Studies on the synthesis of chiral nonracemic 3,4-disubstituted azepanes, a formal synthesis of (+)- and (-)-balanol

Article abstract of DOI:10.1016/S0957-4166(99)00466-8

Sugar lactones were converted to 3,4-disubstituted azepanes and caprolactam derivatives by selective deoxygenation, functionalization and reductive cyclization. The cyclization proved troublesome with 6-azidolactols but led to good results with the corres

Full text of DOI:10.1016/S0957-4166(99)00466-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4521–4537
Studies on the synthesis of chiral nonracemic 3,4-disubstituted
azepanes, a formal synthesis of (+)- and (−)-balanol
Claus Herdeis,a,∗ Rafat M. Mohareb,b Reinhard B. Neder,c Franz Schwabenländer c and
Joachim Telser a
aInstitut für Pharmazie und Lebensmittelchemie der Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
bFaculty of Sciences, Cairo University, Giza, Egypt
cMineralogisches Institut der Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
Received 21 October 1999; accepted 22 October 1999
Abstract
Sugar lactones were converted to 3,4-disubstituted azepanes and caprolactam derivatives by selective deoxyge-
nation, functionalization and reductive cyclization. The cyclization proved troublesome with 6-azidolactols but led
to good results with the corresponding lactones. A formal synthesis of (+)- and (−)-balanol is reported. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
Balanol 1, a compound isolated from the fungi Cordyceps ophioglossoides,1 Verticillium balanoides2
and Fusarium merismoides3 has recently become a popular synthetic target because of its potent
inhibitory activity against proteinkinase C. Some syntheses of balanol 1 (Fig. 1) or its heterocyclic
azepane core4 have been published to date and several series of acyclic and heterocyclic analogues
have been prepared and evaluated for pharmacological properties.5 Investigations have shown that the
remarkable inhibitory activity of balanol 1 is to be attributed to its binding to the ATP docking site of
protein kinase.6
In our group, sugar lactones are frequently used as an inexpensive and versatile source of chirality for
the synthesis of chiral nonracemic piperidine derivatives.7 Therefore, we tried to extend our methodolo-
gies to the synthesis of the azepane ring system. We chose homochiral lactones with a nitrogen containing
functional group at C-6 and a protected hydroxy group at C-5 as the key intermediates. Ring closure by
formation of a C−N bond between the already functionalized C-1 atom and the nitrogen connected to
C-6 should lead to 3,4-disubstituted heterocycles of the balanol type (see Schemes 3 and 4).
∗
Corresponding author. E-mail: herdeis@pharmazie.uni-wuerzburg.de
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00466-8
tetasy 3102

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Fig. 1.
2. Results and discussion
Appropriate starting materials were obtained by the reaction sequence shown in Scheme 1. Compound
2 is readily available from L-ascorbic acid by catalytic hydrogenation8 and subsequent treatment accord-
ing to a procedure published by Chittenden and Vekemans.9 Compound 3 is obtained from calcium-D-
gluconate according to a method by Lundt.10
Silylation of 2 with tert-butyldimethylchlorosilane in DMF with an excess of imidazole gave 4a
and the chlorinated byproduct 4b as a chromatographically inseparable mixture. Therefore the exact
yield of 4a and 4b could not be determined. A similar chlorination reaction in the presence of tert-
butyldimethylchlorosilane and imidazole has been described by Peyrat et al.11 The reaction of 2 and
tert-butyldiphenylchlorosilane under identical conditions resulted in the isolation of 4c. Compound 3
was converted to the silyl ethers 5a and 5b by analogous procedures.
The azido group was introduced by nucleophilic substitution with lithium azide in DMF as a solvent
to yield the azidolactones 6a, 6b, 7a and 7b. The bromolactones 4a, 4c, 5a and 5b reacted promptly but
the chlorolactone 4b required longer reaction times to obtain complete conversion.
Reduction of 6a with diisobutyl aluminium hydride (DIBAH) in THF at –78°C gave 86% of the
corresponding lactol 8a. The product was obtained as an equilibrium mixture of anomers; 1H NMR data
indicated the presence of a small equilibrium concentration of open chain aldehyde. When the DIBAH
reduction protocol was applied to the lactones 6b, 7a and 7b, respectively, the lactols 8b, 9a and 9b
could be isolated. The syntheses of the four azidolactols are outlined in Scheme 1. Table 1 summarizes
the isolated yields and reaction times.
We addressed the formation of azepanes from the lactols by means of a tandem Wittig–[2+3]cyclo-
addition reaction. This methodology has been employed successfully for the synthesis of various
piperidine derivatives.7,12 Therefore 8a and 9a were reacted with ethoxycarbonylmethylene-(triphenyl)-
phosphorane. However, the resulting α,β-unsaturated esters 10 and 11 failed to give the expected
intramolecular [2+3]cycloaddition reaction. They proved to be very stable at room temperature for
months (Scheme 2). When 10 was reacted with triphenylphosphine in aqueous THF13,14 in order to
induce a Staudinger reduction–Michael addition type reaction sequence a complex mixture of products
was obtained.
Since the work of Paulsen15 it is known that 6-azidolactols undergo a reductive ring enlargement in the
presence of excess hydrogen and a catalyst to yield azepanes. Paulsen found evidence for an intermediate
equilibrium involving a bicyclic N,O-acetal and a cyclic imine. The latter species is reduced by hydrogen

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4523
Scheme 1. (i) RCl, imidazole, DMF, 12–24 h; (ii) LiN3, DMF, 60°C; (iii) DIBAH, THF, −78°C, 130 min–6.5 h. Yields and
reaction times are given in Table 1
to the azepane. When 8a was submitted to catalytic hydrogenation in methanol or ethanol using 10% Pd
on charcoal the bicyclic N,O-acetal 12a could be isolated (Scheme 3). This compound was very resistant
to further hydrogenation and was converted quantitatively only after a period of seven days. Protic
solvents were necessary to drive the reaction to completion but under these conditions a mixture of the
regioisomers 13a and 13b was isolated due to migration of the silyl protecting group. The product ratio
varied with the reaction time. The reaction rate could not be enhanced by changing the catalyst; identical
results were obtained with 10% Pt on charcoal. We concluded that the small equilibrium concentration of
the 12a derived cyclic imine (see the literature15) limited the reaction rate. Efforts to reduce 12a directly

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C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
Table 1
Synthesis of the azidolactols 8a, 8b, 9a and 9b
Scheme 2. (i) Ph3PCHCOOEt, PhMe, rt, 48 h, 93% of 10, 85% of 11
with hydride transfer agents like NaBH4, LiBHEt3 or LiAlH4 led to unsatisfying yields since extractive
workup of the free amines proved to be cumbersome and inefficient.
To overcome the problem of silyl migration, the lactol 8b with the more bulky and stable TBDPS
group was hydrogenated in the presence of 10% Pd/C. In this case the bicyclic product 12b was isolated
which could not be transformed further to an azepane.
Complete hydrogenation of 8a, therefore, was the only suitable alternative to obtain azepanes. When
the regioisomers 13a and 13b in the mixture were converted to their N-Boc derivatives 14a and 14b
immediately after the hydrogenation step, it was possible to obtain pure fractions of both isomers
by column chromatography. Conversion of the free hydroxy group to the mesylate and subsequent
substitution by sodium azide in DMPU resulted in the azido azepanes 15a and 15b in moderate yields
(57% of 15a, 37% of 15b). These compounds can be regarded as precursors of balanol isomers with
3,4-cis-orientation of the substituents.
Catalytic hydrogenation of 9a with 10% Pd/C in ethanol led to an intermediate 16a which was detected
by capillary GC (RIp=1535). After filtration and evaporation of the solvent a colourless oil was obtained
that solidified within some hours and then was insoluble in all organic solvents. It could only be dissolved
in a mixture of dilute aqueous HCl and methanol. Therefore, a sample of 16a was hydrogenated in

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4525
Scheme 3. (i) H2, 10% Pd/C, MeOH or EtOH, 91% of 12a, 67% of 12b; (ii) H2, 10% Pd/C, MeOH or EtOH, 7 days, 77% of
isomeric mixture of 13a and 13b; (iii) Boc2O, 2 h, rt, 55% of 14a, 13% of 14b for the two-step conversion starting from 8a;
(iv) (a) MsCl, Et3N, CH2Cl2, −20°C, 20 min, (b) NaN3, DMPU, 80°C, 7 days, 57% of 15a, 34% of 15b
1
CD3OD, the catalyst was removed by filtration and the filtrate was submitted to 13C and H NMR
spectroscopy. The spectra indicated a bicyclic N,O-acetal. Attempts to trap 16a by the addition of Boc2O
to the reaction mixture either before hydrogenation or thereafter resulted in the formation of complex
product mixtures. Similar observations were made during the hydrogenation of 9b. The resulting bicyclus
17b solidified more slowly and allowed spectroscopic characterization.
Obviously, the bicyclic N,O-acetals of the (4S,5R)-diastereomeric series had polymerized after workup
and polyimines had been formed. The appearance of a band at 1730 cm−1 in the IR spectrum of
17b within some hours after isolation furnished additional evidence for this hypothesis. Since no
polymerization was observed with the bicyclic N,O-acetals of the (4S,5S)-series, there must be a
significant difference in their stability. Most likely, the (4S,5S)-diastereomers are more stable because
the six-membered moiety in the bicyclic system may form a chair conformer with the silyloxy group
in an equatorial position, whereas in the (4S,5R)-diastereomers either a boat-shaped conformer with an
equatorially disposed silyloxy group is formed or the bulky substituent is forced into an axial position in
a chair-like conformation (Scheme 4).
In analogy to 8a, the complete hydrogenation of 9a led to a mixture of regioisomeric azepanes that
were converted to their N-Boc derivatives 17a and 17b to facilitate workup and purification (isomeric
ratio ∼1:1, determined by capillary GC). Unfortunately, this mixture was not separable by column
chromatography. Conversion of 17a and 17b to the azido azepanes 18a and 18b was carried out without
isolation of the intermediate mesylates in a two-step sequence. The azepanes 18a and 18b were isolated as
a chromatographically inseparable mixture (isomeric ratio ∼7:3, determined by capillary GC). In analogy
to its diastereomer 12b, the TBDPS protected bicyclus 17b was unreactive towards further hydrogenation.
This behaviour might be explained by the strong steric hindrance of the bulky TBDPS group.
Another approach to seven-membered heterocycles was the reduction of 6a and 7a to the corre-
sponding aminolactones that gave the ring enlarged ε-caprolactam16 derivatives 19 and 20 in aqueous
methanol (Scheme 5). Both compounds were crystalline and could be obtained in moderate to good
yields.
Since the NMR spectra of 20 exhibited broad signals due to conformational equilibria, the structure

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C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
Scheme 4. (i) H2, 10% Pd/C, MeOH or EtOH, 2.5 h; (ii) H2, 10% Pd/C, MeOH or EtOH, 7 days, then Boc2O, 2 h, rt, 69% of
isomeric mixture of 17a and 17b (1:1); (iii) (a) MsCl, Et3N, CH2Cl2, −20°C, 30 min, (b) NaN3, DMPU, 80°C, 7 days, 34% of
isomeric mixture of 18a and 18b (7:3, determined by GC)
Scheme 5. (i) H2, 10% Pd/C, MeOH/H2O (9+1), 16–24 h, 65% of 19, 85% of 20; (ii) a.) 1 N HCl/MeOH, rt 10 min, (b) AlCl3,
acetone, ether, −20°C, 61% of 21

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4527
was elucidated by 600 MHz HMQC and HMBC experiments that provided evidence for the presence of
the seven-membered ring system. Furthermore, an X-ray diffraction experiment17 revealed that, at least
in the solid state, a conformation with the bulky OTBDMS group in a quasi-axial position is favoured
(Fig. 2). This may be explained by the lipophilic interactions of the neighbouring silyl groups at the edge
of each cell and the ‘head to head’ position of the more polar caprolactam rings in the middle.
Fig. 2. Crystal structure of the lactam 20
It proved cumbersome to reduce the lactams 19 and 20 with BH3·SMe2 or with BH3·THF because the
resulting borane–amine complexes were more stable towards hydrolysis than the silyl protecting group.
The selective protection of the amide group in the presence of the hydroxy group with Boc2O and a base
caused severe problems, so that this problem could not be overcome. Therefore, we decided to exchange
the silyl group in 20 by an isopropylidene moiety. The TBDMS group was then cleaved by 1 M HCl.
Since ring contraction occurred under acidic conditions in the free diol, it was immediately exposed to
AlCl3 and acetone in ether.18 Thus, the bicyclic compound 21 was obtained in 61% yield which is a
known precursor of (+)- and (−)-balanol.4g,n,p
3. Experimental
General procedures: 1H-, HH COSY and 13C-NMR: Bruker AC 200; HMBC and HMQC: Bruker AC
600. Chemical shifts are given referring to the solvent as internal standard. IR spectra: Perkin–Elmer
681. Gas chromatography: Carlo Erba HRGC 5160 Mega Series, Macherey + Nagel Optima 5 column
(25 m×0.2 mm ID, 0.1 µm film thickness), helium at 27 cm/s. Retention indices (RIp) were determined

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C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
according to the method of Van den Dool and Kratz19 referring to a standard of n-paraffins C8–C22.
Zone temperatures: inj. 250°C, det. 290°C, oven 60//5/290/20. TLC: Merck silica gel 60 F254 plates.
Optical rotation: Perkin–Elmer 241. Melting points are uncorrected. Column chromatography: silica gel
60 (0.063–0.2 mm). Petroleum ether (PE) with a boiling range of 30–50°C was used. All reactions were
carried out under nitrogen. THF and ether were distilled from potassium sodium couple; acetone from
calcium chloride; DMF, dichloromethane and triethylamine from calcium hydride.
3.1. Silylation of the lactones 2 and 3
General procedure for the silylation: 2 or 3 and imidazole are dissolved in DMF (abs). The silylating
agent is added and the mixture is stirred at ambient temperature for 12 or 24 h. Water is then added
followed by extraction with four portions of ether. The combined organic layers are washed with water,
dried over Na2SO4 and evaporated. The residue is purified by column chromatography and dried at 0.01
mbar for two days.
3.1.1. 6-Bromo-5-tert-butyldimethylsilyloxy-2,3,6-trideoxy-L-threo-hexono-1,4-lactone 4a and 5-tert-
butyldimethylsilyloxy-6-chloro-2,3,6-trideoxy-L-threo-hexono-1,4-lactone 4b
Starting materials: 8.00 g (38.45 mmol) of 2, 5.76 g (84.60 mmol, 2.2 equivalents) of imidazole, 10.43
g (69.22 mmol, 1.8 equivalents) of tert-butyldimethylchlorosilane in 50 ml of DMF; reaction time: 12 h;
yield: not determined, the colourless oil contains 11.12 g of an inseparable mixture of the two halogenated
silylation products 4a and 4b which may be used without further workup; RIp=1848a, RIp=1765b; IR
(neat): ν (cm−1)=1775 (C_O), 1465, 1455, 1250; 1H NMR (200 MHz, CDCl3): δ (ppm)=−0.54, −0.52
(s, 6H, Si(CH3)2), 0.81 (s, 9H, SiC(CH3)3), 1.95–2.41 (2H, m, 3-H), 2.44–2.58 (2H, m, 2-H), 3.18–3.58
(2H, m, 6-H), 3.73–3.82 (1H, m, 5-H), 4.68–4.88 (1H, m, 4-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ
(ppm)=−4.8, −4.5 (CH3, Si(CH3)2), 17.8, 18.0 (SiC(CH3)3), 23.4 (CH2, C-3b), 23.5 (CH2, C-3a), 25.6
(CH3, SiC(CH3)3), 28.1 (CH2, C-2), 31.5 (CH2, C-6a), 43.4 (CH2, C-6b), 74.1 (CH, C-5a), 74.4 (CH,
C-5b), 78.3 (CH, C-4b), 78.6 (CH, C-4a), 176.8 (C-1).
3.1.2. 6-Bromo-5-tert-butylphenylylsilyloxy-2,3,6-trideoxy-L-threo-hexono-1,4-lactone 4c
Starting materials: 2.51 g (12.00 mmol) of 2, 2.45 g (36.0 mmol, 3 equivalents) of imidazole and 4.29
g (15.60 mmol, 1.3 equivalents) of tert-butyldiphenylchlorosilane in 10 ml of DMF; reaction time: 24
h; purification: column chromatography (Et2O/PE 1+1, Rf=0.38); yield: 4.03 g (9.01 mmol, 75%) as
colourless crystals; mp=76°C; [α]D20=+36.7 (c=2.0, tBuOMe); IR (neat): ν (cm−1)=3090, 2990, 2860,
1775 (C_O), 1590 (C_C), 1430, 1110; 1H NMR (200 MHz, CDCl3): δ (ppm)=1.07 (9H, s, SiC(CH3)3),
2.03–2.33 (2H, m, 3-H), 2.42–2.73 (2H, m, 2-H), 3.17 (1H, dd, J5,6A=3.7, JAB=10.1 Hz, 6-HA), 3.45
(1H, dd, J5,6B=9.0, JAB=10.1 Hz, 6-HB), 3.85 (1H, ddd, J4,5=2.6, J5,6A=3.7, J5,6B=9.0 Hz, 5-H), 4.92 (1H,
ddd, J4,5=2.6, J3,4=6.1, J3,4=8.1 Hz, 4-H), 7.36–7.49 (6H, m, arom.-H), 7.66–7.73 (4H, m, arom.-H); 13
C
NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=19.3 (SiC(CH3)3), 23.2 (CH2, C-3), 26.8 (CH3, SiC(CH3)3),
28.3 (CH2, C-2), 31.7 (CH2, C-6), 74.4 (CH, C-5), 78.9 (CH, C-4), 127.8 (CH), 128.0 (CH), 130.1 (CH),
130.3 (CH), 132.0, 133.0, 135.6 (CH), 176.7 (C-1); C22H27BrO3Si (447.45); calcd: C 59.06, H 6.08;
found: C 59.31, H 6.33.
3.1.3. 6-Bromo-5-tert-butyldimethylsilyloxy-2,3,6-trideoxy-D-erythro-hexono-1,4-lactone 5a
Starting materials: 22.51 g (107.7 mmol) of 3, 16.14 g (237 mmol, 2.2 equivalents) of imidazole,
29.23 g (193.9 mmol, 1.8 equivalents) of tert-butyldimethylchlorosilane in 100 ml of DMF; reaction
time: 24 h; purification: column chromatography (Et2O/PE 2+1, Rf=0.54); yield: 32.93 g (102 mmol,

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4529
95%) as a colourless oil. RIp=1829; [α]D20=+0.4 (c=2.3, tBuOMe); IR (neat): ν (cm−1)=3000, 2940,
1
1800 (C_O), 1485, 1275, 1200; H NMR (200 MHz, CDCl3): δ (ppm)=0.09 (6H, s, Si(CH3)2), 0.88
(9H, s, SiC(CH3)3), 2.14–2.26 (2H, m, 3-H), 2.48–2.57 (2H, m, 2-H), 3.24 (1H, dd, J5,6A=7.8, JAB=10.7
Hz, 6-HA), 3.38 (1H, dd, J5,6B=4.4, JAB=10.7 Hz, 6-HB), 4.10 (1H, ddd, J4,5=3.5, J5,6B=4.4, J5,6A=7.8
Hz, 5-H), 4.80 (1H, dt, J4,5=3.5, J3,4=7.0 Hz, 4-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=−4.8
(CH3, Si(CH3)2), 18.0 (SiC(CH3)3), 21.0 (CH2, C-3), 25.6 (CH3, SiC(CH3)3), 28.4 (CH2, C-2), 31.8
(CH2, C-6), 72.1 (CH, C-5), 79.9 (CH, C-4), 176.8 (C-1); C12H23BrO3Si (323.31); calcd: C 44.58, H
7.17; found: C 44.43, H 7.23.
3.1.4. 6-Bromo-5-tert-butyldiphenylsilyloxy-2,3,6-trideoxy-D-erythro-hexono-1,4-lactone 5b
Starting materials: 2.51 g (12.00 mmol) of 3, 2.45 g (36.0 mmol, 3 equivalents) of imidazole and
4.29 g (15.60 mmol, 1.3 equivalents) of tert-butyldiphenylchlorosilane in 10 ml of DMF; reaction time:
24 h; purification: column chromatography (Et2O/PE 1+1, Rf=0.45; yield: 4.35 g (9.72 mmol, 81%) as
colourless crystals; mp=121°C; [α]D20=+13.2 (c=1.3, tBuOMe); IR (KBr): ν (cm−1)=3060, 3080, 2870,
2780, 1785 (C_O), 1590 (C_C), 1430; 1H NMR (200 MHz, CDCl3): δ (ppm)=1.08 (9H, s, SiC(CH3)3),
2.14–2.29 (2H, m, 3-H), 2.43–2.53 (2H, m, 2-H), 3.18 (1H, dd, J5,6A=6.7, JAB=10.8 Hz, 6-HA), 3.28 (1H,
dd, J5,6B=3.5, JAB=10.8 Hz, 6-HB), 4.02 (1H, ddd, J5,6B=3.5, J4,5=4.7, J5,6A=6.7 Hz, 5-H), 4.80 (1H, dt,
J4,5=4.7, J3,4=7.1 Hz, 4-H), 7.37–7.48 (6H, m, arom.-H), 7.66–7.72 (4H, m, arom.-H); 13C NMR (50.3
MHz, CDCl3) DEPT: δ (ppm)=19.3 (SiC(CH3)3), 22.1 (CH2, C-3), 26.9 (CH3, SiC(CH3)3), 28.3 (CH2,
C-2), 32.8 (CH2, C-6), 72.2 (CH, C-5), 79.9 (CH, C-4), 127.9 (CH), 128.0 (CH), 130.2 (CH), 130.3
(CH), 132.1, 133.2, 135.8 (CH), 135.9 (CH), 176.5 (C-1); C22H27BrO3Si (447.50); calcd: C 59.06, H
6.08; found: C 58.75, H 6.06.
3.2. Introduction of the azido group
General procedure for the introduction of the azido group: The silylated bromolactone (4 or 5) is
dissolved in dry DMF. LiN3 is added. The mixture is stirred at 60°C until complete conversion has
occurred. The reaction is monitored by GC. If necessary, another portion of about 1.4 equivalents of
lithium azide is added after some hours. Then water is added and the mixture is extracted with ether. The
combined organic extracts are dried over Na2SO4 and purified by column chromatography.
3.2.1. 6-Azido-5-tert-butyldimethylsilyloxy-2,3,6-trideoxy-L-threo-hexono-1,4-lactone 6a
Starting materials: 11.12 g of a mixture of 4a and 4b, 2×2.64 g (54 mmol) of lithium azide in 50 ml
of DMF; reaction time: 26 h; column chromatography: EtOAc/PE 1+2 (Rf=0.45); yield: 8.13 g (28.48
mmol, 74% over two steps from compound 2) of 6a as a colourless oil; RIp=1860; [α]D20=+30.17 (c=1.1,
1
MeOH); IR (neat): ν (cm−1)=2100 (N3), 1780 (C_O), 1120; H NMR (200 MHz, CDCl3): δ (ppm)
0.07 (6H, s, Si(CH3)2), 0.85 (9H, s, SiC(CH3)3), 1.97–2.37 (2H, m, 3-H), 2.45–2.52 (2H, m, 2-H), 3.24
(1H, dd, J5,6A=5.4, JAB=12.4 Hz, 6-HA), 3.45 (1H, dd, J5,6B=6.2, JAB=12.4 Hz), 3.72 (1H, ddd, J4,5=3.8,
J5,6A=5.4, J5,6B=6.2 Hz, 5-H), 4.56 (1H, ddd, J4,5=3.8, J3A,4=6.2, J3B,4=6.6 Hz, 4-H); 13C NMR (50.3
MHz, CDCl3) DEPT: δ (ppm)=−4.9, −4.8 (CH3, Si(CH3)2), 17.8 (SiC(CH3)3), 23.3 (CH2, C-3), 25.5
(CH3, SiC(CH3)3), 28.1 (CH2, C-2), 52.8 (CH2, C-6), 72.9 (CH, C-5), 79.7 (CH, C-4), 176.6 (C-1);
C12H23N3O3Si (285.47); calcd: C 50.49, H 8.12, N 14.72; found: C 50.43, H 8.00, N 14.64.
3.2.2. 6-Azido-5-tert-butyldiphenylsilyloxy-2,3,6-trideoxy-L-threo-hexono-1,4-lactone 6b
Starting materials: 3.49 g (7.80 mmol) of 4c, 527 mg (10.76 mmol, 1.4 equivalents) of LiN3 in 10
ml of DMF; reaction time: 20 h; column chromatography: Et2O/PE 1+1 (Rf=0.0.28); yield: 2.90 g (7.08

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mmol, 91%) as a colourless oil; [α]D20=+39.8 (c=0.8, tBuOMe); IR (neat): ν (cm−1)=3090, 2950, 2880,
1
2110 (N3), 1775 (C_O), 1590 (C_C), 1430, 1110; H NMR (200 MHz, CDCl3): δ (ppm)=1.07 (9H,
s, SiC(CH3)3), 2.09–2.23 (2H, m, 3-H), 2.39–2.62 (2H, m, 2-H), 3.19 (1H, dd, J5,6A=4.6, JAB=12.3 Hz,
6-HA), 3.44 (1H, dd, J5,6B=7.4, JAB=12.3 Hz, 6-HB), 3.77 (1H, ddd, J4,5=3.3, J5,6A=4.6, J5,6B=7.4 Hz,
5-H), 4.61 (1H, ddd, J4,5=3.3, J3,4=6.8, J3,4=7.6 Hz, 4-H), 7.34–7.43 (6H, m, arom.-H), 7.66–7.73 (4H,
m, arom.-H); 13C NMR (50.3 MHz, CDCl3): δ (ppm)=19.4 (SiC(CH3)3), 23.1 (CH2, C-3), 26.8 (CH3,
SiC(CH3)3), 28.3 (CH2, C-2), 52.3 (CH2, C-6), 73.1 (CH, C-5), 79.3 (CH, C-4), 127.9 (CH), 128.0 (CH),
130.1 (CH), 130.2 (CH), 132.2, 133.0, 135.7 (CH), 135.8 (CH), 176.7 (C-1); C22H27N3O3Si (409.56);
calcd: C 64.52, H 6.64, N 10.26; found: C 64.33, H 6.83, N 9.89.
3.2.3. 6-Azido-5-tert-butyldimethylsilyloxy-2,3,6-trideoxy-D-erythro-hexono-1,4-lactone 7a
Starting materials: 19.35 g (59.85 mmol) of 5a, 4.11 g (84 mmol, 1.4 equivalents) of LiN3 in 50 ml
of DMF; reaction time: 20 h; column chromatography: Et2O/PE 2+1 (Rf=0.40); yield: 10.39 g (39.89
mmol, 67%) as a colourless oil; RIp=1864; [α]D20=+5.6 (c=0.9, tBuOMe); IR (neat): ν (cm−1)=2970,
2890, 2100 (N3), 1800 (C_O), 1480, 1280, 1190; 1H NMR (200 MHz, CDCl3): δ (ppm)=0.09, 0.13 (6H,
2s, Si(CH3)2), 0.88 (9H, s, SiC(CH3)3), 2.16–2.35 (2H, m, 3-H), 2.48–2.56 (2H, m, 2-H), 3.26 (1H, dd,
J5,6A=5.0, JAB=12.8 Hz, 6-HA), 3.39 (1H, dd, J5,6B=5.2, JAB=12.8 Hz, 6-HB), 4.00 (1H, ddd, J4,5=3.9,
J5,6A=5.0, J5,6B=5.2 Hz, 5-H), 4.52 (1H, dt, J4,5=3.9, J3,4=7.2 Hz, 4-H); 13C NMR (50.3 MHz, CDCl3):
δ (ppm)=−4.8, −4.7 (CH3, Si(CH3)2), 17.9 (SiC(CH3)3), 21.9 (CH2, C-3), 25.6 (CH3, SiC(CH3)3), 28.4
(CH2, C-2), 53.5 (CH2, C-6), 71.7 (CH, C-5), 80.1 (CH, C-4), 176.6 (C-1); C12H23N3O3Si (285.42);
calcd: C 50.50, H 8.12, N 14.72; found: C 50.34, H 7.83, N 14.96.
3.2.4. 6-Azido-5-tert-butyldiphenylsilyloxy-2,3,6-trideoxy-D-erythro-hexono-1,4-lactone 7b
Starting materials: 4.13 g (9.23 mmol) of 5b, 625 mg (12.75 mmol, 1.4 equivalents) of LiN3 in 10 ml
of DMF; reaction time: 20 h; column chromatography: Et2O/PE 1+1 (Rf=0.33); yield: 3.50 g (8.42 mmol,
93%) as a colourless oil; [α]D20=+7.9 (c=2.3, tBuOMe); IR (neat): ν (cm−1)=3090, 2950, 2870, 2120
(N3), 1775 (C_O), 1590 (C_C), 1110; 1H NMR (200 MHz, CDCl3): δ (ppm)=1.09 (9H, s, SiC(CH3)3),
2.15–2.28 (2H, m, 3-H), 2.42–2.53 (2H, m, 2-H), 3.21 (1H, dd, J5,6A=4.5, JAB=13.0 Hz, 6-HA), 3.30
(1H, dd, J5,6B=4.5, JAB=13.0 Hz, 6-HB), 3.97 (1H, td, J5,6=4.5, J4,5=4.7 Hz, 5-H), 4.59 (dt, J4,5=4.7,
J3,4=7.2 Hz, 4-H), 7.38–7.48 (6H, m, arom.-H), 7.69–7.75 (4H, m, arom.-H); 13C NMR (50.3 MHz,
CDCl3) DEPT: δ (ppm)=19.2 (SiC(CH3)3), 22.5 (CH2, C-3), 26.8 (CH3, SiC(CH3)3), 28.1 (CH2, C-2),
52.7 (CH2, C-6), 72.2 (CH, C-5), 79.8 (CH, C-4), 127.8 (CH), 128.8 (CH), 130.1 (CH), 130.2 (CH),
131.9, 133.0, 135.7 (CH), 136.2 (CH), 176.7 (C-1); C22H27N3O3Si (409.56); calcd: C 64.52, H 6.64, N
10.26; found: C 64.43, H 6.39, N 9.80.
3.3. Reduction of lactones to lactols with DIBAH
General procedure for the reduction with DIBAH: The azidolactones 6a, 6b, 7a, or 7b are dissolved
in THF (abs), cooled to –78°C and a solution of DIBAH is added. The mixture is kept at –78°C. The
reaction is monitored by capillary GC (for the compounds 8a and 9a) or by IR spectroscopy (for 8b
and 9b). Reaction times are variable and depend strongly on the quality of DIBAH. If the reaction is
not complete after 40 minutes, another portion of DIBAH is added and the mixture is stirred at –78°C
until no more starting material can be detected. Then water is added very carefully at –78 to −60°C,
the mixture is warmed to room temperature, acidified with 2 M HCl and extracted with five portions
of dichloromethane. The combined organic extracts are washed twice with satd NaHCO3, dried over

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4531
Na2SO4 and the solvent is distilled. The residue is purified by filtration over silica gel or by column
chromatography.
3.3.1. 6-Azido-5-tert-butyldiphenylsilyloxy-2,3,6-trideoxy-D-threo-hexofuranose 8a
Starting materials: 8.13 g (28.48 mmol) of 6a, 38 ml (38 mmol, 1.33 equivalents)+20 ml (20 mmol,
0.70 equivalents) of DIBAH (1 M in hexane) in 40 ml of THF; reaction time: 130 min; purification:
filtration over silica gel (Et2O); yield: 7.03 g (24.47 mmol, 86%) as a colourless oil; RIp=1764; IR
(neat): ν (cm−1)=3400 (OH), 2100 (N3), 1255, 1110; 1H NMR (200 MHz, CDCl3): δ (ppm)=0.12 (6H,
s, Si(CH3)2), 0.90 (9H, s, SiC(CH3)3), 1.69–2.06 (4H, m, 2-H, 3-H), 3.10–3.41 (2H, m, 6-H), 3.49–3.58
(1H, m), 3.66–3.77 (1H, m), 4.17–4.28 (1H, m, 4-H), 5.37–5.52 (1H, m, OH); 13C NMR (50.3 MHz,
CDCl3) DEPT: δ (ppm)=−4.7, −4.8 (CH3, Si(CH3)2), 18.0 (SiC(CH3)3) 23.9, 25.7 (CH2, C-3), 25.7
(CH3, SiC(CH3)3), 33.3, 34.4 (CH2, C-2), 53.6, 53.9 (CH2, C-6), 73.1, 73.2 (CH, C-5), 78.9, 80.4 (CH,
C-4), 98.4, 98.7 (CH, C-1); C12H25N3O3Si (287.44); calcd: C 50.14, H 8.77, N 14.62; found: C 50.10, H
8.81, N 15.06.
3.3.2. 6-Azido-5-tert-butyldiphenylsilyloxy-2,3,6-trideoxy-D-threo-hexofuranose 8b
Starting materials: 2.83 g (6.91 mmol) of 6b, 9.0 ml (9.0 mmol, 1.3 equivalents)+3×4.1 ml (4.1 mmol,
0.6 equivalents) of DIBAH (1 M in CH2Cl2) in 20 ml of THF; reaction time: ca. 5 h; purification: column
chromatography (Et2O/PE 1+1, Rf=0.43); yield: 980 mg (2.38 mmol, 34%) as a colourless oil; IR (neat):
1
ν (cm−1)=3420 (OH), 3090, 2950, 2100 (N3), 1590 (C_C), 1430; H NMR (200 MHz, CDCl3): δ
(ppm)=1.10 (9H, s, SiC(CH3)3), 1.69–2.05 (4H, m, 2-H, 3-H), 3.08–3.59 (2H, m, 6-H), 3.69–3.83 (1H,
m, 5-H), 4.20–4.31 (1H, m, 4-H), 5.24–5.48 (1H, m, 1-H), 7.26–7.48 (6H, m, arom.-H), 7.69–7.79 (4H,
m, arom.-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=19.4 (SiC(CH3)3), 24.1, 24.6 (CH2, C-3),
33.0, 34.2 (CH2, C-2), 53.1, 53.4 (CH2, C-6), 75.2, 75.5 (CH, C-5), 78.5, 80.5 (CH, C-4), 98.1, 98.7
(CH, C-1), 127.7 (CH), 129.8 (CH), 129.9 (CH), 133.0, 133.7, 135.9 (CH), 135.1 (CH); C22H29N3O3Si
(411.58); calcd: C 64.20, H 7.10, N 10.21; found: C 64.34, H 6.85, N 9.32.
3.3.3. 6-Azido-5-tert-butyldimethylsilyloxy-2,3,6-trideoxy-D-erythro-hexofuranose 9a
Starting materials: 9.34 g (32.70 mmol) of 7a, 42.5 ml (42.5 mmol, 1.3 equivalents)+19.6 ml
(19.6 mmol, 0.6 equivalents) of DIBAH (1 M in hexane); reaction time: 5 h; purification: column
chromatography (Et2O/PE 2+1, Rf=0.48); yield: 7.85 g (27.29 mmol, 83%) as a colourless oil; RIp=1766;
1
IR (neat): ν (cm−1)=3370 (OH), 2900, 2830, 2100 (N3), 1440, 1235; H NMR (200 MHz, CDCl3):
δ (ppm)=0.05, 0.08, 0.10 (6H, s, Si(CH3)2), 0.88 (9H, s, SiC(CH3)3), 1.77–2.23 (4H, m, 2-H, 3-H),
3.13–3.52 (2H, m, 6-H), 3.69–3.76 (1H, m, 5-H), 3.99–4.23 (1H, m, 4-H), 5.43–5.51 (1H, m, 1-H); 13
C
NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=−4.7, −4.6, −4.3 (CH3, Si(CH3)2), 17.9 (SiC(CH3)3), 24.4,
26.5 (CH2, C-3), 25.7 (CH3, SiC(CH3)3), 32.7, 33.4 (CH2, C-2), 54.5, 54.6 (CH2, C-6), 73.0, 75.0 (CH,
C-5), 79.0, 80.5 (CH, C-4), 98.4, 98.5 (CH, C-1); C12H35N3O3Si (287.44); calcd: C 50.14, H 8.77, N
14.62; found: C 49.94, H 8.73, N 14.46.
3.3.4. 6-Azido-5-tert-butyldiphenylsilyloxy-2,3,6-trideoxy-D-erythro-hexofuranose 9b
Starting materials: 3.42 g (8.36 mmol) of 7b, 10.9 ml (10.9 mmol, 1.3 equivalents)+3×5.0 (5.0 mmol,
0.6 equivalents) of DIBAH (1 M in CH2Cl2) in 20 ml of THF; reaction time: 6.5 h; purification: column
chromatography (Et2O/PE 1+1, Rf=0.41); yield: 2.36 g (5.73 mmol, 69%) as a colourless oil; IR (neat):
1
ν (cm−1)=3400 (OH), 3090, 2950, 2110 (N3), 1596 (C_C), 1430; H NMR (200 MHz, CDCl3): δ
(ppm)=1.09 (9H, s, SiC(CH3)3), 1.71–2.09 (4H, m, 2-H, 3-H), 2.86–3.39 (2H, m, 6-H), 3.67–3.81 (1H,
m, 5-H), 4.11–4.33 (1H, m, 4-H), 5.40–5.43 (1H, m, 1-H), 7.26–7.46 (6H, m, arom.-H), 7.66–7.76 (4H,

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C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
m, arom.-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=19.3 (SiC(CH3)3), 24.9, 26.9 (CH2, C-3),
26.9 (CH3, SiC(CH3)3), 32.5, 33.4 (CH2, C-2), 53.8, 54.0 (CH2, C-6), 73.4, 75.1 (CH, C-5), 78.9, 80.6
(CH, C-4), 98.4, 98.5 (CH, C-1), 127.7 (CH), 127.8 (CH), 129.8 (CH), 133.0, 133.2, 133.4, 135.8 (CH),
135.9 (CH); C22H29N3O3Si (411.58); calcd: C 64.20, H 7.10, N 10.21; found: C 64.15, H 6.98, N 9.40.
3.4. Ethyl (6S,7S)-8-azido-7-tert-butyldimethylsilyloxy-6-hydroxy-oct-2-enoate 10
A mixture of 240 mg (0.83 mmol) of 8a and 291 mg (0.83 mmol, 1 equivalent) of triphenylcarbethoxy-
methylenphosphorane in 5 ml of toluene is stirred at ambient temperature for 48 h. Then the solvent is
distilled in vacuo at room temperature and the residue is purified by column chromatography (EtOAc/PE
1+2). 276 mg (0.77 mmol, 93%) of 10 are isolated as a colourless oil (Rf=0.48); [α]D20=−20.6 (c=1.2,
1
MeOH); IR (neat): ν (cm−1)=2100 (N3), 1720 (C_O); H NMR (200 MHz, CDCl3): δ (ppm)=0.07
(6H, s, Si(CH3)2), 0.91 (9H, s, SiC(CH3)3), 1.25 (3H, t, J=7.1 Hz, OCH2CH3), 1.51–1.65 (2H, m, 5-H),
2.17–2.48 (2H, m, 4-H), 3.24 (1H, dd, J7,8A=5.4, JAB=12.3 Hz, 8-HA), 3.46 (1H, dd, J7,8B=5.5, JAB=12.3
Hz, 8-HB), 3.54–3.64 (2H, m, 6-H, 7-H), 4.16 (2H, q, J=7.1, OCH2CH3), 5.83 (1H, dt, J2,4=1.5, J2,3=15.6
Hz, 2-H), 6.95 (1H, dt, J3,4=7.0, J2,3=15.6 Hz, 3-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=−4.8
(CH3, Si(CH3)2), 14.2 (CH3, OCH2CH3), 18.0 (SiC(CH3)3), 25.7 (CH3, SiC(CH3)3), 28.6 (CH2, C-5),
32.1 (CH2, C-4), 53.7 (CH2, OCH2CH3), 60.1 (CH2, C-8), 71.1 (CH, C-7), 73.9 (CH, C-6), 121.8 (CH,
C-2), 148.2 (CH, C-3), 166.5 (C-1); C16H31N3O4Si (357.53); calcd: C 53.75, H 8.74, N 11.75; found: C
53.48, H 8.54, N 15.06.
3.5. Ethyl (6S,7R)-8-azido-7-tert-butyldimethylsilyloxy-6-hydroxy-oct-2-enoate 11
The compound is synthesized according to the procedure described for 10 starting from 230 mg (0.80
mmol) of 9a and 279 mg (0.80 mmol, 1 equivalent) of triphenylcarbethoxymethylenphosphorane in
5 ml of toluene; column chromatography: Et2O/PE 2+1 (Rf=0.53), yield: 243 mg (0.68 mmol, 85%)
as a colourless oil; RIp=1864; [α]D20=−1.4 (c=1.0, tBuOMe); IR (neat): ν (cm−1)=3450 (OH), 2890,
1
2820, 2080 (N3), 1700 (C_O), 1630 (C_C), 1230; H NMR (200 MHz, CDCl3): δ (ppm)=0.09, 0.13
(6H, s, Si(CH3)2), 0.90 (9H, s, SiC(CH3)3), 1.26 (3H, t, J=7.1 Hz, OCH2CH3), 1.41–1.69 (2H, m,
5-H), 2.16–2.51 (2H, m, 4-H), 3.20–3.39 (2H, m, 8-H), 3.54–3.76 (2H, m, 6-H, 7-H), 4.16 (2H, q,
J=7.1, OCH2CH3), 5.82 (1H, dt, J2,4=1.5, J2,3=15.6 Hz, 2-H), 6.95 (1H, dt, J3,4=7.0, J2,3=15.6 Hz, 3-H);
13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=−4.9, −4.6 (CH3, Si(CH3)2), 14.2 (CH3, OCH2CH3),
17.9 (SiC(CH3)3), 25.7 (CH3, SiC(CH3)3), 28.7 (CH2, C-5), 30.6 (CH2, C-4), 52.8 (CH2, OCH2CH3),
60.2 (CH2, C-8), 72.5 (CH, C-7), 74.5 (CH, C-6), 121.8 (CH, C-2), 148.1 (CH, C-3), 166.5 (C-1);
C16H31N3O3Si (357.53); calcd: C 53.75, H 8.74, N 11.75; found: C 53.84, H 8.64, N 10.75.
3.6. (1R,4S,5S)-4-tert-Butyldimethylsilyloxy-2-aza-8-oxabicyclo[3,2,1]octane 12a
8a (1.40 g, 4.87 mmol) is dissolved in 60 ml of ethanol and hydrogenated at 30 bar in the presence
of 200 mg 10% Pd/C over 2.5 h at ambient temperature. The catalyst is then removed by filtration, the
solvent is distilled and the residue is purified by column chromatography (EtOAc/MeOH 9+1, Rf=0.37);
yield: 1.08 g (4.44 mmol, 91%) as a colourless oil; RIp=1546; [α]D20=−12.8 (c=0.89, Et2O); IR (neat): ν
(cm−1)=2100 (N3), 1720 (C_O); 1H NMR (200 MHz, CDCl3) COSY: δ (ppm)=0.06 (6H, s, Si(CH3)2),
0.88 (9H, s, SiC(CH3)3), 1.61–2.13 (4H, m, 6-H, 7-H), 2.64 (1H, dd, J3A,4=10.0, JAB=14.1 Hz, 3-HA),
2.89 (1H, dd, J3B,4=6.0, JAB=14.1 Hz, 3-HB), 3.60–3.73 (1H, m, 4-H), 4.18 (1H, ddd, J=1.2, J=4.2, J=5.4
Hz, 5-H), 4.93 (1H, d, J1,7=5.8 Hz, 1-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=−4.7 (CH3,

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4533
Si(CH3)2), 18.0 (SiC(CH3)3), 22.8 (CH2, C-6), 25.7 (CH3, SiC(CH3)3), 28.1 (CH2, C-7), 44.5 (CH2,
C-3), 66.5 (CH, C-4), 78.1 (CH, C-5), 85.9 (CH, C-1); C12H25NO2Si (243.42); calcd: C 59.21, H 10.35,
N 5.75; found: C 59.02, H 10.09, N 5.92.
3.7. (1R,4S,5S)-4-tert-Butyldiphenylsilyloxy-2-aza-8-oxabicyclo[3,2,1]octane 12b
8b (505 mg, 1.23 mmol) is reacted according to the method described for 12a using 30 mg of 10%
Pd/C in 12 ml of ethanol; reaction time: 34 h at 50 bar; column chromatography: EtOAc/MeOH 9+1
(Rf=0.51); yield: 298 mg (0.81 mmol, 67%) as a colourless oil; [α]D20=+4.6 (c=1.0, MeOH); IR (neat):
ν (cm−1)=3340 (NH), 3080, 2960, 1595 (C_C), 1475; 1H NMR (200 MHz, CDCl3): δ (ppm)=1.07 (9H,
s, SiC(CH3)3), 1.80–2.34 (4H, m, 6-H, 7-H), 2.75–2.80 (2H, m, 3-H), 3.73 (1H, ddd, J=3.8, J=7.2, J=8.4
Hz, 4-H), 4.15–4.21 (1H, m, 5-H), 4.87 (1H, d, J=5.3 Hz, 1-H), 7.33–7.48 (6H, m, arom.-H), 7.62–7.67
(4H, m, arom.-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ (ppm)=19.1 (SiC(CH3)3), 23.0 (CH2, C-6),
26.9 (CH3, SiC(CH3)3), 28.1 (CH2, C-7), 44.3 (CH2, C-3), 67.0 (CH, C-4), 77.6 (CH, C-5), 85.9 (CH,
C-1), 127.6 (CH), 129.8 (CH), 133.8, 133.9, 136.6 (CH); C22H29NO2Si (367.57); calcd: C 71.99, H 7.95,
N 3.81; found: C 71.66, H 7.90, N 3.66.
3.8. (3S,4S)-3-tert-Butyldimethylsilyloxy-4-hydroxyazepane 13a and (3S,4S)-4-tert-butyldimethylsilyloxy-
3-hydroxyazepane 13b
8a (520 mg, 1.81 mmol) is hydrogenated at room temperature in the presence of 120 mg of 10% Pd/C
in 20 ml of methanol at a pressure of 50 bar. After 7 days the catalyst is removed by filtration, the solvent
is distilled and the residue is submitted to Kugelrohr distillation (oven temperature: 100–250°C, 0.05
mbar); yield: 340 mg (1.39 mmol, 77%) of a mixture of 13a and 13b as colourless crystals; RIp=1610b,
RIp=1621a; mp=85°C; IR (KBr): ν (cm−1)=3300 (OH, NH), 1480, 1270; 1H NMR (200 MHz, CD3OD):
δ (ppm)=0.21 (6H, s, Si(CH3)2), 1.07 (9H, s, SiC(CH3)3), 1.63–2.12 (4H, m, 5-H, 6-H), 2.70–3.06 (4H,
m, 2-H, 7-H), 3.68–3.97 (2H, m, 3-H, 4-H); 13C NMR (50.3 MHz, CD3OD) DEPT: δ (ppm)=−4.7, −4.6,
−4.4 (CH3, Si(CH3)2), 18.9 (SiC(CH3)3), 22.5, 23.0 (CH2, C-6), 26.4 (CH3, SiC(CH3)3), 29.8, 30.0
(CH2, C-5), 47.9, 48.6, 48.9 (CH2, C-2 and C-7), 74.7, 75.2, 73.3, 77.0 (CH, C-3, C-4); C12H27NO2Si
(245.44); calcd: C 58.72, H 11.09, N 5.74; found: C 58.78, H 10.71, N 5.61.
3.9. (3S,4S)-3-tert-Butyldimethylsilyloxy-1-tert-butoxycarbonyl-4-hydroxyazepane 14a and (3S,4S)-4-
tert-butyldimethylsilyloxy-1-tert-butoxycarbonyl-3-hydroxyazepane 14b
12a (2.19 g, 8.98 mmol) is dissolved in 50 ml of ethanol p.a. and hydrogenated over 7 days in the
presence of 200 mg of 10% Pd/C at room temperature. The catalyst is removed by filtration, 2.38 g (10.88
mmol, 1.2 equivalents) of di-tert-butyldicarboxylate are added and the mixture is stirred for 2 h until the
evolution of gas ceases. The solvent is distilled and the residue is purified by column chromatography
(Et2O/PE 1+1). 1.71 g (4.95 mmol, 55%) of 14a are obtained as a colourless oil (Rf=0.34); 399 mg (1.15
mmol, 13%) of 14b are obtained as a colourless oil (Rf=0.48).
14a: RIp=1975; [α]D20=−6.4 (c=1, tBuOMe); IR (neat): ν (cm−1)=3500 (OH), 2950, 2900, 1700
1
(C_O), 1430, 1180; H NMR (200 MHz, [D6]DMSO, 353 K): δ (ppm)=0.18 (6H, s, Si(CH3)2), 0.98
(9H, s, SiC(CH3)3), 1.58 (9H, s, CO2C(CH3)3), 1.59–1.93 (4H, m, 5-H, 6-H), 3.10–3.21 (2H, m, 7-H),
3.48–3.55 (2H, m, 2-H), 3.59–3.69 (2H, m, 3-H, 4-H), 4.22 (1H, d, J=4.4 Hz, OH); 13C NMR (50.3
MHz, [D6]DMSO, 353 K): δ (ppm)=−4.6, −4.4 (CH3, Si(CH3)2), 17.9 (SiC(CH3)3), 21.4 (CH2, C-6),
26.0 (CH3, SiC(CH3)3), 28.4 (CH3, CO2C(CH3)3), 30.2 (CH2, C-5), 46.3 (CH2, C-7), 47.6 (CH2, C-

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C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
2), 74.5 (CH), 75.2 (CH), 78.5 (CO2C(CH3)3), 154.9 (CO2C(CH3)3); C17H35NO4Si (345.56); calcd: C
59.05, H 10.21, N 4.05; found: C 58.74, H 9.92, N 3.84.
14b: RIp=1982; [α]D20=−16.4 (c=1.0, tBuOMe); IR (neat): ν (cm−1)=3450 (OH), 2960, 2860, 1680
1
(C_O), 1420, 1255; H NMR (200 MHz, [D6]DMSO, 353 K): δ (ppm)=0.15 (6H, s, Si(CH3)2), 0.98
(9H, s, SiC(CH3)3), 1.50 (9H, s, CO2C(CH3)3), 1.62–1.92 (4H, m, 5-H, 6-H), 3.18–3.30, 3.45–3.64 (4H,
m, 2-H, 7-H), 3.71–3.78 (1H, m, 4-H), 4.30–4.31 (1H, m, 3-H); 13C NMR (50.3 MHz, [D6]DMSO,
353 K) DEPT: δ (ppm)=−5.9, −5.7 (CH3, Si(CH3)2), 17.0 (SiC(CH3)3), 20.4 (CH2, C-6), 24.7 (CH3,
SiC(CH3)3), 27.1 (CH3, CO2C(CH3)3), 28.7 (CH2, C-5), 45.2, 46.9 (CH2, C-2 and C-7), 72.3, 74.4 (CH,
C-3 and C-4), 77.3 (CO2C(CH3)3), 158.5 (CO2C(CH3)3); C17H35NO4Si (345.56); calcd: C 59.05, H
10.21, N 4.05; found: C 58.97, H 9.84, N 4.13.
3.10. (3S,4R)-4-Azido-3-tert-butyldimethylsilyloxy-1-tert-butoxycarbonylazepane 15a
14a (1.0 g, 2.89 mmol) and 1.2 ml (8.67 mmol, 3 equivalents) of triethylamine in 20 ml of dichloro-
methane are cooled to –20°C. Mesyl chloride (270 µl, 3.47 mmol, 1.2 equivalents) is slowly added. The
mixture is stirred for 20 min at −20°C, then it is warmed to room temperature. Water is added followed
by extraction with 3 portions of ether. The combined organic extracts are dried (Na2SO4), the solvent is
distilled and the residue is purified by column chromatography (Et2O, Rf=0.65). The resulting pale yellow
oil (1.06 g, 2.50 mmol) is dissolved in 5 ml of DMPU and 813 mg (12.50 mmol, 5 equivalents) of NaN3
are added. The mixture is heated to 80°C for 7 days under intense magnetic stirring. Then water is added,
the mixture is extracted with two portions of ether, the combined organic extracts are dried over Na2SO4
and the solvent is distilled. The residue is purified by column chromatography (Et2O/PE 1+4, Rf=0.38).
Yield: 525 mg (1.42 mmol, 57%) as a colourless oil; RIp=2084; [α]D20=−24 (c=1.0, tBuOMe); IR (neat):
ν (cm−1)=2950, 2880, 2100 (N3), 1695 (C_O), 1420, 1260; 1H NMR (200 MHz, [D6]DMSO, 353 K):
δ (ppm)=0.22 (6H, s, Si(CH3)2), 0.99 (9H, s, SiC(CH3)3), 1.58 (9H, s, CO2C(CH3)3), 1.60–2.07 (4H, m,
5-H, 6-H), 3.10–3.34 (2H, m, 7-H), 3.58–3.74 (2H, m, 2-H), 3.83–3.87 (1H, m, 4-H), 4.03–4.11 (1H, m,
3-H); 13C NMR (50.3 MHz, [D6]DMSO, 353 K): δ (ppm)=−4.9, −4.7 (Si(CH3)2), 17.7 (SiC(CH3)3),
22.2 (C-6), 25.8 (C-5, SiC(CH3)3), 46.2, 48.0 (C-2, C-7), 65.1 (C-4), 73.5 (C-3), 79.0 (CO2C(CH3)3),
154.7 (CO2C(CH3)3); C17H34N4O3Si (370.57); calcd: C 55.10, H 9.25, N 15.12; found: C 55.32, H 9.00,
N 14.84.
3.11. (3R,4S)-3-Azido-4-tert-butyldimethylsilyloxy-1-tert-butoxycarbonylazepane 15b
14b (212 mg, 0.61 mmol) is treated with 260 µl (185 mg, 1.83 mmol, 3 equivalents) of triethylamine
and 60 µl (84 mg, 0.73 mmol, 1.2 equivalents) of mesyl chloride in 6 ml of dichloromethane. The
resulting mesylate (242 mg, 0.57 mmol) is reacted with 186 mg (2.86 mmol, 5 equivalents) of NaN3 in 1
ml of DMPU as described above; column chromatography: Et2O/PE 1+4 (Rf=0.47); yield: 79 mg (0.21
mmol, 34%) as a colourless oil; RIp=2089; [α]D20=+50.4 (c=0.9, tBuOMe); IR (neat): ν (cm−1)=2940,
2100 (N3), 1700 (C_O), 1410, 1255; 1H NMR (200 MHz, [D6]DMSO, 343 K) DEPT: δ (ppm)=−5.4,
−5.2 (CH3, Si(CH3)2), 17.4 (SiC(CH3)3), 21.0 (CH2, C-6), 28.1 (CH3, CO2C(CH3)3), 29.9 (CH2, C-5),
44.5, 46.1 (C-2 and C-7), 64.2 (CH, C-3), 72.0 (CH, C-4), 78.6 (CO2C(CH3)3), 154.3 (CO2C(CH3)3); 13
C
NMR (50.3 MHz, [D6]DMSO, 343 K) DEPT: δ (ppm)=−5.4, −5.2 (CH3, Si(CH3)2), 17.4 (SiC(CH3)3),
21.0 (CH2, C-6), 28.1 (CH3, CO2C(CH3)3), 29.9 (CH2, C-5), 44.5, 46.1 (CH2, C-2, C-7), 64.2 (CH, C-3),
72.0 (CH, C-4), 78.6 (CO2C(CH3)3), 154.3 (CO2C(CH3)3); C17H34N4O3Si (370.57); calcd: C 55.10, H
9.25, N 15.12; found: C 55.08, H 8.93, N 15.23.

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4535
3.12. (3R,4S)-3-tert-Butyldimethylsilyloxy-1-tert-butoxycarbonyl-4-hydroxyazepane 17a and (3R,4S)-4-
tert-butyldimethylsilyloxy-1-tert-butoxycarbonyl-3-hydroxyazepane 17b
9a is hydrogenated and derivatized according to the procedure described for 14a and 14b. Starting
materials: 2.42 g (8.43 mmol) of 9a, 200 mg 10% Pd/C in 50 ml ethanol, then 2.21 g (10.12 mmol,
1.2 equivalents) of di-tert-butyldicarboxylate; column chromatography: Et2O/PE 1+1 (Rf=0.41–0.48);
yield: 2.00 g (5.79 mmol, 69%) of a mixture of 17a and 17b (1:1, determined by GC) as a colourless
1
oil; RIp=1957, RIp=2001; IR (neat): ν (cm−1)=3480 (OH), 2940, 1700 (C_O), 1470, 1410; H NMR
(200 MHz, [D6]DMSO, 353 K): δ (ppm)=0.16, 0.18, 0.19 (6H, s, Si(CH3)2), 1.00 (9H, s, SiC(CH3)3),
1.56 (9H, s, CO2C(CH3)3), 1.60–1.98 (4H, m, 5-H, 6-H), 3.08–3.30 (2H, m, 7-H), 3.53–3.67 (2H, m, 2-
H), 3.70–4.17 (2H, m, 3-H, 4-H); 13C NMR (50.3 MHz, [D6]DMSO, 353 K); δ (ppm)=−5.4, −5.3, −5.1
(Si(CH3)2), 17.3, 17.4 (SiC(CH3)3), 21.3 (C-6), 25.4 (SiC(CH3)3), 27.8 (CO2C(CH3)3), 28.2, 28.6 (C-5),
45.8, 47.7 (C-2, C-7), 71.1, 71.7, 73.4, 73.6 (C-3, C-4), 77.8, 78.0 (CO2C(CH3)3), 154.2 (CO2C(CH3)3);
C17H35NO4Si (345.56); calcd: C 59.05, H 10.21, N 4.05; found: C 58.87, H 9.99, N 4.12.
3.13. (3S,4S)-3-Azido-4-tert-butyldimethylsilyloxy-1-tert-butoxycarbonylazepane 18a and (3R,4R)-4-
azido-3-tert-butyldimethylsilyloxy-1-tert-butoxycarbonylazepane 18b
According to the procedure described for 15a, a mixture of the compounds 17a and 17b is reacted.
Starting materials: mesylation: 1.08 g (3.12 mmol) of 17a and 17b, 1.30 ml (9.36 mmol, 3 equivalents)
of triethylamine, 290 µl (3.74 mmol, 1.2 equivalents) of mesyl chloride in 30 ml of CH2Cl2, the reaction
time of the mesylation is 40 min at –20°C, yield of mesylation: 1.11 g (ca. 2.63 mmol) of crude product;
azidation: 855 mg (13.15 mmol, 5 equivalents) of NaN3 in 5 ml of DMPU; column chromatography:
Et2O/PE 1+4 (Rf=0.38); yield: 398 mg (1.07 mmol, 34%) as an inseparable mixture (7:3, capillary GC)
of 18a and 18b as a colourless oil; RIp=2078, RIp=2066; IR (neat): ν (cm−1)=2920, 2095 (N3), 1695
1
(C_O), 1410; H NMR (200 MHz, [D6]DMSO, 343 K): δ (ppm)=0.18, 0.20, 0.24 (6H, s, Si(CH3)2),
0.99 (9H, s, SiC(CH3)3), 1.60 (9H, s, CO2C(CH3)3), 1.62–2.01 (4H, m, 5-H, 6-H), 2.99–3.56 (4H, m, 2-
H, 7-H), 3.71–3.83 (2H, m, 3-H, 4-H); 13C NMR (50.3 MHz, [D6]DMSO, 343 K): δ (ppm)=−5.3, −5.1,
−5.0 (Si(CH3)2), 17.2 (SiC(CH3)3), 20.9, 22.0 (C-6), 25.3 (SiC(CH3)3), 26.7, 27.7 (CO2C(CH3)3), 31.2,
44.6, 45.1, 45.5, 48.3, 66.8, 68.1, 73.4, 74.3, 78.6 (CO2C(CH3)3), 155.0 (CO2C(CH3)3); C17H34N4O3Si
(370.57); calcd: C 55.10, H 9.25, N 15.12; found: C 55.40, H 8.95, N 14.70.
3.14. (5S,6S)-6-tert-Butyldimethylsilyloxy-5-hydroxyazepane-2-one 19
6a (10.35 g, 36.56 mmol) is hydrogenated in 200 ml of MeOH/H2O (9+1) in the presence of 500 mg
10% Pd/C for 24 h at 50 bar at ambient temperature. The catalyst is removed by filtration, the solvent
is distilled and the residue is filtered over a layer of silica gel. The solvent is removed and the residue is
recrystallized from acetone/EtOAc. Yield: 6.16 g (23.72 mmol, 65%) as colourless crystals; mp=154°C;
RIP=1971; [α]D20=+33.5 (c=1.0, MeOH); IR (KBr): ν (cm−1)=3300 (OH), 3100 (NH), 1650 (C_O),
1
1250, 1130; H NMR (200 MHz, [D6]acetone) COSY: δ (ppm)=0.10 (6H, s, Si(CH3)2), 0.90 (9H, s,
SiC(CH3)3), 1.58–1.70 (1H, m, 4-HA), 1.90–1.96 (1H, m, 4-HB), 2.07–2.20 (1H, m, 3-HA), 2.51–2.63
(1H, m, 3-HB), 3.01–3.15 (1H, m, 7-HA), 3.41–3.48 (1H, m, 7-HB), 3.51–3.60 (1H, m, 6-H), 3.64–3.73
(1H, m, 5-H), 4.01 (1H, d, J=3.8 Hz, O-H), 6.51 (1H, s, N-H); 13C NMR (50.3 MHz, [D6]acetone)
DEPT: δ (ppm)=−4.7 (CH3, Si(CH3)2), 18.9 (SiC(CH3)3), 26.3 (CH3, SiC(CH3)3), 27.3 (CH2), 29.6
(CH2), 42.2 (CH2, C-7), 71.2 (CH, C-6), 73.4 (CH, C-5), 181.0 (C-2); C12H25NO3Si (259.42); calcd: C
55.56, H 9.71, N 5.40; found: C 55.35, H 9.46, N 5.36.

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C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
3.15. (5S 6R)-6-tert-Butyldimethylsilyloxy-5-hydroxyazepane-2-one 20
7a (6.00 g, 21.02 mmol) is hydrogenated in 120 ml MeOH/H2O (9+1) in the presence of 200 mg
10% Pd/C for 16 h at 50 bar at room temperature. The catalyst is removed by filtration, the solvent is
distilled and 5.45 g (21.00 mmol, 99%) of crude product are obtained as colourless crystals. The product
is further purified by column chromatography (EtOAc/MeOH 9+1); yield: 4.64 g (17.88 mmol, 85%)
of colourless crystals. Recrystallization from tert-butylmethyl ether:petroleum ether 30:50 gives crystals
for crystallographic purposes; mp=139°C; RIp=1951; [α]D20=+4.7 (c=1.5, EtOAc); IR (KBr): ν=3400
(O–H), 1710 (C_O), 1485, 1280, 1090 cm−1; 1H NMR (600 MHz, [D6]acetone): δ (ppm)=0.12 (6H, s,
Si(CH3)2), 0.91 (9H, s, SiC(CH3)3), 1.70–1.75 (1H, m, 4-HA), 1.89–1.94 (1H, m, 4-HB), 2.0–2.1 (1H, m,
3-HA), 2.67–2.71 (1H, m, 3-HB), 2.83–2.94 (1H, m, 7-HA), 3.52–3.58 (1H, m, 7-HB), 3.78 (1H, td, J=2.1,
J=9.2 Hz, 6-H), 3.85–3.88 (1H, m, 5-H), 6.67 (1H, br s, 1-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ
(ppm)=−4.9, −4.8 (CH3, Si(CH3)2), 17.9 (SiC(CH3)3), 25.6 (CH3, SiC(CH3)3), 27.0 (CH2, C-4), 28.6
(CH2, C-3), 41.8 (CH2, C-7), 71.2 (CH, C-6), 72.5 (CH, C-5), 178.6 (C-2); C12H25NO3Si (259.42); the
assignment of 1H- and 13C-NMR signals is verified by 600 MHz HMBC and HMQC; calcd: C 55.56, H
9.71, N 5.40; found: C 55.31, H 9.45, N 5.30.
3.16. (5S,6R)-5,6-O-Isopropylidene-azepane-2-one 21
20 (260 mg, 1.00 mmol) is dissolved in 4.2 ml of methanol (abs). 1.0 ml of 5.2 M methanolic HCl
is added and the mixture is stirred at ambient temperature for 10 min. Then the solvent and the HCl
are distilled at room temperature under vacuum (0.05 mbar) into a cooling trap. The residue is taken
up in 2 ml of dry acetone and the solution is cooled to –20°C. A solution of 266 mg (2.00 mmol, 2
equivalents) of water-free AlCl3 in 4.0 ml of ether (abs) is freshly prepared at –20°C. This solution is
carefully added to the solution of the substrate in acetone. The resulting mixture is first stirred over 15 min
at –20°C, then for 30 min at 0°C and finally at room temperature for 2.25 h. During this time a colourless
precipitate is formed and the colour of the reaction mixture changes to yellow. After this, the mixture
is once more cooled to –20°C and 3 ml of concd NaHCO3 are added. The mixture is warmed to room
temperature, diluted with water until the precipitate is dissolved and is then extracted with 3 portions
of dichloromethane.The combined organic extracts are dried over Na2SO4 and the solvent is distilled.
The residue crystallizes spontaneously and requires no further purification. Yield: 113 mg (0.61 mmol,
61%) as colourless crystals: mp=87°C (lit.4p: mp=85–86°C); RIP=1614; [α]D20=+43 (c=1.3, CHCl3);
lit. 4p: [α]D20=+46.1 (c=0.98, CHCl3); IR (KBr): ν (cm−1)=3220 (NH), 2950, 1670 (C_O), 1220, 1095;
1H NMR (200 MHz, CDCl3): δ (ppm)=1.35 (3H, s, CH3), 1.47 (3H, s, CH3), 1.95–2.32 (3H, m, 3-HA,
4-H), 2.78–2.92 (1H, m, 3-HB), 3.03 (1H, ddd, J6,7A=4.1, J1,7A=7.0, JAB=14.7 Hz, 7-HA), 3.44 (1H,
ddd, J1,7B=5.0, J6,7B=10.5, JAB=14.7 Hz, 7-HB), 4.47 (1H, ddd, J6,7A=4.1, J5,6=4.6, J5,7B=10.5 Hz, 6-H),
4.35 (1H, dd, J5,6=4.6, J4,5=8.7 Hz, 5-H), 6.28 (1H, br s, 1-H); 13C NMR (50.3 MHz, CDCl3) DEPT: δ
(ppm)=24.0 (CH2, C-2), 25.7 (CH3, OCH3), 28.2 (CH3, OCH3), 29.5 (CH2, C-3), 42.0 (CH2, C-7), 74.6
(CH), 74.9 (CH), 108.0 (O2C(CH3)2), 177.4 (C-2); C9H15NO3 (185.22); calcd: C 58.36, H 8.16, N 7.56;
found: C 58.09, H 8.07, N 7.33.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (He 1513/5-1, He 1513/5-2) and the Fonds der
Chemischen Industrie for their financial support and the Humboldt-Gesellschaft for funding Professor
R. M. Mohareb. We express our gratitude to Mrs. A. Betz for the preparation of starting materials.

C. Herdeis et al. / Tetrahedron: Asymmetry 10 (1999) 4521–4537
4537
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