β-Oxy-α-diazo-carbonyl compounds. Part 6: Synthesis and reactivity of 3-deoxy-2-diazo-esters derived from monosaccharides. Applications in the synthesis of 2-C-alkyl-KDO analogues and related compounds

Article abstract of DOI:10.1016/S0040-4039(01)01532-5

Reactions of 6-O-protected diazo derivatives 8, 9 and 10 with transition metals Rh(II) and Cu(II) under a variety of different conditions of solvents and temperatures, were studied in order to obtain 2-C-alkyl analogues of KDO. In fact, these types of products (11, 12) were obtained in good yields when Rh(II) was used as a catalyst in benzene. The interesting seven-membered ring products (13) were obtained only for 8 and 9, as single diastereoisomers and their formations were favored when Cu(II) catalysts were used.

Full text of DOI:10.1016/S0040-4039(01)01532-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8805–8809
b-Oxy-a-diazo-carbonyl compounds. Part 6: Synthesis and
reactivity of 3-deoxy-2-diazo-esters derived from
monosaccharides. Applications in the synthesis of
2-C-alkyl-KDO analogues and related compounds
Francisco Sarabia and Fidel Jorge Lo´pez-Herrera*
Departamento de Bioqu´ımica, Biolog´ıa Molecular y Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Ma´laga,
29071 Ma´laga, Spain
Received 12 July 2001; accepted 21 August 2001
Abstract—Reactions of 6-O-protected diazo derivatives 8, 9 and 10 with transition metals Rh(II) and Cu(II) under a variety of
different conditions of solvents and temperatures, were studied in order to obtain 2-C-alkyl analogues of KDO. In fact, these
types of products (11, 12) were obtained in good yields when Rh(II) was used as a catalyst in benzene. The interesting
seven-membered ring products (13) were obtained only for 8 and 9, as single diastereoisomers and their formations were favored
when Cu(II) catalysts were used. © 2001 Elsevier Science Ltd. All rights reserved.
The biological importance of 3-deoxy-
D
-manno-2-octu-
efficient inhibitors, and consequently, to new leads for
the fighting against Gram-negative bacteria.7 Not sur-
prisingly, intense activity in this direction has been
achieved in recent years with the synthesis of variety of
analogues including deoxy-derivatives,3r,8 aza-9 or
carba-cyclic analogues,10 side or terminal chain
modified derivatives11 and C-glycoside analogues.3r,12
Among the wide variety of modified KDO structures,
2-deoxy-KDO (2) appears to be the most potent
inhibitor of CMP-KDO synthetase identified to date.13
losonic acid (KDO, 1) as an essential component of the
LPS (lipopolysaccharides) contained in the outer mem-
brane of Gram-negative bacteria1 has led to important
biological and synthetic efforts in recent decades,
including the identification of the enzymes involved in
the biosynthetic pathway of LPS2 and efficient and
convergent syntheses of KDO3 and KDO-conjugates.4
From these studies, the potential inhibition against
CMP-KDO or KDO-8-phosphate synthetases, the
enzymes responsible for incorporation of KDO into the
LPS, has been deemed to be important for the design of
a new emerging class of novel antibiotics against Gram-
negative bacteria. Two important factors draw atten-
tion to the consideration of KDO analogues as
potential new antibiotics. Firstly, the increase of resis-
tant Gram-negative bacteria strains towards conven-
tional antibiotics,5 which in turn have directed
clinicians and pharmaceutical companies towards the
discovery of new antibiotics with different mechanisms
of action. Secondly, the recent disclosure of the 3D
structure of the protein KDO-8-phosphate synthetase6
provides access to the rational design of potent and
Our research program has been directed towards the
synthesis of complex sugar derivatives of biological
importance and has led us to convergent syntheses of
KDO and 2-deoxy-KDO based on the chemistry of
b-oxy-a-diazo esters derived from monosaccharides.14
In the preceding paper,15 we reported an efficient and
high yielding synthesis of these types of products, by
using diethyl zinc as a promoter for enhancing the
reactivity of ethyl diazoacetate. These products repre-
sent common precursors for the synthesis of KDO (1),
2-deoxy-KDO (2), KO (3a) and its epimer at C-3 (3b)
as is depicted in Scheme 1. In the present paper, we
wish to report the syntheses of 2-deoxy-2-C-alkyl ana-
logues of KDO via diazo chemistry.16 Thus, based on
our previous work, the diazo ester 7,14 used for the
synthesis of 2, represented an interesting synthetic inter-
mediate for the synthesis of the above mentioned 2-C-
alkyl analogues of KDO.
Keywords: KDO analogues; CMP-KDO synthetase inhibitors; diazo;
carbenoids; monosaccharides.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01532-5

8806
F. Sarabia, F. J. Lo´pez-Herrera / Tetrahedron Letters 42 (2001) 8805–8809
OH
OH
derivatives (11 and 12) was Rh(II), using benzene as a
HO
HO
HO
HO
solvent under reflux conditions. The use of methylene
chloride and Cu(II) as the catalyst in the form of
Cu(acac)2 or Cu(hfacac)2 favored the formation of the
seven-membered ring derivative (13) by a stereoselective
intramolecular CH insertion. The elimination products
14a, 14b and 14c were formed in different proportions
depending on the reaction conditions; however, when
Cu(II) was employed using CH2Cl2 as solvent they were
the main products. In the particular case of the allyl
derivative 8, the resulting six-membered ring derivative
11a/12a was obtained as a 1:1 mixture of isomers at
C-2. These structures were confirmed by comparison
with the NMR data reported in the literature.12a For
the six-membered ring products 11b/12b and 11c/12c,
their structures were also confirmed by comparison
with the literature NMR data reported by Claesson et
al.11a As we mentioned above, the corresponding
oxepanes 13a and 13b, were obtained as single isomers.
The configurational assignments were established
according to NMR information and two-dimensional
COSY and NOESY experiments.19 Similarly, the com-
parison of the coupling constants J1,2 values for 13a
and 13b, with those of related oxepane systems20 led us
to establish the cis relationship of the system contained
in 13. In addition, for a final tentative absolute configu-
ration assignment, conformational analysis of the four
possible diastereoisomers revealed an agreement
between the theoretical and experimental J1,2 values for
the cis stereoisomer.21 Finally, in the case of the O-
propargyl derivative 10, it was found out that neither
O
O
CO2H
HO
CO2H
OH
HO
H
KDO (1)
2-deoxy-KDO (2)
Ref. 14
Ref. 14
O
O
O
O
O
O
Ref. 14
OR
OH
N2
N2
O
O
OH
CO2Et
CO2Et
7
R = H (4); Ac (5); TBS (6)
Ref. 15
OH
OH
HO
HO
HO
HO
OH
O
O
CO2H
OH
3-epimer-KO (3b)
HO
CO2H
OH
HO
OH
KO (3a)
Scheme 1. Syntheses of KDO (1), 2-deoxy-KDO (2) and KO
(3).
The protection of the free hydroxyl group at C-6 of 7 as
an ether, followed by exposure of the resulting diazo
compound to the action of metals such as Rh(II) or
Cu(II), should lead to the desired 2-C-alkyl KDO
derivatives. This insertion reaction involves initial for-
mation of an oxonium ylide, followed by a [1,2] or [2,3]
sigmatropic rearrangement resulting in the migration of
the alkyl group to the diazo carbon (path a).17 In fact,
one can find prominent examples of this reaction
applied towards the synthesis of natural products in the
literature.18 Nevertheless, the polyfunctional substrate
offers other reaction pathways from the highly reactive
carbenoid species such as CH insertion (path b), oxo-
nium ylide formation from different oxygen atoms and
subsequent rearrangements (path c) (Scheme 2).
O
O
O
O
O
O
R
O
O
N2
O
CO2Et
O
CO2Et
R
Metal = Rh (II), Cu (II)
O
path a
path b
path c
O
O
R
O
CO2Et
O
Me
path a
path b
In order to evaluate the different possible pathways and
others not indicated in Scheme 2 and to optimize the
formation of the desired 2-C-alkyl derivatives for bio-
logical evaluations as CMP-KDO synthetase inhibitors,
we prepared the 6-O-allyl, benzyl and propargyl deriva-
tives by conventional procedures (Scheme 3). With the
products 8, 9 and 10 in hand, and taking into account
that factors such as the nature of the transition metal,
solvent and temperature can influence the ratio of the
possible products, we carried out an extensive study of
the insertion reaction by modification of these factors.
The results from these studies are summarized in Table
1.
path c
O
O
O
O
O
O
O
R
O
O
R
O
CO2Et
CO2Et
Side Products
Scheme 2. Formation of carbenoids species from O-protected
derivatives of 7 and possible reactions.
From these results, we concluded that the most suitable
transition metal to obtain the six-membered ring

F. Sarabia, F. J. Lo´pez-Herrera / Tetrahedron Letters 42 (2001) 8805–8809
8807
O
O
O
O
H
R
H
R
O
O
O
CO2Et
O
O
See table 1
O
O
O
CO2Et
OR
CO2Et
O
O
N2
a
R = H (7)
11a, R = CH2CH=CH2
11b, R = CH2Ph
11c, R = CH2C≡CH
12a, R = CH2CH=CH2
12b, R = CH2Ph
12c, R = CH2C≡CH
R = CH2CH=CH2 (8)
R = CH2Ph (9)
b
c
R = CH2C≡CH (10)
O
O
O
H
O
O
O
R
O
14a, R = CH2CH=CH2
14b, R = CH2Ph
13a, R = CH=CH2
13b, R = Ph
13c, R = C≡CH
OR
CO2Et
O
14c, R = CH2C≡CH
CO2Et
O
Scheme 3. Reactions of O-protected diazo derivatives with transition metals. Reagents and conditions: (a) 1.5 equiv. NaH, 2.0
equiv. BrCH2CHꢀCH2, THF, 0°C, 12 h, 68%; (b) 1.5 equiv. NaH, 3.0 equiv. BrCH2Ph, THF, 0°C, 12 h, 75%; (c) 2.5 equiv. NaH,
3.0 equiv. BrCH2CCH, THF, 0°C, 2 h, 88%.
Table 1. Reactions of diazo compounds 8, 9 and 10 with Rh(II) and Cu(II) catalysts
Diazo
Catalyst
Solvent
Conditions
Time (h)
11/12 (%)
13 (%)
14 (%)
8
8
8
8
8
8
8
8
8
9
9
10
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(hfacac)2
Cu(hfacac)2
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
CH2Cl2
Benzene
Benzene
CH2Cl2
CH2Cl2
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
rt
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
Reflux
Reflux
Reflux
0.5
0.5
0.5
1.0
1.0
12
1.0
24
1.0
1.0
1.0
1.0
30
40
35
0
0
0
10
0
0
35
5
85
65
50
65
10
30
95
80
90
100
55
85
0
5
10
0
90
70
5
10
10
0
10
10
15
solvent nor temperature affected the ratio of the prod-
ucts when Rh(II) was used as catalyst. On the other
hand, the expected allene, which would be formed after
a sigmatropic rearrangement of the corresponding oxo-
nium ylide intermediate, was not detected, indicating a
different mechanism of the alkyl group migration.
Recently, these allenes have been synthesized using a
similar reaction by use of a ruthenium catalyst.22
Acknowledgements
This work was financially supported by the Direccio´n
General de Investigacio´n y Cient´ıfica Te´cnica (ref.
PB97-1091) and by the Direccio´n General de Universi-
dades e Investigacio´n, Consejer´ıa de Educacio´n y Cien-
cia, Junta de Andaluc´ıa (FQM 0158). We thank Dr. J.
I. Trujillo from The Scripps Research Institute (La
Jolla, CA) for assistance in the preparation of this
manuscript. We thank Unidad de Espectroscop´ıa de
Masas de la Universidad de Sevilla for exact mass
spectroscopic assistance.
In conclusion, insertion reactions of O-alkyl diazo
derivatives of
D-mannose, promoted by transition
metals, were investigated in order to synthesize 2-
deoxy-2-C-alkyl analogues of KDO. Specific reaction
conditions and catalysts favored the formation of the
desired analogues in reasonably good yields, although
with a no stereoselectivity. However, the seven-mem-
bered ring products, formed by a CH insertion showed
complete stereoselectivity. All the synthesized products
provide access to complex analogues of KDO via chem-
ical modifications of the pendant groups at C-2 and will
be tested as inhibitors of CMP-KDO synthetase.
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1
anes); H NMR (400 MHz, CDCl3) l 5.89 (ddd, J=17.2,
10.4, 6.8 Hz, 1H, CHꢀCH2), 5.29 (d, J=17.2 Hz, 1H,
CHꢀCH2), 5.19 (d, J=10.4 Hz, 1H, CHꢀCH2), 4.37–4.32
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F. Sarabia, F. J. Lo´pez-Herrera / Tetrahedron Letters 42 (2001) 8805–8809
8809
3.98 (dd, J=8.9, 4.7 Hz, 1H, H-10), 3.50 (dd, J=7.6, 0.8
Hz, 1H, H-7), 2.80 (ddd, J=8.0, 6.1, 1.2 Hz, 1H, H-2),
2.32–2.26 (m, 1H, H-3), 2.08 (ddd, J=13.1, 4.1, 1.0 Hz,
1H, H-4), 1.55, 1.46, 1.38 and 1.36 (4s, 12H, 2×C(CH3)2),
1.25 (t, J=7.2 Hz, 3H, CO2CH2CH3); 13C NMR (50.3
MHz, CDCl3) l 171.3, 134.9, 117.8, 109.4, 108.3, 76.2,
76.1, 75.2, 66.9, 60.6, 43.5, 27.8, 27.5, 27.1, 25.6, 25.4,
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C19H30O7: 393.1884. Compound 13b: Rf=0.42 (silica gel,
CO2CH2CH3); 13C NMR (50.3 MHz, CDCl3) l 171.1,
139.4, 127.9, 127.7, 126.5, 109.4, 108.4, 81.9, 76.4, 76.3,
75.2, 66.9, 60.4, 44.9, 29.7, 28.0, 27.7, 27.0, 25.7, 25.3,
13.7; FAB HRMS (NBA) m/e 443.2025, M+Na calcd for
C23H32O7: 443.2038.
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13a and 13b revealed a concordance between theoretical
J1,2 values for the minimized conformers and experimen-
tal J1,2. Thus, theoretical coupling constants J1,2 were of
4.0 and 5.0 Hz for 13a and 13b, respectively, finding 6.1
and 6.3 Hz for experimental values, respectively. On the
other hand, a similar analysis carried out on the other
three possible diastereoisomers showed J1,2 values quite
different respect to the experimental ones.
1
50% EtOAc in hexanes); H NMR (400 MHz, CDCl3) l
7.35–7.30 (m, 5H, Ph), 4.97 (d, J=6.3 Hz, 1H, H-1), 4.40
(dd, J=6.0, 0.8 Hz, 1H, H-6), 4.36 (ddd, J=7.4, 6.2, 4.7
Hz, 1H, H-8), 4.27 (ddd, J=10.0, 6.0, 4.3 Hz, 1H, H-5),
4.10 (dd, J=8.8, 6.4 Hz, 1H, H-9), 4.00 (dd, J=8.9, 4.6
Hz, 1H, H-10), 3.93–3.77 (m, 2H, CO2CH2CH3), 3.63
(dd, J=7.6, 1.1 Hz, 1H, H-7), 3.09 (ddd, J=8.2, 6.4, 1.5
Hz, 1H, H-2), 2.57 (ddd, J=14.4, 9.3, 8.2 Hz, 1H, H-3),
2.09 (ddd, J=14.4, 4.0, 1.4 Hz, 1H, H-4), 1.57, 1.41, 1.39
and 1.37 (4s, 12H, 2×C(CH3)2), 1.04 (t, J=7.1 Hz, 3H,
22. Del Zotto, A.; Baratta, W.; Miani, F.; Verardo, G.; Rigo,
P. Eur. J. Org. Chem. 2000, 3731–3735.