Scalable synthesis of a mycosamine donor. Overcoming difficult reactivity in allose systems

Article abstract of DOI:10.1055/s-2005-918474

Mycosamine is a dideoxyaminosugar found in medicinally relevant macrolides, including amphotericin B and nystatin. Herein we report a reliable, high yielding, scalable synthesis of a mycosamine donor. A major goal of our approach was to minimize purificat

Full text of DOI:10.1055/s-2005-918474

3380
PAPER
Scalable Synthesis of a Mycosamine Donor. Overcoming Difficult Reactivity in
Allose Systems
Scalable
S
e
ynthesis of
f
a
Myco
f
D
r
onor ey M. Manthorpe, Alex M. Szpilman, Erick M. Carreira*
Laboratorium für Organische Chemie, ETH Hönggerberg, 8093 Zürich, Switzerland
Fax +41(44)6321328; E-mail: carreira@org.chem.ethz.ch
Received 14 September 2005
ployed by Alais and David6b is incompatible with the
functionalities of amphotericin B.
Abstract: Mycosamine is a dideoxyaminosugar found in medici-
nally relevant macrolides, including amphotericin B and nystatin.
Herein we report a reliable, high yielding, scalable synthesis of a
mycosamine donor. A major goal of our approach was to minimize
purifications via judicious selection of protecting groups; the inher-
ent properties of the allose framework created some deprotection
obstacles that were ultimately solved.
Within the context of our ongoing research program to ex-
plore the behavior of amphotericin B and its conjugates8
we required significant amounts of a mycosamine donor.
We initially considered following the existing route that
has been employed in the context of the total synthesis of
amphotericin B (sketched in Scheme 1). However the re-
Key words: asymmetric synthesis, natural products, glycosyla-
tions, protecting groups, medicinal chemistry
9
ported use of stoichiometric amounts of HgCl2 was not
acceptable for the scale we required. This 15-step route
also necessitated 13 to 14 chromatographic purifications
and produced only 900 mmol of the donor. Given the large
number of chromatographic unit operations and its untest-
ed scalability it was not clear whether the existing route
would serve our needs. In our analysis, we attributed the
lack of clean reactions to the potential lability of the THP
and acetate groups and therefore elected to employ sturdi-
er alternatives.
Amphotericin B1 is the most prominent member of the
family of mycosamine macrolides and an important clini-
cal agent for the treatment of systemic and chronic fungal
infections. Despite being known for over a half century,
its mechanism of action is still not clearly understood.2
Amphotericin B (Figure 1) contains several intriguing do-
mains: a conjugated heptaene (which gives amphotericin
B its distinctive yellow color), a polyacetate segment, and
two polypropionate derived subunits.
O
OCH3
OH
O
OCH3
OAc
O
O
NH2
Ph
O
Ph
O
HO
O
OH
Me
OH
OH
Mycosamine
O
H
Me
HO
O
Me
O
HN
CCl3
O
OH OH
OH OH
O
OH
H3C
O
O
O
OCH3
OAc
Me
OH
O
OH
OH
TBSO
OAc
Ph
O
Figure 1 Amphotericin B.
N3
OTHP
Scheme 1 Synthesis of a mycosamine donor by Nicolaou et al.
An additional domain is the mycosamine, an unusual
dideoxyaminomannose that is linked to the aglycon as the
b-anomer. Although syntheses of the related mycosamine
macrolide aglycons of rimocidin3 and candidin4 have been
reported, successful coupling with a mycosamine donor
has only been achieved by Nicolaou and co-workers in
their synthesis of amphotericin B.5 Two other reports of
mycosamine donors exist in the literature.6 The donor pre-
pared by Packard and Rychnovsky was obtained in 6%
yield and used nystatin,7 another mycosamine macrolide,
as starting material.6a The protecting group scheme em-
The reported step for the glycosylation of amphoterono-
lide relied on anchimeric assistance from a C(2)-acetate
group to ensure selective b-glycosylation (Scheme 2).5
However this reaction also produced a virtually equal
amount of the corresponding orthoester [19% yield as
compared to a 20% yield of the desired glycoside (50% of
the aglycon was also recovered)]. As it has been demon-
strated that the amount of orthoester formation can be re-
duced by changing from acetate to a more sterically
demanding ester (e.g. pivaloate or benzoate),10 we decid-
ed to include a benzoate ester in our synthetic design. This
would have the additional benefit of providing the in-
creased stability we sought in the C(2)-ester.
SYNTHESIS 2005, No. 19, pp 3380–3388
x
x.
x
x
.
2
0
0
5
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918474; Art ID: C06505SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Scalable Synthesis of a Mycosamine Donor
3381
O
OCH3
OH
O
OCH3
OH
a
O
O
Me
O
Ph
O
Ph
O
OBz
Me
O
OH
OH
TBSO
Me
O
O
O
O
OTBSO
OMe
OTBS
2
1
OMe
O
b,c
N3
AcO
O
OTBS
Me
O
OCH3
PPTS cat., hexane
O
OCH3
OBz
O
d
O
O
N3
O
Ph
O
OBz O
Ph
O
HN
CCl3
AcO
O
OTBS
O
OH
O
Me
3
4
H
Me
O
Scheme 3 Reagents and conditions: (a) BzCl (1.2 equiv), K2CO3
(2.0 equiv), Me2SnCl2 cat., THF, r.t., 72 h, 81%; (b) PDC (5.0 equiv),
3 Å MS, CH2Cl2, 24 h; (c) NaBH4 (1.0 equiv), MeOH–THF (8.5:1),
–15 °C, 45 min, 89% over 2 steps; (d) levulinic acid (2.0 equiv), DCC
(2.0 equiv), DMAP (0.7 equiv), CH2Cl2, r.t., 21 h, 88%.
Me
O
TBSO
Me
O
O
O
O
OTBSO
OMe
OTBS
OTBS
Me
OMe
N3
O
sults to inherent reactivity afforded by the allose scaffold
and this led us to seek a protecting group that could be re-
moved under conditions completely orthogonal to the
benzoate.
O
O
O
O
Me
O
Levulinate esters are known to be readily cleaved in the
presence of hydrazine, generally requiring only a small
excess of reagent and short reaction time (<15 min) to
achieve deprotection.14 The levulinate group has also been
shown to be less prone to migration than acetate or ben-
zoate.14e,f Under standard esterification conditions (DCC,
DMAP), protection of 3 was achieved in 88% yield.
Me
TBSO
Me
O
O
O
O
OTBSO
OMe
OTBS
O
OMe
O
Scheme 2 Reported glycosylation of protected amphoteronolide.
Our approach to a mycosamine donor began from methyl
4,6-O-benzylidene-a-D-glucopyranoside (1) (Scheme 3).
The stoichiometric use of stannylidene acetals for the se-
lective acylation of the C(2) of glucose systems is widely
used.11 However, as removal of tin by-products is known
to be problematic and/or tedious, especially on large scale,
we elected to employ the one-step method of Matsumura
et al., which utilizes only a catalytic amount of dimethyl-
tin dichloride.12 On a >900 mmol scale we obtained 81%
of the desired product 2.
Hydrogenolysis of 4 using palladium on carbon proved a
clean reaction, needing no purification step, save filtration
to remove the catalyst (Scheme 4). Regioselective iodina-
tion at C(6) of diol 5 was readily achieved using Appel-
like conditions,15 affording hydroxy iodide 6 in 86% yield
over 2 steps. Although the use of benzene as solvent at
45 °C for 4 hours has been reported necessary to achieve
full conversion,5 we found that the use of THF16 led to
complete conversion of 7 in 30 to 60 minutes at room tem-
perature. It is unclear the extent to which this disparity is
a solvent effect or altered reactivity resulting from the dif-
ferent protecting groups in 5 and 7.
Inversion of configuration at the C(3) was achieved
through a two-step sequence involving PDC oxidation
and NaBH4 reduction. Notably, the only purification re-
quired after either of these reactions was filtration over
Florisil® after the PDC oxidation. With allose derivative
3 in hand, we had to select an appropriate protecting group
for the C(3)-hydroxyl group. As discussed, a THP group
was not deemed suitable. As the protecting group would
have to survive hydrogenolysis, iodination, silylation and
radical reduction and be orthogonal to a TBS ether, ben-
zoate ester and methyl acetal, our options were limited.
We chose to utilize a second ester that could be readily re-
moved in the presence of the benzoate. Phenoxyacetate
and methoxyacetate are both known to hydrolyze at rates
much higher than benzoate.13 Much to our surprise, initial
experiments revealed that in this system the rate of ben-
zoate cleavage was competitive. We attributed these re-
While the highly reactive, expensive TBSOTf has been
employed to silylate the C(4)-hydroxyl group in high
yield in a similar system,5 we were concerned that this re-
agent would lead to formation of the silyl enol ether of the
levulinate ketone; consequently, we opted for the mild
and cheap reagent, TBSCl. The use of this reagent could
however create the possibility of halogen exchange at
C(6). In order to avoid this potential pitfall, the reaction
was performed at high concentration (0.44 M with respect
to 6) in CH2Cl2 – conditions which caused precipitation of
the imidazole hydrochloride byproduct. The silyl ether 8
was isolated in 95% yield and no iodide–chloride ex-
change could be detected by NMR or mass spectrometry.
Reduction of iodide 8 proceeded in 95% yield.
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

3382
J. M. Manthorpe et al.
PAPER
O
OCH3
OBz
O
O
OCH3
OBz
could lead to deleterious results (vide supra). Being weary
of such issues we nevertheless elected to revisit the use of
hydrazine in a mixture of pyridine and acetic acid as sol-
vent. Using 20 equivalents of hydrazine for 24 hours, we
found that the levulinate could be removed from 8 to af-
ford the desired 6-deoxyallose derivative 9 in an opti-
mized yield of 95%, along with only minimal amounts
(<2%) of the silyl migrated compound 10. This extraordi-
nary stability is testament to the sterically congested envi-
ronment created around the levulinate carboxyl function
by the adjacent cis-benzoate and TBS groups.
a
O
HO
HO
Ph
O
O
O
O
O
O
4
5
b
O
OCH3
O
OCH3
OBz
c
Although the triflation of 9 proceeded cleanly, the reac-
tion time increased noticeably compared to the corre-
sponding acetate 11 (16 h vs. 2 h,5 Scheme 5). The crude
triflate 12 rapidly reacted with sodium azide to afford the
desired azido sugar 13 in a crude yield of 93% over two
steps. Isolated 13 from the reaction mixture was of such
purity that it could be used directly in the next step without
additional purification. The sensitive functionalities of the
subsequent compounds prompted us to store material at
this stage and proceed in smaller batches from this point.
The efficiency of this synthesis to this point has allowed
us to prepare >98 mmol of 13 from a single batch of 1.
I
I
TBSO
OBz
O
HO
O
O
O
O
O
8
6
d,e
H3C
R1O
O
OCH3
OBz
O
OCH3
OAc
HO
HO
Conversion of the methyl acetal of 13 to the correspond-
ing anomeric ester 14 was carried out using catalytic
amounts of H2SO4 in Ac2O. We found that the formation
OR2
OTHP
7
R
R
1 = TBS, R2 = H 9
1 = H, R2 = TBS 10
Scheme 4 Reagents and conditions: (a) H2, 10% Pd/C cat., EtOAc,
r.t., 16 h; (b) PPh3 (2.0 equiv), I2 (2.0 equiv), imidazole (7.5 equiv),
THF, r.t., 1 h, 86% over 2 steps; (c) TBSCl (2.0 equiv), imidazole (4.5
equiv), CH2Cl2, r.t., 50 h, 95%; (d) Bu3SnH (2.0 equiv), AIBN cat.,
toluene, D, 2 h, 95%; (e) NH2NH2·H2O (20 equiv), pyridine–AcOH
(3:2), r.t., 24 h, 95%.
H3C
O
OCH3
OR
H3C
O
OCH3
OBz
a
TBSO
TBSO
OH
OTf
12
R = Bz 9
R = Ac 11
At this stage we needed to carry out the selective cleavage
of the levulinate ester – typically a facile endeavor (vide
supra). However, in this instance this group proved to be
extraordinarily recalcitrant to cleavage. The use of hydra-
zine acetate in methanol or anhydrous hydrazine in THF
led to isolation of an E/Z mixture of hydrazones and only
traces of desired product. Heating the hydrazones in either
the presence or absence of base did not lead to cleavage.
Attempts to effect removal using hydroxylamine hydro-
chloride in pyridine–ethanol were equally unsuccessful.
NaBH4 has been shown to readily cleave levulinates via
ketone reduction followed by rapid spontaneous lacton-
ization.14g In the case of levulinate 9 ketone reduction oc-
curred readily but lactone formation was not observed.
We also scanned a variety of bases, including KHMDS,
t-BuOK, LDA, and NaH, in an attempt to induce lacton-
ization. This afforded either no reaction or TBS and/or
benzoate migration occurred. The same battery of bases
was investigated in an attempt to induce cleavage via a
Dieckmann-like reaction but only complex mixtures of
products were observed.
b
O
H3C
O
OCH3
OBz
H3C
O
O
c
TBSO
TBSO
OBz
N3
N3
14
13
d
HN
CCl3
H3C
O
OH
OR
H3C
O
O
e
TBSO
TBSO
OBz
N3
N3
17
R = Bz 15
R = Ac 16
Scheme 5 Reagents and conditions: (a) Tf2O (1.5 equiv), pyridine
(3.0 equiv), CH2Cl2, –40 °C – r.t., 16 h; (b) NaN3 (1.1 equiv), 15-
crown-5 (1.1. equiv), DMF, r.t., 30 min, 93% over 2 steps (crude); (c)
Ac2O, H2SO4 cat., 0 °C to r.t., 55 min, 60% over 3 steps; (d)
NH2NH2·AcOH (1.2 equiv), DMF, r.t., 3 h, 94% (crude); (e) NaH
(1.1. equiv), Cl3CCN (10 equiv), CH2Cl2, 89% over 2 steps, based on
The 2,3,4-cis,cis arrangement of hydroxyl groups in allose
should be well poised for migrations of protecting groups.
During our attempts to hydrolyze the levulinate ester we
were mindful that strongly acidic or basic conditions
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

PAPER
Scalable Synthesis of a Mycosamine Donor
3383
evaporation at 40 °C at the appropriate pressure. Purified com-
pounds were further dried under high vacuum (0.01–0.05 Torr).
Yields refer to purified and spectroscopically pure compounds un-
less explicitly indicated as crude.
of anomeric acetate 14 was quite rapid, commonly being
complete as the reaction reached room temperature. Al-
lowing the reaction to proceed for two hours at room tem-
perature, as previously reported,5 resulted in nearly
complete conversion of the TBS ether to the correspond-
ing acetate. Moreover, to the best of our knowledge, this
work and Nicolaou’s report5 constitute the only examples
in the literature of a secondary TBS ether surviving these
reaction conditions.17 Careful TLC monitoring of this re-
action allowed us to isolate the desired anomeric acetate
14 in 60% yield over three steps. While the isolation of
only a-acetate5 has been reported, we isolated a mixture of
anomeric acetates. Typically the a-anomer is the thermo-
dynamically favored product, as governed by the exo-ano-
meric effect.18 However, with a benzoate at C(2) it is
reasonable to expect that the b-acetate would be kinetical-
ly favored. As prolonged reaction time resulted in destruc-
tion of the C(4)-TBS ether, the reaction was quenched
before the thermodynamic equilibrium was reached.19
Optical rotations were measured on a Jasco DIP-1000 polarimeter
operating at the sodium D line with a 100 mm path length cell. NMR
spectra were recorded on a Varian Mercury 300 spectrometer.
Chemical shifts are reported in ppm with the solvent resonance as
the internal standard. Coupling constants (J values) are reported in
Hz. IR spectra were recorded on a Perkin-Elmer Spectrum RXI
FT-IR spectrophotometer. Absorptions are given in wavenumbers
(cm–1). Mass spectra were recorded by the MS service at ETH
Zurich using an IonSpec Ultima Fourier transform mass spectrom-
eter (MALDI-MS) or a Finnigan TSQ 7000 mass spectrometer
(ESI-MS). Low resolution peaks are given in percent (m/z).
(2R,4aR,6S,7R,8S,8aR)-8-Hydroxy-6-methoxy-2-phenyl-7-phe-
nylcarbonyloxyperhydropyrano[3,2-d][1,3]dioxine (2)
Me2SnCl2 (9.91 g, 45.1 mmol, 0.05 equiv) was added to a stirred
mixture of methyl 4,6-O-benzylidene-a-D-glucopyranoside (1;23
254.59 g, 902 mmol, 1.0 equiv) and flame-dried K2CO3 (249.3 g,
1800 mmol, 2.0 equiv) in THF (4 L) at r.t. After 5 min, benzoyl
chloride (125.6 mL, 1080 mmol, 1.2 equiv) was added and stirring
was continued for 20 h at which time another portion of Me2SnCl2
(9.91 g, 45.1 mmol, 0.05 equiv) was added and stirring was contin-
ued for an additional 72 h. Approximately half of the reaction mix-
ture was poured into a 6-L separatory funnel containing CH2Cl2 (3
L) and H2O (1 L). The layers were separated and the aqueous layer
was washed with CH2Cl2 (2 × 1 L). The second half of the reaction
mixture was worked up in the same manner and the combined or-
ganic layers were dried (Na2SO4), filtered and concentrated onto
Celite. The material was purified in two equal portions via dry-col-
umn vacuum chromatography (15-cm diameter funnel, 10 cm silica,
400-mL fractions, gradient of 10% → 100% EtOAc–hexanes) to af-
ford 2;24 yield: 282.04 g (81%); white solid; mp 153–164 °C (Lit.24a
We elected to access the lactol 15 in a single step from the
anomeric acetate 14 using hydrazine acetate.20 Whereas
the C(2)-acetate lactol 16 required at least two iterations
of silica gel chromatography to obtain primarily the a-
anomer,5 C(2)-benzoate hemiacetal 15 upon workup was
found to be solely the a-anomer (as detected by 1H NMR
spectroscopy) and of sufficient purity to be used directly
in the subsequent reaction.
Formation of the trichloroacetimidate donor 17 was
achieved in 89% yield over two steps (based on 25% re-
covered lactol 15) using NaH and trichloroacetonitrile in
methylene chloride. It was originally reported that the b-
anomer of lactol 16 does not react under these conditions.5
We have found that the b-anomer does indeed react but
the b-trichloroacetimidate is not stable to silica gel chro-
matography.
32
mp 169–170 °C); Rf 0.17 (25% EtOAc–hexanes); [a]D +106.4
(c = 0.712, CHCl3) {Lit.24a [a]D25 +107.0 (c = 1.3, CHC13)}.
IR (film): 3478 (s), 2936 (m), 2862 (m), 1716 (s), 1602 (w), 1452
(m), 1378 (m), 1334 (w), 1316 (w), 1275 (s), 1147 (w), 1095 (s),
1040 (m), 992 (m), 918 (w), 752 (m), 712 (m), 699 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.08–8.12 (m, 2 H), 7.36–7.61 (m,
8 H), 5.58 (s, 1 H), 5.02–5.09 (m, 2 H), 4.31–4.39 (m, 2 H), 3.92 (m,
1 H), 3.80 (dd, J = 10.2, 10.2 Hz, 1 H), 3.63 (dd, J = 9.3, 9.3 Hz, 1
H), 3.40 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.0, 136.8, 133.2, 129.8, 129.3,
129.2, 128.3, 128.2, 126.2, 102.0, 97.7, 81.4, 76.6, 74.0, 68.9, 68.8,
62.0, 55.5.
In conclusion, we have developed an alternate, readily
scalable synthesis of a mycosamine donor, which pro-
ceeds in an overall yield of 25% and requires only 8 puri-
fications, thus making it amenable to preparing the
multigram quantities we require for our ongoing investi-
gations of this important natural product.
HRMS (MALDI): m/z [M + Na+] calcd for C21H22O7 + Na:
409.1258; found: 409.1251.
Unless otherwise noted, all reagents were purchased from commer-
cial sources. All non-aqueous reactions were carried out using
oven-dried or flame-dried glassware under a positive pressure of
dry nitrogen or argon, unless otherwise noted. THF, toluene, and
CH2Cl2 were dried by passage over activated alumina under argon
(H2O content <30 ppm, Karl Fischer titration)21 or for volumes
greater than 500 mL, HPLC grade solvents (<200 ppm H2O) were
used. Except as indicated otherwise, reactions were magnetically
stirred and monitored by TLC using Merck Silica Gel 60 F254
plates and visualized by fluorescence quenching under UV light and
staining using ceric ammonium molybdate. Flash chromatographic
purification of products was performed on Merck Silica Gel 60 (32–
63 mm) using a forced flow of eluent.22 Dry column vacuum chro-
matography was performed on Merck Silica Gel 60 (18–32 mm).
Concentration under reduced pressure was performed by rotary
(2R,4aR,6S,7R,8R,8aR)-8-Hydroxy-6-methoxy-2-phenyl-7-phe-
nylcarbonyloxyperhydropyrano[3,2-d][1,3]dioxine (3)
Pyridinium dichromate (128.7 g, 339.5 mmol, 5.0 equiv) was added
to a mixture of 2 (26.24 g, 67.9 mmol, 1.0 equiv) and dried, pow-
dered 3Å molecular sieves (133 g) in CH2Cl2 (540 mL). The result-
ing heterogeneous mixture was stirred at r.t. for 24 h and filtered
over Celite. The filter cake was washed with a 1:1 mixture of EtOAc
and CH2Cl2 (4 × 100 mL). The resulting liquid was poured onto a
column of Florisil (approx. 250 mL) and allowed to filter through
the column. The column was washed with a 1:1 mixture of EtOAc
and CH2Cl2 (700 mL) and all of the collected solvent was evaporat-
ed to afford (2R,4aR,6S,7S,8aR)-6-methoxy-8-oxo-2-phenyl-7-phe-
nylcarbonyloxyperhydropyrano[3,2-d][1,3]dioxine.25
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

3384
J. M. Manthorpe et al.
PAPER
(2R,4aR,6S,7S,8aR)-6-Methoxy-8-oxo-2-phenyl-7-phenylcarbo-
nyloxyperhydropyrano[3,2-d][1,3]dioxine
equiv) in one portion to afford a suspension. The reaction was
stirred for 10 min during which time the internal temperature rose
to 35 °C. DMAP (28.55 g, 233.6 mmol, 0.7 equiv) was added in 3–
4 gram portions every 5 min over 40 min. The reaction flask was fit-
ted with a mechanical stirrer and the mixture was stirred for 17 h.
The brown mixture was poured into sat. aq NH4Cl solution (1.5 L)
and the resulting emulsion was filtered over Celite and the phases
were separated. The filter cake was washed with EtOAc (5 × 250
mL). Each portion was in turn used to extract the aqueous phase.
The combined organic phases were washed with sat. aq NaHCO3
solution (1 L) and brine (500 mL), dried (Na2SO4), filtered and con-
centrated onto Celite. Purification by three consecutive dry-column
vacuum chromatographies (15-cm diameter funnel, 10 cm silica,
400-mL fractions, gradient 10% → 55% EtOAc–hexanes) afforded
4; yield: 143.0 g (88% or 78% over 3 steps); pale yellow oil; Rf 0.16
(30% EtOAc–hexanes); [a]D32 +78.1 (c = 2.67, CHCl3).
Crude yield: 23.26 g (89%) (attempts to scale this reaction to 175 g
resulted in lower yield but the reaction could be reproducibly run at
approximately 30-g scale); white solid; mp 197–198 °C (dec.)
(Lit.25a mp 210–213 °C; Lit.25b mp 211–213 °C); Rf 0.69 (1%
32
23
MeOH–CH2Cl2); [a]D +96.6 (c = 0.635, CHCl3) {Lit.25a [a]D
+69.6 (c = 1.02, CHCl3)}.
IR (film): 2946 (m), 2931 (m), 2872 (m), 1754 (vs), 1736 (vs), 1602
(w), 1582 (w), 1445 (m), 1283 (m), 1263 (m), 1214 (w), 1190 (w),
1136 (w), 1111 (s), 1092 (s), 1072 (m), 1048 (m), 979 (m), 773 (m),
748 (m), 714 (m), 694 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.12–8.15 (m, 2 H), 7.36–7.63 (m,
8 H), 5.63 (dd, J = 1.2, 4.5 Hz, 1 H), 5.60 (s, 1 H), 5.34 (d, J = 4.4
Hz, 1 H), 4.40–4.48 (m, 2 H), 4.19 (ddd, J = 4.6, 9.9, 9.9 Hz, 1 H),
3.98 (dd, J = 10.2, 10.2 Hz, 1 H), 3.49 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 191.9, 165.1, 136.3, 133.6, 130.3,
130.1, 129.3, 128.7, 128.4, 128.2, 126.3, 101.9, 101.4, 82.1, 74.8,
69.3, 65.4, 55.7.
HRMS (MALDI): m/z [M + Na+] calcd for C21H20O7 + Na:
407.1101; found: 407.1100.
IR (film): 2937 (m), 2863 (m), 1743 (s), 1731 (s), 1601 (w), 1584
(w), 1452 (m), 1408 (w), 1365 (m), 1216 (m), 1272 (s), 1201 (w),
1179 (m), 1158 (m), 1108 (s), 1070 (m), 1050 (s), 1009 (m), 989
(m), 763 (m), 714 (m), 700 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.99–8.02 (m, 2 H), 7.30–7.53 (m,
8 H), 5.80 (dd, J = 2.7, 2.7 Hz, 1 H), 5.50 (s, 1 H), 5.10 (dd, J = 3.7,
3.7 Hz, 1 H), 4.99 (m, 1 H), 4.18–4.34 (m, 2 H), 3.66–3.73 (m, 2 H),
3.37 (s, 3 H), 2.60–2.76 (m, 4 H), 2.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.8, 133.4, 129.9, 129.3, 128.5,
96.2, 75.2, 73.3, 67.7, 65.3, 55.1, 25.9, 18.1, –4.2, –4.3.
HRMS (MALDI): m/z [M + Na+] calcd for C26H28O9 + Na:
507.1626; found: 507.1617.
NaBH4 (9.92 g, 262 mmol, 1.0 equiv) was added to a stirred solution
of (2R,4aR,6S,7S,8aR)-6-methoxy-8-oxo-2-phenyl-7-phenylcarbo-
nyloxyperhydropyrano[3,2-d][1,3]dioxine prepared above (100.76
g, 262 mmol, 1.0 equiv) in THF (1.65 L) and MeOH (187 mL) at
–15 °C (internal temperature). The resulting mixture was stirred at
this temperature for 45 min and then poured into a separatory funnel
containing ice (300 g) and sat. aq NH4Cl solution (300 mL) – Cau-
tion! Gas evolution! – The mixture was gently shaken with frequent
venting every few min for 15 min, at which point the aqueous layer
was saturated with solid NaCl and diluted with EtOAc (1 L). The
layers were separated and the aqueous layer was washed with
EtOAc (4 × 300 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo to afford 326 which
was used in the next step without further purification.
(2S,3R,4R,5R,6R)-5-Hydroxy-6-hydroxymethyl-2-methoxy-4-
(3-oxobutylcarbonyloxy)-3-phenylcarbonyloxytetrahydro-2H-
pyran (5)
Compound 4 (114 g, 235 mmol, 1.0 equiv) was dissolved in EtOAc
(1.7 L) and the resulting solution was split into 8 equal portions.
Each portion was placed in a 1-L round-bottomed flask and Pd/C
(1.1 g, 10%, w/w Pd) was added. The flask was fitted with a septum
and placed in a well-ventilated hood. An argon atmosphere was in-
troduced by placing the flask under a strong argon flow for 1 h with
vigorous stirring. A H2 atmosphere was then introduced by flushing
the flask twice with ca. 1 L of H2. The flask was then fitted with two
1.5-L balloons of H2 and stirred for 12 h. The H2 atmosphere was
removed with a strong flux of argon for 1 h and remaining H2 was
quenched by the addition of 2-methylbut-2-ene (20 mL). The con-
tents of all 8 flasks were then filtered through a Celite pad on top of
anhyd Na2SO4. The filter cake was washed with EtOAc (1.5 L) and
the solvent was removed in vacuo to afford 5, which was used in the
next step without further purification; crude yield: 92.1 g (99%);
3
Crude yield: 102.0 g (‘101%’); white solid; mp 97–98 °C [Lit.26a mp
114–116 °C (EtOH), Lit.26b mp 110–115 °C]; Rf 0.63 (1% MeOH–
CH2Cl2); [a]D32 +77.3 (c = 1.355, CHCl3) {Lit.26a [a]D23 +71 (c = 1,
CHCl3); Lit.26b [a]D23 +74 (c = 1.5, CHCl3)}.
IR (film): 3512 (m), 3210 (w), 2936 (m), 2863 (m), 1719 (s), 1601
(w), 1583 (w), 1451 (m), 1378 (m), 1315 (w), 1270 (s), 1218 (w),
1180 (w), 1106 (s), 1070 (m), 1047 (m), 1027 (m), 1011 (m), 988
(m), 918 (w), 872 (w), 757 (m), 712 (m), 700 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.12–8.16 (m, 2 H), 7.27–7.63 (m,
8 H), 5.63 (s, 1 H), 5.04–5.11 (m, 2 H), 4.51 (m, 1 H), 4.43 (dd,
J = 5.1, 10.2 Hz, 1 H), 4.26 (ddd, J = 5.1, 10.0, 10.0 Hz, 1 H), 3.84
(dd, J = 10.2, 10.2 Hz, 1 H), 3.68 (dd, J = 2.6, 9.7 Hz, 1 H), 3.49 (s,
3 H), 3.23 (d, J = 7.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 165.6, 137.0, 133.5, 130.0, 129.2,
129.1, 128.4, 128.2, 126.3, 102.0, 98.7, 78.6, 69.7, 69.1, 68.2, 57.9,
56.1.
HRMS (MALDI): m/z [M + Na+] calcd for C21H22O7 + Na:
409.1258; found: 409.1250.
28
colorless oil; Rf 0.17 (100% EtOAc); [a]D +76.5 (c = 0.971,
CHCl3).
IR (film): 3451 (br, s), 3064 (w), 2931 (m), 2839 (w), 1722 (s), 1601
(w), 1585 (w), 1452 (w), 1405 (w), 1358 (m), 1328 (m), 1273 (s),
1198 (m), 1160 (m), 1098 (s), 1050 (s), 992 (m), 873 (w), 767 (w),
714 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.96–8.00 (m, 2 H), 7.54 (m, 1 H)
7.40–7.49 (m, 2 H), 5.71 (d, J = 2.8 Hz, 1 H), 5.05 (m, 1 H), 5.00
(m, 1 H), 3.79–3.85 (m, 4 H), 3.32 (s, 3 H), 2.60–2.74 (4 × ABXZ,
4 H), 2.07 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 208.0, 172.6, 165.6, 133.3, 129.9,
129.2, 128.4, 96.7, 70.1, 68.8, 67.7, 66.2, 62.1, 55.8, 38.2, 29.7,
28.3.
HRMS (MALDI): m/z [M + Na+] calcd for C19H24O9 + Na:
419.1312; found: 419.1305.
(2R,4aR,6S,7R,8R,8aR)-6-Methoxy-8-(3-oxobutylcarbonyloxy)-
2-phenyl-7-phenylcarbonyloxyperhydropyrano[3,2-d][1,3]di-
oxine (4)
Compound 3 (129 g, 333.8 mmol, 1.0 equiv) was azeotropically
dried with toluene (300 mL) and dissolved in CH2Cl2 (1.7 L). Le-
vulinic acid (68.6 mL, 77.52 g, 667.7 mmol, 2.0 equiv) was added
followed by dicyclohexylcarbodiimide (137.7 g, 667.7 mmol, 2.0
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

PAPER
Scalable Synthesis of a Mycosamine Donor
3385
(2S,3R,4R,5S,6S)-5-Hydroxy-6-iodomethyl-2-methoxy-4-(3-
oxobutylcarbonyloxy)-3-phenylcarbonyloxytetrahydro-2H-
pyran (6)
1H NMR (300 MHz, CDCl3): d = 7.96–8.00 (m, 2 H), 7.56 (m, 1 H),
7.42–7.48 (m, 2 H), 5.58 (dd, J = 3.2 Hz, 1 H), 5.08 (m, 1 H), 4.99
(m, 1 H), 3.84 (ddd, J = 2.7, 7.0, 9.4 Hz, 1 H), 3.64 (dd, J = 3.2, 9.2
Hz, 1 H), 3.55 (dd, J = 2.6, 10.5 Hz, 1 H), 3.26 (dd, J = 7.0, 10.5 Hz,
1 H), 2.62–2.83 (m, 4 H), 2.16 (s, 3 H), 0.86 (s, 9 H), 0.15 (s, 3 H),
0.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 206.2, 172.0, 165.6, 133.3, 130.0,
129.3, 128.4, 97.1, 70.3, 69.7, 68.9, 66.8, 56.2, 37.8, 29.8, 28.2,
25.6, 17.8, 7.40, –4.4, –4.6.
Compound 5 (48.0 g, 121.1 mmol, 1.0 equiv) was azeotropically
dried with benzene (2 × 200 mL) and divided into 5 equal portions
(9.60 g, 24.2 mmol, 1.0 equiv). Each portion was dissolved in THF
(242 mL) and Ph3P (12.70 g, 48.4 mmol, 2.0 equiv), I2 (12.29 g,
48.4 mmol, 2.0 equiv) and imidazole (12.37 g, 182 mmol, 7.5
equiv) were added. The mixture was stirred in a r.t. water bath (to
control an initial exotherm) for 1 h. The contents of the five reaction
flasks were then collectively added to a separatory funnel contain-
ing EtOAc (3 L), sat. aq NaHCO3 solution (750 mL) and sat. aq
Na2S2O3 solution (750 mL). After mixing, the layers were separated
and the aqueous layer was washed with EtOAc (1 × 1 L). The com-
bined organic layers were washed with phosphate buffer (0.8 M,
pH 6.5, 2 L), H2O (1 × 1 L) and brine (1 × 1 L), dried (Na2SO4), fil-
tered and concentrated onto Celite in vacuo. Purification by dry col-
umn vacuum chromatography (15-cm diameter funnel, 10 cm silica
gel, 400-mL fractions, gradient of 30% → 75% EtOAc–hexanes)
afforded 6 (45.18 g) and an impure material which was repurified
by flash chromatography (30% → 40% EtOAc–hexanes) to afford
an additional amount of 6 (7.82 g); combined yield: 53.00 g (86%
over 2 steps); colorless oil; Rf 0.69 (100% EtOAc), 0.28 (50%
EtOAc–hexanes); [a]D23 +46.9 (c = 0.886, CHCl3).
HRMS (MALDI): m/z [M + Na+] calcd for C25H37IO8Si + Na:
643.1195; found: 643.1184.
(2S,3R,4R,5R,6R)-4-Hydroxy-2-methoxy-6-methyl-3-phenyl-
carbonyloxy-5-tert-butyldimethylsilyloxytetrahydro-2H-pyran
(9)
2,2¢-Azobis(isobutyronitrile) (AIBN, 347 mg, 2.11 mmol, 0.05
equiv) was added to a refluxing solution of 8 (65.58 g, 105.7 mmol,
1.0 equiv) and Bu3SnH (56.8 mL, 211 mmol, 2.0 equiv) in degassed
toluene (1 L). The mixture was heated at reflux for 2.5 h, cooled to
r.t. and concentrated in vacuo. The resulting oil was dissolved in
EtOAc (1 L), cooled to 0 °C and KF·xH2O (44.3 g) in H2O (500 mL)
was added. The resulting milky mixture was stirred at 0 °C for 1 h
and filtered over Celite. The two layers were separated and the
aqueous layer was washed with EtOAc (1 × 400 mL). The com-
bined organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. Purification by flash chromatography (10% → 15%
EtOAc–hexanes) afforded (2S,3R,4R,5R,6R)-5-tert-butyldimethyl-
silyloxy-2-methoxy-6-methyl-4-(3-oxobutylcarbonyloxy)-3-phe-
nylcarbonyloxytetrahydro-2H-pyran.
IR (film): 3482 (br, m), 2929 (m), 2842 (w), 1739 (s), 1720 (s), 1601
(w), 1451 (w), 1405 (m), 1363 (m), 1327 (m), 1271 (s), 1200 (m),
1158 (m), 1096 (s), 1070 (m), 1041 (m), 1028 (m), 984 (w), 937 (w),
866 (w), 762 (w), 713 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.96–7.99 (m, 2 H), 7.54–7.60 (m,
1 H), 7.41–7.46 (m, 2 H), 5.69 (dd, J = 3.3, 3.3 Hz, 1 H), 5.02 (m, 1
H), 5.08 (m, 1 H), 3.61–3.79 (m, 3 H), 3.49 (s, 3 H), 3.33 (dd,
J = 7.7, 10.7 Hz, 1 H), 2.96 (br d, J = 9.3 Hz, 1 H), 2.83–2.87
(2 × ABXZ, 2 H), 2.64–2.69 (2 × ABXZ, 2 H), 2.19 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 207.6, 172.2, 165.1, 133.0, 129.6,
128.9, 128.1, 96.6, 69.6, 69.3, 68.6, 67.1, 55.8, 37.9, 29.5, 28.0, 6.8.
HRMS (MALDI): m/z [M + Na+] calcd for C19H23IO8 + Na:
529.0330; found: 529.0321.
(2S,3R,4R,5R,6R)-5-tert-Butyldimethylsilyloxy-2-methoxy-6-
methyl-4-(3-oxobutylcarbonyloxy)-3-phenylcarbonyloxytetra-
hydro-2H-pyran
Yield: 49.58 g (95%); white solid; mp 78–82 °C; Rf 0.72 (50%
27
EtOAc–hexanes), 0.25 (25% EtOAc–hexanes); [a]D +98.4
(c = 0.865, CHCl3).
IR (film): 2931 (m), 1740 (s), 1722 (s), 1601 (w), 1583 (w), 1448
(w), 1408 (w), 1359 (w), 1314 (w), 1265 (s), 1157 (m), 1099 (s),
1072 (m), 1050 (m), 1027 (m), 996 (w), 861 (w), 839 (m), 776 (s),
714 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 7.97–8.00 (m, 2 H), 7.56 (m, 1 H),
7.41–7.46 (m, 2 H), 5.57 (dd, J = 3.1, 3.1 Hz, 1 H), 5.04 (dd, J = 3.9,
3.9 Hz, 1 H), 4.92 (m, 1 H), 4.05 (m, 1 H), 3.48 (dd, J = 3.1, 9.4 Hz,
1 H), 3.38 (s, 3 H), 2.61–2.83 (m, 4 H), 2.16 (s, 3 H), 1.25 (d, J = 6.4
Hz, 3 H), 0.86 (s, 9 H), 0.09 (s, 3 H), 0.08 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 205.5, 171.6, 165.1, 132.8, 129.6,
129.1, 128.0, 96.4, 71.4, 69.6, 68.9, 63.4, 55.4, 37.7, 29.6, 28.2,
25.5, 17.7, 17.4, –4.6, –5.1.
HRMS (MALDI): m/z [M + Na+] calcd for C25H38O8Si + Na:
517.2228; found: 517.2219.
(2S,3R,4R,5S,6S)-5-tert-Butyldimethylsilyloxy-6-iodomethyl-2-
methoxy-4-(3-oxobutylcarbonyloxy)-3-phenylcarbonyloxytet-
rahydro-2H-pyran (8)
Imidazole (34.0 g, 499.5 mmol, 4.5 equiv) was added to a stirred so-
lution of tert-butyldimethylsilyl chloride (33.46 g, 222 mmol, 2.0
equiv) and 6 (56.27 g, 111.1 mmol, 1.0 equiv) in CH2Cl2 (250 mL)
at 0 °C, resulting in the formation of copious amounts of white pre-
cipitate. The ice bath was removed and stirring was continued for
50 h. The mixture was diluted with Et2O (750 mL) and washed with
sat. aq NH4Cl solution (500 mL). The layers were separated and the
aqueous layer was washed with Et2O (1 × 100 mL). The combined
organic layers were washed with sat. aq NaHCO3 solution (500
mL). The layers were separated and the aq NaHCO3 layer was
washed with Et2O (1 × 100 mL). The combined organic layers were
washed with sat. aq CuSO4 solution (1 L). The layers were separat-
ed and the aqueous CuSO4 layer was washed with Et2O (1 × 200
mL). The combined organic layers were dried (Na2SO4), filtered
and concentrated onto Celite. Purification by dry column vacuum
chromatography (15-cm diameter funnel, 8 cm silica gel, 400-mL
fractions, gradient of 10% → 50% EtOAc–hexanes) afforded 8;
Hydrazine monohydrate (108.9 mL, 2.24 mol, 20 equiv) was added
to a stirred solution of (2S,3R,4R,5R,6R)-5-tert-butyldimethylsilyl-
oxy-2-methoxy-6-methyl-4-(3-oxobutylcarbonyloxy)-3-phenylcar-
bonyloxytetrahydro-2H-pyran (55.50 g, 112.2 mmol, 1.0 equiv) in
pyridine (673 mL) and AcOH (445 mL) in a r.t. water bath. The
mixture was stirred at r.t. for 24 h, at which time the reaction was
quenched by the addition of acetone (200 mL). The resulting mix-
ture was stirred for 10 min and then added over 1 h to a mechanical-
ly stirred mixture of Na2CO3 (600 g), NaHCO3 (400 g) and H2O (1.5
L) at 0 °C in an open flask – Caution! gas evolution! – The resulting
mixture was washed with EtOAc (1 × 2 L, 1 × 1 L) and the com-
bined organic layers were washed with sat. aq CuSO4 solution (2 L).
The aqueous CuSO4 layer was washed with EtOAc (1 L). The com-
bined organic layers were washed with brine (1 L), dried (Na2SO4),
filtered and concentrated in vacuo. Residual pyridine was azeotro-
25
65.68 g (95%); colorless oil; Rf 0.62 (50% EtOAc–hexanes); [a]D
+69.2 (c = 0.827, CHCl3).
IR (film): 2949 (m), 2929 (m), 2886 (m), 2856 (m), 1740 (s), 1722
(s), 1602 (w), 1583 (w), 1466 (w), 1448 (w), 1408 (w), 1359 (m),
1323 (m), 1269 (s), 1197 (m), 1269 (s), 1197 (m), 1157 (s)m 1099
(s), 1072 (m), 1045 (m), 1032 (m), 987 (w), 938 (w), 839 (s), 781
(s), 714 cm–1 (s).
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

3386
J. M. Manthorpe et al.
PAPER
pically removed using toluene (1 × 1 L) and the residue was purified
by flash chromatography (20% EtOAc–hexanes) to afford 9.
1H NMR (300 MHz, CDCl3): d = 8.08–8.12 (m, 2 H), 7.59 (m, 1 H),
7.44–7.50 (m, 2 H), 5.00 (d, J = 3.6 Hz, 1 H), 4.87 (dd, J = 3.7, 10.6
Hz, 1 H), 3.90 (dd, J = 9.2, 10.6 Hz, 1 H), 3.73 (m, 1 H), 3.37 (s, 3
H), 3.17 (dd, J = 9.2, 9.2 Hz, 1 H), 1.28 (d, J = 6.3 Hz, 3 H), 0.93 (s,
9 H), 0.20 (s, 3 H), 0.13 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.6, 133.3, 129.8, 129.1, 128.4,
96.1, 75.2, 73.3, 67.7, 65.3, 55.2, 26.0, 18.2, 18.2, –4.0, –4.2.
HRMS (MALDI): m/z [M + H+ – N2] calcd for C20H32NO5Si:
394.2044; found: 394.2035.
MS (ESI): m/z (%) = 444 (40) [M + Na+], 413 (100) [M + H+].
9
Yield: 42.09 g (95%); colorless oil; Rf 0.67 (50% EtOAc–hexanes),
0.62 (30% EtOAc–hexanes); [a]D24 +89.6 (c = 1.23, CHCl3).
IR (film): 3532 (m), 2955 (m), 2931 (m), 2857 (m), 1721 (s), 1602
(w), 1583 (w), 1472 (w), 1463 (w), 1452 (w), 1380 (w), 1317 (w),
1297 (w), 1283 (w), 1272 (s), 1107 (s), 1072 (m), 1051 (m), 1029
(m), 1016 (m), 954 (w), 915 (w), 861 (w), 837 (w), 777 (m), 714
cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.11–8.814 (m, 2 H), 7.55–7.60
(m, 2 H), 5.01 (m, 1 H), 4.94 (m, 1 H), 4.19 (m, 1 H), 3.98 (m, 1 H),
3.43 (s, 3 H), 3.41 (m, 1 H), 3.32 (d, J = 7.1 Hz, 1 H), 1.30 (d,
J = 6.3 Hz, 3 H), 0.92 (s, 9 H), 0.13 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 165.6, 133.2, 129.9, 129.4, 128.3,
97.8, 74.1, 70.6, 70.0, 63.1, 55.8, 25.8, 17.7, –4.1, –4.5.
(3R,4S,5S,6R)-4-Azido-5-tert-butyldimethylsilyloxy-6-methyl-
2-methylcarbonyloxy-3-phenylcarbonyloxytetrahydro-2H-
pyran (14)
H2SO4 in Ac2O (4.29 mL, 10 drops of H2SO4/1 mL Ac2O) was add-
ed to a stirred solution of 13 [9.04 g (crude), 21.44 mmol, 1.0 equiv]
in Ac2O (42.9 mL) at 0 °C. After stirring at 0 °C for 20 min, the
cooling bath was removed and stirring was continued for 35 min
with careful TLC monitoring. The mixture was diluted with CH2Cl2
(25 mL) and added over 2 min to a mechanically stirred mixture of
NaHCO3 (100 g) and H2O (1 L) at 0 °C – Caution! Gas evolution!
– The cooling bath was removed and stirring was continued for 1 h.
The mixture was diluted with Et2O (1 L) and the layers were sepa-
rated. The aqueous layer was washed with Et2O (2 × 500 mL). The
combined organic layers were washed with sat. aq NaHCO3 solu-
tion (200 mL) and brine (200 mL), dried (Na2SO4), filtered and con-
centrated in vacuo. The residue was purified by flash
chromatography (7% EtOAc–hexanes) to afford 14; yield: 6.20 g
(60% over 3 steps); colorless oil; ca. 7.7:1 mixture of b:a anomers;
Rf 0.36 (15% EtOAc–hexanes); [a]D26 +126.3 (c = 1.293, CHCl3).
HRMS (MALDI): m/z [M + Na+] calcd for C20H32O6Si + Na:
419.1860; found: 419.1864.
(2S,3R,4R,5R,6R)-5-tert-Butyldimethylsilyloxy-2-methoxy-6-
methyl-3-phenylcarbonyloxy-4-trifluoromethylsulfonyloxytet-
rahydro-2H-pyran (12)
Trifluoromethanesulfonic anhydride (26.7 mL, 158 mmol, 1.5
equiv) was added over 7 min to stirred solution of pyridine (15.4
mL, 190 mmol, 1.8 equiv) and 9 (41.89 g, 105.6 mmol, 1.0 equiv)
at –40 °C. The cooling bath was removed and the initial thick, pale
yellow slurry became homogeneous as the solution warmed to r.t.
The mixture was stirred at r.t. for 18 h, diluted with Et2O (2 L), se-
quentially washed with H2O (500 mL), aq 2 M HCl (500 mL), sat.
aq NaHCO3 (500 mL), and brine (500 mL), dried (MgSO4), filtered
and concentrated in vacuo to afford 12 as a yellow oil which was
used in the next step without further purification; Rf 0.57 (30%
EtOAc–hexanes).
1H NMR (300 MHz, CDCl3): d = 8.08–8.11 (m, 2 H), 7.58–7.62 (m,
1 H), 7.44–7.49 (m, 2 H), 5.28 (dd, J = 2.5, 2.5 Hz, 1 H), 5.18 (dd,
J = 3.0, 4.1 Hz, 1 H), 4.88 (d, J = 4.1 Hz, 1 H), 4.10 (m, 1 H), 3.60
(dd, J = 2.4, 9.4 Hz, 1 H), 3.42 (s, 3 H), 1.28 (d, J = 6.4 Hz, 3 H),
0.94 (s, 9 H), 0.16 (s, 6 H).
IR (film): 2957 (m), 2931 (m), 2886 (m), 2858 (m), 2107 (vs), 1758
(s), 1732 (s), 1602 (w), 1585 (w), 1472 (w), 1462 (w), 1452 (w),
1371 (w), 1262 (s), 1222 (s), 1146 (s), 1110 (s), 1094 (s), 1062 (m),
1033 (m), 1008 (m), 933 (w), 903 (w), 860 (m), 838 (m), 778 (m),
711 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.00–8.06 (m, 2 H), 7.60 (m, 1 H),
7.43–7.49 (m, 2 H), 6.38 (d, J = 3.7 Hz, 1 H), 5.82* (d, J = 8.3 Hz,
1 H), 5.23* (dd, J = 8.3, 10.2 Hz, 1 H), 5.08 (dd, J = 3.7, 10.6 Hz, 1
H), 3.89 (dd, J = 9.3, 10.7 Hz, 1 H) 3.83 (m, 1 H), 3.61* (dd, J = 9.2,
10.2 Hz, 1 H), 3.59* (dd, J = 6.2, 9.0 Hz, 1 H), 3.28* (dd, J = 9.1,
9.1 Hz, 1 H), 3.24 (dd, J = 9.3, 9.3 Hz, 1 H), 2.13 (s, 3 H), 2.01* (s,
3 H), 1.33* (d, J = 6.2 Hz, 3 H), 1.28 (d, J = 6.2 Hz, 3 H), 0.94 (s, 9
H), 0.92* (s, 9 H), 0.22 (s, 3 H), 0.21* (s, 3 H), 0.14 (s, 3 H), 0.13*
(s, 3 H) (Assignments with * refer to the a-anomer).
13C NMR (75 MHz, CDCl3): d = 165.6, 133.6, 130.0, 128.6, 128.4,
96.5, 84.9, 71.4, 68.0, 63.4, 56.0, 25.9, 18.1, 17.5, –3.8, –4.6.
19F NMR (282.5 MHz, CHCl3): d = –74.7
(2S,3R,4S,5S,6R)-4-Azido-5-tert-butyldimethylsilyloxy-2-meth-
oxy-6-methyl-3-phenylcarbonyloxytetrahydro-2H-pyran (13)
NaN3 (7.55 g, 116 mmol, 1.1 equiv) was added to a solution of 12
prepared above (azeotropically dried with toluene) and 15-crown-5
(23.07 mL, 116 mmol, 1.1 equiv) in DMF (422 mL) and stirred at
r.t. for 1 h. The mixture was poured into H2O (1 L) and a 1:1 mixture
of Et2O and hexane (2 L). The layers were separated and the organic
layer was washed with water (2 × 1 L). The combined aqueous
phases were washed with a 1:1 mixture of Et2O and hexane (500
mL). The combined organic layers were washed with a 1:1 mixture
of H2O and sat. aq NaHCO3 solution, brine (500 mL), dried
(MgSO4), filtered and concentrated in vacuo to afford 13; crude
yield: 41.47 g (93% over 2 steps); yellow oil; Rf 0.72 (30% EtOAc–
13C NMR (75 MHz, CDCl3): d = 168.9, 165.2, 133.5, 129.8, 129.7,
128.9, 128.5, 92.0*, 88.8, 74.6, 74.5, 71.5, 70.5, 68.5*, 65.1, 25.8,
20.9, 20.8, 18.1 –4.2, –4.3 (Assignments with * refer to the a-ano-
mer).
HRMS (MALDI): m/z [M + Na+] calcd for C21H31N3O6Si + Na:
472.1874; found: 472.1867.
MS (ESI): m/z (%) = 472 (47) [M + Na+], 390 (100) [M + H+ –
AcOH], 347 (60) [M + H+ – AcOH – HN3].
(2S,3R,4S,5S,6R)-4-Azido5-tert-butyldimethylsilyloxy-2-hy-
droxy-6-methyl-3-phenylcarbonyloxytetrahydro-2H-pyran
(15)
23
hexanes), 0.48 (15% EtOAc–hexanes); [a]D +165.7 (c = 0.863,
CHCl3).
Hydrazine acetate (307 mg, 3.33 mmol, 1.3 equiv) was added to a
solution of 14 (1.15 g, 2.56 mmol, 1.0 equiv) in DMF (12.8 mL) at
r.t. The mixture was stirred for 3 h and poured into a separatory fun-
nel containing H2O (100 mL) and 1:1 mixture of Et2O and hexane
(100 mL). The layers were separated and the aqueous layer was
washed with a 1:1 mixture of Et2O and hexane (2 × 50 mL). The
combined organic layers were washed with sat. aq NaHCO3 (50
mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated in
IR (film): 2954 (m), 2932 (m), 2904 (m), 2858 (m), 2109 (s), 1727
(s), 1602 (w), 1583 (w), 1472 (w), 1462 (w), 1452 (w), 1379 (w),
1362 (w), 1332 (w), 1316 (w), 1262 (s), 1108 (s), 1060 (s), 998 (w),
976 (w), 925 (w), 906 (w), 862 (m), 837 (s), 778 (m), 743 (w), 711
cm–1 (s).
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

PAPER
Scalable Synthesis of a Mycosamine Donor
3387
vacuo to afford 15 as a single anomer (a) by 1H NMR spectroscopy,
which was used in the next step without further purification; crude
yield: 0.98 g (94%); white crystalline solid; mp 112–116 °C; Rf 0.25
(15% EtOAc–hexanes); [a]D28 +142.8 (c = 0.930, CHCl3).
References
(1) Vandeputte, J.; Watchtel, J. L.; Stiller, E. T. Antibiot. Annu.
1956, 587.
(2) (a) Huang, W.; Zhang, Z.; Han, X.; Tang, J.; Wang, J.;
Wang, S.; Dong, S.; Wang, E. Biophys. J. 2002, 83, 3245.
(b) Cotero, B. V.; Rebolledo-Antunez, S.; Ortega-Blake, I.
Biochim. Biophys. Acta 1998, 1375, 43. (c) Fujii, G.;
Chang, J.-E.; Coley, T.; Steere, B. Biochemistry 1997, 36,
4959. (d) Baginski, M.; Borowski, E. J. Mol. Struct.
(Theochem) 1997, 389, 139.
(3) (a) Isolation: Davisson, J. W.; Tanner, F. W.; Finlay, A. C.;
Solomons, I. A. Antibiot. Chemother. 1951, 1, 289.
(b) Synthesis of aglycon: Packard, G. K.; Hu, Y.; Vescovi,
A.; Rychnovsky, S. D. Angew. Chem. Int. Ed. 2004, 43,
2822.
(4) (a) Isolation: Taber, W. A.; Vining, L. C.; Waksman, S. A.
Antibiot. Chemother. 1954, 4, 455. (b) For the synthesis of a
protected algycon, see: Kadota, I.; Hu, Y.; Packard, G. K.;
Rychnovsky, S. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
11992.
(5) (a) Nicoloau, K. C.; Daines, R. A.; Ogawa, Y.; Chakraborty,
T. K. J. Am. Chem. Soc. 1988, 110, 4696. (b) Daines, R. A.
Ph.D. Dissertation; University of Pennsylvania:
Philadelphia, 1987.
IR (film): 3439 (br, m), 2956 (m), 2931 (m), 2891 (m), 2859 (m),
2110 (vs), 1727 (s), 1602 (w), 1585 (w), 1473 (w), 1452 (w), 1386
(w), 1362 (w), 1337 (w), 1277 (s), 1148 (m), 1107 (s), 1061 (m),
1028 (m), 997 (w), 936 (w), 915 (w), 861 (s), 838 (s), 778 (s), 751
(w), 710 (s), 686 (w), 665 cm–1 (w).
1H NMR (300 MHz, CDCl3): d = 8.03–8.09 (m, 2 H), 7.56 (m, 1 H),
7.39–7.46 (m, 2 H), 5.49 (d, J = 3.6 Hz, 1 H), 4.85 (dd, J = 3.6, 10.6
Hz, 1 H), 4.10 (br s, 1 H), 3.96 (m, 1 H), 3.16 (dd, J = 9.2, 9.2 Hz,
1 H), 1.23 (d, J = 6.3 Hz, 3 H), 0.93 (s, 9 H), 0.20 (s, 3 H), 0.12 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 165.9, 133.4, 129.8, 129.0, 128.4,
89.3, 75.1, 73.6, 67.8, 64.8, 25.8, 18.0, –4.2, –4.4.
HRMS (MALDI): m/z [M + H+ – H2O] calcd for C19H28N3O4Si:
390.1844; found: 390.1839; [M + H+ – N2] calcd for C19H30NO5Si:
380.1888; found: 380.1867.
MS (ESI): m/z (%) = 430 (100) [M + Na+].
(2R,3R,4S,5S,6R)-4-Azido-5-tert-butyldimethylsilyloxy-6-meth-
yl-3-phenylcarbonyloxy-2-(2,2,2-trichloro-1-iminoethoxy)tetra-
hydro-2H-pyran (17)
(6) (a) Packard, G. K.; Rychnovsky, S. D. Org. Lett. 2001, 3,
3393. (b) Alais, J.; David, S. Carbohydrate Res. 1992, 230,
79. For a synthesis of a fully protected, acyclic mycosamine
compound, see: (c) Frank-Neumann, M.; Miesch-Gross, L.;
Gateau, C. Eur. J. Org. Chem. 2000, 3693. (d) Frank-
Neumann, M.; Miesch-Gross, L.; Gateau, C. Tetrahedron
Lett. 1999, 40, 2829.
NaH [60% (w/w) in oil, 106 mg, 2.65 mmol, 1.1 equiv] was added
to a stirred solution of 15 (0.98 g, 2.40 mmol, 1.0 equiv) and trichlo-
roacetonitrile (2.41 mL, 24.0 mmol, 10.0 equiv) in CH2Cl2 (4.8 mL)
at 0 °C – Caution! Gas evolution! – The resulting mixture was
stirred at 0 °C for 1.5 h, diluted with Et2O (100 mL), poured into
H2O (25 mL) and the resulting layers were separated. The aqueous
layer was washed with Et2O (2 × 25 mL). The combined organic
layers were washed with brine (25 mL), dried (Na2SO4), filtered and
concentrated in vacuo. The residue was purified by flash chroma-
tography (5–10% EtOAc–hexanes) to afford 17; yield: 0.92 g (65%
over 2 steps, 89% over 2 steps based on recovered lactol 15); color-
(7) Lancelin, J.-M.; Beau, J.-M. Tetrahedron Lett. 1989, 30,
4521.
(8) (a) Zumbuehl, A.; Jeannerat, D.; Martin, S. E.; Sohrmann,
M.; Stano, P.; Vigassy, T.; Clark, D. D.; Hussey, S. L.; Peter,
M.; Peterson, B. R.; Pretsch, E.; Walde, P.; Carreira, E. M.
Angew. Chem. Int. Ed. 2004, 43, 5181. (b) Zumbuehl, A.;
Stano, P.; Heer, D.; Walde, P.; Carreira, E. M. Org. Lett.
2004, 6, 3683.
30
less oil; Rf 0.47 (15% EtOAc–hexanes); [a]D +106.1 (c = 0.551,
CHCl3); and 0.24 g (25%) of lactol 15.
IR (film): 3343 (w), 2958 (m), 2931 (m), 2887 (m), 2858 (m), 2110
(s), 1732 (s), 1674 (s), 1602 (w), 1587 (w), 1474 (w), 1464 (w),
1450 (w), 1258 (s), 1146 (m), 1106 (s), 1097 (s), 1062 (s), 1033 (m),
1018 (m), 964 (m), 905 (m), 861 (m), 837 (s), 792 (m), 778 (m), 709
(s), 645 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 8.55 (br s, 1 H), 8.03-8.07 (m, 2
H), 7.57 (m, 1 H), 7.40–7.46 (m, 2 H), 6.56 (d, J = 3.6 Hz, 1 H), 5.16
(dd, J = 3.6, 10.5 Hz, 1 H), 3.97 (dd, J = 9.4, 10.4 Hz, 1 H), 3.95 (m,
1 H), 3.30 (dd, J = 9.3, 9.3 Hz, 1 H), 1.32 (d, J = 6.3 Hz, 3 H), 0.95
(s, 9 H), 0.23 (s, 3 H), 0.15 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 165.1, 160.5, 133.5, 129.7, 128.7,
128.4, 92.8, 74.6, 71.9, 71.0, 65.2, 26.0, 18.3, –4.0, –4.1.
HRMS (MALDI): m/z [M + H+ – C2H2Cl3NO] calcd for
C19H28N3O4Si: 390.1844; found: 390.1850; [M + H+ – C2H2Cl3NO
– HN3] calcd for C19H27O4Si: 347.1673; found: 347.1672.
(9) (a) Eby, R.; Webster, K. T.; Schuerch, C. Carbohydr. Res.
1984, 129, 111. The use of ZnCl2 chelates has also been
reported. However, this procedure is not as highly selective
and required chromatographic purification that was
untenable on our requisite scale, see: (b) Hanessian, S.;
Kagotani, M. Carbohydr. Res. 1990, 202, 67.
(10) For suppression of orthoester formation using C(2)-
pivaloate esters see: (a) Harrues, A.; Kunz, H. Liebigs Ann.
Chem. 1986, 717. However the harsh conditions required
for pivaloate removal immediately preclude its use in our
studies. For cleavage conditions, see: (b) Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis;
Wiley: New York, 1999, 170; and references cited therein.
For examples of orthoester suppression using C(2)-
benzoates, see: (c) Seeberger, P. H.; Eckhardt, M.;
Gutteridge, C. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1997,
119, 10064.
MS (ESI): m/z (%) = 579 (6), 578 (10), 577 (34), 576 (32), 575
(100), 574 (28), 573 (99) [all M + Na+].
(11) Manavu, R. M.; Szmant, H. H. J. Org. Chem. 1976, 41,
1832.
(12) Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.;
Matsumura, Y. J. Org. Chem. 2000, 65, 996.
(13) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1999, 165; and references cited
therein.
Acknowledgment
We thank ETH for generous support of this research. J.M.M. thanks
Fonds NATEQ and A.M.S. thanks the Carlsberg Foundation for
support in the form of postdoctoral fellowships. The authors also
wish to thank Dr. Jeroen Codée for helpful discussions.
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York

3388
J. M. Manthorpe et al.
PAPER
(14) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; Wiley: New York, 1999, 168. (b) van
Boeckel, C. A. A.; Visser, G. M.; van Boom, J. H.
Tetrahedron 1985, 41, 4557. (c) Love, K. R.; Andrade, R.
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Carbohydr. Res. 1989, 189, 135. (f) Glushka, J. N.; Perlin,
A. S. Carbohydr. Res. 1990, 205, 305. (g) Hassner, A.;
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1975, 97, 1614.
(15) (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801.
For similar reaction conditions involving iodides, see:
(b) Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20,
1473.
(16) Skaanderup, P. K.; Poulson, C. S.; Hyldtoft, L.; Jørgensen,
M. R.; Madsen, R. Synthesis 2002, 1721.
(20) (a) Excoffier, G.; Gagnaire, D.; Utille, J. P. Carbohydr. Res.
1975, 39, 368. (b) Belorizky, N.; Excoffier, G.; Gagnaire,
D.; Utille, J. P.; Vignon, M.; Vottero, P. Bull. Soc. Chim. Fr.
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(21) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R.
K.; Timmers, F. J. Organometallics 1996, 15, 1518.
(22) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(23) While methyl 4,6-O-benzylidene-a-D-glucopyranoside(1) is
commercially available, we prepared it using a procedure
reported for the preparation of methyl 4,6-O-benzylidene-b-
D-glucopyranoside: Roën, A.; Padrón, J. I.; Vázquez, J. T. J.
Org. Chem. 2003, 68, 4615.
(24) This compound has been partially characterized previously:
(a) Kim, S.; Chang, H.; Kim, W. J. J. Org. Chem. 1985, 50,
1751. (b) Jeanloz, R. W.; Jeanloz, D. A. J. Am. Chem. Soc.
1957, 79, 2579. (c) Collins, P. M.; Gardiner, D.; Kumar, S.;
Overend, W. G. J. Chem. Soc., Perkin Trans. 1 1972, 2596.
(25) This compound has been partially characterized previously:
(a) Rauter, A.; Ferreira, M.; Borges, C.; Duarte, T.; Piedade,
F.; Silva, M.; Santos, H. Carbohydr. Res. 2000, 325, 1.
(b) Criegee, R.; Marchand, B.; Wannowius, H. Justus
Liebigs Ann. Chem. 1942, 550, 99.
(17) The conversion of a methyl glycoside to the corresponding
anomeric acetate in the presence of 6-tert-butyldiphenylsilyl
group using ZnCl2 in AcOH–Ac2O has been reported: Lam,
S. N.; Gervery-Hague, J. Carbohydr. Res. 2002, 337, 1953.
(18) For a review on the anomeric effect, see: Jauristi, E.; Cuevas,
G. Tetrahedron 1992, 48, 5019.
(19) A similar result has been previously reported in a glucose
system: Fairweather, J. K.; Hrmova, M.; Rutten, S. J.;
Fincher, G. B.; Driguez, H. Chem. Eur. J. 2003, 9, 2603.
(26) This compound has been partially characterized previously:
(a) Ishido, Y.; Sakairi, N.; Sekiya, M.; Nakazaki, N.
Carbohydr. Res. 1981, 97, 51. (b) Hönig, H.; Weidmann, H.
Carbohydr. Res. 1975, 39, 374.
Synthesis 2005, No. 19, 3380–3388 © Thieme Stuttgart · New York