2000, 24, 187È194
193

View Article Online
The mixture was stirred for 30 min and added to a suspension
of CuBr (123 mg, 0.86 mmol) in THF (3.1 mL) at 0 ¡C. After
stirring for 30 min the resulting dark brown suspension
Acknowledgement
This work has been supported by the European Commission
through the TMR network ERB FMRX CT-960011.
was cooled to [78 ¡C and
a solution of (5R)-1-tert-
butoxycarbonyl-3,5-dimethyl-3-pyrrolin-2-one (31)6,7 (95 mg,
0.45 mmol) in THF (1 mL) was added rapidly. The mixture
was allowed to warm slowly to [20 ¡C and was stirred at this
temperature for 90 min. Methanol (2 mL) was added and the
mixture was poured into brine (10 mL). The mixture was
extracted with ether (3 ] 5 mL) and the combined organic
References and notes
1
2
3
D. L. Boger and H. Cai, Angew. Chem., 1999, 111, 470; Angew.
Chem., Int. Ed., 1999, 38, 448 and references therein.
Y. Kato, N. Fusetani, S. Matsunaga, K. Hashimoto and K.
Koseki, J. Org. Chem., 1988, 53, 3930.
R. W. Ho†mann, Angew. Chem., 1992, 104, 1147; Angew. Chem.,
Int. Ed. Engl., 1992, 31, 1124; R. Gottlich, B. C. Kahrs, J. Kruger
and R. W. Ho†mann, Chem. Commun., 1997, 247.
D. L. Boger, T. M. Ramsey, H. Cai, S. T. Hoehn and J. Stubbe, J.
Am. Chem. Soc., 1998, 120, 9149.
phases were washed with water (2 ] 3 mL), dried (MgSO )
4
and concentrated. PuriÐcation of the yellow residue (73 mg)
4
5
by Ñash chromatography with pentaneÈethyl acetate (4 : 1)
a†orded a 1 : 1.5 mixture of the epimeric pyrrolidinones 32 (22
mg, 60%) as a colourless oil. The NMR data were consistent
with those given in ref. 7.
R. W. Ho†mann, M. A. Lazaro, F. Caturla, E. Framery, I. Valan-
cogne and C. A. G. N. Montalbetti, T etrahedron L ett., 1999, 40,
5983.
6
7
8
A. M. P. Koskinen and P. M. Pihko, T etrahedron L ett., 1994, 35,
7417.
P. M. Pihko and A. M. P. Koskinen, J. Org. Chem., 1998, 63, 92
and references therein.
16. Methyl (2R/S,3S,4R)-4-(tert-butoxycarbonylamino)-
3-deutero-2-methylpentanoate (33 and 34)
C. R. Noller and C. E. Pannell, J. Am. Chem. Soc., 1955, 77, 1862;
N. L. Allinger, J. Am. Chem. Soc., 1959, 81, 232; P. A. Bartlett
and J. L. Adams, J. Am. Chem. Soc., 1980, 102, 337.
For leading references see: P. J. Kocienski, R. C. D. Brown, A.
Pommier, M. Procter and B. Schmidt, J. Chem. Soc., Perkin
T rans. 1, 1998, 9.
Aqueous lithium hydroxide (1 M, 0.26 mL) was added to a
solution of the pyrrolidinones 32 (18 mg, 0.084 mmol) in THF
(0.42 mL) at 0 ¡C. After stirring for 6 h at 0 ¡C water (10 mL)
was added, the phases were separated and the aqueous phase
was extracted with diethyl ether (3 ] 5 mL). The aqueous
layer was acidiÐed at 0 ¡C with aqueous hydrochloric acid and
extracted with ethyl acetate (3 ] 5 mL). The combined
organic layers were washed with brine (3 ] 3 mL), dried
9
10 R. W. Ho†mann, H.-J. Zei, W. Ladner and S. Tabche, Chem.
Ber., 1982, 115, 2357.
11 P. L. Stotter and K. A. Hill, T etrahedron L ett., 1975, 21, 1679.
12 R. W. Ho†mann, K. Ditrich, G. Koster and R. Sturmer, Chem.
Ber., 1989, 122, 1783 and references therein.
13 M. F. Semmelhack, R. D. Stau†er and A. Yamashita, J. Org.
Chem., 1977, 42, 3180.
(MgSO ), and concentrated to a†ord 15 mg (77%) of acids,
4
which were taken up in diethyl ether (1 mL). A solution of
14 What matters is the relative topicity of the hydrogen atoms at
C-3 to the stereocenters at C-2 and C-4. Assigning the hydrogen
atom at C-3 as pro-R or pro-S therefore only makes sense if the
conÐguration at C-2 and C-4 is deÐned, which has been arbi-
trarily done in the manner shown in the heading of the table.
15 Based on the molecular geometry found in the crystal structure,
coupling constants may be predicted (MACROMODEL) for 6a
diazomethane in ether was added dropwise until the yellow
colour persisted. The solution was stirred for 16 h and concen-
trated to a†ord 16 mg (100%) of a mixture of the esters 33 and
34 as a colourless oil. The esters were separated by pre-
parative HPLC using pentaneÈtert-butyl methyl ether (8 : 2)
as eluent.
as C-3-H
to H-2 \ 12.1 and to H-4 \ 1.5 Hz. The experi-
(provR)
mentally found coupling constants of 10.7 and 3.3 Hz, respec-
tively, represent the population weighted average in solution.
16 T. Hintermann, K. Gademann, B. Jaun and D. Seebach, Helv.
Chim. Acta, 1998, 81, 983; S. Hanessian, X. Luo and R. Schaum,
T etrahedron L ett., 1999, 40, 4925.
Methyl (2S,3S,4R)-4-(tert-butoxycarbonylamino)-3-deutero-
2-methylpentanoate (33). 1H NMR (300 MHz, CDCl ):
3
17 S. Hanessian, X. Luo, R. Schaum and S. Michnick, J. Am. Chem.
Soc., 1998, 120, 8569.
d \ 1.06 (d, J \ 6.5 Hz, 3 H), 1.11 (d, J \ 7.0 Hz, 3 H), 1.49 (s,
9 H), 1.71 (dd, J \ 10.0 and 7.4 Hz, 1 H), 2.44 (quint, J \ 7.0
18 L. Lapatsanis, G. Milias, K. Froussios and M. Kolovos, Synthe-
sis, 1983, 671.
Hz, 1 H), 3.61 (s, 3 H), 3.68 (m, 1 H), 4.20 (m, 1 H).
19 J. E. Nordlander and F. G. Njoroge, J. Org. Chem., 1987, 52,
1627.
Methyl (2R,3S,4R)-4-(tert-butoxycarbonylamino)-3-deutero-
20 H. J. C. Deboves, R. F. W. Jackson, C. A. G. N. Montalbetti and
I. A. Valancogne, in preparation.
21 R. D. Smith and H. E. Simmons, Org. Synth., 1961, 41, 72.
2-methylpentanoate (34). 1H NMR (300 MHz, CDCl ):
3
d \ 1.02 (d, J \ 6.6 Hz, 3 H), 1.10 (d, J \ 7.1 Hz, 3 H), 1.37 (s,
9 H), 1.40 (m, 1 H), 2.50 (quint, J \ 7 Hz, 1 H), 3.61 (s, 3 H),
3.60 (m, 1 H), 4.20 (m, 1 H).
Paper a910179i
194
New J. Chem., 2000, 24, 187È194