Samarium diiodide induced reductive coupling of D-threose- and D-erythrose-derived nitrones with methyl acrylate

Article abstract of DOI:10.1055/s-2008-1072732

An application of the samarium diiodide promoted coupling between nitrones and methyl acrylate using nitrones derived from D-erythrose and D-threose is described. The reaction course of coupling is dependent on the structure of the starting chiral nitrone

Full text of DOI:10.1055/s-2008-1072732

1260
LETTER
Samarium Diiodide Induced Reductive Coupling of D-Threose- and
D-Erythrose-Derived Nitrones with Methyl Acrylate
R
eductive
u
Coupling of
r
D
-Threo
a
se- and
D
-
E
j
rythrose-Der
R
ive
d
N
itrones ehák,a Lubor Fišera,*a Gabriel Podolan,a Jozef Kožíšek,b Lucia Perašínováb
a
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology,
Radlinskeho 9, 81237 Bratislava, Slovak Republic
Fax +421(2)52968560; E-mail: lubor.fisera@stuba.sk
Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology,
Radlinskeho 9, 81237 Bratislava, Slovak Republic
b
Received 4 February 2008
diastereomeric control. On the other hand, D-xylose-de-
rived nitrone 5 in the SmI2-induced coupling with methyl
acrylate afforded the g-N-hydroxylamino ester 6 as the
minor product. The major product, nitrone 7, is formed by
Abstract: An application of the samarium diiodide promoted cou-
pling between nitrones and methyl acrylate using nitrones derived
from D-erythrose and D-threose is described. The reaction course of
coupling is dependent on the structure of the starting chiral nitrone.
The results show that the method has potential use in the preparation unusual reductive deoxygenation of the starting nitrone
(Scheme 1).7 In this communication we wish to describe
the SmI2-induced coupling of readily available chiral sug-
g-N-hydroxylamino esters, pyrrolidinones, and pyrrolidines con-
taining carbohydrate residues.
Key words: samarium, C-glycosyl nitrones, amino acids, pyrrolid-
inones, stereoselective synthesis
ar D-threose- and D-erythrose-derived nitrones 8, 9 and
10, 11 to methyl acrylate with the subsequent conversion
of the formed g-N-hydroxylamino esters into g-lactams.
D-threo-Nitrone 8 reacted smoothly with methyl acrylate
in THF in the presence of three equivalents of samarium
diiodide and eight equivalents of H2O at –78 °C over two
hours to give g-N-hydroxylamino ester 12 in 72% yield
along with unreacted 8 (14%, Scheme 2).8 The addition
proceeded with excellent diastereoselectivity (>95:5),
with only the anti diastereomer 12 being detected. The rel-
ative configuration at the new stereogenic center in 12
could not be assigned at this stage; however, it was de-
duced from the structure of cyclized derivative 13, pre-
pared by desilylation of pyrrolidinone 16, whose structure
was established by X-ray diffraction studies
(Scheme 2).9,10
Over the years, nitrones have become important building
blocks in organic synthesis.1 During the last years we have
learned about the preparation of optically active nitrone
templates for the asymmetric 1,3-dipolar cycloaddi-
tions.2,3 Py, Vallée, and co-workers4a,b have recently de-
scribed the first samarium diiodide induced umpolung of
nitrones, which were able to undergo reductive coupling
with a,b-unsaturated esters. D-Glyceraldehyde-derived
nitrone 1 reacted with methyl acrylate in the presence of
two equivalents SmI2 in THF at –78 °C with the formation
of g-N-hydroxylamino esters 2 in fairly good yields, with
a 85:15 diastereomeric ratio (Scheme 1). When chiral ni-
trones were used as substrates, significant diastereoselec-
tivities were observed in these reactions.4,5 This
methodology provides a general route to g-N-hydroxyl-
amino esters.4,5 The derivatives of g-amino buryric acid
(GABA) could be potential, selective, and irreversible in-
hibitors of GABA amino transferase, the enzyme involved
in the catabolism of GABA.6
On the other hand, the addition of TBDMS-substituted D-
threo-nitrone 9 with methyl acrylate under the same con-
ditions proceeded less diastereoselectively and gave two
diastereomers 14 and 15 in a 88:12 ratio and 68% yield
with anti-14 being predominant (Scheme 3). The ratio of
diastereoisomeric esters was determined from quantita-
tive 13C NMR spectra, by interpretation of the peaks from
CO2CH3 of the esters; purification by flash chromatogra-
phy provided pure 14. The relationship between the ste-
reogenic centers was confirmed by conversion of major
isomer 14 into pyrrolidinone 16, whose structure was es-
tablished unambiguously by X-ray diffraction studies
(Figure 1).9 This allowed us to propose the structures
shown in Scheme 3 for diastereomeric esters 14 and 15.
The formation of major anti isomers 12 and 15 is consis-
tent with b-chelation transition state suggested by Py and
Skrydstrup.4,5
As in principle g-lactams should be easily obtained from
the corresponding g-N-hydroxylamino esters we have
paid attention to the synthesis of biologically important g-
amino acids from the sugar-derived nitrones previously
used by us in the chiral cycloadditions. In our first paper
we reported that the reaction course of samarium diiodide
induced reductive coupling of chiral nitrones with methyl
acrylate is dependent on the structure of the starting chiral
nitrone.7 D-Lyxose-derived nitrone 3 was found effective-
ly to undergo an SmI2-mediated radical addition to methyl
acrylate affording g-N-hydroxylamino ester 4 with high
In contrast, when D-erythrose-derived nitrone 10 was
treated with three equivalents of SmI2 and eight equiva-
lents of H2O in THF at –78 °C over two hours with methyl
acrylate, the expected g-N-hydroxylamino ester 19 was
obtained in low 35% yield along with dimethyl adipate
SYNLETT 2008, No. 8, pp 1260–1264
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072732; Art ID: D04108ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Reductive Coupling of D-Threose- and D-Erythrose-Derived Nitrones
1261
O
Bn
HO
O
Bn
CO2Me
SmI2, THF, H2O, –78 °C
81%, 85:15
N
N
OMe
O
O
O
O
1
2
O
Bn
HO
Bn
N
N
CO2Me
SmI2, THF, H2O, –78 °C
83%, 90:10
OMe
O
O
MeO
MeO
O
O
O
O
O
3
4
O
OH
Bn
N
OMe
O
O
O
Bn
O
N
CO2Me
SmI2, THF, H2O, –78 °C
O
6, 19%, >95:5
O
O
O
O
Bn
N
O
O
5
O
OH
7, 39%
Scheme 1 Samarium diiodide promoted coupling between sugar-derived nitrones and methyl acrylate
CO2Me
O
O
O
O
O
N
SmI2, THF, H2O, –78 °C
72%
CO2Me
Bn
HO
N
OH
HO
Bn
8
12
Zn, AcOH
47%
O
O
O
O
TBAF
TBDMSO
N
HO
N
92%
Bn
16
Bn
Figure 1 The molecular structure of 16, with the numbering
scheme11 of the asymmetric unit; displacement ellipsoids are drawn at
the 30% probability level
O
O
13
Scheme 2 Samarium diiodide promoted coupling between D-threo-
nitrone 8 and methyl acrylate
The TBDMS-substituted D-erythro-nitrone 11 showed by
samarium diiodide reductive coupling with methyl acry-
late different behavior (Scheme 5). Treatment of nitrone
11 with three equivalents of SmI2 and eight equivalents of
H2O in THF at –78 °C over two hours with methyl acry-
late led to the expected g-N-hydroxylamino ester 22 as the
(25%) and substantial amounts of unreacted 10 (34%,
Scheme 4). On the other hand, the reaction is completely
diastereoselective (>95:5) within the limits of NMR anal-
ysis of the crude product.
Synlett 2008, No. 8, 1260–1264 © Thieme Stuttgart · New York

1262
J. Rehák et al.
LETTER
11 under the same conditions in the absence of methyl
acrylate where 23 and 24 were formed in 8% and 49%
yield, respectively.
O
O
CO2Me
This kind of reductive cleavage of the starting a-alkoxy-
substituted nitrone 11, producing nitrone 24 by SmI2-in-
duced reduction, was previously observed in the forma-
tion of nitrone 7 from nitrone 5 (Scheme 1).7 The origin of
the further unexpected b-N-hydroxylamino alcohol 25 can
be explained by the coupling of the starting nitrone 11
with in situ formed acetaldehyde by aforementioned
deoxygenation of nitrone 11. The formation of dimer 20
suggests that the C–C bond-forming reaction between D-
erythro-nitrone 11 and methyl acrylate is comparable with
the radical dimerization–addition step involving the acry-
late. The formation of the corresponding dimers in 70%
yield has been described by Skrydstrup by the treatment
of alkyl acrylates with SmI2 (3 equiv) and H2O (8 equiv)
in THF at –78 °C in the absence of the alkylating re-
agent.11 However, in the presence of the alkylating re-
agent only traces of the dimers of alkyl acrylates were
obtained.
TBDMS
N
CO2Me
HO
Bn
O
O
O
15
SmI2, THF, H2O, –78 °C
N
Bn
68% (14/15 = 88:12)
OTBDMS
O
O
9
CO2Me
TBDMSO
HO
N
Bn
14
O
O
Zn, AcOH
82%
TBDMSO
N
Bn
O
O
17, 49%
LiAlH4, THF
TBDMSO
N
O
O
Bn
O
16
O
O
OH
N
Bn
CO2Me
18, 17%
TBDMSO
N
HO
Bn
Scheme 3 Samarium diiodide promoted coupling betweenTBDMS-
substituted D-threo-nitrone 9 and methyl acrylate
22, 5%
O
O
OH
N
CO2Me
O
O
O
O
O
N
SmI2, THF, H2O, –78 °C
35%
Bn
CO2Me
CO2Me
OTBDMS
Bn
O
O
O
N
SmI2, THF, H2O, –78 °C
HO
N
OH
23, 13%
HO
Bn
Bn
10
19
OTBDMS
OH
O
N
Zn, AcOH
43%
11
Bn
MeO2C
OTBDMS
CO2Me
MeO2C
20
24, 12%
CO2Me
O
O
20, 17%
O
O
OH
HO
N
Bn
O
TBDMSO
N
21
HO
Bn
25, 5%
Scheme 4 Samarium diiodide promoted coupling between D-ery-
thro-nitrone 10 and methyl acrylate
Scheme 5 Samarium diiodide promoted coupling between TB-
DMS-substituted D-erythro-nitrone 11 and methyl acrylate
minor product in very low yield (5%) along with two N-
hydroxylamino derivatives 23 (13%) and 25 (5%), nitrone
24 (12%), and dimethyl adipate (17%, Scheme 5). Purifi-
cation by flash chromatography allowed the isolation of
all reaction products; their structure is supported by NMR
analysis. The compounds 23 and 24 are the products of the
overreduction of the starting nitrone 11 that undergoes
deoxygenation and reduction, respectively, instead of
coupling. This was proved by the reaction of the nitrone
As has been mentioned in our previous communication,
we have found that the reaction course of samarium diio-
dide induced reductive coupling of chiral nitrones with
methyl acrylate is dependent on the structure of the start-
ing chiral nitrone.7 The results obtained using diastereo-
meric D-threo-nitrones 8, 9 and D-erythro-nitrones 10, 11
support this observation. In both cases the coupling of the
nitrones 5, 10, and 11 possessing a C2/C3 erythro config-
Synlett 2008, No. 8, 1260–1264 © Thieme Stuttgart · New York

LETTER
Reductive Coupling of D-Threose- and D-Erythrose-Derived Nitrones
1263
Cyranski, M. K.; Hametner, C.; Prónayová, N.; Obranec, M.
Helv. Chim. Acta 2005, 88, 1432. (i) Hýrošová, E.; Fišera,
L.; Jame, R. M.-A.; Prónayová, N.; Medvecký, M.; Koóš, M.
Chem. Heterocycl. Compd. (N.Y.) 2007, 14.
uration with methyl acrylate proceeded slower and there-
fore the products resulting from overreduction,
deoxygenation, and radical dimerization–addition step in-
volving the acrylate are formed.
(3) Fišera, L.In Topics in Heterocyclic Chemistry. Heterocycles
from Carbohydrate Precursors; El Ashry, E. S. H., Ed.;
Springer: Berlin/Heidelberg, 2007, 287.
Considering the well-known propensity of N-hydroxy-
lamines to be reduced to amines, we have prepared pyrro-
lidinones 13, 16, and 21 in a single step from the g-N-
hydroxylamino esters involving N–O cleavage with Zn/
AcOH and subsequent spontaneous cyclization from
moderate to good yields. The newly created stereogenic
center in 16 was assigned the R-configuration on the basis
of a single-crystal X-ray structure of the pyrrolidinone 16
(Figure 1). Finally, the pyrrolidinone 16 was reduced with
LiAlH4 in THF to afford the pyrrolidines 17 and 18 in
moderate yield (Scheme 3).
(4) (a) Masson, G.; Py, S.; Vallée, Y. Angew. Chem. Int. Ed.
2002, 41, 1172. (b) Masson, G.; Cividino, P.; Py, S.; Vallée,
Y. Angew. Chem. Int. Ed. 2003, 42, 2265. (c) Masson, G.;
Zeghida, W.; Cividino, P.; Py, S.; Vallée, Y. Synlett 2003,
1527. (d) Chavarot, M.; Rivard, M.; Rose-Munch, F.; Rose,
E.; Py, S. Chem. Commun. 2004, 2330. (e) Masson, G.;
Philouze, C. h.; Py, S. Org. Biomol. Chem. 2005, 3, 2067.
(f) Desvergnes, S.; Py, S.; Vallée, Y. J. Org. Chem. 2005, 70,
1459. (g) Desvergnes, S.; Desvergnes, V.; Martin, O. R.;
Itoh, K.; Liu, H.; Py, S. Bioorg. Med. Chem. 2007, 15, 6443.
(5) (a) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5, 229.
(b) Johannesen, S. A.; Albu, S.; Hazell, R. G.; Skrydstrup, T.
Chem. Commun. 2004, 1962. (c) Zhong, Y.-W.; Xu, M.-H.;
Lin, G.-Q. Org. Lett. 2004, 6, 3953. (d) Ebran, J.-P.; Hazell,
R. G.; Skrydstrup, T. Chem. Commun. 2005, 5402.
(6) (a) Nanavati, S. M.; Silverman, R. B. J. Am. Chem. Soc.
1991, 113, 9341. (b) Loukas, V.; Noula, C.; Kokotos, G.
J. Peptide Sci. 2003, 9, 312.
In conclusion, an application of the samarium diiodide
promoted coupling between nitrones and methyl acrylate
using nitrones derived from D-erythrose and D-threose is
described. The reaction course of coupling is dependent
on the structure of the starting chiral nitrone. The results
show that the method has potential use in the preparation
g-N-hydroxylamino esters, pyrrolidinones, and pyrro-
lidines containing carbohydrate residues.
(7) Rehák, J.; Fišera, L.; Kožíšek, J.; Perašínová, L.; Steiner, B.;
Koóš, M. ARKIVOC 2008, (viii), 18.
(8) Typical Experimental Procedure for Samarium Diiodide
Mediated Coupling
Acknowledgment
A stirred and carefully deoxygenated solution of the
corresponding nitrone (0.5 mmol) in dry THF (5 mL) was
cooled to –78 °C under argon. Methyl acrylate and H2O were
degassed by boiling under a stream of argon for 20 min.
Methyl acrylate (0.7 mmol), H2O (4 mmol), and a solution
of SmI2 (15 mL of 0.1 M in THF, 1.5 mmol) were then
added. The temperature was kept at –78 °C until the reaction
was judged to be complete by TLC (2 h), whereupon a sat.
aq solution of Na2S2O3 (40 mL) was added. The mixture was
extracted with EtOAc (4 × 30 mL) and the combined organic
layers were washed with brine, dried over MgSO4, filtered,
and concentrated in a rotatory evaporator. The residue was
purified by silica gel column chromatography using EtOAc–
hexanes (1:2).
The authors are grateful to the Slovak Grant Agency (No. 13549/06
and 1/0817/08) and APVV (No. 20/000305). NMR experimental
part was facilitated by the support of Slovak National Research (No
2003SP200280203). Research (No 2003SP200280203) as well as
the Structural Funds IIIA for the financial support in purchasing the
diffractometer. We are also grateful to Prof. Dr. H.-U. Reissig from
FU Berlin for the discussions.
References and Notes
(1) (a) Frederickson, M. Tetrahedron 1997, 53, 403.
(b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863. (c) Merino, P.; Franco, S.; Merchan, F. L.; Romero, P.;
Tejero, T.; Uriel, T. S. Tetrahedron: Asymmetry 2003, 14,
3731. (d) Merino, P. In Science of Synthesis, Vol. 27; Padwa,
A., Ed.; Thieme: Stuttgart, 2004, 511. (e) Osborn, H. M. I.;
Gemmel, N.; Harwood, L. M. J. Chem. Soc., Perkin Trans.
1 2002, 2419. (f) Koumbis, A. E.; Gallos, J. K. Curr. Org.
Chem. 2003, 7, 585. (g) Fišera, L.; Ondruš, V.; Kubán, J.;
Micúch, P.; Blanáriková, I.; Jäger, V. J. Heterocycl. Chem.
2000, 37, 551. (h) Pellissier, H. Tetrahedron 2007, 63, 3235.
(2) (a) Fischer, R.; Drucková, A.; Fišera, L.; Rybár, A.;
Hametner, C.; Cyraski, M. K. Synlett 2002, 1113.
(9) Crystal Data
C22H35NO4Si, M = 405.60, orthorhombic, P212121,
a = 7.800(2) Å, 13.749(3) Å, 22.468(5) Å, V = 2409.5(9) Å3,
Z = 4, Dx = 1.118 Mg m–3, m (Mo-Ka) = 0.1220 mm–1,
F(000) = 880, colorless block, 0.305 × 0.492 × 0.739 mm–3,
42540 diffractions measured (Rint = 0.021), 4901 unique,
wR2 = 0.0951, conventional R = 0.044 on I values of 4507
diffractions with I > 2.0 s(I), (D/s)max = 0.001, S = 1.160 for
all data and 254 parameters. Unit cell determination and
intensity data collection (qmax = 26.40o) were performed on a
Gemini R diffractometer12 at 100 (1) K. Structure solution
was direct methods13 and refinements were achieved by full-
matrix least-squares method13 on F**2. Further details of the
crystal structure investigation can be obtained from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK (CCDC deposition 677669).
Representative Data for Products
(b) Kubán, J.; Blanáriková, I.; Fišera, L.; Jarošková, L.;
Fengler-Veith, M.; Jäger, V.; Kožíšek, J.; Humpa, O.;
Prónayová, N.; Langer, V. Tetrahedron 1999, 55, 9501.
(c) Kubán, J.; Kolarovič, A.; Fišera, L.; Jäger, V.; Humpa,
O.; Prónayová, N.; Ertl, P. Synlett 2001, 1862. (d) Kubán,
J.; Kolarovič, A.; Fišera, L.; Jäger, V.; Humpa, O.;
Compound 12: [a]D25 –19.3 (c 0.28, CHCl3); mp 59–61 °C.
1H NMR (300 MHz, CDCl3): d = 1.46 (d, 3 H, J = 5.0 Hz,
CHCH3), 2.01–2.3 (m, 2 H, H-3), 2.51–2.71 (m, 2 H, H-2),
3.17 (dt, J = 6.1, 7.9 Hz, 1 H, H-4), 3.71 (s, 3 H, CO2CH3),
3.76 (s, 1 H, H-5¢), 4.03 (d, J = 7.9 Hz, 1 H, H-4¢), 4.07 (d,
J = 13.1 Hz, 1 H, H-6¢A), 4.14 (d, J = 13.1 Hz, 1 H, H-6¢B),
3.80–4.20 (br s, 2 H, NOH, OH), 3.96–4.20 (dd, J = 12.2 Hz,
Prónayová, N. Synlett 2001, 1866. (e) Blanáriková-
Hlobilová, I.; Kopaničáková, Z.; Fišera, L.; Cyranski, M. K.;
Salanski, P.; Jurczak, J.; Prónayová, N. Tetrahedron 2003,
59, 3333. (f) Fischer, R.; Drucková, A.; Fišera, L.;
Hametner, C. ARKIVOC 2002, (viii), 80. (g) Dugovič, B.;
Wiesenganger, T.; Fišera, L.; Hametner, C.; Prónayová, N.
Heterocycles 2005, 65, 591. (h) Dugovič, B.; Fišera, L.;
Synlett 2008, No. 8, 1260–1264 © Thieme Stuttgart · New York

1264
J. Rehák et al.
LETTER
2 H, NCH2Ph), 4.85 (q, J = 5.0 Hz, 1 H, H-2¢), 7.36–7.51 (m,
5 H, NCH2Ph) ppm. 13C NMR (75 MHz, CDCl3): d = 20.9
(q, CHCH3), 22.0 (t, C-3), 32.2 (t, C-2), 51.6 (q, CO2CH3),
61.3 (t, C-6¢), 64.1 (d, C-5¢), 64.5 (d, C-4), 71.8 (t, NCH2Ph),
79.8 (d, C-4¢), 99.7 (d, C-2¢), 127.2, 128.3, 129.0, 138.3 (3 d,
s, NCH2Ph), 175.1 (s, C-1) ppm. IR (KBr): n = 3502, 3471,
3032, 3000, 2965, 2923, 2868, 2845, 1710 cm–1. Anal. Calcd
for C17H25NO6 (339.3): C, 60.16; H, 7.42; N, 4.13. Found: C,
59.87; H, 7.41; N, 3.92.
J = 4.9 Hz, 1 H, H-2¢), 7.26–7.47 (m, 5 H, NCH2Ph) ppm.
13C NMR (75 MHz, CDCl3): d = 20.4 (q, CHCH3), 20.8 (t,
C-3), 32.3 (t, C-2), 51.5 (q, CO2CH3), 61.0 (t, C-6¢), 67.4 (d,
C-5¢), 68.5 (d, C-4), 69.8 (t, NCH2Ph), 79.9 (d, C-4¢), 99.1
(d, C-2¢), 127.8, 128.6, 129.5, 136.6 (3 d, s, NCH2Ph), 174.4
(s, C-1) ppm. IR (KBr): n = 3362, 3063, 2994, 2967, 2950,
2881, 1728 cm–1. Anal. Calcd for C17H25NO6 (339.3): C,
60.16; H, 7.42; N, 4.13. Found: C, 60.09; H, 7.16; N, 3.79.
Compound 21: [a]D25 –19.8 (c 0.05, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.22 (d, J = 5.0 Hz, 3 H, CHCH3), 1.89–
2.15 (m, 2 H, H-4), 2.16–2.59 (m, 2 H, H-3), 3.24 (dd,
J = 9.8, 11.2 Hz, 1 H, H-6¢A), 3.46 (d, J = 9.6 Hz, 1 H, H-4¢),
3.53 (dd, J = 5.1, 9.6 Hz, 1 H, H-5¢), 3.59–3.79 (br s, 1 H,
OH), 3.91–3.97 (m, 1 H, H-5), 4.03 (dd, J = 5.1, 11.2 Hz, 1
H, H-6¢B), 4.25 (q, J = 5.0 Hz, 1 H, H-2¢), 4.32–4.64 (dd,
J = 15.3 Hz, 2 H, NCH2Ph), 7.22–7.33 (m, 5 H, NCH2Ph)
ppm. 13C NMR (75 MHz, CDCl3): d = 18.8 (t, C-4), 20.3 (q,
CHCH3), 30.5 (t, C-3), 44.8 (t, NCH2Ph), 58.1 (d, C-5), 61.5
(d, C-5¢), 70.8 (t, C-6¢), 79.2 (d, C-4¢), 98.6 (d, C-2¢), 127.3,
127.8, 128.3, 136.8 (3 d, s, NCH2Ph), 176.5 (s, C-2) ppm. IR
(KBr): 3388, 3029, 2991, 2964, 2935, 2861, 1662 cm–1.
Anal. Calcd for C16H21NO4 (291.3): C, 65.96; H, 7.27; N,
4.81. Found: C, 65.78; H, 7.38; N, 4.86.
Compound 13: [a]D25 –19.8 (c 0.40, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.29 (d, J = 5.2 Hz, 3 H, CHCH3), 1.96–
2.38 (m, 2 H, H-4), 2.24–2.63 (m, 2 H, H-3), 3.15–3.20 (br
s, 1 H, OH), 3.42 (s, 1 H, H-5¢), 3.59–3.67 (m, 2 H, H-5, H-
4¢), 3.74 (d, J = 12.0 Hz, 1 H, H-6¢A), 3.98 (d, J = 12.0 Hz,
1 H, H-6¢B), 4.49 (q, J = 5.2 Hz, 1 H, H-2¢), 4.24–4.85 (d, d,
J = 14.0 Hz, 2 H, NCH2Ph), 7.23–7.32 (m, 5 H, NCH2Ph)
ppm. 13C NMR (75 MHz, CDCl3): d = 20.7 (q, CHCH3),
21.2 (t, C-4), 29.9 (t, C-3), 45.1 (t, NCH2Ph), 58.7 (d, C-5),
64.4 (d, C-5¢), 72.1 (t, C-6¢), 77.4 (d, C-4¢), 99.5 (d, C-2¢)
127.3, 127.8, 128.3, 136.9 (3 d, s, CH2Ph), 176.2 (s, C-2)
ppm. IR (KBr): 3430, 3030, 2991, 2967, 2939, 2864, 1675
cm–1. Anal. Calcd for C16H21NO4 (291.3): C, 65.96; H, 7.27;
N, 4.81. Found: C, 65.63; H, 7.22; N, 4.79.
Compound 16: [a]D25 +9.4 (c 0.5, CHCl3); mp 93–95 °C. 1H
NMR (300 MHz, CDCl3): d = –0.03, 0.03 [2 s, 6 H,
Si(CH3)2C(CH3)3], 0.88 [s, 9 H, Si(CH3)2C(CH3)3], 1.28 (d,
J = 5.0 Hz, 3 H, CHCH3), 1.87–2.05 (m, 1 H, H-4A), 2.25–
2.38 (m, 1 H, H-3A), 2.53–2.74 (m, 2 H, H-3B, H-4B), 3.36
(d, J = 1.9 Hz, 1 H, H-5¢), 3.49 (d, J = 8.9 Hz, 1 H, H-5),
3.61–3.66 (m, 1 H, H-6¢A), 3.65 (s, 1 H, H-4¢), 3.91–3.85
(dd, J = 1.0, 12.1 Hz, 1 H, H-6¢B), 4.35 (q, J = 5.0 Hz, 1 H,
H-2¢), 4.34–4.71 (d, d, J = 15.3 Hz, 2 H, NCH2Ph), 7.19–
7.35 (m, 5 H, NCH2Ph) ppm. 13C NMR (75 MHz, CDCl3):
d = –4.7, –4.6 [2 q, Si(CH3)2C(CH3)3], 17.9 [s,
Si(CH3)2C(CH3)3], 20.4 (t, C-4), 20.8 (q, CHCH3), 25.7 [q,
Si(CH3)2C(CH3)3], 30.9 (t, C-3), 44.9 (t, NCH2Ph), 61.3 (d,
C-5), 66.4 (d, C-5¢), 72.1 (t, C-6¢), 76.6 (d, C-4¢), 98.8 (d, C-
2¢), 127.3, 127.4, 128.5, 136.8 (3 d, s, NCH2Ph), 176.5 (s, C-
2) ppm. IR (KBr): 3031, 2952, 2930, 2887, 2857, 1683
cm–1. Anal. Calcd for C22H35NO4Si (437.6): C, 65.15; H,
8.70; N, 3.45. Found: C, 65.34; H, 8.78; N, 3.25.
Compound 23: [a]D25 –23.8 (c = 0.34, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 0.01, 0.03 [2 s, 6 H,
Si(CH3)2C(CH3)3], 0.81 [s, 9 H, Si(CH3)2C(CH3)3], 1.31 (d,
J = 5.1 Hz, 3 H, CHCH3), 2.79 (dd, J = 8.1, 13.2 Hz, 1 H,
CH2NCH2PhA), 3.07 (dd, J = 2.1, 13.2 Hz, 1 H,
CH2NCH2PhB), 3.35 (t, J = 10.2 Hz, 1 H, H-6A), 3.53 (dt,
J = 4.9, 9.3 Hz, 1 H, H-5), 3.71 (dt, J = 2.1, 9.3 Hz, 1 H, H-
4), 3.80–3.92 (d, d, J = 13.2 Hz, 2 H, NCH2Ph), 3.99 (dd,
J = 4.9, 10.2 Hz, 1 H, H-6B), 4.67 (q, J = 5.1 Hz, 1 H, H-2),
6.12–6.31 (br s, OH), 7.22–7.38 (m, 5 H, NCH2Ph) ppm. 13
NMR (75 MHz, CDCl3): d = –4.9, –4.2 [2 q,
Si(CH3)2C(CH3)3], 17.8 [s, Si(CH3)2C(CH3)3], 20.5 (q,
C
CHCH3), 25.6 [q, Si(CH3)2C(CH3)3], 59.9 (t, CH2NCH2Ph),
64.2 (d, C-5), 64.5 (t, NCH2Ph), 71.2 (t, C-6), 80.5 (d, C-4),
98.8 (d, C-2), 128.3, 128.9, 129.6, 136.8 (3 d, s, NCH2Ph)
ppm. IR (KBr): 3423, 3298, 3063, 3030, 2956, 2930, 2886,
2857, 1583, 1472, 1411 cm–1. Anal. Calcd for C19H33NO4Si
(367.5): C, 62.09; H, 9.05; N, 3.81. Found: C, 62.16; H, 8.99;
N, 3.52.
Compound 17: [a]D25 +31.7 (c 0.45, CHCl3). 1H NMR (300
MHz, CDCl3): d = 0.04, 0.12 [2 s, 6 H, Si(CH3)2C(CH3)3],
0.92 [s, 9 H, Si(CH3)2C(CH3)3], 1.35 (d, J = 5.0 Hz, 3 H,
CHCH3), 1.64–1.75 (m, 2 H, H-3), 1.79–1.90 (1 H, m, H-
4A), 2.00–2.10 (m, 1 H, H-4B), 2.23–2.33 (m, 1 H, H-2A),
2.84–2.92 (1 H, m, H-2B), 2.96–3.04 (1 H, m, H-5), 3.28 (d,
J = 7.3 Hz, 1 H, H-4¢), 3.54 (d, J = 13.1 Hz, 1 H, NCH2PhA),
3.72 (d, J = 11.9 Hz, 1 H, H-6¢A), 3.79 (1 H, s, H-5¢), 4.04
(d, J = 11.9 Hz, 1 H, H-6¢B), 4.13 (d, J = 13.1 Hz, 1 H,
NCH2PhB), 4.72 (q, J = 5.0 Hz, 1 H, H-2¢), 7.20–7.33 (m, 5
H, NCH2Ph) ppm. 13C NMR (75 MHz, CDCl3): d = –3.9, –
3.7 [2 q, Si(CH3)2C(CH3)3], 18.4 [s, Si(CH3)2C(CH3)3], 21.1
(q, CHCH3), 24.3 (t, C-3), 26.0 [q, Si(CH3)2C(CH3)3], 27.0
(t, C-4), 54.6 (t, C-2), 60.8 (t, NCH2Ph), 63.3 (d, C-5), 65.4
(d, C-5¢), 71.7 (t, C-6¢), 82.2 (d, C-4¢), 99.2 (d, C-2¢), 126.8,
128.2, 128.6, 140.2 (3 d, s, NCH2Ph) ppm. IR (KBr): 2956,
2885, 2856, 2790, 1685, 1604 cm–1. Anal. Calcd for
C22H37NO3Si (391.6): C, 67.47; H, 9.52; N, 3.58. Found: C,
67.47; H, 9.57; N, 3.36.
Compound 24: [a]D25 +1.36 (c 0.22, MeOH). 1H NMR (300
MHz, CD3OD): d = 1.01, 1.04 [2 s, 6 H, Si(CH3)2C(CH3)3],
1.83 [s, 9 H, Si(CH3)2C(CH3)3], 3.65 (t, J = 5.1 Hz, 2 H, H-
2), 4.25–4.28 (br s, 1 H, OH), 4.34 (dd, J = 6.0, 11.2 Hz, 1
H, H-4B), 4.45 (dd, J = 5.1, 11.2 Hz, 1 H, H-4A), 4.96–5.01
(m, 1 H, H-3), 5.92 (s, 2 H, NCH2Ph), 8.27 (t, 1 H, J = 5.1
Hz, H-1), 8.34–8.41 (m, 5 H, NCH2Ph) ppm. 13C NMR (75
MHz, CD3OD): d = –4.7, –4.3 [2 q, Si(CH3)2C(CH3)3], 18.9
[s, Si(CH3)2C(CH3)3], 26.3 [q, Si(CH3)2C(CH3)3], 33.3 (t, C-
2), 66.9 (t, C-4), 69.5 (t, NCH2Ph), 71.3 (d, C-3), 129.9,
130.1, 130.5, 134.4 (3 d, s, NCH2Ph), 143.2 (C-1) ppm. IR
(KBr): 3355, 2957, 2926, 2873, 1728, 1708, 1662 cm–1.
Anal. Calcd for C17H29NO3Si (323.5): C, 63.12; H, 9.04; N,
4.33. Found: C, 62.94; H, 8.91; N, 4.01.
(10) Brandenburg, K. DIAMOND; Visual Information System for
Crystal Structures: Bonn Germany, 1998.
(11) Hansen, A. M.; Lindsay, K. B.; Antharjanam, P. K. S.;
Karaffa, J.; Daasbjerg, K.; Flowers, R. A. II; Skrydstrup, T.
J. Am. Chem. Soc. 2006, 128, 9616.
(12) Oxford Diffraction (2007). CrysAlis CCD and CrysAlis
RED. Oxford Diffraction Ltd, Abingdon, Oxfordshire,
England.
Compound 19: [a]D25 +25.0 (c 0.2, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.27 (d, J = 4.9 Hz, 3 H, CHCH3), 1.93–
2.31 (m, 2 H, H-3), 2.45–2.69 (m, 2 H, H-2), 2.96–3.04 (m,
1 H, H-4), 3.16–3.23 (m, 1 H, H-5¢), 3.44–3.56 (m, 2 H, H-
4¢, H-6¢A), 3.68 (s, 3 H, CO2CH3), 3.91–3.96 (m, 1 H, H-
6¢B), 3.91–4.09 (2 d, J = 12.5 Hz, 2 H, NCH2Ph), 4.58 (q,
(13) Sheldrick, G. M. SHELXS97 and SHEXL97; University of
Göttingen: Germany, 1997.
Synlett 2008, No. 8, 1260–1264 © Thieme Stuttgart · New York

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