Synthesis of azasugars through a proline-catalyzed reaction

Article abstract of DOI:10.1021/jo060568b

We report an efficient route to obtain azasugars from the enantiomerically pure L- and D-diethyltartrate. The key step is a proline-catalyzed aldol condensation, in which both enantiomers of proline have been used as catalyst, affording complementary anti

Full text of DOI:10.1021/jo060568b

5-one1b (1, dioxanone) or hydroxyacetone (2), to afford the
corresponding aldol which, after hydrogenation, leads to the final
azasugar (Scheme 1). Both enantiomers of diethyl tartrate have
been used in combination with D- and L-proline as catalyst,
obtaining the complementary anti-aldol products and, therefore,
broadening the number of compounds that can be obtained.
Synthesis of Azasugars through a
Proline-Catalyzed Reaction
Fe´lix Caldero´n, Elisa G. Doyagu¨ez, and
Alfonso Ferna´ndez-Mayoralas*
Instituto de Qu´ımica Orga´nica General,
C/Juan de la CierVa, 3. 28006, Spain
Aldehyde 3 and its enantiomer ent-3 were readily prepared
following the route described in Scheme 2. The azide group
was introduced by nucleophilic attack to the cyclic sulfide form-
ed on 4.6 Afterward, reduction of the esters with NaBH4/LiCl
in ethanol, transketalation with benzaldehyde dimethylacetal and
oxidation with TEMPO,7 afforded the desired aldehyde 3.
mayoralas@iqog.csic.es
ReceiVed March 14, 2006
The results of the reaction of 3 and ent-3 with ketones 1 and
2 in the presence of D- and L-proline are shown in Scheme 3.
1
The diastereoselectivity was determined by H NMR analysis
of the crude reaction mixture, and the absolute configuration
of the major diastereoisomer was determined on the basis of
NMR spectral data.8
Reaction of 3 with ketone 1 catalyzed by L-proline at 4 °C
gave the anti-aldol 9a in 70% yield and >20:1 diastereoselec-
tivity (Scheme 3). In contrast, D-proline afforded the anti-aldol
9b in similar yield (60%) but lower diastereoselectivity (dias-
tereoselectivity ratio (d.r.) 5:1). Similar pattern of results were
observed in reactions between ketone 2 and aldehyde 3.
However, reactions had to be carried out at higher temperature
( room temperature), and lower yields of products were obtained.
This topicity was confirmed when aldehyde ent-3 was used as
an acceptor affording the enantiomeric aldols (Scheme 3).
Therefore, the best results for the reaction of 3 with both ketones
were found when L-proline was the catalyst, while in the case
of ent-3 when D-proline was used. These results show the
importance of the choice of the proline enantiomer in the
reactions of chiral R-branched aldehydes. We are currently
investigating the origin of this double asymmetric induction on
the basis of the transition states postulated by Houk et al.9
We report an efficient route to obtain azasugars from the
enantiomerically pure L- and D-diethyltartrate. The key step
is a proline-catalyzed aldol condensation, in which both
enantiomers of proline have been used as catalyst, affording
complementary anti-aldol products.
The use of asymmetric enamine organocatalysis in the form-
ation of new C-C bonds has emerged as an important tool in
the synthesis of carbohydrates.1 Continuing in this field2 and
because of their major interest to medicinal chemistry, we have
focused our efforts on the application of this methodology to
the synthesis of iminocyclitols. Our interest in these com-
pounds,3 also called azasugars as the ring oxygen of a carbo-
hydrate is replaced by nitrogen, starts from their ability to act
as potent inhibitors of enzymes involved in carbohydrate pro-
cessing, such as glycosidases and glycosyltransferases.4 This
fact, together with their functional and stereochemical complexi-
ties, has stimulated the development of a variety of synthetic
routes, and a number of synthetic analogues have been pre-
pared.5
Hydrogenation (H2, 45 psi) of the anti-aldols 9a and 10a in
the presence of HCl afforded unprotected iminocyclitols 11 and
13a (Scheme 3), respectively, with high stereoselectivity;
however, aldols 9b and 10b gave a nearly equimolecular
mixtures of diastereosiomers 12a,b and 14a,b, respectively. The
results obtained seem to indicate that the stereoselectivity of
the hydrogenation is rather dependent on the relative orientation
of the 3,4-diol of the imine intermediate. Nevertheless, further
work is currently underway to control the stereochemistry of
the hydrogenation using other reducing agents.
Herein we present a novel route to obtain azasugars from
diethyl tartrate 4 in which the key step is a proline-catalyzed
aldol reaction of aldehyde 3 with either 2,2-dimethyl-1,3-dioxan-
* To whom correspondence should be addressed. Fax: +34915644853.
Phone: +34915622900.
(1) (a) Kazmaier, U. Angew. Chem., Int. Ed. 2005, 44, 2186-2188. (b)
Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210-1212. (c)
Cordova, A.; Engqvist, M.; Ibrahem, I.; Casas, J.; Sunde´n, H. Chem.
Commun. 2005, 2047-2049. (d) Northrup, A. B.; MacMillan, W. C.;
Science 2004, 305, 1752-1755. (d) Suri, J. T.; Mitsumori, S.; Albertshofer,
K.; Tanaka, F.; Barbas, C. F., III. J. Org. Chem. 2006, 71, 3822-3828.
(2) Caldero´n F.; Ferna´ndez R.; Sa´nchez, F.; Ferna´ndez-Mayoralas, A.
AdV. Synth. Catal. 2005, 347, 1395-1403
The NMR spectral data and optical rotation values for 11
and 13a were in good agreement with previously reported data.10
The structure of 12a,b and 14a,b was determined by a
(6) Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051-7091.
(7) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041-
3043.
(3) Bastida, A.; Ferna´ndez-Mayoralas, A.; Go´mez, R.; Iradier, F.;
Carretero, J. C.; Garc´ıa-Junceda, E. Chem.sEur. J. 2001, 7, 2390-2397.
(b) Carpintero, M.; Bastida, A.; Garc´ıa-Junceda, E.; Jime´nez-Barbero, J.;
Ferna´ndez-Mayoralas, A. Eur. J. Org. Chem. 2001, 4127-4135. (c)
Caldero´n, F.; Carpintero, M.; Garc´ıa-Junceda, E.; Ferna´ndez-Mayoralas,
A.; Bastida, A. Lett. Org. Chem. 2005, 2, 247-254.
(8) Final absolute configuration of compounds 9a and 9b was determined
by a combination of measurement of coupling constants and NOESY spectra.
The configuration of compounds 10a and 10b was assigned by comparison
1
of the ∆δRS signs of their H NMR spectra of the corresponding diesters
(R)- and (S)-methoxyphenylacetic acid (see Supporting Information). The
assigned configuration data were reconfirmed in the final cyclized com-
pounds.
(4) Stutz, A. E. In Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH: Weinheim, Germany, 1999.
(5) Pearson, M. S. M.; Mathe´-Allainmat, M.; Fargeas, V.; Lebreton, J.
Eur. J. Org. Chem. 2005, 2159-2191.
(9) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem.
Soc. 2003, 125, 2475-2479.
10.1021/jo060568b CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/06/2006
6258
J. Org. Chem. 2006, 71, 6258-6261

SCHEME 1. RetrosyntheticPathToObtainAzasugarsfrom 4
inhibitors, such as â-homomannojirimycin (11) and â-homo-
fuconojirimycin (13a).
Experimental Section
General Procedure for the Catalytic Asymmetric Aldol
Reaction of Ketone 1 and Aldehyde 3 Using (R)- or (S)-Proline.
To a solution of ketone 1 (0.26 g, 2 mmol) in DMF (0.5 mL),
aldehyde 3 (0.23 g, 1 mmol) and proline (30% mol) were added.
The suspension was stirred at 4 °C for 96 h. After this time, the
suspension was quenched with saturated aqueous ammonium
chloride solution and extracted with ethyl acetate (3 × 2 mL). The
combined organic layers were concentrated and purified by flash
chromatography (hexane/AcOEt, 4:1). Yields, reaction conditions,
and dr are reported in Scheme 3.
6-Azido-5,7-O-benzylidene-6-deoxy-1,3-isopropylidene-D-man-
no-hept-2-ulose (9a). [R]25D -92.3 (c 0.1, CH2Cl2). 1H NMR (300
MHz, CDCl3): δ 7.5-7.3 (m, 5H), 5.45 (s, 1H), 4.58 (d, J ) 9
Hz, 1H), 4.45 (dd, J ) 5.1, 10.8 Hz, 1H), 4.30 (d, J ) 15.7 Hz,
1H), 4.2-4.1 (ddd, 1H), 4.1-4.0 (m, 2H), 3.83 (dd, J ) 12.4 Hz,
1H), 3.68 (dd, 1H), 3.38 (s, 1H), 1.43 (s, 3H), 1.38 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 212.6, 137.3, 129.3, 128.5, 126.2, 101.7,
101.6, 78.1, 70.7, 69.2, 68.2, 66.7, 52.2, 23.9, 23.6. MS(EI): m/z
364.1 (M + 1). Anal. Calcd for C17H21N3O6: C, 56.1; H, 5.8; N,
11.5. Found: C, 56.0; H, 6.3; N, 11.2.
SCHEME 2. Synthesis of Aldehyde 3a
6-Azido-5,7-O-benzylidene-6-deoxy-1,3-isopropylidene-D-allo-
1
hept-2-ulose (9b). [R]25 +20.5 (c 0.7, CH2Cl2). H NMR (300
D
MHz, CDCl3): δ 7.5-7.2 (m, 5H), 5.49 (s, 1H), 4.58 (dd, J ) 9,
3.0 Hz, 1H), 4.38 (dd, J ) 12.0, 6.2 Hz, 1H), 4.25 (m, 1H), 4.20
(dd, J ) 18, 1.2 Hz, 1H), 4.0-3.8 (m, 3H), 3.66.(dd, J ) 12.0,
1H), 3.48 (s, 1H), 1.51 (s, 3H), 1.45 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 210.9, 137.4, 129.6, 128.7, 126.6, 102.1, 101.1, 80.6,
73.2, 71.4, 69.7, 66.9, 54.9, 24.3, 24.0. MS(EI): m/z 364.1 (M +
1). Anal. Calcd for C17H21N3O6: C, 56.1; H, 5.8; N, 11.5. Found:
C, 56.1; H, 5.4; N, 11.2.
General Procedure for the Catalytic Asymmetric Aldol
Reaction of Hydroxyacetone (2) and Aldehyde 3 Using (R)- or
(S)-Proline. To a solution of 2 (2.2 g, 30 mmol) in DMF (0.5 mL),
aldehyde 3 (0.23 g, 1 mmol) and proline (30% mol) were added.
The suspension was stirred at room temperature for 48 h. After
this time the suspension was quenched with saturated aqueous
ammonium chloride solution and extracted with ethyl acetate (3 ×
2 mL). The combined organic layers were concentrated and purified
by flash chromatography (hexane/AcOEt, 3:1). Yields, reaction
conditions, and d.r. are reported in Scheme 3.
6-Azido-5,7-O-benzylidene-1,6-dideoxy-D-manno-hept-2-ul-
ose (10a). [R]25 +4.5 (c 0.14, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ 7.5-D7.3 (m, 5H), 5.59 (s, 1H), 4.50 (dd, J ) 12.9, 6.6,
1H), 4.26 (d, J ) 12.9, 1H), 4.0-3.7 (m, 4H), 2.40 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 210.2, 137.1, 129.8, 128.8, 126.4, 101.4,
78.7, 76.4, 70.8, 69.3, 52.6, 29.7. MS(EI): m/z 330.1 (M + 23).
Anal. Calcd for C14H17N3O5: C, 54.7; H, 5.5; N, 13.6. Found: C,
55.0; H, 5.2; N, 13.5.
6-Azido-5,7-O-benzylidene-1,6-dideoxy-D-allo-hept-2-ulose (10b).
1H NMR (300 MHz, CDCl3): δ 7.6-7.4 (m, 5H), 5.50 (s, 1H),
4.50-3.4 (m, 6H), 2.22 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
208.6, 136.7, 129.6, 128.6, 126.2, 101.4, 79.5, 77.7, 71.0, 69.1,
53.1, 26.7. MS(EI): m/z 308.1 (M + 1). Anal. Calcd for
C14H17N3O5: C, 54.7; H, 5.5; N, 13.6. Found: C, 54.1; H, 5.4; N,
13.6.
a Reaction conditions: (a) Et3N, thionyl chloride, 3 h, 100%; (b) NaN3,
DMF, 5 h, 70%; (c) NaBH4, LiCl, EtOH, 4 h, 63%; (d) benzaldehyde
dimethylacetal, p-TsOH, MeCN, 3 h, 45%; (e) TEMPO, trichloroisocianuric
acid, CH2Cl2, 30 min, 60%.
combination of the measurement of the coupling constant and
NOESY spectra (see Supporting Information).
When the hydrogenation of 9a and 10a was performed under
milder conditions (H2, 10 psi) in the absence of HCl, the pro-
tected azasugars 15 and 18/19 were obtained (Scheme 4), which
are useful intermediates for further modifications. Interestingly,
when the same conditions were applied to the isomers 9b and
10b poor yields of protected azasugars 16/17 and 20/21 were
obtained, owing to the rapid formation of the unprotected 12a,b
and 14a,b.
We hypothesized that the favorable disposition of the axially
oriented hydroxyl goup in 16 and 20, to form a hydrogen bond
with the adjacent oxygen of the benzylidene acetal, can catalyze
the cleavage of this protecting group. This was confirmed when
the same reductive conditions were applied to the acetylated
22, which gave the protected 23 in high yield (80%, Scheme 4).
In conclusion, we have described a novel asymmetric route
to obtain a diversity of azasugars in seven steps from diethyl
tartrate, where the key step is a proline-catalyzed aldol reaction.
The best results in terms of yield and stereoselectivity were
obtained with matched substrate/catalyst pairs 3/L-proline and
ent-3/D-proline, providing efficient access to known glycosidase
General Procedure for Hydrogenation. To a solution of aldol
product (0.055 mmol) in MeOH/HCl (2.6/ 0.5 mL), 10% Pd/C was
added (20 mg). The suspension was stirred under H2 (45 psi) during
48 h atroom temperature. After this time, the reaction mixture was
filtered through Celite, and the solvent was evaporated affording
the final azasugar.
(10) Asano, N.; Nishida, M.; Kato, A.; Kizu, H.; Matsui, K.; Shimada,
Y.; Itoh, T.; Baba, M.; Watson, A. A.; Nash, R. J.; de Q. Lilley, P. M.;
Watkin, D. J.; G. Fleet, G. W. J. J. Med. Chem. 1998, 41, 2565-2571.
(11) Byun, H.-S.; He, L.; Bittman, R. Tetrahedron 2000, 56, 7051-
7091.
â-Homomannojirimycin (11). [R]25 +16.4 (c 1, H2O) {lit.10
D
1
[R]25 +12.0 (c 0.27, H2O)}. H NMR (300 MHz, D2O, Ph ) 9):
D
J. Org. Chem, Vol. 71, No. 16, 2006 6259

SCHEME 3. Two-Step Synthesis of Iminociclitols from Aldehyde 3
δ 4.05 (dd, 1H), 3.9.3.6 (m, 5H), 3.51 (dd, J ) 2.7, 9.6 Hz, 1H),
3.31 (dt, J ) 6.3 Hz, 1H), 2.9 (m, 1H). 13C NMR (75 MHz, D2O,
Ph ) 9): δ 76.8, 70.5, 69.2, 64.0, 63.4, 62.5, 61.5. MS (EI): m/z
194.1 (M + 1), 217.3 (M + 23). Anal. Calcd for C7H15NO5: C,
43.5; H, 7.8; N, 7.25. Found: C, 44.0; H, 7.8; N, 7.2.
Compound 12 (Obtained as a Mixture of Diastereoisomers
12a and 12b). 1H NMR (300 MHz, D2O, Ph ) 9): δ 4.0-3.6 (m,
4H), 3.5.3.2 (m, 5H). 13C NMR (75 MHz, D2O, Ph ) 9): δ 72.2,
72.1, 72.0, 71.2, 71.0, 65.8, 65.4, 63.5, 62.7, 58.1, 57.2. MS (EI):
m/z 194.1 (M + 1), 217.3 (M + 23). Anal. Calcd for C7H15NO5:
C, 43.5; H, 7.8; N, 7.25. Found: C, 43.4; H, 7.2; N, 7.8.
â-Homofuconojirimycin (13a) (Major Product). 1H NMR (300
MHz, D2O): δ 4.8 (m, 1H), 3.9-3.7 (m, 2H), 3.69 (m, 1H), 3.54
(dd, J ) 2.7, 9.6, 1H), 3.3-3.2 (m, 1H), 3.1-3.0 (m, 1H), 1.21 (d,
3H, J ) 6.3). 13C NMR (75 MHz, D2O): δ 74.1, 70.8, 66.5, 61.1,
59.2, 55.5, 14.9. MS (EI): m/z 178.1 (M + 1). Anal. Calcd for
C7H15NO4: C, 47.4; H, 8.5; N, 7.9. Found: C, 47.4; H, 8.4; N,
7.8.
(3.0 mL), 10% Pd/C was added (20 mg). The suspension was stirred
under H2 (10 Psi) during 18 h at room temperature. After this time,
the reaction mixture was filtered through Celite, and the solvent
was evaporated affording final azasugar.
Compound 15. [R]25 +34.4 (c 0.7, MeOH). H NMR (300
1
D
MHz, C6D6): δ 7.7-7.1 (m, 5H), 5.28 (s, 1H), 4.15 (dd, J ) 5.1,
12.1 Hz, 1H), 3.63-3.41 (m, J ) 10.8, 8.7, 3.0 Hz, 5H), 3.07 (dd,
J ) 10.5, 12.1 Hz, 1H), 2.53 (m, J ) 10.8, 8.7, 5.1 Hz, 1H), 1.74
(ddd, J ) 8.7, 4.8, 3.0 Hz, 1H), 1.36 (s, 3H), 1.08 (s, 3H). 13C
NMR (75 MHz, C6D6): δ 139.0, 129.8, 128.8, 126.8, 101.8, 99.0,
81.6, 71.9, 70.7, 69.8, 63.7, 53.3, 51.4, 29.7, 18.0. MS (EI): m/z
322.2 (M + 1). Anal. Calcd for C17H23NO5: C, 63.5; H, 7.2; N,
4.3. Found: C, 63.1; H, 7.2; N, 4.4.
1
Compound 16 (Major Product). H NMR (300 MHz, C6D6):
δ 7.4-7.2 (m, 5H), 5.49 (s, 1H), 4.58 (dd, J ) 12.2, 1H), 4.5-4.3
(m, 2H), 4.3-4.2 (m, 1H), 4.15 (dd, J ) 14, 1H), 4.0-3.9 (m,
2H), 3.8-3.5 (m,2H), 1.51 (s, 3H), 1.46 (s, 3H). 13C NMR (75
MHz, C6D6): δ 139.2, 129.4, 128.2, 127.2, 101.3, 100.1, 76.1, 72.4,
69.2, 67.3, 64.2, 57.2, 56.1, 26.2, 19.2. MS (EI): m/z ) 322.2 (M
+ 1).
Compound 18 (Major Product). 1H NMR (300 MHz, MeOD):
δ 7.5-7.3 (m, 5H), 5.57 (s, 1H), 4.16 (dd, J ) 11.4, 4.2 Hz, 1H),
3.7-3.6 (m, 5H), 2.89 (dd, J ) 6.6, 1.3 Hz, 1H), 2.68 (ddd, J )
10.3, 10.5, 4.2 Hz, 1H), 1.17 (d, J ) 6.6, 3H). 13C NMR (75 MHz,
C6D6): δ 139.5, 129.8, 129.0, 127.4, 103.2, 81.4, 74.3, 73.9, 70.3,
Compound 14 (Obtained as a Mixture of Diastereoisomers
14a and 14b). 1H NMR (300 MHz, D2O): δ 4.2-3.0 (m, 7H), 1.4
(d, J ) 6.3, 3H). 13C NMR (75 MHz, D2O): δ 79.1, 77.3, 77.0,
68.2, 56.8, 53.5, 18.1. MS (EI): m/z 178.1 (M + 1). Anal. Calcd
for C7H15NO4: C, 47.4; H, 8.5; N, 7.9. Found: C, 47.2; H, 8.2; N,
7.9.
General Procedure for Partial Hydrogenation (Preparation
of 15-21). To a solution of aldol product (0.055 mmol) in MeOH
6260 J. Org. Chem., Vol. 71, No. 16, 2006

SCHEME 4. Partial Hydrogenation of Aldol Products
7.8-7.2 (m, 5H), 5.42 (s, 1H), 4.8 (m, 1H), 3.96 (dd, J ) 4.5,
10.8 Hz, 1H), 3.56 (dd, J ) 4.2, 9.0 Hz, 1H), 3.25 (dd, J ) 10.5
Hz, 1H), 2.53 (ddd, J ) 4.5, 9.8,0.13.8 Hz, 1H), 2.3 (m, J ) 6.6,
2.1 Hz, 1H), 2.24 (m, J ) 4.2, 3.8 Hz, 1H), 1.68 (s, 3H), 1.66 (s,
3H), 0.78 (d, J ) 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
169.9, 169.8, 139.8, 129.2, 128.6, 127.0, 102.4, 80.6, 76.9, 72.3,
57.3, 54.2, 33.7, 23.9, 22.2, 18.6. MS (EI): m/z ) 350.7 (M + 1).
Anal. Calcd for C18H23NO6: C, 61.8; H, 6.6; N, 4.0. Found: C,
61.9; H, 6.2; N, 3.9.
6-Azido-5,7-O-benzylidene-6-deoxy-1,3-isopropylidene-L-gulo-
hept-2-ulose (ent-9a). [R]25D +89.3 (c 0.6, CH2Cl2). MS(EI): m/z
364.1 (M + 1); Anal. Calcd for C17H21N3O6: C, 56.1; H, 5.8; N,
11.5. Found: C, 56.3; H, 6.3; N, 11.8.
6-Azido-5,7-O-benzylidene-6-deoxy-1,3-isopropylidene-L-talo-
hept-2-ulose (ent-9b). [R]25D -23.2 (c 0.3, CH2Cl2). MS(EI): m/z
364.1 (M + 1). Anal. Calcd for C17H21N3O6: C, 56.1; H, 5.8; N,
11.5. Found: C, 55.9; H, 5.8; N, 11.8.
6-Azido-5,7-O-benzylidene-1,6-dideoxy-L-gulo-hept-2-ulose (ent-
10a). [R]25D -5.1 (c 1.3, CH2Cl2). MS (EI): m/z 330.1 (M + 23).
Anal. Calcd for C14H17N3O5: C, 54.7; H, 5.5; N, 13.6. Found: C,
54.2; H, 5.5; N, 13.2.
6-Azido-5,7-O-benzylidene-1,6-dideoxy-D-talo-hept-2-ulose (ent-
10b). MS(EI): m/z 308.1 (M + 1); Anal. Calcd for C14H17N3O5:
C, 54.7; H, 5.5; N, 13.6. Found: C, 54.8; H, 5.7; N, 13.8.
R-Homogulojirimycin (ent-11). [R]25D -21.6 (c 0.3, H2O). MS
(EI): m/z 194.1 (M + 1), 217.3 (M + 23). Anal. Calcd for C7H15-
NO5: C, 43.5; H, 7.8; N, 7.2. Found: C, 43.0; H, 7.8; N, 7.3.
Compound ent-12 (Obtained as a Mixture of Diastereoiso-
mers ent-12a + ent-12b). MS (EI): m/z 194.1 (M + 1), 217.3 (M
+ 23). Anal. Calcd for C7H15NO5: C, 43.5; H, 7.8; N, 7.25.
Found: C, 43.0; H, 7.6; N, 7.3.
Compound ent-13a (Major Product). MS (EI): m/z 178.1 (M
+ 1). Anal. Calcd for C7H15NO4: C, 47.4; H, 8.5; N, 7.9. Found:
C, 47.7; H, 8.0; N, 7.6.
Compound ent-14a (Obtained as a Mixture of Diastereoiso-
mers ent-14a + ent-14b). MS (EI): m/z 178.1 (M + 1). Anal.
Calcd for C7H15NO4: C, 47.4; H, 8.5; N, 7.9. Found: C, 47.4; H,
8.6; N, 7.9.
54.9, 54.7, 17.6. MS (EI): m/z ) 266.1 (M + 1). Anal. Calcd for
C14H19NO4: C, 63.8; H, 7.2; N, 5.2. Found: C, 63.9; H, 7.0; N,
5.6.
Acknowledgment. Financial support by the Spanish Gov-
ernment is gratefully acknowledged (Project CTQ2004-03523/
BQU). F.C. and E.G.D. thank Ministerio de Educacio´n y Ciencia
and CSIC for predoctoral fellowships (BQU2001-1503 and I3P-
BPD2005, respectively).
1
Compound 20 (Major Product). H NMR (300 MHz, C6D6):
δ 7.5-7.3 (m, 5H), 5.57 (s, 1H), 4.23 (dd, J ) 3.0, 12.2 Hz, 1H),
3.8-3.4 (m, 4H), 3.05 (m, J ) 3.0, 9.0, 1H), 2.87 (m, 1H), 1.08
(d, J ) 6.2, 3H). MS (EI): m/z ) 266.1 (M + 1).
Compound 23. To a solution of 22 (24 mg, 0.06 mmol) in
MeOH (3.0 mL), 10% Pd/C was added (20 mg). The suspension
was stirred under H2 (10 psi) during 18 h at room temperature.
After this time, the reaction mixture was filtered through Celite,
and the solvent was evaporated. The crude reaction was chromato-
graphed (hexane/AcOEt, 4:1) yielding 23 (13.9 mg, 80%) as a palid
oil. [R]25D -72.3 (c 0.1, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ
Supporting Information Available: Structural data and copies
1
of H and 13C NMR and experimental procedures for compounds
5-8, 3, ent-5, ent-6, ent-7, ent-8, and ent-3. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO060568B
J. Org. Chem, Vol. 71, No. 16, 2006 6261