Enantioselective synthesis of key intermediates in a novel approach towards the Iboga-alkaloid family

Article abstract of DOI:10.1002/hlca.200390125

Significant improvements in the realm of a recently disclosed, novel synthetic concept towards the Iboga alkaloid family are presented. The key step for the construction of the bicyclic aliphatic core consists of an intramolecular nitrone-olefin 1,3-dipolar cycloaddition reaction of a 1:1 mixture 15/16 yielding the two diastereoisomeric tricyclic isoxazolidine derivatives 17 and 18. The required nitrones were prepared from the readily available (S)-hydroxylactone 6 in twelve steps with an oyerall yield of 15% (average: 83.5% per step). The relative configuration of the minor isomer was deduced unambiguously by single-crystal X-ray analysis of the derived tricyclic carbamate 21. As four out of five asymmetric centers in the pair 17/18 have opposite configuration, destruction of the one possessing the same absolute configuration transforms the original set of diastereoisomers into a pair of enantiomers. We verified this contention by oxidizing the two alcohols 20 and 22 to yield the two antipodal forms of ketone 23. The absence of significant amounts of by-product and the high reproducibility of the crucial cycloaddition reaction represent marked improvements over our earlier attempts. In addition, the new route, which starts from L-glutamate, should provide access to both naturally occurring antipodal series of the targeted alkaloid class.

Full text of DOI:10.1002/hlca.200390125

Helvetica Chimica Acta Vol. 86 (2003)
1397
Enantioselective Synthesis of Key Intermediates in a Novel Approach
towards the Iboga-Alkaloid Family
by Stefan Hˆck1) and Hans-J¸rgBorschberg*
Laboratorium f¸r Organische Chemie der Eidgenˆssischen Technischen Hochschule, ETH Hˆnggerberg,
CH-8093 Z¸rich
Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday
Significant improvements in the realm of a recently disclosed, novel synthetic concept towards the Iboga
alkaloid family are presented. The key step for the construction of the bicyclic aliphatic core consists of an
intramolecular nitroneÀolefin 1,3-dipolar cycloaddition reaction of a 1:1 mixture 15/16 yielding the two
diastereoisomeric tricyclic isoxazolidine derivatives 17 and 18. The required nitrones were prepared from the
readily available (S)-hydroxylactone 6 in twelve steps with an overall yield of 15% (average: 83.5% per step).
The relative configuration of the minor isomer was deduced unambiguously by single-crystal X-ray analysis of
the derived tricyclic carbamate 21. As four out of five asymmetric centers in the pair 17/18 have opposite
configuration, destruction of the one possessing the same absolute configuration transforms the original set of
diastereoisomers into a pair of enantiomers. We verified this contention by oxidizing the two alcohols 20 and 22
to yield the two antipodal forms of ketone 23. The absence of significant amounts of by-product and the high
reproducibility of the crucial cycloaddition reaction represent marked improvements over our earlier attempts.
In addition, the new route, which starts from l-glutamate, should provide access to both naturally occurring
antipodal series of the targeted alkaloid class.
1. Introduction. Recently, we reported some results concerning a new flexible
approach to the Iboga alkaloid family, a class of natural products of high pharmaco-
logical interest (for pertinent references to books and reviews, see [1][2]). The chosen
retro-synthetic strategy towards these alkaloids, endowed with the general structure A,
is disclosed in Scheme 1. It involves a dissection along the dashed line to give a
tryptophyl unit B and an aliphatic isoquinuclidine core. In our first approach, the latter
was represented by the isoxazolidine derivative (Æ)-1 prepared by an intramolecular
nitroneÀolefin 1,3-dipolar cycloaddition reaction of (Æ)-2, prepared in situ from the
piperidine derivative (Æ)-3. Apart from (Æ)-3 not being as readily available as one
might wish, its crucial transformation into (Æ)-1 suffered from poor reproducibility and
low yields, especially when conversions on a larger scale were attempted [1 3].
Therefore, we decided to investigate an alternative approach to an appropriate
nitrone. Instead of the unrewarding amine-oxidation route, a straightforward intra-
molecular condensation between a hydroxylamine and an aldehyde group was
envisaged (see structure C). A convenient method to introduce the required
primary-hydroxylamine function consists of reduction of the corresponding aldoxime
[4]. As the carbonyl group of its precursor and the olefinic CˆC bond bear a 1,4-
relationship to each other, a Claisen-type rearrangement represents an obvious concept
1
)
Taken from the forthcoming Ph.D. thesis of S. H.

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 1
to incorporate the unsaturated C4-side chain. Such a disconnection leads to a chiral
1,2,5-trifunctionalized pentane fragment, a substitution pattern that suggests l-
glutamic acid ((‡)-4) (Scheme 2) as a suitable and cheep starting material from the
chiral pool.
2. Results and Discussion. Known methods were applied for the conversion of
(‡)-4 to (‡)-6 via (‡)-5 [5]2). The primary OH group of (‡)-6 was protected as trityl
ether ( ! (‡)-7) and the lactone opened with NaOH, prepared in situ by allowing NaH
to react in benzene with the required amount of H2O. The resulting secondary
alcoholate was etherified directly with benzyl bromide (for a similar procedure, see
[6]). The resulting acid was esterified with racemic but-3-en-2-ol by using the
Mitsunobu method [7] to yield 8 as a 1:1 mixture of two optically pure diaster-
eoisomers3). The trityl group of ester 8 was selectively removed with ZnBr2 in MeOH/
CH2Cl2 [8] and the resulting primary-alcohol derivative oxidized by means of Swern×s
2
)
As some important experimental parameters are lacking in the original procedures, the exact procedure
we were following is included in the Exper. Part.
Though this and the subsequent 1:1 mixtures could not be separated in the early stages, this had no
deleterious effect on our synthesis as an efficient separation at the level 17/18 (Scheme 3) subsequently
provided the desired building blocks for both naturally occurring antipodal series within this alkaloid class
(for a discussion, see below).
3
)

Helvetica Chimica Acta Vol. 86 (2003)
1399
Scheme 2
a) NaNO2, HCl. b) BH3 ¥ SMe2, THF. c) Ph3CCl, Et3N, CH2Cl2. d) 1. NaH, H2O, [15]crown-5, benzene; 2.
PhCH2Br, benzene. e) (Æ)-But-3-en-2-ol, diisopropyl azodicarboxylate (DIAD), PPh3, THF. f) ZnBr2, MeOH,
CH2Cl2. g) DMSO, (COCl)2, Et3N, CH2Cl2. h) HC(OMe)3, MeOH, TsOH. i) Lithium diisopropylamide, THF,
hexamethylphosphorous triamide (HMPT), tBuMe2SiCl. k) LiAlH4, THF. l) NH2OH ¥ HCl, MeOH, pyridine.
m) NaBH3CN, AcOH/THF.
protocol [9]. The ensuing aldehyde was protected as dimethyl acetal 9 (method
according to [10]) without previous purification. Application of a slight modification
[11] of the original Ireland Claisen rearrangement procedure [12] furnished silyl ester
10, which was reduced in situ to the primary alcohol 11. This intermedidate, again
obtained as a 1:1 mixture of two diastereoisomers, was transformed in straightforward
fashion via aldehyde 12 into oxime 13, which was isolated as a 2 :1 mixture of (E)-
isomer 13A and a (Z)-isomer 13B. This mixture was reduced with NaBH3CN in THF/
AcOH [4] at 08 to yield the rather labile hydroxylamine derivative 14.
The next reaction sequence proved difficult to follow by TLC and became clear
only after extensive experimental work carried out in NMR tubes with deuterated
solvents and reagents. As it turned out, the hydrolysis of the dimethyl acetal unit of 14
4
with 3n D2SO4 in D2O/(D8)-1,4-dioxane 1:1 at 608 was complete within 30min ). A
workup at this time failed to furnish any separable, well-defined products. However,
when the reaction was allowed to proceed at 608 for several hours, we noticed the
appearance of a d (J ˆ 6.3 Hz) at 1.29 ppm at the expense of the signal of the former
olefinic Me group at 1.65 ppm. This event was paralleled by a considerably slower
The progress could be followed conveniently by monitoring the appearance of a s in the 1H-NMR
spectrum at 3.39 ppm (CH3OD) at the expense of the intensity of the four original MeO signals of 14,
which are situated between 3.55 and 3.50ppm.
4
)

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Helvetica Chimica Acta Vol. 86 (2003)
manifestation of an additional d (J ˆ 6.3 Hz) at 1.40ppm. After 30h at 60 8, the 2 d were
of similar intensity, and the broad s at 1.65 ppm as well as the olefinic protons of 14 had
vanished. The material giving rise to the above signals could be isolated in 58%
combined yield by flash chromatography (silica gel) and was shown to consist of a
59 :41 mixture of the two expected isoxazolidines 17 and 18 (see Scheme 3). Seemingly,
the cis-nitrone 15 reacts faster and more efficiently than the trans-nitrone 16, to give the
endo-product 17. Indeed, when, in another run, the reaction was stopped prematurely, a
3 :1 mixture of 17 and 18 in favor of the former was isolated.
Scheme 3
a) 1.5m H2SO4/1,4-dioxane, 24 h at 608. b) 1. Zn, AcOH/MeOH; 2. (Im)2CO, ClCH2CH2Cl. c) H2, Pd/C, EtOH/
AcOH. d) DMSO, (COCl)2, Et3N, CH2Cl2.
At first, these cycloaddition products could not be separated, and the mixture was
transformed into the cyclic carbamates (‡)-19 and (À)-21 via reductive cleavage of the
NÀO bond with Zn/AcOH, followed by treatment with 1,1'-carbonylbis[1H-imida-
zole]. The resulting mixture could now be separated by chromatography, and the more-
polar isomer was obtained in crystalline form. An X-ray analysis established structure

Helvetica Chimica Acta Vol. 86 (2003)
1401
(À)-21 for this isomer in which the benzyloxy group occupies the −exo× position5). From
the drawing and the pertinent data revealed in Fig. 1, it can be seen that, due to the
bridging in the tricyclic system, the N-atom cannot assume the standard sp2 geometry
expected for a urethane derivative. Instead, it can be viewed as the top of a flattened
pyramid, positioned ca. 0.4 ä above the plane defined by its three bonding partners
C(2), C(10), and C(11) (see Fig. 2). In addition, the 1,3-oxazin-2-one ring prefers a
slightly deformed twist conformation (Fig. 2,a). The isoquinuclidine-part system is
somewhat deformed and, when examined along the axis C(7)/C(10), it looks like a top
view of the lid of a jar being twisted off (see Fig. 2,b). This deformation leads to boat
forms with dihedral angles that deviate considerably from the idealized values (see
bottom of Fig. 1). The configuration of (À)-21 being firmly established, the structures
of the remaining compounds were readily deduced, and the NMR data collected are
fully consistent with the proposed structures (see Tables 1 and 2).
Table 1. 1H-NMR Chemical-Shift Values of Compounds 1 [2] and 17 23. In CDCl3; d in ppm rel. to SiMe4.
1a)
17a)
18a)
19
20
21
22
23
HÀC(4)
4.07
2.57
1.85
1.52
1.78
2.61
1.62
4.04
2.28
2.05
1.501.48
1.67
4.06
2.04
1.75
4.36
2.23
1.94
4.45
2.33
2.01
4.48
1.83
1.84
4.48
1.87
1.83
4.57
2.25
2.18
HÀC(5)
HAÀC(6)
HBÀC(6)
HÀC(7)
1.18
1.24
1.29
1.28
1.57
1.70
1.87
1.51
4.04
3.55
3.48
2.99
1.201.25
1.86
2.16
1.38
4.04
3.23
3.16
3.52
1.93
2.27
1.33
4.43
3.14
3.25
3.58
2.01
1.76
1.86
3.87
3.52
3.59
3.66
2.02
1.84
1.73
4.19
3.35
3.56
3.62
2.45
2.45
2.45
HAÀC(8)
HBÀC(8)
HÀC(9)
1.87
1.47
4.12
3.37
3.17
2.94
1.15
HÀC(10)
HAÀC(11)
HBÀC(11)
MeÀC(4)
3.72
3.32
2.87
1.23
3.60
3.95
3.30
1.36
1.35
1.37
1.40
a) For convenience, the numbering system fitting the carbamates 19 23 was employed for the other compounds
as well.
Table 2. 13C-NMR Chemical-Shift Values of Compounds 1 [2] and 17 23. In CDCl3; d rel. to SiMe4.
1a)
17a)
18a)
19
20
21
22
23
C(2)
163.0163.2
163.3
163.8
161.4
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
MeÀC(4)
86.2
40.3
86.085.0 84.9
39.7
85.1
84.084.5
32.8
83.8
36.4
29.8
42.4
33.2
30.6
36.5
37.3
34.3b)
22.021.4
32.7b)
51.1
34.8b)
22.3
34.5b)
30.8
29.3
29.0
26.026.2
26.5
26.6
27.2
34.5b)
69.8
33.8b)
32.9
71.6
49.3
53.4
20.2
34.6
64.6
52.2
53.3
20.2
33.1
72.6
48.0
53.5
20.4
35.4
66.3
51.3
53.7
20.5
43.2
205.7
58.4
55.4
20.4
70.6
59.2
61.2
20.8
59.2
59.4
20.8
59.2
60.9
20.8
a) For convenience, the numbering system fitting the carbamates 19 23 was employed for the other compounds
as well. b) Assignments may be interchanged.
5
)
We thank Dr. B. Schweizer, Laboratory for Organic Chemistry (ETH Z¸rich) for his expeditious
determination of the X-ray crystal structure.

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 1. ORTEP View of ( À )-21 and some selected measurements. Arbitrary atom numbering; the thermal
ellipsoids are scaled at the 30% level.
Hydrogenolytic removal of the benzyl groups of (‡)-19 and (À)-21 furnished the
alcohols (‡)-20 and (À)-22, respectively. Whereas the absolute configuration at C(9) is
the same for both compounds due to their preparation from l-glutamate as the
common precursor, the remaining four asymmetric centers all have mutually opposite
configurations. To verify this contention, we destroyed the asymmetry at the center
C(9) by oxidizing the corresponding OH group of both diastereoisomeric alcohols.
Indeed, the two resulting ketones (‡)- and (À)-23 proved to be enantiomers. This

Helvetica Chimica Acta Vol. 86 (2003)
1403
Fig. 2. Views of ( À )-21 in CS Chem3D Pro, created from imported X-ray data: a) conformation of the 1,3-
oxazin-2-one ring; b) conformation of the isoquinuclidine part system with the two bridgeheads aligned in the y
direction
means that both naturally occurring, antipodal series of the Iboga alkaloid family
should eventually be accessible starting from l-glutamate as the single source from the
chiral pool.
Subsequent investigations showed that the mixture 17/18 can be at least partly
separated by FC. The less-polar, minor isomer 18 was obtained in crystalline state, and
it turned out that inoculation of the original mixture with seed crystals of 18 led to
crystallization of most of this isomer. Consequently, the mother liquor contained mostly
17, the more-valuable synthetic precursor, endowed with the absolute configuration
shared by most naturally occurring Iboga alkaloids [13].
3. Conclusions. The described new route to an appropriately functionalized,
optically pure isoquinuclidine core is by far superior to an earlier attempt as far as
reproducibility and overall yield is concerned. The flexible approach chosen should
eventually pave the way to numerous representatives of the Iboga alkaloid family in
both antipodal forms.

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Helvetica Chimica Acta Vol. 86 (2003)
We express our gratitude to the Swiss National Science Foundation for generous financial support. We also
thank our chemical-technician apprentices, Miss N. Meggiolaro and Mr. M. Aschwanden for their most-valuable
contributions to the presented project.
Experimental Part
General. See [14].
(2S)-Tetrahydro-5-oxofuran-2-carboxylic Acid ((‡)-5). According to [5b]. To a suspension of l-glutamic
acid ((‡)-4; 100 g, 0.68 mol; Fluka, puriss.) in H2O (500 ml) was added slowly conc. aq. HCl soln. (140 ml,
1.68 mol; J. T. Baker), whereupon a homogeneous soln. resulted. Within 8 h, a soln. of NaNO2 (70g, 1.02 mol;
Fluka, puriss.) in H2O (300 ml) was added at 228. After stirring for 16 h, the mixture was evaporated completely
and the residue extracted repeatedly with a total of 1.4 l of hot AcOEt. The hot extracts were filtered, dried
(MgSO4), and evaporated. The crude product was recrystallized 3 times from hot benzene/AcOEt 1:1 (60ml)
by adding cyclohexane until the mixture became slightly turbid. The resulting (‡)-5 (56.01 g, 63.3%) was anal.
pure. M.p. 72.1 73.28 ([5b]: 71 728).
(5S)-Tetrahydro-5-(hydroxymethyl)furan-2-one ((‡)-6). According to [5b]. To a soln. of (‡)-5 (30.96 g,
0.238 mmol) in dry THF (110 ml) was added a soln. of borane-dimethylsulfide complex (27 ml, 0.274 mol;
Fluka, 95%) in THF (110ml) within 20min, under external cooling with ice to keep the temp. in the flask at 15
208. After stirring for 3 h at 208 with constant monitoring of the temp. and cooling when required, the mixture
was cooled to 08 and quenched by adding dry MeOH (180ml). Most of the solvent was removed by distillation
at normal pressure. The residue was diluted with MeOH (180ml) and the mixture evaporated at 15 Torr. The
crude product was distilled at 1108/0.08 Torr: 23.52 g (85.1%) of (‡)-6. Colorless oil.
(5S)-Tetrahydro-5-[(triphenylmethoxy)methyl]furan-2-one ((‡)-7). To
a
soln. of (‡)-6 (16.836 g,
0.145 mol) in dry CH2Cl2 (280ml) were added triphenylmethyl chloride (41.673 g, 0.145 mol; Fluka, 97%)
and dry Et3N (36.4 ml, 0.261 mol) while cooling externally with ice. The mixture was stirred at 228 under Ar for
20h. The resulting violet mixture was extracted twice with sat. aq. CuSO 4 soln. (400 ml) and once with sat. aq.
NaCl soln. (400 ml), the org. phase dried (MgSO4) and evaporated, and the crude product recrystallized twice
from hot AcOEt: 40.37 g (77.7%) of (‡)-7. Slightly yellow crystals. M.p. 151.1 1528. [a]D ˆ ‡35.8 (c ˆ 0.1,
CH2Cl2). IR (CHCl3): 3062, 3006, 2948, 2874, 1772, 1597, 1491, 1449, 1178, 1083, 1035, 1001, 950, 901, 632.
1H-NMR (400 MHz, CDCl3): 7.43 (m, 6 H); 7.27 (m, 9 H); 4.62 (dddd, J ˆ 7.9, 5.8, 4.3, 3.5, 1 H); 3.41 (dd, J ˆ
10.4, 3.5, 1 H); 3.15 (dd, J ˆ 10.4, 4.3, 1 H); 2.66 (ddd, J ˆ 17.8, 10.1, 6.6, 1 H); 2.49 (ddd, J ˆ 17.7, 10.1, 6.9, 1 H);
2.21 (dddd, J ˆ 12.8, 10.1, 7.9, 6.6, 1 H); 2.01 (dddd, J ˆ 12.8, 10.1, 6.9, 5.8, 1 H). 13C-NMR (100 MHz, CDCl3):
177.4 (s); 143.5 (3s); 128.6 (6d); 127.9 (6d); 127.2 (3d); 87.0( s); 79.1 (d); 65.3 (t); 28.4 (t); 24.2 (t). EI-MS: 358
‡
(11, M ), 281 (46), 258 (20), 243 (100), 242 (16), 241 (23), 239 (15), 228 (14), 166 (15), 165 (51), 105 (13), 99
(48).
(1R)- and (1S)-1-Methylprop-2-enyl (4S)-4-(Benzyloxy)-5-(triphenylmethoxy)pentanoate (8; 1 :1 mixture).
To a soln. of (‡)-7 (20.0 g, 55.8 mmol) in dry benzene (500 ml; J. T. Baker) under Ar were added at 228 NaH
(9.374 g, 391 mmol; Fluka, pract.; 55 65% in oil, washed 3 times with hexane) and [15]crown-5 (1.1 ml,
5.6 mmol; Fluka, purum). Then H2O (2.5 ml, 139 mmol) was added dropwise, and the mixture was stirred under
reflux for 6 h. After cooling the mixture in an ice bath, benzyl bromide (16.6 ml, 139 mmol; Fluka, purum) was
added, and stirring was continued at reflux temp. for 17 h. The mixture was cooled to 08 and poured onto 1m aq.
phosphate buffer soln. of pH 3 (600 ml). The resulting pH was again adjusted to 3 by adding conc. aq. HCl soln.,
and the mixture was extracted 3 times with tBuOMe. The combined extract was dried (MgSO4) and evaporated
to give 36.08 g of a yellow viscous liquid which was used as such for the next step. This doubly protected
dihydroxy acid was dissolved in anh. THF (160ml) at 22 8 under Ar. Then were added triphenylphosphine
(45.159 g, 167 mmol; Fluka, 97%), (Æ)-but-3-en-2-ol (14.4 ml, 167 mmol; Acros, 100%; dest. from Na), and 3-ä
molecular sieves (5 g; powder). To the stirred mixture was added slowly diisopropyl azodicarboxylate
(ˆdiisopropyl diazenedicarboxylate ˆ DIAD; 34 ml, 167 mmol; Fluka, 95%) with external cooling in an ice
bath. When the addition was complete, stirring was continued at 238 for 3 h. Most of the solvent was evaporated
t
and the residue diluted with BuOMe (240ml) and stored at 4 8 for 90min after addition of a seed crystal of
triphenylphosphine oxide. The filtrate was washed with H2O (440ml), which was re-extracted twice with
tBuOMe (440ml), the combined org. extract dried (MgSO 4) and evaporated, and the residue chromatographed
(silica gel (1 kg), pentane/Et2O 15 :1 ! 2 :1): 22.73 g (78.2% over 3 steps) of 8. Slightly yellow, viscous oil. IR
(CHCl3): 3088, 3063, 3006, 2933, 2873, 1725, 1491, 1449, 1375, 1348, 1177, 1077, 990, 935, 900, 649, 633. 1H-NMR
(400 MHz, CDCl3): 7.46 (m, 12 H); 7.32 7.19 (m, 28 H); 5.801 (ddd, J ˆ 17.3, 10.5, 5.8, 1 H); 5.795 (ddd, J ˆ 17.3,

Helvetica Chimica Acta Vol. 86 (2003)
1405
10.5, 5.9, 1 H); 5.31 (m, 2 H); 5.205 (dt, J ˆ 17.3, 1.3, 1 H); 5.195 (dt, J ˆ 17.3, 1.3, 1 H); 5.098 (dt, J ˆ 10.5, 1.3,
1 H); 5.092 (dt, J ˆ 10.5, 1.3, 1 H); 4.67 (d, J ˆ 11.5, 2 H); 4.478 (d, J ˆ 11.6, 1 H); 4.476 (d, J ˆ 11.6, 1 H); 3.60
(m, 2 H); 3.23 (dd, J ˆ 9.9, 5.5, 2 H); 3.15 (dd, J ˆ 9.9, 4.5, 2 H); 2.35 (m, 4 H); 1.90( m, 4 H); 1.265 (d, J ˆ 6.5,
3 H); 1.263 (d, J ˆ 6.5, 3 H). 13C-NMR (100 MHz, CDCl3): 172.73 (2s); 144.02 (6s); 138.61 (s); 137.77 (s); 128.71
(12d); 128.30(4 d); 127.82 (2d); 127.80(4 d); 127.77 (12d); 127.51 (2d); 126.96 (6d); 115.65 (2t); 86.68 (2s); 77.33
(2d); 72.11 (t); 72.10( t); 70.79 (2d); 65.64 (2t); 30.41 (2t); 27.37 (2t); 19.90( q); 19.89 (q). EI-MS: 333 (4, [M À
‡
187] ), 277 (3), 247 (4), 243 (100), 241 (9), 193 (15), 165 (34), 117 (26), 91 (59).
(1R)- and (1S)-1-Methylprop-2-enyl (4S)-4-(Benzyloxy)-5,5-dimethoxypentanoate (9; 1:1 mixture). To a
soln. of 8 (11.385 g, 21.9 mmol) in dry CH2Cl2 (45 ml) was added at 08 6m ZnBr2 in dry MeOH (36.4 ml,
219 mmol). After stirring for 3 h at 238, the starting material had disappeared (TLC control: cyclohexane/
AcOEt 4 :1), and the mixture was poured onto 1m aq. phosphate buffer (350ml; pH 8). The white precipitate
was removed by filtration through Celite, which was rinsed several times with a total amount of 150ml of
CH2Cl2. The aq. phase was extracted twice with CH2Cl2 (2 Â 250ml) and the combined org. extract dried
(MgSO4) and evaporated to yield 11.72 g of a slightly yellow oil, which was processed as follows without
purification. To a soln. of oxalyl chloride (2.3 ml, 26.8 mmol; Fluka, purum) in dry CH2Cl2 (25 ml) was added at
À788 under Ar a soln. of DMSO (4.0ml, 56.3 mmol; Fluka, puriss.) in CH2Cl2 (15 ml). After stirring for 30min
at À788, a soln. of the crude intermediate 5-hydroxy derivative in CH2Cl2 (100 ml) was added dropwise, and
stirring was continued for another 30min. Then Et 3N (15 ml, 108 mmol; Fluka, puriss.; dist. from CaH2) was
added, and the cooling bath was removed. After reaching 228, the mixture was washed with sat. aq. CuSO4 soln.
(2 Â 250ml) and sat. aq. NaCl soln. (1 Â 250ml). The aq. phases were extracted with CH 2Cl2 (2 Â 350ml) and
the combined org. extracts dried (MgSO4) and evaporated to yield 11.71 g of an orange oil. To a soln. of this
crude aldehyde derivative in dry MeOH (25 ml) and trimethyl orthoformate (25 ml; Fluka, purum), TsOH ¥
H2O (104 mg, 0.547 mmol; Fluka, puriss.) was added, and the mixture was stirred at 238 for 1 h. The mixture was
worked up with tBuOMe and sat. aq. NaHCO3 soln. to furnish 12.68 g of crude 9. Purification by FC (silica gel,
cyclohexane/AcOEt 5 :1) yielded 5.885 g (83.5% over 3 steps) of 9. Colorless oil. IR (CHCl3): 3005, 2935, 2835,
1725, 1496, 1454, 1375, 1308, 1261, 1090, 989. 1H-NMR (400 MHz, CDCl3): 7.35 7.25 (m, 10H); 5.82 ( ddd, J ˆ
17.3, 10.5, 5.9, 2 H); 5.329 (quint. t, J ˆ 6.5, 1.3, 1 H); 5.326 (quint. t, J ˆ 6.5, 1.3, 1 H); 5.22 (dt, J ˆ 17.3, 1.3, 2 H);
5.11 (dt, J ˆ 10.5, 1.2, 2 H); 4.74 (d, J ˆ 11.4, 2 H); 4.55 (d, J ˆ 11.4, 2 H); 4.25 (d, J ˆ 5.6, 2 H); 3.48 (ddd, J ˆ 8.9,
5.5, 3.4, 2 H); 3.45 (s, 6 H); 3.41 (s, 6 H); 2.5 2.4 (m, 4 H); 2.0 1.9 ( m, 2 H); 1.8 (m, 2 H); 1.285 (d, J ˆ 6.5,
3 H); 1.283 (d, J ˆ 6.5, 3 H). 13C-NMR (100 MHz, CDCl3): 172.81 (2s); 138.54 (2d); 137.79 (s); 137.78 (s); 128.31
(4d); 127.94 (2d); 127.92 (2d); 127.59 (2d); 115.64 (2t); 106.94 (d); 106.93 (d); 78.26 (d); 78.25 (d); 73.15 (2t);
‡
70.81 (2d); 55.67 (2q); 54.96 (2q); 30.29 (2t); 25.57 (2t); 19.90( q); 19.88 (q). EI-MS: 322 (0.2, M ), 247 (2), 193
(5), 129 (15), 91 (60), 75 (100).
(2S,4R,6E)- and (2S,4S,6E)-2-(Benzyloxy)-4-(hydroxymethyl)oct-6-enal Dimethyl Acetal (11; 1 :1 mix-
ture). To a soln. of iPr2NH (4.9 ml, 34.7 mmol; Fluka, puriss.) in THF (25 ml) was added 1.6m BuLi in hexane
(22 ml, 35.2 mmol; Fluka) at À788. At À788, a soln. of 9 (10.118 g, 31.4 mmol) in THF (75 ml) was added. After
stirring for 20min, a soln. of ( tert-butyl)chlorodimethylsilane (4.879 g, 31.5 mmol; Fluka, 97%) in hexamethyl-
phosphorous triamide (HMPT; 4.6 ml; dist. from NaH) and THF (75 ml) was added dropwise at À788. The
cooling bath was replaced by an oil bath adjusted to 658, and stirring was continued for 5.5 h. The mixture was
cooled to 238, and then LiAlH4 (2.380g, 62.7 mmol; Fluka, purum) was added in small portions. After stirring
for 16 h at 228, the mixture was poured carefully and slowly onto 1m aq. phosphate buffer soln. of pH 6 (500 ml)
kept at 08. The mixture was filtered through Celite, which was washed thoroughly with CH2Cl2. The aq. phase
was extracted 3 times with CH2Cl2, the combined org. extract dried and evaporated, and the residue
chromatographed (silica gel (350g), cyclohexane/AcOEt 3 :1 ! 1 :1): 7.982 g (82.4% over 2 steps) of 11.
Yellowish oil. IR (CHCl3): 3443, 3005, 2935, 2837, 1454, 1379, 1074, 969. 1H-NMR (400 MHz, CDCl3): 7.37 7.25
(m, 10H); 5.48 5.30( m, 4 H); 4.80( d, J ˆ 11.3, 1 H); 4.77 (d, J ˆ 11.4, 1 H); 4.57 (d, J ˆ 11.4, 1 H); 4.55 (d, J ˆ
11.3, 1 H); 4.29 (d, J ˆ 5.8, 1 H); 4.25 (d, J ˆ 5.3, 1 H); 3.59 3.28 (m, 18 H); including s (6 H) at 3.41 and s (6 H)
at 3.46); 2.43 (br. s, 1 H); 2.30(br. s, 1 H); 2.07 1.91 (m, 4 H); 1.80 1.48 ( m, 12 H). 13C-NMR (100 MHz,
CDCl3): 138.4 (s); 138.3 (s); 129.3 (d); 129.1 (d); 128.4 (4d); 128.2 (2d); 128.1 (2d); 127.75 (d); 127.73 (d); 126.8
(d); 126.7 (d); 107.4 (d); 107.2 (d); 78.2 (d); 77.5 (d); 73.2 (t); 73.0( t); 65.9 (t); 65.4 (t); 55.98 (q); 55.91 (q); 55.20
‡
(q); 55.16 (q); 37.8 (d); 37.3 (d); 35.6 (t); 34.7 (t); 32.3 (t); 32.1 (t); 17.9 (2q). EI-MS: 258 (0.001, [M À 50] ), 244
(0.5), 233 (0.6), 138 (2), 125 (5), 91 (80), 75 (100), 55 (9).
(2R,4S)- and (2S,4S)-4-(Benzyloxy)-2-[(2E)-but-2-enyl]-5,5-dimethoxypentanal (E)-Oxime (13A; 1:1
mixture) and (Z)-Oxime (13B; 1:1 mixture) (13A/13B 2 :1). To a soln. of oxalyl chloride (2.7 ml, 31.4 mmol;
Fluka, purum) in dry CH2Cl2 (40ml) was added at À788 under Ar a soln. of DMSO (4.8 ml, 67.6 mmol; Fluka,
puriss.) in CH2Cl2 (40ml). After stirring for 30min at À788, a soln. of 11 (7.96 g, 25.8 mmol) in CH2Cl2 (70ml)

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Helvetica Chimica Acta Vol. 86 (2003)
was added dropwise, and stirring was continued for another 30min. Then, Et 3N (18 ml, 127 mmol; Fluka, puriss.;
dist. from CaH2) was added, and the cooling bath was removed. After 228 was reached, the mixture was washed
with half-sat. aq. CuSO4 soln. (2 Â 150ml) and sat. aq. NaCl soln. (1 Â 150ml). The aq. phases were extracted
with CH2Cl2 (2 Â 150ml) and the combined org. extracts dried (MgSO 4) and evaporated. To a soln. of this crude
aldehyde 12 in dry EtOH (32 ml; J. T. Baker, 99.9%) and pyridine (6.4 ml; Fluka, puriss.), NH2OH ¥ HCl (2.69 g,
38.7 mmol; Fluka, puriss.) was added. After stirring for 1 h at 238, the mixture was worked up with 1m aq.
t
phosphate buffer (pH 3) and BuOMe. The crude material was purified by FC (silica gel, cyclohexane/AcOEt
6 :1 ! 2 :1): 7.926 g (95.6% over two steps) of 13A/13B 2 :1. Colorless oil. IR (CHCl3): 3664, 3586, 3323 (br.),
3067, 3006, 2934, 2837, 1496, 1454, 1379, 1322, 1256, 1078, 1028, 968, 917. 1H-NMR (400 MHz, CDCl3): 13A: 8.15
(br. s, 1 H); 8.08 (br. s, 1 H); 7.31 (d, J ˆ 7.7, 1 H); 7.23 (d, J ˆ 7.8, 1 H); 3.436 (s, 3 H); 3.429 (s, 3 H); 3.398
(s, 3 H); 3.395 (s, 3 H); 2.62 (m, 1 H); 2.51 (m, 1 H); 1.80 1.71 ( m, 2 H); 13B: 8.55 (br. s, 1 H); 8.50(br. s, 1 H);
6.58 (d, J ˆ 7.9, 1 H); 6.51 (d, J ˆ 8.3, 1 H); 3.438 (s, 3 H); 3.429 (s, 3 H); 3.401 (s, 3 H); 3.393 (s, 3 H); 13A/13B
first integral for the two (E)-epimers, second integral for the two (Z)-epimers: 7.39 7.24 (m, 10and 10H);
5.50 5.27 ( m, 4 and 4 H); 4.7 (m, 2 and 2 H); 4.55 (m, 2 and 2 H); 4.52 (m, 2 and 2 H); 4.21 (m, 2 and 2 H); 3.45
(m, 2 and 2 H); 2.09 (m, 4 and 6 H); 1.60( m, 8 and 10H). 13C-NMR (100 MHz, CDCl3): 13A: 155.66 (d); 154.96
(d); 138.61 (s); 138.44 (s); 128.28 (4d); 128.18 (2d); 128.16 (d); 128.12 (2d); 127.69 (d); 127.60( d); 127.56 (d);
127.53 (d); 127.51 (d); 107.14 (d); 107.11 (d); 77.69 (d); 77.43 (d); 73.48 (t); 72.76 (t); 55.90( q); 55.89 (q); 55.43
(q); 55.26 (q); 37.06 (d); 36.90( t); 36.03 (d); 35.92 (t); 33.09 (t); 32.90( t); 17.86 (2q); 13B (some signals
overlaping with those of 13A): 156.21 (d); 155.78 (d); 138.72 (s); 138.47 (s); 128.26 (5d); 128.18 (3d); 128.16 (d);
127.77 (d); 127.56 (d); 127.53 (d); 127.33 (d); 127.19 (d); 107.03 (d); 106.92 (d); 78.20( d); 78.11 (d); 73.84 (t);
72.97 (t); 55.90( q); 55.89 (q); 55.31 (q); 55.26 (q); 36.16 (t); 35.42 (t); 33.16 (t); 32.72 (t); 32.09 (d); 31.39 (d);
‡
17.86 (2q). EI-MS: 246 (2, [M À 75] ), 91 (48), 75 (100).
(2S,4R,6E)- and (2S,4S,6E)-2-(Benzyloxy)-4-[(hydroxyamino)methyl]oct-6-enal Dimethyl Acetal (14; 1:1
mixture). To a soln. of 13A/13B (2.592 g, 8.06 mmol) in dry THF (14 ml) and AcOH (28 ml; Scharlau, 100%)
was added NaBH3CN (608 mg, 9.19 mmol; Merck, 95%) at 08. The mixture was stirred at 08 for 70min and then
poured onto cold aq. 2m NaOH. The pH was adjusted to 9 10by adding solid NaOH in small portions. The
combined extracts (4 Â 120ml of tBuOMe) were dried (K2CO3) and evaporated. Purification by FC (silica gel
(60g), cyclohexane/AcOEt 1:1 ! 1 :3) furnished 1.951 g (74.8%) of 14. Colorless oil. IR (CHCl3): 3587, 3279
(br.), 3006, 2935, 2837, 1731, 1496, 1454, 1378, 1324, 1078 (br.), 969, 916. 1H-NMR (400 MHz, CDCl3): 7.37 7.25
(m, 10H); 6.2 5.6 (br. s, 4 H); 5.5 5.3 (m, 4 H); 4.78 (d, J ˆ 11.4, 1 H); 4.76 (d, J ˆ 11.4, 1 H); 4.57 (d, J ˆ 11.4,
1 H); 4.55 (d, J ˆ 11.4, 1 H); 4.23 (d, J ˆ 5.3, 1 H); 4.22 (d, J ˆ 5.4, 1 H); 3.6 3.5 (m, 2 H); 3.459 (s, 3 H); 3.458
(s, 3 H); 3.413 (s, 3 H); 3.399 (s, 3 H); 2.91 (dd, J ˆ 12.2, 5.4, 1 H); 2.80( m, 2 H); 2.71 (dd, J ˆ 12.3, 6.9, 1 H);
2.1 1.75 (m, 6 H); 1.65 1.45 (m, 10 H). 13C-NMR (100 MHz, CDCl3): 138.66 (s); 138.54 (s); 128.83 (d); 128.51
(d); 128.30(2 d); 128.29 (2d); 128.12 (2d); 128.00 (2d); 127.59 (d); 127.54 (d); 126.96 (d); 126.89 (d); 107.55 (d);
107.40 (d); 77.58 (d); 77.49 (d); 73.16 (t); 73.00 (t); 57.92 (t); 57.16 (t); 55.91 (q); 55.90( q); 55.31 (q); 54.99 (q);
‡
36.68 (t); 35.22 (t); 32.93 (t); 32.84 (t); 32.10( d); 31.77 (d); 17.92 (q); 17.91 (q). EI-MS: 232 (4, [M À 91] ), 216
(6), 200 (7), 184 (7), 124 (9), 91 (82), 75 (100).
(3R,4S,6R,8S)- and (3S,4R,6S,8S)-8-(Benzyloxy)-3-methyl-2-oxa-1-azatricyclo[4.3.1.04,9]decane (17 and 18,
resp.; mixture 59 :41). To a soln. of 14 (1.912 g, 5.91 mmol) in 1,4-dioxane (20ml; Fluka, puriss.), aq. 1.5m H2SO4
(20ml) was added, and the mixture was stirred at 60 8 for 24 h. The cold mixture was poured onto aq. 2m NaOH
(100 ml) and extracted with CH2Cl2 (4 Â 70ml). The combined extracts were dried (MgSO 4) and evaporated,
and the crude material was submitted to FC (silica gel (50g, cyclohexane/AcOEt 1:1 ! 100% AcOEt): 896 mg
(58.4%) of 17/18 59 :41. IR (CHCl3): 3068, 3005, 2940, 2669, 1496, 1454, 1380, 1352, 1097, 1066, 1028, 1002. EI-
‡
MS: 259 (20, M ), 214 (28), 168 (40), 124 (24), 108 (32), 107 (25), 91 (100), 79 (34), 77 (21).
From the first fractions of the above FC, a small amount of the less-polar minor 18 could be isolated in pure
form as colorless crystals. When the 41:59 mixture was inoculated with a seed crystal and kept at À208 for 3
days, most of this isomer crystallized. This material was recrystallized from hot AcOEt/cyclohexane to give pure
18 (for data, see below). The remaining material consisted of the major isomer 17, contaminated with ca. 21% of
18 (by 1H-NMR). The value of the optical rotation of this sample was corrected accordingly to give an estimate
of the rotation of pure 17.
Data of 17: More-polar isomer (AcOEt). Colorless oil. [a]D ˆ ‡15.7 (c ˆ 0.1, CHCl3); corrected. 1H-NMR
(400 MHz, CDCl3): 7.38 7.25 (m, 5 H); 4.63 (d, J ˆ 12.0, 1 H); 4.54 (d, J ˆ 12.0, 1 H); 4.12 (dt, J ˆ 9.5, 3.6, 1 H);
4.04 (q, J ˆ 6.3, 1 H); 3.37 (br. t, J ˆ 3.3, 1 H); 3.17 (br. d, J ˆ 14.3, 1 H); 2.94 (dt, J ˆ 14.4, 3.1, 1 H); 2.28
(br. dd, J ˆ 9.5, 3.3, 1 H); 2.05 (dddd, J ˆ 13.7, 9.5, 2.9, 1.7, 1 H); 1.87 (ddt, J ˆ 13.1, 9.8, 3.0, 1 H); 1.67 (m, 1 H);
1.50( m, 1 H); 1.47 (dq, J ˆ 13.6, 3.1, 1 H); 1.15 (d, J ˆ 6.3, 3 H). 13C-NMR (100 MHz, CDCl3): 138.4 (s); 128.4

Helvetica Chimica Acta Vol. 86 (2003)
1407
(2d); 127.7 (d); 127.6 (2d); 86.0( d); 70.9 (t); 69.8 (d); 60.9 (t); 59.2 (d); 39.7 (d); 34.8 (t); 34.5 (t); 21.4 (d); 20.83
(q).
Data of 18: Less-polar isomer (AcOEt). Colorless crystals. M.p. 80.1 80.98. [a]D ˆ À11.3 (c ˆ 0.14,
1
CHCl3). H-NMR (400 MHz, CDCl3): 7.38 7.24 (m, 5 H); 4.65 (d, J ˆ 12.2, 1 H); 4.59 (d, J ˆ 12.2, 1 H); 4.06
(q, J ˆ 6.3, 1 H); 4.04 (ddd, J ˆ 10.0, 3.8, 2.8, 1 H); 3.55 (t, J ˆ 3.0, 1 H); 3.48 (ddd, J ˆ 14.4, 2.8, 1.4, 1 H); 2.99
(dt, J ˆ 14.4, 3.1, 1 H); 2.04 (dd, J ˆ 9.3, 3.4, 1 H); 1.87 (ddt, J ˆ 13.2, 10.0, 3.1, 1 H); 1.75 (dddd, J ˆ 13.3, 9.4, 2.9,
1.5, 1 H); 1.70( m, 1 H); 1.55 1.48 (m, 2 H); 1.20( d, J ˆ 6.3, 3 H). 13C-NMR (100 MHz, CDCl3): 138.4 (s); 128.3
(2d); 127.7 (2d); 127.5 (d); 85.0( d); 70.6 (d); 70.0 (t); 61.2 (t); 59.2 (d); 42.4 (d); 34.5 (t); 33.8 (t); 22.3 (d); 20.79
(q).
(4R,5S,7R,9S)-9-(Benzyloxy)-4-methyl-3-oxa-1-azatricyclo[5.3.1.05,10]undecan-2-one ((‡)-19) and
(4S,5R,7S,9S)-9-(Benzyloxy)-4-methyl-3-oxa-1-azatricyclo[5.3.1.05,10]undecan-2-one ((À)-21). To a mixture 17/
18 20:80(133 mg, 0.513 mmol) in MeOH (1 ml; J. T. Baker; dist. from Mg) and AcOH (4 ml; Scharlau, 100%),
activated Zn dust (168 mg; Fluka, purum; powder, washed successively with aq. 1m HCl, EtOH, and Et2O) was
added at 238. After stirring for 3 h, the mixture was filtered through Celite and evaporated under vacuum at 308
and the residue dissolved in MeOH (5 ml). This soln. was poured onto cold (08) aq. 2m NaOH (20ml) and
extracted with CH2Cl2 (4 Â 15 ml). The combined extracts were dried (K2CO3) and evaporated. The yellow
residue was dissolved in 1,2-dichloroethane (5 ml; Riedel-de H‰en, 99.8%; dist. from P2O5). After addition of
1,1'-carbonylbis[1H-imidazole] (514 mg, 3.17 mmol; Fluka, >97%) at 238, the mixture was stirred for 24 h at 758
under Ar, poured onto aq. 1m HCl (20ml), and extracted 3 times with CH 2Cl2. The combined extract was dried
(MgSO4) and evaporated and the residue chromatographed (silica gel (5 g), cyclohexane/AcOEt 1:1 !
AcOEt): 16 mg (10.9%) of (‡)-19 and 73 mg (49.5%) of (À)-21.
Data of (‡)-19: Less-polar component. Colorless oil. [a]D ˆ ‡134 (c ˆ 0.14, CHCl3). IR (CHCl3): 3006,
2952, 2868, 1703, 1455, 1384, 1112, 1075, 1020, 888. 1H-NMR (400 MHz, CDCl3): 7.33 7.22 (m, 5 H); 4.56 (d, J ˆ
12.0, 1 H); 4.49 (d, J ˆ 12.0, 1 H); 4.36 (q, J ˆ 6.5, 1 H); 4.04 (ddd, J ˆ 9.4, 6.9, 2.7, 1 H); 3.52 (dddd, J ˆ 12.1, 4.7,
2.5, 0.9, 1 H); 3.23 (d, J ˆ 2.7, 1 H); 3.16 (dd, J ˆ 12.1, 1.8, 1 H); 2.23 (br. dd, J ˆ 10.0, 6.0, 1 H); 2.16 (dddd, J ˆ
13.1, 9.2, 5.0, 2.5, 1 H); 1.94 (dddd, J ˆ 14.2, 10.5, 4.0, 1.9, 1 H); 1.86 (m, 1 H); 1.38 (dddd, J ˆ 13.1, 6.9, 2.5, 1.5,
1 H); 1.25 (d, J ˆ 6.5, 3 H); 1.18 (ddt, J ˆ 13.9, 5.9, 2.2, 1 H). 13C-NMR (100 MHz, CDCl3): 163.0( s); 137.9 (s);
128.5 (2d); 127.9 (d); 127.6 (2d); 84.9 (d); 71.6 (d); 71.1 (t); 53.4 (t); 49.3 (d); 33.2 (d); 32.9 (t); 30.6 (t); 26.0( d);
‡
20.2 (q). EI-MS: 287 (2, M ), 243 (2), 242 (3), 212 (11), 152 (55), 137 (31), 136 (25), 131 (11), 122 (10), 91
(100), 81 (18), 65 (12), 55 (19), 41 (13).
Data of ( À )-21: More-polar component. Colorless crystals. M.p. 125.4 125.98. [a]D ˆ À121 (c ˆ 0.113,
CHCl3). IR (CHCl3): 3006, 2952, 2868, 1698, 1476, 1455, 1384, 1354, 1297, 1267, 1100, 1070, 1013, 970. 1H-NMR
(400 MHz, CDCl3): 7.38 7.27 (m, 5 H); 4.67 (d, J ˆ 11.8, 1 H); 4.58 (d, J ˆ 11.8, 1 H); 4.48 (q, J ˆ 6.5, 1 H); 3.87
(ddt, J ˆ 8.3, 4.0, 1.0, 1 H); 3.66 (dddd, J ˆ 11.0, 4.7, 2.5, 0.7, 1 H); 3.59 (br. d, J ˆ 11.7, 1 H); 3.52 (d, J ˆ 3.8, 1 H);
2.0( m, 1 H); 1.9 1.8 (m, 3 H); 1.76 (br. ddt, J ˆ 14.2, 8.3, 2.0, 1 H); 1.35 (d, J ˆ 6.5, 3 H); 1.29 (m, 1 H).
13C-NMR (100 MHz, CDCl3): 163.3 (s); 137.9 (s); 128.4 (2d); 127.7 (d); 127.6 (2d); 84.0( d); 72.6 (d); 70.2 (t);
‡
53.5 (t); 48.0( d); 36.4 (d); 33.1 (t); 29.8 (t); 26.5 (d); 20.4 (q). EI-MS: 288 (0.4, [M ‡ 1] ), 243 (2), 212 (4), 181
(17), 138 (18), 137 (59), 108 (11), 107 (10), 94 (32), 92 (16), 91 (100), 79 (25), 65 (16), 55 (16), 41 (15).
(4R,5S,7R,9S)-9-Hydroxy-4-methyl-3-oxa-1-azatricyclo[5.3.1.05,10]undecan-2-one ((‡)-20). To a soln. of 19
(100 mg, 0.348 mmol) in EtOH (1 ml) and AcOH (0.1 ml; Scharlau, 100%) was added 10% Pd/C (20 mg; Fluka,
puriss.). The mixture was stirred under H2 at 1 atm for 52 h at 238. The mixture was filtered through silica gel
(0.5 g), the filtrate evaporated, and the residue recrystallized from hot AcOEt/CH2Cl2; 49 mg (71.4%) of (‡)-
20. Colorless crystals. M.p. 151 1538. [a]D ˆ ‡245 (c ˆ 0.099, CHCl3). IR (CHCl3): 3401, 3006, 2952, 2867, 1700,
1618, 1480, 1457, 1384, 1299, 1109, 1050, 1016, 960. 1H-NMR (400 MHz, CDCl3): 4.45 (q, J ˆ 6.5, 1 H); 4.43
(br. t, J ˆ 8.4, 1 H); 3.58 (dddd, J ˆ 12.1, 4.7, 2.4, 0.9, 1 H); 3.25 (dd, J ˆ 12.1, 1.8, 1 H); 3.14 (d, J ˆ 2.8, 1 H); 2.33
(br. dd, J ˆ 10.3, 6.5, 1 H); 2.27 (dddd, J ˆ 13.2, 9.4, 5.1, 2.6, 1 H); 2.27 (br. s, 1 H); 2.01 (dddd, J ˆ 14.2, 10.4, 3.9,
2.0, 1 H); 1.93 (m, 1 H); 1.36 (d, J ˆ 6.5, 3 H); 1.33 (dddd, J ˆ 13.2, 6.9, 2.5, 2, 1 H); 1.24 (ddt, J ˆ 14.2, 6.0, 2.1,
1 H). 13C-NMR (100 MHz, CDCl3): 163.2 (s); 85.1 (d); 64.6 (d); 53.3 (t); 52.2 (d); 34.6 (t); 32.8 (d); 30.8 (t); 26.2
‡
(d); 20.2 (q). EI-MS: 197 (28, M ), 154 (16), 153 (78), 152 (38), 138 (25), 136 (100), 124 (20), 110 (15), 109
(29), 108 (61), 96 (31), 95 (36), 94 (27), 82 (73), 80(35), 71 (37), 70(82), 69 (37), 68 (91), 67 (90), 58 (24), 55
(36), 43 (31), 41 (33).
(4S,5R,7S,9S)-9-Hydroxy-4-methyl-3-oxa-1-azatricyclo[5.3.1.05,10]undecan-2-one ((À)-22). As described
for (‡)-20, with 21 (150mg, 0.522 mmol), EtOH (3 ml; J. T. Baker, 99.9%), AcOH (0.3 ml), 10% Pd/C
(60mg) and H 2 for 20h at 23 8: 78 mg (73.8%) of (À)-22. Colorless crystals. M.p. 178.4 179.98. [a]D ˆ À319 (c ˆ
0.102, CHCl3). IR (CHCl3): 3412, 3006, 2936, 2867, 1699, 1476, 1456, 1384, 1289, 1112, 1020, 976. 1H-NMR
(400 MHz, CDCl3): 4.48 (q, J ˆ 6.5, 1 H); 4.19 (br. dt, J ˆ 8.3, 4.1, 1 H); 3.62 (dddd, J ˆ 11.8, 4.7, 2.5, 0.7, 1 H);

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Helvetica Chimica Acta Vol. 86 (2003)
Table 3. Crystallographic Data of (À)-21
Index ranges
Empirical formula
C17H21NO3
À 13 ꢀ h ꢀ 13, À16 ꢀ k ꢀ 16,
À16 ꢀ l ꢀ 16
Mr
287.359
298 K
l ˆ 0.71073
Reflections collected
Independent reflections
Refinement method
4042
Temperature
Wavelength
4019 (Rint ˆ 0.026)
Full-matrix least-squares
on F2
Crystal system
Space group
Orthorhombic
P212121
Data, restraints, parameters 4019, 0, 274
R(all)
0.0872
Unit-cell dimensions a ˆ 10.1906(3) ä a ˆ 90.008 R(gt)
0.0528
0.1696
0.1416
1.071
2.0(15)
0.227 and À0.287 e ¥ AÀ3
b ˆ 11.9127(3) ä b ˆ 90.008 wR(ref)
c ˆ 12.4091(4) ä g ˆ 90.008 wR(gt)
Volume
Z
1506.43(8) ä3
4
S(ref)
Flack parameter
D1(max; min)
Density (calculated) 1.267 Mg/m3
q Range
0.998 29.1318
3.56 (br. d, J ˆ 11.7, 1 H); 3.35 (d, J ˆ 4.0, 1 H); 2.82 (br. d, J ˆ 3.6, 1 H); 2.02 (m, 1 H); 1.9 1.8 (m, 3 H); 1.73
(dm, J ˆ 14.3, 1 H); 1.37 (d, J ˆ 6.5, 3 H); 1.28 (m, 1 H). 13C-NMR (100 MHz, CDCl3): 163.8 (s); 84.5 (d); 66.3
‡
(d); 53.7 (t); 51.3 (d); 36.5 (d); 35.4 (t); 29.3 (t); 26.6 (d); 20.5 (q). MS: 197 (64, M ), 153 (34), 152 (26), 138
(29), 137 (11), 137 (100), 128 (14), 124 (22), 110 (20), 108 (40), 95 (37), 82 (50), 70 (34), 68 (57).
(4S,5R,7S)-4-Methyl-3-oxa-1-azatricyclo[5.3.1.05,10]undecane-2,9-dione ((À)-23). To a soln. of oxalyl
chloride (38 ml, 0.442 mmol; Fluka, purum) in dry CH2Cl2 (0.5 ml) was added at À788 under Ar a soln. of
DMSO (63 ml, 0.886 mmol; Fluka, puriss.) in CH2Cl2 (1 ml). After stirring for 30min at À788, a soln. of (À)-22
(67 mg, 0.34 mmol) in CH2Cl2 (2.5 ml) was added dropwise, and stirring was continued for another 30min.
Then, Et3N (0.24 ml, 1.72 mmol; Fluka, puriss.; dist. from CaH2) was added, and the cooling bath was removed.
After reaching 228, the mixture was poured onto aq. 0.1m HCl (25 ml) and extracted with CH2Cl2 (3 Â 20ml).
The combined extract was dried (MgSO4) and evaporated and the residue purified by chromatography (silica
gel (3 g), AcOEt): 48 mg (72.3%) of (À)-23. Colorless crystals. M.p. 120.3 120.98. [a]D ˆ À123 (c ˆ 0.101,
CHCl3). IR (CHCl3): 2985, 2956, 1739, 1714, 1478, 1456, 1406, 1374, 1103, 1017, 955. 1H-NMR (500 MHz,
CDCl3): 4.57 (q, J ˆ 6.5, 1 H); 3.95 (ddd, J ˆ 12.5, 4.6, 2.8, 1 H); 3.60( s, 1 H); 3.30( dd, J ˆ 12.5, 1.7, 1 H); 2.51
2.41 (m, 3 H); 2.25 (br. dd, J ˆ 10.5, 5.3, 1 H); 2.18 (dddd, J ˆ 13.8, 10.5, 3.3, 1.8, 1 H); 1.57 (ddt, J ˆ 13.9, 4.7, 2.1,
1 H); 1.40( d, J ˆ 6.5, 3 H). 1H-NMR (400 MHz, C6D6): 3.80( q, J ˆ 6.5, 1 H); 3.69 (dddd, J ˆ 12.5, 4.8, 3.1, 0.6,
1 H); 3.35 (s, 1 H); 2.68 (dd, J ˆ 12.5, 1.8, 1 H); 1.70( dddd, J ˆ 18.9, 3.3, 2.5, 0.5, 1 H); 1.59 (dt, J ˆ 18.8, 2.6,
1 H); 1.27 (m, 1 H); 1.16 (br. dd, J ˆ 10.3, 5.4, 1 H); 1.05 (dddd, J ˆ 14.0, 10.5, 3.6, 1.9, 1 H); 0.72 (ddt, J ˆ 14.1,
5.5, 2.3, 1 H); 0.71 (d, J ˆ 6.5, 3 H). 13C-NMR (125 MHz, CDCl3): 205.7 (s); 161.4 (s); 83.8 (d); 58.4 (d); 55.4 (t);
‡
43.2 (t); 37.3 (d); 29.0( t); 27.2 (d); 20.4 (q). EI-MS: 195 (100, M ), 151 (10), 123 (75), 122 (41), 109 (16), 108
(46), 107 (14), 106 (21), 95 (65), 94 (36), 82 (92), 81 (89), 80 (24), 79 (33), 68 (100), 57 (47), 55 (70), 54 (22), 41
(49).
(4R,5S,7R)-4-Methyl-3-oxa-1-azatricyclo[5.3.1.05,10]undecane-2,9-dione ((‡)-23). As described for (À)-23,
with (‡)-20 (28 mg, 0.143 mmol): 22 mg (79.0%) of (‡)-23. Colorless crystals. M.p. 119.2 120.18. [a]D ˆ ‡124
(c ˆ 0.102, CHCl3).
X-Ray Crystal-Structure Determination of 21. Details of the structure determination are listed in Table 3. A
crystal was mounted on a Nonius-KappaCCD diffractometer. Data collection and integration were carried out
with a Nonius collect suite [15]. The structure was solved by direct methods by using the program SIR92 [16].
The absolute configuration at C(9) was assumed to be (S), since it is derived from l-glutamic acid (4). All
diagrams and calculations were performed by using maXus [17]. ORTEP Drawing according to [18].
Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as deposition no.
CCDC 201931.

Helvetica Chimica Acta Vol. 86 (2003)
1409
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Received February 6, 2003