Synthesis of oxa-aza spirobicycles by intramolecular hydrogen atom transfer promoted by N-radicals in carbohydrate systems

Article abstract of DOI:10.1016/j.tet.2009.05.049

The nitrogen-centred radical generated by reaction of an N-phosphoramidate or N-cyanamide, attached to a tri- or tetramethylene tether extended from the C-1 of a carbohydrate, with (diacetoxyiodo)benzene (DIB) and iodine can undergo a regio- and stereosel

Full text of DOI:10.1016/j.tet.2009.05.049

Tetrahedron 65 (2009) 6147–6155
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Tetrahedron
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Synthesis of oxa-aza spirobicycles by intramolecular hydrogen atom
transfer promoted by N-radicals in carbohydrate systems
*
*
´
´
´
´
´
Angeles Martın , Ines Perez-Martın, Ernesto Suarez
Instituto de Productos Naturales y Agrobiolog´ıa del C.S.I.C., Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The nitrogen-centred radical generated by reaction of an N-phosphoramidate or N-cyanamide, attached
to a tri- or tetramethylene tether extended from the C-1 of a carbohydrate, with (diacetoxyiodo)benzene
(DIB) and iodine can undergo a regio- and stereoselective intramolecular hydrogen atom transfer (HAT)
reaction to furnish four different oxa-azaspirobicyclic systems: 1-oxa-6-azaspiro[4.4]nonane, 1-oxa-6-
azaspiro[4.5]decane, 6-oxa-1-azaspiro[4.5]decane and 1-oxa-7-azaspiro[5.5]undecane. A tandem 1,5- or
1,6-HAT-oxidation-nucleophilic cyclisation mechanism is proposed.
Received 24 March 2009
Received in revised form 8 May 2009
Accepted 18 May 2009
Available online 27 May 2009
Keywords:
Intramolecular hydrogen atom transfer
N-Radical
Ó 2009 Elsevier Ltd. All rights reserved.
(Diacetoxyiodo)benzene
N-Phosphoramidate
N-Cyanamide
1. Introduction
opportunity to demonstrate the synthetic potential of this metho-
dology for the preparation of different heterocyclic compounds.
Hydrogen abstraction, also referred to as hydrogen atom
transfer (HAT), is one of the most common and simplest reactions
of a neutral radical with an organic substrate. It is particularly
useful since the functionalisation of a position considered to be
unreactive under classical conditions could be possible.1 Within
their intramolecular version 1,5- and 1,6-HAT reactions promoted
by carbon-centred radicals have driven a good deal of research due
to their wide range of synthetic applications,2 especially combining
this process with a subsequent radical cyclisation to the effective
construction of five and six-membered carbo- and heterocyclic
compounds.3 On the contrary, few studies have been developed for
the intramolecular HAT reactions generated by heteroatom-centred
radicals and N-radicals in particular.1c,4 In our group we have de-
voted some attention to this field since in previous papers we have
reported on the synthesis of different pyrrolidines and piperidines
in carbohydrate and steroidal systems employing N-radicals.5 For
that study, intramolecular 1,5- and 1,6-HAT reactions were pro-
moted by aminyl radicals derived from the treatment of a suitably
protected amine6 with a hypervalent iodine reagent in the presence
of iodine. These results together with those previously obtained
from the O-centred radical studies7 have provided an excellent
In a preliminary communication we have reported the synthesis
of some oxa-aza spirobicycles in carbohydrate models performed
by employing our 1,5- or 1,6-HAT radical protocol (Scheme 1).5d
PG
N
PG
N
O
O
RO
(n = m = 1)
1,5-HAT
RO
A
B
PG
(n = 1, m = 2)
N
H
O
1,6-HAT
( )m
RO
( )n
PG
PG
N
O
N
O
RO
(n = 2, m = 1)
RO
C
D
(n = m = 2)
Scheme 1. Oxa-azaspirobicycles by 1,5- or 1,6-HAT reaction; PG¼PO(OR1)2, CN;
R¼R1¼alkyl, aryl.
In an extension to this article, the purposes of the present work
were: (a) to show that the electrophilic C-1 propylidene or butyli-
dene N-radical abstracts a hydrogen atom in a regio- and stereo-
selective manner at the pseudoanomeric position of a C-glycoside,
* Corresponding authors. Tel.: þ34 922 251004; fax: þ343 922 260135.
E-mail addresses: angelesmartin@ipna.csic.es (A. Martı´n), esuarez@ipna.csic.es
´
(E. Suarez).
(b) to confirm that intramolecular 1,5-HAT, through a six-
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.049

6148
A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
membered transition state (TS) is more favourable and better
yielded process than 1,6-HAT, through a more unstable seven-
membered TS,8 (c) to explore the influence of the bulkiness of the
amino-protective group employed on the hydrogen abstraction
process and (d) to investigate whether electron-withdrawing group
(EWG) substituents may perhaps influence the reaction course. It
therefore offers the opportunity to study the consecutive HAT-oxi-
dation–nucleophilic cyclisation sequence to synthesise four espe-
cially interesting oxa-aza spirocompound systems (spiroaminals)9
(Scheme 1), which are widespread substructures common to
a number of natural products such as: manzamine X,10 having a 1-
oxa-6-azaspiro[4.4]nonane structure A, solanum alkaloids11 and
azaspiracid,12 with a 1-oxa-6-azaspiro[4.5]decane B, stemotinine
and isostemotinine alkaloids,13 with a 6-oxa-1-azaspiro[4.5]decane
mediated C-glycosidation with allyltrimethylsilane afforded the
oct-7-enitols and non-8-enitols, in general with high stereo-
selectivity,15 which upon subsequent oxidative hydroboration
provided the alcohols 2, 67e and 18 in good yield, with the exception
of the known alcohol 137e derived from the corresponding butenyl
derivative by reductive ozonolysis (Scheme 2). Transformation of
the primary unprotected alcohols into the corresponding azide
derivatives by Mitsunobu azidation16 or conversion into the cor-
responding mesyl product and subsequent nucleophilic sub-
stitution with azide ion gave products 3, 7, 14 and 19. Azides 3, 7
and 14 were hydrogenated to the consequent amines whereas 19
was submitted to a radical reduction with n-tributyltin hydride to
avoid the 5-O-benzyl deprotection. On the other hand, the known
cyanide derivatives 95b and 115b,17 were reduced to the respective
amine products with LiAlH4 treatment. The resulting crude free
amines were all treated with the corresponding diethyl, diphenyl,
or dibenzylchlorophosphate reagent in the presence of TEA to give
the required phosphoramidates 4, 8, 10, 12, 15 and 20. It is note-
worthy that the choice of phosphonates as protective groups was
made regarding their certain application in the amino and amino
acid chemistry,18 to avoid oxidation of the amine group during the
formation of the iodoamide intermediate and, at the same time, to
control the stability of the N-radical during the HAT reaction, but it
merits mention that probably the use of other functionalities such
as carbamoyl or amide derivatives could be more practical re-
garding further manipulation at the nitrogen centre because of its
facile deprotection. However, in preceding works from this labo-
ratory it was observed that in some cases apparently a lower nu-
cleophilicity of the carbamate group was responsible for the
competitive intermolecular attack of the acetate anion coming from
the reagent preventing the cyclisation step.5a
structure
[5.5]undecane D.
C a 1-oxa-7-azaspiro-
and sanglifehrin A,14 with
2. Synthesis of substrates and results
Preparation of the majority of the required C-1 three methylene
tethered N-phosphoramidate C-glycoside derivatives was accom-
plished following a general well-established four-step protocol
starting from suitably protected carbohydrates. A Lewis acid-
MeO
MeO
O
O
a
X
MeO
OMe
MeO
OMe
1
2 X = OH
3 X = N3
4 X = NHPO(OPh)2
b
c
O
To further test the scope of the HAT reaction, we also prepared
a number of precursors whose phosphoramidyl groups were at-
tached to a four-carbon tether extended from the C-1 of the sugar
(Scheme 3). The alcohol 6 was submitted to iodination and cyan-
ation to obtain 22 in 77% yield. Treatment with LiAlH4 gave the
O
O
O
O
a
O
X
O
O
O
O
6 X = OH
7 X = N3
5
d
c
X
HO
O
O
8 X = NHPO(OBn)2
O
O
6
a
RO
RO
RO
RO
O
O
O
CN
O
NHPO(OR2)2
e
O
O
O
O
OR1
OR1
21 X = I
22 X = CN
OR
OR
b
c
9 R = R1 = Me; D-Man
10 R = R1= Me; R2 = Et; D-Man
12 R = Bn; R1= Ac; R2 = Ph; D-Glc
d
23 X = CH2NHPO(OBn)2
24 X = CH2NHCN
11 R = Bn; R1 = Ac; D-Glc
HO
O
X
O
O
OMe
OMe
O
OMe
OMe
O
HO
d
O
X
e
O
O
MeO
MeO
O
O
OMe
O
O
OMe
14 X = N3
13
c
15 X = NHPO(OBn)2
26 X = N3
23/27 (1.4:1) X = NHPO(OBn)2
25
f
OTBS
OTBS
O
O
OH
O
O
f
a
X
X
O
OMe
OMe
O
OMe
OMe
e
O
OBn
OBn
MeO
16
17
18 X = OH
d
g
MeO
19 X = N3
OMe
28
OMe
20 X = NHPO(OBn)2
29 X = N3
30 X = NHPO(OBn)2
f
Scheme 2. Synthesis of C-1 propylidenphosphoramidate precursors: (a) (i) BH3$THF
1 M, THF, 0 ꢀC to rt; (ii) NaOH 3 M, H2O2 (30%), 0 ꢀC to rt, 1 h; (b) ZnN6$2Py, Ph3P, DIAD,
rt; (c) (i) H2, Pd/C 10%, EtOAc; (ii) (BnO)2POCl, TEA, CHCl3, rt; (d) (i) MsCl, Py, 0 ꢀC to rt;
(ii) NaN3, DMF, 80 ꢀC, 2 h; (e) (i) LiAlH4, Et2O, rt; (ii) (R2O)2POCl, TEA, CHCl3, rt; (f) (i)
CeCl3$7H2O, NaBH4, MeOH, 0 ꢀC to rt; (ii) H2, Pd/C 10%; (iii) NaH, BnBr, DMF, 0 ꢀC to rt,
71% from 16; (iv) ATMS, BF3$Et2O, CH3CN, 0 ꢀC to rt, 1.5 h, 93%; (v) TBSCl, imidazole,
DMF, rt, 3 h, 83%; (g) (i) Bu3SnH, AIBN, PhH, reflux; (ii) (BnO)2POCl, TEA, CHCl3, rt, 95%.
Scheme 3. Synthesis of C-1 butylidenphosphoramidate precursors: (a) I2, Ph3P,
imidazole, PhH, reflux, 0.5 h, 75%; (b) NaCN, DMF, rt, 14 h, 99%; (c) (i) LiAlH4, Et2O, rt;
(ii) TEA, (BnO)2POCl, CHCl3, rt; (d) (i) LiAlH4, Et2O, rt; (ii) NaOCN, EtOH, H2O, AcOH,
reflux, 1.5 h; (iii) MsCl, Py, 0 ꢀC to rt, 41%; (e) ZnN6$2Py, Ph3P, DIAD, rt; (f) (i) H2, Pd/C
10%, EtOAc, 23 h; (ii) TEA, (BnO)2POCl, CHCl3, rt.

A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
6149
Table 1
corresponding amine, which was protected without further puri-
fication as N-phosphoramidate 23 and N-cyanamide 24, the latter
with minor steric hindrance. The phosphoramidates 27 and 30
were prepared accordingly by azidation–reduction–protection
starting from the known alcohols 257e and 28,7e respectively.
The HAT reactions were performed under the oxidative condi-
tions previously developed in our group, by treatment of the cor-
responding precursors with (diacetoxyiodo)benzene and iodine,
and presented in Tables 1 and 2 for the production of different oxa-
azaspirocompound structures.5 Firstly we carried out the synthesis
of 1-oxa-6-azaspiro[4.4]nonane and 6-oxa-1-azaspiro[4.5]decane
models (substructures A and C, Scheme 1) to verify the feasibility of
this methodology, the results being summarised in Table 1.
Synthesis of 1-oxa-6-azaspiro[4.4]nonane and 6-oxa-1-azaspiro[4.5]decane bicycles
by 1,5-HATa
Entry
Substrate
PO(OPh)2
Products
Yield (%)
PO(OPh)2
MeO
HN
MeO
1
N
O
O
1
64
OMe
MeO
OMe
MeO
31
4
PO(OBn)2
HN
O
O
O
O
O
The 1,5-HAT reaction of the phenyl and benzyl phosphoramidate
furanose derivatives 4 and 8, derived from D-ribose and D-mannose,
respectively, proceeded smoothly to give the expected spirobicyclic
products 31 and 32 in good yields (Table 1, entries 1 and 2). In-
terestingly, the abstraction, in the case of 32, occurred on the ste-
1
O
N
PO(OBn)2
O
2
74b
O
N
O
O
32
8
rically crowded
cyclisation step tentatively took place in a selective manner on the
less hindered -side. In both cases, no NOE correlations were ob-
b-side of the furanose ring while the subsequent
PO(OBn)2
O
OMe
a
5
1
O
OMe
OMe
served between any proton of the furanose ring and 3-H2 of the
pyrrolidine ring and thus the stereochemistry of the quaternary
centre was cautiously assigned as indicated.
In order to synthesize a derivative with the spirocentre at C-5,
phosphoramidate 15, derived from D-glucose, was prepared in good
NH
MeO
OMe
(BnO)2OP
3
84 (1.5:1)
OMe
MeO
OMe
33 (5 R)
34 (5 S)
15
yield (entry 3). The HAT reaction gave the two corresponding spi-
rocompounds 33 and 34 in a global yield of 84% and a proportion of
1.5:1, respectively. Assignment of the C-5 stereochemistry was
made by contrasting the NOE correlation observed in both isomers:
epimer 33 showed an NOE interaction between 1-H and the ben-
zylic protons of the phosphoramidyl group while in 34 the in-
teraction was observed between 1-H and 6-H.
PO(OEt)2
HN
MeO
MeO
MeO
MeO
O
O
1
N
PO(OEt)2
OMe
4
52c
OMe
OMe
OMe
10
The HAT reaction of the diethyl phosphoramidate 10 and
dibenzyl derivative 20 gave the oxa-azaspirobicycles 35 and 36 in
moderate yields (entries 4 and 5). The stereochemistry of the spi-
rocentre was established on the basis of an NOE correlation be-
tween 5-H and the protons of the ethoxyl of the phosphoramidate
group in 35, and an NOE interaction of 3-H with a benzylic hy-
drogen of the 5-OBn group in 36. These results indicate that,
analogously to the case of furanose 32 (entry 2), in these two py-
35
PO(OBn)2
HN
TBSO
TBSO
O
5
1
O
N
PO(OBn)2
5
47
OBn
OBn
36
20
ranose models the abstraction occurs on the
while the nucleophilic cyclisation step takes place on the less
hindered -side.
b-side of the molecules
PO(OPh)2
HN
BnO
BnO
a
O
The influence of the protective group at C-5, next to the sup-
posed reacting centre C-4, was subsequently studied in entry 6. The
substitution of a methyl ether by an EWG such as an acetyl group
inhibited completely the radical abstraction at C-4 and under these
conditions the starting material was recovered unchanged.5b,7a,c,19
We next tested the 1,6-HAT reaction to assess whether this
methodology could prove practical for the synthesis of 1-oxa-6-
azaspiro[4.5]decane and 1-oxa-7-azaspiro[5.5]undecane bicycles
(substructures B and D, Scheme 1). The results obtained are sum-
marised in Table 2.
6
NR
5
OAc
OBn
12
a
All reactions were performed in dry CH2Cl2 (80 mL) containing (diacetoxy-
iodo)benzene (2.5 mmol), and iodine (1.4 mmol) per mmol of substrate and irradi-
ating with two 80 W tungsten filament lamps at room temperature. Yields of pure
products isolated after silica gel chromatography.
b
Solid NaHCO3 (25 mmol %) was added.
Acetonitrile (80 mL) was used instead of CH2Cl2.
c
We started our study with phosphoramidate 23 but un-
fortunately it failed to undergo 1,6-HAT on the sterically crowded
b
-side of the molecule (Table 2, entry 1). A more unstable seven-
with an overall yield of 47%, the formation of the acetyl side product
40 in a substantial amount (29%) decreased the spirocycle 39 yield
(Scheme 4). This product 40 might arise from external nucleophilic
attack of the acetate anion, coming from the DIB, to the oxy-
carbenium ion intermediate in competition with the intramolecular
cyclisation reaction. The stereochemistry of the quaternary centre in
the acetyl derivative could not be determined on the basis of NOE
experiments because no clear interactions were observed. The pro-
posed stereochemistry, where the acetate anion adds to the less
hindered side of the molecule, was consistent with the deshielding
membered TS in comparison with precursor 8 (Table 1, entry 2) was
postulated as responsible for the failure. In this case only monoiodine
37 and diiodine 38, which are both produced by 1,5-HAT reactions,
were isolated in low yields. Their structures were confirmed spec-
troscopically and by reductive dehalogenation to the starting amide
23 with the n-Bu3SnH/AIBN system. In contrast, the bicycle 39 could
be formed in low yield using the 6S-isomeric phosphoramidate 27
where the 1,6-HAT reaction proceeded on the less hindered side of
the substrate (entry 2). Although the hydrogen abstraction occurred

6150
A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
undergone by the furanose ring protons in its 1H NMR spectrum
according to similar products found in the literature.20 The strong
hindrance of the b-side of the molecule may also be responsible for
Table 2
Synthesis of 1-oxa-6-azaspiro[4.5]decane and 1-oxa-7-azaspiro[5.5]undecane bi-
cycles by 1,6-HATa
Entry
Substrate
Products
(BnO)2OP
HN
Yield % (dr)
the formation of only one isomer of products 39 and 40.
The model described in entry 3 demonstrates that the steric
demand of the amine protector proved to be crucial to the 1,6-HAT
and the subsequent cyclisation step. The cyanamide 24 is trans-
formed exclusively into the 1-oxa-6-azaspiro[4.5]decane 41 with
absolute regio- and stereoselectivity, albeit in moderate yield. With
the voluminous phosphoramidate group only products 37 and 38
derived from more stable 1,6-transition states were formed (entry
1).21 Also in this model the hydrogen abstraction took place on the
(BnO)2OP
HN
O
O
O
O
O
6
O
R
14b
30
O
O I
1
O
O
37 R = H
38 R = I
23
more congested
b-side of the furanose ring while the cyclisation
step occurred on the opposite
a
-side. The configuration of the
O
O
spirocentre was tentatively established as indicated because no
NOE interactions were observed between 7-H2 and any of the fu-
ranose protons.
O
O
6
O
O
HN
PO(OBn)2
N
2
PO(OBn)2 18b,c
O
O
O
O
Finally, this HAT-cyclisation sequence was further extended to
pyranose model 30 derived from
D-glucose yielding smoothly the
expected bicycles 42 and 43 in moderate yield together with
b-iodo
27
39
ester 44 as a side product. The stereochemistry of the quaternary
centre was established on the basis of an NOE correlation between
1-H and 6-H in 43, an interaction that was not observed in 42. The
formation of 44 can be explained by a trans electrophilic addition of
CN
HN
O
O
O
7
O
O
6
O
N
CN
acetyl hypoiodite22 to the hypothetical Z-olefin 45, resembling
3
48b
O
O
O
O
23
´
Prevost reaction (Scheme 5). Plausibly, this olefin could be gen-
erated from the oxycarbenium ion intermediate or by acid-cata-
lysed ring opening of the oxa-azaspirobicycles 42 and 43. The
stereochemistry of 44 was assigned taking into account the strong
deshielding of the axial protons at C-1 and C-3 in comparison with
those of the starting amine 30, which suggest an axial acetyl group
at C-5.
24
41
PO(OBn)2
PO(OBn)2
NH
N
O
OMe
5
O
OMe
41d
(3:1)
MeO
OMe
4
OMe
MeO
OMe
OMe
I
O
42 (5R)
43 (5S)
AcO
NH
MeO
OMe
OMe
O
OMe
OMe
30
[AcOI]
5
1
R
NH
MeO
R
a
All reactions were performed in dry CH2Cl2 (80 mL) containing (diacetoxy-
iodo)benzene (2.5 mmol), and iodine (1.4 mmol) per mmol of substrate and irradi-
ating with two 80 W tungsten filament lamps at room temperature. Yields of pure
products isolated after silica gel chromatography.
MeO
44
MeO
45
b
Solid NaHCO3 (25 mmol %) was added.
Acetate 40 (29%) was also obtained.
Compound 44 (22%) was also obtained.
Scheme 5. Minor product 44 from Table 2, entry 4; R¼PO(OBn)2.
c
d
It is important to stand out that all the structures were con-
firmed by 1H and 13C NMR spectra (DEPT, COSY, HSQC and HMBC
experiments), revealing in all cases a selective abstraction of the
corresponding protons. Likewise, the stereochemistry of the qua-
ternary centre was tentatively assigned in base of intramolecular
NOE experiments as it is portrayed in Experimental section in each
case.
O
O
O
N
PO(OBn)2
O
O
3. Conclusions
39
With these examples we have now demonstrated the possibility
of using N-radicals, generated in situ from the reaction of N-phos-
phoramidates and N-cyanamides with the DIB/I2 system, for the
synthesis of four different types of oxa-aza spirobicycles, which are
not readily accessible by other methods. The virtues of this reagent
are the mildness of the conditions and high protective group tol-
erance. As observed, the process may be conceptually considered to
be an intramolecular N-glycosidation via selective oxidation of the
pseudoanomeric position of a C-glycoside using a 1,5- or 1,6-HAT
reaction as the key step. The polarity of the amine protecting group
may be very important since the nitrogen acts with an umpolung
reactivity during the reaction, first as an electrophilic N-radical and
then as a nucleophile in the cyclisation step.
O
-H+
+
O
1,6-HAT
O
HN
R
27
-
AcO
O
O
O
O
NR
O
H
OAc
O
O
40
Scheme 4. Side product 40 from Table 2, entry 2; R¼PO(OBn)2.

A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
6151
4. Experimental
4.1. General
4.7 Hz), 4.38 (1H, dd, J¼6.2, 0 Hz), 4.68 (1H, dd, J¼6.0, 3.8 Hz), 5.04
(4H, d, JP¼7.3 Hz), 7.31–7.37 (10H, m); 13C NMR dC 24.5 (CH3), 25.0
(CH3), 26.0 (CH3), 26.8 (CH3), 27.5 (CH2), 28.0 (CH2), 40.9 (CH2), 66.8
(CH2), 67.9 (2ꢂCH2), 73.3 (CH), 79.8 (CH), 80.6 (CH), 83.7 (CH), 85.2
(CH), 109.0 (C), 112.5 (C), 127.7 (4ꢂCH), 128.2 (2ꢂCH), 128.4 (4ꢂCH),
136.3 (2ꢂC); MS m/z (rel intens) 560 (Mþꢁ1, <1), 546 (5), 91 (100);
HRMS m/z calcd for C29H39NO8P 560.2413, found 560.2404. Anal.
Calcd for C29H40NO8P: C, 62.02; H, 7.18; N, 2.49. Found: C, 62.22; H,
6.82; N, 2.74.
Melting points were determined with a hot-stage apparatus and
are uncorrected. Optical rotations were measured at the sodium
line at ambient temperature in CHCl3 solutions. IR spectra were
recorded in CCl4 unless otherwise stated. NMR spectra were de-
termined at 400 MHz for 1H and 100.6 MHz for 13C in CDCl3 unless
otherwise indicated, in the presence of TMS as internal standard.
Mass spectra were determined at 70 eV. Merck silica gel 60 PF
(0.063–0.2 mm) was used for column chromatography. Circular
layers of 1 mm of Merck silica gel 60 PF254 were used on a Chro-
matotron for centrifugally assisted chromatography. Commercially
available reagents and solvents were of analytical grade or were
purified by standard procedures prior to use. All reactions involving
air- or moisture-sensitive materials were carried out under a ni-
trogen atmosphere. The spray reagents for TLC analysis were con-
ducted with 0.5% vanillin in H2SO4/EtOH (4:1) and further heating
until development of colour.
4.2.4. 2,6-Anhydro-7,8,9-trideoxy-9-[(diethoxyphosphoryl)amino]-
1,3,4,5-tetra-O-methyl-D-glycero-D-manno-nonitol (10)
Following the general procedure starting from cyanide 9
(1.11 g, 4.07 mmol), 10 (926 mg, 2.24 mmol, 55%) was obtained as
a colourless oil: [
a
]
þ7.5 (c, 1.20); IR 3563, 1660, 1455 cmꢁ1
;
1H
D
NMR dH 1.29 (6H, t, J¼7.1 Hz), 1.46–1.58 (2H, m), 1.58–1.67 (2H, m),
2.75 (1H, m), 2.92 (1H, m), 3.31 (1H, dd, J¼4.8, 3.3 Hz), 3.35 (3H, s),
3.38 (3H, s), 3.39 (1H, dd, J¼6.2, 3.3 Hz), 3.44 (3H, s), 3.45 (3H, s),
3.48 (1H, dd, J¼7.4, 2.6 Hz), 3.52–3.58 (2H, m), 3.62 (1H, m), 3.88
(1H, ddd, J¼9.0, 4.3, 4.3 Hz), 3.97–4.06 (4H, m), 1H from the NH
group is missing; 13C NMR (50.4 MHz) dC 16.2 (2ꢂCH3), 26.4 (CH2),
28.2 (CH2), 41.0 (CH2), 57.5 (CH3), 57.9 (CH3), 59.1 (CH3), 59.5 (CH3),
62.1 (2ꢂCH2), 71.5 (CH2), 71.8 (CH), 72.5 (CH), 76.6 (CH), 78.4 (CH),
79.1 (CH); MS m/z (rel intens) 414 (Mþþ1, 2), 88 (100); HRMS m/z
calcd for C17H37NO8P 414.2256, found 414.2281. Anal. Calcd for
C17H36NO8P: C, 49.38; H, 8.78; N, 3.39. Found: C, 49.44; H, 8.83; N,
3.13.
4.2. Synthesis of precursors for HAT reactions
4.2.1. General procedure for N-phosphoramidate precursors
Starting from azide precursors (1 mmol) in dry EtOAc (29 mL)
and with Pd/C 10% (187 mg), the mixture was hydrogenated at rt for
24 h. The suspension was filtered over Celite and concentrated
under reduced pressure. Starting from cyanide precursors (1 mmol)
in dry THF or Et2O (6 mL), LiAlH4 (4 mmol) was portionwise added
at 0 ꢀC. The mixture was stirred at rt until completion and then
a saturated solution of Na2SO4 was dropwise added until the grey
mixture turned to white. It was filtered and evaporated. The
resulting crude amine (1 mmol) in dry CHCl3 (16 mL) was treated at
0 ꢀC with triethylamine (3.5 mmol) and (RO)2POCl (2 mmol) and
stirred at rt. Then it was concentrated and poured directly into the
column to chromatography (hexanes/EtOAc).
4.2.5. 2,6-Anhydro-1,3,4-tri-O-benzyl-7,8,9-trideoxy-9-
[(diphenoxyphosphoryl)amino]-D-glycero-L-gulo-nonitol (12)
Following the general procedure starting from cyanide 11
(370 mg, 0.70 mmol), a deprotected 5-OH product was obtained
(319 mg, 0.44 mmol, 63%), which was submitted to acylation with
Ac2O/Py to give 12 (60% overall yield) as a colourless oil: [
a
]
D þ23.1
(c, 0.13); IR 3221, 3066, 2934, 2871, 1746, 1454 cmꢁ1 1H NMR dH
;
1.42 (1H, m), 1.53 (1H, m), 1.60–1.74 (2H, m), 1.96 (3H, s), 3.10–3.16
(2H, m), 3.32 (1H, m), 3.57–3.67 (4H, m), 3.75 (1H, dd, J¼8.1, 8.1 Hz),
4.07 (1H, m), 4.47 (1H, d, J¼11.0 Hz), 4.48 (1H, d, J¼12.4 Hz), 4.57
(1H, d, J¼12.4 Hz), 4.69 (1H, d, J¼11.4 Hz), 4.73 (1H, d, J¼11.0 Hz),
4.74 (1H, d, J¼11.4 Hz), 5.01 (1H, dd, J¼8.6, 5.2 Hz), 7.13–7.33 (25H,
m); 13C NMR dC 20.9 (CH3), 22.9 (CH2), 27.5 (CH2), 41.4 (CH2), 68.8
(CH2), 71.9 (CH), 72.1 (CH), 72.8 (CH), 73.4 (CH2), 74.5 (CH2), 74.7
(CH2), 77.4 (CH), 79.8 (CH), 120.2–129.7 (25ꢂCH), 137.9 (2ꢂC), 138.3
(C), 150.8 (2ꢂC), 170.0 (C); MS m/z (rel intens) 766 (Mþþ1, 1), 91
(100); HRMS m/z calcd for C44H49NO9P, 766.3144, found 766.3145.
Anal. Calcd for C44H48NO9P: C, 69.01; H, 6.32; N, 1.83. Found: C,
69.37; H, 6.49; N, 1.76.
4.2.2. 4,7-Anhydro-1,2,3-trideoxy-1-[(diphenoxyphosphoryl)-
amino]-5,6,8-tri-O-methyl-D-altro-octitol (4)
Following the general procedure of phosphoramido protection
starting from azide 3 (374 mg, 1.44 mmol), diphenylphosphor-
amidate 4 (342 mg, 0.74 mmol, 51%) was obtained as a colourless
oil: [
a]
D þ16.1 (c, 1.30); IR 3271, 2937, 1591, 1487 cmꢁ1; 1H NMR dH
1.48–1.67 (4H, m), 1.93 (1H, m), 3.07–3.13 (2H, m), 3.37 (3H, s), 3.41
(3H, s), 3.42 (1H, dd, J¼10.9, 3.8 Hz), 3.45 (3H, s), 3.50 (1H, dd,
J¼10.9, 3.3 Hz), 3.69 (1H, dd, J¼4.5, 4.5 Hz), 3.75 (1H, dd, J¼6.2,
4.8 Hz), 3.91 (1H, ddd, J¼8.6, 4.3, 4.3 Hz), 3.99 (1H, ddd, J¼6.4, 3.8,
3.8 Hz), 7.12–7.33 (10H, m); 13C NMR (50.4 MHz) dC 26.5 (CH2), 28.1
(CH2, JP¼6.1 Hz), 41.8 (CH2), 58.5 (CH3), 59.4 (CH3), 59.7 (CH3), 73.1
(CH2), 79.2 (CH), 79.8 (CH), 80.2 (CH), 81.8 (CH),120.2 (2ꢂCH),124.8
(4ꢂCH), 129.6 (4ꢂCH), 150.8 (2ꢂC); MS m/z (rel intens) 466 (Mþþ1,
<1), 262 (100); HRMS m/z calcd for C23H33NO7P 466.1994, found
466.2011. Anal. Calcd for C23H32NO7P: C, 59.35; H, 6.93; N, 3.01.
Found: C, 59.38; H, 6.85; N, 2.92.
4.2.6. Methyl 8-{[bis(benzyloxy)phosphoryl]amino}-6,7,8-trideoxy-
2,3,4-tri-O-methyl-b-D-gluco-octopyranoside (15)
Following the general procedure of phosphoramido protection
starting from azide 14 (101.5 mg, 0.33 mmol), dibenzylphosphor-
amidate 15 (66.7 mg, 0.12 mmol, 38%) was obtained as a colourless
oil: [
a
]
D ꢁ5.3 (c, 0.94); IR 3217, 2933, 1456, 1234 cmꢁ1; 1H NMR dH
1.40 (1H, dddd, J¼13.8, 9.0, 9.0, 5.0 Hz), 1.50 (1H, m), 1.66 (1H, m),
1.81 (1H, m), 2.77 (1H, dd, J¼9.2, 9.2 Hz), 2.87–2.93 (2H, m), 2.92
(1H, dd, J¼8.5, 8.5 Hz), 3.01 (1H, ddd, J¼9.3, 9.3, 2.5 Hz), 3.09 (1H,
dd, J¼8.9, 8.9 Hz), 3.43 (3H, s), 3.48 (3H, s), 3.54 (3H, s), 3.59 (3H, s),
4.04 (1H, d, J¼7.5 Hz), 5.03 (4H, d, JP¼7.0 Hz), 7.30–7.35 (10H, m),1H
from the NH group is missing; 13C NMR dC 27.8 (CH2), 28.4 (CH2),
41.2 (CH2), 56.8 (CH3), 60.4 (CH3), 60.6 (CH3), 60.7 (CH3), 67.9
(2ꢂCH2), 74.3 (CH), 83.6 (CH), 83.8 (CH), 86.5 (CH), 104.1 (CH), 127.7
(4ꢂCH), 128.2 (2ꢂCH),128.5 (4ꢂCH),136.5 (2ꢂC); MS (FAB) m/z (rel
intens) 546 (MþþNa, 3), 524 (1), 91 (100). Anal. Calcd for
C26H38NO8P: C, 59.64; H, 7.32; N, 2.68. Found: C, 59.52; H, 7.60; N,
2.54.
4.2.3. 3,6-Anhydro-9-{[bis(benzyloxy)phosphoryl]amino}-7,8,9-
trideoxy-1,2:4,5-di-O-isopropylidene-D-glycero-D-manno-
nonitol (8)
Following the general procedure of phosphoramido protection
starting from azide 7 (85 mg, 0.26 mmol), dibenzylphosphor-
amidate 8 (85.5 mg, 0.15 mmol, 59%) was obtained as a colourless
oil: [
a
]
ꢁ3.4 (c, 1.0); IR 3217, 2937, 1549, 1456 cmꢁ1
;
1H NMR dH
D
1.32 (3H, s), 1.35 (1H, m), 1.36 (3H, s), 1.43 (3H, s), 1.46 (1H, m), 1.48
(3H, s), 1.58–1.65 (2H, m), 2.59 (1H, br s), 2.88 (2H, m), 3.67 (1H, dd,
J¼7.5, 3.7 Hz), 3.96 (1H, ddd, J¼8.7, 5.0, 0 Hz), 3.98 (1H, dd, J¼8.6,
4.4 Hz), 4.06 (1H, dd, J¼8.6, 6.3 Hz), 4.36 (1H, ddd, J¼6.6, 6.6,

6152
A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
4.2.7. 2,6-Anhydro-5-O-benzyl-9-{[bis(benzyloxy)phosphoryl]-
amino}-1-O-[tert-butyl(dimethyl)silyl]-3,4,7,8,9-pentadeoxy-
29.9 (CH2), 45.8 (CH2), 66.7 (CH2), 73.3 (CH), 79.9 (CH), 80.6 (CH),
83.8 (CH), 85.1 (CH), 109.0 (C), 112.5 (C), 116.3 (C); MS m/z (rel
intens) 325 (MþꢁMe, 39), 101 (100); HRMS m/z calcd for
C16H25N2O5 325.1763, found 325.1768. Anal. Calcd for C17H28N2O5:
C, 59.98; H, 8.29; N, 8.23. Found: C, 59.64; H, 8.31; N, 8.59.
D-arabino-nonitol (20)
To a solution of the azide 19 (39.4 mg, 0.09 mmol) in dry ben-
zene (3 mL), Bu3SnH (126 mL, 0.468 mmol) and AIBN (2 mg) were
added and the mixture was refluxed for 1.5 h. Then it was evapo-
rated and the obtained crude was submitted to the general pro-
tection procedure to give dibenzylphosphoramidate 20 (58.3 mg,
0.09 mmol, 95%) as a colourless oil and as a mixture of two con-
4.2.10. 3,6-Anhydro-10-{[bis(benzyloxy)phosphoryl] amino}-
7,8,9,10-tetradeoxy-1,2:4,5-di-O-isopropylidene-glycero-D-manno-
decitol (23 and 27)
formers in equilibrium A/B (1:3):24
[
a]
þ14.2 (c, 0.39); IR 3220,
Following the general procedure starting from azide 26 (35 mg,
0.10 mmol), 23 and 27 (32.2 mg, 0.06 mmol, 55%) were obtained as
a mixture 23/27 (1.4:1) and as a colourless oil: IR 3217, 2988, 2935,
D
2929, 2857, 1455, 1252 cmꢁ1; 1H NMR dH 0.04 (12H, s), 0.87 (18H, s),
1.26–1.82 (16H, m), 2.66 (2H, br s), 2.88–2.90 (4H, m), 3.08–3.14
(2H, m), 3.45–3.49 (2H, m), 3.54–3.70 (6H, m), 4.34 (1H, d,
J¼12.3 Hz, A), 4.46 (1H, d, J¼12.0 Hz, A), 4.56 (1H, d, J¼12.0 Hz, B),
4.63 (1H, d, J¼12.2 Hz, B), 5.00–5.06 (8H, m), 7.24–7.36 (30H, m);
13C NMR dC ꢁ5.29 (4ꢂCH3), 18.2 (2ꢂC), 23.4 (2ꢂCH2), 23.6 (4ꢂCH2),
25.7 (6ꢂCH3), 27.6 (2ꢂCH2), 27.8 (2ꢂCH2), 41.2 (2ꢂCH2), 64.3 (CH2,
B), 66.5 (CH2, A), 67.8 (2ꢂCH2), 70.3 (CH2, B), 70.5 (CH2, A), 71.0 (CH,
B), 72.1 (CH, A), 74.3 (CH, B), 75.4 (CH, A), 78.5 (CH, B), 79.2 (CH, A),
128.5–127.5 (30ꢂCH), 136.5 (4ꢂC), 138.5 (2ꢂC); MS m/z (rel intens)
654 (Mþþ1, <1), 596 (17); HRMS m/z calcd for C36H53NO6PSi
654.3379, found 654.3370. Anal. Calcd for C36H52NO6PSi: C, 66.13;
H, 8.02; N, 2.14. Found: C, 66.13; H, 8.04; N, 2.12.
2871, 1456, 1380, 1232 cmꢁ1 1H NMR dH 1.25–1.29 (2H, m), 1.29
;
(3H, s), 1.32 (3H, s), 1.33–1.43 (6H, m), 1.34 (3H, s), 1.37 (3H, s), 1.40–
1.44 (2H, m), 1.42 (6H, s), 1.43 (3H, s), 1.49 (3H, s), 1.61 (2H, m), 1.80
(2H, br s), 2.85 (4H, m), 3.36 (1H, ddd, J¼6.7, 6.7, 3.8 Hz), 3.40 (1H,
dd, J¼7.4, 3.3 Hz), 3.67 (1H, dd, J¼7.6, 3.4 Hz), 3.96 (1H, ddd, J¼9.1,
5.3, 0 Hz), 4.00 (2H, dd, J¼8.5, 4.7 Hz), 4.04 (1H, dd, J¼8.0, 6.5 Hz),
4.07 (1H, dd, J¼8.5, 6.4 Hz), 4.37 (2H, m), 4.43 (1H, dd, J¼6.0, 0 Hz),
4.52 (1H, dd, J¼6.2, 3.8 Hz), 4.69 (1H, dd, J¼6.2, 3.3 Hz), 4.72 (1H,
dd, J¼5.9, 3.8 Hz), 5.04 (8H, d, JP¼8.1 Hz), 7.31–7.37 (20H, m); 13C
NMR dC 22.6 (CH2), 22.8 (CH2), 24.5 (2ꢂCH3), 25.0 (CH3), 25.1 (CH3),
25.6 (CH3), 26.0 (CH3), 26.8 (2ꢂCH3), 27.5 (CH2), 30.0 (CH2), 31.1
(CH2), 31.3 (CH2), 41.0 (CH2), 41.2 (CH2), 66.8 (CH2), 66.9 (CH2), 67.8
(4ꢂCH2), 73.0 (CH), 73.3 (CH), 79.9 (CH), 80.6 (2ꢂCH), 81.1 (CH),
81.4 (CH), 81.8 (CH), 83.8 (CH), 85.1 (CH), 108.9 (C), 109.0 (C), 112.1
(C), 112.5 (C), 127.7 (8ꢂCH), 128.1 (2ꢂCH), 128.2 (2ꢂCH), 128.4
(8ꢂCH), 136.4 (2ꢂC), 137.7 (2ꢂC); MS m/z (rel intens) 560
(MþꢁCH3, 2), 484 (2), 91 (100); HRMS m/z calcd for C29H39NO8P
560.2413, found 560.2419. Anal. Calcd for C30H42NO8P: C, 62.60; H,
7.35; N, 2.43. Found: C, 62.44; H, 7.73; N, 2.57.
4.2.8. 3,6-Anhydro-10-{[bis(benzyloxy)phosphoryl]amino}-
7,8,9,10-tetradeoxy-1,2:4,5-di-O-isopropylidene-
-manno-decitol (23)
Following the general procedure starting from cyanide 22
(213 mg, 0.68 mmol), 23 (228.3 mg, 0.40 mmol, 58%) was obtained as
a colourless oil: [
ꢁ1.75 (c, 0.286); IR 3219, 2937, 1455, 1380,
D-glycero-
D
a]
D
1232 cmꢁ1; 1H NMR dH 1.25–1.29 (2H, m), 1.32 (3H, s), 1.35–1.40 (2H,
m), 1.37 (3H, s), 1.40–1.44 (2H, m), 1.42 (3H, s), 1.49 (3H, s), 2.58 (1H,
m), 2.84 (2H, ddd, J¼16.6, 6.9, 6.9 Hz), 3.67 (1H, dd, J¼7.6, 3.4 Hz), 3.96
(1H, ddd, J¼9.1, 5.3, 0 Hz), 4.00 (1H, dd, J¼8.5, 4.7 Hz), 4.07 (1H, dd,
J¼8.5, 6.4 Hz), 4.37 (1H, ddd, J¼7.0, 7.0, 4.4 Hz), 4.43 (1H, dd, J¼6.0,
0 Hz), 4.72 (1H, dd, J¼5.9, 3.8 Hz), 5.04 (4H, d, JP¼8.1 Hz), 7.31–7.37
(10H, m); 13C NMR dC 22.6 (CH2), 24.5 (CH3), 25.0 (CH3), 26.0 (CH3),
26.8 (CH3), 30.0 (CH2), 31.1 (CH2), 41.2 (CH2), 66.9 (CH2), 67.8 (2ꢂCH2),
73.3 (CH), 79.9 (CH), 80.6 (CH), 83.8 (CH), 85.1 (CH), 109.0 (C), 112.5
(C), 127.7 (4ꢂCH), 128.2 (2ꢂCH), 128.4 (4ꢂCH), 136.4 (2ꢂC); MS m/z
(rel intens) 575 (Mþ, <1), 560 (7), 91 (100); HRMS m/z calcd for
C30H42NO8P 575.2648, found 575.3074. Anal. Calcd for C30H42NO8P:
C, 62.60; H, 7.35; N, 2.43. Found: C, 62.44; H, 7.33; N, 2.57.
4.2.11. Methyl 9-{[bis(benzyloxy)phosphoryl]amino}-6,7,8,9-
tetradeoxy-2,3,4-tri-O-methyl-b-D-gluco-nonopyranoside (30)
Following the general procedure starting from azide 29 (39.3 mg,
0.14 mmol), 30 (36.6 mg, 0.07 mmol, 52%) was obtained as a crys-
talline solid: mp 59.6–60.6 ꢀC (n-hexane/EtOAc); [
a
]D ꢁ2.6 (c, 1.29);
IR 3216, 2934, 1456, 1233 cmꢁ1; 1H NMR dH 1.30 (1H, m), 1.36–1.54
(4H, m),1.75 (1H, m), 2.78 (1H, dd, J¼9.2, 9.2 Hz), 2.84–2.91 (2H, m),
2.93 (1H, dd, J¼8.4, 8.4 Hz), 3.01 (1H, ddd, J¼9.3, 9.3, 2.4 Hz), 3.10
(1H, dd, J¼8.9, 8.9 Hz), 3.46 (3H, s), 3.50 (3H, s), 3.54 (3H, s), 3.60 (3H,
s), 4.05 (1H, d, J¼8.0 Hz), 5.03 (4H, d, JP¼7.5 Hz), 7.29–7.36 (10H, m),
1H from the NH group is missing; 13C NMR dC 22.6 (CH2), 31.1 (CH2),
31.5 (CH2), 41.3 (CH2), 56.7 (CH3), 60.3 (CH3), 60.6 (CH3), 60.7 (CH3),
68.0 (2ꢂCH2), 74.4 (CH), 83.7 (CH), 83.9 (CH), 86.5 (CH), 104.0 (CH),
127.7 (4ꢂCH), 128.2 (2ꢂCH), 128.5 (4ꢂCH), 136.4 (2ꢂC); MS m/z (rel
intens) 537 (Mþ, <1), 88 (100); HRMS m/z calcd for C27H40NO8P
537.2491, found 537.2520. Anal. Calcd for C27H40NO8P: C, 60.32; H,
7.50; N, 2.61. Found: C, 60.42; H, 7.49; N, 2.79.
4.2.9. 3,6-Anhydro-10-cyanoamino-7,8,9,10-tetradeoxy-1,2:4,5-
di-O-isopropylidene-D-glycero-D-manno-decitol (24)
The cyanide 22 (334 mg, 1.07 mmol) was submitted to LiAlH4
reduction as in the general procedure. The resulting crude amine
was dissolved in EtOH (48 mL), water (1.4 mL) and acetic acid
(0.13 mL), and sodium cyanate was added (104 mg, 1.60 mmol). The
mixture was refluxed for 2 h and then it was poured into brine and
extracted with ethyl acetate. The organic solution was dried over
Na2SO4 and evaporated. To a solution of the crude urea in pyridine
(4.8 mL), at 0 ꢀC, methanesulphonyl chloride (0.26 mL, 3.39 mmol)
was added. After 30 min, the solution was allowed to warm to rt
and then it was stirred for 2 h. It was poured into water and
extracted with CHCl3. The organic layer was washed with aqueous
NaHCO3 and water and evaporated. Column chromatography
(hexanes/EtOAc, 7:3) gave the cyanamide 24 (150 mg, 0.44 mmol,
4.3. General procedure for HAT reactions
To a solution of the N-phosphoramidate or N-cyanamide pre-
cursor (1 mmol) in dry CH2Cl2 (1.5 mL), DIB (2.5 mmol) and I2
(1.5 mmol) were added and the mixture was irradiated with two
80 W tungsten lamps at rt. When the starting material was com-
pletely consumed, the mixture was poured into a solution of
Na2S2O3 and extracted with CH2Cl2. The organic extracts were dried
over Na2SO4 and evaporated. Column chromatography of the resi-
due (hexanes/EtOAc) gave the title compound.
41%) as a colourless oil: [
a
]
ꢁ7.2 (c, 2.50); IR 3251, 2227,
D
1381 cmꢁ1; 1H NMR dH 1.29 (3H, s), 1.32 (3H, s), 1.32–1.49 (4H, m),
1.40 (3H, s), 1.44 (3H, s), 1.52–1.64 (2H, m), 3.01 (2H, ddd, J¼13.5,
6.9, 0 Hz), 3.69 (1H, dd, J¼7.4, 3.7 Hz), 3.97 (2H, dd, J¼8.5, 4.5 Hz),
4.04 (1H, dd, J¼8.5, 6.1 Hz), 4.26 (1H, br t, J¼5.0 Hz), 4.33 (1H, m),
4.45 (1H, dd, J¼6.1, 0 Hz), 4.71 (1H, dd, J¼6.1, 3.7 Hz); 13C NMR dC
22.4 (CH2), 24.5 (CH3), 25.0 (CH3), 26.0 (CH3), 26.7 (CH3), 29.1 (CH2),
4.3.1. (4S)-1,4:4,7-Dianhydro-1,2,3-trideoxy-1-[(diphenoxy-
phosphoryl)amino]-5,6,8-tri-O-methyl-D-ribo-oct-4-ulose (31)
Following the general procedure, diphenylphosphoramide 4
(69.6 mg, 0.15 mmol) gave 31 (44.4 mg, 0.10 mmol, 64%) as a col-
ourless oil: [
a
]
D ꢁ37.9 (c, 0.14); IR 2933, 1490, 1279 cmꢁ1; 1H NMR

A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
6153
dH 1.82 (1H, m), 1.90–1.99 (2H, m), 2.20 (1H, m), 3.22 (1H, m), 3.29
(1H, m), 3.29 (3H, s), 3.30 (3H, s), 3.36 (3H, s), 3.38 (1H, dd, J¼9.8,
7.4 Hz), 3.62 (1H, m), 3.65 (1H, dd, J¼5.7, 1.4 Hz), 3.90 (1H, ddd,
J¼7.6, 7.6, 1.4 Hz), 4.73 (1H, d, J¼5.7 Hz), 7.13–7.32 (10H, m); NOE
correlation between 3-H and 5-H was observed; 13C NMR
(50.4 MHz) dC 23.0 (CH2), 33.9 (CH2), 48.4 (CH2), 57.6 (CH3), 58.4
(CH3), 59.1 (CH3), 73.1 (CH2), 79.1 (CH), 79.2 (CH), 79.5 (CH), 102.9
(C), 120.3 (CH), 120.6 (CH), 124.7 (2ꢂCH), 124.9 (2ꢂCH), 129.3
(2ꢂCH), 129.6 (2ꢂCH), 150.7 (C), 150.9 (C); MS m/z (rel intens) 463
(Mþ, 1), 101 (100); HRMS m/z calcd for C23H30NO7P 463.1759, found
463.1745. Anal. Calcd for C23H30NO7P: C, 59.61; H, 6.52; N, 3.02.
Found: C, 59.69; H, 6.80; N, 3.03.
J¼11.9 Hz, JP¼6.6 Hz), 5.09 (1H, dd, J¼12.2 Hz, JP¼6.2 Hz), 5.12 (1H,
dd, J¼12.2 Hz, JP¼7.2 Hz), 7.27–7.38 (10H, m); an NOE correlation
between 1-H and 6-H was observed; 13C NMR dC 23.3 (CH2, d,
JP¼9.2 Hz), 30.5 (CH2, d, JP¼9.2 Hz), 47.9 (CH2), 56.3 (CH3), 60.3
(2ꢂCH3), 60.7 (CH3), 67.3 (CH2), 67.4 (CH2), 80.4 (CH), 83.0 (2ꢂCH),
84.5 (CH), 95.8 (C), 100.7 (CH), 127.5 (2ꢂCH), 127.7 (2ꢂCH), 127.9
(2ꢂCH), 128.1 (CH), 128.3 (2ꢂCH), 136.5 (C, d, JP¼9.2 Hz), 137.1 (C, d,
JP¼9.2 Hz); MS m/z (rel intens) 490 (MþꢁOCH3, 1), 88 (100); HRMS
m/z calcd for C25H33NO7P 490.1994, found 490.2022. Anal. Calcd for
C26H36NO8P: C, 59.87; H, 6.96; N, 2.69. Found: C, 59.98; H, 6.67; N,
2.77.
4.3.4. (4S)-1,4:4,8-Dianhydro-1,2,3-trideoxy-1-[(diethoxy-
4.3.2. (4S)-1,4:4,7-Dianhydro-1-{[bis(benzyloxy)phosphoryl]-
phosphoryl)amino]-5,6,7,9-tetra-O-methyl-D-manno-non-
amino}-1,2,3-trideoxy-5,6:8,9-di-O-isopropylidene-
D-manno-
4-ulose (35)
non-4-ulose (32)
Following the general procedure but using acetonitrile as sol-
Following the general procedure but adding also NaHCO3
vent, phosphoramide 10 (30 mg, 0.07 mmol) gave 35 (15.5 mg,
(25 mmol %), dibenzylphosphoramide 8 (10.7 mg, 0.02 mmol) gave
0.04 mmol, 52%) as a colourless oil: [
a
]
D
þ44.5 (c, 1.10); IR 2933,
32 (5.1 mg, 0.01 mmol, 74%) as a colourless oil: [
a]
D þ22.0 (c, 1.03);
1715, 1455, 1252 cmꢁ1
;
1H NMR dH 1.29 (6H, t, J¼6.9 Hz), 1.72 (1H,
IR 2986, 1380, 1265, 1070 cmꢁ1; 1H NMR dH 1.34 (3H, s), 1.36 (3H, s),
1.44 (3H, s),1.46 (3H, s),1.73 (1H, m),1.88 (1H, m), 2.00 (1H, m), 2.09
(1H, m), 3.08 (1H, ddd, J¼8.8, 8.8, 8.8 Hz), 3.20 (1H, ddd, J¼8.8, 8.8,
0 Hz), 3.97 (1H, dd, J¼8.5, 4.6 Hz), 4.04 (1H, dd, J¼8.5, 6.2 Hz), 4.33
(1H, ddd, J¼6.4, 6.4, 5.0 Hz), 4.52 (1H, dd, J¼7.1, 3.8 Hz), 4.96 (1H, d,
J¼11.9 Hz), 4.98 (1H, d, J¼11.4 Hz), 5.01 (1H, m), 5.02 (2H, d,
J¼12.0 Hz), 5.14 (1H, dd, J¼5.9, 0 Hz), 7.30–7.38 (10H, m); there was
no NOE correlation between any of the hydrogen atoms on the
furanose system and 3-H; 13C NMR dC 22.6 (CH2, JP¼9.1 Hz), 24.4
(CH3), 25.4 (CH3), 25.9 (CH3), 26.9 (CH3), 36.6 (CH2, JP¼9.1 Hz), 48.4
(CH2), 66.6 (CH2), 67.3 (CH2), 67.7 (CH2), 73.8 (CH), 79.9 (CH), 81.7
(CH), 86.5 (CH), 104.8 (C), 108.8 (C), 112.0 (C), 127.7 (2ꢂCH), 128.1
(2ꢂCH), 128.2 (2ꢂCH), 128.3 (2ꢂCH), 128.4 (2ꢂCH), 136.2 (2ꢂC);
MS m/z (rel intens) 559 (Mþ, <1), 544 (4), 91 (100); HRMS m/z calcd
for C29H38NO8P 559.2335, found 559.2344. Anal. Calcd for
C29H38NO8P: C, 62.24; H, 6.84; N, 2.50. Found: C, 62.32; H, 6.45; N,
2.68.
m), 1.85 (1H, m), 1.98 (1H, m), 2.19 (1H, ddd, J¼13.2, 9.0, 9.0 Hz),
3.14–3.18 (2H, m), 3.23 (1H, dd, J¼9.0, 3.5 Hz), 3.33 (3H, s), 3.41 (3H,
s), 3.44–3.46 (2H, m), 3.50 (3H, s), 3.51 (3H, s), 3.83 (1H, dd, J¼3.5,
3.5 Hz), 3.97–4.10 (5H, m), 4.57 (1H, d, J¼3.5 Hz); NOE correlations
were observed between 5-H and PO(OCH2CH3)2 and between 3-H
and the C-5–OMe; 13C NMR (50.4 MHz) dC 16.1 (2ꢂCH3), 22.4 (CH2,
JP¼6.1 Hz), 37.1 (CH2, JP¼9.1 Hz), 47.5 (CH2), 58.0 (2ꢂCH3), 59.0
(CH3), 59.2 (CH3), 61.9 (2ꢂCH2), 71.3 (CH), 73.0 (CH2), 77.8 (CH),
78.6 (CH), 79.4 (CH), 96.9 (C, JP¼9.1 Hz); MS m/z (rel intens) 411
(Mþ, <1), 366 (3), 88 (100); HRMS m/z calcd for C17H34NO8P
411.2022, found 411.2070. Anal. Calcd for C17H34NO8P: C, 49.63; H,
8.33; N, 3.41. Found: C, 49.33; H, 8.70; N, 3.46.
4.3.5. (4S)-1,4:4,8-Dianhydro-1-{[bis(benzyloxy)phosphoryl]-
amino}-9-O-[tert-butyl(dimethyl)silyl]-1,2,3,6,7-pentadeoxy-
D-threo-non-4-ulose (36)
Following the general procedure, phosphoramide 20 (16.2 mg,
0.02 mmol) gave 36 (7.6 mg, 0.01 mmol, 47%) as a colourless oil: [a]
D
4.3.3. Methyl (5R)-5,8-anhydro-8-{[bis(benzyloxy)-
phosphoryl]amino}-6,7,8-trideoxy-2,3,4-tri-O-methyl-b-D-xylo-
octo-5-ulopyranoside (33) and methyl (5S)-5,8-anhydro-8-
{[bis(benzyloxy)phosphoryl]amino}-6,7,8-trideoxy-2,3,4-tri-O-
methyl-b-D-xylo-octo-5-ulopyranoside (34)
Following the general procedure, dibenzylphosphoramide 15
(72.8 mg, 0.14 mmol) gave 33 (37 mg, 0.07 mmol, 51%) and 34
þ13.5 (c, 1.0); IR 2929, 2857, 1254, 1101 cmꢁ1; 1H NMR dH 0.01 (6H,
s), 0.87 (9H, s), 1.65–1.86 (4H, m), 1.86–1.95 (2H, m), 2.21–2.33 (2H,
m), 3.23 (1H, m), 3.35 (1H, m), 3.54 (1H, dd, J¼10.0, 5.9 Hz), 3.64 (1H,
dd, J¼10.4, 4.8 Hz), 4.23 (1H, m), 4.65 (1H, d, J¼11.1 Hz), 4.67 (1H, dd,
J¼9.4, 5.2 Hz), 4.73 (1H, d, J¼11.8 Hz), 4.98 (1H, dd, J¼11.8 Hz,
JP¼6.9 Hz), 5.03 (1H, dd, J¼11.8 Hz, JP¼6.2 Hz), 5.13 (2H, d,
JP¼6.9 Hz), 7.26–7.45 (15H, m); no NOE correlation was observed
between 3-H and 5-H; 13C NMR dC ꢁ5.3 (2ꢂCH3),18.2 (C), 23.1 (CH2),
23.3 (CH2), 23.6 (CH2), 25.8 (3ꢂCH3), 35.0 (CH2), 48.2 (CH2), 65.9
(CH2), 67.2 (2ꢂCH2), 71.2 (CH), 71.7 (CH2), 75.1 (CH), 98.0 (C), 127.2–
128.3 (15ꢂCH),136.5 (C),136.9 (C),139.0 (C); MS m/z (rel intens) 594
(16.4 mg, 0.03 mmol, 33%) as colourless oils. Compound 33: [a]
D
ꢁ26.9 (c, 0.87); IR 2952, 1273, 1090 cmꢁ1; 1H NMR dH 1.75 (1H, m),
1.99–2.04 (2H, m), 2.11 (1H, ddd, J¼12.0, 7.3, 0 Hz), 3.01 (1H, dd,
J¼8.2, 8.2 Hz), 3.26 (1H, m), 3.37 (1H, d, J¼9.3 Hz), 3.39 (3H, s), 3.43
(1H, ddd, J¼9.6, 8.7, 0 Hz), 3.56 (3H, s), 3.59 (3H, s), 3.66 (3H, s), 4.79
(1H, dd, J¼8.7, 8.7 Hz), 4.83 (1H, d, J¼8.0 Hz), 5.00 (1H, dd,
J¼11.7 Hz, JP¼6.7 Hz), 5.03 (1H, dd, J¼11.8 Hz, JP¼6.1 Hz), 5.12 (2H,
d, JP¼7.0 Hz), 7.29–7.40 (10H, m); an NOE correlation between 1-H
and benzylic hydrogen atoms was observed; 13C NMR dC 21.5 (CH2,
d, JP¼6.1 Hz), 42.0 (CH2, d, JP¼9.2 Hz), 50.5 (CH2), 56.4 (CH3), 59.6
(CH3), 60.2 (CH3), 61.5 (CH3), 67.3 (CH2), 67.9 (CH2), 83.3 (CH), 83.6
(CH), 84.4 (CH), 95.4 (C, d, JP¼6.1 Hz), 99.5 (CH), 127.6 (2ꢂCH), 127.7
(2ꢂCH), 127.9 (CH), 128.1 (CH), 128.3 (2ꢂCH), 128.4 (2ꢂCH), 136.6
(C, d, JP¼6.1 Hz), 137.2 (C, d, JP¼6.1 Hz); MS (FAB) m/z (rel intens)
521 (Mþ, 2), 490 (100); HRMS m/z calcd for C25H33NO7P 490.1994,
found 490.1997. Anal. Calcd for C26H36NO8P: C, 59.87; H, 6.96; N,
t
(Mþꢁ Bu, 6), 91 (100); HRMS m/z calcd for C32H41NO6PSi 594.2440,
found 594.2461. Anal. Calcd for C36H50NO6PSi: C, 66.33; H, 7.73; N,
2.15. Found: C, 66.00; H, 8.12; N, 2.17.
4.3.6. 5,8-Anhydro-1-{[bis(benzyloxy)phosphoryl]amino}-1,2,3,4-
tetradeoxy-4-iodo-6,7:9,10-di-O-isopropylidene-D-erythro-L-altro-
decitol (37) and 3,6-anhydro-10-{[bis(benzyloxy)phosphoryl]-
amino}-7,8,9,10-tetradeoxy-7,7-diiodo-1,2:4,5-di-O-isopropylidene-
D-glycero-D-manno-decitol (38)
Following the general procedure but adding also NaHCO3
(25 mmol %), dibenzylphosphoramide 23 (204 mg, 0.35 mmol)
gave the diastereomeric mixture of monoiodides 37 (34.6 mg,
0.05 mmol, 14%), and diiodide 38 (80.4 mg, 0.10 mmol, 30%) as
2.69. Found: C, 59.55; H, 7.21; N, 2.63. Compound 34: [
a
]D ꢁ8.4 (c,
2.4); IR 2935, 1274, 1094 cmꢁ1 1H NMR dH 1.81–1.90 (3H, m), 2.14
;
colourless oils. Compound 37: IR 3216, 2936, 1745, 1252 cmꢁ1
;
(1H, ddd, J¼12.2, 8.7, 7.3 Hz), 3.07 (1H, dd, J¼9.4, 9.4 Hz), 3.14 (1H,
dd, J¼8.5, 8.5 Hz), 3.16 (1H, m), 3.38 (1H, m), 3.41 (3H, s), 3.57 (3H,
s), 3.59 (3H, s), 3.63 (3H, s), 4.20 (1H, d, J¼8.0 Hz), 4.36 (1H, d,
J¼9.8 Hz), 5.03 (1H, dd, J¼11.9 Hz, JP¼6.9 Hz), 5.07 (1H, dd,
complex 1H and 13C NMR spectra; MS m/z (rel intens) 686
(MþꢁCH3, 1), 91 (100); HRMS m/z calcd for C29H38INO8P 686.1379,
found 686.1382. Anal. Calcd for C30H41INO8P: C, 51.36; H, 5.89; N,
2.00. Found: C, 51.25; H, 5.88; N, 1.89. Compound 38: [
a
]
D
ꢁ2.6 (c,

6154
A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
0.154); IR 3209, 2989, 1381, 1257 cmꢁ1; 1H NMR dH 1.36 (3H, s), 1.41
(3H, s), 1.43 (3H, s), 1.53 (3H, s), 1.81 (2H, dq, J¼7.3, 7.3, 7.3, 7.3 Hz),
2.07 (1H, m), 2.36 (1H, m), 2.79 (1H, m), 2.96 (2H, dq, J¼10.2, 6.8,
6.8, 6.8 Hz), 3.82 (1H, d, J¼2.1 Hz), 3.99 (1H, dd, J¼8.7, 4.9 Hz), 4.05
(1H, dd, J¼8.7, 6.1 Hz), 4.35 (1H, ddd, J¼6.3, 6.3, 5.1 Hz), 4.77 (1H,
dd, J¼7.6, 4.2 Hz), 4.87 (1H, dd, J¼5.9, 2.5 Hz), 4.94 (1H, dd, J¼5.9,
3.8 Hz), 5.05 (4H, d, JP¼7.6 Hz), 7.31–7.38 (10H, m); 13C NMR dC 23.2
(C), 24.9 (CH3), 25.2 (CH3), 26.5 (CH3), 26.8 (CH3), 33.8 (CH2), 40.0
(CH2), 48.1 (CH2), 66.6 (CH2), 68.0 (2ꢂCH2), 73.7 (CH), 81.0 (CH),
84.1 (CH), 88.7 (CH), 95.0 (CH), 109.2 (C), 113.4 (C), 127.7 (4ꢂCH),
128.3 (2ꢂCH), 128.5 (4ꢂCH), 136.3 (2ꢂC); MS m/z (rel intens) 812
(MþꢁCH3, 1), 573 (1), 91 (100); HRMS m/z calcd for C29H37I2NO8P,
812.0346, found 812.0307. Anal. Calcd for C30H40I2NO8P: C, 43.55;
H, 4.87; N, 1.69. Found: C, 43.59; H, 4.65; N, 1.81.
1.63 (2H, m), 1.64–1.78 (4H, m), 3.19 (1H, m), 3.37 (1H, m), 4.01
(1H, dd, J¼8.8, 4.5 Hz), 4.04 (1H, dd, J¼7.7, 3.7 Hz), 4.10 (1H, dd,
J¼8.8, 6.4 Hz), 4.37 (1H, m), 4.87 (1H, d, J¼5.8 Hz), 4.91 (1H, dd,
J¼5.8, 3.4 Hz); no NOE correlation was observed between 4-H and
any of the protons of the sugar ring; 13C NMR dC 19.7 (CH2), 23.7
(CH2), 24.4 (CH3), 25.3 (CH3), 25.7 (CH3), 26.8 (CH3), 29.5 (CH2),
47.2 (CH2), 66.9 (CH2), 72.9 (CH), 80.1 (CH), 80.2 (CH), 84.0 (CH),
95.7 (C), 109.4 (C), 113.2 (C), 116.0 (C); MS m/z (rel intens) 323
(MþꢁCH3, 10), 101 (100); HRMS m/z calcd for C16H23N2O5
323.1607, found 323.1601. Anal. Calcd for C17H26N2O5: C, 60.34; H,
7.74; N, 8.28. Found: C, 60.04; H, 7.76; N, 8.59.
4.3.9. Methyl (5R)-5,9-anhydro-9-{[bis(benzyloxy)phosphoryl]-
amino}-6,7,8,9-tetradeoxy-2,3,4-tri-O-methyl-
b-D-xylo-non-5-
ulopyranoside (42), methyl (5S)-5,9-anhydro-9-{[bis(benzyloxy)-
4.3.7. (5S)-1,5:5,8-Dianhydro-1-{[bis(benzyloxy)phosphoryl]-
phosphoryl]amino}-6,7,8,9-tetradeoxy-2,3,4-tri-O-methyl-b-D-xylo-
amino}-1,2,3,4-tetradeoxy-6,7:9,10-di-O-isopropylidene-
D
-manno-
non-5-ulopyranoside (43) and methyl (5S)-5-O-acetyl-9-
dec-5-ulose (39) and 5-O-acetyl-1-{[bis(benzyloxy)phosphoryl]-
{[bis(benzyloxy)phosphoryl]amino}-6,7,8,9-tetradeoxy-2,3,4-tri-O-
methyl-6-iodo- -xylo-non-5-ulopyranoside (44)
amino}-1,2,3,4-tetradeoxy-6,7:9,10-di-O-isopropylidene-
a
-D-
b-D
manno-dec-5-ulofuranose (40)
Following the general procedure starting from 30 (135 mg,
0.25 mmol), a mixture of spirocompound 42 (41.3 mg, 0.08 mmol,
31%) and its epimer 43 (14 mg, 0.03 mmol, 10%) was obtained as
colorless oils, jointly with the iodo-acetate 44 (38.2 mg,
Starting from a mixture of phosphoramidates (23/27¼1.4:1)
(98 mg, 0.17 mmol) and following the general procedure adding
solid NaHCO3 (25 mmol%) also, the mixture of diastereomers
monoiodo 37 (13.6 mg, 0.02 mmol, 25%), diiodo 38 (5.4 mg,
0.01 mmol, 7%), the spirocompound 39 (7.5 mg, 0.01 mmol, 18%)
and the acetate 40 (13.2 mg, 0.02 mmol, 29%) were obtained as
0.05 mmol, 22%) as a yellow oil. Compound 42: [
a
]
ꢁ3.5 (c, 1.9);
D
IR 2935, 1747, 1456, 1261 cmꢁ1 1H NMR dH 1.41 (1H, m), 1.49–1.63
;
(2H, m), 1.92 (1H, m), 2.12–2.18 (2H, m), 3.01 (1H, dd, J¼8.2,
8.2 Hz), 3.14–3.18 (1H, m), 3.15 (1H, d, J¼8.9 Hz), 3.43 (1H, m),
3.44 (3H, s), 3.54 (3H, s), 3.56 (3H, s), 3.61 (3H, s), 4.41 (1H, d,
J¼8.5 Hz), 4.46 (1H, dd, J¼8.7, 8.7 Hz), 4.98–5.10 (4H, m), 7.29–7.38
(10H, m); no NOE correlation was observed between 1-H and 6-H;
13C NMR dC 20.2 (CH2), 24.1 (CH2), 35.5 (CH2), 43.6 (CH2), 56.9
(CH3), 59.9 (CH3), 60.0 (CH3), 61.7 (CH3), 68.0 (CH2, d, JP¼6.1 Hz),
68.1 (CH2, d, JP¼6.1 Hz), 81.5 (CH), 84.5 (CH), 87.3 (CH), 88.4 (C),
99.0 (CH), 127.4 (2ꢂCH), 127.8 (CH), 128.0 (2ꢂCH), 128.1 (CH),
128.3 (2ꢂCH), 128.5 (2ꢂCH), 136.6 (C, d, JP¼6.1 Hz), 137.1 (C, d,
JP¼6.1 Hz); MS m/z (rel intens) 504 (MþꢁOCH3, 1), 91 (100);
HRMS m/z calcd for C26H35NO7P, 504.2151, found 504.2055. Anal.
Calcd for C27H38NO8P: C, 60.55; H, 7.15; N, 2.62. Found: C, 60.19;
colourless oils. Compound 39: [
a]
ꢁ5.2 (c, 0.65); IR 2926, 2856,
D
1730, 1456, 1380, 1260 cmꢁ1 1H NMR dH 1.21–1.75 (4H, m), 1.24
;
(3H, s), 1.35 (6H, s), 1.44 (3H, s), 1.98–2.07 (2H, m), 3.14 (1H, m),
3.49 (1H, m), 3.86 (1H, dd, J¼7.9, 3.6 Hz), 3.97 (1H, dd, J¼8.6,
4.3 Hz), 4.06 (1H, dd, J¼8.6, 6.2 Hz), 4.33 (1H, ddd, J¼6.9, 6.9,
5.0 Hz), 4.57 (1H, dd, J¼5.7, 3.8 Hz), 4.94–5.08 (4H, m), 5.32 (1H, d,
J¼5.7 Hz), 7.32–7.38 (10H, m); no NOE correlation was observed
between 4-H and any of the furanose protons; 13C NMR dC 20.8
(CH2), 24.4 (CH3), 25.3 (CH3), 25.8 (CH3), 26.9 (CH3), 29.7 (CH2),
30.8 (CH2), 43.1 (CH2), 67.0 (CH2), 68.2 (CH2), 68.3 (CH2), 73.2
(CH), 78.9 (CH), 80.5 (CH), 83.9 (CH), 95.9 (C), 109.0 (C), 111.9 (C),
127.9 (4ꢂCH), 128.3 (2ꢂCH), 128.6 (4ꢂCH), 136.0 (2ꢂC); MS m/z
(rel intens) 573 (Mþ, <1), 558 (2), 91 (100); HRMS m/z calcd for
C30H40NO8P, 573.2491, found 573.2601. Anal. Calcd for
C30H40NO8P: C, 62.81; H, 7.03; N, 2.44. Found: C, 62.66; H, 7.42; N,
H, 7.53; N, 2.55. Compound 43: [
a
]
D
ꢁ3.7 (c, 1.6); IR 2927, 1747,
1455, 1260, 1087 cmꢁ1 1H NMR dH 1.44 (1H, m), 1.52–1.68 (3H,
;
m), 1.76 (1H, m), 1.99 (1H, m), 3.12 (1H, dd, J¼9.4, 8.0 Hz), 3.17–
3.29 (2H, m), 3.26 (1H, dd, J¼9.4, 6.4 Hz), 3.49 (3H, s), 3.57 (3H, s),
3.58 (3H, s), 3.67 (3H, s), 4.24 (1H, d, J¼8.0 Hz), 4.71 (1H, d,
J¼9.4 Hz), 4.99–5.14 (4H, m), 7.29–7.39 (10H, m); NOE correlation
between 1-H and 6-H was observed; 13C NMR dC 16.2 (CH2), 23.1
(CH2), 24.5 (CH2, d, JP¼6.1 Hz), 42.4 (CH2), 56.4 (CH3), 60.3 (CH3),
60.4 (2ꢂCH3), 67.4 (CH2), 67.5 (CH2), 81.3 (CH), 83.7 (CH), 84.6
(CH), 88.8 (C), 99.8 (CH), 127.5 (CH), 127.9 (4ꢂCH), 128.1 (CH),
128.4 (2ꢂCH), 128.5 (2ꢂCH), 136.6 (2ꢂC); MS m/z (rel intens) 504
(MþꢁOCH3, 1), 88 (100); HRMS m/z calcd for C26H35NO7P,
504.2151, found 504.2067. Anal. Calcd for C27H38NO8P: C, 60.55; H,
2.14. Compound 40: [
a]
D þ13.6 (c, 0.81); IR 3220, 2937, 1738, 1380,
1252 cmꢁ1; 1H NMR dH 1.31–1.48 (4H, m), 1.32 (3H, s), 1.37 (3H, s),
1.44 (3H, s), 1.46 (3H, s), 2.00 (3H, s), 2.07 (2H, ddd, J¼9.6, 6.8,
6.8 Hz), 2.70 (1H, m), 2.87–2.91 (2H, m), 3.99 (1H, dd, J¼8.7,
4.5 Hz), 4.01 (1H, dd, J¼7.0, 4.0 Hz), 4.07 (1H, dd, J¼8.9, 6.6 Hz),
4.36 (1H, ddd, J¼7.3, 6.6, 4.7 Hz), 4.81 (1H, d, J¼6.1 Hz), 4.88 (1H,
dd, J¼5.6, 3.7 Hz), 5.02 (2H, d, JP¼7.4 Hz), 5.04 (2H, d, JP¼7.4 Hz),
7.31–7.36 (10H, m); no NOE correlations was observed between
any of the furanose protons and 4-H nor –OAc hydrogen atoms;
13C NMR dC 20.1 (CH2), 21.8 (CH3), 24.4 (CH3), 25.1 (CH3), 25.8
(CH3), 26.9 (CH3), 31.0 (CH2), 31.2 (CH2, d, JP¼6.1 Hz), 40.9 (CH2),
66.8 (CH2), 67.9 (2ꢂCH2), 73.0 (CH), 79.5 (CH), 81.3 (CH), 84.7
(CH), 109.2 (C), 113.0 (C), 113.6 (C), 127.7 (4ꢂCH), 128.2 (2ꢂCH),
128.5 (4ꢂCH), 136.4 (2ꢂC), 169.5 (C); MS (FAB) m/z (rel intens)
7.15; N, 2.62. Found: C, 60.19; H, 7.52; N, 2.55. Compound 44: [a]
D
þ41.8 (c, 0.3); IR 3331, 2935, 1748, 1456, 1238 cmꢁ1
;
1H NMR dH
1.47 (1H, m), 1.60 (1H, m), 1.68 (1H, m), 1.94 (1H, m), 2.10 (3H, s),
2.83–2.99 (2H, m), 3.14 (3H, s), 3.28 (1H, dd, J¼7.0, 1.9 Hz), 3.43
(3H, s), 3.44 (3H, s), 3.53 (3H, s), 3.67 (1H, dd, J¼4.7, 1.9 Hz), 4.73
(1H, d, J¼4.7 Hz), 4.99 (1H, dd, J¼10.3, 3.8 Hz), 5.03 (2H, d,
JP¼7.5 Hz), 5.04 (2H, d, JP¼7.5 Hz), 5.86 (1H, d, J¼7.0 Hz), 7.30–7.37
(10H, m), the hydrogen from the NH group is missing; a NOE
correlation between 4-H and –OAc hydrogen atoms was observed;
13C NMR dC 21.1 (CH3), 29.7 (CH2), 30.8 (CH2), 31.8 (CH), 40.4
(CH2), 57.2 (CH3), 58.1 (CH3), 59.5 (CH3), 60.1 (CH3), 67.9 (2ꢂCH2),
77.2 (CH), 78.6 (CH), 82.8 (CH), 97.7 (CH), 104.3 (C), 127.8 (4ꢂCH),
128.2 (2ꢂCH), 128.4 (4ꢂCH), 136.4 (2ꢂC), 170.7 (C); MS (FAB) m/z
(rel intens) 744 (MþþNa, 10), 722 (3), 91 (100); HRMS m/z calcd
656 (MþþNa, 16), 574 (100); HRMS m/z calcd for C32H44NNaO10
P
656.2600, found 656.2568. Anal. Calcd for C32H44NO10P: C, 60.65;
H, 7.00; N, 2.21. Found: C, 60.47; H, 7.43; N, 2.11.
4.3.8. (5S)-1,5:5,8-Dianhydro-1-cyanoamino-1,2,3,4-tetradeoxy-
6,7:9,10-di-O-isopropylidene-D-manno-dec-5-ulose (41)
Following the general procedure starting from N-cyanamide 24
(69.2 mg, 0.20 mmol) but adding solid NaHCO3 (25 mmol %) also,
oxa-azaspirocompound 41 (33 mg, 0.10 mmol, 48%) was obtained
as a colourless oil: [
a]
ꢁ15.2 (c, 3.1); IR 2990, 2210, 1372 cmꢁ1
;
D
1H NMR dH 1.34 (3H, s), 1.38 (3H, s), 1.46 (3H, s), 1.48 (3H, s), 1.54–
for C29H41INO10P 721.1513, found 721.1481. Anal. Calcd for

A. Mart´ın et al. / Tetrahedron 65 (2009) 6147–6155
6155
J. Org. Chem. 1996, 61, 3999–4006; For other HAT reactions in carbohydrate
chemistry, see: (f) Robins, M. J.; Guo, Z.; Samano, M. C.; Wnuk, S. F. J. Am. Chem. Soc.
1999,121,1425–1433; (g) Chatgilialoglu, C.; Giminis, T.; Spada, G. P. Chem.dEur. J.
1999, 5, 2866–2876; (h) Descotes, G. J. Carbohydr. Chem. 1988, 7, 1–20.
8. For competition between 1,5-, 1,6- and 1,7-intramolecular hydrogen transfer
see: Denenmark, D.; Winkler, T.; Waldner, A.; De Mesmaeker, A. Tetrahedron
Lett. 1992, 33, 3613–3616.
9. For a recent review on the synthesis of spiroaminals, see: Sinibaldi, M.-E.;
Canet, I. Eur. J. Org. Chem. 2008, 4391–4399.
10. Kobayashi, M.; Yin-Ju, C.; Aoki, S.; In, Y.; Ishida, T.; Kitagawa, I. Tetrahedron 1995,
51, 3727–3736.
C29H41INO10P: C, 48.27; H, 5.73; N, 1.94. Found: C, 48.28; H, 5.90;
N, 2.09.
Acknowledgements
This work was supported by the research programmes
´
BQU2000-0650 and BQU2001-1665 of the Direccion General de
´
´
´
Investigacion Cientıfica y Tecnica, Spain. I.P.-M. thanks the I3P-CSIC
programme for a fellowship.
11. (a) Fuiwara, Y.; Takaki, A.; Uehara, Y.; Ikeda, T.; Okawa, M.; Yamauchi, K.; Ono,
M.; Yoshimitsu, H.; Hohara, T. Tetrahedron 2004, 60, 4915–4920; (b) Ripperger,
H.; Schreiber, K. Solanum Steroid Alkaloids. In The Alkaloids; Rodrigo, R. G. A.,
Ed.; Academic: New York, NY, 1981; Vol. XIX, pp 81–192.
Supplementary data
12. For some recent publications on the synthesis of azaspiracid, see: (a) Li, Y. F.;
Zhou, F.; Forsyth, C. J. Angew. Chem., Int. Ed. 2007, 46, 279–282; (b) Yadav, J. S.;
Venugopal, C. Synlett 2007, 2262–2266; (c) Evans, D. A.; Dunn, T. B.; Kvoerno, L.;
Beauchemin, A.; Raymer, B.; Olhava, E. J.; Mulder, J. A.; Juhl, M.; Kagechika, K.;
Favor, D. A. Angew. Chem., Int. Ed. 2007, 46, 4698–4703; (d) Zhou, X. T.; Lu, L.;
Furkert, D. P.; Wells, C. E.; Carter, R. G. Angew. Chem., Int. Ed. 2006, 45, 7622–
7626; (e) Nicolaou, K. C.; Frederick, M. O.; Petrovic, G.; Cole, K. P.; Loizidou, E. Z.
Angew. Chem., Int. Ed. 2006, 45, 2609–2615; (f) Oikawa, M.; Uehara, T.; Iwayama,
T.; Sasaki, M. Org. Lett. 2006, 8, 3943–3946; (g) Nicolaou, K. C.; Koftis, T. V.;
Vyskocil, S.; Petrovic, G.; Tang, W. J.; Frederick, M. O.; Chen, D. Y. K.; Li, Y. W.;
Ling, T. T.; Yamada, Y. M. A. J. Am. Chem. Soc. 2006, 128, 2859–2872; (h) Nic-
olaou, K. C.; Pihko, P. M.; Bernal, F.; Frederick, M. O.; Qian, W. Y.; Uesaka, N.;
Diedrichs, N.; Hinrichs, J.; Koftis, T. V.; Loizidou, E.; Petrovic, G.; Rodriguez, M.;
Sarlah, D.; Zou, N. J. Am. Chem. Soc. 2006, 128, 2244–2257; (i) Nicolaou, K. C.;
Vyskocil, S.; Koftis, T. V.; Yamada, Y. M. A.; Ling, T. T.; Chen, D. Y. K.; Tang, W. J.;
Petrovic, G.; Frederick, M. O.; Li, Y. W.; Satake, M. Angew. Chem., Int. Ed. 2004,
43, 4312–4318; (j) Nicolaou, K. C.; Li, Y. W.; Uesaka, N.; Koftis, T. V.; Vyskocil, S.;
Ling, T. T.; Govindasamy, M.; Qian, W.; Bernal, F.; Chen, D. Y. K. Angew. Chem.,
Int. Ed. 2003, 42, 3643–3648; (k) Nicolaou, K. C.; Chen, D. Y. K.; Li, Y. W.; Ling, T.
T.; Vyskocil, S.; Koftis, T. V.; Govindasamy, M.; Uesaka, N. Angew. Chem., Int. Ed.
2003, 42, 3649–3653; (l) Forsyth, C. J.; Hao, J. L.; Aiguade, J. Angew. Chem., Int.
Ed. 2001, 40, 3663–3667; (m) Nicolaou, K. C.; Pihko, P. M.; Diedrichs, N.; Zou, N.;
Bernal, F. Angew. Chem., Int. Ed. 2001, 40, 1262–1265 and references cited in all
of them; For the first isolation and characterization of azaspiracid, see: (n)
Satake, M.; Ofuji, K.; Naoki, H.; James, K. J.; Furey, A.; McMahon, T.; Silke, J.;
Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 9967–9968.
Detailed experimental procedures and spectral and analytical
data for all compounds are provided. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tet.2009.05.049.
References and notes
1. Recent reviews: (a) Tanko, J. M. Annu. Rep. Prog. Chem., Sect. B 2006, 102, 247–
268; (b) Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94–103; (c)
Feray, L.; Kuznersov, N.; Renaud, P. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 246–278; (d) Majetich,
G. Tetrahedron 1995, 51, 7095–7129.
2. For reviews, see: (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001; (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereo-
chemistry of Radical Reactions; VCH: Weinheim, 1996; (c) Snider, B. B. Chem. Rev.
1996, 96, 339–363; (d) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991,
91, 1237–1286; (e) Curran, D. P. Synthesis 1988, 489–513; (f) Giese, B. Radicals in
Organic Synthesis: Formation of Carbon–Carbon Bonds; Pergamon: Oxford, 1986.
3. For some 1,5-HAT from sp3 to sp2 carbons followed by radical cyclisation see:
(a) De´ne`s, F.; Beaufils, F.; Renaud, P. Org. Lett. 2007, 9, 4375–4378 and references
cited therein; (b) Sha, C.-K.; Hsu, C.-W.; Chen, Y.-T.; Cheng, S.-Y. Tetrahedron Lett.
2000, 41, 9865–9869; (c) Robertson, J.; Peplow, M. A.; Pillai, J. Tetrahedron Lett.
1996, 37, 5825–5828; (d) Bosch, E.; Bachi, M. D. J. Org. Chem. 1993, 58, 5581–
5582; (e) Brown, C. D. S.; Simpkins, N. S. Tetrahedron Lett. 1993, 34, 131–132; (f)
Borthwick, A. D.; Caddick, S.; Parsons, P. J. Tetrahedron 1992, 48, 10655–10666;
(g) Curran, D. P.; Abraham, A. C.; Liu, H. J. Org. Chem. 1991, 56, 4335–4337; (h)
Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc.
1990, 112, 896–898; (i) Borthwick, A. D.; Caddick, S.; Parsons, P. J. Tetrahedron
Lett. 1990, 31, 6911–6914; (j) Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc.,
Chem. Commun. 1988, 81–82; (k) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am.
Chem. Soc. 1988, 110, 5900–5902.
13. Xu, R.-S.; Lu, Y.-J.; Chu, J.-H.; Iwashita, T.; Naoki, H.; Naya, Y.; Nakanishi, K.
Tetrahedron 1982, 38, 2667–2670.
14. Total synthesis: (a) Paquette, L. A.; Duan, M.; Konetzki, I.; Kempmann, C.
J. Am. Chem. Soc. 2002, 124, 4257–4270; (b) Duan, M.; Paquette, L. A. Angew.
Chem., Int. Ed. 2001, 40, 3632–3636; (c) Nicolaou, K. C.; Murphy, F.; Bar-
luenga, S.; Ohshima, T.; Wei, H.; Xu, J.; Gray, D. L. F.; Baudoin, O. J. Am. Chem.
Soc. 2000, 122, 3830–3838; (d) Nicolaou, K. C.; Xu, J.; Murphy, F.; Barluenga,
S.; Baudoin, O.; Wei, H.; Gray, D. L. F.; Ohshima, T. Angew. Chem., Int. Ed.
1999, 38, 2447–2451.
4. For recent reviews on the chemistry of nitrogen-centred radicals see: (a) Stella, L.
In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Wein-
heim, 2001; Vol. 2, pp 407–426; (b) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543–17594; (c) Zard, S. Z. Synlett 1996,1148–1155; (d) Esker, J. L.; Newcomb, M.
In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic: New York,
NY, 1993; Vol. 58, pp 1–45; (e) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337–
350; For previous reviews, see: (f) Mackiewicz, P.; Furstoss, R. Tetrahedron 1978,
34, 3241–3260; (g) Neale, R. S. Synthesis 1971, 1–15; For a recent review on the
synthesis of heterocycles by radical cyclisation see: (h) Bowman, W. R.; Bridge, C.
F.; Brookes, P. J. Chem. Soc., PerkinTrans.12000,1–14; For the pioneering works on
intramolecular HAT reacions promoted by N-radicals see: (i) Hoffman, A. W. Ber.
1883,16, 558–560; (j) Loe¨ffler, K.; Freytag, C. Ber.1909, 42, 3427–3431; (k) Barton,
D. H. R.; Beckwith, A. L. J.; Goosen, A. J. Chem. Soc.1965,181–190; (l) Baldwin, J. E.;
Barton, D. H. R.; Dainis, I.; Pereira, J. L. C. J. Chem. Soc. 1968, 2283–2289; (m)
Carruthers, W. Some Modern Methods of Organic Synthesis, 2nd ed.; Cambridge
University Press: Cambridge, 1978, pp 255–257; For 1,5-hydrogen atom transfer
from sp3 carbons to oxygen radicals followed by radical addition reactions, see:
(n) Petrovic, G.; Cekovic, Z. Tetrahedron 1999, 55, 1377–1390; (o) Tsunoi, S.; Ryu,
I.; Ohuda, T.; Tanaka, M.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1998, 120,
8692–8701 and references cited therein.
15. (a) Richter, P. K.; Tomaszewski, M. J.; Miller, R. A.; Patron, A. P.; Nicolaou, K. C. J.
Chem. Soc., Chem. Commun. 1994, 1151–1152; (b) Luengo, J. I.; Gleason, J. G.
Tetrahedron Lett. 1992, 33, 6911–6914; (c) Giannis, A.; Sandhoff, K. Tetrahedron
Lett. 1985, 26, 1479–1482.
16. Viand, M. C.; Rollin, P. Synthesis 1990, 130–132.
17. Parrish, J. D.; Little, R. D. Org. Lett. 2002, 4, 1439–1442.
18. Gupta, A. K.; Acharya, J.; Dubey, D. K.; Kaushik, M. P. Synth. Commun. 2007, 37,
3403–3407.
19. (a) Gonza´lez, C. C.; Kennedy, A. R.; Leo´ n, E. I.; Riesco-Fagundo, C.; Sua´rez, E.
´
Angew. Chem., Int. Ed. 2001, 40, 2326–2328; (b) Francisco, C. G.; Gonzalez, C. C.;
Sua´rez, E. J. Org. Chem. 1998, 63, 8092–8093; For an example of the influence of
the substituents on the 1,5-HAT reaction compared with competing
b-frag-
mentation of alkoxyl radicals see: Allen, P. R.; Brimble, M. A.; Fare`s, F. A. J. Chem.
Soc., Perkin Trans. 1 1998, 2403–2411.
20. Dondoni, A.; Marra, A.; Rojo, I.; Sherrmann, M.-C. Tetrahedron 1996, 52, 3057–3074.
21. The structures of 37 and 38 were confirmed by n-Bu3SnH reductive deiodina-
tion to give the starting material 23 (see Supplementary data section).
22. Acetyl hypoiodite has never been isolated but its presence has been demon-
strated in solutions of DIB and iodine, see: (a) Ogata, Y.; Aoki, K. J. Am. Chem.
Soc. 1968, 90, 6186–6191; (b) Merkushev, E. B.; Simakhina, N. D.; Kovedhnikiva,
G. M. Synthesis 1980, 486–487; (c) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tet-
rahedron Lett. 1994, 94, 1003–1006.
5. (a) Francisco, C. G.; Herrera, A. J.; Martı´n, A.; Pe´rez-Martı´n, I.; Sua´rez, E. Tetrahedron
´
´
´
´
Lett. 2007, 48, 6384–6388; (b) Martın, A.; Perez-Martın, I.; Suarez, E. Org. Lett.
2005, 7, 2027–2030; (c) Francisco, C. G.; Herrera, A. J.; Sua´rez, E. J. Org. Chem. 2003,
68, 1012–1017; (d) Freire, R.; Martı´n, A.; Pe´rez-Martı´n, I.; Sua´rez, E. Tetrahedron
23. Although we have only found a brief mention on the reactivity of DIB/I2 with
olefins ( Aoki, K.; Ogata, Y. Bull. Chem. Soc. Jpn. 1968, 41, 1476–1477 ), in our
´
Lett. 2002, 43, 5113–5116; (e) Dorta, R. L.; Francisco, C. G.; Suarez, E. J. Chem. Soc.,
laboratory we have observed that this system reacts with tri-O-acetyl-
to give a diastereomeric mixture from which the major product 1,3,4,6-tetra-O-
acetyl-2-deoxy-2-iodo- -manno-pyranose was isolated in 65% yield. For
D-glucal
Chem. Commun. 1989, 1168–1169; (f) Armas, P.; Francisco, C. G.; Herna´ndez, R.;
´
Salazar, J. A.; Suarez, E. J. Chem. Soc., PerkinTrans.11988, 3255–3265; (g) Carrau, R.;
a-D
Herna´ndez, R.; Sua´rez, E.; Betancor, C. J. Chem. Soc., Perkin Trans. 11987, 937–943.
6. N-Nitroamines, N-cyanamides, N-phosphoramidates and N-tert-butoxy-
carbonylamides tethers that were one, two, three, or four carbons long were used.
7. (a) Francisco, C. G.; Freire, R.; Herrera, A. J.; Pe´rez-Martı´n, I.; Sua´rez, E. Tetrahedron
other related studies see: (a) Kirschning, A.; Plumeier, C.; Rose, L. Chem. Com-
mun. 1998, 33–34; (b) Kirschning, A.; Jesberger, M.; Monenschein, H.
Tetrahedron Lett. 1999, 40, 8999–9002.
´
24. As observed by 1H NMR this is presumably a mixture of conformational iso-
2007, 63, 8910–8920; (b) Francisco, C. G.; Herrera, A. J.; Suarez, E. J. Org. Chem.
1
mers. Variable temperature H NMR experiments were performed (70 ꢀC) but
2002, 67, 7439–7445; (c) Francisco, C. G.; Freire, R.; Herrera, A. J.; Pe´rez-Martı´n, I.;
´
´
at this temperature the equilibrium between conformers was not significantly
affected.
Suarez, E. Org. Lett. 2002, 4, 1959–1961; (d) Dorta, R. L.; Martın, A.; Salazar, J. A.;
Sua´rez, E. J. Org. Chem.1998, 63, 2251–2261; (e) Martı´n, A.; Salazar, J. A.; Sua´rez, E.