Straightforward synthesis of α-substituted prolines by cross-metathesis

Article abstract of DOI:10.1002/ejoc.200800044

The synthesis of several α-substituted N-Boc-protected prolines has been achieved by cross metathesis (CM) of N-Bocallylproline 5 with terminal long chain alkenes and alkenes bearing hydroxy, silyloxy, ester, and O-acetylglucosamido groups. The CM occurred with good selectivity and short reaction time under microwave heating conditions, affording yields in the range of 40-92%. Addition of Ti(OiPr)₄ as a Lewis acid allowed a slight increase of the yield in the case of alkenes with Lewis basic substituents. The CM was also successfully applied to allylproline protected with trichloroacetaldehyde 4, but the intermediate products were less practical for further deprotection and elaboration. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800044

FULL PAPER
DOI: 10.1002/ejoc.200800044
Straightforward Synthesis of α-Substituted Prolines by Cross-Metathesis
Marco Lumini,[a] Franca M. Cordero,*[a] Federica Pisaneschi,[a] and Alberto Brandi[a]
Keywords: Amino acids / Nitrogen heterocycles / Cross-coupling / Metathesis / Microwave
The synthesis of several α-substituted N-Boc-protected pro-
lines has been achieved by cross metathesis (CM) of N-Boc-
allylproline 5 with terminal long chain alkenes and alkenes
bearing hydroxy, silyloxy, ester, and O-acetylglucosamido
groups. The CM occurred with good selectivity and short re-
action time under microwave heating conditions, affording
yields in the range of 40–92%. Addition of Ti(OiPr)4 as a
Lewis acid allowed a slight increase of the yield in the case
of alkenes with Lewis basic substituents. The CM was also
successfully applied to allylproline protected with trichloro-
acetaldehyde 4, but the intermediate products were less
practical for further deprotection and elaboration.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
In view of the potential biological role of these types of
α,α-disubstituted α-amino acids and their many uses in sev-
eral branches of science,[12] we have focused our attention
on preparing collections of enantiomerically pure 2-substi-
tuted prolines employing common advanced building
blocks that could be easily functionalised.[13] Protected al-
lylprolines 1 are examples of enantiopure building blocks
with the terminal double bond suggesting the well-known
and versatile olefin cross-metathesis (CM) reaction as the
method of choice for introducing various functionalised
chains.[14] Even though olefin CM has emerged as a power-
ful and convenient synthetic technique in organic chemistry,
it has been limited by the lack of predictability in product
selectivity and stereoselectivity, although this problem can
be overcome by a judicious choice of reagents.[15]
In this paper, the selective olefin CM of protected 2--
allylprolines 1 and terminal olefins followed by catalytic hy-
drogenation is described as a general approach towards the
synthesis of α-substituted prolines 3 containing various
functionalities.[16–18] This versatile process allows the
achievement of various novel amino acids containing lipo-
philic and functionalized side chains from a common enan-
tiomerically pure single precursor (Scheme 1).
Introduction
It is well known that proline residues play key roles in
many biological processes, such as protein folding and pro-
tein recognition. Due to its unique structural properties, im-
portant conformational attributes are observed when pro-
line is introduced into a peptide sequence. Among the natu-
rally occurring amino acids, proline is unique in that it can
form cis amide bonds and undergo cis–trans isomerization,
and is often involved in nucleation of reverse turns, such as
β-turns.[1] The induction and stabilization of peptide sec-
ondary structures are often adopted in peptidomimetics to
induce a 3D arrangement both of the protein backbone and
of the side chains, the key features of a pharmacophore.[2]
Proline enhances the constraint in a peptide chain, as well
as protecting biologically active peptides against enzymatic
degradation by limiting their susceptibility to proteolysis.[3]
The therapeutic use of many potentially bioactive peptides
is limited by their insufficient bioavailability, which is re-
lated mainly to their poor membrane solubility. Peptidomi-
metics and synthetic peptide conjugates have been devised
as a way to increase the metabolic stability of peptides, to
shape their physical properties with beneficial effects on
pharmacokinetics, and to improve their receptor affin-
ity.[4–6] For example, α-amino acids containing long-chain
alkyl substituents may favour the interaction of peptides
with hydrophobic pockets, and furnish better resistance to-
ward proteolytic enzymes.[7]
α-Substituted proline derivatives[8] show important bio-
logical activities.[9] α-Alkylprolines have also found utility
as starting materials in the synthesis of natural products[10]
and as probes for polymeric structures.[11]
Scheme 1. General approach to α-substituted prolines.
[a] Dipartimento di Chimica Organica “Ugo Schiff”, Università
degli studi di Firenze, Laboratorio di Progettazione, Sintesi e
Studio di Eterocicli Biologicamente Attivi,
Results and Discussion
The enantiomerically pure building blocks 4[19] and 5,[20]
both possible candidates for the cross-coupling reaction,
via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39-055-4573531
E-mail: franca.cordero@unifi.it
Eur. J. Org. Chem. 2008, 2817–2824
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2817

M. Lumini, F. M. Cordero, F. Pisaneschi, A. Brandi
FULL PAPER
were prepared according to the Seebach methodology of Table 1. CM between allylproline 4 and hept-1-ene (9) under dif-
ferent reaction conditions.[a]
self-reproduction of chirality.[21]
With the aim of synthesizing protected prolines suitable
for peptide synthesis, and allowing the best conditions for
CM, i.e. absence of nucleophilic unprotected nitrogen
atoms, two different strategies could originate from these
two building blocks. The CM could be run on oxazolid-
inone 4 and the resulting product 6 could undergo sequen-
tial hydrolysis and N-protection to afford prolines 7 (Route
A, Scheme 2). On the other hand, allylproline 5, obtained
from 4 by oxazolidinone hydrolysis followed by N-Boc pro-
tection,[22] could be directly used in CM without protection
of the carboxylic group (Route B, Scheme 2). As both stra-
tegies could furnish advantages to the synthesis, were both
tested, starting with examination of Route A.
Entry
9
Temp.
Time
Yield
(%)[b]
E/Z[c]
(equiv.)
[d]
1
2
3
4
5
1.0
1.0
2.0
1.0
2.0
25 °C
40 °C
40 °C
10 d
2 h
2 h
–
3.7:1
4.8:1
6.3:1[e]
5:1
53
61
60
74
80 °C (MW)[f] 20 min
80 °C (MW)[f] 20 min
4.4:1
[a] A 0.1  solution of 4 in DCM, 1–2 equiv. of 9, and 5 mol-% of
8 were heated conductively (entries 1–3) or by MW irradiation (en-
tries 4 and 5). [b] Isolated yield after flash chromatography. [c] Ra-
tios by 13C NMR analysis of the crude reaction mixture. [d] Low
conversion. [e] Ratios by 1H NMR analysis of the purified product.
[f] 150 W with simultaneous cooling.
The reaction occurred very slowly at room temperature
(Table 1, entry 1). The desired product 10 was obtained in
moderate yield with refluxing DCM (Table 1, entries 2 and
3). A slight increase of the yield was obtained by doubling
the amount of 9 with respect to 4. Under MW irradiation,
a 74% yield of 10 was reached after 20 min at 80 °C when
2 equiv. of 9 were used (Table 1, entry 5). The oxazolidinone
homocoupling product was not detected in any of the reac-
tion mixtures. In all cases, the heterocoupling product 10
was obtained as an inseparable mixture of two isomers in a
ratio ranging from 4:1 to 6:1. The two isomers were as-
signed as the E/Z diastereomers, although only the major
E isomer could be assigned by H NMR spectroscopy. The
observed variation of E/Z ratios under different reaction
conditions did not show any rational trend.
Application of the optimised reaction conditions to
longer chain substrates 11 and 12 gave somewhat lower
yields of cross products 13 and 14, respectively (Scheme 3).
Scheme 2. Two complementary synthetic routes for prolines 7.
The success of a CM reaction relies on the use of olefin
partners with sufficiently diverse steric and/or electronic
properties. This brings about a different reactivity in me-
tathesis reactions and usually leads to the selective forma-
tion of the heterodimer, avoiding the statistical product dis-
tributions of hetero- and homodimers.[15] Allylprolines 4
and 5, despite having the bulky substitution in the homoal-
lyl position, both appeared to be sufficiently bulky to re-
duce the homodimerization rate under the reaction condi-
tions. Another important parameter in improving the yield
of the cross product is the ratio of the two olefins, however
this opportunity is, of course, dependent on the cost of the
reagent.
1
The second-generation Grubbs’ catalyst 8 was used in
our investigation for its demonstrated efficiency,[14] and for
the verified possibility of its use under microwave (MW)
induced heating conditions.[23,17a,17d]
Scheme 3. CM of allylproline 4 with alkenes 11 and 12.
The successful CM of allylproline 4, bearing a quater-
nary homoallylic carbon, needs further comment. Proline 4
must be a type II or III olefin, according to Grubbs’ classi-
Allyloxazolidinone 4 was treated with hept-1-ene 9 in a fication,[15] as it undergoes a selective CM with various type
0.1  solution of dichloromethane (DCM) in the presence I terminal olefins. Nevertheless, the reported result appears
of 8 (5 mol-%) under various reaction conditions in order quite remarkable as, to the best of our knowledge, only few
to determine the best parameters (Table 1).
examples of CM of similar bulky homoallylic substrates
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2817–2824

Synthesis of α-Substituted Prolines by Cross-Metathesis
with alkenes have been reported,[24] including a few with protection of the hydroxyl group in 18 as a silyl ether did
electron-deficient alkenes.[25]
not improve the CM yield (Table 2 entry 6).
Unfortunately, masked amino acids 10 and 13 led to un-
It is known that Lewis acids like Ti(OiPr)4 can be used
acceptably low product yields under common deprotection to improve metathesis yields when Lewis base groups are
and N-protection reaction conditions, due to their low solu- present in reagents.[26,27] The use of Ti(OiPr)4 (20 mol-%)
bility in water and low stability under the reaction condi- with 8 (5 mol-%) and 2 equiv. of alkenes 12 and 17 led to a
tions (Scheme 4). Moreover, the double bond could not be slight yield increase of products 20 and 21.[28] The control
reduced in the presence of the (trichloromethyl)oxazolidi- reaction using unsubstituted alkene 9 gave, as expected, the
none moiety.
same yield (Scheme 5).
Scheme 4. Hydrolysis and N-protection of oxazolidinones 10 and
13.
Scheme 5. CM between 5 and olefins 9, 12, and 17 (2 equiv.) in
the presence of catalyst 8 (5 mol-%) and Ti(OiPr)4 (20 mol-%). In
parentheses are yields of products under the same conditions in the
absence of Ti(OiPr)4.
Therefore, route B, i.e. CM between allylproline 5 and a
series of terminal olefins catalyzed by 8, was examined un-
der the reaction conditions optimized in the previous study
(Table 2).
The α-substituted prolines 15, 16, 20–23 could be easily
reduced by catalytic hydrogenation on Pd(OH)2, in contrast
to the corresponding oxazolidinone derivatives 10, 13, and
14, affording the N-Boc-protected prolines 24–29 in good
yield (Scheme 6).[29]
Table 2. CM of allylproline 5 with alkenes 9, 11, 12, 17, 18, and
19.[a]
Entry
X
n
Alkene
8
Solvent
Prod. Yield
(%)[b]
(equiv.) (mol) (concd., )
1
2
3
4
5
6
7
Me
Me
CO2Me
OH
OH
4
9
8
9
9
9
8
9 (7.0) 5%
DCM (0.1) 15
DCM (0.1) 16
DCM (0.1) 20
DCM (0.1) 21
THF (0.5)[c] 21
DCM (0.5) 22
92
86
63
40
11 (7.0) 5%
12 (2.0) 5%
17 (2.0) 5%
17 (5.0) 10%
18 (2.0) 10%
19 (2.0) 10%
Scheme 6. Hydrogenations of alkenes 15, 16, 20–23.
56
OTBDPS
CONHGlc
40
THF (0.3)
23
48[d]
Conclusions
[a] MW irradiation power of 150 W, ramp time of 5 min, with a
run time of 40 min at 80 °C and simultaneous cooling was used. [b]
Isolated yield after flash chromatography. [c] Reaction temperature:
40 °C. [d] H2NGlc: 2,3,4,6-tetra-O-acetyl-β--glucopyranosyl-
amine.
The synthesis of a collection of new N-Boc-protected α-
functionalized prolines has been achieved by applying the
cross metathesis reaction between N-Boc allylproline 5 and
the appropriate alkenes followed by hydrogenation. The re-
A comparison of the results obtained for CM on the two action conditions have been accurately investigated in order
different scaffolds shows that product yields are compar- to make the method generally available for several different
1
able. The H NMR analysis of the N-Βoc α-alkylated pro- terminal alkene substrates. The new prolines 24 and 25 con-
lines 15, 16, 20–23 in CDCl3 showed the presence of a mix- tain long-chain alkyl groups, suggesting their use as lipid-
ture of two conformers, apparently with exclusive E config- ated amino acids.[7] The glucosyl-conjugated proline 29 of-
uration (Jtrans = 15 Hz), as the Z isomers could not be de- fers a new interesting example of a glycosylated amino acid,
tected in the crude reaction mixtures. Analogous to allyl- which are objects of intense synthetic efforts for their appli-
proline 4, the shorter the aliphatic alkene was, the better cations as biological tools in glycopeptidomimetics.[30]
the reaction occurred (Table 2, entries 1, 2). CM of 5 with Functionalised chains with hydroxy and carboxylic groups
ω-functionalized alkenes such as alcohol 17 and amide 19 in prolines 26–28 might serve to link the amino acids to
was more sluggish, but a higher catalyst loading (10 mol- other functionalities, to favor the receptor interactions, or
%) provided acceptable yields of the corresponding cross to link them to a solid phase. Peptidomimetic syntheses
products in these cases (Table 2 entries 4, 5 and 7). Previous along these lines will be further studied in our laboratories.
Eur. J. Org. Chem. 2008, 2817–2824
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2819

M. Lumini, F. M. Cordero, F. Pisaneschi, A. Brandi
FULL PAPER
(dd, J = 10.0, 9.5 Hz, 1 H, 4-H), 4.98 (dm, J = 17.1 Hz, 1 H,
CH=CHH), 4.92 (dm, J = 10.2 Hz, 1 H, CH=CHH), 4.91 (t, J =
9.5 Hz, 1 H, 3-H), 4.31 (dd, J = 12.5, 4.3 Hz, 1 H, 6-H), 4.07 (dd,
J = 12.5, 2.1 Hz, 1 H, 6-H), 3.81 (ddd, J = 10.0, 4.3, 2.1 Hz, 1 H,
5-H), 2.24–2.07 (m, 2 H, 2-H[ch]), 2.07 (s, 3 H, CH3), 2.03 (s, 3 H,
CH3), 2.02 (s, 3 H, CH3), 2.01 (s, 3 H, CH3), 1.63–1.50 (m, 2 H, 9-
Experimental Section
General Remarks: Reactions were carried out in a CEM Dis-
1
coverTM microwave reactor. H NMR and 13C NMR spectra were
recorded with Varian Gemini (200 MHz) and Varian Mercury plus
(400 MHz) instruments using CDCl3 as solvent. The NMR spec-
troscopic data are reported in δ (ppm) from TMS at 25 °C. In the
assignment of NMR spectroscopic data of compounds 10, 13, 14,
and 15, 16, 20–29, [ch] notation indicates atoms (H or C) of the
alkyl chain on C-7a and C-2 of the cyclic system. The notation
[Glc] indicates atoms (H or C) of the glucosyl residue in compounds
23 and 29. IR spectra were recorded with a Perkin–Elmer 881 spec-
trophotometer using CDCl3 as solvent. Optical rotations were mea-
sured with a Perkin–Elmer 343 polarimeter. Mass spectra were re-
corded with a QMD 1000 Carlo–Erba instrument by direct inlet;
relative percentages are shown in brackets. Elemental analyses were
performed with a Perkin–Elmer 2400 analyzer. Flash column
chromatography (FCC) was accomplished on SiO2 32–63 Mesh. Rf
= values refer to TLC on 0.25 mm silica gel plates (Merck F254).
H[ch]), 1.40–1.22 (m, 12 H, 3-H[ch], 4-H[ch], 5-H[ch], 6-H[ch], 7-H[ch]
,
8-H[ch]) ppm. 13C NMR (50 MHz): δ = 173.3 (s; CONH), 170.9 (s;
COO), 170.5 (s; COO), 169.8 (s; COO), 169.5 (s; COO), 139.0 (d;
CH=CH2), 114.1 (t; CH=CH2), 78.1 (d; C-1), 73.5 (d; C-5), 72.7
(d; C-2), 70.6 (d; C-3), 68.1 (d; C-4), 61.6 (t; C-6), 36.6 (t; C[ch]-2),
33.7, 29.2, 29.1, 29.0, 28.9, 28.8 (t; C[ch]-3, C[ch]-4, C[ch]-5, C[ch]-6,
C[ch]-7, C[ch]-8), 25.1 (t; C[ch]-9), 20.7 (q; CH3), 20.64 (q; CH3), 20.57
(q, 2 C; CH ) ppm. IR ν = 3427, 3077, 2923, 2856, 1755, 1697,
˜
3
1367, 1235, 1043 cm–1. MS (70 eV, EI): m/z (%) = 513 (1.51) [M+],
389 (22), 320 (22), 278 (31), 169 (37), 81 (84), 55 (100). C25H39NO10
(513.58): calcd. C 58.47, H 7.65, N 2.73; found C 58.08, H 7.80, N
2.46.
(E)- and (Z)-(3R,7aR)-3-(Trichloromethyl)-7a-(tridec-2-enyl)tetra-
hydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one (13): To a solution of al-
lylproline 4 (185 mg, 0.65 mmol) in DCM (6.5 mL) and alkene 11
(220 mg, 1.3 mmol) was added the catalyst 8 (27.6 mg, 0.03 mmol).
The solution was heated at 40 °C for 150 min under vigorous stir-
ring, then concentrated under vacuum. The crude product was
purified by chromatography on silica gel (petroleum ether/Et2O =
10:1) to afford the desired product 13 (163 mg, 0.38 mmol, 58%)
as a colorless oil. Oxazolidinone 13 was obtained as a mixture of
isomers tentatively assigned as E and Z isomers in ca 4:1 ratio.
Only the major isomer is reported. Rf = 0.61 (petroleum ether/Et2O
= 6:1), 1H NMR (400 MHz): δ = 5.65–5.53 (m, Jtrans = 15 Hz, 1
H, 3-H[ch]), 5.52–5.41 (m, Jtrans = 15 Hz, 1 H, 2-H[ch]), 4.96 (s, 1 H,
3-H), 3.24–3.10 (m, 2 H, 5-H), 2.56 (ddd, J = 13.8, 6.3, 1.1 Hz, 1
H, 1-H[ch]a), 2.47 (dd, J = 13.8, 7.7 Hz, 1 H, 1-H[ch]b), 2.17–2.07
(m, 1 H, 7-Ha), 2.06–1.96 (m, 3 H, 7-Hb, 4-H[ch]), 1.94–1.83 (m, 1
H, 6-Ha), 1.70–1.56 (m, 1 H, 6-Hb), 1.42–1.16 and 0.92–0.80 (m,
19 H, 5-H[ch], 6-H[ch], 7-H[ch], 8-H[ch], 9-H[ch], 10-H[ch], 11-H[ch], 12-
Abbreviations: CDMT
DCM = dichloromethane, NMM = N-methylmorpholine.
= 2-chloro-4,6-dimethoxy-1,3,5-triazine,
tert-Butyl(diphenyl)(undec-10-enyloxy)silane (18): Freshly distilled
diisopropylethylamine (DIPEA) (420 µL, 2.4 mmol) and tert-butyl-
diphenylchlorosilane (TBDPSCl) (300 µL, 1.2 mmol) were added
to a solution of 10-undecen-1-ol (120 mg, 0.8 mmol) in dry DCM
under nitrogen atmosphere, at 0 °C. The reaction mixture was
stirred at room temp. for 1 d and then concentrated. The residue
was dissolved in H2O (10 mL), and the aqueous solution was ex-
tracted with Et2O (10 mLϫ3). The ethereal phase was dried with
Na2SO4, filtered, and concentrated. Purification of the crude resi-
due by chromatography on silica gel (Et2O/petroleum ether = 1:5)
afforded the pure 18 (196 mg, 60%) as a colorless oil. Rf = 0.83
(Et2O/petroleum ether = 1:10). 1H NMR (400 MHz): δ = 7.71–7.66
(m, 4 H, HPh), 7.46–7.35 (m, 6 H, HPh), 5.83 (ddt, J = 17.1, 10.2,
6.7 Hz, 1 H, CH=CH2), 5.00 (ddt, J = 17.1, 2.1, 1.6 Hz, 1 H,
CH=CHH), 4.94 (ddt, J = 10.2, 2.1, 1.2 Hz, 1 H, CH=CHH), 3.67
(t, J = 6.5 Hz, 2 H, 1-H), 2.09–2.02 (m, 2 H, 9-H), 1.61–1.53 (m,
2 H, 2-H), 1.43–1.24 (m, 12 H, H-3, H-4, H-5, H-6, H-7, H-8), 1.06
(s, 9 H, tBu) ppm. 13C NMR (50 MHz): δ = 139.1 (d; CH=CH2),
135.5 (d; 4 C; CPh), 134.1 (s, 2 C; CPh), 129.4 (d, 2 C; CPh), 127.5
(d, 4 C; CPh), 114.1 (t; CH=CH2), 64.0 (t; C-1), 33.9 (t; C-9), 32.6
(t; C-2), 29.6, 29.5, 29.4, 29.2, 29.0, 25.8 (t, C-3, C-4, C-5, C-6, C-
H
[ch], 13-H[ch]) ppm. 13C NMR (50 MHz): δ = 177.0 (s; CO), 136.3
(d; C[ch]-2), 122.8 (d; C[ch]-3), 102.3 (d; C-3), 100.2 (s; CCl3), 71.6
(s; C-7a), 58.4 (t; C-5), 40.4 (t; C[ch]-1), 35.2 (t; C-7), 32.8, 32.0,
29.6, 29.4, 29.2 (t, C[ch]-4, C[ch]-5, C[ch]-6, C[ch]-7, C[ch]-8, C[ch]-9,
C[ch]-10, C[ch]-11), 25.4 (t, C-6), 22.8 (t; C[ch]-12), 14.2 (q; C[ch]-13)
ppm. IR ν = 2927, 2855, 1799, 1457, 1354, 1323, 1275, 1261, 1193,
˜
1105 cm–1. MS (70 eV, EI): m/z (%) = 424 (3.10) [M+], 369 (4), 268
(13), 209 (28), 85 (36), 83 (43), 71 (65), 57 (100), 55 (99).
C20H32Cl3NO2 (424.83): calcd. C 56.54, H 7.59, N 3.30; found C
56.38, H 7.68, N 3.20.
7, C-8), 26.9 (q, 3 C; CH ), 19.3 (s; CMe ) ppm. IR ν = 3072, 2929,
˜
3
3
1472, 1428, 1111 cm–1. MS (70 eV, EI): m/z (%) = 365 (3), 351 (33),
199 (100), 183 (20), 91 (5), 77 (10). C27H40OSi (408.69): calcd. C
79.35, H 9.87; found C 79.24, H 9.65.
2,3,4,6-Tetra-O-acetyl-N-(10-undecenoyl)-β-
D
-glucopyranosylamine
General Procedure for Cross-Metathesis under Microwave Irradia-
tion: To a solution of allylprolines 4 or 5, in DCM or in THF (10–5–
10–1 ), was added the alkene (2–7 equiv.) followed by the Grubbs’
catalyst 8 (5–10 mol-%). The vial was sealed and irradiated in the
microwave reactor using an irradiation power of 150 W (with si-
multaneous cooling) at the appropriate temperature (from 40 °C to
80 °C), under vigorous stirring for the appropriate time. The solu-
tion was then concentrated under vacuum, and the crude reaction
mixture was purified by chromatography on silica gel. In the case
of oxazolidinone products, a second purification was necessary to
remove all the traces of Ru catalyst to get analytically pure samples,
whereas prolines 15, 16, 20–23, remained as brownish oils after
purification, not allowing exact elemental analyses. The structural
identity of prolines 15, 16, 20–23 was indirectly confirmed by the
(19): NMM (148 µL, 1.3 mmol) and CDMT (231 mg, 1.3 mmol)
were added under nitrogen to a solution of undecenoic acid
(279 mg, 1.5 mmol) in dry THF (1 mL). After 1 h, a solution of
2,3,4,6-tetra-O-acetyl-β--glucopyranosylamine (408 mg,
1.3 mmol) in dry THF (1.9 mL) was added, and the reaction mix-
ture was stirred overnight at room temp. The solvent was removed
under reduced pressure, and the residue was dissolved in EtOAc
(8 mL) and H2O (5 mL). The separated organic phase was washed
sequentially with H2O, a saturated solution of NaHCO3, and brine,
then dried with Na2SO4 and concentrated. The crude product was
purified by chromatography on silica gel (EtOAc/petroleum ether
= 2:3) to afford the desired product 19 (409 mg, 0.8 mmol, 61%)
25
as a colorless oil. Rf = 0.14 (EtOAc/petroleum ether = 1:2), [α]D
1
= +15.6 (c = 1.0, CHCl3). H NMR (400 MHz): δ = 6.18 (d, J = following analysis of the corresponding reduction products (see be-
9.3 Hz, 1 H, NH), 5.79 (ddt, J = 17.1, 10.2, 6.7 Hz, 1 H, CH=CH2), low). Oxazolidinones 10 and 14 were obtained as mixtures of iso-
5.30 (t, J = 9.5 Hz, 1 H, 2-H), 5.25 (t, J = 9.5 Hz, 1 H, 1-H), 5.05
mers tentatively assigned as E and Z isomers in ca 4:1 ratio. Pro-
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Synthesis of α-Substituted Prolines by Cross-Metathesis
lines 15, 16, 20–23 were obtained as mixtures of conformers in ca
2:1 ratio. NMR spectra of the major isomer/conformer are re-
ported.
10.6, 7.0 Hz, 1 H, 5-Hb), 2.87 (broad dd, J = 14.1, 6.5 Hz, 1 H, 1-
[ch]a), 2.51 (dd, J = 14.1, 8.0 Hz, 1 H, 1-H[ch]b), 2.26–1.76 (m, 6
H, 3-H, 4-H, 4-H[ch]), 1.53 (s, 9 H, Boc), 1.55–1.23 (m, 16 H, 5-
H
H[ch], 6-H[ch], 7-H[ch], 8-H[ch], 9-H[ch], 10-H[ch], 11-H[ch], 12-H[ch]);
(E)- and (Z)-(3R,7aR)-7a-(Oct-2-enyl)-3-(trichloromethyl)tetra-
hydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one (10): According to the ge-
neral procedure using 4 (89 mg, 0.31 mmol), the product 10 (81 mg,
0.23 mmol, 74%) was obtained as a colorless oil. Rf = 0.38 (petro-
leum ether/Et2O = 6:1). 1H NMR (400 MHz): δ = 5.66–5.53 (m,
0.88 (t J = 6.8 Hz, 3 H, 13-H[ch]) ppm. IR ν = 2928, 2855, 1740,
˜
1686, 1608, 1436, 1406, 1369, 1162 cm–1. MS (70 eV, EI): m/z (%)
= 395 (0.32) [M+], 308 (18), 294 (45), 250 (32), 186 (19), 114 (100),
96 (21), 57 (90).
Jtrans = 15 Hz, 1 H, 3-H[ch]), 5.52–5.42 (m, Jtrans = 15 Hz, 1 H, 2- 1-(tert-Butoxycarbonyl)-2-[(2E)-12-methoxy-12-oxododec-2-enyl]-
H[ch]), 4.96 (s, 1 H, 3-H), 3.24–3.10 (m, 2 H, 5-H), 2.56 (broad dd, proline (20): According to the general procedure using 5 (49 mg,
J = 14; 6.3 Hz, 1 H, 1-H[ch]), 2.47 (dd, J = 13.9, 7.8 Hz, 1 H, 1- 0.19 mmol), the product 20 (51 mg, 0.12 mmol, 63%) was obtained.
L-
1
H[ch]), 2.17–1.94 (m, 4 H, 7-H, 4-H[ch]), 1.93–1.82 (m, 1 H, 6-H),
Rf = 0.31 (EtOAc/petroleum ether = 1:2). H NMR (400 MHz): δ
1.72–1.58 (m, 1 H, 6-H), 1.40–1.21 (m, 6 H, 5-H[ch], 6-H[ch], 7- = 5.60–5.50 (m, Jtrans = 15 Hz, 1 H, 3-H[ch]), 5.28–5.17 (m, Jtrans
=
H[ch]), 0.88 (t, J = 6.9 Hz, 3 H, 8-H[ch]) ppm. 13C NMR (50 MHz):
δ = 176.4 (s; CO), 136.4 (d, C[ch]-2), 122.9 (d; C[ch]-3), 102.4 (d; C-
15 Hz, 1 H, 2-H[ch]), 3.66 (m, 3 H, OMe), 3.52–3.45 (m, 1 H, 5-
Ha), 3.30–3.21 (m, 1 H, 5-Hb), 2.85–2.77 (m, 1 H, 1-H[ch]a), 2.67–
3), 100.5 (s; CCl3), 71.6 (s; C-7a), 58.3 (t; C-5), 40.4 (t; C[ch]-1), 35.1 2.57 (m, 1 H, 1-H[ch]b), 2.29 (t, J = 7.5 Hz, 2 H, 11-H[ch]), 2.03–
(t; C-7), 32.6 (t; C[ch]-4), 31.3, 29.0 (t; C[ch]-5, C[ch]-6), 25.3 (t; C-6), 1.71 (m, 6 H, 3-H, 4-H, 4-H[ch]), 1.65–1.56 (m, 2 H, 10-H[ch]), 1.48
22.4 (t; C[ch]-7), 14.0 (q; C[ch]-8) ppm. IR ν = 2958, 2928, 1799,
(s, 9 H, Boc), 1.46–1.43 and 1.36–1.23 (m, 10 H, 5-H[ch], 6-H[ch], 7-
˜
1458, 1354, 1323, 1275, 1192, 1105 cm–1. MS (70 eV, EI): m/z (%)
H[ch], 8-H[ch], 9-H[ch]) ppm. IR ν = 2930, 2856, 1732, 1689, 1609,
˜
= 354 (0.45) [M+], 246 (30), 244 (91), 242 (93) [M – C8H15], 96 1436, 1401, 1368, 1167 cm–1, MS (70 eV, EI): m/z (%) = 425 (8.3)
(100), 68 (33), 55 (20). C15H22Cl3NO2 (354.70): calcd. C 50.79, H
6.25, N 3.95; found C 50.50, H 6.48, N 4.02.
[M+], 280 (22), 220 (8), 114 (50), 165 (20), 83 (43), 57 (100).
1-(tert-Butoxycarbonyl)-2-[(2E)-12-hydroxydodec-2-enyl]- -proline
L
Methyl (E)- and (Z)-12-[(3R,7aR)-1-Oxo-3-(trichloromethyl)dihy-
dro-1H-pyrrolo[1,2-c][1,3]oxazol-7a(5H)-yl]dodec-10-enoate (14):
According to the general procedure using 4 (105 mg, 0.37 mmol),
the product 14 (95 mg, 0.21 mmol, 57%) was obtained as a color-
less oil. Rf = 0.39 (petroleum ether/Et2O = 6:1). 1H NMR
(21): According to the general procedure using 5 (46 mg,
0.18 mmol), the product 21 (41 mg, 0.10 mmol, 56%) was obtained.
Rf = 0.31 (n-hexane/EtOAc = 1:5). 1H NMR (400 MHz): δ = 5.59–
5.50 (m, Jtrans = 15 Hz, 1 H, 3-H[ch]), 5.29–5.18 (m, Jtrans = 15 Hz,
1 H, 2-H[ch]), 3.63 (t, J = 6.6 Hz, 2 H, 12-H[ch]), 3.53–3.45 (m, 1 H,
(400 MHz): δ = 5.65–5.53 (m, Jtrans = 15 Hz, 1 H, 3-H[ch]), 5.52– 5-Ha), 3.31–3.21 (m, 1 H, 5-Hb), 2.83–2.76 (m, 1 H, 1-H[ch]), 2.66–
5.42 (m, Jtrans = 15 Hz, 1 H, 2-H[ch]), 4.96 (s, 1 H, 3-H), 3.66 (s, 3 2.60 (m, 1 H, 1-H[ch]), 2.06–1.51 (m, 8 H, 3-H, 4-H, 4-H[ch], 11-
H, OCH3), 3.24–3.11 (m, 2 H, 5-H), 2.55 (broad dd, J = 14, 6.3 Hz,
H[ch]), 1.48 (s, 9 H, Boc), 1.40–1.24 (m, 12 H, 5-H[ch], 6-H[ch], 7-
1 H, 1-H[ch]a), 2.47 (dd, J = 13.9, 7.6 Hz, 1 H, 1-H[ch]b), 2.30 (t, J H[ch], 8-H[ch], 9-H[ch], 10-H[ch]) ppm. IR ν = 3507, 2931, 2856, 1742,
˜
= 7.5 Hz, 2 H, 11-H[ch]), 2.15–2.07 (m, 1 H, 7-Ha), 2.06–1.93 (m, 1607, 1407, 1265, 1161 cm–1. MS (70 eV, EI): m/z (%) = 352 (0.3),
3 H, 7-Hb, 4-H[ch]), 1.92–1.83 (m, 1 H, 6-Ha), 1.71–1.57 (m, 3 H,
338 (0.3), 324 (0.5), 310 (0.3), 297 (1.2), 252 (34), 114 (100), 96 (15),
57 (97).
6-Hb, 10-H[ch]), 1.40–1.23 (m, 10 H, 5-H[ch], 6-H[ch], 7-H[ch], 8-H[ch]
,
9-H[ch]) ppm. 13C NMR (100 MHz): δ = 176.3 (s; CO), 174.2 (s;
1-(tert-Butoxycarbonyl)-2-[(2E)-12-{[tert-butyl(diphenyl)silyl]oxy}-
dodec-2-enyl]-L-proline (22): According to the general procedure
C[ch]O), 136.2 (d; C[ch]-2), 123.0 (d; C[ch]-3), 102.3 (d; C-3), 100.5
(s; CCl3), 71.6 (s; C-7a), 58.3 (t; C-5), 51.4 (q; OMe), 40.3 (t; C[ch]
-
using 5 (50 mg, 0.20 mmol), the product 22 (52 mg, 0.08 mmol,
1), 35.1 (t; C-7), 34.0 (t; C[ch]-11), 32.6 (t; C[ch]-4), 29.3, 29.2 (2 C),
29.1, 29.0, (t, C[ch]-5, C[ch]-6, C[ch]-7, C[ch]-8, C[ch]-9), 25.2 (t; C-6),
1
40%) was obtained. Rf = 0.30 (EtOAc/petroleum ether = 1:3). H
NMR (400 MHz): δ = 7.69–7.65 (m, 4 H, HPh), 7.44–7.34 (m, 6 H,
24.9 (t; C[ch]-10) ppm. IR ν = 2929, 2856, 1799, 1730, 1437, 1354,
˜
HPh), 5.63–5.51 (m, Jtrans = 15 Hz, 1 H, 3-H[ch]), 5.28–5.17 (m, Jtrans
1323, 1275, 1193, 1105 cm–1. MS (70 eV, EI): m/z (%) = 455 (0.1)
[M+], 424 (0.76), 280 (6), 246 (30), 244 (97), 242 (100), 96 (95), 68
(37), 55 (35). C20H30Cl3NO4 (454.82): calcd. C 52.82, H 6.65, N
3.08; found C 52.47, H 6.76, N 2.82.
= 15 Hz, 1 H, 2-H[ch]), 3.65 (t, J = 6.5 Hz, 2 H, 12-H[ch]), 3.53–3.44
(m, 1 H, 5-Ha), 3.33–3.20 (m, 1 H, 5-Hb), 2.85–2.76 (m, 1 H, 1-
H[ch]a), 2.72–2.60 (m, 1 H, 1-H[ch]b), 2.07–1.67 (m, 6 H, 3-H, 4-H,
4-H[ch]), 1.59–1.51 (m, 2 H, 11-H[ch]), 1.49 (s, 9 H, Boc), 1.38–1.22
1-(tert-Butoxycarbonyl)-2-[(2E)-oct-2-enyl]-
L
-proline (15): Accord-
(m, 12 H, 5-H[ch], 6-H[ch], 7-H[ch], 8-H[ch], 9-H[ch], 10-H[ch]), 1.01 (s,
ing to the general procedure using 5 (35 mg, 0.14 mmol), the prod-
uct 15 (41 mg, 0.13 mmol, 92%) was obtained. Rf = 0.33 (n-hexane/
9 H, CH3 TBDPS) ppm. IR: ν = 2931, 2857, 1686, 1611, 1467,
˜
1428, 1368, 1171, 1112 cm–1. MS (70 eV, EI): m/z (%) = 536 (1.41)
EtOAc = 2:1). 1H NMR (400 MHz): δ = 5.61–5.47 (m, Jtrans
=
[M+], 522 (1), 477 (1), 234 (2), 199 (15), 114 (21), 83 (13), 57 (100).
15 Hz, 1 H, 3-H[ch]), 5.36–5.15 (m, Jtrans = 15 Hz, 1 H, 2-H[ch]),
3.55–3.45 (m, 1 H, 5-H), 3.30–3.20 (m, 1 H, 5-H), 2.85 (dd, J =
13.5, 7.5 Hz 1 H, 1-H[ch]), 2.60 (dd, J = 13.5, 7.5 Hz 1 H, 1-H[ch]),
2.04–1.70 (m, 6 H, 3-H, 4-H, 4-H[ch]), 1.48 (s, 9 H, Boc), 1.38–1.21
1-(tert-Butoxycarbonyl)-2-[(2E)-12-oxo-12-(2,3,4,6-tetra-O-acetyl-β-
D
-glucopyranosylamino)dodec-2-enyl]-L-proline (23): According to
the general procedure using 5 (80 mg, 0.31 mmol), the product 23
(110 mg, 0.15 mmol, 48%) was obtained. Rf = 0.32 (DCM/MeOH
(m, 6 H, 5-H[ch], 6-H[ch], 7-H[ch]); 0.88 (t, J = 6.9 Hz, 3 H, 8-H[ch]
)
1
= 25:1). H NMR (400 MHz): δ = 6.22 (d, J = 9.8 Hz, 1 H, NH),
ppm. IR ν = 2929, 2856, 1739, 1711, 1689, 1609, 1403, 1162 cm–1.
˜
5.71–5.57 (m, 1 H, 3-H[ch]), 5.30 (t, J = 9.5 Hz, 1 H, 2-H[Glc]), 5.26
(broad t, J = 9.1 Hz, 1 H, 1-H[Glc]), 5.23–5.09 (m, 1 H, 2-H[ch]),
5.06 (dd, J = 10.1, 9.4 Hz, 1 H, 4-H[Glc]), 4.91 (dt, J = 2.6, 9.6 Hz,
1 H, 3-H[Glc]), 4.31 (dd, J = 12.5, 4.3 Hz, 1 H, 6-H[Glc] a), 4.07 (dd,
J = 12.5, 2.1 Hz, 1 H, 6-H[Glc] b), 3.81 (ddd, J = 10.1, 4.3, 2.1 Hz,
1 H, 5-H[Glc]), 3.55–3.45 (m, 1 H, 5-Ha), 3.34–3.21 (m, 1 H, 5-Hb),
2.90 (dd, J = 13.7, 7.1 Hz, 1 H, 1-H[ch] a), 2.85–2.49 (m, 4 H, 3-
MS (70 eV, EI): m/z (%) = 327 (0.03) [M+], 224 (33), 180 (26), 114
(86), 96 (17), 57 (100).
1-(tert-Butoxycarbonyl)-2-[(2E)-tridec-2-enyl]-L-proline (16): Ac-
cording to the general procedure using 5 (56 mg, 0.22 mmol), the
product 16 (75 mg, 0.19 mmol, 86%) was obtained. Rf = 0.14 (pe-
troleum ether/Et2O = 1:1). 1H NMR (400 MHz): δ = 5.60–5.46 (m,
Jtrans = 15 Hz, 1 H, 3-H[ch]), 5.37–5.26 (m, Jtrans = 15 Hz, 1 H, 2- Ha, 1-H[ch] b, 4-H[ch]), 2.24–2.09 (m, 2 H, 11-H[ch]), 2.07 (s, 3 H,
H[ch]), 3.68 (ddd J = 10.6, 7.6, 5.8 Hz, 1 H, 5-Ha), 3.37 (dt, J = OAc), 2.04 (s, 3 H, OAc), 2.03 (s, 3 H, OAc), 2.01 (s, 3 H, OAc),
Eur. J. Org. Chem. 2008, 2817–2824
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2821

M. Lumini, F. M. Cordero, F. Pisaneschi, A. Brandi
FULL PAPER
2.03–1.52 (m, 5 H, 3-Hb, 4-H, 10-H[ch]), 1.48 (s, 9 H, Boc), 1.47– 1-(tert-Butoxycarbonyl)-2-(12-hydroxydodecyl)-
1.38 and 1.36–1.22 (m, 10 H, 5-H[ch], 6-H[ch], 7-H[ch], 8-H[ch], 9-
L
-proline (27): Yel-
lowish oil, 76% yield, Rf = 0.34 (n-hexane/EtOAc = 2:1), [α]2D5
–22.1 (c = 0.8, CHCl3). 1H NMR (400 MHz): δ = 3.64 (t, J =
=
H[ch]) ppm. IR: ν = 3427, 2931, 2856, 1747, 1711, 1689, 1404, 1369,
˜
1228, 1040 cm–1. MS (70 eV, EI): m/z (%) = 741 (0.52) [M+], 595 6.6 Hz, 2 H, 12-H[ch]), 3.52–3.44 (m, 1 H, 5-Ha), 3.34–3.25 (m, 1
(33), 266 (11), 248 (21), 169 (31), 114 (98), 96 (40), 70 (53), 57 (100), H, 5-Hb), 2.80–2.71 (m, 1 H, 3-Ha), 2.26–2.15 (m, 1 H, 1-H[ch]a),
55 (57).
1.85–1.70 (m, 4 H, 1-H[ch]b, 3-Hb, 4-H), 1.56 (tt, J = 7.1, 6.9 Hz,
2 H, 11-H[ch]), 1.49 (s, 9 H, Boc), 1.37–1.22 (m, 18 H, 2-H[ch], 3-
General Procedure for Catalytic Hydrogenation: A solution of CM
products in MeOH (10–1 ), along with 20% Pd(OH)2/C (10 mol-
%) was stirred under H2 at atmospheric pressure overnight. The
reaction mixture was filtered, concentrated and purified by column
chromatography to afford the hydrogenated products. A mixture of
two conformers was obtained in unresolved ratio. Only signals of
the major conformers are reported.
H
[ch], 4-H[ch], 5-H[ch], 6-H[ch], 7-H[ch], 8-H[ch], 9-H[ch], 10-H[ch]) ppm.
13C NMR (50 MHz): δ = 173.8 (s; CO2H), 157.3 (s; CO Boc), 82.3
(s; CMe3), 70.9 (s; C-2), 63.2 (t; C[ch]-12), 49.6 (t; C-5), 35.1 (t; C-
3), 34.3 (t; C[ch]-1), 33.0 (t; C[ch]-11), 29.8 (6 C), 29.6 (2 C), 25.9 (t,
9 C; C[ch]-2, C[ch]-3, C[ch]-4, C[ch]-5, C[ch]-6, C[ch]-7, C[ch]-8, C[ch]-9,
C[ch]-10), 28.5 (q, 3 C; CH Boc), 22.9 (t; C-4) ppm. IR: ν = 2930,
˜
3
2855, 1736, 1610, 1406, 1265, 1162 cm–1. MS (70 eV, EI): m/z (%)
= 341 (3), 254 (7), 120 (68), 108 (26), 91 (100), 77 (45), 57 (53).
C22H41NO5 (399.56): calcd. C 66.13, H 10.34, N 3.51; found C
65.82, H 10.35, N 3.15.
1-(tert-Butoxycarbonyl)-2-octyl-L-proline (24): Colorless oil, 83%
yield, Rf = 0.31 (n-hexane/EtOAc = 1:1), [α]2D4 = –29.1 (c = 0.6,
CHCl3). 1H NMR (400 MHz): δ = 3.53–3.45 (m, 1 H, 5-Ha), 3.34–
3.25 (m, 1 H, 5-Hb), 2.77–2.66 (m, 1 H, 3-Ha), 2.22–2.07 (m, 1 H,
1-H[ch]a), 1.89–1.69 (m, 4 H, 3-Hb, 4-H, 1-H[ch]b), 1.49 (s, 9 H,
1-(tert-Butoxycarbonyl)-2-(12-{[tert-butyl(diphenyl)silyl]oxy}-
dodecyl)-L-proline (28): Colorless oil, 82% yield, Rf = 0.30 (EtOAc/
Boc), 1.35–1.12 (m, 12 H, 2-H[ch], 3-H[ch], 4-H[ch], 5-H[ch], 6-H[ch]
,
1
petroleum ether = 1:3), [α]2D5 = –15.7 (c = 0.6, CHCl3). H NMR
(400 MHz): δ = 7.69–7.64 (m, 4 H, HPh), 7.44–7.34 (m, 6 H, HPh),
3.65 (t, J = 6.6 Hz, 2 H, 12-H[ch]), 3.53–3.46 (m, 1 H, 5-Ha), 3.35–
3.25 (m, 1 H, 5-Hb), 2.79–2.70 (m, 1 H, 3-Ha), 2.25–2.16 (m, 1 H,
1-H[ch]a), 1.88–1.70 (m, 4 H, 1-H[ch]b, 3-Hb, 4-H), 1.55 (tt, J = 6.8,
6.5 Hz, 2 H, 11-H[ch]), 1.49 (s, 9 H, Boc), 1.37–1.21 (m, 18 H, 2-
H[ch], 3-H[ch], 4-H[ch], 5-H[ch], 6-H[ch], 7-H[ch], 8-H[ch], 9-H[ch], 10-
7-H[ch]), 0.87 (t, J = 6.8 Hz, 3 H, 8-H[ch]) ppm. 13C NMR
(100 MHz): δ = 174.3 (s; COOH), 157.5 (s; CO Boc), 82.2 (s;
CMe3), 70.9 (s; C-2), 49.4 (t; C-5), 34.9 (t; C-3), 34.4 (t; C[ch]-1),
31.8 (t; C[ch]-2), 29.5, 29.4, 29.1, 24.0, 22.7, 22.6 (t; 6 C; C-4, C[ch]
-
3, C[ch]-4, C[ch]-5, C[ch]-6, C[ch]-7), 28.4 (q, 3 C; CH3 Boc), 14.1 (q;
C[ch]-8) ppm. MS (70 eV, EI): m/z (%) = 226 (52), 212 (9), 182 (28),
96 (12), 83 (26), 57 (100), 55 (39). C18H33NO4 (327.46): calcd. C
66.02, H 10.16, N 4.28; found C 65.69, H 10.38, N 3.96.
H
[ch]), 1.05 (s, 9 H, CH3 tBu) ppm. 13C NMR (100 MHz): δ = 174.0
(s; COOH), 157.5 (s; CO Boc), 135.5 (d, 4 C; CPh), 134.1 (d, 2 C;
CPh), 129.4 (d, 2 C; CPh), 127.5 (d, 4 C; CPh), 82.3 (s; OCMe3),
71.0 (s; C-2), 64.0 (t; C[ch]-12), 49.4 (t; C-5), 34.9 (t; C-3), 34.4 (t;
C[ch]-1), 32.6 (t; C[ch]-11), 29.8 (2 C), 29.6 (2 C), 29.3 (2 C), 25.8,
24.0, 22.7, 19.2, (t; 10 C; C-4, C[ch]-2, C[ch]-3, C[ch]-4, C[ch]-5, C[ch]
6, C[ch]-7, C[ch]-8, C[ch]-9, C[ch]-10), 28.4 (q, 3 C; CH3 Boc), 26.9 (q,
1-(tert-Butoxycarbonyl)-2-tridecyl-L-proline (25): Colorless oil, 86%
yield, Rf = 0.28 (n-hexane/EtOAc = 5:1), [α]2D4 = –7.3 (c = 0.7,
CHCl3). 1H NMR (400 MHz): δ = 3.54–3.45 (m, 1 H, 5-Ha), 3.36–
3.26 (m, 1 H, 5-Hb), 2.79–2.68 (m, 1 H, 3-Ha), 2.24–2.09 (m, 1 H,
1-H[ch]a), 1.91–1.70 (m, 4 H, 3-Hb, 4-H, 1-H[ch]b), 1.49 (s, 9 H,
-
3 C; CH3 TBDPS), 19.3 (s; SiCMe ) ppm. IR: ν = 2930, 2856,
˜
3
Boc), 1.34–1.23 (m, 22 H, 2-H[ch], 3-H[ch], 4-H[ch], 5-H[ch], 6-H[ch]
,
1738, 1609, 1428, 1407, 1369, 1159, 1111 cm–1. MS (70 eV, EI): m/z
(%) = 493 (8), 481 (9), 466 (10), 199 (24), 96 (20), 83 (32), 57 (100),
55 (59). C38H59NO5Si (637.96): calcd. C 71.54, H 9.32, N 2.20;
found C 71.14, H 9.44, N 2.16.
7-H[ch], 8-H[ch], 9-H[ch], 10-H[ch], 11-H[ch], 12-H[ch]); 0.88 (t, J =
6.8 Hz, 3 H, 13-H[ch]) ppm. 13C NMR (100 MHz): δ = 174.1 (s;
COOH), 157.6 (s; CO Boc), 82.3 (s; CMe3), 71.0 (s; C-2), 49.4 (t;
C-5), 34.9 (t; C-3), 34.5 (t; C[ch]-1), 31.9 (t; C[ch]-2), 29.6, 29.5 (4
C), 29.4 (2 C), 29.2, 23.9, 22.7, 22.6 (t; 11 C; C-4, C[ch]-3, C[ch]-4,
C[ch]-5, C[ch]-6, C[ch]-7, C[ch]-8, C[ch]-9, C[ch]-10, C[ch]-11, C[ch]-12),
1-(tert-Butoxycarbonyl)-2-[12-oxo-12-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosylamino)dodecanoyl]-L-proline (29): Colorless oil, 78%
28.3 (q, 3 C; CH3 Boc), 14.0 (q; C[ch]-13) ppm. IR: ν = 2928, 2855,
˜
yield, Rf = 0.17 (n-hexane/EtOAc = 5:1), [α]2D5 = 8.7 (c = 0.3,
1741, 1689, 1405, 1369, 1162 cm–1. MS (70 eV, EI): m/z (%) = 398
(0.05) [M+], 296 (100), 282 (29), 252 (55), 114 (29), 96 (24), 57 (93).
C23H43NO4 (397.59): calcd. C 69.48, H 10.90, N 3.52; found C
69.29, H 11.14, N 3.45.
1
CHCl3). H NMR (400 MHz): δ = 6.19 (d, J = 9.4 Hz, 1 H, NH),
5.30 (t, J = 9.5 Hz, 1 H, 2-H[Glc]), 5.26 (t, J = 9.4 Hz, 1 H, 1-H[Glc]),
5.06 (t, J = 9.6 Hz, 1 H, 4-H[Glc]), 4.91 (t, J = 9.6 Hz, 1 H, 3-H[Glc]),
4.31 (dd, J = 12.5, 4.3 Hz, 1 H, 6-H[Glc]), 4.07 (dd, J = 12.5, 2.1 Hz,
1-(tert-Butoxycarbonyl)-2-(12-methoxy-12-oxododecyl)-L-proline 1 H, 6-H[Glc]), 3.81 (ddd, J = 10.1, 4.3, 2.1 Hz, 1 H, 5-H[Glc]), 3.53–
(26): Yellowish oil, 81% yield, Rf = 0.24 (n-hexane/EtOAc = 3:2),
3.45 (m, 1 H, 5-Ha), 3.34–3.25 (m, 1 H, 5-Hb), 2.81–2.71 (m, 1 H,
3-Ha), 2.36–2.09 (m, 3 H, 1-H[ch]a, 11-H[ch]), 2.08 (s, 3 H, OAc),
1
[α]2D6 = –27.3 (c = 0.4, CHCl3). H NMR (400 MHz): δ = 3.66 (m,
3 H, OMe), 3.52–3.46 (m, 1 H, 5-Ha), 3.34–3.25 (m, 1 H, 5-Hb), 2.04 (s, 3 H, OAc), 2.03 (s, 3 H, OAc), 2.02 (s, 3 H, OAc), 1.88–
2.80–2.72 (m, 1 H, 3-Ha), 2.30 (t, J = 7.5 Hz, 2 H, 11-H[ch]), 2.26– 1.10 (m, 22 H, 3-Hb, 4-H, 1-H[ch]b, 2-H[ch], 3-H[ch], 4-H[ch], 5-H[ch]
2.15 (m, 1 H, 1-H[ch]a), 1.86–1.68 (m, 4 H, 3-Hb, 4-H, 1-H[ch]b), 6-H[ch], 7-H[ch], 8-H[ch], 9-H[ch], 10-H[ch]), 1.49 (s, 9 H, CH3 Boc)
1.61 (tt, J = 7.5, 7.1 Hz, 2 H, 10-H[ch]), 1.49 (s, 9 H, Boc), 1.32–
ppm. 13C NMR (50 MHz): δ = 173.8 (s; COOH), 173.3 (s; CONH),
1.22 (m, 16 H, 2-H[ch], 3-H[ch], 4-H[ch], 5-H[ch], 6-H[ch], 7-H[ch], 8- 170.9 (s; MeCO), 170.5 (s; MeCO), 169.7 (s; MeCO), 169.5 (s;
H[ch], 9-H[ch]) ppm. 13C NMR (100 MHz): δ = 174.3 (s, 2 C; CO-
MeCO), 157.6 (s; CO Boc), 82.4 (s; CMe3), 78.1 (d; C[Glc]-1), 73.5
,
OMe, CO Boc), 82.4 (s; CMe3), 69.9 (s; C-2), 51.4 (q; OMe), 49.6 (d; C[Glc]-5), 72.7 (d; C[Glc]-4), 70.6 (d; C[Glc]-2), 68.1 (d; C[Glc]-3),
(t; C-5), 34.4 (t; C[ch]-10), 34.1 (t; C[ch]-11), 34.8 (t; C-3), 31.6, 29.5 61.6 (t; C[Glc]-6), 49.5 (t; C-5), 36.7 (t; C[ch]-11), 34.9 (t; C-3), 34.4,
(2 C), 29.4, 29.2, 29.1, 24.9, 24.0, 22.7, 22.6 (t, 10 C; C-4, C[ch]-1, 34.2, 29.6 (2 C), 29.5 (2 C), 29.3 (2 C), 29.1, 26.2, 25.2 (t, 11 C; C-2,
C[ch]-2, C[ch]-3, C[ch]-4, C[ch]-5, C[ch]-6, C[ch]-7, C[ch]-8, C[ch]-9), 28.4 C[ch]-1, C[ch]-2, C[ch]-3, C[ch]-4, C[ch]-5, C[ch]-6, C[ch]-7, C[ch]-8, C[ch]-9,
(q, 3 C; CH3 Boc) ppm. IR: ν = 2929, 2855, 1732, 1438, 1408,
C[ch]-10), 28.3 (q, 3 C; CH3 Boc), 22.7 (t; C-4), 20.8 (q; CH3CO),
˜
1369, 1164 cm–1. MS (70 eV, EI): m/z (%) = 412 (4.7), 282 (83), 268
(37), 114 (10), 96 (30), 57 (100). C23H41NO6 (427.57): calcd. C
64.61, H 9.67, N 3.28; found C 64.21, H 9.57, N 3.33.
20.7 (q; CH CO), 20.6 (q, 2 C; CH CO) ppm. IR: ν = 3427, 2930,
˜
3
3
2855, 1746, 1694, 1369, 1227, 1039 cm–1. MS (70 eV, EI): m/z (%)
= 724 (7), 366 (9), 244 (11), 169 (87), 109 (77), 97 (55), 81 (94), 70
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Eur. J. Org. Chem. 2008, 2817–2824

Synthesis of α-Substituted Prolines by Cross-Metathesis
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Acknowledgments
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The authors thank Ministry of University and Research (MiUR-
Rome) for financial support (FIRB 2001 and PRIN 2005 projects).
Mrs. Brunella Innocenti and Mr. Maurizio Passaponti are ac-
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2823

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Published Online: April 16, 2008
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