Preparation of sugar β-amino acid derivatives with cyclic structures by ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.201000923

Efficient syntheses of β-amino acid derivatives with cyclic structures were developed. The key steps involve aza-Michael addition and ruthenium-catalyzed allylation for the construction of new acyclic β-amino acid dienes incorporating a sugar fragment, an

Full text of DOI:10.1002/ejoc.201000923

FULL PAPER
DOI: 10.1002/ejoc.201000923
Preparation of Sugar β-Amino Acid Derivatives with Cyclic Structures by
Ring-Closing Metathesis
Basker Sundararaju,[a] Tailor Sridhar,[b] Mathieu Achard,[a] Gangavaram V. M. Sharma,[b]
and Christian Bruneau*[a]
Keywords: Amino acids / Metathesis / Ruthenium / Carbohydrates
Efficient syntheses of β-amino acid derivatives with cyclic
structures were developed. The key steps involve aza-
Michael addition and ruthenium-catalyzed allylation for the
construction of new acyclic β-amino acid dienes incorporat-
ing a sugar fragment, and a ruthenium-catalyzed ring-clos-
ing metathesis for the construction of the seven- and nine-
membered ring compounds.
able positions, namely, the Cα-, Cβ-, O-, and N-atoms. N-
Allylated substrates led to cyclic amines with α-substitution
by an alkoxycarbonylmethyl group,[9] or β-substitution by
an alkoxycarbonyl group[10] starting from Cβ-allylated and
Cα-allylated substrates, respectively. Complementarily, an-
other family of β-amino acid products, 1-amino-2-carboxyl-
ate cycloalkenes, was obtained when the reactive unsatu-
rated groups were attached to the Cα- and Cβ-positions.[11]
These studies revealed that the ring-closing metathesis reac-
tion was very sensitive to the chemical and steric environ-
ment of the reactive olefinic groups.
We now report the preparation of a new family of β-
amino esters I–IV, with a carbohydrate substituent at the
Cβ-position and unsaturated groups at selected positions,
and their transformations through ruthenium-catalyzed
ring-closing metathesis to novel cyclic derivatives V–VIII
(Figure 1).
Introduction
The modification of amino acid derivatives through the
introduction of cyclic motives in their structures makes
them more rigid, which is assumed to play a crucial role in
biological properties and thus has a potential impact in
drug design and development.[1] The ring-closing metathesis
reaction is particularly appropriate to create such cyclic
substructures from unsaturated substrates.[2] Indeed, it has
been efficiently used in amino acid, peptide, and peptidomi-
metic science.[3] The first examples reported the transforma-
tions of α-amino esters modified by introduction of two
allylic groups at the Cα- and N-positions of glycine deriva-
tives, which led to piperidine ring structures.[2a,4] Because of
the growing interest in fluorinated organic compounds due
to their specific biological interest,[5] monofluorinated cyclic
α-amino esters have been prepared by using the same strat-
egy starting from N-2-fluoroprop-2-enyl substrates.[6] We
have also explored the formation of various cyclic deriva-
tives from α-amino esters containing α-CF3 and phos-
phonate analogs.[7] Other types of non-natural cyclic 1-
amino-1-carboxylic acid derivatives of different sizes were
also prepared from substrates with two geminal olefinic
branches grafted at the α-carbon atom of the final prod-
uct.[8] β-Amino esters have also been used as starting sub-
strates for the preparation of cyclic derivatives, wherein, the
unsaturated fragments were introduced at all the four avail-
[a] UMR 6226: CNRS-Université de Rennes 1,
Sciences Chimiques de Rennes,
Catalyse et Organométalliques,
Campus de Beaulieu, 35042 Rennes Cedex, France
Fax: +33-2-23236939
E-mail: christian.bruneau@univ-rennes1.fr
[b] Organic Chemistry Division III, D 211,
Discovery Laboratory,
Indian Institute of Chemical Technology,
Hyderabad 500007, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000923.
Figure 1. Cyclization of amino acid dienes I, II, III, IV.
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Sugar β-Amino Acid Derivatives with Cyclic Structures by RCM
Scheme 1. Synthesis of β-Caa I.
Compound I featuring an allyl group at the Cα-position Synthesis of II
and an acrylamide functionality at the Cβ-position would
β-Amino ester diene II was prepared from 4. Base-medi-
lead to the formation of seven-membered amide ring V,
whereas compound II containing an allyl group at the Cα-
position and an allyl ester moiety, likewise, may allow the
formation of seven-membered unsaturated lactone VI. The
amine and acid groups in compounds III/IV both function-
alized with an allyl group may lead after ring-closing
metathesis to the formation of the nine-membered ring in
VII/VIII.
ated hydrolysis of ester 4 with LiOH in a THF/MeOH/H2O
(3:1:1) mixture at room temperature furnished acid 6 in
80% yield. Further, ruthenium-catalyzed allylation of the
carboxylic group[12] in 6 at room temperature gave metathe-
sis precursor II in 78% yield (Scheme 2).
Results and Discussion
Synthesis of I
The DBU-mediated aza-Michael addition of benzyl-
amine to ester 1 gave 2 (59%, 94%de), which upon catalytic
debenzylation with 10% Pd/C in methanol, followed by
subsequent treatment with (Boc)2O afforded the C-linked
carbo-β-amino acid ester (β-Caa) 3 in 74% yield. Allylation
of ester 3 at the Cα-position with allyl bromide by using in
situ generated LDA led to the stereoselective formation of
4 in moderate yield (45%). Finally, deprotection of the
amine with CF3COOH (TFA), followed by functionaliza-
Scheme 2. Preparation of II.
Synthesis of III
Diene compound III was prepared in four steps starting
tion of 5 with acryloyl chloride and Et3N gave acrylamide from α,β-unsaturated ester 1. Compound 1 was subjected
derivative I in 70% yield (Scheme 1).
to aza-Michael addition with allylamine to give N-allylated
Scheme 3. Synthesis of β-Caa III.
Eur. J. Org. Chem. 2010, 6092–6096
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FULL PAPER
β-Caa 7 in 78% yield. Further, protection of 7 with (Boc)2O Table 1. Concentration effects in ring-closing metathesis of I.[a]
afforded ester 8 in 80% yield. Treatment of 8 with LiOH
gave the corresponding acid 9 in 74% yield, which upon
allylation in the presence of a catalytic amount of ruthe-
nium precatalyst gave III in 82% yield (Scheme 3).
Synthesis of IV
Ester 2, upon reaction with LiOH, was converted into Entry Catalyst Solvent Conc.
acid 10 (78%), which upon further ruthenium-catalyzed al-
Temp
[°C]
Time
[h]
Conv.
[%][b]
[]
lylation of the amine and acid functionalities in the pres-
ence of allyl chloride in dichloromethane at room tempera-
ture afforded the expected N- and O-allyl β-amino ester IV
in 80% yield (Scheme 4).
1
2
3
4
5
6
7
GII
GII
GII
GI
GII
GII
HGII
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0.01
0.01
0.05
0.004
0.004
0.004
0.004
40
80
40
40
40
40
40
20
20
20
12
12
20
20
0
0
0
10
90
95(74)[c]
75
[a] All reactions were carried out under an inert atmosphere. [b] GC
conversion by using tetradecane as an internal standard.
[c] Number in parentheses is isolated yield.
Ester I, upon RCM in the presence of catalyst (5 mol-
%; Table 1, Entry 1), did not give any product and did not
undergo a ring-closing or oligomerization reaction. Similar
results were observed in refluxing toluene or dichlorometh-
ane (Table 1, Entries 2 and 3). Attempts to increase the cat-
alyst loading up to 30 mol-% were unsuccessful. This might
be attributed to a substrate concentration that was too high.
Interestingly, a lower substrate concentration of 0.004  led
to the complete conversion of I (95% after 20 h; Table 1,
Entries 5 and 6) and the selective formation of seven-mem-
bered unsaturated lactam V in 74% yield (Table 1, Entry 6).
The first generation GI catalyst showed low activity
(Table 1, Entry 4), whereas the second generation Grubbs–
Hoveyda catalyst HGII was able to perform the cyclization
of I with slightly lower efficiency (Table 1, Entry 7). This
reactivity showed high functional group tolerance to ruthe-
nium catalysts GII and HGII, which accommodate ether,
acetal, ester, and amide functionalities. The beneficial effect
of low concentration in ring-closing metathesis of func-
tional substrates has recently been observed during the for-
mation of lactones from acrylates[16] and seven-membered
cyclic amines, whereas this effect was not observed in the
preparation of five- and six-membered rings.[17]
Scheme 4. Synthesis of IV.
Ring-Closing Metathesis
With the expected four dienes I–IV in hand, we next in-
vestigated the ring-closing metathesis with the benzylidene
ruthenium catalysts GI, GII, and HGII (Figure 2).
These optimal conditions were then applied to the ring-
closing metathesis of substrates II, III, and IV (Scheme 5).
In the presence of catalyst GII (5 mol-%) at 80 °C in toluene
Figure 2. Metathesis catalysts used for RCM reactions.
Ring-closing metathesis of dienes involving an acryl- for 20 h with a substrate concentration of 0.004 , the ex-
amido group has already been reported,[13] wherein five- pected seven- and nine-membered lactones VI, VII, and
and six-membered lactams were shown to be formed easily VIII were obtained in 84, 65, and 49% isolated yield,
with Grubbs catalyst.[14] However, the construction of respectively. The low yield obtained from IV is due to N-
seven-membered rings was more difficult and was reported deallylation during metathesis. The deallylation is attributed
to be more catalyst dependent.[15] Moreover, in our pre- to the isomerization of the N-allyl group into an enamine,
pared compounds that contain carbohydrate moieties, the which can concomitantly lead after hydrolysis to undesired
presence of these later would interact with the catalysts and deallylated amine. In all the cases, exclusive formation of
could modify the metathesis process. The results obtained the Z-type isomer was observed. Cyclization product VII
from diene I, which is expected to result in a seven-mem- was found to be present in different conformers due to the
bered ring, are presented in Table 1.
presence of the Boc-carbamate group.
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Eur. J. Org. Chem. 2010, 6092–6096

Sugar β-Amino Acid Derivatives with Cyclic Structures by RCM
(TLC analysis), the reaction mixture was filtered, and the filtrate
was evaporated. The amine was used as such for further reactions
without purification. To the above free amine in CH2Cl2 (5 mL)
at 0 °C under a nitrogen atmosphere was added Et3N (0.67 mL,
4.77 mmol). After 10 min, (Boc)2O (0.46 mL, 2.1 mmol) was
added, and the reaction mixture was allowed to stir for 2 h. The
solvent was evaporated under reduced pressure, and the residue was
purified by column chromatography (15% ethyl acetate in petro-
leum ether) to give 3 (0.52 g, 74%) as a pale-yellow solid. M.p. 72–
75 °C. [α]2D0 = –26.9 (c = 1.1, CHCl ). IR (neat): ν = 3385, 2980,
˜
3
2938, 1725, 1705, 1502, 1308, 1161, 1071, 1013 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 5.91 (d, J = 3.8 Hz, 1 H), 5.09 (br. s, 1 H),
4.57 (d, J = 3.8 Hz, 1 H), 4.30 (m, 1 H), 4.298 (m, 1 H), 3.68 (d, J
= 3.1 Hz, 1 H), 3.68 (s, 3 H, OCH3), 3.37 (s, 3 H, OCH3), 2.71 (dd,
J = 3.2, 14.6 Hz, 1 H), 2.67 (dd, J = 7.9, 14.6 Hz, 1 H), 1.48 (s, 3
H, CMe2), 1.43 (s, 9 H, CMe3), 1.31 (s, 3 H, CMe2) ppm. MS
(FAB): m/z (%) = 752 (4) [2M + H]+, 376 (23) [M + H]+, 276 (100)
[M + H – Boc]+, 320 (12), 218 (11), 133 (15).
Scheme 5. Synthesis of cyclized β-amino acid derivatives.
tert-Butyl (1S,2S)-2-(Methoxycarbonyl)-1-{(3aR,5R,6S,6aR)-tetra-
hydro-6-methoxy-2,2-dimethylfuro[2,3-d][1,3]dioxol-5-yl}pent-4-
enylcarbamate (4): To a solution of N,N-diisopropylamine
(0.65 mL, 4.66 mmol) in THF (5 mL) was added nBuLi (2.6  in
n-hexane, 1.79 mL, 4.66 mmol) at –78 °C under a nitrogen atmo-
sphere, and the mixture was stirred for 30 min at 0 °C. A solution
of 3 (0.5 g, 1.33 mmol) in THF (8 mL) was added at –78 °C, and
the mixture was stirred for an additional 30 min at the same tem-
Conclusions
In conclusion, a series of new β-amino acid derivatives
having a carbohydrate side chain at the Cβ-position and
olefinic groups located at different positions of the core
structure were prepared. Efficient procedures were devel-
oped to perform the ring-closing metathesis of β-amino
acid derivatives to form conformationally constrained cyclic perature. Allyl bromide (0.17 mL, 1.99 mmol) was added to the re-
action mixture at –78 °C, and the mixture was stirred for 2 h. The
reaction mixture was quenched with cold aqueous NH4Cl solution
(8 mL), and the product was extracted with EtOAc (2ϫ20 mL).
The extracts were washed with water (2 ϫ 10 mL) and brine
(10 mL) and then dried (Na2SO4). The solvent was evaporated un-
der reduced pressure, and the residue purified by column
chromatography (12% ethyl acetate in petroleum ether) to give 4
(0.25 g, 45%) as a light-yellow syrup. [α]2D0 = –67.84 (c = 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3, 298 K): δ = 5.84 (d, J =
3.9 Hz, 1 H), 5.80–5.70 (m, 1 H), 5.13–5.01 (m, 3 H), 4.49 (d, J =
3.9 Hz, 1 H), 4.24–4.19 (m, 1 H), 4.00–3.98 (m, 1 H), 3.67 (s, 3 H,
OCH3), 3.59 (d, J = 3.1 Hz, 1 H), 3.36 (s, 3 H, OCH3), 2.57–2.53
(m, 1 H), 2.45–2.28 (m, 2 H), 1.44 (s, 12 H, CMe2 + CMe3), 1.28
(s, 3 H, CMe2) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ =
174.1, 155.7, 134.8 117.1, 111.3, 104.6, 84.1, 81.1, 80.0, 79.0, 57.4,
51.6, 49.7, 46.8, 33.4, 28.3, 26.6, 26.2 ppm. HRMS (ESI): calcd. for
C20H33NO8 [M + Na] 438.2103; found 438.2119.
structures. This study has shown the drastic influence of
the substrate concentration and also underlined that low
concentrations were appropriate for highly selective cycliza-
tion reactions in the presence of the second generation
Grubbs catalyst. The new cyclic compounds incorporate
both the Cα- and a β-amido group in V, the ester and the
Cα-carbon in VI, or the ester and the amino groups in VII
and VIII.
Experimental Section
Synthesis of Metathesis Precursor I
Methyl
(3S)-(Benzylamino)-3-{6-methoxy-2,2-dimethyl-(3aR,5R,
6S,6aR)-perhydrofuro[2,3-d][1,3]dioxol-5-yl}propanoate (2): To
a
stirred solution of compound 1 (0.86 g, 3.33 mmol) and benzyl-
amine (0.36 mL, 3.33 mmol) in THF (5 mL) was added DBU
(0.50 mL, 3.33 mmol), and the reaction mixture was stirred at room
temperature for 8 h. THF was removed, and the residue was puri-
fied by column chromatography (15% ethyl acetate in petroleum
ether) to give 2 (0.72 g, 59%) as a pale-yellow syrup. [α]2D0 = –31.1
(S)-Methyl 2-[(S)-(acrylamido){(3aR,5R,6S,6aR)-tetrahydro-6-
methoxy-2,2-dimethylfuro[2,3-d][1,3]dioxol-5-yl}methyl]pent-4-
enoate (I): A solution of ester 4 (0.60 g, 1.44 mmol) and CF3COOH
(0.60 mL) in CH2Cl2 (3 mL) was stirred at room temperature under
a nitrogen atmosphere for 2 h. The solvent was evaporated under
reduced pressure to get intermediate amine 5, which was dried un-
der high vacuum and used as such without any further purification.
To a stirred solution of amine 5 in dry CH2Cl2 (5 mL) was added
sequentially Et3N (0.3 mL, 2.16 mmol) and acryloyl chloride
(0.14 mL, 1.73 mmol) under a nitrogen atmosphere at 0 °C, and the
mixture was stirred at room temperature for 8 h. The reaction mix-
ture was diluted with CH2Cl2 (8 mL) and washed with aqueous 1 
HCl (10 mL), saturated NaHCO3 (10 mL), water (8 mL), and brine
(15 mL). The organic layers were dried (Na2SO4) and evaporated
(c = 1.0, CHCl ). IR (neat): ν = 3370, 2980, 2918, 1718, 1449, 1368,
˜
3
1072, 1013 cm–1. H NMR (500 MHz, CDCl3): δ = 7.32 (m, 2 H),
1
7.29 (m, 2 H), 7.22 (m, 1 H), 5.91 (d, J = 3.8 Hz, 1 H), 4.59 (d, J
= 3.9 Hz, 1 H), 4.23 (dd, J = 3.2, 8.7 Hz, 1 H), 3.86 (ABq, J =
12.9 Hz, 2 H), 3.73 (d, J = 3.2 Hz, 1 H), 3.69 (s, 3 H, OCH3), 3.41
(dt, J = 5.6, 8.7 Hz, 1 H), 3.37 (s, 3 H, OCH3), 2.57 (dd, J = 5.6,
14.9 Hz, 1 H), 2.46 (dd, J = 5.6, 14.9 Hz, 1 H), 1.48 (s, 3 H, CMe2),
1.32 (s, 3 H, CMe2) ppm. MS (FAB): m/z (%) = 366 (100) [M +
H]+, 192 (50), 106 (9), 91 (82), 57 (17).
Methyl (3S)-3-[(tert-Butoxy)carbonylamino]-3-{6-methoxy-2,2-di- under reduced pressure, and the residue was purified by column
methyl-(3aR,6S,6aR)-perhydrofuro[2,3-d][1,3]dioxol-5-yl}propan-
oate (3): A mixture of ester 2 (0.7 g, 1.91 mmol) and 10% Pd/C
(0.5 g) in methanol (3 mL) was stirred at room temperature under
a hydrogen atmosphere for 12 h. After completion of the reaction
chromatography (35% ethyl acetate in petroleum ether) to give I
(0.37 g, 70%) as a light-yellow syrup. [α]2D0 = –82.6 (c = 0.5, CHCl3).
1H NMR (300 MHz, CDCl3, 298 K): δ = 6.42–6.08 (m, 3 H), 5.83
(d, J = 3.77 Hz, 1 H), 5.79–5.60 (m, 1 H), 5.09–5.00 (m, 2 H), 4.69
Eur. J. Org. Chem. 2010, 6092–6096
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B. Sundararaju, T. Sridhar, M. Achard, G. V. M. Sharma, C. Bruneau
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(m, 1 H), 4.48 (d, J = 3.7 Hz, 1 H), 4.06 (dd, J = 3.3, 6.4 Hz, 1 H),
3.69 (s, 3 H, OCH3), 3.62 (d, J = 3.02 Hz, 1 H), 3.36 (s, 3 H,
OCH3), 2.70–2.60 (m, 1 H), 2.35 (m, 2 H), 1.44 (s, 3 H, CMe2),
1.29 (s, 3 H, CMe2) ppm. 13C NMR (125 MHz, CDCl3, 298 K): δ
= 174.6, 165.5, 134.4, 131.1, 126.4, 117.4, 111.3, 104.6, 83.9, 81.1,
79.8, 57.4, 51.9, 47.9, 46.1, 33.7, 26.7, 25.9 ppm. HRMS (ESI):
calcd. for C18H27NO7 [M + Na]+ 392.1685; found 392.1669.
General Procedure for Ring-Closing Metathesis (RCM): In a typical
experiment, a solution of the diene substrate in toluene or CH2Cl2
(c = 0.004 ) was stirred under an inert atmosphere. The solution
was purged under an atmosphere of argon for 10 min and then
Grubbs II catalyst (5 mol-%) was added, and the reaction mixture
was stirred at the specified temperature. The conversion was deter-
mined by gas chromatography and also TLC indicated when the
reaction was complete. The reaction mixture was then concentrated
under vacuum. The product was purified by column chromatog-
raphy with the appropriate solvent mixture.
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Methyl (2R,3S)-2-{(3aR,6S,6aR)-6-methoxy-2,2-dimethyltetra-
hydrofuro[2,3-d][1,3]dioxol-5-yl}-7-oxo-2,3,4,7-tetrahydro-1H-
azepine-3-carboxylate (V): RCM reaction on I (0.19 g, 0.53 mmol)
at 40 °C in CH2Cl2 (120 mL, c = 0.004 ) for 20 h, as described
above gave V (0.13 g, 74%) as a colorless oil. [α]2D0 = –70.0 (c = 0.1,
CH2Cl2). 1H NMR (500 MHz, CD2Cl2): δ = 6.33–6.25 (m, 1 H),
6.07 (br. s, 1 H, NH), 5.93–5.87 (m, 2 H), 4.67 (d, J = 3.8 Hz, 1
H), 4.52 (dd, J = 3.2, 8.9 Hz, 1 H HC=CH), 3.96 (m, 1 H), 3.81
(d, J = 3.4 Hz, 1 H), 3.74 (s, 3 H, OCH3), 3.42 (s, 3 H, OCH3),
3.0–2.98 (m, 1 H), 2.88–2.81 (m, 1 H), 2.60–2.53 (m, 1 H), 1.51 (s,
3 H, CMe2), 1.35 (s, 3 H, CMe2) ppm. 13C NMR (125 MHz,
CD2Cl2): δ = 171.8, 168.5, 138.0, 125.8, 111.7, 104.9, 83.7, 81.1,
79.5, 57.3, 52.2, 51.9, 45.3, 31.4, 26.5, 26.0 ppm. HRMS: calcd. for
C16H24NO7 [M + H]+ 342.1544; found 342.1552.
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Acknowledgments
The authors wish to thank Indo-French Centre for the Promotion
of Advanced Research CEFIPRA/IFCPAR (IFC/A/3805-2/2008/
1720) for a grant to B.S. T.S. thanks the Council of Scientific and
Industrial Research (CSIR) India for a research fellowship.
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Received: June 28, 2010
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