Alkaloids from alkaloids: total synthesis of (±)-7a-epi-hyacinthacine A1 from Z-protected tropenone via Baeyer-Villiger oxidation

Article abstract of DOI:10.1016/j.tet.2009.05.071

Baeyer-Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones 15a-c underwent exclusive epoxidation to 21a-c, the corresponding 6-oxotropane derivative 28 yielded the desired lactone 29. Baeyer-Villiger oxidation was

Full text of DOI:10.1016/j.tet.2009.05.071

Tetrahedron 65 (2009) 6626–6634
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Alkaloids from alkaloids: total synthesis of (ꢀ)-7a-epi-hyacinthacine
A1 from Z-protected tropenone via Baeyer–Villiger oxidation
*
Olena Affolter, Angelika Baro, Wolfgang Frey, Sabine Laschat
Institut fu¨r Organische Chemie, Universita¨t Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Baeyer–Villiger oxidations of several tropane derivatives have been investigated. Whereas tropenones
15a–c underwent exclusive epoxidation to 21a–c, the corresponding 6-oxotropane derivative 28
yielded the desired lactone 29. Baeyer–Villiger oxidation was also possible for the O-isopropylidene-
protected diols 32a,b. The resulting lactones 33a,b were employed in the total synthesis of (ꢀ)-7a-epi-
hyacinthacine A1 (7a-epi-7) via an intramolecular nucleophilic alkyllithium addition to a carbamate as
the key lactamization step. The target compound was prepared from tropenone 15b in 10 steps and
14% overall yield. Enzymatic resolution of pyrrolidine (ꢀ)-36 provided a formal total synthesis to both
enantiomers of 7.
Received 16 March 2009
Received in revised form 26 May 2009
Accepted 26 May 2009
Available online 3 June 2009
Dedicated to Professor Larry E. Overman
for his great accomplishments in Organic
Synthesis
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolizidine alkaloids
Tropane alkaloids
Baeyer–Villiger oxidation
1. Introduction
nale.1 These compounds act as a constitutive plant defence
mechanism, and depending on the structure and substitution pat-
Pyrrolizidine alkaloids are common constituents of a large
number of plants, among them are medicinal plants such as but-
terbur, coltsfoot Tussilago farfara, and comfrey Symphytum offici-
tern of the pyrrolizidine ring system several derivatives display
hepatoxic and cancerogenic properties.1,2 The toxicity is particularly
high for those derivatives, which contain at least one ester moiety,
HO
CH2OH
CH2OH
CH2OH
HO
HO
CH2OH
H
N
H
N
H
N
N
(+)-supinidine 1
OH
HO
(+)-heliotridine 2
(+)-retronecine 3
pyrroloretronecine 4
HO
OH
OH
OH
OH
H
H
N
H
N
H
N
H
7
1
7a
6
2
OH
OH
OH
OH
OH
5
3
N
N
OH
OH
OH
OH
OH
alexine 5
australine 6
hyacinthacine A1
7
hyacinthacine A2 8 hyacinthacine A3
9
OH
OH
H
OH
H
OH
OH
H
H
N
HO
OH
OH
OH
N
OH
OH
N
N
HN
OH
OH
OH
OH
OH
DMDP 14
hyacinthacine A4 10 hyacinthacine A5 11 hyacinthacine A6 12 hyacinthacine A7 13
Scheme 1.
usually at the hydroxymethyl group, and a C]C double bond at the
C-1 position.3 Prominent examples of pyrrolizidines with toxic
properties are supinidine (1), heliotridine (2), and retronecine (3)
(Scheme 1) and their corresponding esters. The cancerogenic
* Corresponding author. Tel.: þ49 711 685 64565; fax: þ49 711 685 64285.
E-mail address: sabine.laschat@oc.uni-stuttgart.de (S. Laschat).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.071

O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
6627
R
(DMDP) (14) compounds 7–13 were intensively investigated with
regard to their selective glycosidase inhibition. Total syntheses of
hyacinthacines and their epimers mostly relied on ex chiral pool
approaches, starting from carbohydrates,5,10 amino acids11 or
diethyltartrate,12 which provided the proper stereochemistry. An-
other route utilized a sequence of partial reduction of N-Boc-pyrrole
and enzymatic resolution as the key steps.13 The first auxiliary-
mediated approach involved a [2þ2] cycloaddition of dichloroketene
to StericolÒ-based enol ethers,14 and furthermore, a chemo-
enzymatic route employing aldolases has been reported.15
During our work on tropane derivatives we envisaged an
alternative route to hyacinthacines utilizing functionalized trope-
nones as valuable starting materials. We recently reported that
N-protected tropenone 15 can be easily converted to enantiomerically
pure 6-hydroxytropinone 16 via enantioselective hydroboration16
or enzymatic desymmetrization17 and to mono-protected dihy-
droxytropinone 17 via enzymatic resolution (Scheme 2).18,19
Motivated by an early report of Donnini20 on the conversion of
O-protected dihydroxytropenone to the pyrrolidine we anticipated
that a sequence of Baeyer–Villiger oxidation followed by lactone
opening should allow the transformation of tropenones 15–17 to
the corresponding pyrrolidines 18–20 as precursors to hyacintha-
cine derivatives. The results toward this goal and the application in
the total synthesis of 7a-epi-hyacinthacine A1 are reported.
N
R
R
N
O
N
15
HO
MOMO
HO
1) Baeyer-
Villiger
oxidation
2) lactone
opening
O
O
16
17
R1O2C
CO2R1
R1O2C
OMOM
OH
OH
N
N
N
R
R
R
OH
OH
OH
18
19
20
Scheme 2.
R
R
N
N
MCPBA
O
N
R
+
CH2Cl2
rt, 4 d
O
O
O
O
2. Results and discussion
15a−c
21a 77%
b 82%
22a−c 0%
c 55%
Baeyer–Villiger oxidations of tropane derivatives are rarely
reported.20 For norbornenone derivatives, however, Mehta has
shown that the chemoselectivity strongly depended on the reaction
condition.21 Whereas the use of MCPBA produced a (60:40) mixture
of epoxide and unsaturated lactone, the use of H2O2/NaOH resulted
in exclusive lactone formation.21 When carbamate protected tro-
penone 15b was submitted to H2O2/NaOH either in MeOH at 0 ꢁC
for 2 h or in Et2O/H2O at room temperature for 2 h the starting
material 15b could be recovered quantitatively. In contrast, MCPBA
treatment of N-protected tropenones 15a–c in CH2Cl2 at room
temperature yielded only the epoxides 21a–c in 55–82% (Scheme 3).
No traces of the corresponding lactones 22 were found.
In analogy to Donnini’s method, next the epoxide 21a was treated
with MCPBA in the presence of 2,4,6-tri(tert-butyl)phenol in di-
chloroethane at 55 ꢁC (Scheme 3). However, even after 7 days, only
traces of the desired lactone 23a were detected at very low conversion.
Surprisingly, also MOM-protected hydroxytropenone acetal 25a,
which was obtained from hydroxyacetal 24a16 by treatment with
MOMCl in the presence of Hu¨nig’s base and DMAP in CH2Cl2 in 95%
yield, gave the expected regioisomeric Baeyer–Villiger products
26a, 27a only in traces after cleavage of the acetal moiety with PPTS
in acetone and subsequent Baeyer–Villiger oxidation (Scheme 4).
MCPBA, ClCH2CH2Cl
2,4,6-(t-Bu)3-C6H2OH
55 °C, 7 d
for 21a
O
15,21−23
R =
a CO2Me
b
N
R
Z
Boc
c
O
23a
O
Scheme 3.
properties arise from hepatic metabolism of pyrrolizidines such as
retronecine (3) to pyrrole derivatives like 4. Pyrroles such as 4 are
strong alkylating agents and induce DNA cross-linking.1d,g,4
On the other hand, polyhydroxylated pyrrolizidines gained at-
tention for medicinal chemistry.5 Alexine (5) and australine (6),
which were isolated in 1988 by Nash from Leguminosae possess
potent antiviral properties.6,7 In 2000 Asano isolated hyacinthacines
A1–A3 (7–9) from Muscari armeniacum (Hyacinthaceae)8 and later in
2002 the hyacinthacines A4–A7 (10–13).9 Due to their structural
similarity with one of the most potent glycosidase inhibitors
(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine
R
R
1) PPTS
for 24a
MOMCl, i-Pr2NEt
DMAP
MOMO
MOMO
acetone/H2O
reflux, 2 h
N
N
HO
MOMO
N
R
N
R
+
CH2Cl2, rt, 2 h
95%
2) MCPBA
O
O
O
O
ClCH2CH2Cl
O
O
O
O
2,4,6-(t-Bu)3-C6H2OH
24a,b
25a
26a
27a
55 °C, 5 d
24−27
a
R =
CO2Me
Z
for 24b DMSO, (CF3CO)2O, NEt3, CH2Cl2, −70 °C, 3 h, 70%
b
Z
Z
Z
N
N
N
O
O
MCPBA, NaHCO3
CH2Cl2, rt, 18 h
+
O
O
O
O
O
O
O
O
O
28
29 57%
30 0%
Scheme 4.

6628
O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
In contrast, treatment of Z-protected ketone 28, which was
C-2. Thus, the methodology was applied in the total synthesis of 7a-
epi-hyacinthacine A1 (7a-epi-7). The retrosynthesis is shown in
Scheme 6. 7a-epi-Hyacinthacine A1 (7a-epi-7) should be available
from the pyrrolizidinone 34, which can be traced back to the pro-
tected pyrrolidine derivative 35. It was planned to prepare com-
pound 35 from the pyrrolidine 36 by a sequence of protection of the
primary hydroxy group, reduction, and chain extension. Compound
36 is derived from the lactone 33b via opening and esterification.
obtained by modified Swern oxidation of alcohol 24b in 70% yield,
with MCPBA in the presence of NaHCO3 in CH2Cl2 at room tem-
perature gave exclusively lactone 29 in 57%. The regioisomeric
lactone 30 was not detected. Presumably, the 1,2-migration of the
bridgehead C–C bond is favored due to neighbor group assistance of
the carbamate nitrogen. It should be noted, that Chambers22 and
Ruiz23 reported 1,2-migration of the ‘internal’ C1–C2 bond rather
than the bridgehead C2–C3 bond for Baeyer–Villiger oxidations of
norcamphor derivatives.
OH
OH
H
N
H
Finally, the diols 31a,b24,18 were acetalized with dimethoxy-
propane to give the tricyclic acetals 32a,b in 93% and >99% yield,
respectively (Scheme 5). Acetals 32a,b were oxidized with MCPBA
under Donnini’s conditions20 and the desired lactones 33a,b were
isolated in 50% and 55% yield, respectively. At this point it is not
clear why tropane derivatives 15a–c, 21, and 24 behaved differ-
ently under the Baeyer–Villiger conditions as compared to 28 and
32a,b.
OH
OH
OH
N
O
OH
7a-epi-7
34
O
OR1
O
4
2
5
X
MeO2C
O
OR1
N1
N
3
Z
Z
OH
OR2
R
R
36
35
N
N
(MeO)2CMe2
TsOH
HO
HO
O
O
acetone, rt, 2 h
33b
O
O
Scheme 6.
31a,b
32a,b
MCPBA, ClCH2CH2Cl
2,4,6-(t-Bu)3C6H2OH
55 °C, 4 d
As shown in Scheme 7, tricyclic lactone 33b was treated with
K2CO3 in MeOH according to the method by Ogawa25 to give
quantitatively pyrrolidine methylester 36. The relative stereo-
chemistry of 36 was proven by a NOESY NMR experiment, which not
only displayed cross peaks for 2-H/5-H and 3-H/4-H but also cross
peaks between the cis-oriented methylene groups and the hydro-
gen atoms, i.e., 2-CH2/3-H, 5-CH2/4-H, and 2-CH2/5-CH2. Sub-
sequent protection of the primary hydroxy group in 36 with TBSCl
in the presence of imidazole in DMF at room temperature yielded
TBS ether 37 in 97%, which was then treated with LiAlH4 in Et2O.
When the reaction was carried out at 0 ꢁC and warmed to room
temperature over 1 h, the desired alcohol 38 was isolated in 87%
together with the tricyclic hemiaminal 39 in 8%. This byproduct is
probably due to intramolecular nucleophilic attack of the primary
O
O
O
31−33
a
b
R
CO2Me
Z
N
R
Yield 32 93%
Yield 33
>99%
O
50%
55%
33a,b
Scheme 5.
From these results we concluded that those pyrrolizidine
alkaloids should be easily accessible via Baeyer–Villiger oxidation/
lactone opening sequence, which contain a cis-diol subunit at C-1,
O
MeO2C
TBSCl, imidazole
DMF, rt, 18 h, 97%
K2CO3, MeOH
O
33b
36
N
rt, 18 h, quant.
Z
OTBS
37
LiAlH4, Et2O, 1 h
O
O
O
O
Br
HO
CBr4, PPh3, CH2Cl2
rt, 3 h, quant.
O
O
+
N
O
N
N
Z
Z
OTBS
OTBS
OTBS
40
38
39
0°C → rt
87%
8%
3%
t-BuLi, THF, −80°C, 1 h, 59%
−5°C → rt 94%
O
H
N
TFA, THF/H2O (7:1)
reflux, 1.5 h, quant.
O
34
O
OTBS
41
LiAlH4, THF, 70 °C, 5 h
OH
H
1) BH3 SMe2, THF, rt, 6 h
2) MeOH, reflux, 3.5 h, 60%
O
H
N
1) HCl, MeOH, reflux, 1 h
2) H2O, DOWEX 1x8 (OH−)
1.5 h, quant.
O
OH
OH
N
OTBS
42
7a-epi-7
Scheme 7.

O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
6629
hydroxy group at the carbamate C]O, followed by extrusion of
benzylic alcohol. The intermediate hexahydropyrrolo[1,2-
c][1,3]oxazin-1-one is then further reduced by LiAlH4 to the hemi-
aminal 39. The formation of this byproduct could be minimized by
lowering the reaction temperature to ꢂ5 ꢁC and the yield of the
desired product 38 was improved to 94%. Subsequent bromination
of 38 under Appel conditions26 with CBr4 and PPh3 in CH2Cl2 at
room temperature yielded the bromide 40 almost quantitatively.
For the conversion of the bromide 40 to the pyrrolizidinone 41 we
applied a one step lactamization discovered by Dominguez.27 Upon
addition of pyrrolidine 40 to a solution of t-BuLi in THF at ꢂ80 ꢁC
followed by aqueous workup the desired lactam 41 could be iso-
lated in 59% yield. Our assignment of the relative configuration in 36
was confirmed by an X-ray crystal structure analysis of 41 (Fig. 1).28
with BH3$SMe2 in THF at room temperature, followed by refluxing
in MeOH according to a method by Izquierdo.29 Final deprotection
was achieved by sequential treatment of 42 with HCl in MeOH
under reflux and DOWEX 1ꢃ8 ion exchange resin following the
method by Landais and Renaud.30 In this way, the target compound
7a-epi-7 was isolated quantitatively in analytically pure form.
In order to allow access to enantiomerically pure compound 7
as well, the lipase-catalyzed resolution of hydroxymethyl pyrro-
lidine 36 was investigated (Table 1). Treatment of (ꢀ)-36 with
Novozyme 435 from Candida antarctica or Chirazyme L-6 from
Pseudomonas cepacia and vinyl acetate in Et2O or toluene31 yiel-
ded (ꢂ)-acetate (ꢂ)-43 and (þ)-alcohol (þ)-36. The best results
were obtained with Chirazyme L-6 (entries 4, 6, and 8). In toluene
(ꢂ)-acetate (ꢂ)-43 was obtained in 42% yield with 99% ee and the
remaining (þ)-alcohol (þ)-36 was isolated in 48% yield albeit with
75% ee (entry 8).
When the reaction was performed in Et2O (ꢂ)-acetate (ꢂ)-43
was isolated with decreased optical purity (56% ee), however, the
enantiomeric excess of the alcohol (þ)-36 could be raised to 99% ee
(entry 6).
3. Conclusion
In conclusion, we have demonstrated that N-protected trope-
nones 15 could be converted into the pyrrolizidine alkaloid (ꢀ)-7a-
epi-hyacinthacine A1 (7a-epi-7) in 10 steps and 14% overall yield
employing a Baeyer–Villiger oxidation/lactone opening sequence
and a lactamization via intramolecular nucleophilic attack of an
alkyllithium species to a carbamate as the key steps. This route
gives also access to both enantiomeric series of 7 as was shown by
the enzymatic resolution of the pyrrolidine intermediate 36. At-
tempts toward the synthesis of other pyrrolizidines from tropane
alkaloids are currently in progress.
4. Experimental section
4.1. General
Figure 1. ORTEP presentation of lactam 41 in the solid state.
For completion of the synthesis of 7a-epi-7 we first anticipated
a deprotection of lactam 41 followed by reduction of the lactam
moiety. Although 41 was deprotected with TFA in THF/H2O (7:1)
under reflux, all attempts failed to isolate the product from sub-
sequent LiAlH4 treatment. Therefore, protected lactam 41 was re-
duced with LiAlH4 in THF to pyrrolizidine 42 albeit with 24% yield.
The yield was improved to 60% by alternative reduction of lactam 41
Melting points (uncorrected) were determined on a Bu¨chi 510
melting point apparatus. Optical rotations were determined with
a Perkin–Elmer 241 LC polarimeter. IR spectra: Bruker Vektor 22 FT-
IR spectrometer. Mass spectra: Finnigan MAT 95, Varian MAT 711,
and Bruker Daltonics micrOTOF_Q spectrometers. NMR spectra:
Bruker AC-250F, Bruker ARX 300, and Bruker ARX 500
Table 1
Enzymatic resolution of hydroxymethyl pyrrolidine (ꢀ)-36 under various conditionsa,b
O
O
MeO2C
Lipase, solvent
MS 4Å,
MeO2C
O
O
( )-36
+
N
N
OAc
Z
Z
OAc
OH
(−)-43
(+)-36
Entry
Lipase
Solvent
Temp [ꢁC]
Time [h]
Conversion [%]
(ꢂ)-43 Yield [%]
d
[% ee]
Ec
(þ)-36 Yield [%]
[% ee]
E
1
2
3
4
5
6
7
8
Novozyme 435
Chirazyme L-6
Novozyme 435
Chirazyme L-6
Novozyme 435
Chirazyme L-6
Novozyme 435
Chirazyme L-6
Et2O
Et2O
Toluene
Toluene
Et2O
Et2O
Toluene
Toluene
40
40
40
40
20
20
20
20
0.5
0.5
2.0
0.5
0.5
1.0
3.5
1.5
65
70
45
52
60
65
50
48
d
d
d
4
d
d
d
5
d
d
50
44
d
d
d
48
d
d
d
3
16
14
16
3
d
d
d
39
47
d
45
94
79
56
48
99
35
80
93
99
32
75
dd
d
42
>100
22
a
The following lipases were used: Novozyme 435 from C. antarctica, Chirazyme L-6 from P. cepacia.
b
c
Conversions were determined by capillary GC. Enantioselectivities were determined by chiral HPLC (see Experimental section for details). Yields refer to isolated yields.
E¼ln{1ꢂc[1þee(43)]}/ln[1ꢂc[1ꢂee(43)]},32 (whereby c was determined by GC).
d
Not isolated.

6630
O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
spectrometers. The spectra were recorded with TMS as an internal
standard. 13C NMR multiplicities were determined by DEPT135
4.2.4. Methyl 6-(methoxymethoxy)-8H-spiro[8-azabicyclo-
[3.2.1]octane-3,20-[1,3]dioxolane]-8-carboxylate (25a)
experiments. Signals of the second rotamer are indicated by
*
.
To a cooled solution of 24a (110 mg, 453
mmol) in CH2Cl2
Column chromatography: Fluka silica gel 60 (40–63
m
m). Com-
(2 mL) were added MOMCl (170 L, 2.26 mmol), i-Pr2NEt (384 m
m
L,
pounds 24a,b were prepared according to Ref. 16
2.26 mmol), and DMAP (10 mg) and the reaction mixture was
stirred for 30 min at 0 ꢁC, then warmed to rt and stirred for 16 h.
The mixture was diluted with CH2Cl2 (30 mL), washed with a satd
NH4Cl solution, dried (Na2SO4), and evaporated. The residue was
purified by flash chromatography (silica gel, EtOAc/hexane 2:1) to
4.2. Synthesis and characterization
4.2.1. Methyl 7-oxo-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-
carboxylate (21a)
To a solution of 15a (52 mg, 287
added MCPBA (193 mg, 861 mol, 77%) and the mixture was
stirred at rt for 2 days. The reaction mixture was filtered, the
filtrate was diluted with CH2Cl2, dried (Na2SO4), concentrated in
vacuo, and purified by column chromatography (silica gel, EtOAc/
give 25a (124 mg, 432
(EtOAc/hexane 2:1). 1H NMR (500 MHz, CDCl3):
J¼13.8, 4.1, 2.1 Hz, 2H, Ha-4, Ha-4), 1.82–1.89 (m, 2H, Ha-7, Ha
1.86 (ddd, J¼13.8, 2.4, 2.1 Hz, 2H, Ha-2, Ha-2), 1.89–1.95 (br m, 1H,
Hb
-4), 1.93 (dd, J¼13.8, 4.1 Hz, 1H, Hb-2), 2.00–2.06 (br m, 2H, Hb
2, Hb-4), 2.55 (dd, J¼13.3, 7.3 Hz, 1H, Hb-7), 2.58 (dd, J¼13.3,
7.3 Hz, 1H, Hb-7), 3.36 (s, 3H, CH2OCH3), 3.37 (s, 3H, CH2OCH3),
3.70 (s, 3H, COOCH3), 3.71 (s, 3H, COOCH3), 3.80–3.86 (m, 4H,
OCH2, OCH2), 3.92–3.98 (m, 4H, OCH2, OCH2), 4.21–4.24 (br m, 1H,
H-1), 4.30–4.33 (br m, 1H, H -1), 4.35–4.39 (br m, 1H, H -5), 4.44
(dd, J¼7.3, 2.4 Hz, 1H, H -6), 4.45–4.48 (br m, 1H, H-5), 4.45 (dd,
J¼7.4, 2.4 Hz, 1H, H-6), 4.62 (d, J¼7.2 Hz, 1H, CHaOCH3), 4.64 (br s,
2H, CH2OCH3), 4.65 (d, J¼7.2 Hz, 1H, CHbOCH3
). 13C NMR
(125 MHz, CDCl3): 37.1 (C-7), 37.8 (C-7 ), 38.5 (C-2 ), 39.3 (C-2),
39.8 (C-4), 40.6 (C-4 ), 52.4 (COOCH3, COOCH3), 52.8 (C-5 ), 52.9
(C-5), 55.4 (CH2OCH3), 55.5 (CH2OCH3), 59.3 (C-1 ), 59.6 (C-1),
63.5, 64.5 (OCH2, OCH2), 78.8 (C-6 ), 79.7 (C-6), 95.6 (CH2OCH3,
CH2OCH3), 106.9 (C-3, C-3 ), 154.4 (COO ), 154.5 (COO). IR (neat,
m
mol, 95%) as a colorless oil. Rf¼0.40
1.71 (ddd,
-7),
m
mol) in CH2Cl2 (2 mL) was
d
m
*
*
*
*
*
-
hexane 1:1) to give 21a (43 mg, 220
m
mol, 77%) as a colorless oil.
*
*
Rf¼0.21 (EtOAc/hexane 1:1). 1H NMR (500 MHz, CDCl3):
d
2.36–
*
2.38 (m, 1H), 2.38–2.41 (m, 2H), 2.42–2.44 (m, 1H) (Ha-2, Ha-4,
*
*
Ha
J¼5.1 Hz, 1H), 2.72 (d, J¼5.1 Hz, 1H) (Hb-2, Hb-4, Hb
(d, J¼3.0 Hz, 2H), 3.51 (d, J¼3.0 Hz, 2H) (H-6, H-7, H
3.75 (s, 6H, CH3, CH3
), 4.60 (d, J¼4.4 Hz, 2H), 4.73 (d, J¼4.4 Hz,
2H) (H-1, H-5, H -1, H 42.4, 42.5
-5). 13C NMR (125 MHz, CDCl3):
(C-2, C-4, C-2 , C-4 ), 52.1, 52.4 (C-1, C-5, C-1 , C-5 ), 52.7, 53.1 (C-
6, C-7, C-6 , C-7 ), 53.0 (CH3, CH3), 156.9 (COO, COO ), 205.0 (C-3,
C-3
*
-2, Ha
*
-4), 2.65 (d, J¼5.1 Hz, 1H), 2.67 (d, J¼5.1 Hz, 1H), 2.69 (d,
-2, Hb-4), 3.49
-6, H -7),
*
*
*
*
*
*
*
*
*
*
*
*
d
d
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
). IR (neat, cmꢂ1): nmax 2959, 2916, 1695, 1447, 1384, 1330,
*
*
1294, 1192, 1103, 1036, 922, 867, 704. MS (ESI): m/z 220 [MNa]þ,
182, 164. HRMS (ESI, [MNa]þ): calcd for C9H11NO4þNa 220.0586,
found 220.0582.
*
*
*
cmꢂ1): nmax 2995, 2978, 2890, 1681, 1455, 1406, 1323, 1217, 1098,
1029, 982, 912, 868, 818, 760, 685, 641. MS (APCI): m/z 288 [MH]þ,
256, 226, 212, 194, 182, 151, 140. HRMS (APCI): calcd for
C13H21NO6þH 288.1447, found 288.1445.
4.2.2. Benzyl 7-oxo-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-
carboxylate (21b)
Following the procedure described for 21a, epoxide 21b (19 mg,
4.2.5. Methyl 2,2-dimethyl-6-oxohexahydro-3aH-4,8-
epiminocyclohepta[d][1,3]dioxole-9-carboxylate (32a)
Following the procedure described for 32b, compound 32a
70.0
hexane 1:1). 1H NMR (500 MHz, CDCl3):
2.40 (m, 2H), 2.42–2.44 (m, 1H) (Ha-2, Ha-4, Ha
J¼5.1 Hz, 1H), 2.67 (d, J¼5.1 Hz, 1H), 2.69 (d, J¼5.1 Hz, 1H), 2.73 (d,
J¼5.1 Hz, 1H) (Hb-2, Hb-4, Hb-2, Hb-4), 3.48 (d, J¼3.0 Hz, 2H), 3.51
(d, J¼3.0 Hz, 2H) (H-6, H-7, H -6, H -7), 4.63–4.66 (m, 2H), 4.73–
4.76 (m, 2H) (H-1, H-5, H -1, H -5), 5.17 (s, 4H, CH2Ph, CH2Ph ),
7.29–7.38 (m, 10H, Ph, Ph 42.4, 42.5
). 13C NMR (125 MHz, CDCl3):
(C-2, C-4, C-2 , C-4 ), 52.2, 52.5 (C-1, C-5, C-1 , C-5 ), 52.7, 53.1 (C-6,
C-7, C-6 , C-7 ), 67.7 (CH2Ph, CH2Ph ), 128.1, 128.3, 128.4 (Ph, Ph ),
136.1 (C-10, C-10
), 156.4 (COO, COO ), 204.9 (C-3, C-3 ). IR (neat,
m
mol, 82%) was obtained as a colorless oil. Rf¼0.34 (EtOAc/
2.34–2.35 (m, 1H), 2.37–
-2, Ha-4), 2.63 (d,
d
*
*
(34 mg, 133 m
mol, 93%) was obtained as a colorless solid. Mp 121 ꢁC.
Rf¼0.6 (EtOAc). 1H NMR (500 MHz, CDCl3):
d 1.25 (s, 3H, CH3), 1.41
*
*
(s, 3H, CH3), 2.43 (dd, J¼16.4, 9.4 Hz, 2H, Ha-2, Ha-4), 2.64 (dd,
J¼16.4, 5.3 Hz, 1H, Hb-4), 2.69 (dd, J¼16.4, 5.3 Hz, 1H, Hb-2), 3.77 (s,
3H, CH3), 4.43 (s, 2H, H-6, H-7), 4.48 (d, J¼5.0 Hz, 1H, H-1), 4.59 (d,
*
*
*
*
*
*
d
J¼5.0 Hz, 1H, H-5). 13C NMR (125 MHz, CDCl3):
d 24.2, 25.9
*
*
*
*
[C(CH3)2], 44.9, 45.1 (C-2, C-4), 52.9 (CH3), 58.8 (C-1, C-5), 82.5, 83.0
(C-6, C-7), 111.6 [C(CH3)2], 155.4 (COO), 205.3 (C-3). IR (neat, cmꢂ1):
nmax 2991, 1697, 1451, 1402, 1204, 1113, 1047, 989, 869, 761, 693. MS
(EI): m/z (%) 225 ([Mþ]), 240 (100), 196 (15), 155 (65), 101 (20), 43
(25). C12H17NO5 (255): calcd C, 56.46%; H, 6.71%; N, 5.49%. Found: C,
56.34%; H, 6.64%; N, 5.35%.
*
*
*
*
*
*
*
cmꢂ1): nmax 2941, 2906, 1698, 1465, 1420, 1365, 1330, 1296, 1220,
1198,1105,1032, 992, 929, 857, 765, 739. MS (EI): m/z 273 [Mþ], 228,
186, 166, 139, 107, 91 ([C7H7þ]), 65. HRMS (APCI, [MH]þ): calcd for
C15H15NO4þH 274.1079, found 274.1078.
4.2.6. Benzyl 2,2-dimethyl-6-oxohexahydro-3aH-4,8-
epiminocyclohepta[d][1,3]dioxole-9-carboxylate (32b)
4.2.3. tert-Butyl 7-oxo-3-oxa-9-azatricyclo[3.3.1.02,4]nonane-9-
carboxylate (21c)
To a stirred solution of 31b (150 mg, 583
was added dimethoxypropane (340 L, 3.26 mmol) and p-
TsOH$H2O (20 mg, 113 mol) and the reaction mixture was kept at
mmol) in acetone (5 mL)
Following the procedure described for 21a, epoxide 21c (13 mg,
m
54.3
hexane 1:2). 1H NMR (500 MHz, CDCl3):
C(CH3)3], 2.33–2.34 (m, 1H), 2.35–2.38 (m, 2H), 2.39–2.41 (m, 1H)
(Ha-2, Ha-4, Ha-2, Ha
-4), 2.64 (d, J¼5.1 Hz, 1H), 2.68 (d, J¼5.1 Hz,
2H), 2.71 (d, J¼5.1 Hz, 1H) (Hb-2, Hb-4, Hb-2, Hb-4), 3.46 (d,
J¼3.0 Hz, 2H), 3.48 (d, J¼3.0 Hz, 2H) (H-6, H-7, H -6, H -7), 4.54 (d,
J¼4.8 Hz, 2H), 4.68 (d, J¼4.8 Hz, 2H) (H-1, H-5, H -1, H
-5). 13C NMR
(125 MHz, CDCl3): 28.3 [C(CH3)3, C(CH3)3], 42.4, 42.5 (C-2, C-4, C-
, C-4), 51.6, 52.7 (C-1, C-5, C-1 , C-5 ), 52.8, 53.2 (C-6, C-7, C-6 , C-
), 81.0 [C(CH3)3, C(CH3)3], 155.9 (COO, COO ), 205.6 (C-3, C-3 ). IR
m
mol, 55%) was obtained as a colorless oil. Rf¼0.17 (EtOAc/
m
d
1.47 [s, 18H, C(CH3)3,
rt for 2 h. The reaction mixture was diluted with NaHCO3 solution
(5 mL) and extracted with EtOAc (10 mL). The extract was dried
(MgSO4) and EtOAc removed in vacuo. The residue was purified by
flash chromatography (silica gel, EtOAc/hexane 1:2) to give 32b as
*
*
*
*
*
*
*
a colorless solid (173 mg, 582
m
mol, quant.). Mp 92 ꢁC. Rf¼0.22
*
*
(EtOAc/hexane 1:2). 1H NMR (500 MHz, CDCl3):
d
1.24 (CH3, CH3),
*
d
*
1.35 (CH3, CH3
Ha-4, Ha-2, Ha
5.3 Hz, 2H) (Hb-2, Hb-4, Hb
7), 4.54–4.58 (m, 2H), 4.61–4.65 (m, 2H) (H-1, H-5, H
5.16–5.25 (m, 4H, CH2Ph, CH2Ph ), 7.29–7.40 (m, 10H, Ph, Ph
NMR (125 MHz, CDCl3): 24.2, 25.9 (CH3, CH3), 45.0, 45.2 (C-2, C-4,
C-2 , C-4 ), 58.8, 58.9 (C-1, C-5, C-1 , C-5 ), 67.4 (CH2Ph, CH2Ph ),
*
), 2.39 (br s, 1H), 2.43 (br s, 2H), 2.46 (br s, 1H) (Ha-2,
-4), 2.60 (dd, J¼16.4, 5.3 Hz, 2H), 2.71 (dd, J¼16.4,
-2, Hb-4), 4.44 (s, 4H, H-6, H-7, H -6, H
-1, H -5),
). 13
2
7
*
*
*
*
*
*
*
*
*
*
*
*
*
*
-
(neat, cmꢂ1): nmax 2970, 2930, 1691, 1480, 1393, 1333, 1297, 1160,
1099, 1033, 963, 862, 705. MS (ESI): m/z 262 [MNa]þ, 224, 206, 184,
162, 145, 140, 122, 94, 84. HRMS (ESI, [MNa]þ): calcd for
C12H17NO4þNa 262.1056, found 262.1045.
*
*
*
*
C
d
*
*
*
*
*
*

O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
6631
82.5, 83.0 (C-6, C-7, C-6
*
, C-7
*
),111.6 [C(CH3)2, C(CH3)2
*
],128.0,128.2,
(35 mg, 110
1:1). 1H NMR (500 MHz, CDCl3):
Ha-2), 1.93–2.14 (br m, 4H, Ha-4, Ha
2H, Hb-2, Hb
-2), 2.54 (dd, J¼17.6, 7.6 Hz, 2H, Ha-7, Ha
J¼17.6 Hz, 2H, Hb-7, Hb-7), 3.83–3.88 (m, 4H, OCH2, OCH2
3.97 (m, 4H, OCH2, OCH2), 4.16–4.29 (br m, 2H, H-5, H -5), 4.68–
4.81 (br m, 2H, H-1, H -1), 5.10–5.22 (br m, 4H, CH2Ph, CH2Ph ),
7.29–7.41 (m, 10H, Ph, Ph 38.8 (br,
). 13C NMR (125 MHz, CDCl3):
C-2), 39.2 (br, C-2 ), 39.6 (br, C-4 ), 40.1 (br, C-4), 42.5 (br, C-7),
42.9 (br, C-7 ), 51.2 (br, C-1), 51.4 (br, C-1
64.1, 64.8 (OCH2, OCH2), 67.4 (CH2Ph, CH2Ph
128.1, 128.3, 128.6 (Ph, Ph ), 153.5 (COO, COO
), 136.1 (C-10, C-10
210.9 (br, C-6, C-6
m
mol, 70%) as a colorless oil. Rf¼0.38 (EtOAc/hexane
1.85 (br d, J¼13.8 Hz, 2H, Ha-2,
-4, Hb-4, Hb-4), 2.16–2.33 (m,
-7), 2.69 (d,
), 3.89–
128.6 (Ph, Ph ), 136.3 (C-10, C-10
*
), 154.8 (CO, CO
*
), 205.3 (C-3, C-3 ).
*
d
IR (neat, cmꢂ*1): nmax 2985, 2934, 1716, 1700, 1418, 1367, 1232, 1205,
1123, 1053, 987, 870, 734, 695. MS (APCI): m/z 332 [MHþ], 302, 288,
244, 198, 182, 142, 91 [C7H7]þ. HRMS (ESI, [MNa]þ): calcd for
C18H21NO5þNa 354.1314, found 354.1318.
*
*
*
*
*
*
*
*
*
*
*
4.2.7. Methyl 2,2-dimethyl-7-oxohexahydro-3aH-4,9-
epimino[1,3]dioxolo[4,5-d]oxocine-10-carboxylate (33a)
Following the procedure described for 33b, compound 33a
*
d
*
*
*
*
), 59.8 (br, C-5, C-5
), 106.3 (C-3, C-3
*
*
*
),
),
),
(18 mg, 66.4
(EtOAc/hexane 1:1). 1H NMR (500 MHz, CDCl3):
CH3), 1.49 (s, 6H, CH3, CH3), 2.67–2.92 (br m, 4H, Ha-5, Ha
Hb
3.96 (m, 2H, Hb-2, Hb
m
mol, 50%) was obtained as a colorless oil. Rf¼0.26
1.33 (s, 6H, CH3,
-5, Hb-5,
-2), 3.73 (s, 6H, OCH3, OCH3), 3.79–
-1), 4.14 (br, 1H, H-1), 4.28–
-7), 4.58 (d,
-8). 13C NMR
), 37.4 (br, C-
), 62.4, 63.0 (br, C-2, C-
), 67.1 (br, C-1), 81.2 (br, C-8), 82.0 (br, C-8 ), 83.6
), 84.0 (br, C-7), 112.2 [C(CH3)2, C(CH3)2], 155.8, 156.1 (CO,
), 174.7 (C-4, C-4 ).
*
*
d
*
*
*
*
*
*
). IR (neat, cmꢂ1): nmax 3034, 2958, 2916, 2849,
*
-5), 3.69–3.75 (m, 2H, Ha-2, Ha
*
*
1765, 1701, 1603, 1563, 1406, 1357, 1304, 1200, 1116, 1097, 1046,
948, 823, 698, 641. MS (ESI): m/z 340 [MNaþ], 318.1 [MHþ], 274,
212, 91 [C7H7]þ. HRMS (ESI, [MH]þ): calcd for C17H19NO5þH
318.1341, found 318.1336.
*
-2), 4.06 (br, 1H, H
*
4.42 (br m, 2H, H-6, H
J¼5.8 Hz, 1H, H-7), 4.74 (br, 1H, H-8), 4.76 (br, 1H, H
(125 MHz, CDCl3): 25.2, 27.3 (CH3, CH3), 36.8 (br, C-5
5), 53.0 (OCH3, OCH3), 61.0, 61.9 (br, C-6, C-6
), 66.2 (br, C-1
(br, C-7
CO
*
-6), 4.57 (d, J¼5.8 Hz, 1H, H
*
*
d
*
*
*
*
4.2.10. Benzyl 70-oxo-90H-spiro[1,3-dioxolane-2,30-
[6]oxa[9]azabicyclo[3.3.1]nonane]-90-carboxylate (29)
2
*
*
*
*
*
MCPBA (111 mg, 495
mmol, 77%) and NaHCO3 (17 mg) were
*
*
added to a stirred solution of 28 (30 mg, 94.6 mmol) in CH2Cl2
(2 mL) at rt. After stirring overnight, CH2Cl2 (10 mL) was added and
the mixture washed successively with aqueous solutions of Na2SO3
(5 mL) and NaHCO3 (3 mL). The organic layer was dried (Na2SO4),
concentrated in vacuo, and purified by column chromatography
4.2.8. Benzyl 2,2-dimethyl-7-oxohexahydro-3aH-4,9-
epimino[1,3]dioxolo[4,5-d]oxocine-10-carboxylate (33b)
To
a stirred solution of 32b (124 mg, 375 mmol) in di-
chloroethane (6 mL) was added MCPBA (252 mg, 1.46 mmol, 77%)
and 2,4,6-tri(tert-butyl)phenol (2 mg). After stirring at 55 ꢁC for 3
days, the reaction mixture was cooled, the solid filtered off and the
filtrate diluted with CH2Cl2 (6 mL). The filtrate was washed suc-
cessively with aqueous solutions of Na2SO3 and NaHCO3 (3 mL
each) and brine (3 mL). The organic layer was dried (Na2SO4),
concentrated in vacuo, and purified by column chromatography
(silica gel, EtOAc/hexane 1:1) to give the 29 (18 mg, 54.0 mmol, 57%)
as a colorless oil. Rf¼0.29 (EtOAc/hexane 1:1). 1H NMR (500 MHz,
CDCl3):
d
1.89 (br d, J¼14.1 Hz, 1H, Ha-6), 1.98 (dd, J¼14.1, 3.3 Hz, 1H,
Ha-8), 2.12 (ddd, J¼14.0, 4.8, 1.0 Hz, 1H, Hb-6), 2.36 (br d, J¼14.1 Hz,
1H, Hb-8), 2.66 (d, J¼18.0 Hz, 1H, Ha-4), 2.76–2.96 (br m, 1H, Hb-4),
3.87–3.96 (m, 2H, OCH2), 3.99–4.07 (m, 2H, OCH2), 4.78 (br s, 1H, H-
5), 5.18 (d, J¼12.1 Hz, 1H, CHaPh), 5.23 (d, J¼12.1 Hz, 1H, CHbPh),
6.39 (br s, 1H, H-1), 7.33–7.41 (m, 5H, Ph). 13C NMR (125 MHz,
(silica gel, EtOAc/hexane¼1:2) to give 33b (72 mg, 207
mmol, 55%)
as a colorless oil. Rf¼0.21 (EtOAc/hexane 1:2). 1H NMR (500 MHz,
CDCl3): d 34.9 (br, C-4), 38.7 (br, C-8), 38.9 (br, C-6), 45.3 (br, C-5),
CDCl3):
3H, CH3
1H, Ha
-5), 3.06 (dt, J¼16.5, 5.8 Hz, 2H, Hb-5, Hb
J¼13.3 Hz, 1H, Ha-2 or Ha-2), 4.31 (d, J¼13.3 Hz, 1H, Ha-2 or Ha
4.36 (dd, J¼13.3, 4.5 Hz, 1H, Hb-2 or Hb-2), 4.35–4.38 (m, 1H, H-6 or
-6), 4.41 (dd, J¼13.3, 4.5 Hz, 1H, Hb-2 or Hb-2), 4.44 (dt, J¼5.8,
1.4 Hz, 1H, H-6 or H -1), 4.57 (d,
-6), 4.52 (d, J¼4.6 Hz, 1H, H-1 or H
J¼5.6 Hz, 2H, H-7, H -7), 4.62 (d, J¼4.6 Hz, 1H, H-1 or H-1 ), 4.88 (d,
J¼5.6 Hz, 2H, H-8, H -8), 5.15 (d, J¼12.3 Hz, 1H), 5.16 (d, J¼12.3 Hz,
1H), 5.21 (d, J¼12.3 Hz,1H), 5.22 (d, J¼12.3 Hz,1H) (CH2Ph, CH2Ph ),
7.31–7.39 (m, 10H, Ph, Ph 24.0, 25.9
). 13C NMR (125 MHz, CDCl3):
(CH3, CH3), 41.1 (C-5), 41.6 (C-5 ), 57.8, 57.9 (C-6, C-6 ), 62.4, 62.6 (C-
1, C-1 ), 67.6 (CH2Ph, CH2Ph ), 71.3, 71.4 (C-2, C-2 ), 80.4, 81.0 (C-8,
C-8 ), 82.6, 83.1 (C-7, C-7 ), 111.9 [C(CH3)2, C(CH3)2], 128.0, 128.4,
128.6 (Ph, Ph ), 154.2, 154.3 (CO, CO ), 171.9, 172.0
), 136.1 (C-10, C-10
(C-4, C-4
d
1.27 (s 3H), 1.28 (s, 3H) (CH3, CH3
*
), 1.34 (s, 3H, CH3), 1.35 (s,
63.8 (OCH2), 65.1 (OCH2), 68.5 (CH2Ph), 81.6 (C-1), 105.0 (C-7),
128.3, 128.6, 128.7 (C-20, C-30, C-40), 135.3 (C-10), 153.3 (NCOO), 167.3
(C-3). IR (neat, cmꢂ1): nmax 2925, 2854, 1747, 1708, 1422, 1388, 1343,
1262, 1213, 1116, 1054, 960, 912, 887, 754, 695, 671. MS (APCI): m/z
334 [MHþ], 290, 246, 230, 204,186, 149,117, 91 [C7Hþ7 ]. HRMS (APCI,
[MH]þ): calcd for C17H19NO6þH 334.1290, found 333.1286.
*
), 2.79 (dd, J¼16.5, 1.8 Hz, 1H, Ha-5), 2.89 (dd, J¼16.5, 1.8 Hz,
-5), 4.23 (d,
-2),
*
*
*
*
*
H
*
*
*
*
*
*
4.2.11. Benzyl 4-(hydroxymethyl)-6-(2-methoxy-2-oxoethyl)-
2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-
carboxylate (36)
To a solution of 33b (482 mg, 1.39 mmol) in MeOH (15 mL) was
added K2CO3 (20 mg, 147 mmol) and the reaction mixture stirred at
rt overnight. The reaction mixture was diluted with water (5 mL)
and extracted with CH2Cl2 (3ꢃ10 mL). The combined organic layers
were dried (Na2SO4) and concentrated. The residue was purified by
column chromatography (silica gel, EtOAc/hexane 1:1) to give 36
(496 mg, 1.31 mmol, 94%) as a colorless oil. Rf¼0.24 (EtOAc/hexane
*
*
*
d
*
*
*
*
*
*
*
*
*
*
*
*
*
). IR (neat, cmꢂ1): nmax 2987, 2939, 1697, 1411, 1323, 1208,
1118, 1050, 869, 813, 697. MS (APCI): m/z 348 [MHþ], 304, 256, 240,
138, 91 [C7H7]þ. HRMS (ESI, [MNa]þ): calcd for C18H21NO6þNa
370.1264, found 370.1267.
1:1). 1H NMR (500 MHz, CDCl3):
d
1.32 (s, 6H, CH3, CH3
), 1.63–1.84 (m, 6H, CH2COOMe, CH2COOMe
3.57 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.62–3.74 (m, 2H, CH2OH,
CH2OH ), 3.93 (d, J¼10.6 Hz, 1H,
), 3.85 (d, J¼10.6 Hz, 1H, CHaOH
CHbOH), 4.04–4.12 (br m, 1H, H -2), 4.12–4.20 (br m, 1H, H-2), 4.41
(br t, J¼7.1 Hz, 2H, H-5, H -5), 4.52 (2d, J¼5.7 Hz, 2H, H-4, H -4),
4.69–4.74 (br m, 1H, H-3), 4.74–7.80 (br m, 1H, H -3), 5.07–5.18 (m,
4H, CH2Ph, CH2Ph ), 7.29–7.38 (m, 10H, Ph, Ph
). 13C NMR (125 MHz,
CDCl3): 25.3, 27.3 (CH3, CH3), 36.8 (CH2COOMe ), 37.6
(CH2COOMe), 51.9 (OMe), 52.1 (OMe ), 61.1 (C-5), 61.7 (C-5 ), 62.7
(CH2OH ), 63.1 (CH2OH), 66.5 (C-2 ), 67.3 (C-2), 67.4 (CH2Ph
(CH2Ph), 81.2 (C-3), 82.0 (C-3 ), 83.5 (C-4
[C(CH3)2, C(CH3)2], 127.7, 128.1, 128.6 (Ph, Ph
10
), 154.8 (CO ), 155.4 (CO), 171.5 (COOMe), 172.2 (COOMe
*
), 1.47 (s, 6H,
CH3, CH3
*
*
, OH, OH ),
*
*
4.2.9. Benzyl 6-oxo-8H-spiro[8-azabicyclo[3.2.1]octane-3,20-
[1,3]dioxolane]-8-carboxylate (28)
*
*
*
Trifluoroacetic anhydride (36
m
m
L, 0.256 mmol) was added
L, 513 mol) in CH2Cl2 (1 mL)
*
*
dropwise to a solution of DMSO (36
m
*
at ꢂ78 ꢁC. Then a solution of 24b (50 mg, 157
mmol) in CH2Cl2
*
*
(100
mL) and DMSO (10
mL) was added dropwise. After stirring for
d
*
*
30 min, NEt3 (70
mL) was added and the mixture warmed to rt and
*
*
stirred for 3 h. EtOAc (20 mL) was added and the mixture washed
with water (3ꢃ10 mL) and aqueous NaCl solution (3ꢃ10 mL). The
organic layer was dried (Na2SO4) and evaporated. Purification by
column chromatography (silica gel, EtOAc/hexane 1:1) gave 28
*
*
*
), 67.5
*
*
), 84.1 (C-4), 112.2
), 136.1, 136.3 (C-10, C-
*
*
*
*
*
). IR

6632
O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
(neat, cmꢂ1): nmax 3462, 2987, 2950, 1735, 1698, 1409, 1325, 1209,
1120, 1053, 869, 698. MS (EI): m/z (%) 379 ([Mþ], 5), 348 (15), 304
(30), 214 (5), 186 (5), 156 (5), 91 ([C7Hþ7 ], 100), 65 (5), 43 (5). HRMS
(ESI, [MNa]þ): calcd for C19H25NO7þNa 402.1529, found 402.1528.
HPLC: Chromasil ODH, hexane/isopropanol (70:30), flow rate
0.5 mL minꢂ1, tR¼10.84 min and tR¼12.65 min.
[CH2CH2OH], 58.5 [CH2CH2OH], 61.2 (C-5), 63.2 (CH2OSi), 66.8 (C-
2), 67.6 (CH2Ph), 81.6 (C-3), 84.7 (C-4), 111.8 [C(CH3)2], 127.8, 128.2,
128.6 (Ph), 136.3 (C-10), 156.4 (CO). IR (neat, cmꢂ1): nmax 3460, 2952,
2930, 2857, 1680, 1410, 1360, 1328, 1252, 1212, 1159, 1119, 1065, 966,
939, 835, 777, 734, 697. MS (ESI): m/z 466 [MHþ], 422, 408, 364,
334, 290, 272, 226, 204, 91 [C7Hþ7 ]. HRMS (ESI, [MH]þ): calcd for
C24H39NO6SiþH 466.2626, found 466.2611.
4.2.12. Benzyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-
6-(2-methoxy-2-oxoethyl)-2,2-dimethyltetrahydro-5H-[1,3]-
dioxolo[4,5-c]pyrrole-5-carboxylate (37)
4.2.14. 4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-
hexahydro[1,3]dioxolo[3,4]pyrrolo[1,2-c][1,3]oxazine (39)
A solution of 36 (254 mg, 0.67 mmol) in DMF (1.5 mL) was added
to a solution of tert-butyldimethylsilylchloride (136 mg, 0.89 mmol)
and imidazole (61 mg, 0.89 mmol) in DMF (1.5 mL). After stirring
overnight, the reaction mixture was diluted in CH2Cl2 (15 mL) and
washed with brine (10 mL) and water (10 mL). The combined or-
ganic layers were dried (Na2SO4), concentrated, and purified by
flash chromatography (silica gel, EtOAc/hexane 1:4) to give 37
Rf¼0.44 (EtOAc/hexane 1:2). 1H NMR (500 MHz, CDCl3):
d 0.53
[s, 3H, Si(CH3)2], 0.55 [s, 3H, Si(CH3)2], 0.88 [s, 9H, C(CH3)3], 1.32 (s,
3H, CH3), 1.52 (s, 3H, CH3), 1.58–1.75 (br m, 1H, Ha-4), 1.89 (d,
J¼12.5 Hz, 1H, Hb-4), 2.53–2.63 (br m, 1H, H-4a), 2.78–2.86 (m, 1H,
H-7), 3.45 (td, J¼11.8, 2.7 Hz, 1H, Ha-3), 3.76–3.82 (m, 2H, CH2OSi),
3.97 (d, J¼8.4 Hz, 1H, Ha-1), 4.06 (dd, J¼11.8, 4.8 Hz, 1H, Hb-3), 4.21–
4.29 (br m, 1H, H-5), 4.33 (dd, J¼7.0, 3.8 Hz, 1H, H-6), 4.86 (d,
(321 mg, 651
1:4). 1H NMR (500 MHz, CDCl3):
Si(CH3)2], 0.06 [s, 3H, Si(CH3)2], 0.87 [s, 9H, C(CH3)3
C(CH3)3], 1.32 (s, 6H, CH3, CH3), 1.45 (s, 3H, CH3), 1.47 (s, 3H, CH3
2.59 (dd, J¼15.9, 10.5 Hz, 1H, CHaCOOCH3), 2.67 (dd, J¼15.9, 10.5 Hz,
1H, CHaCOOCH3), 2.76 (dd, J¼15.9, 4.5 Hz, 1H, CHbCOOCH3), 2.93
(dd, J¼15.9, 4.5 Hz, 1H, CHbCOOCH3), 3.63–3.70 (m, 2H, CH2OSi ),
3.65 (s, 3H, OCH3), 3.69 (s, 3H, OCH3
), 3.73 (dd, J¼10.5, 2.7 Hz, 1H,
CHaOSi), 3.85 (dd, J¼10.5, 2.7 Hz, 1H, CHbOSi), 4.07–4.10 (br m, 1H,
-2), 4.15–4.18 (br m,1H, H-2), 4.35 (dd, J¼4.5,1.7 Hz,1H, H-5), 4.37
(dd, J¼4.5, 1.7 Hz, 1H, H -5), 4.50 (dd, J¼5.9, 1.7 Hz, 1H, H-4), 4.53
(dd, J¼5.9, 1.7 Hz, 1H, H -4), 4.67 (d, J¼5.9 Hz, 1H, H-3), 4.70 (d,
J¼5.9 Hz,1H, H -3), 5.08 (d, J¼12.3 Hz,1H, CHaPh or CHaPh ), 5.18 (s,
2H, CH2Ph or CH2Ph ),
), 5.18 (d, J¼12.3 Hz, 1H, CHbPh or CHbPh
7.28–7.37 (m, 10H, Ph, Ph
). 13C NMR (125 MHz, CDCl3):
ꢂ5.6
[Si(CH3)2], ꢂ5.4 [Si(CH3)2], 18.4 [C(CH3)3, C(CH3)3], 25.2 [C(CH3)2,
C(CH3)2], 26.0 [C(CH3)3, C(CH3)3], 27.3 [C(CH3)2, C(CH3)2], 36.9
(CH2COOCH3), 37.8 (CH2COOCH3), 51.7 (OCH3, OCH3), 61.7, 62.4 (C-5,
C-5 ), 62.8 (CH2OSi), 63.5 (CH2OSi ), 65.8 (C-2 ), 66.6 (C-2), 67.0, 67.1
(CH2Ph, CH2Ph ), 81.1 (C-3), 82.1 (C-3 ), 84.0 (C-4 ), 84.8 (C-4), 111.8
[C(CH3)2, C(CH3)2],127.6,127.9,128.0,128.1,128.5 (Ph, Ph ),136.5 (C-
10, C-10
), 154.2, 154.3 (CO, CO ), 171.4, 171.5 (COOCH3, COOCH3). IR
m
mol, 97%) as a colorless oil. Rf¼0.59 (EtOAc/hexane
0.02 [s, 6H, Si(CH3)2], 0.05 [s, 3H,
], 0.89 [s, 9H,
),
J¼8.4 Hz, 1H, Hb-1). 13C NMR (125 MHz, CDCl3):
d
ꢂ5.5, ꢂ5.4
d
[Si(CH3)2], 18.2 [C(CH3)3], 25.1 [C(CH3)2], 25.9 [C(CH3)3], 27.1
[C(CH3)2], 29.7 (C-4), 64.9 (CH2OSi), 66.6 (C-3), 67.2 (C-4a), 68.2 (C-
7), 81.1 (C-6), 83.0 (C-5), 83.9 (C-1), 113.8 [C(CH3)2]. IR (neat, cmꢂ1):
nmax 2930, 2856, 1471, 1380, 1253, 1209, 1189, 1168, 1109, 1068, 976,
872, 837, 777, 632. GC–MS (EI): m/z (%) 343 ([Mþ], 5), 328 (5), 286
(10), 270 (5), 228 (5), 198 (100), 156 (5), 140 (5), 124 (5), 101 (5), 73
(5), 59 ([COOCHþ3 ], 5), 41 (5). C17H33NO4Si (343.54): calcd C, 59.44;
H, 9.68; N, 4.08. Found: C, 59.60; H, 9.62; N, 3.92.
*
*
*
*
*
*
*
*
*
H
*
*
4.2.15. Benzyl 4-(2-bromoethyl)-6-({[tert-butyl(dimethyl)-
silyl]oxy}methyl)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]-
pyrrole-5-carboxylate (40)
*
*
*
*
*
To a solution of 38 (35 mg, 75.3
mmol) in CH2Cl2 (1 mL) was added
*
d
tetrabromoethane (35 mg, 105 mmol) and triphenylphosphine
(24 mg, 90.3 mmol) and the mixture was stirred at rt for 2 h and then
diluted with water (2 mL). The layers were separated and the
aqueous layer was extracted with CH2Cl2 (4ꢃ2 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue
purified by flash chromatography (silica gel, EtOAc/hexane 1:5) to
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
give 40 (38 mg, 72
1:4). 1H NMR (500 MHz, CDCl3):
Si(CH3)2], 0.88 [s, 9H, C(CH3)3], 0.89 [s, 9H, C(CH3)3
CH3),1.43 (s, 6H, CH3, CH3), 2.03–2.11 (m, 2H, CHaCH2Br, CHaCH2Br
2.22–2.32 (m, 1H, CHbCH2Br), 2.33–2.42 (m, 1H, CHbCH2Br ), 3.28–
3.51 (m, 4H, CH2Br, CH2Br
), 3.64 (dd, J¼10.5, 3.5 Hz, 1H, CHaOSi),
3.70 (dd, J¼10.5, 2.3 Hz, 1H, CHbOSi), 3.75 (dd, J¼10.5, 2.3 Hz, 1H,
CHaOSi ), 4.06–4.11 (br m, 3H,
), 3.82 (dd, J¼10.5, 3.5 Hz,1H, CHbOSi
2-H , H-5, H
-5), 4.16 (br s, 1H, H-2), 4.38 (d, J¼5.7 Hz, 1H, H-4), 4.41
(d, J¼5.7 Hz, 1H, H -4), 4.68 (d, J¼5.7 Hz, 1H, H-3), 4.71 (d, J¼5.7 Hz,
1H, H
-3), 5.11 (d, J¼12.4 Hz, 1H, CHaPh), 5.18 (d, J¼12.4 Hz, 3H,
CHbPh, CH2Ph ), 7.29–7.39 (m, 10H, Ph, Ph
). 13C NMR (125 MHz,
CDCl3): ], 18.4 [C(CH3)3, C(CH3)3
ꢂ5.5 [Si(CH3)2), ꢂ5.4 (Si(CH3)2
25.4 [C(CH3)2, C(CH3)2], 26.0 [C(CH3)3, C(CH3)3
C(CH3)2], 29.1 (CH2Br, CH2Br ), 37.1 (CH2CH2Br), 37.3 (CH2CH2Br
62.9 (CH2OSi ), 63.5 (CH2OSi), 63.6 (C-5), 64.6 (C-5 ), 66.0 (C-2
66.7 (C-2), 67.1 (CH2Ph), 67.2 (CH2Ph ), 81.1 (C-3
(C-4 ), 84.6 (C-4), 111.9 [C(CH3)2, C(CH3)2], 127.8, 128.0, 128.1, 128.5
(Ph, Ph
), 136.4 (C-10 ), 136.5 (C-10), 155.0 (CO, CO ). IR (neat, cmꢂ1):
m
mol, 96%) as a yellow oil. Rf¼0.58 (EtOAc/hexane
0.02–0.06 [m, 12H, Si(CH3)2,
],1.32 (s, 6H, CH3,
),
*
*
*
d
(neat, cmꢂ1): nmax 2952, 2857, 1741, 1704, 1409, 1383, 1327, 1255,
1160,1118,1065, 836, 632. MS (ESI): m/z 494 ([MHþ]), 462, 450, 404,
392, 358, 318, 286, 260, 232, 210, 168, 152, 91 ([C7Hþ7 ]). HRMS (ESI,
[MNa]þ): calcd for C25H39NO7SiþNa 516.2394, found 516.2381.
*
*
*
*
*
*
*
4.2.13. Benzyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-
6-(2-hydroxyethyl)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo-
[4,5-c]pyrrole-5-carboxylate (38)
*
*
*
*
*
A solution of 37 (617 mg, 1.25 mmol) in Et2O (15 mL) was added
*
dropwise to
a
cooled (0 ꢁC) suspension of LiAlH4 (95 mg,
*
*
2.50 mmol) in Et2O (10 mL). After stirring at rt for 1 h, the reaction
mixture was diluted with Et2O (10 mL), hydrolyzed with a satd
Na2SO4 solution (2 mL) and filtered. The filtrate was evaporated and
purified by flash chromatography (silica gel, EtOAc/hexane 1:2) to
d
*
*
],
*
*
], 27.4 [C(CH3)2,
*
*
*
),
),
*
*
*
give in a first fraction 39 (12 mg, 35.0
m
mol, 3%) as a colorless oil
*
*
), 82.0 (C-3), 84.0
and in a second fraction 38 (548 mg, 1.18 mmol, 94%) as the major
*
*
product. Compound 38: Rf¼0.28 (EtOAc/hexane 1:2). 1H NMR
*
*
*
(500 MHz, CDCl3):
d
ꢂ0.02 [s, 3H, Si(CH3)2], 0.00 [s, 3H, Si(CH3)2],
nmax 2953, 2930, 2857,1703,1462,1409,1383,1326,1254,1212,1160,
1117, 1067, 1004, 836, 779, 632. MS (ESI): m/z 528 ([MHþ]), 484, 470,
426, 392, 358, 334, 314, 294, 226, 187, 168, 91 ([C7Hþ7 ]). HRMS (ESI,
[MH]þ): calcd for C24H38BrNO5SiþH 528.1782, found 528.1775.
0.86 [br s, 9H, C(CH3)3], 1.32 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.59 (dt,
J¼11.8, 2.6 Hz, 1H, CHaCH2OH), 1.82–1.90 (m, 1H, CHbCH2OH), 3.53
(td, J¼11.8, 2.6 Hz, 1H, CH2CHaOH), 3.58–3.64 (m, 1H, CH2CHbOH),
3.62 (dd, J¼10.5, 4.8 Hz, 1H, CHaOSi), 3.69 (dd, J¼10.5, 3.3 Hz, 1H,
CHbOSi), 4.05–4.08 (m, 1H, H-2), 4.38 (dd, J¼11.8, 4.1 Hz, 1H, H-5),
4.41 (d, J¼5.7 Hz, 1H, H-4), 4.73 (dd, J¼5.7, 2.1 Hz, 1H, H-3), 5.13 (d,
J¼12.4 Hz, 1H, CHaPh), 5.24 (d, J¼12.4 Hz, 1H, CHbPh), 7.29–7.38 (m,
4.2.16. 4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-
hexahydro-6H-[1,3]-dioxolo[4,5-a]pyrrolizin-6-one (41)
A solution of 40 (133 mg, 252 mmol) in THF (3.5 mL) was added
5H, Ph). 13C NMR (125 MHz, CDCl3):
[C(CH3)3], 25.4 [C(CH3)2], 25.9 [C(CH3)3], 27.4 [C(CH3)2], 36.3
d
ꢂ5.6, ꢂ5.5 [Si(CH3)2], 18.4
dropwise to a cooled solution of t-BuLi (478 mL, 758 mmol, 1.7 M in
pentane) in THF (1 mL) at ꢂ78 ꢁC. After stirring for 1 h at ꢂ78 ꢁC,

O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
6633
a satd NH4Cl solution (1 mL) was added and the solvent was re-
4.2.19. 7a-epi-Hyacinthacine A1 (7a-epi-7)
A solution of 42 (5.8 mg, 16.2 mol) in a (2:1) mixture of MeOH/
moved. The residue was extracted with CH2Cl2 (3ꢃ5 mL) and the
combined organic layers were dried (Na2SO4) and evaporated. The
residue was purified by column chromatography (silica gel, EtOAc/
m
H2O (450 mL) was refluxed for 1 h. The solvent was removed and the
residue diluted with water and purified on DOWEX 1ꢃ8 (OHꢂ) to
hexane 1:1) to give 41 (51 mg, 149
m
mol, 59%) as a yellow oil.
give 7a-epi-7 (2.8 mg, 16.2 m
mol, quant.) as a colorless oil. 1H NMR
Rf¼0.34 (EtOAc/hexane 1:1). 1H NMR (500 MHz, CDCl3):
d
0.49 [s,
(500 MHz, CD3OD):
d
1.49 (ddt, J¼12.6, 10.6, 7.7 Hz, 1H, Ha-7), 1.64–
3H, Si(CH3)2], 0.64 [s, 3H, Si(CH3)2], 0.88 [s, 9H, C(CH3)3], 1.34 [s, 3H,
C(CH3)2], 1.54 [s, 3H, C(CH3)2], 1.77 (ddt, J¼12.2, 10.0, 8.8 Hz, 1H, Ha-
7), 2.30–2.35 (m, 1H, Hb-7), 2.38 (dd, J¼16.5, 8.8 Hz, 1H, Ha-6), 2.58
(dddd, J¼16.5, 12.2, 7.9, 1.3 Hz, 1H, Hb-6), 3.71 (dd, J¼10.3, 2.0 Hz,
1H, CHaOSi), 3.84–3.86 (br m, 1H, H-4), 3.96 (dt, J¼10.0, 6.1 Hz, 1H,
H-7a), 4.23 (dd, J¼6.1, 5.7 Hz, 1H, H-7b), 4.59 (dd, J¼10.3, 2.8 Hz, 1H,
CHbOSi), 4.75 (dd, J¼5.7, 0.9 Hz, 1H, H-3a). 13C NMR (125 MHz,
1.74 (m, 1H, Ha-6), 1.83–1.89 (m, 1-H, Hb-6), 2.11–2.17 (m, 1H, Hb-7),
2.76 (ddd, J¼10.3, 9.5, 5.8 Hz, 1H, Ha-5), 2.88 (ddd, J¼9.5, 6.6, 2.7 Hz,
1H, Hb-5), 3.19 (ddd, J¼8.5, 8.2, 4.2 Hz, 1H, H-3), 3.36 (dt, J¼7.7,
2.7 Hz, 1H, H-7a), 3.75 (dd, J¼5.4, 2.7 Hz, 1H, H-1), 3.79–3.89 (m,
3H, CH2OH, H-2). 13C NMR (125 MHz, CD3OD):
d 27.3 (C-6), 31.0 (C-
7), 48.6 (C-5), 61.3 (CH2OH), 67.0 (C-3), 71.3 (C-7a), 72.7 (C-2), 77.4
(C-1). IR (neat, cmꢂ1): nmax 3367, 2923, 2360, 2341, 1622, 1572, 1418,
1338, 1302, 1103, 978, 823, 669, 592. MS (ESI): m/z 174 [MHþ], 156,
138, 125, 120, 110, 100, 96. HRMS (ESI, [MH]þ): calcd for
C8H15NO3þH 174.1130, found 174.1117.
CDCl3):
d
ꢂ5.7 [Si(CH3)2], ꢂ5.5 [Si(CH3)2], 18.2 [C(CH3)3], 25.7
[C(CH3)2], 25.8 [C(CH3)3], 26.9 (C-7), 28.0 [C(CH3)2], 36.2 (C-6), 58.6
(CH2OSi), 61.2 (C-4), 69.2 (C-7a), 81.7 (C-7b), 87.5 (C-3a), 112.5
[C(CH3)2], 173.3 (C-5). IR (neat, cmꢂ1): nmax 2929, 2857, 1698, 1605,
1471, 1382, 1329, 1257, 1214, 1157, 1116, 1074, 1008, 967, 838, 779.
GC–MS (CI): m/z (%) 342 ([MHþ], 50), 326 (20), 284 (100), 268 (5),
226 (10), 210 (10), 143 (5), 89 (5), 75 (5), 43 (5). HRMS (ESI, [MH]þ):
calcd for C17H31NO4SiþH 342.2100, found 342.2080.
4.2.20. Benzyl 4-[(acetyloxy)methyl]-6-(2-methoxy-2-oxoethyl)-
2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-c]pyrrole-5-
carboxylate (43)
Ac2O (8.4
mL, 84.4
mmol) was added to a solution of 36 (16 mg,
42.2 mol), DMAP (2 mg), and NEt3 (20
m
mL) in CH2Cl2 (1 mL) and the
4.2.17. 4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-
hexahydro-4H-[1,3]dioxolo[4,5-a]pyrrolizine (42)
mixture stirred at rt for 0.5 h. Then CH2Cl2 was added (2 mL) and the
mixture washed successively with 0.1 N NaOH and brine (2 mL
each). The organic layer was dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by flash chromatography
To a solution of 41 (10 mg, 29.3
mmol) in THF (0.5 mL) was added
dropwise BH3$SMe2 (31 L, 293
m
mmol) and the reaction mixture
stirred for 6 h. Then the mixture was diluted slowly with MeOH
(0.2 mL) and concentrated. The residue was dissolved in MeOH
(0.5 mL), refluxed for 5 h, concentrated, and purified by flash
chromatography (silica gel, EtOAc/MeOH 10:1) to give 42 (5.8 mg,
(silica gel, EtOAc/hexane 1:2) to give 43 (16 mg, 38.0 mmol, 90%) as
a colorless oil. Rf¼0.21 (EtOAc/hexane 1:2). 1H NMR (500 MHz,
CDCl3):
CH3, Ac-CH3
CHaCOOCH3
), 2.76 (dd, J¼15.6, 4.0 Hz, 1H, CHbCOOCH3
J¼15.6, 4.0 Hz, 1H, CHbCOOCH3), 3.66 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3), 4.09–4.22 (m, 4H, CH2OAc, CH2OAc ), 4.24 (br s, 1H, H-2),
4.32 (br s, 1H, H -2), 4.37–4.44 (m, 2H, H-5, H -5), 4.56–4.62 (m, 2H,
H-4, H -3), 5.15 (br s, 4H,
-4), 4.63 (dd, J¼5.8, 1.5 Hz, 2H, H-3, H
CH2Ph, CH2Ph ), 7.29–7.38 (m, 10H, Ph, Ph
). 13C NMR (125 MHz,
CDCl3): 20.9 (Ac-CH3, Ac-CH3), 25.1, 27.2 (CH3, CH3), 37.2
(CH2COOCH3), 38.1 (CH2COOCH3), 51.9 (OCH3, OCH3), 61.5, 62.2 (C-
5, C-5 ), 63.2 (C-2), 63.6 (CH2OAc ), 63.9 (C-2 ), 64.1 (CH2OAc), 67.4
(CH2Ph, CH2Ph ), 81.3 (C-3 ), 82.1 (C-3), 83.6 (C-4), 84.5 (C-4 ), 112.3
[C(CH3)2, C(CH3)2], 127.8, 127.9, 128.2, 128.6 (Ph, Ph
), 136.2 (C-10, C-
10
),154.4 (CO, CO ),170.4 (OCOCH3, OCOCH3),170.9 (COOCH3),171.1
d
1.31 (s, 6H, CH3, CH3
*
),1.46 (s, 6H, CH3, CH3), 2.08 (s, 6H, Ac-
*
*
), 2.51 (dd, J¼15.6, 10.0 Hz, 2H, CHaCOOCH3,
17.7
m
mol, 60%) as a colorless oil. Rf¼0.23 (EtOAc/MeOH 10:1). 1H
*
*
), 2.90 (dd,
NMR (500 MHz, CDCl3):
d
0.07 [s, 3H, Si(CH3)2], 0.08 [s, 3H,
*
Si(CH3)2], 0.90 [s, 9H, C(CH3)3], 1.32 [s, 3H, C(CH3)2], 1.53 [s, 3H,
C(CH3)2], 1.54–1.70 (br m, 1H, H-7), 1.79–1.94 (br m, 2H, H-6), 2.08–
2.20 (br m,1H, H-7), 2.83 (br s, 2H, H-5), 3.27 (br s,1H, H-4), 3.54 (br
s, 1H, H-7a), 3.80 (dd, J¼11.2, 5.8 Hz, 1H, CHaOSi), 3.96 (d, J¼11.2 Hz,
1H, CHbOSi), 4.36 (dd, J¼6.4, 3.8 Hz, 1H, H-7b), 4.61–4.68 (m, 1H, H-
*
*
*
*
*
*
*
d
*
*
3a). 13C NMR (125 MHz, CDCl3):
d
ꢂ5.6 [Si(CH3)2], ꢂ5.5 [Si(CH3)2],
*
*
18.3 [C(CH3)3], 25.5 [C(CH3)2], 25.9 [C(CH3)3], 26.6 (C-6), 27.6
[C(CH3)2], 28.8 (C-7), 48.2 (C-5), 61.6 (CH2OSi), 67.9 (C-4), 70.9 (C-
7a), 82.5 (C-3a), 85.3 (C-7b), 113.4 [C(CH3)2]. IR (neat, cmꢂ1): nmax
2929, 2857, 2360, 2341, 1636, 1541, 1462, 1379, 1254, 1211, 1109,
1068, 836, 777, 631. GC–MS (CI): m/z (%) 328 ([MHþ], 20), 312 (15),
298 (5), 270 (20), 254 (5), 212 (5), 182 (100), 124 (5), 96 (5), 73 (5).
HRMS (ESI, [MH]þ): calcd for C17H33NO3SiþH 328.2308, found
328.2307.
*
*
*
*
*
*
*
*
*
*
*
*
(COOCH3). IR (neat, cmꢂ1): nmax 2987, 2952, 1737, 1699, 1498, 1407,
1381, 1324, 1232, 1158, 1123, 1059, 870, 770, 699, 632. MS (EI): m/z
422 [MHþ], 378, 364, 348, 320, 304, 286, 272, 260, 240, 228,121,170,
91 [C7Hþ7 ]. HRMS (ESI, [MH]þ): calcd for C21H27NO8þH 422.1815,
found 422.1810. HPLC: Chromasil ODH, hexane/isopropanol
(70:30), flow rate 0.5 mL minꢂ1, tR¼14.53 min and tR¼16.20 min.
4.2.18. 6,7-Dihydroxy-5-(hydroxymethyl)hexahydro-3H-pyrrolizin-
3-one (34)
To a solution of 41 (10 mg, 29.3
m
mol) in THF (0.5 mL) was added
4.2.21. Enzymatic resolution of benzyl 4-(hydroxymethyl)-6-(2-
methoxy-2-oxoethyl)-2,2-dimethyltetrahydro-5H-[1,3]dioxolo[4,5-
c]pyrrole-5-carboxylate ((ꢀ)-36)
TFA (67 L, 870 mol) in water (200 m
m
m
L) and the reaction mixture
refluxed for 1.5 h. After azeotropic codestillation with toluene
(0.5 mL), the residue was directly purified by flash chromatography
To a solution of rac-36 (67 mg, 177
mmol) in toluene (3 mL) was
(silica gel, EtOAc/MeOH 5:1) to give 34 (5.5 mg, 29.3
m
mol, quant.)
added vinyl acetate (82 mL, 883 mmol), molecular sieves (4 Å; 10
as a colorless amorphous solid. Rf¼0.17 (EtOAc/MeOH 5:1). 1H NMR
pellets), and Chirazyme L-6 (122 mg). The mixture was stirred at rt
for 1.5 h, and then filtered through Celite. The filtrate was con-
centrated and the residue purified by flash chromatography
(500 MHz, CD3OD):
d
1.87 (tt, J¼12.3, 9.3 Hz, 1H, Ha-1), 2.31 (dddd,
J¼12.3, 8.3, 6.1, 1.0 Hz, 1H, Hb-1), 2.45 (dd, J¼16.5, 8.8 Hz, 1H, Ha-2),
2.72 (dddd, J¼16.5, 12.3, 8.3, 1.5 Hz, 1H, Hb-2), 3.53–3.56 (m, 1H, H-
5), 3.76 (dd, J¼11.7, 4.1 Hz, 1H, CHaOH), 3.81 (dd, J¼8.5, 4.9 Hz, 1H,
H-7), 4.00–4.05 (m, 1H, H-7a), 4.07 (dd, J¼11.7, 4.1 Hz, 1H, CHbOH),
(EtOAc/hexane 1:1) to give as a colorless oil in the first fraction
20
(ꢂ)-43 (31 mg, 73.6
m
mol, 42%); [
a
]
D
ꢂ19.3 (c 1.00, CHCl3), 98.5%
20
ee, and in the second fraction (þ)-36 (32 mg, 84.3
mmol, 48%); [a]
D
4.16 (dd, J¼4.9, 1.5 Hz, 1H, H-6). 13C NMR (125 MHz, CD3OD):
d 27.1
þ12.4 (c 1.00, CHCl3), 75% ee.
(C-1), 37.1 (C-2), 59.8 (CH2OH), 66.2 (C-5), 67.1 (C-8), 76.2 (C-7), 78.9
(C-6), 176.2 (C-3). IR (neat, cmꢂ1): nmax 3277, 2888, 2361, 2341, 1647,
1547, 1426, 1375, 1203, 1113, 1046, 721, 630. MS (ESI): m/z 188
[MHþ],170,152,124,110. HRMS (ESI, [MH]þ): calcd for C8H13NO4þH
188.0923, found 188.0907.
Acknowledgements
Generous financial support by the Deutsche For-
schungsgemeinschaft, the Fonds der Chemischen Industrie and the

6634
O. Affolter et al. / Tetrahedron 65 (2009) 6626–6634
11. (a) Sengoku, T.; Sato, Y.; Oshima, M.; Takahashi, M.; Yoda, H. Tetrahedron 2008,
64, 8052–8058; (b) Dressel, M.; Restorp, P.; Somfai, P. Chem.dEur. J. 2008, 14,
3072–3077; (c) Izquierdo, I.; Plaza, M. T.; Yanez, V. Tetrahedron: Asymmetry
2005, 16, 3887–3891; (d) Izquierdo, I.; Plaza, M. T.; Tamayo, J. A. Tetrahedron:
Asymmetry 2004, 15, 3635–3642.
Ministerium fu¨r Wissenschaft, Forschung und Kunst des Landes
Baden-Wu¨rttemberg is gratefully acknowledged.
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