Ti-mediated synthesis of aminocyclopropl-substituted carbohydrates

Article abstract of DOI:10.1002/ejoc.200500406

Carbohydrates bearing aminocyclopropyl moieties were conveniently prepared from the corresponding nitriles by titanium-mediated addition of Grignard reagents. A wide range of protective groups are tolerated. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500406

FULL PAPER
DOI: 10.1002/ejoc.200500406
Ti-Mediated Synthesis of Aminocyclopropyl-Substituted Carbohydrates
Christophe Laroche,[a] Jean-Bernard Behr,[a] Jan Szymoniak,[a] Philippe Bertus,*[a] and
Richard Plantier-Royon*[a]
Keywords: Carbohydrates / Cyanides / Cyclopropanes / Grignard reagents / Titanium
Carbohydrates bearing aminocyclopropyl moieties were con-
veniently prepared from the corresponding nitriles by tita-
nium-mediated addition of Grignard reagents. A wide range
of protective groups are tolerated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Incorporation of cyclopropane units onto carbohydrates
has recently been shown to be of great interest, due to the
combination of the reactivity of cyclopropanes with the op-
tical purity and functional density associated with
sugars.[1,2] The classical methods used in the formation of
cyclopropanated carbohydrates are the Simmons–Smith re-
action,[3] dihalocarbene cycloaddition[3c,4] and diazoester
cyclopropanation[5] of unsaturated carbohydrates, with
most of these works having been devoted to the cyclopro-
panation of glycal derivatives.
Whereas cyclopropylamines are crucial moieties in a
variety of biologically active compounds,[6,7] there are only
a few examples of carbohydrates bearing aminocyclopropyl
units.[8] Recently, synthetic approaches towards monosac-
charide-containing cyclopropylamines[9] and spirocyclic cy-
clopropylamines[10] have been described. These multi-step
approaches typically involve diazoester cyclopropanation,
followed by the Curtius rearrangement.
Scheme 1. Synthesis of cyclopropylamines from nitriles.
Since nitriles can be incorporated into a carbohydrate
skeleton in various ways,[13] the latter procedure should be
convenient for the preparation of new carbohydrate deriva-
tives incorporating aminocyclopropyl groups. In this con-
text, we attempted to evaluate the scope and the limitations
of this method by targeting several Grignard reagents and
sugar-derived nitriles as substrates and by focusing on the
tolerance of protecting groups.
We have recently reported a convenient synthesis of cy-
clopropylamines from nitriles and Grignard reagents in the
presence of titanium isopropoxide (Scheme 1).[11,12] The
contraction of the intermediate metallacycle thus formed
Results and Discussion
Open-chain or cyclic nitriles 1–4 feature a range of repre-
is usually achieved by the addition of BF3·OEt2 [Scheme 1 sentative carbohydrate protecting groups such as acetals,
(i)].[11a] In a particular case, that of α-alkoxynitriles, how- ethers and esters (Figure 1).
ever, the spontaneous ring contraction of the metallacycle
Compounds 1–3 were prepared from the known oximes
occurred without addition of a Lewis acid [Scheme 1 5–7 (Table 1).[14] Initial attempts to convert the oxime 5 into
(ii)].[11b] The chelation of the nitrogen atom by a metal salt the nitrile 1 under the conditions described by Vasella et al.
is believed to be responsible for the ring contraction.
(PPh3, CBr4)[15] failed. Under these conditions, the removal
of the labile 4,5-O-isopropylidene protecting group oc-
curred, due to the effect of HBr formed in situ. We have
found that the dehydration can be achieved in higher yield
by use of methanesulfonyl chloride in pyridine (Entry 2).[16]
Accordingly, treatment of -arabino-aldoxime 6 with pival-
oyl chloride as the dehydrating agent gave nitrile 2 in quan-
titative yield (Entry 3). The nitrile 3 has been prepared by
[a] Laboratoire “ Réactions Sélectives et Applications ”, Université
de Reims Champagne-Ardenne, UMR URCA/CNRS 6519,
UFR Sciences,
B. P. 1039, 51687 Reims cedex 2, France
Fax: +33-3-26913166
E-mail: philippe.bertus@univ-reims.fr
richard.plantier-royon@univ-reims.fr
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5084–5088

Ti-Mediated Synthesis of Aminocyclopropyl-Substituted Carbohydrates
FULL PAPER
(Entry 2). Remarkably, neither the benzyl protective groups,
nor the pivaloate ester group were affected during the pro-
cess.
Table 2. Preparation of cyclopropylamines 8–14 from nitriles 1–4.
Figure 1. Nitriles 1–4.
dehydration of the corresponding aldoxime 7 with ruthe-
nium salts.[17] We performed the same transformation in
high yield by employing the conditions used for the prepa-
ration of 1 (Entry 4). Finally, the known nitrile 4 was pre-
pared in one step from commercial 1-O-acetyl-2,3,5-tri-O-
benzoyl--ribofuranose by the described procedure.[18]
Table 1. Synthesis of nitriles 1–3 from the corresponding oximes.
Nitrile 1 was used as a model substrate to check the opti-
mal conditions for the cyclopropanation reaction (Table 2).
Ethylmagnesium bromide was added at room temperature
to a solution of 1 and Ti(OiPr)4 in Et2O. As there is an
oxygen atom in the α-position relative to the nitrile group,
the subsequent addition of BF3·OEt2 was avoided. Unfortu-
[a] Isolated yields; the diastereoisomeric ratios are indicated in pa-
rentheses.
Preliminary assays conducted on nitriles 3 afforded a low
nately, cyclopropylamine 8 was obtained only in low yield yield (27%) of the corresponding cyclopropylamine 10 (En-
(32%) among other unidentified products. Further assays try 3), under the conditions used for 1 and 2. The major
clearly demonstrated that the amount of cyclopropylamine side-product was the ketone 15, arising from the hydrolysis
was increased by adding the Grignard reagent at a lower of the five-membered titanacycle intermediate (Scheme 2).
temperature, after which the reaction mixture was warmed In this case, the rigid cyclic system might prevent the neigh-
to room temperature. The addition of EtMgBr at 0 °C or bouring assistance of the α-alkoxy group and thus preclude
–78 °C gave 50% or 57% yields, respectively, of the desired an efficient spontaneous ring contraction occurring with
product (Table 2, Entry 1). The addition of BF3·OEt2 did acyclic compounds. Fortunately, addition of BF3·OEt2 in-
not improve the yield, as had been expected. When the creased the yield of 10 to 54% without noticeable degrada-
pivaloyl-protected nitrile 2 was treated under the above con- tion (Entry 4). Similarly, nitrile 4 was converted into 11 in
ditions, the cyclopropylamine 9 was obtained in good yield 55% yield (Entry 5).
Eur. J. Org. Chem. 2005, 5084–5088
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5085

C. Laroche, J.-B. Behr, J. Szymoniak, P. Bertus, R. Plantier-Royon
FULL PAPER
multiplet. Optical rotations were determined with a Perkin–Elmer
Model 241 polarimeter in the specified solvents. Mass spectra were
recorded with a ThermoFinnigan Trace MS spectrometer. High-
resolution mass spectra (HRMS) were performed with a Q-TOF
Micro micromass positive ESI (CV = 30 V).
2,3:4,5-Di-O-isopropylidene-D-xylononitrile (1): A solution of the
aldoxime 5[14a] (0.964 g, 3.9 mmol) in pyridine (5 mL) was added
at 0 °C to a solution of MsCl (1.93 mL, 25 mmol) in pyridine
(5 mL). After the mixture had been stirred at room temp. for 3 h,
cold water was added and the solution was extracted twice with
ethyl acetate. The combined organic layers were dried (MgSO4) and
concentrated to give a yellow oil, which was purified by flash
chromatography on silica gel with petroleum ether/ethyl acetate
(7:3). The nitrile 1 was obtained as a white solid (0.473 g, 53%).
Scheme 2. Formation of the side-product 15.
1
[α]2D0 = –22.6 (c = 2.2, CHCl3). H NMR (CDCl3, 250 MHz): δ =
Other substituted cyclopropanes can also be obtained by
employing higher Grignard reagents (Entries 6–8). Thus,
treatment of the nitrile 1 with iPrMgBr or nBuMgBr in
place of ethylmagnesium bromide gave the corresponding
cyclopropylamines 12 and 13, respectively, in good yields
(Entries 6 and 7). In each case a mixture of the four possible
diastereomers was obtained. Low diastereoselectivity was
already observed when achiral nitriles were treated with
nBuMgBr.[11b] Here, the sugar moiety was not able to in-
duce a significant diastereoselection. The use of the more
rigid nitrile 3 did not increase the diastereoselectivity of the
reaction (Entry 8). The four stereoisomers of 12–14 were
separated only as mixtures of two pairs of diastereomers
(see Exp. Sect.), and so the stereochemistry on the cyclopro-
pane moiety has not been elucidated.
1.32 (s, 3 H), 1.45 (s, 3 H), 1.48 (s, 3 H), 1.50 (s, 3 H), 3.89 (dd, J
= 5.5, 8.9 Hz, 1 H), 4.11 (dd, J = 6.9, 8.9 Hz, 1 H), 4.36 (m, 1 H),
4.50 (dd, J = 3.9, 6.5 Hz, 1 H), 4.65 (d, J = 6.5 Hz, 1 H) ppm. 13C
NMR (CDCl3, 62.5 MHz): δ = 25.1, 25.2, 26.5, 26.7, 64.7, 65.3,
74.1, 80.2, 110.8, 113.8, 118.3 ppm. IR (neat): ν = 2992, 2244,
˜
1456, 1384, 1371 cm–1. HRMS (ESI): calcd. for C11H17NO4Na
[M + Na]+: m/z = 250.1055; found 250.1049.
2,3,5-Tri-O-benzyl-4-O-pivaloyl-D-arabinononitrile (2): The oxime
6[14b] (1.5 g, 3.44 mmol) afforded the nitrile 2 as a colourless oil
(1.70 g, 98%) by a procedure analogous to that employed for the
synthesis of 1, but with use of PivCl (2.46 mL, 20 mmol) instead
of MsCl. [α]2D0 = –58.5 (c = 0.43, CHCl3). 1H NMR (CDCl3,
250 MHz): δ = 1.10 (s, 9 H), 3.65 (d, J = 3.7 Hz, 2 H), 4.06 (dd, J
= 7.3, 3.2 Hz, 1 H), 4.24 (d, J = 3.7 Hz, 1 H), 4.40 (s, 2 H), 4.44
(d, J = 10.8 Hz, 1 H), 4.62 (d, J = 10.8 Hz, 1 H), 4.80 (d, J =
10.8 Hz, 2 H), 5.14 (td, J = 7.3, 3.7 Hz, 1 H), 7.25–7.35 (m, 15 H)
ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 27.3, 40.2, 67.8, 67.9,
71.0, 73.0, 73.8, 75.6, 77.9, 116.8, 127.7–128.7 (15 C), 135.3, 137.1,
Conclusions
137.7, 173.9 ppm. IR (neat): ν = 3032, 2970, 1732, 1455 cm–1.
˜
HRMS (ESI): calcd. for C31H35NO5Na [M + Na]+: m/z =
We have shown that the titanium-mediated synthesis of
cyclopropylamines from nitriles can be applied to polyfunc- 524.2413; found 524.2418.
tional compounds such as carbohydrate analogues. A wide
range of protecting groups is tolerated, including acetals,
esters or ethers. Work to study the properties of these cyclo-
propane-substituted carbohydrates and to synthesize new
carbohydrate-derived cyclopropylamines is in progress in
our laboratory.
3-O-Benzyl-1,2-O-isopropylidene-α-
D
-xylofuranurononitrile (3): The
procedure described for the synthesis of 1 was used with the oxime
7[14c] (0.545 g, 1.86 mmol), to afford the nitrile 3 as a colourless oil
(0.462 g, 91%). [α]2D0 = –14.2 (c = 1.07, CHCl3); 1H NMR (CDCl3,
250 MHz): δ = 1.32 (s, 3 H), 1.48 (s, 3 H), 4.15 (d, J = 3.4 Hz, 1
H), 4.62 (d, J = 3.4 Hz, 1 H), 4.77 (s, 2 H), 4.88 (d, J = 3.4 Hz, 1
H), 6.00 (d, J = 3.4 Hz, 1 H), 7.30–7.42 (m, 5 H) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ = 26.6, 27.4, 69.8, 73.3, 81.9, 82.5, 106.1,
113.5, 115.2, 128.5, 128.8, 129.1, 136.7 ppm. IR (neat): ν = 2990,
˜
Experimental Section
2258, 1455, 1377 cm–1. HRMS (ESI): calcd. for C15H17NO4Na [M
+ Na]+: m/z = 298.1055; found 298.1046.
General Remarks: All reactions were performed under argon. Di-
ethyl ether was distilled from sodium/benzophenone ketyl before
use. Ti(OiPr)4 was used as received. Grignard reagents were titrated
in THF with menthol in the presence of orthophenanthroline.
Merck silica gel (F254, 0.2 mm) was used for TLC plates, with de-
tection being carried out by spraying with an alcoholic solution of
phosphomolybdic acid, followed by heating. Flash column
chromatography was performed on silica gel (Merck 9385, 40–
63 µm, Kieselgel 60). IR spectra were recorded with an IRTM plus
MIDAC spectrophotometer. NMR spectra were recorded with a
General Experimental Procedure for the Synthesis of Cyclopropyl-
amines 8–14: The Grignard reagent (1.1 mL, 2.2 mmol, 2  in
Et2O) was added under argon at –78 °C to a solution of the nitrile
1–4 (1 mmol) and Ti(OiPr)4 (0.33 mL, 1.1 mmol) in Et2O (10 mL).
The solution was slowly warmed to room temperature during 1 h
and was then stirred at room temp. for 30 min. At this stage,
BF3·OEt2 (0.25 mL, 2 mmol) could be added (see Table 2), and stir-
ring was continued for 30 min. Water (1 mL) was added, followed
by 10% aq. HCl (10 mL) and Et2O (20 mL). A 10% aq. NaOH
solution was added to the resulting clear mixture until the pH be-
came basic. The product was extracted with Et2O (2×20 mL). The
combined organic extracts were dried with MgSO4. After evapora-
tion of the solvent, the product was purified by flash chromatog-
raphy on silica gel (Et2O/Et3N, 98:2).
Bruker AC 250 spectrometer (250 MHz for H, 62.5 MHz for 13C)
or a Bruker AC 500 (500 MHz for H) instrument when indicated.
Chemical shifts are expressed in ppm from TMS (δ = 0 ppm) for
1H and from CDCl3 (δ = 77.00 ppm) for 13C as internal standards.
Coupling constants are in Hz and splitting pattern abbreviations
are: br, broad; s, singlet; d, doublet; t, triplet; q, quadruplet; m,
1
1
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5084–5088

Ti-Mediated Synthesis of Aminocyclopropyl-Substituted Carbohydrates
(1S)-1-C-(1-Aminocyclopropyl)-1,2:3,4-di-O-isopropylidene-
FULL PAPER
= 8.1 Hz, 1 H), 4.03–4.18 (m, 3 H) ppm. 13C NMR (CDCl3,
D
-
threitol (8): Yellow oil (0.146 g, 57%). Rf = 0.26 (diethyl ether/NEt3, 62.5 MHz): δ = 14.2, 19.5, 21.2, 26.1, 26.6, 27.3, 27.7, 36.0, 66.6,
98:2). [α]2D0 = –7.3 (c = 0.99, CHCl3). 1H NMR (CDCl3, 500 MHz):
δ = 0.53 (ddd, J = 9.8, 6.0, 4.3 Hz, 1 H), 0.63 (ddd, J = 9.8, 6.0,
3.7 Hz, 1 H), 0.69 (ddd, J = 9.2, 5.7, 4.3 Hz, 1 H), 0.75 (ddd, J =
9.2, 5.7, 3.7 Hz, 1 H), 1.39 (s, 3 H), 1.43 (s, 3 H), 1.45 (s, 3 H), 1.49
(s, 3 H), 1.60 (brs, 2 H, NH2), 3.41 (d, J = 8.1 Hz, 1 H), 3.93 (t, J
= 8.1 Hz, 1 H), 4.03 (dd, J = 8.2, 3.8 Hz, 1 H), 4.08 (dd, J = 8.2,
6.6 Hz, 1 H), 4.14 (ddd, J = 8.1, 6.6, 3.8 Hz, 1 H) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ = 11.4, 14.6, 26.1, 26.6, 27.3, 27.8, 32.7, 66.5,
75.8, 76.8, 80.1, 109.1, 110.0 ppm.
Isomer 12b: Rf = 0.42 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.41 (dd, J = 6.0, 5.7 Hz, 1 H), 0.79–0.93 (m, 2 H),
1.14 (d, J = 6.4 Hz, 3 H), 1.39 (s, 3 H), 1.42 (s, 3 H), 1.43 (s, 3 H),
1.48 (s, 3 H), 1.79 (brs, 2 H, NH2), 3.84 (d, J = 8.4 Hz, 1 H), 3.98
(t, J = 8.4 Hz, 1 H), 4.03–4.18 (m, 3 H) ppm. 13C NMR (CDCl3,
62.5 MHz): δ = 14.8, 20.3, 22.5, 26.2, 26.5, 27.1, 27.8, 35.6, 66.6,
73.8, 75.4, 81.9, 108.8, 109.7 ppm. IR (neat) of 12a and 12b: ν =
˜
75.7, 77.1, 84.0, 109.1, 110.0 ppm. IR (neat): ν = 3368, 2986, 2927,
˜
2984, 2929, 1454, 1375, 1070 cm–1. HRMS (ESI): calcd. for
1597, 1456, 1375, 1158, 1071 cm–1. HRMS (ESI): calcd. for
C14H26NO4 [M + H]+: m/z = 272.1862; found 272.1866.
C13H24NO4 [M + H]+: m/z = 258.1705; found 258.1711.
(1R)-1-C-(1-Aminocyclopropyl)-1,2,4-tri-O-benzyl-3-O-pivaloyl-
D
-
Isomer 12c: Rf = 0.12 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.18 (t, J = 5.5 Hz, 1 H), 0.65 (dd, J = 9.4, 5.5 Hz,
1 H), 0.74–0.89 (m, 1 H), 1.17 (d, J = 6.0 Hz, 3 H), 1.38 (s, 3 H),
erythritol (9): Colourless oil (0.329 g, 62 %). Rf = 0.14 (diethyl
ether/NEt3, 98:2). [α]2D0 = –0.7 (c = 2.03, CHCl3). 1H NMR (CDCl3,
500 MHz): δ = 0.42 (m, 1 H), 0.50 (m, 1 H), 0.74 (m, 2 H), 1.21 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47 (s, 3 H), 1.77 (brs, 2 H, NH2), 3.29
(s, 9 H), 1.80 (brs, 2 H, NH2), 2.85 (d, J = 6.2 Hz, 1 H), 3.83 (d,
J = 5.0 Hz, 2 H), 3.98 (dd, J = 6.2, 3.1 Hz, 1 H), 4.45 (d, J =
10.7 Hz, 1 H), 4.47 (d, J = 10.7 Hz, 1 H), 4.67 (d, J = 11.1 Hz, 1
H), 4.70 (d, J = 11.1 Hz, 1 H), 4.74 (d, J = 11.0 Hz, 1 H), 4.76 (d,
J = 11.0 Hz, 1 H), 5.37 (td, J = 5.0, 3.1 Hz, 1 H) ppm. 13C NMR
(CDCl3, 62.5 MHz): δ = 11.3, 16.5, 27.6, 34.5, 39.3, 68.9, 72.9,
73.7, 74.8, 75.9, 83.2, 85.3, 128.1–128.9 (15 C), 138.5, 138.6, 138.9,
(d, J = 8.4 Hz, 1 H), 3.84 (t, J = 8.4 Hz, 1 Hz), 4.03–4.15 (m, 3 H)
ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 13.1, 17.7, 18.5, 26.1,
26.6, 27.4, 27.7, 36.0, 66.6, 75.9, 77.0, 85.5, 109.0, 109.9 ppm.
Isomer 12d: Rf = 0.12 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.32 (t, J = 4.6 Hz, 1 H), 0.74–0.89 (m, 2 H), 1.17
(d, J = 6.0 Hz, 3 H), 1.38 (s, 3 H), 1.41 (s, 3 H), 1.43 (s, 3 H), 1.47
(s, 3 H), 1.77 (brs, 2 H, NH2), 3.32 (d, J = 8.0 Hz, 1 H), 3.91 (t, J
= 8.0 Hz, 1 H), 3.98 (dd, J = 8.4, 4.0 Hz, 1 H), 4.03–4.15 (m, 2 H)
ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 12.4, 16.1, 20.7, 26.1,
26.6, 27.4, 27.7, 36.0, 66.2, 76.0, 77.2, 85.3, 109.0, 109.9 ppm. IR
178.7 ppm. IR (neat): ν = 3374, 3064, 3031, 2972, 2926, 2870, 1722,
˜
1455, 1284, 1160, 1096 cm–1. HRMS (ESI): calcd. for C33H42NO5
[M + H]+: m/z = 532.3063; found 532.3077.
(4R)-4-C-(1-Aminocyclopropyl)-3-O-benzyl-1,2-O-isopropylidene-α-
(neat) of 12c and 12d: ν = 2987, 2932, 1373, 1249, 1218, 1159,
˜
D
-threofuranose (10): Colourless oil (0.165 g, 54%). Rf = 0.43 (di-
1069 cm–1. HRMS (ESI): calcd. for C14H26NO4 [M + H]+: m/z =
1
ethyl ether/NEt3, 98:2). [α]2D0 = –84.3 (c = 0.79, CHCl3). H NMR
(CDCl3, 500 MHz): δ = 0.41 (ddd, J = 9.7, 5.7, 4.2 Hz, 1 H), 0.56
(ddd, J = 9.7, 5.9, 4.2 Hz, 1 H), 0.69 (ddd, J = 9.8, 5.7, 4.2 Hz, 1
H), 0.73 (ddd, J = 9.8, 5.9, 4.2 Hz, 1 H), 1.33 (s, 3 H), 1.45 (s, 3
272.1862; found 272.1867.
(1S)-1-C-(1-Amino-2-ethylcyclopropyl)-1,2:3,4-di-O-isopropylidene-
D-threitol (13): Treatment of the nitrile 1 (227 mg, 1 mmol) with
H), 2.07 (brs, 2 H, NH2), 3.52 (d, J = 3.6 Hz, 1 H), 3.97 (d, J = nBuMgBr (1.1 mL, 2.2 mmol, 2  in Et2O) in the presence of
3.6 Hz, 2 H), 4.53 (d, J = 11.9 Hz, 1 H), 4.62 (d, J = 3.9 Hz, 1 H), Ti(OiPr)4 (0.33 mL, 1.1 mmol) afforded 13a–b (60 mg, 21%) as a
4.75 (d, J = 11.9 Hz, 1 H), 6.01 (d, J = 3.9 Hz), 7.20–7.30 (m, 5 H) 66:34 mixture of isomers and 13c–d (120 mg, 42%) as a 68:32 mix-
ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 11.4, 15.4, 26.7, 27.3, ture of isomers.
32.8, 72.4, 82.6, 84.5, 85.2, 105.6, 111.8, 128.3 (2 C), 128.7, 129.0
Isomer 13a: Rf = 0.59 (diethyl ether/NEt3 98:2). 1H NMR (CDCl3,
(2 C), 137.6 ppm. IR (neat): ν = 3377, 2986, 2930, 2872, 1599, 1455,
˜
500 MHz): δ = 0.22 (t, J = 5.4 Hz, 1 H), 0.63 (dd, J = 9.1, 5.4 Hz,
1 H), 0.65–0.75 (m, 1 H), 1.00 (t, J = 7.2 Hz, 3 H), 1.38 (s, 3 H),
1.41 (s, 3 H), 1.43 (s, 3 H), 1.46 (s, 3 H), 1.49–1.59 (m, 2 H), 3.33
(d, J = 8.1 Hz, 1 H), 3.90 (t, J = 8.1 Hz, 1 H), 4.01–4.15 (m, 3 H)
ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 14.5, 15.7, 16.4, 21.7,
26.1, 26.6, 27.4, 27.8, 36.3, 66.6, 76.0, 77.0, 85.4, 109.0, 109.9 ppm.
1378, 1216, 1075, 1031 cm–1. HRMS (ESI): calcd. for C17H24NO4
[M + H]+: m/z = 306.1705; found 306.1700.
1-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)cyclopropylamine (11):
Yellow oil (0.276 g, 55 %). Rf = 0.12 (diethyl ether/NEt3, 98:2).
[α]2D0 = +7.3 (c = 3.9, CHCl3). 1H NMR (CDCl3, 500 MHz): δ =
0.67 (m, 3 H), 0.78 (m, 1 H), 1.91 (brs, 2 H, NH2), 3.70 (m, 1 H),
4.61 (m, 1 H), 4.64 (m, 1 H), 4.82 (m, 1 H), 5.80 (m, 2 H), 7.42–
7.43 (m, 4 H), 7.49–7.51 (m, 2 H), 7.52–7.54 (m, 3 H), 7.97–8.02
(m, 4 H), 8.14–8.16 (m, 2 H) ppm. 13C NMR (CDCl3, 62.5 MHz):
δ = 11.1, 14.4, 33.5, 64.6, 72.4, 73.6, 80.2, 88.0, 128.9–130.1 (15 C),
Isomer 13b: Rf = 0.59 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.37 (t, J = 5.2 Hz, 1 H), 0.65–0.75 (m, 2 H), 1.00
(t, J = 7.2 Hz, 3 H), 1.39 (s, 3 H), 1.41 (s, 3 H), 1.43 (s, 3 H), 1.48
(s, 3 H), 1.49–1.59 (m, 2 H), 3.36 (d, J = 8.4 Hz, 1 H), 3.97 (dd, J
= 8.4, 3.7 Hz, 1 H), 4.01–4.15 (m, 3 H) ppm. 13C NMR (CDCl3,
62.5 MHz): δ = 14.5, 14.9, 16.4, 21.7, 26.1, 26.6, 27.4, 27.8, 36.3,
66.3, 75.7, 77.0, 85.1, 109.0, 109.9 ppm. IR (neat) of 13a and 13b:
133.8 (3 C), 165.8, 165.9, 166.7 ppm. IR (neat): ν = 3385, 3064,
˜
3009, 2954, 1717, 1602, 1452, 1315, 1268, 1123 cm–1. HRMS (ESI):
calcd. for C29H28NO7 [M + H]+: m/z = 502.1866; found 502.1863.
ν = 2986, 2931, 1375, 1219, 1157, 1069 cm–1. HRMS (ESI): calcd.
˜
(1S)-1-C-(1-Amino-2-methylcyclopropyl)-1,2:3,4-di-O-isopropyl-
idene-D-threitol (12): Treatment of the nitrile 1 (227 mg, 1 mmol)
for C15H28NO4 [M + H]+: m/z = 286.2018; found 286.2029.
with iPrMgBr (1.1 mL, 2.2 mmol, 2  in Et2O) in the presence of
Ti(OiPr)4 (0.33 mL, 1.1 mmol) afforded 12a–b (50 mg, 18%) as a
60:40 mixture of isomers and 12c–d (110 mg, 41%) as a 78:32 mix-
ture of isomers.
Isomer 13c: Rf = 0.26 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.17 (t, J = 5.5 Hz, 1 H), 0.79 (dd, J = 9.1, 5.5 Hz,
1 H), 0.82–0.92 (m, 1 H), 1.02 (t, J = 7.4 Hz, 3 H), 1.38 (s, 3 H),
1.41 (s, 3 H), 1.44 (s, 3 H), 1.48 (s, 3 H), 1.50–1.57 (m, 2 H), 1.92
(brs, 2 H, NH2), 3.60 (d, J = 8.3 Hz, 1 H), 3.90 (t, J = 8.3 Hz,
Isomer 12a: Rf = 0.42 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.16 (t, J = 5.5 Hz, 1 H), 0.79–0.93 (m, 2 H), 1.14 1 H), 4.03–4.15 (m, 3 H) ppm. 13C NMR (CDCl3, 62.5 MHz): δ =
(d, J = 6.4 Hz, 3 H), 1.39 (s, 3 H), 1.42 (s, 3 H), 1.43 (s, 3 H), 1.48
(s, 3 H), 1.79 (brs, 2 H, NH2), 3.60 (d, J = 8.1 Hz, 1 H), 3.89 (t, J
14.2, 17.9, 22.9, 26.2, 26.6, 27.3, 27.7, 29.3, 36.0, 66.6, 75.7, 76.8,
80.1, 109.0, 110.0 ppm.
Eur. J. Org. Chem. 2005, 5084–5088
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5087

C. Laroche, J.-B. Behr, J. Szymoniak, P. Bertus, R. Plantier-Royon
FULL PAPER
Isomer 13d: Rf = 0.26 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.39 (t, J = 5.3 Hz, 1 H), 0.82–0.92 (m, 2 H), 1.02
(t, J = 7.4 Hz, 3 H), 1.38 (s, 3 H), 1.41 (s, 3 H), 1.44 (s, 3 H), 1.48
(s, 3 H), 1.50–1.57 (m, 2 H), 1.92 (brs, 2 H, NH2), 3.83 (d, J =
8.4 Hz, 1 H), 3.98 (t, J = 8.4 Hz, 1 H), 4.03–4.15 (m, 3 H) ppm;
13C NMR (CDCl3, 62.5 MHz): δ = 14.5, 21.1, 22.6, 26.2, 26.5, 27.1,
27.8, 30.7, 35.7, 66.6, 73.9, 75.4, 82.1, 108.7, 109.7 ppm. IR (neat)
Acknowledgments
The authors thank the Ministère de l’Enseignement Supérieur et
de la Recherche for a doctoral fellowship (C. L.) and the Université
de Reims-Champagne-Ardenne (programme BQR 2004) for finan-
cial support and are also grateful to D. Harakat for ESI MS mea-
surements.
of 13c and 13d: ν = 2986, 2931, 1370, 1220, 1158, 1070 cm–1
.
˜
HRMS (ESI): calcd. for C15H28NO4 [M + H]+: m/z = 286.2018;
[1] a) H. U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151–1196;
b) M. Yu, B. L. Pagenkopf, Tetrahedron 2005, 61, 321–347.
[2] G. S. Cousins, J. O. Hoberg, Chem. Soc. Rev. 2000, 29, 165–
174.
found 286.2011.
(4R)-4-C-(1-Amino-2-ethylcyclopropyl)-3-O-benzyl-1,2-O-isopropyl-
[3] a) J. O. Hoberg, J. J. Bozell, Tetrahedron Lett. 1995, 36, 6831–
6834; b) R. Murali, C. V. Ramana, M. Nagarajan, J. Chem.
Soc., Chem. Commun. 1995, 217–218; c) C. V. Ramana, R. Mu-
rali, M. Nagarajan, J. Org. Chem. 1997, 62, 7694–7703.
[4] J. S. Brimacombe, M. E. Evans, E. J. Forbes, A. B. Foster, J. M.
Weber, Carbohydr. Res. 1967, 4, 239–243.
idene-α-D-threofuranose (14): Treatment of the nitrile 3 (275 mg,
1 mmol) with nBuMgBr (1.1 mL, 2.2 mmol, 2  in Et2O) in the
presence of Ti(OiPr)4 (0.33 mL, 1.1 mmol) afforded 14a–b (56 mg,
17%) as a 65:35 mixture of isomers and 14c–d (111 mg, 33%) as a
61:39 mixture of isomers.
[5] a) J. O. Hoberg, D. J. Claffey, Tetrahedron Lett. 1996, 37, 2533–
2536; b) K. J. Henry, B. Fraser-Reid, Tetrahedron Lett. 1995,
36, 8901–8904; c) C. M. Timmers, M. A. Leeuwenburgh, J. C.
Verheijen, G. A. Vandermarel, J. H. van Boom, Tetrahedron:
Asymmetry 1996, 7, 49–52.
Isomer 14a: Rf = 0.57 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.33 (t, J = 5.3 Hz, 1 H), 0.80–0.95 (m, 2 H), 1.00
(t, J = 7.2 Hz, 3 H), 1.24–1.33 (m, 2 H), 1.34 (s, 3 H), 1.44 (s, 3
H), 2.49 (brs, 2 H, NH2), 3.67 (d, J = 3.6 Hz, 1 H), 3.94 (d, J =
3.8 Hz, 1 H), 4.53 (d, J = 11.7 Hz, 1 H), 4.61 (d, J = 3.7 Hz, 1 H),
4.74 (d, J = 12.0 Hz, 1 H), 6.01 (d, J = 4.0 Hz, 1 H), 7.28–7.39 (m,
5 H) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 14.1, 18.6, 22.8,
26.9, 27.5, 28.6, 36.6, 72.5, 80.6, 82.6, 85.3, 105.6, 111.9, 128.4,
128.4, 128.5, 129.0 (2 C), 137.6 ppm.
[6] J. Salaün, Top. Curr. Chem. 2000, 1–67.
[7] See for example: a) Abacavir: S. M. Daluge, M. T. Martin,
B. R. Sickles, D. A. Livingston, Nucleosides Nucleotides Nucleic
Acids 2000, 19, 297–327; b) Ciprofloxacin: R. Wise, J. M. And-
rews, L. J. Edwards, Antimicrob. Agents Chemother. 1983, 23,
559–564; c) Tranylcypromine: T. Fujita, J. Med. Chem. 1973,
16, 923–930.
[8] a) H. H. Baer, U. Williams, B. Radatus, Carbohydr. Res. 1988,
174, 291–303; b) J. Ammenn, K.-H. Altmann, D. Bellus, Helv.
Chim. Acta 1997, 80, 1589–1606.
[9] L. Remen, A. Vasella, Helv. Chim. Acta 2002, 85, 1118–1127.
[10] C. Blüchel, C. V. Ramana, A. Vasella, Helv. Chim. Acta 2003,
86, 2998–3036.
[11] a) P. Bertus, J. Szymoniak, Chem. Commun. 2001, 1792–1793;
b) P. Bertus, J. Szymoniak, J. Org. Chem. 2002, 67, 3965–3968;
c) P. Bertus, J. Szymoniak, Synlett 2003, 265–267; d) C. Laro-
che, P. Bertus, J. Szymoniak, Tetrahedron Lett. 2003, 44, 2485–
2487; e) P. Bertus, J. Szymoniak, J. Org. Chem. 2003, 68, 7133–
7136.
[12] For the related Kulinkovich conversion of esters to cyclopropa-
nols and the de Meijere synthesis of tertiary cyclopropylamines
from tertiary amides, see: A. de Meijere, O. G. Kulinkovich,
Chem. Rev. 2000, 100, 2789–2834.
[13] a) K. Friedrich, K. Wallensfels, in: The Chemistry of the Cyano
Group (Ed.: Z. Rappoport), Wiley-Interscience, New York,
1970; b) M. North, in: Comprehensive Organic Functional
Group Transformation (Eds.: A. R. Katritzky, O. Meth-Conn,
C. W. Rees), Pergamon, Oxford, 1995; c) A. D. Dorsey, J. E.
Barbarow, D. Trauner, Org. Lett. 2003, 5, 3237–3239; d) S. Ta-
lukdar, J.-L. Hsu, T.-C. Chou, J.-M. Fang, Tetrahedron Lett.
2001, 42, 1103–1105.
Isomer 14b: Rf = 0.57 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.51 (t, J = 5.0 Hz, 1 H), 0.80–0.95 (m, 2 H), 1.00
(t, J = 7.2 Hz, 3 H), 1.24–1.33 (m, 2 H), 1.34 (s, 3 H), 1.44 (s, 3
H), 2.49 (brs, 2 H, NH2), 3.68 (d, J = 3.7 Hz, 1 H), 3.97 (d, J =
3.7 Hz, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 4.64 (d, J = 3.7 Hz, 1 H),
4.75 (d, J = 12.0 Hz, 1 H), 6.02 (d, J = 4.0 Hz, 1 H), 7.28–7.39 (m,
5 H) ppm. 13C NMR (CDCl3, 62.5 MHz): δ = 14.6, 21.7, 23.0,
26.7, 27.3, 28.2, 36.2, 72.4, 83.0, 83.7, 84.5, 104.9, 111.8, 128.4 (2
C), 128.6, 129.0 (2C), 137.6 ppm. IR (neat) of 14a and 14b: ν =
˜
2960, 2930, 2870, 1455, 1374, 1216, 1165, 1075, 1029 cm–1. HRMS
(ESI): calcd. for C19H28NO4 [M + H]+: m/z = 334.2018; found
334.2031.
Isomer 14c: Rf = 0.10 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.36 (t, J = 5.2 Hz, 1 H), 0.60–0.74 (m, 1 H), 0.94–
1.01 (m, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 1.32 (s, 3 H), 1.45 (s, 3 H),
1.51–1.62 (m, 2 H), 2.24 (brs, 2 H, NH2), 3.95 (d, J = 3.6 Hz, 1
H), 4.51 (d, J = 11.7 Hz, 1 H), 4.53 (d, J = 11.7 Hz, 1 H), 4.59 (d,
J = 3.7 Hz, 1 H), 4.72 (d, J = 11.9 Hz, 1 H), 5.99 (d, J = 3.7 Hz,
1 H), 7.27–7.39 (m, 5 H) ppm. 13C NMR (CDCl3, 62.5 MHz): δ =
14.1, 16.7, 21.7, 26.7, 27.3, 28.1, 36.5, 72.4, 82.5, 84.3, 86.8, 105.6,
111.9, 127.3, 128.0, 128.2, 128.4, 128.5, 137.6 ppm.
[14] a) B. Joseph, P. Rollin, Carbohydr. Res. 1995, 266, 321–325; b)
A. T. Carmona, R. H. Wightman, I. Robina, P. Vogel, Helv.
Chim. Acta 2003, 86, 3066–3073; c) J. M. J. Tronchet, F. Barba-
lat-Rey, N. Le-Hong, U. Burger, Carbohydr. Res. 1973, 29, 297–
310.
[15] P. Ermert, A. Vasella, Helv. Chim. Acta 1991, 74, 2043–2053.
[16] J. G. Buchanan, K. W. Lumbard, R. J. Sturgeon, D. K. Thomp-
son, R. H. Wightman, J. Chem. Soc., Perkin Trans. 1 1990,
699–706.
Isomer 14d: Rf = 0.10 (diethyl ether/NEt3, 98:2). 1H NMR (CDCl3,
500 MHz): δ = 0.51 (dd, J = 9.4, 5.0 Hz, 1 H), 0.60–0.74 (m, 1 H),
0.94–1.01 (m, 1 H), 1.21 (t, J = 7.0 Hz, 3 H), 1.32 (s, 3 H), 1.45 (s,
3 H), 1.51–1.62 (m, 2 H), 2.24 (brs, 2 H, NH2), 3.44 (d, J = 3.7 Hz,
1 H), 3.99 (d, J = 3.7 Hz, 1 H), 4.60 (d, J = 3.7 Hz, 1 H), 4.71 (d,
J = 11.9 Hz, 1 H), 4.73 (d, J = 11.9 Hz, 1 H), 6.00 (d, J = 3.7 Hz,
1 H), 7.27–7.39 (m, 5 H) ppm. 13C NMR (CDCl3, 62.5 MHz): δ =
14.0, 20.8, 21.1, 26.7, 27.3, 28.6, 36.3, 72.6, 82.3, 85.0, 86.4, 105.4,
111.8, 127.3 (2 C), 128.4 (3 C), 137.6 ppm. IR (neat) of 14c and
[17] A. Talukdar, Synth. Commun. 2002, 32, 3503–3508.
[18] P. J. Dudfield, V.-D. Le, S. D. Lindell, C. W. Rees, J. Chem.
Soc., Perkin Trans. 1 1999, 2937–2942.
14d: ν = 2960, 2931, 2870, 1689, 1455, 1377, 1216, 1165 cm–1.
˜
HRMS (ESI): calcd. for C19H28NO4 [M + H]+: m/z = 334.2018;
Received: June 7, 2005
found 334.2009.
Published Online: October 12, 2005
5088
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2005, 5084–5088