Cope-House cyclization strategy for the synthesis of pyrrolidines: An expedient route to 5-epi-hyacinthacine A3 and 5-epi-hyacinthacine A5

Article abstract of DOI:10.1055/s-2008-1042898

An expedient Cope-House cyclization strategy is reported here for the synthesis of several polyhydroxy pyrrolizidine alkaloids starting from sugar-derived nitrones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042898

LETTER
841
Cope–House Cyclization Strategy for the Synthesis of Pyrrolizidines: An
Expedient Route to 5-epi-Hyacinthacine A3 and 5-epi-Hyacinthacine A5
E
xpedient Route to
r
5-epi-H
i
yacinthsacines 3
A
h
andA5 na P. Kaliappan,* Prasanta Das
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax +91(22)25723480; E-mail: kpk@chem.iitb.ac.in
Received 14 December 2007
In continuation of our ongoing program directed towards
the synthesis of natural products and natural-product-like
molecules,4 we developed interest in devising a simple
and straightforward strategy to some of these alkaloids.
While investigating novel approaches as compared with
the aforementioned syntheses5 for hyacinthacines, it oc-
curred to us that Cope–House cyclization6 could be an
ideal reaction to construct the key five-membered ring in
a single step. Cope–House cyclization, believed to be the
reverse of Cope elimination (Scheme 1), was serendipi-
tously observed by House and co-workers,7 and well stud-
ied by Oppolzer8 and Ciganek.9 Though this reaction
offers an excellent path to 2-substituted pyrrolidines, it
has seldom been exploited in the total synthesis of natural
products. In this communication, we present a short and
efficient synthesis of 5-epi-hyacinthacine A3 and 5-epi-
hyacinthacine A5 and also of a few closely related alka-
loids using Cope–House cyclization6 as the key step.
Abstract: An expedient Cope–House cyclization strategy is report-
ed here for the synthesis of several polyhydroxy pyrrolizidine alka-
loids starting from sugar-derived nitrones.
Key words: nitrone, Grignard reaction, Cope–House cyclization,
hydrogenation, hyacinthacine
Natural products having polyhydroxylated pyrrolizidine
ring as their structural subunit are quite abundant and
many of them show remarkable inhibitory activity against
different kinds of glycoprotein-processing glycosidases
and hence have high potential as chemotherapeutic
agents.1 Among them, densely polyhydroxylated pyrroliz-
idines namely hyacinthacines (Figure 1) having one car-
bon branch both at C(3) and at C(5) show significant
activity against viral infections, cancer and diabetes.1b,2 In
view of their promising biological activity coupled with
interesting structures, considerable efforts have been di-
rected towards the isolation of new pyrrolizidine-type al-
kaloids as well as the development of new
stereocontrolled synthetic routes3 for the synthesis of
these alkaloids and their unnatural analogues.
–
R
O
H
O
R
OH
R
H
N
N
N
n
n
n
n = 1, 2
10
n = 1, 2
12
OH
OH
OH
H
H
N
H
N
11
OH
OH
OH
OH
OH
OH
Scheme 1 Cope–House cyclization
N
R
As depicted in the Scheme 2, our retrosynthetic analysis
revealed that the pyrrolizidine alkaloid 15 could be syn-
thesized from 14 by Cope–House cyclization followed by
hydrogenolysis. The unsaturated cyclic hydroxylamine 14
could then be easily furnished by the addition of 3-bute-
nylmagnesium bromide to cyclic nitrone 15, which could
in turn be derived from L-xylose.
1 hyacinthacine A1
2 hyacinthacine A2, R = H
3 hyacinthacine A3, R = Me
4 hyacinthacine A4
OH
H
OH
H
OH
H
OH
OH
7 hyacinthacine B2
OH
N
OH
N
N
OH
OH
HO
HO
HO
5 hyacinthacine A5
BnO
BnO
6 hyacinthacine B1
–
OH
O
N
H
N
N
OH
HO
HO
H
OH
HO
BnO
BnO
H
N
H
OH
OH
HO
HO
OH
OH
BnO
BnO
15
N
13
14
Scheme 2 Retrosynthesis
8 hyacinthacine B3
9 hyacinthacine C1
Figure 1 Hyacinthacine family
This strategy is more viable and attractive as several cy-
clic nitrones, as shown in Figure 2, could be easily made
from various sugars using well-established proce-
dures.5a,10
SYNLETT 2008, No. 6, pp 0841–0844
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042898; Art ID: G41007ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

842
K. P. Kaliappan, P. Das
LETTER
O–
OBn
OBn
O
O–
O–
–
O
N
N
N
+
BnO
BnO
BnO
BnO
+
H
+
BnO
+
N
N
O
O
BnO
BnO
OBn
O–
BnO
OBn
Figure 3
Me
Me
17
15
16
To complete the synthesis, the cyclized product 20 was
subjected to global hydrogenolysis, which effectively re-
moved the benzyl groups as well as cleaved the N–O bond
in the presence of 6 N HCl, 10% Pd/C and a hydrogen at-
mosphere to provide the pyrrolizidine 13 in good yield
(91%).15,16
O–
N
N
+
+
BnO
BnO
OBn
BnO
OBn
18
19
The configuration of newly generated C-5 center was de-
termined on the basis of extensive NOE experiment. The
distinct NOE effects (see Figure 4) between C(5)H and
C(3)H, and also between C(9)H and C(8)H indicated that
the exocyclic methyl group at C-5 was syn to the hy-
droxymethyl group at C-3. Hence, the configuration at C-
5 was determined to be S and we successfully accom-
plished the synthesis of 5-(+)-epi-hyacinthacine A3.
Figure 2 Nitrones
Our synthesis of hyacinthacine A3 was started with the ad-
dition of 3-butenylmagnesium Grignard reagent to a pre-
viously cooled solution of nitrone 15 in THF at –78 °C to
furnish the hydroxylamine 14 as a single diastereomer.
The stereochemistry of the hydroxylamine 14 could be
easily explained by the anti attack of the organometallic
reagent with respect to the adjacent benzyl ether, as a re-
sult of steric and stereoelectronic effects.11 This hydrox-
ylamine was then subjected to Cope–House cyclization12
without further purification by dissolving it in chloroform
and stirring the solution for 24 hours. TLC analysis
showed complete consumption of the starting material as
well as the formation of a highly polar compound, which
was later proved from the spectral data13 to be the Cope–
House cyclized product 20 (quantitative yield for two
steps) as a single diastereomer (Scheme 3).
8
HO
9
HO
H
H
N
3
1
5
7
H
N
7a
6
2
HO
HO
H
H
HO
HO
H
13
Figure 4 NOE interactions in 13
After successfully synthesizing the 5-(+)-epi-hyacinthaci-
ne A3 we wanted to extend this strategy to the synthesis of
hyacinthacine A5 starting from D-ribose-derived nitrone
19 where the stereochemistry of all protected hydroxy
groups were syn to each other.
BnO
BnO
–
O
MgBr
OH
CHCl3, 24 h
N
N
BnO
BnO
99%
two steps
THF, –78 °C
H
BnO
15
BnO
BnO
BnO
–
MgBr
THF, –78 °C
OH
O
14
CHCl3, 24 h
N
H
N
BnO
BnO
HO
BnO
80%
two steps
–
O
N
Pd/C (10%), H2
BnO
BnO
19
N
H
MeOH–THF (4:1)
6 N HCl
HO
BnO
21
3 d, 91%
H
HO
BnO
HO
–
BnO
O
N
13
Pd/C (10%), H2
MeOH–THF (4:1)
6 N HCl
20
N
BnO
HO
Scheme 3 Synthesis of 5-(+)-epi-hyacinthacine A3 (13)
3 d, 99%
H
H
BnO
HO
23
22
It is noteworthy to mention here that the corresponding
Cope–House cyclization of acyclic unsaturated hydroxyl-
amine often gives a mixture of diastereomers.14 The ste-
reochemistry of the Cope–House cyclized product 20
could be assigned on the assumption that it proceeds via a
planar five-membered transition state, wherein the double
bond occupies the pseudoequatorial position (Figure 3).
Hence, in the product 20, the N-oxide function and the
newly formed alkyl (methyl) group were found to be cis
with respect to each other.
Scheme 4 Synthesis of 5-(–)-epi-hyacinthacine A5 (23)
The nucleophilic addition of 3-butenylmagnesium bro-
mide to nitrone 19 afforded again only one diastereomer
21, which was subjected to the Cope–House cyclization in
CHCl3 at room temperature to provide 22 (80% yield over
two steps). The N-oxide compound 22 was then hydroge-
nated under acidic conditions in the presence of 10% Pd/
Synlett 2008, No. 6, 841–844 © Thieme Stuttgart · New York

LETTER
Expedient Route to 5-epi-Hyacinthacine A3 and A5
843
C for three days to afford the pyrrolizidine 23 in 99% yield
Acknowledgment
(Scheme 4).15,16
K.P.K. thanks DAE Young Scientist Research Grant from BRNS,
Mumbai for financial support and SAIF, IIT Bombay for providing
spectral facilities. P.D. thanks CSIR, New Delhi for a fellowship.
NOE experiments were again used to assign the stere-
ochemistry at the newly generated center C(5) (Figure 5).
The observed NOE effects between C(5)H and C(3)H,
C(9)H and C(8)H, C(8)H and C(7a)H and C(1)H and
C(2)H suggested that C(1)H, C(2)H, C(3)H, C(7a) and
C(5)H, were on the same side of the molecule. Thus, the
configuration was tentatively assigned as R at C(5) and
utilizing this strategy, we completed the synthesis of 5-
(–)-epi-hyacinthacine A5.
References and Notes
(1) (a) Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R.
Cancer Res. 1988, 48, 1091. (b) Asano, N.; Nash, R. J.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645. (c) Compain, P.; Martin, O. R. Bioorg. Med.
Chem. 2001, 9, 3077. (d) Watson, A. A.; Fleet, G. W. J.;
Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry
2001, 56, 265.
(2) (a) Pearson, M. S. M.; Mathé-Allainmat, M.; Fargeas, V.;
Lebreton, J. Eur. J. Org. Chem. 2005, 2159. (b) Lillelund,
V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002,
102, 515.
(3) (a) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65,
2875. (b) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000,
65, 2887. (c) Yoda, H.; Katoh, H.; Takabe, K. Tetrahedron
Lett. 2000, 41, 7661. (d) Pearson, W. H.; Hines, J. V. J. Org.
Chem. 2000, 65, 5785. (e) White, J. D.; Hrnciar, P. J. Org.
Chem. 2000, 65, 9129. (f) Gallos, J. K.; Sarli, V. C.; Koftis,
T. V.; Argyropoulou, E. C. Tetrahedron Lett. 2000, 41,
4819. (g) Denmark, S. E.; Cottell, J. J. J. Org. Chem. 2001,
66, 4276.
(4) (a) Kaliappan, K. P.; Ravikumar, V. Synlett 2007, 977.
(b) Kaliappan, K. P.; Gowrisankar, P. Synlett 2007, 1537.
(c) Kaliappan, K. P.; Ravikumar, V. Org. Lett. 2007, 9,
2417. (d) Kaliappan, K. P.; Ravikumar, V. J. Org. Chem.
2007, 72, 6116. (e) Kaliappan, K. P.; Subrahmanayam, A.
V. Org. Lett. 2007, 9, 1121.
(5) (a) Desvergnes, S.; Py, S.; Vallée, Y. J. Org. Chem. 2005,
70, 1459. (b) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A.;
Rodríguez, M.; Martos, A. Tetrahedron 2006, 62, 6006.
(c) Zhou, L.; Chen, J.; Cao, X.-P. Synthesis 2007, 1359.
(6) (a) Cooper, N. J.; Knight, D. W. Tetrahedron 2004, 60, 243.
(b) Brainbridge, N. P.; Currie, A. C.; Cooper, N. J.; Muir, J.
C.; Knight, D. W.; Walton, J. M. Tetrahedron Lett. 2007, 48,
7782.
(7) (a) House, H. O.; Manning, D. T.; Melillo, D. G.; Lee, L. F.;
Haynes, O. R.; Wilkes, B. E. J. Org. Chem. 1976, 41, 855.
(b) House, H. O.; Lee, L. F. J. Org. Chem. 1976, 41, 863.
(8) Oppolzer, W.; Spivey, A. C.; Bochet, C. G. J. Am. Chem.
Soc. 1994, 116, 3139.
(9) (a) Ciganek, E. J. Org. Chem. 1990, 55, 3007. (b) Ciganek,
E.; Read, J. M.; Calabrese, J. C. J. Org. Chem. 1995, 60,
5795. (c) Ciganek, E. J. Org. Chem. 1995, 60, 5803.
(10) (a) Cicchi, S.; Höld, I.; Brandi, A. J. Org. Chem. 1993, 58,
5274. (b) Tamura, O.; Toyao, A.; Ishibashi, H. Synlett 2002,
1344.
8
9
HO
HO
H
H
3
H
5
7
N
7a
N
2
6
HO
HO
1
H
H
HO
HO
H
23
Figure 5 NOE interactions in 23
In view of its simplicity and potential diversity in synthe-
sizing several analogues of these alkaloids, this strategy
was then extended to synthesize a range of unnatural pyr-
rolizidine alkaloids as shown in Table 1. The yields of
Cope–House cyclization as well as the hydrogenation
steps were consistently excellent.
Table 1 Synthesis of Unnatural Pyrrolizidine Alkaloids
Entry Nitrones Cope–House product
Pyrrolizidines
O
N
N
89%
98%
O
1
2
3
16
17
18
HO
H
O
H
HO
25
HO
27
24
O
N
N
96%
BnO
87%
96%
H
HO
H
BnO
26
BnO
HO
O
N
N
(11) Merino, P.; Revuelta, J.; Tejero, T.; Cicchi, S.; Goti, A. Eur.
J. Org. Chem. 2004, 776.
BnO
HO
99%
H
H
(12) General Procedure for the Cope–House Cyclization: To a
stirred solution of nitrone (1.2 mmol) in anhyd THF (20
mL), a previously prepared (4.8 mmol of 4-bromobutene and
7.2 mmol Mg in 15 mL anhyd THF) Grignard solution was
slowly added under a nitrogen atmosphere at –78 °C and
allowed to come to r.t. Then the reaction mixture was
quenched by sat. NH4Cl solution and extracted with EtOAc
(3 × 50 mL). The combined organic extracts were dried over
Na2SO4, washed with brine and filtered. The filtrate was
evaporated under vacuum to afford the hydroxylamine.
Without further purification, the hydroxylamine was
dissolved in CHCl3 (15 mL) and stirred for 24 h at r.t. to
BnO
HO
29
28
In summary, we have successfully accomplished the syn-
thesis of 5-epi-hyacinthacine A3 and 5-epi-hyacinthacine
A5 in three steps using Cope–House cyclization as the key
step. This strategy is general and has very good potential
to synthesize several simpler analogues of hyacinthacine
alkaloids.
Synlett 2008, No. 6, 841–844 © Thieme Stuttgart · New York

844
K. P. Kaliappan, P. Das
LETTER
provide the cyclized product which upon purification by
silica gel column chromatography (MeOH in CHCl3)
afforded the product.
127.8, 127.6, 127.5, 127.4, 86.9, 83.5, 83.4, 74.5, 73.2, 72.6,
72.1, 71.6, 66.0, 29.6, 26.3, 12.8. IR (neat): 3060, 3030,
2928, 2867, 1655, 1496, 1454, 1367, 1105, 1028, 740, 698
cm–1. HRMS (ESI–TOF): m/z [M + 1]+ calcd for C30H36NO4:
474.2644; found: 474.2658.
(13) Spectral data for selected compounds: Compound 20: Rf
0.65 (CHCl3–MeOH, 3:0.5); [a]D25 8.4 (c = 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.22–7.36 (m, 15 H), 4.42–
4.61 (m, 6 H), 4.35 (t, J = 3.9 Hz, 1 H), 4.24 (dd, J = 5.8, 10.1
Hz, 1 H), 4.07–4.12 (m, 1 H), 3.86 (dd, J = 6.4, 10.1 Hz, 1
H), 3.76 (dd, J = 3.4, 6.4 Hz, 1 H), 3.66–3.73 (m, 1 H), 3.61
(dd, J = 5.8, 10.4 Hz, 1 H), 2.36–2.41 (m, 1 H), 2.03–2.09
(14) (a) Palmer, A. M.; Jäger, V. Eur. J. Org. Chem. 2001, 2547.
(b) Palmer, A. M.; Jäger, V. Synlett 2000, 1405. (c) Palmer,
A. M.; Jäger, V. Eur. J. Org. Chem. 2001, 1293.
(15) General Procedure for Hydrogenation: To a solution of
N-oxide (0.65 mmol) in a mixture of MeOH and THF (4:1,
20 mL) was added 10% Pd/C (111 mg). After the reaction
flask was purged with H2, 10 drops of 6 N HCl were added
and the reaction mixture was stirred for 3 d at r.t. under a H2
atmosphere. The mixture was then filtered through a pad of
Celite, and the filtrate was concentrated under vacuum. The
residue was dissolved in minimum amount of H2O and
stirred with IRA450 resin (OH– form) until pH 11. After
filtration, the filtrate was concentrated in vacuo to give the
pure pyrrolizidine.
(m, 2 H), 1.71–1.95 (m, 1 H), 1.32 (d, J = 6.4 Hz, 3 H). 13
NMR (100 MHz, CDCl3): d = 137.5, 136.8, 128.1, 128.0,
127.7, 127.6, 127.5, 127.4, 127.3, 86.7, 83.5, 83.4, 74.3,
73.0, 72.5, 72.0, 71.5, 65.9, 29.5, 26.2, 12.7. IR (neat): 3063,
3031, 2933, 2868, 1650, 1496, 1454, 1367, 1107, 1027, 740,
699 cm–1. HRMS (ESI–TOF): m/z [M + 1]+ calcd for
C
C30H36NO4: 474.2644; found: 474.2632. Compound 22: Rf
0.63 (CHCl3–MeOH, 3:0.5); [a]D25 –13.6 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.24–7.36 (m, 15 H), 4.78–
4.81 (m, 2 H), 4.52–4.69 (m, 5 H), 4.36 (t, J = 3.6 Hz, 1 H),
4.14 (dd, J = 5.8, 10.4 Hz, 1 H), 3.83–3.93 (m, 3 H), 3.43–
3.45 (m, 1 H), 2.01–2.28 (m, 2 H), 1.96–1.99 (m, 1 H), 1.69–
1.71 (m, 1 H), 1.31 (d, J = 6.4 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 137.8, 137.6, 137.1, 128.3, 128.2, 128.1, 127.8,
127.7, 127.6, 127.5, 83.3, 82.1, 78.3, 77.5, 76.2, 73.8, 73.1,
72.3, 64.2, 32.2, 25.5, 11.7. IR (neat): 3064, 3031, 2936,
2873, 1650, 1497, 1454, 1368, 1153, 1073, 1028, 748, 698
cm–1. HRMS (ESI–TOF): m/z [M + 1]+ calcd for C30H36NO4:
474.2644; found: 474.2641. Compound 24: Rf 0.63 (CHCl3–
MeOH, 2:1); [a]D25 –1.6 (c = 1.00, CHCl3). 1H NMR (400
MHz, CDCl3): d = 4.78 (q, J = 6.4 Hz, 1 H), 4.44 (dd, J = 4.9,
6.7 Hz, 1 H), 4.15–4.19 (m, 1 H), 3.99 (dd, J = 6.7, 13.1 Hz,
1 H), 3.70 (dd, J = 6.1, 12.8 Hz, 1 H), 3.06–3.15 (m, 1 H),
2.51–2.60 (m, 1 H), 2.15–2.25 (m, 1 H), 2.05–2.13 (m, 1 H),
1.85–1.93 (m, 1 H), 1.60 (s, 3 H), 1.39 (d, J = 6.4 Hz, 3 H),
1.32 (s, 3 H). 13C NMR (100 MHz, CDCl3): d = 114.7, 85.1,
84.4, 76.3, 71.9, 68.7, 30.0, 27.0, 25.1, 24.9, 12.2. IR (neat):
2988, 2934, 1659, 1460, 1385, 1214, 1160, 1054, 992, 854,
758 cm–1. HRMS (ESI–TOF): m/z [M + 1]+ calcd for
C11H20NO3: 214.1443; found: 214.1435. Compound 26: Rf
0.67 (CHCl3–MeOH, 2:1); [a]D25 –8.1 (c = 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3): d = 7.24–7.39 (m, 10 H), 4.44–
4.58 (m, 4 H), 4.30–4.35 (m, 1 H), 4.27 (d, J = 5.8 Hz, 1 H),
3.94 (dd, J = 6.1, 13.4 Hz, 1 H), 3.82 (br d, J = 3.4 Hz, 1 H),
3.66–3.77 (m, 2 H), 2.37–2.45 (m, 1 H), 2.14–2.25 (m, 1 H),
1.98–2.03 (m, 1 H), 1.68–1.78 (m, 1 H), 1.37 (d, J = 6.1 Hz,
3 H). 13C NMR (100 MHz, CDCl3): d = 136.7, 136.4, 128.4,
128.3, 128.1, 127.8, 127.6, 127.5, 86.7, 86.3, 81.8, 72.9,
71.8, 71.4, 68.1, 30.7, 26.8, 11.9. IR (neat): 3060, 3027,
2925, 2851, 1660, 1495, 1454, 1368, 1113, 1026, 753, 700
cm–1. HRMS (ESI–TOF): m/z [M + 1]+ calcd for C22H28NO3:
354.2069; found: 354.2081. Compound 28: Rf 0.60 (CHCl3–
MeOH, 3:0.5); [a]D25 –9.4 (c = 1.00, CHCl3). 1H NMR (400
MHz, CDCl3): d = 7.22–7.36 (m, 15 H), 4.42–4.61 (m, 6 H),
4.36 (t, J = 3.9 Hz, 1 H), 4.26 (dd, J = 5.5, 10.1 Hz, 1 H),
4.16–4.21 (m, 1 H), 3.87 (dd, J = 6.4, 10.1 Hz, 1 H), 3.76 (dd,
J = 3.4, 6.4 Hz, 1 H), 3.66–3.72 (m, 1 H), 3.62 (dd, J = 5.8,
10.4 Hz, 1 H), 2.36–2.44 (m, 1 H), 2.00–2.15 (m, 2 H), 1.69–
1.78 (m, 1 H), 1.33 (d, J = 6.4 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 137.7, 136.9, 36.9, 128.3, 128.2, 128.1, 127.9,
(16) Spectral data for selected compounds: Compound 13: Rf
0.46 (CHCl3–MeOH, 2:1); [a]D25 24.8 (c = 1.00, H2O). 1H
NMR (300 MHz, D2O): d = 3.89–3.94 (m, 2 H), 3.81 (dd,
J = 4.4, 12.2 Hz, 1 H), 3.72 (dd, J = 6.3, 12.6 Hz, 1 H), 3.57–
3.64 (m, 1 H), 3.36–3.42 (m, 1 H), 3.11–3.15 (m, 1 H), 2.10–
2.27 (m, 2 H), 1.83–1.95 (m, 1 H), 1.55–1.68 (m, 1 H), 1.20
(d, J = 6.3 Hz, 3 H). 13C NMR (100 MHz, D2O): d = 79.2,
77.1, 70.0, 68.5, 65.1, 60.0, 32.5, 27.9, 17.4. HRMS (ESI–
TOF): m/z [M + 1]+ calcd for C9H18NO3: 188.1287; found:
188.1277. Compound 23: Rf 0.44 (CHCl3–MeOH, 2:1);
[a]D25 –8.0 (c = 1.00, H2O). 1H NMR (300 MHz, D2O): d =
4.34 (t, J = 3.7 Hz, 1 H), 4.08 (dd, J = 3.7, 8.4 Hz, 1 H), 3.82–
3.98 (m, 3 H), 3.40–3.66 (m, 2 H), 2.11–3.31 (m, 2 H), 1.83–
1.94 (m, 1 H), 1.66–1.78 (m, 1 H), 1.24 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, D2O): d = 75.6, 72.5, 69.5, 68.7, 65.2,
5.3, 31.8, 26.8, 17.2. HRMS (ESI–TOF): m/z [M + 1]+ calcd
for C9H18NO3: 188.1287; found: 188.1287. Compound 25:
Rf 0.42 (CHCl3–MeOH, 2:1); [a]D25 32.5 (c = 1.00, H2O). 1H
NMR (300 MHz, D2O): d = 4.43 (d, J = 3.4 Hz, 1 H), 4.11
(br m, 1 H), 3.90–3.92 (m, 1 H), 3.18–3.43 (m, 3 H), 2.15–
2.28 (m, 2 H), 1.64–1.86 (m, 2 H), 1.27 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, D2O): d = 77.7, 73.6, 72.1, 68.0, 57.8,
35.5, 29.9, 18.3. HRMS (ESI–TOF): m/z [M + 1]+ calcd for
C8H16NO2: 158.1181; found: 158.1186. Compound 27: Rf
0.46 (CHCl3–MeOH, 2:1); [a]D25 –33.5 (c = 1.00, H2O). 1H
NMR (400 MHz, D2O): d = 4.34 (dd, J = 3.1, 7.3 Hz, 1 H),
4.17 (t, J = 2.7 Hz, 1 H), 3.89–3.94 (m, 1 H), 3.52–3.61 (m,
2 H), 3.22 (dd, J = 2.7, 12.9 Hz, 1 H), 2.56–2.33 (m, 1 H),
2.17–2.23 (m, 1 H), 1.96–2.06 (m, 1 H), 1.59–1.69 (m, 1 H),
1.33 (d, J = 6.2 Hz, 3 H). 13C NMR (100 MHz, D2O): d =
81.2, 79.6, 76.2, 69.8, 58.5, 36.2, 31.1, 18.6. HRMS (ESI–
TOF): m/z [M + 1]+ calcd for C8H16NO2: 158.1181; found:
158.1176. Compound 29: Rf 0.59 (CHCl3–MeOH, 2:1);
[a]D25 –22.0 (c = 1.00, H2O). 1H NMR (400 MHz, D2O): d =
3.98–4.04 (m, 2 H), 3.89 (dd, J = 3.9, 12.4 Hz, 1 H), 3.78–
3.85 (m, 2 H), 3.36–3.64 (m, 1 H), 3.33–3.34 (m, 1 H), 2.21–
2.35 (m, 2 H), 1.97–2.04 (m, 1 H), 1.67–1.87 (m, 1 H), 1.31
(d, J = 6.6 Hz, 3 H). 13C NMR (100 MHz, D2O): d = 81.2,
78.9, 73.1, 72.3, 68.9, 61.2, 35.1, 30.5, 19.1. HRMS (ESI–
TOF): m/z [M + 1]+ calcd for C9H18NO3: 188.1296; found:
188.1287.
Synlett 2008, No. 6, 841–844 © Thieme Stuttgart · New York