Synthesis of functionalized heterocycles via a tandem Staudinger/aza- Wittig/Ugi multicomponent reaction

Article abstract of DOI:10.1016/j.tetasy.2004.11.079

By combining a Staudinger/aza-Wittig and an Ugi three-component reaction in a one-pot process (SAWU-3CR), a new and efficient multicomponent reaction was developed. The application of this reaction on readily available azido-aldehydes gave easy access to

Full text of DOI:10.1016/j.tetasy.2004.11.079

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 177–185
Synthesis of functionalized heterocycles via a tandem
Staudinger/aza-Wittig/Ugi multicomponent reaction
Mattie S. M. Timmer, Martijn D. P. Risseeuw, Martijn Verdoes, Dmitri V. Filippov,
Jasper R. Plaisier, Gijsbert A. van der Marel, Herman S. Overkleeft*
and Jacques H. van Boom*,z
Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands
Received 28 October 2004; accepted 29 November 2004
Available online 5 January 2005
With deep sadness the authors inform the reader that our colleague, Jacques van Boom, died on July 31st, at the age of 67
Abstract—By combining a Staudinger/aza-Wittig and an Ugi three-component reaction in a one-pot process (SAWU-3CR), a new
and efficient multicomponent reaction was developed. The application of this reaction on readily available azido-aldehydes gave
easy access to highly functionalized, enantiomerically pure pipecolic acid amides and bridged morpholine amide derivatives. The
versatility of this methodology is demonstrated by the construction of a molecular library.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Ugi
1. Introduction
O
R3
IV
O
Multicomponent reactions (MCRs), processes in which
three or more reactants are combined in one reaction
vessel resulting in the formation of products featuring
characteristics of all reactants, have found wide applica-
tion in the synthesis of many structurally diverse mole-
cules.1 In 1959, Ugi et al. reported2 the one-pot
condensation of an aldehyde I, an amine II, a carboxylic
acid IV and an isocyanide V (Scheme 1). This reaction,
now referred to as the Ugi 4-component reaction (Ugi-
4CR), provides an efficient entry to the construction of
functionalized acylamidoacetamides VI. In the first step
of the Ugi-4CR, aldehyde I is condensed with amine II
to produce an intermediate imine III that further reacts
with the isocyanide and carboxylic acid entities to the
bisamide end product.
OH
R1
R1
O
R3
N
O
R1
N
H
N
+
H2N
R2
R2
R2
R4
R4 NC
I
II
III
V
VI
O
R3P=O
R2
Aza-Wittig
I
R
R
R
R3P
R1 N3
R1
N P
Staudinger
VIII
VII
Scheme 1. Ugi four component and Staudinger/aza-Wittig reactions.
It occurred to us that the generation of the bis-substi-
tuted imine III, which plays a pivotal role in the
Ugi-4CR process, could be accomplished by executing
a tandem Staudinger/aza-Wittig event.3 Thus, reaction
of the azide VII with trialkyl(aryl)phosphine would lead
to the formation of the intermediate phosphazene VIII
which, in turn, undergoes an aza-Wittig reaction with
the aldehyde I to produce the imine III and the inert tri-
alkyl(aryl)phosphine oxide. An attractive and important
aspect of performing a tandem Staudinger/aza-Wittig
sequence is depicted in Scheme 2. It can be seen that a
substrate containing both an azide and an aldehyde,
as well as functional groups (R) will give access to a
substituted cyclic imine, thus opening the way to the
*
Corresponding authors. Tel.: +31 71 5274342; fax: +31 71
5274307; e-mail: h.s.overkleeft@chem.leidenuniv.nl
z Deceased.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.079

178
M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
struction of morpholine-based (from 2) and piperidine-
O
O
R1
based (from 6) bisamides. To this end, compound 2
was subjected to trimethylphosphine in methanol at
0 ꢁC for 15 min until evolution of nitrogen gas ceased
(Scheme 4). At this stage, the intermediate imine 7 was
brought to ꢀ78 ꢁC upon which benzoic acid and cyclo-
hexyl isocyanide were added. After stirring for 2 h at
room temperature, removal of the solvent and purifica-
tion by silica gel column chromatography afforded the
homogeneous SAWU-3CR product 8 as a single dia-
stereoisomer in 36% yield.10 In a similar fashion, the
intermediate imine 9, formed upon subjection of the
azido-aldehyde 6 to the Staudinger–aza-Wittig condi-
tions, was condensed with Boc–Ala–OH and cyclohexyl
isocyanide to give the pipecolic amide 10 (34%), also as a
single diastereoisomer.
N3
OH
R3P
N
N
R1
O
O
R2 NC
R
R
R
NH
R2
Scheme 2. Tandem Staudinger/aza-Wittig/Ugi (SAWU-3CR).
construction of cyclic dipeptides via an overall one-pot
Staudinger/aza-Wittig/Ugi (SAWU-3CR) process.
Herein we report the development of a tandem one-pot
SAWU-3CR process for the synthesis of highly func-
tionalized chiral piperidines and morpholines, starting
from orthogonally protected carbohydrate-derived azi-
do-aldehydes. In addition it will be shown that the chiral
information embedded in the starting carbohydrate tem-
plates provides control over the stereochemical outcome
of the overall transformations, resulting in the exclusive
formation of a single diastereomer in each case.
TBDPSO
N3
O
OH
N
O
TBDPSO
i
OH
N
O
O
O
TBDPSO
OH
HN
O
7
2
8
N3
2. Results
O
O
OH
N
BocHN
HO
O
O
N
i
N
H
HO
O
O
O
As starting carbohydrate-derived azido-aldehydes we
selected the partially protected 6-azido-2,5-anhydro-
D-glucofuranoside 2 and 5-azido-D-ribofuranoside 6,
which were prepared by the following sequence of events
(Scheme 3). Selective oxidation of the primary hydroxyl4
in the known anhydroglucoside 15 employing the Dess–
Martin periodinane6 afforded the target azido-aldehyde
2 in 85% yield. Selective tosylation7 of the primary hy-
droxyl in 2,3-O-cyclohexylidene-D-ribose 38 and benzoy-
lation of the anomeric hydroxyl in the resulting tosylate
4 gave the fully protected ribofuranoside 5. Treatment
of 5 with sodium azide in DMF at elevated temperature
and subsequent anomeric debenzoylation using a cata-
lytic amount of sodium methoxide in methanol afforded
the target azido hemi-acetal 6 in good overall yield.9
O
O
10
6
9
Scheme 4. SAWU-3CR. Reagents and conditions: (i) Me3P, MeOH,
0 ꢁC, 15 min, then Ph–COOH or Boc–Ala–OH, cyclohexyl–NC,
ꢀ78 ꢁC, 2 h (8: 36%, 10: 34%).
Complete diastereoselectivity was observed in the for-
mation of SAWU-3CR products 8 and 10. The absolute
configuration of the newly formed stereocentre in 8 was
readily determined by NOE NMR experiments. Long
range NOE interaction between the hydroxyl proton
and H-1 of the morpholine ring (see Scheme 5) con-
firmed the axial orientation of the newly introduced N-
(cyclohexyl) carboxamide functionality. In contrast,
the assignment of the absolute configuration of the
new stereocentre in 10 by NMR proved to be more com-
plicated. No long range NOEs were detected, and the
observed coupling constant between H-1 and H-2 could
O
O
O
N3
OH
N3
i
TBDPSO
OH
TBDPSO
OH
1
2
OH
O
O
O
OH
O
OR
OH
TBDPSO
TsO
N3
OH
N
NOE
OH
H
iv, v
TBDPSO
ii
TBDPSO
OH
N
O
O
O
O
O
H
O
N
H
7
H
O
O
O
O
NC
N
O
HN
O
3
6
4 R = H
O
iii
O
5 R = Bz
11
BocHN
HO
8
Scheme 3. Synthesis of SAWU substrates 2 and 6. Reagents and
conditions: (i) Dess–Martin periodinane, DCM, 0 ꢁC, 2 h, 85%; (ii)
TsCl (1.1 equiv), py, ꢀ5 ꢁC!rt, 16 h; (iii) BzCl (2.5 equiv), pyridine,
1.5 h; (iv) NaN3, DMF, 120 ꢁC, 16 h; (v) NaOMe (cat.), MeOH, 2 h,
51% over four steps; Ts = p-toluenesulfonyl, Bz = benzoyl,
TBDPS = t-butyl-diphenyl-silanyl.
O
NHBoc
O
O
BocHN
O
CN
O
O
4
5
2
HO
3
O
NH
N
HO
N
H
N
O
O
N
H
1
O
O
O
H
10
9
12
With both azido-aldehydes in hand, we set out to estab-
lish their potential as precursors in the SAWU-3CR con-
Scheme 5. Mode of diastereoselective formation of 8 and 10.

M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
179
indicate either a cis or a trans relationship between the
two substituents at C-1 and C-2, depending on the con-
formation of the piperidine ring. Fortunately, analysis
of the X-ray diffraction data of compound 10 (Fig. 1),
readily crystallized from chloroform/n-heptane, unam-
biguously established the trans relationship at C-1 and
C-2, with the piperidine ring adopting a pseudo-boat
conformation.
SAWU-3CR is demonstrated in the synthesis of a small
library of two sets of compounds (see Fig. 2): that is six
bridged morpholines (starting from 2) and 12 piper-
idines (starting from 6). The stereochemical outcome
of the SAWU-3CRs was in both series highly diastereo-
selective. Comparison of the NMR data with those of
the corresponding analogues revealed that the stereo-
chemistry of the newly introduced stereogenic centres
is the same as those of 8 (morpholines) and 10 (piper-
idines). The results clearly demonstrate that a variety
of carboxylic acids and isocyanides can participate in a
SAWU-3CR, with yields ranging from 22% 28 to a max-
imum of 78% 18. Interestingly, the nature of the isocya-
nide has a considerable influence on the overall yield of
the process, which is reflected in the decrease in yield
going from t-butyl isocyanide to cyclohexyl isocyanide
to n-butyl isocyanide (see e.g., 18, 22 and 25).
3. Conclusion
In summary, a new and efficient multicomponent reac-
tion by combining the Staudinger–aza-Wittig mediated
synthesis of imines with the Ugi-3CR mediated synthesis
of functionalized bisamides has been developed. The
versatility of the SAWU-3CR process is demonstrated
in the preparation of a small library of diverse, chiral
and enantiomerically pure functionalized piperidines
and morpholines. We believe that the piperidine and
morpholine scaffolds will be of great value in the field
of combinatorial chemistry. The nature of the carboxylic
acid- and isocyanide components can be altered,
whereas the orthogonality of the hydroxyl functional-
ities inherent to the parent sugars opens the way to fur-
ther selective derivatization. Moreover, the pipecolinic
acid scaffold (e.g., 10) holds great promise in the con-
struction of pharmacologically active agents. Finally,
Figure 1. ORTEP representation of the X-ray crystal structure of 10.
The stereochemical outcome of both transformations
can be explained (Scheme 5) by assuming the approach
of the isocyanide and acid components from the less hin-
dered convex side of the intermediate cyclic imines 7 and
9. Rearrangement of the resulting intermediate anhy-
drides 11 and 12 then leads to the exo-products 8 and
10, respectively. The general applicability of the
H
H
H
O
O
O
O
O
O
TBDPSO
TBDPSO
O
O
BocHN
HO
O
O
TBDPSO
O
O
OH
N
OH
N
N
OH
N
H
N
N
N
N
N
H
N
N
H
N
H
N
H
O
O
O
O
O
HO
HO
HO
O
HO
HO
HO
HO
HO
HO
O
NH
O
NH
O
O
NH
O
O
O
18
19
20
21
13
14
15
(78%)
(62%)
(54%)
(51%)
(51%)
(61%)
(45%)
TBDPSO
TBDPSO
O
TBDPSO
O
O
O
O
O
O
OH
N
OH
O
O
OH
N
H
BocHN
HO
N
N
N
N
H
O
O
N
O
N
H
N
O
O
N
H
O
H
O
NH
O
NH
O
NH
O
O
O
O
O
O
O
22
23
10
24
16
(46%)
17
(53%)
8
(51%)
(36%)
(34%)
(51%)
(36%)
O
O
O
O
O
O
O
O
O
BocHN
HO
N
N
N
H
N
N
H
N
N
H
H
O
O
O
O
O
O
O
25
26
27
28
(22%)
(24%)
(26%)
(25%)
Figure 2. Morpholine and pipecolic amide SAWU-3CR products. Yields of isolated products are given in parentheses.

180
M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
the transformation of carbohydrates, rich in structural
and functional variation, into other azido-aldehyde
derivatives opens the way to the one-pot synthesis of
analogous, highly functionalized heterocyclic scaffolds.
light petroleum ether, 1/4, v/v) yielded compound 6 (a/
b, 6/1) as a pale yellow oil (6.51 g, 25.5 mmol, 51%) as
well as a minor fraction of the starting material 2,3-O-
cyclohexylidene-D-ribofuranose 3 (2.26 g, 4,9 mmol,
20
D
3422, 2936, 2838, 2098, 1450, 1369, 1269, 1231, 1161,
9.8%). ½aŠ ¼ þ40 (c = 0.1, MeCN); IR (thin film)
1
4. Experimental
1096, 1057, 999, 968, 937 cmꢀ1; a-anomer: H NMR
(200 MHz, CDCl3): d 5.47 (d, J1,OH = 4.8 Hz, 1H, H-
1), 4.66 (dd, J2,3 = 5.9 Hz, J3,4 = 1.1 Hz, 1H, H-3), 4.62
(d, 1H, H-2), 4.35 (ddd, J4,5a = 6.8 Hz, J4,5b = 5.5 Hz,
1H, H-4), 3.58 (dd, J5a,5b = 12.5 Hz, 1H, H-5a), 3.41
(dd, 1H, H-5b), 3.04 (br d, 1H, OH), 1.76–1.38 (m,
10H, CH2–Cy); 13C NMR (100.6 MHz, CDCl3): d
112.5, 102.4, 84.7, 81.1, 53.1, 35.4, 33.6, 24.2, 23.2,
22.9; ESI-MS (m/e): 278.2 [M+Na]+, 533.1 [2M+Na]+.
4.1. 2,5-Anhydro-6-azido-4-O-(t-butyl-diphenyl-silanyl)-
6-deoxy-D-glucose 2
Dess–Martin periodinane (1.1 equiv, 4.68 g, 11 mmol)
was added to a stirred, dry solution of diol 1 (4.27 g,
10 mmol) in DCM (50 mL), under an argon atmo-
sphere, at 0 ꢁC. After stirring for 30 min, a mixture of
satd aq NaS2O3 and satd aq NaHCO3 (50 mL, 7/3, v/v)
was added. After stirring for an additional 15 min, the
organic layer was separated, washed with H2Oand
brine, dried (MgSO4) and concentrated. The residue
was purified by column chromatography (tolu-
ene!ethyl acetate/toluene, 1/4, v/v) yielding the title
compound as a colourless oil (3.61 g, 8.5 mmol, 85%):
IR (thin film) 3429, 3065, 2932, 2897, 2858, 2098,
4.3. General procedure for the SAWU-3CR
Azido-aldehyde 2 (0.16 mmol) or 4 (0.25 mmol) was
coevaporated with toluene and dissolved in MeOH
(0.5 mL) under an argon atmosphere at 0 ꢁC. After drop-
wise addition of a solution of trimethylphosphine
(0.5 mmol, 0.50 mL, 1 M in toluene), stirring was contin-
ued until nitrogen evolution ceased. The mixture was
cooled to ꢀ78 ꢁC, carboxylic acid (0.5 mmol) and isocy-
anide (0.5 mmol) were added and stirring was continued
for 12 h at rt. The mixture was concentrated and the
SAWU-3CR product was isolated by flash column chro-
matography (toluene ethyl!acetate/toluene, 1/4, v/v).
1736, 1427, 1252, 1103, 1065, 997, 821, 741, 702 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 9.69 (d, J1,2 = 1.1 Hz,
1H, C(O)H), 7.70–7.58 (m, 4H, CHPh), 7.43–7.38 (m,
6H, CHPh), 4.23–3.83 (m, 4H, H-2, H-3, H-4 and H-
5), 3.04–2.88 (m, 2H, H-6), 1.08 (s, 9H, tBu); 13C
NMR (50.1 MHz, CDCl3): d 201.0 (C(O)H), 135.5
(CHPh), 132.6, 132.4 (CPh), 129.9, 127.7 (CHPh),
86.4, 81.1, 80.0, 79.0 (C-2, C-3, C-4, C-5), 51.7 (C-6),
29.7 (CtBu), 26.8 (CH3tBu), ESI-MS (m/e): 426.2
[M+H]+, 448.2 [M+Na]+.
4.4. (1S,2S,5R,6S,7R)-3-Benzoyl-6-(t-butyl-diphenyl-
silanyloxy)-7-hydroxy-8-oxa-3-aza-bicyclo[3.2.1]octane-
2-carboxylic acid cyclohexylamide 8
4.2. 5-Azido-2,3-O-cyclohexylidene-5-deoxy-a/b-D-
ribofuranose 6
(36 mg, 58 lmol, 36%, 1.2:1 ratio of rotamers11):
20
D
½aŠ ¼ ꢀ3:8 (c 0.25, CDCl3); IR (thin film) 3394, 3304,
3071, 2930, 2856, 1651, 1624, 1539, 1448, 1427, 1391,
1362, 1252, 1192, 1151, 1103, 1060, 1028, 1005, 966,
906, 860, 843, 822, 779, 729, 700 cmꢀ1; Major rotamer:
1H NMR (400 MHz, CDCl3): d 7.76–7.07 (m, 15H,
CHPh), 6.12 (d, JNH,CH = 8.4 Hz, 1H, NH), 4.71 (d,
J1,7 = 6.7 Hz, 1H, H-1), 4.26 (br d, 1H, H-7), 4.13 (d,
J6,7 = 1.3 Hz, 1H, H-6), 4.12 (br s, 1H, H-5), 4.09 (s,
p-Toluenesulfonyl chloride (9.45 g, 49.5 mmol) was
added to a cooled (0 ꢁC) and stirred solution of 2,3-O-
cyclohexylidene-D-ribofuranose 3 (11.5 g, 50 mmol) in
dry pyridine (250 mL). The mixture was allowed to
warm to room temperature and stirring was continued
for 16 h. Benzoyl chloride (14.5 mL, 125 mmol,
2.5 equiv) was added and after stirring for an additional
90 min the mixture was concentrated, taken up in ethyl
acetate and subsequently washed with saturated aque-
ous NaHCO3 (2·), saturated aqueous NH4Cl and brine
(2·). The organic layer was dried (MgSO4) and concen-
trated to obtain a yellow oil, which was coevaporated
with toluene and dissolved in 250 mL dry DMF. Sodium
azide (16.25 g, 250 mmol, 5 equiv) was added and the
resulting suspension was stirred for 12 h at 120 ꢁC.
The mixture was concentrated, taken up in ethyl acetate
and washed with saturated aqueous NaHCO3 (2·) and
brine (2·). The organic layer was dried (MgSO4) and
concentrated. The residue was dissolved in methanol
(300 mL), brought to pH 9 with sodium methanolate
and stirred for 14 h. After neutralization of the solution
with amberlyte H+, the mixture was filtered and concen-
trated in vacuo yielding a yellow oil. The residue was
taken up in ethyl acetate and washed with brine (3·), dried
(MgSO4) and concentrated. Purification by flash column
chromatography (light petroleum ether ! ethyl acetate/
2
1H, H-2), 4.08 (d, J4ax,4eq = 13.0 Hz, 1H, H-4eq), 3.79
(m, 1H, CHCy), 3.08 (dd, J4ax,5 = 2.7 Hz, 1H, H-4ax),
1.97–1.11 (m, 10H, Cy), 1.11 (s, 9H, tBu); 13C NMR
(100.6 MHz, CDCl3):
d
172.5 (PhC(O)), 168.0
(C(O)NCy), 135.8, 135.7 (CHPh), 134.8, 133.7, 132.8
(CPh), 130.2, 130.1, 130.0, 128.7, 128.1, 127.9, 126.7
(CHPh), 82.6 (C-6), 81.5 (C-5), 80.6 (C-7), 77.8 (C-1),
58.7 (C-2), 48.7 (CH Cy), 43.2 (C-4), 32.9, 32.8
(CH2Cy), 29.7 (CtBu), 26.9 (CH3tBu), 25.4, 24.9, 24.7
(CH2Cy); Minor rotamer: 1H NMR (400 MHz, CDCl3):
d 7.76–7.07 (m, 15H, CHPh), 6.23 (d, JNH,CH = 7.7 Hz,
1H, NH), 5.12 (s, 1H, H-2), 4.82 (d, J1,7 = 6.5 Hz, 1H,
H-1), 4.45 (br dd, J6,7 = 1.5 Hz, 1H, H-7), 3.92 (d,
J6,7 = 1.9 Hz, 1H, H-6), 3.79 (m, 1H, CHCy), 3.63 (br
2
s, 1H, H-5), 3.41 (dd, J4ax,4eq = 12.7 Hz, J4ax,5 = 1.6
Hz, 1H, H-4ax), 2.71 (d, 1H, H-4eq), 1.97–1.11 (m,
10H, Cy), 1.05 (s, 9H, tBu); 13C NMR (100.6 MHz,
CDCl3): d 173.2 (PhC(O)), 167.8 (C(O)NCy), 135.7,
135.5 (CHPh), 134.5, 133.3, 132.9 (C Ph), 130.25,
130.15, 130.07, 128.4, 128.1, 127.8, 126.9 (CHPh), 82.5

M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
181
(C-6), 81.0 (C-5), 80.9 (C-7), 78.6 (C-1), 52.2 (C-2), 49.4
(C-4), 48.4 (CHCy), 33.1, 33.0 (CH2Cy), 29.7 (CtBu),
26.8 (CH3tBu), 25.5, 24.8, 24.6 (CH2Cy); ESI-MS (m/
z): 613.5 [M+H]+, 635.6 [M+Na]+; HRMS m/z calcd
for C36H44N2O5Si: 613.3092, obsd: 613.3068.
4.7. (1S,2S,5R,6S,7R)-6-(t-Butyl-diphenyl-silanyloxy)-7-
hydroxy-3-(4-methyl-pentanoyl)-8-oxa-3-aza-bicyclo-
3.2.1]octane-2-carboxylic acid t-butylamide 14
20
D
(58 mg, 98 lmol, 61%, 4:3 ratio of rotamers): ½aŠ
¼
ꢀ5:1 (c 0.25, CDCl3); IR (thin film) 3385, 3298, 3064,
2957, 2930, 2858, 1663, 1630, 1558, 1456, 1427, 1393,
1364, 1286, 1223, 1196, 1111, 1063, 962, 908, 822, 735,
4.5. (2S,3S,4R,5R)-1-(N-Benzyloxycarbonyl-L-alanyl)-
3,4-O-cyclohexylidene-3,4,5-trihydroxy-pipecolic acid
cyclohexylamide 10
702 cmꢀ1
;
Minor rotamer: 1H NMR (400 MHz,
CDCl3): 7.73–7.60 (m, 4H, CHPh), 7.50–7.37 (m, 6H,
CHPh), 5.92 (s, 1H, NH), 4.75 (s, 1H, H-2), 4.71 (d,
J1,7 = 6.7 Hz, 1H, H-1), 4.41 (br dd, J6,7 = 2.2 Hz, 1H,
H-7), 3.93 (br s, 1H, H-5), 3.87 (d, 1H, H-6), 3.39 (dd,
2J4ax,4eq = 12.5 Hz, J4ax,5 = 2.5 Hz, 1H, H-4ax), 2.76 (d,
20
(43 mg, 85 lmol, 34%): ½aŠ ¼ þ140 (c 0.1, CDCl3); IR
D
(thin film) 3294, 2924, 2844, 1676.0, 1655, 1626, 1537,
1524, 1452, 1427, 1369, 1273, 1252, 1159, 1115, 1092,
1069, 1051, 1020, 945 cmꢀ1
;
1H NMR (400 MHz,
CDCl3): d 6.83 (d, JNH,CH(Cy) = 7.5 Hz, 1H, NH–Cy),
5.17 (d, NH,a = 6.9 Hz, 1H, BocNH), 5.15 (d,
J1,2 = 2.0 Hz, 1H, H-1), 5.02 (d, J2,3 = 7.5 Hz, 1H, H-
2), 4.58 (dd, J3,4 = 3.4 Hz, 1H, H-3), 4.51 (app p,
Ja,b = 6.9 Hz, 1H, H-a), 3.99 (ddd, J4,5ax = 10.6 Hz,
1H, H-4eq), 2.20 (dt, JH-aa,H-ab = 16.0 Hz, JH-aa,H-b =
J
7.6 Hz, 1H, H-aa), 2.09 (dt, JH-ab,H-b = 7.6 Hz, 1H,
H-ab), 1.93 (dhept, JH-,H-c = JH-c,H-d = 7.6 Hz, 1H, H-
c), 1.40 (m, 2H, H-b), 1.29 (s, 9H, tBuN), 1.08 (s, 9H,
tBuTBDPS), 0.82 (d, 6H, H-d); 13C NMR
(100.6 MHz, CDCl3): d 174.0 (CH2C(O)N), 167.1
(C(O)NtBu), 135.7 (CHPh), 133.5, 133.1 (CPh), 130.2,
128.0 (CHPh), 82.7 (C-6), 81.0 (C-5), 80.5 (C-7), 78.2
(C-1), 52.2 (C-2), 51.5 (CNtBu), 46.7 (C-4), 33.3 (CH2-
b), 31.3 (CH2-a), 29.7 (CTBDPS), 28.7 (CH3tBuN),
27.8 (CH2-c), 26.8 (CH3TBDPS), 22.4 (CH2-d); Minor
J4,5eq = 4.8 Hz, 1H, H-4), 3.82–3.77 (dd, J5ax,5eq
=
10.7 Hz, 1H, H-5eq), 3.68–3.64 (m, 1H, CHN–Cy),
3.28 (dd, 1H, H-5ax), 2.29 (s, 1H, OH), 1.95–1.12 (m,
20H, CH2–Cy), 1.45 (s, 9H, tBu); 13C NMR
(100.6 MHz, CDCl3): d 175.3, 168.2, 109.5, 72.6, 71.7,
64.4, 54.5, 48.4, 46.8, 43.8, 35.9, 33.5, 32.6, 32.5, 28.3,
25.4, 25.1, 24.7, 23.9, 23.4, 17.1; ESI-MS (m/z): 510.4
[M+H]+; HRMS m/z calcd for C26H44N3O7: 510.3179,
obsd: 510.3181.
1
rotamer: H NMR (400 MHz, CDCl3): d 7.73–7.60 (m,
4H, CHPh), 7.50–7.37 (m, 6H, CHPh), 5.72 (s, 1H,
NH), 4.79 (d, J1,7 = 6.7 Hz, 1H, H-1), 4.23 (br d, 1H,
H-7), 4.17 (s, 1H, H-2), 4.06 (br s, 1H, H-5), 4.03 (d,
2J4ax,4eq = 13.6 Hz, 1H, H-4eq), 3.89 (d, J6,7 = 1.6 Hz,
1H, H-6), 2.84 (dd, J4ax,5 = 2.6 Hz, 1H, H-4ax), 2.20
(dt, JH-aa,H-ab = 16.0, Hz, JH-aa,H-b = 7.6 Hz, 1H, H-
aa), 2.09 (dt, JH-ab,H-b = 7.6 Hz, 1H, H-ab), 1.93 (dhept,
4.6. (1S,2S,5R,6S,7R)-6-(t-Butyl-diphenyl-silanyloxy)-3-
formyl-7-hydroxy-8-oxa-3-aza-bicyclo[3.2.1]octane-2-
carboxylic acid t-butylamide 13
(43 mg, 82 lmol, 51%, 2:1 ratio of rotamers):
JH-b,H-c = JH-c,H-d = 7.6 Hz, 1H, H-c), 1.40 (m, 2H, H-
20
D
½aŠ ¼ ꢀ5:8 (c 0.25, CDCl3); IR (thin film) 3392, 3333,
b), 1.32 (s, 9H, tBuN), 1.08 (s, 9H, tBuTBDPS), 0.82
(d, 6H, H-d); 13C NMR (100.6 MHz, CDCl3): d 174.3
(CH2C(O)N), 168.3 (C(O)NtBu), 135.7 (CHPh), 133.7,
133.2 (CPh), 130.2, 128.0 (CHPh), 83.0 (C-6), 81.7 (C-
5), 80.2 (C-7), 76.7 (C-1), 56.5 (C-2), 51.7 (CNtBu),
42.3 (C-4), 33.4 (CH2-b), 30.4 (CH2-a), 29.7 (CTBDPS),
28.7 (CH3tBuN), 27.6 (CH2-c), 26.8 (CH3TBDPS), 22.3
(CH2-d); ESI-MS (m/z): 581.4 [M+H]+, 603.5 [M+Na]+;
HRMS m/z calcd for C33H48N2O5Si: 581.3405, obsd:
581.3383.
3065, 2957, 2930, 2856, 1663, 1541, 1450, 1427, 1393,
1364, 1223, 1186, 1113, 1063, 1030, 997, 964, 822, 741,
702 cmꢀ1; Major rotamer: 1H NMR (400 MHz, CDCl3):
7.86 (s, 1H, C(O)H), 7.72–7.61 (m, 4H, CHPh), 7.50–
7.37 (m, 6H, CHPh), 5.83 (s, 1H, NH), 4.86 (d,
J1,7 = 6.8 Hz, 1H, H-1), 4.29 (br d, 1H, H-7), 4.03 (br
s, 1H, H-5), 3.98 (s, 1H, H-2), 3.92 (d, J6,7 = 1.6 Hz,
2
1H, H-6), 3.81 (d, J4ax,4eq = 13.5 Hz, 1H, H-4eq), 2.89
(dd, J4ax,5 = 3.0 Hz, 1H, H-4ax), 1.33 (s, 9H, tBuN),
1.07 (s, 9H, tBuTBDPS); 13C NMR (100.6 MHz,
CDCl3): d 167.6 (C(O)NtBu), 164.1 (HC(O)), 135.6
(CHPh), 133.5, 133.0 (CPh), 130.3, 128.1 (CHPh), 82.9
(C-6), 81.3 (C-5), 80.4 (C-7), 77.2 (C-1), 56.7 (C-2),
51.8 (CNtBu), 41.6 (C-4), 29.7 (CTBDPS), 28.7
(CH3tBuN), 26.8 (CH3TBDPS); Minor rotamer: 1H
NMR (400 MHz, CDCl3): d 7.76 (s, 1H, C(O)H),
7.72–7.61 (m, 4H, CHPh), 7.50–7.37 (m, 6H, CHPh),
5.92 (s, 1H, NH), 4.71 (d, J1,7 = 6.8 Hz, 1H, H-1), 4.63
4.8. (1S,2S,5R,6S,7R)-3-Benzoyl-6-(t-butyl-diphenyl-
silanyloxy)-7-hydroxy-8-oxa-3-aza-bicyclo[3.2.1]octane-
2-carboxylic acid t-butylamide 15
(43 mg, 72 lmol, 45%, 1.1:1 ratio of rotamers):
20
D
½aŠ ¼ ꢀ2:7 (c 0.25, CDCl3); IR (thin film) 3395, 3308,
3065, 2957, 2930, 2858, 1663, 1622, 1558, 1427, 1393,
1364, 1286, 1223, 1111, 1059, 1030, 1005, 964, 822,
739, 702 cmꢀ1; Major rotamer: 1H NMR (400 MHz,
CDCl3): 7.78–7.06 (m, 15H, CHPh), 5.88 (s, 1H, NH),
5.04 (s, 1H, H-2), 4.84 (d, J1,7 = 6.7 Hz, 1H, H-1), 4.44
(br s, 1H, H-7), 3.90 (d, J6,7 = 2.4 Hz, 1H, H-6), 3.64
(s, 1H, H-2), 4.37 (br dd, J6,7 = 1.7 Hz, 1H, H-7), 3.97
=
2
(br s, 1H, H-5), 3.92 (d, 1H, H-6), 3.44 (dd, J4ax,4eq
12.5 Hz, J4ax,5 = 2.6 Hz, 1H, H-4ax), 2.65 (d, 1H,
H-4eq), 1.31 (s, 9H, tBuN), 1.08 (s, 9H, tBuTBDPS);
13C NMR (100.6 MHz, CDCl3): d 167.4 (C(O)NtBu),
162.7 (HC(O)), 135.5 (CHPh), 133.3, 133.2 (CPh),
130.2, 128.0 (CHPh), 82.9 (C-6), 81.1 (C-5), 80.3 (C-7),
77.9 (C-1), 51.6 (C-2), 51.5 (CNtBu), 46.8 (C-4), 29.7
(CTBDPS), 28.7 (CH3tBuN), 26.8 (CH3TBDPS); ESI-
MS (m/z): 511.5 [M+H]+, 533.2 [M+Na]+.
2
(br s, 1H, H-5), 3.39 (dd, J4ax,4eq = 13.0 Hz,
J4ax,5 = 2.3 Hz, 1H, H-4ax), 2.76 (d, 1H, H-4eq), 1.35
(s, 9H, tBuN), 1.05 (s, 9H, tBuTBDPS); 13C NMR
(100.6 MHz, CDCl3):
(C(O)NtBu), 135.7, 135.5 (CHPh), 135.0, 133.3, 132.8
d
172.4 (PhC(O)), 167.7
(CPh), 130.0, 129.9, 128.7, 128.1, 127.9 (CHPh), 82.5

182
M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
(C-6), 81.0 (C-5), 80.9 (C-7), 78.5 (C-1), 52.4 (C-2), 51.5
(CNtBu), 49.3 (C-4), 29.7 (CTBDPS), 28.8 (CH3tBuN),
26.8 (CH3TBDPS); Minor rotamer: 1H NMR
(400 MHz, CDCl3): d 7.78–7.06 (m, 15H, CHPh), 5.65
(s, 1H, NH), 4.65 (d, J1,7 = 6.7 Hz, 1H, H-1), 4.21 (br
1250, 1192, 1106, 1063, 1030, 968, 907, 845, 822, 733,
702 cmꢀ1; Major rotamer: 1H NMR (400 MHz, CDCl3):
7.71–7.61 (m, 4H, CHPh), 7.49–7.39 (m, 6H, CHPh),
5.82 (d, JNH,CH = 8.3 Hz, 1H, NH), 4.82 (d,
J1,7 = 4.2 Hz, 1H, H-1), 4.25 (s, 1H, H-2), 4.22 (br d,
=
2
2
1H, H-7), 4.07 (br s, 1H, H-5), 4.04 (d, J4ax,4eq
d, 1H, H-7), 4.18 (d, J4ax,4eq = 13.0 Hz, 1H, H-4eq),
4.15 (d, J6,7 = 1.7 Hz, 1H, H-6), 4.12 (br s, 1H, H-5),
4.01 (s, 1H, H-2), 3.14 (dd, J4ax,5 = 3.0 Hz, 1H, H-
4ax), 1.34 (s, 9H, tBuN), 1.10 (s, 9H, tBuTBDPS); 13C
NMR (100.6 MHz, CDCl3): d 173.1 (PhC(O)), 168.2
(C(O)NtBu), 135.7, 135.6 (CHPh), 134.4, 133.7, 133.2
(CPh), 130.22, 130.16, 128.2, 128.1, 126.7 (CHPh),
82.6 (C-6), 81.6 (C-5), 80.6 (C-7), 77.8 (C-1), 58.8 (C-
2), 51.8 (CNtBu), 43.1 (C-4), 29.7 (CTBDPS), 28.7
(CH3tBuN), 26.9 (CH3TBDPS); ESI-MS (m/z): 587.6
[M+H]+, 609.4 [M+Na]+; HRMS m/z calcd for
C34H42N2O5Si: 587.2936, obsd: 587.2910.
12.7 Hz, 1H, H-4eq), 3.89 (d, J6,7 = 1.5 Hz, 1H, H-6),
3.80 (m, 1H, CHCy), 2.84 (dd, J4ax,5 = 2.9 Hz, 1H,
H-4ax), 2.20–1.10 (m, 15H, Cy and i-pentyl), 1.08 (s,
9H, tBu), 0.82 (d, Jc,d = 6.5 Hz, 6H, H-d); 13C NMR
(100.6 MHz, CDCl3): d 174.4 (CH2C(O)N), 168.0
(C(O)NtBu), 135.7 (CHPh), 133.7, 133.1 (CPh), 130.3,
128.2 (CH Ph), 82.8 (C-6), 81.7 (C-5), 80.6 (C-7), 78.1
(C-1), 56.2 (C-2), 48.5 (CHCy), 42.5 (C-4), 33.3 (CH2-
b), 32.9, 32.8 (CH2Cy), 31.3 (CH2-a), 29.7 (CtBu),
27.6 (CH2-c), 26.8 (CH3tBu), 25.4, 24.8, 24.7 (CH2Cy),
22.3 (CH2-d); Minor rotamer: 1H NMR (400 MHz,
CDCl3): d 7.71–7.61 (m, 4H, CHPh), 7.49–7.39 (m,
6H, CHPh), 5.88 (d, JNH,CH = 7.8 Hz, 1H, NH), 4.84
(s, 1H, H-2), 4.75 (d, J1,7 = 6.7 Hz, 1H, H-1), 4.40 (br
dd, J6,7 = 1.7 Hz, 1H, H-7), 3.94 (br s, 1H, H-5), 3.88
4.9. (1S,2S,5R,6S,7R)-6-(t-Butyl-diphenyl-silanyloxy)-3-
formyl-7-hydroxy-8-oxa-3-aza-bicyclo[3.2.1]octane-2-
carboxylic acid cyclohexylamide 16
2
(d, 1H, H-6), 3.72 (m, 1H, CHCy), 3.38 (dd, J4ax,4-
(41 mg, 74 lmol, 46%, 2:1 ratio of rotamers):
eq = 12.6 Hz, J4ax,5 = 2.3 Hz, 1H, H-4ax), 2.80 (d, 1H,
H-4eq), 2.20–1.10 (m, 15H, Cy and i-pentyl), 1.09 (s,
9H, tBu), 0.82 (d, Jc,d = 6.5 Hz, 6H, H-d); 13C NMR
(100.6 MHz, CDCl3): d 174.0 (CH2C(O)N), 167.8
(C(O)NtBu), 135.6 (CHPh), 133.7, 133.1 (CPh), 130.2,
128.0 (CH Ph), 83.0 (C-6), 81.7 (C-5), 80.6 (C-7), 78.1
(C-1), 51.9 (C-2), 48.2 (CHCy), 46.1 (C-4), 33.3 (CH2-
b), 33.1, 33.0 (CH2Cy), 30.4 (CH2-a), 29.7 (CtBu),
27.6 (CH2-c), 26.8 (CH3tBu), 25.5, 24.8, 24.7 (CH2Cy),
22.4 (CH2-d); ESI-MS (m/z): 607.5 [M+H]+, 629.5
[M+Na]+; HRMS m/z calcd for C35 H50N2 O5 Si:
607.3562, obsd: 607.3542.
20
D
½aŠ ¼ ꢀ3:9 (c 0.25, CDCl3); IR (thin film) 3285, 3065,
2930, 2855, 1655, 1539, 1450, 1427, 1387, 1250, 1113,
1063, 1030, 999, 964, 822, 741, 704 cmꢀ1; Major rot-
amer: 1H NMR (400 MHz, CDCl3): d 7.88 (s, 1H,
C(O)H), 7.72–7.62 (m, 4H, CHPh), 7.50–7.38 (m, 6H,
CHPh), 5.96 (d, JNH,CH = 8.1 Hz, 1H, NH), 4.90 (d,
J1,7 = 6.9 Hz, 1H, H-1), 4.71 (s, 1H, H-2), 4.31 (br d,
1H, H-7), 4.07 (br s, 1H, H-5), 4.03 (s, 1H, H-2), 3.94
=
2
(d, 1H, H-6), 3.88 (m, 1H, CHCy), 3.81 (d, J4ax,4eq
13.5 Hz, 1H, H-4eq), 2.90 (dd, J4ax,5 = 2.8 Hz, 1H,
H-4ax), 1.98–1.10 (m, 10H, CH2Cy), 1.09 (s, 9H, tBu);
13C NMR (100.6 MHz, CDCl3): d 167.4 (C(O)NCy),
164.1 (HC(O)), 135.6 (CHPh), 133.5, 133.0 (CPh),
130.2, 128.1 (CHPh), 82.9 (C-6), 81.3 (C-5), 80.4 (C-7),
77.2 (C-1), 56.3 (C-2), 47.1 (CHCy), 41.6 (C-4), 32.9,
32.8 (CH2Cy), 29.7 (CtBu), 26.8 (CH3tBu), 25.4, 24.7
(CH2Cy); Minor rotamer: 1H NMR (400 MHz, CDCl3):
d 7.79 (s, 1H, C(O)H), 7.72–7.62 (m, 4H, CHPh), 7.50–
7.38 (m, 6H, CHPh), 5.90 (d, JNH,CH = 7.8 Hz, 1H,
NH), 4.85 (d, J1,7 = 6.8 Hz, 1H, H-1), 4.71 (s, 1H,
4.11. (2S,3S,4R,5R)-3,4-O-Cyclohexylidene-1-formyl-
3,4,5-trihydroxy-pipecolic acid t-butylamide 18
20
(66 mg, 195 lmol, 78%): ½aŠ ¼ þ120 (c 0.7, CDCl3); IR
D
(thin film) 3304, 2924, 1682, 1643, 1551, 1450, 1416,
1
1367, 1286, 1165, 1097, 1086, 1042, 988, 949 cmꢀ1; H
NMR (400 MHz, CDCl3): Major rotamer: d 8.21 (s,
1H, C(O)H), 6.82 (s, 1H, NH), 4.95 (d, J1,2 = 2.1 Hz,
1H, H-1), 4.81 (dd, J2,3 = 7.2 Hz, 1H, H-2), 4.67 (dd,
J3,4 = 4.2 Hz, 1H, H-3), 4.04 (dddd, J4,5eq = 4.2 Hz,
J4,5ax = 10.4 Hz, J4,OH = 9.2 Hz, 1H, H-4), 3.47 (dd,
J5ax,5eq = 11.1 Hz, 1H, H-5eq), 3.38 (dd, 1H, H-5ax),
2.45 (d, 1H, OH), 1.74–1.38 (m, 10H, CH2–Cy), 1.34
(s, 9H, tBu); 13C NMR (100.6 MHz, CDCl3): Major rot-
amer: d 168.2, 164.3, 109.4, 72.4, 72.0, 64.5, 53.4, 43.9,
35.8, 33.4, 28.5, 25.0, 23.9, 23.5; ESI-MS (m/z): 341.1
[M+H]+; HRMS m/z calcd for C17 H29N2 O5:
341.2076, obsd: 341.2078.
H-2), 4.40 (br d, 1H, H-7), 3.96 (br s, 1H, H-5), 3.94
=
2
(s, 1H, H-6), 3.88 (m, 1H, CHCy), 3.39 (dd, J4ax,4eq
12.7 Hz, J4ax,5 = 2.5 Hz, 1H, H-4ax), 2.66 (d, 1H,
H-4eq), 1.98–1.10 (m, 10H, CH2Cy), 1.09 (s, 9H, tBu);
13C NMR (100.6 MHz, CDCl3): d 167.1 (C(O)NCy),
163.5 (HC(O)), 135.5 (CHPh), 133.5, 133.2 (CPh),
130.2, 128.0 (CHPh), 82.9 (C-6), 81.1 (C-5), 80.3 (C-7),
77.9 (C-1), 51.4 (C-2), 48.6 (CHCy), 46.8 (C-4), 33.0,
32.9 (CH2Cy), 29.7 (CtBu), 26.8 (CH3tBu), 25.4, 24.7
(CH2Cy); ESI-MS (m/z): 537.2 [M+H]+, 559.4
[M+Na]+; HRMS m/z calcd for C30 H40N2 O5 Si:
537.2779, obsd: 537.2763.
4.12. (2S,3S,4R,5R)-3,4-O-Cyclohexylidene-3,4,5-trihy-
droxy-1-(4-methyl-pentanoyl)-pipecolic acid t-butylamide
19
4.10. (1S,2S,5R,6S,7R)-6-(t-Butyl-diphenyl-silanyloxy)-
7-hydroxy-3-(4-methyl-pentanoyl)-8-oxa-3-aza-bicyclo-
[3.2.1]octane-2-carboxylic acid cyclohexylamide 17
20
(64 mg, 155 lmol, 62%): ½aŠ ¼ þ153 (c 0.6, CDCl3); IR
D
(thin film) 3317, 2934, 1670, 1630, 1541, 1449, 1416,
(53 mg, 85 lmol, 53%, 2:1 ratio of rotamers):
1366, 1225, 1163, 1094, 1045, 949 cmꢀ1 1H NMR
;
20
D
3064, 2930, 2856, 1636, 1539, 1448, 1427, 1387, 1362,
½aŠ ¼ ꢀ3:5 (c 0.25, CDCl3); IR (thin film) 3391, 3304,
(400 MHz, CDCl3): d 7.10 (s, 1H, NH), 5.06 (d,
J1,2 = 2.5 Hz, 1H, H-1), 4.80 (ddd, J2,3 = 7.5 Hz,

M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
183
4J3,5eq = 1.1 Hz, 1H, H-2), 4.64 (dd, J3,4 = 3.9 Hz, 1H,
H-3), 4.04 (app dt, J4,5eq = 4.6 Hz, J4,5ax = 11.0 Hz,
1H, H-4), 3.47 (ddd, J5ax,5eq = 10.6 Hz, 1H, H-5eq),
3.26 (app t, 1H, H-5ax), 2.38–2.31 (m, 3H, OH and
CH2-a), 1.65–1.24 (m, 13H, CH2-b, CH-c and CH2–
Cy), 1.28 (s, 9H, tBu), 0.93 (d, J = 6.4 Hz, 3H, CH3-d),
0.91 (d, J = 6.4 Hz, 3H, CH3-d); 13C NMR
(100.6 MHz, CDCl3): d 175.7, 169.5, 109.2, 72.4, 71.5,
64.8, 54.9, 51.0, 44.3, 35.8, 33.7, 33.3, 31.6, 28.5, 27.8,
25.0, 23.9, 23.4, 22.3, 22.2; ESI-MS (m/e): 411.2
[M+H]+; HRMS m/z calcd for C22H39N2O5: 411.2859,
obsd: 411.2950.
J4,5eq = 4.2, J5ax,5eq = 11.3 Hz, 1H, H-5eq), 3.35 (dd,
J4,5ax = 10.9 Hz, 1H, H-5ax), 2.47 (d, J4,OH = 7.8 Hz,
1H, OH), 1.89–1.14 (m, 20H, CH2–Cy); 13C NMR
(100.6 MHz, CDCl3): Major rotamer: d 173.3, 164.3,
109.4, 72.4, 72.1, 64.5, 53.8, 48.3, 43.9, 35.8, 33.4, 32.5,
25.4, 23.9, 23.5; ESI-MS (m/z): 367.4 [M+H]+; HRMS
m/z calcd for C19H31N2O5: 367.2233, obsd: 367.2202.
4.16. (2S,3S,4R,5R)-3,4-O-Cyclohexylidene-3,4,5-trihy-
droxy-1-(4-methyl-pentanoyl)-pipecolic acid cyclohexyl-
amide 23
20
(40 mg, 91 lmol, 36%): ½aŠ ¼ þ138 (c 0.3, CDCl3); IR
D
(thin film) 3306, 2932, 2853, 1732, 1634, 1533, 1448,
4.13. (2S,3S,4R,5R)-1-(N-Benzyloxycarbonyl-L-alanyl)-
3,4-O-cyclohexylidene-3,4,5-trihydroxy-pipecolic acid
t-butylamide 20
1416, 1366, 1163, 1092, 1045, 947 cmꢀ1 1H NMR
;
(400 MHz, CDCl3): d 7.10 (d, JNH,CH = 7.9 Hz, 1H,
NH), 5.09 (d, J1,2 = 2.4 Hz, 1H, H-1), 4.82 (dd,
J2,3 = 7.4 Hz, 1H, H-2), 4.64 (dd, J3,4 = 3.8 Hz, 1H, H-
3), 4.05–4.01 (m, 1H, H-4), 3.69–3.57 (m, 1H, CHN),
3.45 (dd, J4,5eq = 4.7 Hz, J5ax,5eq = 10.5 Hz, 1H, H-5eq),
3.25 (app t, J5ax,4 = 11.0 Hz, 1H, H-5ax), 2.41–2.36
(m, 3H, OH and CH2-a), 1.95–1.12 (m, 23H, CH2-b,
CH-c and CH2–Cy), 0.93 (d, J = 6.4 Hz, 3H, CH3-d),
0.91 (d, J = 6.4 Hz, 3H, CH3-d0); 13C NMR
(100.6 MHz, CDCl3): d 175.7, 169.2, 109.3, 72.4, 71.5,
64.8, 54.3, 47.9, 44.4, 35.8, 33.7, 33.4, 32.5, 31.6, 27.8,
25.5, 25.1, 24.4, 23.9, 23.5, 22.4, 22.3; ESI-MS (m/z):
437.3 [M+H]+; HRMS m/z calcd for C24H41N2O5:
437.3015, obsd: 437.2949.
20
(65 mg, 135 lmol, 54%): ½aŠ ¼ þ119 (c 0.2, CDCl3); IR
D
(thin film) 3333.7, 2937, 1695, 1643, 1514, 1448, 1433,
1
1366, 1165, 1102, 1093, 1049, 947, 908 cmꢀ1; H NMR
(400 MHz, CDCl3): d 6.74 (s, 1H, NH), 5.10 (d,
J
NH,a = 7.1 Hz, 1H, BocNH), 5.04 (s, 1H, H-1), 4.90
(d, J2,3 = 6.8 Hz, 1H, H-2), 4.57 (dd, J3,4 = 3.4 Hz, 1H,
H-3), 4.51 (app p, Ja,b = 7.1 Hz, 1H, H-a), 4.05–4.01
(m, 1H, H-4), 3.77–3.73 (m, 1H, H-5eq), 3.24 (app t,
J4,5ax = 10.8 Hz, 1H, H-5ax), 2.29 (d, J4,OH = 8.0 Hz,
1H, OH), 1.95–1.12 (m, 10H, CH2–Cy), 1.41 (s, 9H,
OtBu), 1.26 (s, 9H, NtBu); 13C NMR (100.6 MHz,
CDCl3): d 175.5, 168.7, 109.4, 72.4, 71.6, 64.5, 55.2,
51.3, 46.9, 43.8, 35.9, 33.4, 28.5, 28.3, 25.1, 23.8, 23.4,
17.3; ESI-MS (m/z): 484.5 [M+H]+; HRMS m/z calcd
for C24H42N3O7: 484.3023, obsd: 484.3011.
4.17. (2S,3S,4R,5R)-1-Benzoyl-3,4-O-cyclohexylidene-
3,4,5-trihydroxy-pipecolic acid cyclohexylamide 24
20
(56 mg, 128 lmol, 51%): ½aŠ ¼ þ119 (c 1.0, CDCl3); IR
4.14. (2S,3S,4R,5R)-1-Benzoyl-3,4-O-cyclohexylidene-
3,4,5-trihydroxy-pipecolic acid t-butylamid 21
D
(thin film) 3317, 2924, 2862, 1736, 1626, 1531, 1447,
1412, 1371, 1244, 1163, 1102, 1093, 1045, 949 cmꢀ1
;
20
(52 mg, 125 lmol, 51%): ½aŠ ¼ þ105 (c 0.7, CDCl3); IR
1H NMR (400 MHz, CDCl3): d 7.48–7.37 (m, 6H,
CHarom and NH), 5.24 (d, J1,2 = 1.8 Hz, 1H, H-1), 4.88
(dd, J2,3 = 7.0 Hz, 1H, H-2), 4.64 (dd, J3,4 = 3.9 Hz,
1H, H-3), 4.02–3.92 (m, 1H, H-4), 3.84–3.61 (m, 1H,
CHN–Cy), 3.36 (app t, J5ax,4 = J5ax,5eq = 11.1 Hz, 1H,
H-5ax), 3.22 (dd, J4,5eq = 3.9 Hz, 1H, H-5eq), 2.44 (d,
J4,OH = 9.3 Hz, 1H, OH), 1.87–1.12 (m, 20H, CH2–
Cy); 13C NMR (100.6 MHz, CDCl3): d 173.3, 168.8,
135.1, 130.2, 128.6, 126.9, 109.4, 72.5, 71.9, 64.7, 55.1,
48.0, 46.6, 43.4, 35.9, 33.5, 32.6, 32.5, 29.6, 25.5, 25.1,
24.4, 24.0, 23.5; ESI-MS (m/z): 443.2 [M+H]+, 465.2
[M+Na]+, 885.5 [2M+H]+, 907.5 [2M+Na]+; HRMS
m/z calcd for C25H35N2O5: 443.2546, obsd: 443.2539.
D
(thin film) 2924, 2852, 1689, 1674, 1628, 1541, 1448,
1418, 1366, 1226, 1163, 1102, 1093, 1045, 991,
947 cmꢀ1 1H NMR (400 MHz, CDCl3): d 7.59–7.43
;
(m, 5H, CHarom), 6.05 (br s, 1H, NH), 5.21 (d,
J1,2 = 1.8 Hz, 1H, H-1), 4.88 (dd, J2,3 = 7.1 Hz, 1H,
H-2), 4.65 (dd, J3,4 = 4.0 Hz, 1H, H-3), 3.96 (app dt,
J4,5ax = 4.0 Hz, J4,5eq = 10.6 Hz, 1H, H-4), 3.37 (app t,
J3,4 = 11.2 Hz, 1H, H-5ax), 3.24 (dd, 1H, H-5ax), 1.73–
1.26 (m, 10H, CH2–Cy), 1.35 (s, 9H, tBu); 13C NMR
(100.6 MHz, CDCl3): d 173.3, 166.8, 135.2, 133.4,
130.2, 130.1, 128.6, 128.4, 126.9, 109.4, 72.5, 71.9,
64.7, 55.8, 46.6, 35.9, 33.5, 29.7, 28.6, 25.1, 24.0, 23.5;
ESI-MS (m/z): 417.4 [M+H]+; HRMS m/z calcd for
C23H33N2O5: 417.2389, obsd: 417.2433.
4.18. (2S,3S,4R,5R)-3,4-O-Cyclohexylidene-1-formyl-
3,4,5-trihydroxy-pipecolic acid n-butylamide 25
4.15. (2S,3S,4R,5R)-3,4-O-Cyclohexylidene-1-formyl-
3,4,5-trihydroxy-pipecolic acid cyclohexylamide 22
20
(20 mg, 60 lmol, 24%): ½aŠ ¼ þ95 (c 0.3, CDCl3); IR
;
1286, 1163, 1092, 1043, 988, 947 cmꢀ1 1H NMR
(400 MHz, CDCl3): Major rotamer: d 8.18 (s, 1H,
C(O)H), 6.90 (s, 1H, NH), 4.96 (d, J1,2 = 2.0 Hz, 1H,
H-1), 4.79 (dd, J2,3 = 7.2 Hz, 1H, H-2), 4.6 (dd,
J3,4 = 4.2 Hz, 1H, H-3), 4.04–4.00 (m, 1H, H-4), 3.49–
D
(thin film) 3305, 2932, 2834, 1647, 1537, 1416, 1369,
20
(47 mg, 128 lmol, 51%): ½aŠ ¼ þ119 (c 0.2, CDCl3); IR
D
(thin film) 3306, 2932, 2855, 1665, 1645, 1539, 1408,
1
1369, 1163, 1093, 1086, 1043, 988, 949 cmꢀ1; H NMR
(400 MHz, CDCl3): Major rotamer: d 8.18 (s, 1H,
C(O)H), 6.79 (d, JNH,CHN = 7.6 Hz, 1H, NH), 4.95 (d,
J1,2 = 2.1 Hz, 1H, H-1), 4.79 (dd, J2,3 = 7.2 Hz, 1H, H-
2), 4.63 (dd, J3,4 = 4.2 Hz, 1H, H-3), 4.18–4.16 (m, 1H,
H-4), 3.68–3.64 (m, 1H, CHN–Cy), 3.44 (dd,
3.16 (m, 2H, H-5eq and H-5ax), 2.45 (d, J4,OH
9.2 Hz, 1H, OH), 1.74–1.25 (m, 14H, CH2–Cy and
=
CH2–Bu), 0.91 (t, J = 7.5 Hz, 3H, CH3); 13C NMR

184
M. S. M. Timmer et al. / Tetrahedron: Asymmetry 16 (2005) 177–185
(100.6 MHz, CDCl3): Major rotamer: 168.8, 164.3,
109.4, 72.4, 72.0, 64.4, 53.6, 43.9, 39.2, 35.8, 33.4, 31.3,
25.0, 23.9, 23.5, 20.0, 13.6; ESI-MS (m/z): 341.1
[M+H]+; HRMS m/z calcd for C17H29N2O5: 341.2076,
obsd: 341.2081.
1H, OH), 1.74–1.25 (m, 14H, CH2–Cy and CH2–Bu),
0.94 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (100.6 MHz,
CDCl3): d 173.3, 166.8, 135.1, 130.3, 128.6, 127.0,
109.4, 72.5, 71.9, 64.7, 55.0, 46.7, 39.1, 36.0, 33.5, 31.4,
25.1, 24.0, 23.5, 20.0, 13.7; ESI-MS (m/z): 417.2
[M+H]+; HRMS m/z calcd for C23H33N2O5: 417.2389,
obsd: 417.2431.
4.19. (2S,3S,4R,5R)-3,4-O-cyclohexylidene-3,4,5-trihy-
droxy-1-(4-methyl-pentanoyl)-pipecolic acid n-butylamide
26
4.22. X-ray crystallographic data for 10
20
(27 mg, 65 lmol, 26%): ½aŠ ¼ þ132 (c 0.4, CDCl3); IR
C52H88N6O15, Mr = 1037.28, monoclinic, space group
C2, a = 31.9170(14), b = 56.5430(3), c = 13.6200(7)
D
(thin film) 3317, 2934, 2862, 1735, 1634, 1533, 1416,
1367, 1271, 1232, 1163, 1094, 1045, 949 cmꢀ1
;
1H
(A), a = 90, b = 92.491(2), c = 90ꢁ, V = 2841.6(2) (A) 3,
Z = 2, qcalcd = 1.212 g cmꢀ1, T = 293(2), l (MoKa) =
0.089 mmꢀ1, 5763 measured reflections, 3165 indepen-
dent, 346 parameters, R1 = 0.0597 (I > 2r(I)), wR2 =
0.1385 (all data). The intensity data were collected on
a Bruker Kappa CCD diffractometer with graphite-
˚
˚
NMR (400 MHz, CDCl3): d 7.17 (t, JNH = 5.9 Hz, 1H,
CH2NH), 5.14 (d, J1,2 = 2.5 Hz, 1H, H-1), 4.85 (dd,
J2,3 = 7.5 Hz, 1H, H-2), 4.64 (dd, J3,4 = 3.9 Hz, 1H, H-
3), 4.07 (m, 1H, H-4), 3.49 (dd, J5ax,5eq = 10.6 Hz,
J4,5eq = 11.5 Hz, 1H, H-5eq), 3.29 (dd, J4,5ax = 4.9 Hz,
1H, H-5ax), 3.19 (dt, J = 6.8 Hz, 2H, CH2CH2NH),
2.40–2.35 (m, 3H, OH and CH2-a), 1.72–1.27 (m, 17H,
CH2-b, CH-c, 2 · CH2n-Bu and CH2–Cy), 0.961 (d,
˚
monochromated MoKa radiation (k = 0.71073 (A)).
The structures were solved by the direct method and re-
fined by fullmatrix least squares on F2 using SHELXL 97
(G. M. Sheldrick, University of Go¨ttingen, 1997). The
non-hydrogen atoms were refined anisotropically. Three
hydrogen atoms were refined isotropically, the remain-
ing hydrogen atoms were idealized by using the riding
models. CCDC 227314 contains the supplementary crys-
tallographic data. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB21EZ, UK, fax:
(+44)1223-336-033 or deposit@ccdc.cam.ac.uk).
0
Jc,d = 6.4 Hz, 3H, CH3-d), 0.959 (d, Jc,d = 6.4 Hz, 3H,
CH3-d0), 0.93 (t, J = 7.3 Hz, 3H, CH3n-Bu); 13C NMR
(100.6 MHz, CDCl3): d 175.7, 170.1, 109.3, 72.4, 71.5,
64.7, 54.2, 44.3, 38.9, 35.8, 33.6, 33.4, 31.6, 31.4, 27.8,
25.1, 23.9, 23.5, 22.4, 22.2, 20.0, 13.7; ESI-MS (m/e):
411.2 [M+H]+; HRMS m/z calcd for C22H39N2O5:
411.2859, obsd: 411.2932.
4.20. (2S,3S,4R,5R)-1-(N-Benzyloxycarbonyl-L-alanyl)-
3,4-O-cyclohexylidene-3,4,5-trihydroxy-pipecolic acid
n-butylamide 27
20
(30 mg, 63 lmol, 25%): ½aŠ ¼ þ94 (c 0.1, CDCl3); IR
Acknowledgements
D
(thin film) 3304, 2928, 2855, 1715, 1674, 1639, 1524,
1454, 1367, 1252, 1163, 1069, 1020, 947 cmꢀ1
;
1H
This work was financially supported by the Council for
Chemical Sciences of the Netherlands Organization for
Scientific Research (CW-NWO), the Netherlands Tech-
nology Foundation (STW) and Solvay Pharmaceuticals.
We are grateful to Arjan van Langevelde and Jarek
Mazurek (Avantium Technologies BV) for obtaining
X-ray crystallographic data.
NMR (400 MHz, CDCl3): d 7.05 (s, 1H, NH), 5.36 (d,
NH,a = 6.2 Hz, 1H, BocNH), 5.18 (s, 1H, H-1), 5.07
J
(d, J2,3 = 7.5 Hz, 1H, H-2), 4.57 (dd, J3,4 = 3.1 Hz, 1H,
H-3), 4.51 (app p, Ja,b = 6.8 Hz, 1H, H-a), 3.99–3.95
(m, 1H, H-4), 3.86–3.82 (m, 1H, H-5eq), 3.31 (app t,
J4,5ax = 10.4 Hz, 1H, H-5ax), 3.25 (m, 2H, CH2N and
OH), 3.12 (m, 1H, CH2N), 1.66–1.24 (m, 14H, CH2–
Cy and CH2–Bu), 0.90 (t, J = 7.3 Hz, 3H, CH3); 13C
NMR (100.6 MHz, CDCl3): d 175.3, 168.5, 109.6,
80.1, 72.6, 66.0, 54.4, 44.9, 43.8 39.3, 35.9, 33.4, 33.1
32.9, 31.4, 29.7, 25.5, 25.0, 23.8, 23.4, 22.5, 20.2 20.1
20.0; ESI-MS (m/z): 484.3 [M+H]+, 506.4 [M+Na]+;
HRMS m/z calcd for C24H42N3O7: 484.3023, obsd:
484.3032.
References
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4.21. (2S,3S,4R,5R)-1-Benzoyl-3,4-O-cyclohexylidene-
3,4,5-trihydroxy-pipecolic acid n-butylamide 28
20
(23 mg, 55 lmol, 22%): ½aŠ ¼ þ123 (c 0.2, CDCl3); IR
D
2. (a) Ugi, I.; Steinbruckner, C. Patent DE-B 1,103,337,
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1369, 1271, 1232, 1163, 1102, 1093, 1074, 1045, 989,
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J3,4 = 3.9 Hz, 1H, H-3), 4.02–3.98 (m, 1H, H-4), 3.37
(app t, J4,5ax = J5ax,5eq = 11.1 Hz, 1H, H-5ax), 3.33–3.15
(m, 3H, H-5ax and CH2N), 2.37 (d, J4,OH = 8.7 Hz,

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