Exo -Glycals: Intermediates in the synthesis of 1,1-disubstituted c -glycosides

Article abstract of DOI:10.1055/s-0029-1219560

The synthesis of 1,1-disubstituted C-glycosides containing amino and ester containing moieties at what is formally the anomeric site is described. Petasis olefination of pyranosyl lactones provided exo-glycals which underwent regioselective azidoselenatio

Full text of DOI:10.1055/s-0029-1219560

LETTER
A
exo-Glycals: Intermediates in the Synthesis of 1,1-Disubstituted C-Glycosides
e
xo-Glycals: Interm
a
ediates in
n
the Synthesi
n
s
of 1,1-Disu
a
bstituted
C
h
-Glycosides Woodward,a Nichola Smith,b Timothy Gallagher*a
a
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Fax +44(117)9251295; E-mail: t.gallagher@bristol.ac.uk
Novartis Institute for Biomedical Research, Novartis Horsham Research Centre, Horsham RH12 5AB, UK
b
Received 4 January 2010
OAc
O
AcO
AcO
Abstract: The synthesis of 1,1-disubstituted C-glycosides contain-
ing amino and ester containing moieties at what is formally the ano-
meric site is described. Petasis olefination of pyranosyl lactones
provided exo-glycals which underwent regioselective azidoselena-
tion and subsequent radical-mediated C-glycoside formation.
OAc
O
AcO
AcO
(i) PhI(OAc)2, NaN3,
(PhSe)2, CH2Cl2
Me
SePh
(ii) HS(CH2)3SH
(iii) Ac2O, py
R
AcHN
2
1
R = Me
Key words: C-glycosides, azidoselenation, Petasis olefination
OAc
AcO
O
Me
Bu3SnH,
AcO
The synthesis of C-glycosides as carbohydrate mimetics
has been the subject of considerable interest due to the im-
proved stability of this class of carbohydrate derivative
towards acidic and enzymatic hydrolysis while still retain-
ing in many cases the desirable biological profile of the
‘parent’ O-glycoside.1 Consequently, a number of meth-
ods have been developed for the preparation of C-glyco-
side analogues of complex carbohydrates.2 Our
contributions3 in this area have been focused on defining
methods for generating a-C-glycosides based on gluco,
galacto, and manno 2-acetamido sugars, given the biolog-
ical importance of amino sugars associated in particular
with O-linked glycopeptides. We have also extended this
chemistry to a wider range of C-glycosides and this is il-
lustrated in Scheme 1 for a C1-methylated galacto variant
1 (R = Me). Azidoselenation4 of endo-glycal 1 (R = Me)
provided anomeric selenide 2 and C–Se homolysis (and
AcHN
AIBN, PhH
H
3
OAc
AcO
AcO
Bu3SnH,
AIBN, PhH
O
Me
AcHN
CO2t-Bu
CO2t-Bu
4
Scheme 1 b-C-Glycosides and 1,1-disubstituted C-glycosides
manno lactones 5–7, respectively (Scheme 2).8 The olefi-
nation process showed only modest levels of selectivity
for the lactone carbonyl in the presence of competing O-
acetate residues (e.g., 5a) but a higher and synthetically
useful level of discrimination was observed when the cor-
responding O-pivaloyl (Piv)-protected carbohydrates
(e.g., 5b) were employed.
the associated anomeric radical reactivity) was harnessed Our objective was to evaluate exo-glycals 8–10 as sub-
to provide the b-C-glycoside series 3 (by reduction) and strates for a series of addition processes, and these includ-
by trapping the anomeric radical derived from 2 with a ed use of organometallic nucleophiles as well as
reactive alkene, the 1,1-disubstituted C-glycoside 4.3c
OR
OR
RO
However, this chemistry was limited to the use of the C1-
unsubstituted or C1-methyl variants (i.e., 1, R = H or Me)
and attempts to extend this chemistry to include other C1
substituents (1, R = alkyl or aryl) were unsuccessful. The
issue here was that the azidoselenation step (i.e., 1 → 2)
failed when R ≠ H or Me.5 In order to solve this issue and
extend this methodology to a wider range of C1 substitu-
tion patterns, we have explored the use of exo-cyclic gly-
cals (e.g., 8–10) as a more general starting point for C-
glycoside synthesis.
RO
Cp2TiMe2
O
O
RO
RO
150 W, 70 °C
40 psi
O
RO
CH2
RO
5a R = Ac
5b R = Piv
8a R = Ac, 20%
8b R = Piv, 50%
OR
O
OR
O
as above
RO
RO
RO
RO
O
CH2
RO
RO
Our strategy has involved use of O-protected exo-glycals
8–10, which were readily available via Petasis
olefination6 (using Cp2TiMe2 under microwave-mediated
conditions7) from the corresponding galacto, gluco and
6 R = Piv
9 R = Piv, 50%
RO
RO
RO
RO
RO
as above
O
O
RO
RO
RO
O
CH2
7 R = Piv
10 R = Piv, 50%
SYNLETT 2010, No. x, pp 000A–000D
x
x
.xx.
2
0
1
0
Advanced online publication: xx.xx.2010
Scheme 2 Petasis olefination of galacto, gluco, and manno carbohy-
DOI: 10.1055/s-0029-1219560; Art ID: D00210ST
drate lactones
© Georg Thieme Verlag Stuttgart · New York

B
H. Woodward et al.
LETTER
azidoselenation to provide a more general entry to C1- giochemistry of the azidoselenation step was confirmed
substituted glycals.
by 1H NMR: acetamide 14 clearly showed CHHNHAc as
a doublet of doublets (J = 14.5, 3.5 Hz) where coupling
(J = 3.5 Hz) to the amide NH was apparent. C-Glycoside
formation was achieved by homolysis of the C–Se bond in
14 and trapping of the resulting anomeric (and tertiary)
radical species with tert-butyl acrylate to give the 1,1-di-
substituted C-glycoside 15 as a single isomer (see below).
Similar sequences were achieved in the gluco series (9 →
16 → 17) and in the manno series (10 → 19 → 20) to pro-
vide 1,1-disubstituted C-glycosides 18 and 21, respective-
ly.
While a variety of methods were examined, we were un-
able to achieve Pd(0)-mediated allylic displacements in-
volving 8–10. Substrates 8b and 9 were unreactive
towards Pd(0) under a variety of conditions, and this was
demonstrated using a series of control experiments.9 In
the case of the manno derivative 10, in which the allylic
leaving group is positioned in a stereoelectronically more
favorable arrangement for displacement,10 evidence for
the intermediacy of the p-allyl Pd(II) species 11 was ob-
tained. However, this species was unreactive towards a
malonate nucleophile, and the desired adduct 12 was not Regiochemical assignments of 15, 18, and 21 were based
1
observed (Scheme 3).9,11
on H NMR analysis (following from the assignment of
the acetamide 14) but it was not possible to assign ‘ano-
meric’ stereochemistry unambiguously. For this reason,
the structure of azidoselenide 1613 was determined by X-
ray crystallography, which demonstrated the expected
preference of the anomeric radical to undergo axial attack,
with the trapping agent being Ph2Se2. We have assumed
that the galacto and manno adducts and the corresponding
C-glycosides 15, 18, and 21 display the same stereochem-
ical preference, and this is indicated as the outcomes
shown in Scheme 4.
RO
RO
RO
RO
Pd0
O
O
RO
RO
RO
CH2
[PdII]
10 R = Piv
11
CO2Et
CO2Et
Na
RO
RO
RO
O
CO2Et
CO2Et
12 R = Piv
It is also pertinent to note that selenoglycosides function
as glycosyl donors in more conventional O-glycosylation
processes.14 Using the manno adduct 19, activation using
NIS/TMSOTf and employing benzyl alcohol as the accep-
tor, gave O-glycoside 22 which underwent dithiol-mediat-
ed azide reduction and in situ acetylation to give O-
glycoside 23 in 60% overall yield (Scheme 5).15
Scheme 3
Azidoselenation does, however, provide an alternative
means of functionalizing exo-glycals 8b, 9, and 10. In the
case of the galacto derivative 8b, azidoselenation gave the
selenoglycoside adduct 13 in 46% yield.12
The a-stereochemistry of O-glycosides 22 and 23 is as-
sumed (based on an expected preference for an a-manno-
One-pot azide reduction (using a dithiol) and protection
provided the N-acetylated amine 14 in 94% yield. The re-
OR
RO
RO
OR
RO
RO
NaN3 PhI(OAc)2
Ph2Se2, r.t., 24 h
O
O
Bu3SnH, AIBN
8b
Y
NHAc
CO2t-Bu
PhH
RO
RO
CO2t-Bu
SePh
13 Y = N3 (46%)
15 (38%)
HS(CH2)3SH
then Ac2O, py
14 Y = NHAc (94%)
OR
O
OR
O
NaN3 PhI(OAc)2
Ph2Se2, r.t., 24 h
RO
Bu3SnH, AIBN
RO
9
RO
RO
Y
NHAc
CO2t-Bu
PhH
RO
RO
CO2t-Bu
SePh
16 Y = N3 (72%)
18 (35%)
HS(CH2)3SH
then Ac2O, py
(X-Ray)
17 Y = NHAc (69%)
RO
RO
RO
RO
RO
RO
O
O
NaN3 PhI(OAc)2
Ph2Se2, r.t., 24 h
Bu3SnH, AIBN
10
RO
RO
Y
NHAc
CO2t-Bu
PhH
CO2t-Bu
SePh
19 Y = N3 (84%)
21 (61%)
HS(CH2)3SH
then Ac2O, py
20 Y = NHAc (56%)
Scheme 4 Generation of 1,1-disubstituted C-glycosides via C1-substituted selenide intermediates; R = Piv throughout
Synlett 2010, No. x, A–D © Thieme Stuttgart · New York

LETTER
exo-Glycals: Intermediates in the Synthesis of 1,1-Disubstituted C-Glycosides
C
sition) is too efficient. When the C1 substituent carried a
RO
RO
RO
RO
RO
RO
O
pendent alkenyl residue (e.g., allyl), only addition to this less
electron-rich alkene was observed (Gallagher, T.; Wang, J.-
W. unpublished work).
NIS, TMSOTf
BnOH
O
RO
N3
SePh
RO
Y
O
Ph
(6) (a) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392. (b) Csuk, R.; Glanzer, B. I. Tetrahedron 1991, 47,
1655.
(7) Cook, M. J.; Fleming, D. W.; Gallagher, T. Tetrahedron
Lett. 2005, 46, 297.
19 (R = Piv)
22 Y = N3 (63%)
23 Y = NHAc (98%)
HS(CH2)3SH
then Ac2O, py
Scheme 5
(8) Data for exo-Glycals
Conventional carbohydrate numbering (cf. sialic acids) is
used.
1
side) as H NMR did not allow for an unambiguous
assignment of anomeric stereochemistry.
Compound 8b: 1H NMR (400 MHz, CDCl3): d = 1.13, 1.20,
1.23, 1.28 [36 H, 4 × s, 4 × COC(CH3)3], 3.99–4.10 (2 H, m,
H7a + H7b), 4.25 (1 H, m, H6), 4.50 (1 H, t, J = 1.5 Hz,
=CHH, H1a), 4.77 (1 H, t, J = 1.5 Hz, =CHH, H1b), 5.15 (1
H, dd, J = 10.5, 3.0 Hz, H4), 5.53 (1 H, dd, J = 3.0, 1.0 Hz,
H5), 5.76 (1 H, dt, J = 10.5, 1.5 Hz, H3). 13C NMR (100
MHz, CDCl3): d = 27.0, 27.1, 38.7, 38.8, 61.2, 66.6, 67.2,
71.5, 75.8, 95.3, 154.6, 176.7, 176.8, 177.8. ESI-HRMS:
m/z calcd for C27H4409 [M + Na]+: 535.2878; found:
535.2868. Compound 9: 1H NMR (400 MHz, CDCl3): d =
1.14–1.24 [36 H, m, 4 × COC(CH3)3], 3.77–3.78 (1 H, m,
H6), 4.06–4.26 (2 H, m, H7a + H7b), 4.49 (1 H, t, J = 1.5 Hz,
H1a), 4.80 (1 H, t, J = 1.5 Hz, H1b), 5.26 (2 H, dd, J = 7.0,
2.5 Hz, H4 + H5), 5.47 (1 H, m, H3). 13C NMR (100 MHz,
CDCl3): d = 27.1, 27.2, 38.8, 38.9, 61.7, 67.6, 69.0, 72.8,
76.6, 96.2, 154.0, 176.4, 176.5, 177.1, 178.1. ESI-HRMS: m/
z calcd for C27H4409 [M + Na]+: 535.2878; found: 535.2902.
Compound 10: 1H NMR (400 MHz, CDCl3): d = 1.13–1.25
[36 H, m, 4 × COC(CH3)3], 3.87 (1 H, m, H6), 4.23–4.25 (2
H, m, H7a + H7b), 4.71 (1 H, d, J = 1.0 Hz, H1a), 4.83 (1 H,
d, J = 1.0 Hz, H1b), 5.15 (1 H, dd, J = 10.0, 3.5 Hz, H4),
5.62 (1 H, app t, J = 10.0 Hz, H5), 5.69 (1 H, d, J = 3.5 Hz,
H3). 13C NMR (100 MHz, CDCl3): d = 27.0, 27.1, 27.1, 38.7,
38.8, 38.9, 61.4, 64.5, 68.9, 71.0, 77.0, 101.4, 152.9, 176.6,
176.9, 177.3, 178.1. ESI-HRMS: m/z calcd for C27H44O9
[M + Na]+: 535.2877; found: 535.2890.
In summary, radical-mediated azidoselenation, which is
well established for conventional endocyclic glycals, is
also effective with exo-glycals. The resulting adducts
function as intermediates for the synthesis of 1,1-disubsti-
tuted C-glycosides which constitute an unusual class of
carbohydrate-based amino acids derivatives 15, 18, and
21, and also O-glycosides, such as 22 and 23.
Acknowledgment
The authors thank the EPSRC and Novartis Institute for Biomedical
Research for financial support, and Dr. Mairi Haddow for the
crystallographic determination of 16.
References and Notes
(1) (a) Bertozzi, C. R.; Cook, D. R.; Kobertz, W. R.; Gonzalez-
Scarano, F.; Bednarski, M. D. J. Am. Chem. Soc. 1992, 114,
10639. (b) Wei, A.; Boy, K. M.; Kishi, Y. J. Am. Chem. Soc.
1995, 117, 9432. (c) Sutherlin, D. P.; Stark, T. M.; Hughes,
R.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8350.
(2) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545.
(b) Levy, D.; Tang, C. The Chemistry of C-Glycosides;
Pergamon: Oxford, 1995. (c) Nicotra, F. Topics Curr.
Chem. 1997, 187, 55. (d) Togo, H.; He, W.; Waki, Y.;
Yokoyama, M. Synlett 1998, 700. (e) Skrydstrup, T.;
Vauzeilles, B.; Beau, J.-M. In Carbohydrates in Chemistry
and Biology. The Chemistry of Saccharides, Vol. 1; Ernst,
B.; Hart, G. W.; Sinaÿ, P., Eds.; Wiley-VCH: New York,
2000, Chap. 20, 495–530.
(9) To determine whether the carbohydrate substrates were
reactive towards Pd(0), a series of control experiments were
carried using cinnamyl acetate as a standard. Exposure of
cinnamyl acetate and exo-glycal 8b (or 9 or 10) to sodio-
diethyl malonate in the presence of a catalytic quantity of
Pd(0) (Pd2dba3/dppe) led to the expected substituted
cinnamyl adduct as the only product observed and galacto 8b
was recovered unchanged. With the gluco substrates 9
essentially the same outcome was observed: cinnamyl
acetate reacted but exo-glycal 9 did not. In the case of the
manno variant 10, and under the same reaction conditions,
none of the cinnamyl substitution product was detected,
suggesting that coordination of Pd(0) to 10 occurred [to
sequester Pd(0)] but any resulting complex (e.g., 11) was
then unreactive towards the external malonate nucleophile.
(10) (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395. (b) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21,
2591. (c) Dunkerton, L. V.; Euske, J. M.; Serino, A. J.
Carbohydr. Res. 1987, 171, 89. (d) Shi, G.; Huang, X.-H.;
Zhang, F.-J. Tetrahedron Lett. 1995, 36, 6305.
(3) (a) San Martin, R.; Tavassoli, B.; Walsh, K. E.; Walter,
D. S.; Gallagher, T. Org. Lett. 2000, 2, 4051. (b) Grant, L.;
Liu, Y.; Walsh, K. E.; Walter, D. S.; Gallagher, T. Org. Lett.
2002, 4, 4623. (c) Liu, Y.; Gallagher, T. Org. Lett. 2004, 6,
2445.
(4) (a) Czernecki, S.; Randriamandimby, D. Tetrahedron Lett.
1993, 34, 7915. (b) Czernecki, S.; Ayadi, E.;
Randriamandimby, D. J. Chem. Soc., Chem. Commun. 1994,
35. (c) Czernecki, S.; Ayadi, E.; Randriamandimby, D.
J. Org. Chem. 1994, 59, 8256. (d) Santoyo-Gonzalez, F.;
Calvo-Flores, F. G.; Garcia-Mendoza, P.; Hernandez-
Mateo, F.; Isac-Garcia, J.; Robles-Diaz, R. J. Org. Chem.
1993, 58, 6122.
(11) Extensive attempts (varying ligands, reaction temperatures,
solvents and catalysts, including use of palladium and
nickel) to carry out the allylic displacement chemistry using
manno substrate 10 were all unsuccessful.
(5) Using C1-metalated endo-glycals we have prepared a series
of C1-substituted alkyl and aryl glycals (i.e., 1 R = Alk, Ar)
and evaluated these as substrates for azidoselenation. Even
under forcing conditions, no azidoselenation was observed
and this is attributed to the known (and facile) reversible
nature of the azidoselenation process. We assume that
trapping with Ph2Se2 of the intermediate (a tertiary or
benzylic anomeric radical) resulting from initial N3·addition
is slow and expulsion of N3·(and its subsequent decompo-
(12) Spectroscopic data are provided for the galacto series shown
in Scheme 4.
Compound 13: 1H NMR (400 MHz, CDCl3): d = 1.12–1.28
[36 H, m, 4 × COC(CH3)3], 3.12 (1 H, d, J = 13.5 Hz,
1 × CH2N3), 3.62 (1 H, d, J = 13.5 Hz, 1 × CH2N3), 3.94 (1
Synlett 2010, No. x, A–D © Thieme Stuttgart · New York

D
H. Woodward et al.
LETTER
H, dd, J = 11.0, 9.0 Hz, H6a), 4.03 (1 H, dd, J = 11.0, 6.0 Hz,
H6b), 4.71 (1 H, m, H5), 5.48 (1 H, dd, J = 10.5, 3.0 Hz, H3),
5.59 (1 H, dd, J = 3.0, 1.0 Hz, H4), 5.87 (1 H, d, J = 10.5 Hz,
H2), 7.35–7.44 (3 H, m, ArCH), 7.58–7.61 (2 H, m, ArCH).
13C NMR (100 MHz, CDCl3): d = 26.9, 27.0, 27.1, 38.7,
38.8, 38.9, 39.0, 56.1, 60.3, 66.5, 66.7, 70.5, 70.5, 91.9,
124.5, 129.3, 137.6, 176.3, 177.9, 180.4, 180.5. ESI-HRMS:
m/z calcd for C33H49N3O9Se [M + Na]+: 734.2526; found:
734.2556.
J = 3.5, 1.0 Hz, H4). 13C NMR (100 MHz, acetone-d6): d =
20.0, 26.4, 26.5, 26.6, 26.7, 27.0, 27.5, 27.6, 27.7, 38.3, 38.5,
39.0, 42.0, 42.3, 61.9, 65.6, 68.1, 72.4, 76.2, 100.0, 173.2,
176.9, 177.1, 179.8. ESI-HRMS: m/z calcd for C36H61NO12
[M + Na]+: 722.4086; found: 722.4087.
(13) (a) An X-ray diffraction experiment on 16 was carried out at
100 K on a Bruker APEX II diffractometer using MoKa
radiation (l = 0.71073 Å). The data collection was
performed using a CCD area detector from a single crystal
mounted on a glass fibre. Intensities were integrated
(Bruker-AXS SAINT V7.60A) from several series of
exposures measuring 0.5° in w or j. Absorption corrections
were based on equivalent reflections using SADABS
(Sheldrick, G. M. SADABS V2008/1, University of
Göttingen, Germany), and structures were refined against all
Fo2 data with hydrogen atoms riding in calculated positions
using SHELXL Bruker-AXS SAINT V7.60A.13b The
Cambridge Crystallographic Data Centre deposition number
for 16 is CCDC 763564. (b) Sheldrick, G. M. Acta
Crystallogr., Sect. A 2008, 64, 112.
(14) (a) Mehta, S.; Pinto, B. M. Tetrahedron Lett. 1991, 32,
4435. (b) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58,
3269. (c) Demchenko, A. Synlett 2003, 1225. (d) France,
R. R.; Compton, R. G.; Davis, B. G.; Fairbanks, A. J.; Rees,
N. V.; Wadhawan, J. D. Org. Biomol. Chem. 2004, 2, 2195.
(15) Compound 22: 1H NMR (400 MHz, acetone-d6): d = 1.06,
1.10, 1.16, 1.26 [36 H, 4 × s, 4 × COC(CH3)3], 1.97
(NHCOCH3), 3.53 (1 H, dd, J = 15.0, 5.0 Hz, 1 ×
Compound 14: 1H NMR (400 MHz, CDCl3): d = 1.11–1.27
[36 H, m, 4 × COC(CH3)3], 2.09 (3 H, s, NHCOCH3), 3.36
(1 H, dd, J = 14.5, 3.5 Hz, 1 × CH2NHCOCH3), 3.97 (1 H,
m, H6a), 4.06–4.15 (2 H, m, H6b + 1 × CH2NHCOCH3),
4.85 (1 H, m, H5), 5.50–5.53 (2 H, m, H2 + H4), 5.61 (1 H,
m, H3), 6.03 (1 H, m, NH), 7.31–7.38 (3 H, m, ArCH), 7.59–
7.64 (2 H, m, ArCH). 13C NMR (100 MHz, CDCl3): d = 20.7,
26.9, 27.0, 27.1, 27.2, 27.2, 38.7, 38.8, 39.0, 45.0, 60.4, 66.4,
67.1, 70.2, 71.1, 91.6, 124.7, 129.1, 129.2, 129.2, 137.4,
169.3, 176.4, 177.2, 177.9, 178.1. ESI-HRMS: m/z calcd for
C35H53NO10Se [M + Ma]+: 750.2727; found: 750.2712.
Compound 15: 1H NMR (300 MHz, CDCl3): d = 1.11–
1.30 [36 H, m, 4 × COC(CH3)3], 1.40–1.55 [2 H, m,
CH2CH2CO2C(CH3)3], 2.06 (3 H, s, NHCOCH3), 2.17–
2.32 [2 H, m, CH2CH2CO2C(CH3)3], 3.38–3.44 (2 H, m,
CH2NHCOCH3), 3.62 (1 H, m, H5), 3.97–4.04 (2 H, m, H6a
+ H6b), 5.08 (1 H, dd, J = 10.5, 3.0 Hz, H4), 5.20 (1 H, d,
J = 10.0 Hz, H2), 5.48 (1 H, dd, J = 10.0, 3.0 Hz, H3), 6.05
(1 H, d, J = 5.0 Hz, NH). 13C NMR (100 MHz, acetone-d6):
d = 20.2, 23.5, 26.5, 26.6, 26.7, 26.8, 27.1, 27.5, 27.5, 27.6,
27.6, 38.4, 38.8, 39.5, 42.5, 61.3, 66.5, 67.8, 72.5, 77.0,
106.9, 172.1, 172.9. ESI-HRMS: m/z calcd for C36H61NO12
[M + Na]+: 722.4086; found: 722.4098.
CH2NHCOCH3), 3.74 (1 H, dd, J = 15.0, 8.0 Hz, 1 ×
CH2NHCOCH3), 4.09 (1 H, m, H5), 4.16 (1 H, dd, J = 12.0,
4.5 Hz, H6a), 4.32 (1 H, dd, J = 12.0, 2.0 Hz, H6b), 4.67 (1
H, d, J = 12.0 Hz, 1 × CH2Ph), 4.90 (1 H, d, J = 12.0 Hz,
1 × CH2Ph), 5.37 (1 H, app t, J = 2.0 Hz, H2), 5.44–5.46 (2
H, m, H3 + H4), 6.16 (1 H, app t, J = 6.0 Hz, NH), 7.35 (1
H, m, ArCH), 7.40–7.48 (4 H, m, ArCH). 13C NMR (100
MHz, CDCl3): d = 20.3, 26.5, 26.5, 26.6, 26.8, 37.7, 38.3,
38.5, 38.6, 38.7, 59.7, 61.6, 62.7, 65.0, 68.1, 70.1, 101.4,
127.7, 127.8, 128.7, 138.0, 170.0, 176.3, 176.6, 177.1,
177.3. ESI-HRMS: m/z calcd for C36H55NO11 [M + Na]+:
700.3667; found: 700.3679
Compound 18: 1H NMR (300 MHz, acetone-d6): d = 1.09–
1.22 [36 H, m, 4 × COC(CH3)3], 1.44–1.49 [2 H, m,
CH2CH2CO2C(CH3)3], 2.01 (3 H, s, NHCOCH3), 2.40-2.42
(2 H, m, CH2CH2CO2C(CH3)3), 3.26 (1 H, dd, J = 14.5, 4.5,
1 × CH2NHCOCH3), 3.43 (1 H, dd, J = 14.5, 7.5,
1 × CH2NHCOCH3), 4.02 (1 H, m, H5), 4.09–4.11 (2 H, m,
H6a + H6b), 5.00 (1 H, app t, J = 10.0 Hz, H4), 5.17 (1 H, d,
J = 10.0 Hz, H2), 5.49 (1 H, app t, J = 10.0 Hz, H3), 6.42 (1
H, br s, NH). 13C NMR (100 MHz, acetone-d6): d = 20.2,
23.3, 26.5, 26.6, 26.7, 27.5, 27.0, 27.6, 29.5, 29.3, 42.4, 62.7,
68.6, 70.1, 71.2, 104.1, 169.2, 172.0, 176.8, 177.3, 177.3.
ESI-HRMS: m/z calcd for C36H61NO12 [M + Na]+: 722.4086;
found: 722.4109.
Compound 23: 1H NMR (400 MHz, CDCl3): d = 1.12, 1.14,
1.25, 1.30 [36 H, 4 × s, 4 × COC(CH3)3], 3.26 (1 H, d,
J = 13.5 Hz, 1 × CH2N3), 3.70 (1 H, d, J = 13.5 Hz, 1 ×
CH2N3), 3.92 (1 H, app dq, J = 10.0, 2.0 Hz, H5), 4.12
(1 H, app d, J = 3.5 Hz, H6a), 4.14 (1 H, app d, J = 3.5 Hz,
H6b), 4.62 (2 H, ABq, J = 12.0 Hz, CH2Ph), 5.41–5.52 (2 H,
m, H3 + H4), 5.58 (1 H, d, J = 3.0 Hz, H2), 7.35–7.45 (5 H,
m, ArCH). 13C NMR (100 MHz, CDCl3): d = 27.0, 27.1,
38.3, 38.8, 49.5, 61.8, 63.3, 64.7, 68.4, 70.1, 70.6, 100.8,
127.2, 128.7, 131.5, 136.4, 176.7, 177.1, 178.0. ESI-HRMS:
m/z calcd for C34H51N3O11 [M + Na]+: 684.3467; found:
684.3478.
Compound 21: 1H NMR (400 MHz, acetone-d6): d = 1.10–
1.29 [36 H, m, 4 × COC(CH3)3], 1.44–1.50 [2 H, m,
CH2CH2CO2C(CH3)3], 2.12 (3 H, s, NHCOCH3), 2.29–
2.32 [2 H, m, CH2CH2CO2C(CH3)3], 3.22 (1 H, m,
1 × CH2NHCOCH3), 3.40 (1 H, m, 1 × CH2NHCOCH3),
3.90 (1 H, m, H5), 4.12 (1 H, dd, J = 12.0, 4.5 Hz, H6a), 4.24
(1 H, d, J = 12.0, 2.0 Hz, H6b), 5.14 (1 H, dd, J = 10.0, 3.5
Hz, H3), 5.36 (1 H, d, J = 10.0 Hz, H2), 5.41 (1 H, dd,
Synlett 2010, No. x, A–D © Thieme Stuttgart · New York