Efficient preparation of a 1,3-diazidocyclitol as a versatile 2-deoxystreptamine precursor

Article abstract of DOI:10.1021/jo049788k

A synthesis route toward 2-deoxystreptamine, a common structure in many of the clinically important aminoglycosides, is presented. Starting from p-benzoquinone and cyclopentadiene, 2-deoxystreptamine is synthesized with key steps involving Pd(0)-catalyzed

Full text of DOI:10.1021/jo049788k

Efficien t P r ep a r a tion of a 1,3-Dia zid ocyclitol a s a Ver sa tile
2-Deoxystr ep ta m in e P r ecu r sor
Guuske F. Busscher,† Stan Groothuys,† Rene´ de Gelder,‡ Floris P. J . T. Rutjes,† and
Floris L. van Delft*,†
Department of Organic and Inorganic Chemistry, NSRIM, University of Nijmegen,
Toernooiveld, 6525 ED Nijmegen, The Netherlands
fvd@sci.kun.nl
Received February 6, 2004
A synthesis route toward 2-deoxystreptamine, a common structure in many of the clinically
important aminoglycosides, is presented. Starting from p-benzoquinone and cyclopentadiene,
2-deoxystreptamine is synthesized with key steps involving Pd(0)-catalyzed rearrangement, a retro-
Diels-Alder by flash vacuum thermolysis, and Yb(III)-directed regioselective epoxide opening. The
obtained diazidocyclitol 17 is a suitable 2-deoxystreptamine precursor, conveniently protected for
incorporation in new aminoglycoside entities.
In tr od u ction
Since the discovery of the aminoglycoside antibiotic
streptomycin in 1944,1 the family of aminoglycosides has
steadily grown into a powerful class of antibiotics with a
broad antibacterial spectrum and proven efficacy par-
ticularly against aerobic Gram-negative bacteria. Nev-
ertheless, extensive clinical use of the aminoglycosides
is limited, due mostly to the associated nephro- and
ototoxicities.2 Another disadvantage is the global devel-
opment of microbial resistance as the result of structural
modification by bacterial enzymes: aminoglycoside phos-
photransferases (APH), adenyltransferases (AAD or ANT),
and acetyltransferases (AAC).3,4 These circumstances
validate research into novel aminoglycoside analogues
which do not display the undesirable features but main-
tain a strong bactericidal effect. This notion has already
awakened the chemical community and the number of
papers along this line is rapidly increasing.5 Surprisingly,
however, none of these recent reports describes an
efficient way to prepare the core diaminocyclohexanetriol
2-deoxystreptamine common to (nearly) all of the known
aminoglycoside antibiotics (Figure 1).5
F IGURE 1. Retrosynthetic analysis of 2-deoxystreptamine.
as extensive protective group manipulations before in-
corporation in aminoglycoside entities can be ensured.
On the basis of this reasoning we set out to investigate
a practical synthetic route toward a 2-deoxystreptamine
precursor that is suitable to serve as a scaffold for either
4,5- or 4,6-linked aminoglycoside antibiotics.
(5) Some recent representative papers: (a) Greenberg, W. A.;
Priestley, E. S.; Sears, P. S.; Alper, P. B.; Rosenbohm, C.; Hendrix,
M.; Hung, S.-C.; Wong, C.-H. J . Am. Chem. Soc. 1999, 121, 6527-
6541. (b) Sucheck, S. J .; Wong, A. L.; Koeller, K. M.; Boehr, D. D.;
Draker, K.; Sears, P.; Wright, G. D.; Wong, C.-H. J . Am. Chem. Soc.
2000, 122, 5230-5231. (c) Luedtke, N. W.; Baker, T. J .; Goodman, M.;
Tor, Y. J . Am. Chem. Soc. 2000, 122, 12035-12036. (d) Rosenbohm,
C.; Berghe, D. V.; Vlietinck, A.; Wengel, J . Tetrahedron 2001, 57, 6277-
6287. (e) Tok, J . B.-H.; Fenker, J . Bioorg. Med. Chem. Lett. 2001, 11,
2987-2991. (f) Charles, I.; Xue, L.; Arya, D. P. Bioorg. Med. Chem.
Lett. 2002, 12, 1259-1262. (g) Ryu, D. H.; Tan, C. H.; Rando, R. R.
Bioorg. Med. Chem. Lett. 2003, 13, 901-903. (h) Russell, R. J . M.;
Murray, J . B.; Lentzen, G.; Haddad, J .; Mobashery, S. J . Am. Chem.
Soc. 2003, 125, 3410-3411. (i) Hanessian, S.; Tremblay, M.; Swayze,
E. E. Tetrahedron 2003, 59, 983-993. (j) Seeberger, P. H.; Baumann,
M.; Zhang, G.; Kanemitsu, T.; Swayze, E. E.; Hofstadler, S. A.; Griffey,
R. H. Synlett 2003, 9, 1323-1326. (k) Vourloumis, D.; Winters, G. C.;
Takahashi, M.; Simonsen, K. B.; Ayida, B. K.; Shandrick, S.; Zhao,
Q.; Hermann, T. ChemBioChem 2003, 4, 879-885. (l) Simonsen, K.
B.; Ayida, B. K.; Vourloumis, D.; Winters, G. C.; Takahashi, M.;
Shandrick, S.; Zhao, Q.; Hermann, T. ChemBioChem 2003, 4, 886-
890. (m) Ding, Y.; Hofstadler, S. A.; Swayze, E. E.; Griffey, R. H. Chem.
Lett. 2003, 32, 908-909. (n) Chou, C.-H.; Wu, C.-S.; Chen, C.-H.; Lu,
L.-D.; Kulkarni, S. S.; Wong, C.-H.; Hung, S.-C Org. Lett. 2004, 6, 585-
588.
Synthetic routes toward 2-deoxystreptamine that have
appeared in the literature require numerous synthetic
steps and offer minimal flexibility in protective groups6-8
or require expensive starting material. As a result, to
date the most practical method to synthesize 2-deoxy-
streptamine (derivatives) is via degradation of natural
neomycin.9-11 However, the initially obtained “naked”
meso-compound still demands desymmetrization as well
* Corresponding author. Phone: +31(0)24.3652373. Fax: 31(0)-
24.3653393.
† Department of Organic Chemistry.
‡ Department of Inorganic Chemistry.
(1) Schatz, A.; Waksman, S. A. Proc. Soc. Exp. Biol. Med. 1944, 55,
244-248.
(2) Zembower, T. R.; Noskin, G. A.; Postelnick, M. J .; Nguyen, C.;
Peterson, L. R. Int. J . Antimicrob. Agents 1998, 10, 95-105.
(3) Neonakis, I.; Gikas, A.; Scoulica, E.; Manios, A.; Georgiladakis,
A.; Tselentis, Y. Int. J . Antimicrob. Agents 2003, 22, 526-531.
(4) Haddad, J .; Vakulenko, S.; Mobeshary, S. J . Am. Chem. Soc.
1999, 121, 1922-1923.
10.1021/jo049788k CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004
J . Org. Chem. 2004, 69, 4477-4481
4477

Busscher et al.
SCHEME 1a
TABLE 1. Op tim iza tion of th e P a lla d iu m (0)-Ca ta lyzed
1,4-Hyd r ogen Migr a tion Rea ction a
entry
solvent
catalyst
2 yield,b %
3 yield,b %
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
DMF
PdCl2(PPh3)2
PdCl2(MeCN)2
PdCl2(dppf)
Pd(OAc)2(dppe)
PdCl2(PPh3)2
PdCl2(dppf)
16
-
9
100
100
69
71 (49)
c
c
-
89 (77)
-
-
DMF
29 (n.d.)e
a
Standard procedure is used, with given catalyst, and solvent.
b GC yield (isolated yield). c Decomposition. e n.d.) not determined.
conditions according to a known protocol14,15 led to diol
2, which was converted into the enone 3 via a 1,4-
hydrogen migration catalyzed by in situ formed Pd(0),
according to Takano et al.16,17 In our hands, however, it
was not possible to reproduce the reported yield under
the described conditions (PdCl2(PPh3)2 in MeCN), since
an appreciable amount (16%) of starting material re-
mained (Table 1, entry 1).
a
Reagents and conditions: (a) NaBH4, CeCl3‚7H2O, MeOH, 0-5
°C, 1 h; (b) PdCl2(dppf), HCO2NH4, MeCN, ∆, 45 min; (c) H2O2,
NaOH, CH2Cl2/MeOH, 1/1, rt, 30 min; (d) NaBH4, CeCl3‚7H2O,
MeOH, -78 °C, 30 min.
Resu lts a n d Discu ssion
As becomes clear from Figure 1, the target molecule
2-deoxystreptamine shows a remarkable structural sim-
plicity particularly due to the internal plane of symmetry.
An obvious retrosynthetic approach therefore suggests
introduction of both the amino functionalities by double
nucleophilic opening of the bisepoxide A. This bisepoxide
has been described in the literature, but is unstable, and
the synthetic route leading to it is by no means straight-
forward.6,12 Unfortunately, obtention of A by epoxidation
of cyclohexane-2,5-dien-1-ol (not drawn) does not seem
feasible since the latter molecule has not been reported
presumably due to its inherent instability. We have
earlier circumvented the use of unstable intermediates
in a synthesis of enantiopure and fully orthogonally
protected 2-deoxystreptamine by using a stepwise ap-
proach starting from D-allylglycine.13 The latter route
provides a highly useful 2-deoxystreptamine scaffold for
the preparation new aminoglycoside antibiotics but we
anticipated a shorter route toward a versatile 2-deoxy-
streptamine precursor would be of additional value to the
field. As the present paper shows, a more straightforward
route can be achieved via temporary “protection” of a
cyclohexene double bond as schematically represented in
B.
We therefore further investigated the optimal reaction
conditions for this transformation. In DMF we saw minor
amounts of 3 or no product formed (entries 5 and 6),
which also applied to the use of other sources of pal-
ladium in MeCN (entries 2 and 4). On the contrary, with
PdCl2(dppf) as catalyst we found only traces of starting
material and a much improved yield of 3 (entry 3). In
the subsequent step, nucleophilic epoxidation of 3 af-
forded epoxide 4 in 89% yield. Reduction of the ketone
to alcohol 5 proved troublesome and was inevitably
accompanied by varying amounts of the Payne-rear-
ranged product (6). Optimal conditions to keep this side
reaction to a minimum involved a reduction under Luche
conditions15 at -78 °C to afford alcohol 5 and 6 in a
favorable 7:1 ratio of isomers, which could be easily
separated by column chromatography.18-20 In this re-
spect, it is important to note that compound 5 required
additional caution due to its high acid sensitivity; puri-
fication on silica gel led to the formation of two new
products. Separation by selective crystallization of the
p-nitrobenzoate derivatives, followed by X-ray analysis
revealed that the tetracycles 9 and 12 had been formed
(Scheme 2).21
Our synthesis starts from the readily accessible Diels-
Alder condensation product 1 of cyclopentadiene and
p-benzoquinone (Scheme 1). Reduction under Luche
(14) Marchand, A. P.; LaRoe, W. D.; Sharma, G. V. M.; Suri, S. C.;
Reddy, D. S. J . Org. Chem. 1986, 51, 1622-1625.
(15) (a) Luche, J .-L.; Gemal, A. L. J . Am. Chem. Soc. 1979, 101,
5848-5849. (b) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981,
103, 5454-5459.
(6) Formal synthesis of 2-deoxystreptamine: (a) Nakajima, M.;
Hasegawa, A.; Kurihara, N. Liebigs Ann. Chem. 1965, 689, 235-242.
(b) Suami, T.; Lichtenthaler, F. W.; Ogawa, S.; Nakashima, Y.; Sano,
H. Bull. Chem. Soc. J pn. 1967, 40, 1014-1017. (c) Dijkstra, D. Recl.
Trav. Chim. Pays-Bas 1968, 87, 161-180. (d) Ogawa, S.; Ueda, T.;
Funaki, Y.; Hongo, Y.; Kasuga, A.; Suami, T. J . Org. Chem. 1977, 42,
3083-3088. (e) Ku¨hlmeyer, R.; Keller, R.; Schwesinger, R.; Netscher,
T.; Fritz, H.; Prinzbach, H. Chem. Ber. 1984, 117, 1765-1800.
(7) Baer, H. H.; Arai, I.; Radatus, B.; Rodwell, J .; Chinh, N. Can. J .
Chem. 1987, 65, 1443-1451.
(16) Takano, S.; Moriya, M.; Kamikubo, T.; Hiroya, K.; Ogasawara,
K. Tetrahedron Lett. 1993, 34, 8485-8488.
(17) It should be noted that enzymatic resolution of compound 2 may
serve as
a starting point for the preparation of an enantiopure
derivative of 2-deoxystreptamine: Takano, S.; Higashi, Y.; Kamikubo,
T.; Moriya, M.; Ogasawara, K. Synthesis 1993, 948-950.
(18) To establish whether the Payne rearrangement is in equilib-
rium the 2,3-epoxycyclohexanols were individually treated with sodium
hydride. It turned out that only the trans-epoxy alcohol (5) rearranged
to the regioisomeric 1,2-cis-epoxy alcohol 6, whereas the reverse
reaction did not take place.
(19) AM1 and quantum mechanics show that there is little energy
difference between Payne-rearranged product 6 and unrearranged
product 5. Structures were minimized with MOPAC/AM1 and B3LYP
6-31G* predicting ∆E ) 1.8 and 0.75 kcal/mol, respectively.
(20) Mgani, Q. M.; Klunder, A. J . H.; Nkunya, M. H. H.; Zwanen-
burg, B. Tetrahedron Lett. 1995, 26, 4661-4664.
(21) The crystal structures 10, 13, and 16 have been deposited at
the Cambridge Crystallographic Data Centre and allocated the deposi-
tion numbers CCDC 226046, 226045, and 226044, respectively.
(8) da Silva, E. T.; le Hyaric, M.; Machado, A. S.; Almeida, M. V.
Tetrahedron Lett. 1998, 39, 6659-6662.
(9) Canas-Rodriguez, A.; Ruiz-Poveda, S. G. Carbohydr. Res. 1977,
59, 240-243.
(10) Tona, R.; Bertolini, R.; Hunziker, J . Org. Lett. 2000, 2, 1693-
1696.
(11) Swayze, E.; Griffey, R.; Ding, Y.; Mohan, V. Patent Application
WO 01/39726A2, 2001.
(12) Ku¨hlmyer, R.; Seitz, B.; Weller, T.; Fritz, H.; Schwesinger, R.;
Prinzbach, H. Chem. Ber. 1989, 122, 1729-1743.
(13) Busscher, G. F.; Rutjes, F. P. J . T.; van Delft, F. L. Tetrahedron
Lett. 2004, 45, 3629-3632.
4478 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis Route to 2-Deoxystreptamine
SCHEME 2. Su p p osed Mech a n ism for th e F or m a tion of P r od u cts 9 a n d 12a
a
Reagents and conditions: (a) p-NO2-BzCl, Et3N, DMAP, CH2Cl2.
TABLE 2. Op tim iza tion of th e Ep oxid e Op en in g of 16
SCHEME 3. Syn th esis of 1,3-Dia zid ocyclitol a s
2-Deoxystr ep ta m in e P r ecu r sor a
yield of
entry
conditions
solvent 17:19a 17, %
1
2
3
4
NaN3, NH4Cl, 80 °C
NaN3, Yb(OTf)3, Et3N, 80 °C
NaN3, Yb(OTf)3, 60 °C
NaN3, Yb(OTf)3, Et3N, 280 W, toluene >95:5
135 °C
MeOH 1:2
10
49
-
toluene >95:5
b
MeOH
-
70
5
NaN3, Yb(OTf)3, Et3N, 80 °C, toluene >95:5
4 Å MS
79
a
Reagents and conditions: (a) 80 °C, 600 °C, 0.04 mbar, 2 h;
(b) TBDMSCl, DIPEA, DMAP, CH2Cl2, rt, 5 h; (c) NaN3, NH4Cl,
MeOH, ∆, 40 h; (d) m-CPBA, CH2Cl2, rt, 24 h; (e) Yb(OTf)3, Et3N,
NaN3, toluene, 80 °C, 4 d.
a
Regioisomeric ratio determined by 1H NMR. b Major compound
19.
We suggest that the mechanism leading to 9 and 12
involves acid activation (silica gel in this case) of the
epoxide of 5, which has the double bond π-electrons
optimally aligned for nucleophilic attack. The resulting
intermediate carbocation 7 undergoes one of two possible
rearrangements, involving either an H-shift (path a) or
alkyl-shift (path b). Although the R-hydroxy aldehyde 10
as such could not be identified, it seems likely that
formation of the nitrobenzoate 12 can be explained via
R-ketol rearrangement of 10 to the more stable ketone
11. Gratifyingly, rearrangement could be completely
suppressed by eluting the column with 1% Et3N to give
5 in a final isolated yield of 80%.
Having the tricyclic system 5 in hand, the desired
retro-Diels-Alder reaction could be investigated. Such
reactions, typically executed in high-boiling ethereal
solvents, are often accompanied by side products and the
solvent is difficult to remove. These disadvantages can
be elegantly circumvented by making use of flash vacuum
thermolysis (FVT).22 Optimization of the FVT conditions
in our case shows that the best result was obtained with
sublimation at 80 °C, thermolysis at 600 °C, and a
pressure around 0.04 mbar to afford compound 13 cleanly
in 84% yield (Scheme 3). In the following steps the
hydroxyl was protected with a tert-butyldimethylsilyl
group and the epoxide was converted to azido alcohol 15.
The remaining double bond was now also epoxidized, but
this time with m-CPBA, leading to the trans-epoxide 16
stereoselectively (72%) although formation of the cis-
isomer could not be suppressed completely (ratio 4:1). The
final step, involving another regioselective epoxide open-
ing, proved to be more troublesome (Table 2). Our first
attempt to open epoxide 16 with NaN3 in MeOH pre-
dominantly led to the formation of azido alcohol 19 and
only to a lesser extent to the preferred regioisomer 17
(entry 1), presumably due to a favored trans-diaxial
opening of the epoxide as dictated by the Fu¨rst-Plattner
rule.23
After some unsuccessful variation of reaction condi-
tions a paper by Delgado et al. stimulated us to investi-
gate chelation-controlled Yb(OTf)3-catalyzed azidolysis of
epoxides.24 Much to our satisfaction, under the suggested
conditions with sodium azide, ytterbium(III) triflate, and
triethylamine the 1,3-diazidocyclitol 17 was formed as
the only regioisomer (entry 2), most likely from nucleo-
philic attack at the all-axial conformer 18, formed by
chelation of ytterbium(III) with both the free (deproto-
nated) hydroxyl and the epoxide. Unfortunately, after 4
days of refluxing substantial amounts of starting mate-
rial remained and only 49% of the product could be
isolated. Replacement of toluene by MeOH was not a
fortuitous choice, but by carrying out the reaction in a
microwave at 280 W and at 135 °C (entry 4) product 17
was obtained in a yield of 70%. Finally, the optimal result
was achieved by addition of molecular sieves to the
reaction mixture, to give a yield of 79%. The structural
(23) Fu¨rst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275-283.
(24) Serrano, P.; Llebaria, A.; Delgado, A. J . Org. Chem. 2002, 67,
7165-7167.
(22) Klunder, A. J . H.; Zhu, J .; Zwanenburg, B. Chem. Rev. 1999,
99, 1163-1190.
J . Org. Chem, Vol. 69, No. 13, 2004 4479

Busscher et al.
Exp er im en ta l Section
(()-(1R,2R,7R,8S)-Tr icyclo[6.2.1.02,7]u n d eca -4,9-d ien -3-
on e (3). To a solution of 2 (5.1 g, 29 mmol) and HCO2NH4
(2.7 g, 42 mmol) in degassed MeCN (280 mL) was added 1
mol % of PdCl2(dppf) (230 mg, 0.282 mmol). The solution was
refluxed for 45-90 min. The reaction was diluted with Et2O,
washed with brine, and dried (Na2SO4). After evaporation of
the solvent the crude product was purified by flash chroma-
tography (EtOAc/n-heptane, 1/5) to give 3 (3.5 g, 77%) as a
F IGURE 2. Platon visualization25 of the X-ray structures of
9 and 12.
1
yellow oil. H NMR (CDCl3, 300 MHz, ppm): δ 6.66 (dt, J )
4.0, 10.3 Hz, 1H, CH), 6.12 (ddd, J ) 15.8, 5.6, 2.9 Hz, 2H,
CH), 5.86 (dt, J ) 10.4, 2.4 Hz, 1H, CH), 3.38 (br s, 1H, CH),
3.03 (br s, 1H, CH), 2.91 (dd, J ) 10.1, 3.9 Hz, 1H, CH), 2.76
(dt, J ) 10.1, 3.5 Hz, 1H, CH), 2.60 (dddd, J ) 20.6, 10.2, 3.9,
2.4 Hz, 1H, CH), 2.02 (ddd, J ) 20.5, 6.0, 3.4 Hz, 1H, CH),
1.42 (dt, J ) 8.4, 1.8 Hz, 1H, CH), 1.34 (d, J ) 8.4 Hz, 1H,
CH); in agreement with literature.26
(()-(1R,2R,3S,4R,5S,7R,8S)-4,5-Ep oxytr icyclo[6.2.1.02,7]-
u n d ec-9-en -3-ol (5). To a cold solution (-78 °C) of 4 (3.21 g,
18.2 mmol) in MeOH (46 mL) was added NaBH4 (689 mg, 18.2
mmol) and CeCl3‚7H2O (6.77 g, 18.2 mmol). The reaction was
stirred until conversion was completed. The mixture was
quenched with ammonium chloride, extracted with Et2O,
washed with brine, and dried (Na2SO4). The crude mixture was
purified by means of flash chromatography (EtOAc/n-heptane,
1/5 and 1% Et3N) to yield 2.59 g (80%) of compound 5 as a
colorless oil. Rf 0.4 (EtOAc/n-heptane, 1/3). IR υmax film: 3442,
2958, 1439, 1338, 1255, 816, 729 cm-1. H NMR (CDCl3, 400
1
F IGURE 3. Platon visualization25 of the X-ray structure of
17.
MHz, ppm): δ 6.40 (dd, J ) 5.7, 3.1 Hz, 1H, H10), 6.06 (dd, J
) 5.7, 3.1 Hz, 1H, H9), 4.46 (m, 1H, H3), 3.12 (m, 2H, H4, and
H5), 2.93 (br s, 1H, H1), 2.77 (br s, 1H, H8), 2.46-2.38 (m, 1H,
H7), 2.30-2.24 (m, 2H, H2, and H6exo), 1.45 (dt, J ) 8.1, 1.9
Hz, 1H, H11), 1.34 (dd, J ) 14.4, 11.7 Hz, 2H, H6endo, and H11),
1.11 (br d, 1H, OH). 13C NMR (CDCl3, 75 MHz, ppm): δ 137.8,
134.0, 68.9, 51.8, 50.9, 50.7, 46.1, 45.7, 40.8, 36.1, 26.9. HRMS
(CI) m/z calcd for C11H15O2 (M + H)+ 179.1072, found 179.1068.
(()-(1R,2R,3S,4R,5S,7R,8S)-5,6-Ep oxytr icyclo[6.2.1.02,7]-
u n d ec-9-en -4-ol (6). To a solution of 5 (20 mg, 0.11 mmol) in
Et2O (1.5 mL) was added NaH (2.7 mg, 0.11 mmol) at room
temperature. The reaction was followed with TLC (EtOAc/n-
heptane, 2/3). After the mixture was stirred for 3 days water
was added and the product was extracted with Et2O and dried
(MgSO4). Analysis with TLC and NMR showed 100% conver-
sion to 6. Rf 0.30 (EtOAc/n-heptane, 1/3). IR υmax film: 3406,
2960, 1437, 1342, 1049, 735 cm-1. 1H NMR (CDCl3, 200 MHz,
ppm): δ 6.23 (dd, J ) 5.7, 2.9 Hz, 1H, H10), 6.06 (dd, J ) 5.7,
3.2 Hz, 1H, H9), 4.23 (m, 1H, H5), 3.25 (m, 1H, H3), 3.00 (m,
2H, H1 and H4), 2.70 (br s, 1H, H8), 2.47 (dt, J ) 9.8, 2.6 Hz,
1H, H2), 2.35-2.19 (m, 1H, H7), 1.72-1.61 (m, 2H, H6exo and
OH), 1.42 (m, 1H, H11), 1.29-1.21 (m, 2H, H11 and H6endo).
HRMS (CI) m/z calcd for C11H15O2 (M + H)+ 179.1072, found
179.1071.
SCHEME 4. Con ver sion of 17 in to
2-Deoxystr ep ta m in ea
a
Reagents and conditions: (a) 1 N HCl, MeOH, rt, 16 h; (b)
Pd/C, H2, MeOH, 16 h; (c) Ac2O, Et3N, MeOH/H2O, 1/1.
identity of 17 was unequivocally established by X-ray
analysis (Figure 3).21
The convenience of the diazido derivative 17 above
carbamate-protected 2-deoxystreptamines is reflected in
its excellent solubility in organic solvents and straight-
forward spectral analysis. Finally, the applicability of 17
as a versatile scaffold for the preparation of new 4,6-
linked aminoglycoside type compounds6e,7 was established
by its smooth conversion into 2-deoxystreptamine, i.e. by
desilylation and hydrogenation, in 95% yield for the two
steps (Scheme 4). Comparison of spectral data of the
diacetate derivative 21 provided further evidence of the
structural identity of 17.
(()-(1S,5S,6R)-5,6-E p oxycycloh ex-2-en -1-ol (13). The
thermolysis oven was preheated to 600 °C. A solution of 5 (430,
2.41 mmol) in Et2O was brought into the sublimation flask,
and Et2O was evaporated. The vacuum gauge was carefully
opened until vacuum was (0.04 mbar) reached, after which the
collecting cooler was charged with CO2/acetone (-78 °C). The
sublimation oven was heated to 80 °C. The reaction was
finished when no starting material remained in the sublima-
tion flask. The crude mixture was purified by flash chroma-
tography (diethyl ether/n-pentane, 1/2). Compound 13 (226 mg,
84%) was obtained as a colorless liquid. Rf 0.3 (EtOAc/n-
heptane, 2/1). IR υmax film: 3390, 1419, 1011, 929, 986, 798,
In conclusion, the synthetic route described above is a
versatile means to obtain the 1,3-diazidocyclitol as a
2-deoxystreptamine precursor in 10 steps and an overall
yield of 15%. The route is suitable for gram-scale syn-
thesis and we are currently using 17 as the key scaffold
for the synthesis of new RNA-targeted ligands. We
believe that the obtained diazidocyclitol 17 is a suitable
2-deoxystreptamine precursor and moreover conveniently
protected for incorporation in new aminoglycoside enti-
ties.
710 cm-1 1H NMR (CDCl3, 400 MHz, ppm): δ 5.7-5.66 (m,
.
1H, CH), 5.6-5.57 (m, 1H, CH), 4.48 (br s, 1H, CH), 3.31 (br
s, 1H, CH), 3.25 (br s, 1H, CH), 2.63-2.48 (m, 2H, CH), 1.84
(25) Spek, A. L. PLATON, A Multipurpose Crystallographic Tool;
Utrecht University: Utrecht, The Netherlands, 2003.
(26) Kamikubo, T.; Ogasawara, K. J . Chem. Soc., Chem. Commun.
1995, 19, 1951-1952.
4480 J . Org. Chem., Vol. 69, No. 13, 2004

Synthesis Route to 2-Deoxystreptamine
(br s, 1H, OH). 13C NMR (CDCl3, 100 MHz, ppm): δ 124.8,
124.7, 63.0, 53.06, 50.2, and 25.1.
dropwise under argon over Yb(OTf)3 (515 mg, 0.83 mmol) and
MS 4 Å (500 mg) at room temperature. NaN3 (1.08 g, 16.6
mmol) and Et3N (3.47 mL, 24.9 mmol) were added and the
reaction was then stirred at 80 °C for 4 days. The reaction
mixture was cooled, filtered, and evaporated. The crude
product was purified by flash chromatography (EtOAc/n-
heptane, 1/10) to give compound 17 as white crystals (321 mg,
82% based on 114 mg of recovered starting material). Rf 0.2
(EtOAc/n-heptane, 1/10). Mp: 104 °C. IR υmax film: 2932, 2098,
1247, 1130, 841 cm-1. 1H NMR (CDCl3, 400 MHz, ppm): δ 3.35
(s, 5H, CH), 2.41 (s, 2H, OH), 2.18 (m, 1H, CH2), 1.38 (m 1H,
CH2), 0.92 (s, 9H, t-Bu), 0.16 (s, 6H, Me2Si). 13C NMR (CDCl3,
75 MHz, ppm): δ 76.2, 59.7, 31.7, 25.7, 18.1, -4.5. HRMS (CI)
m/z calcd for C12H25O3SiN6 (M + H)+ 329.1758, found 329.1754.
Anal. Calcd for C12H24O3N6Si: C, 43.88; H, 7.37; N, 25.59.
Found: C, 43.84; H, 7.04; N, 25.11. Crystal structure data have
been deposited at the Cambridge Crystallographic Data Cen-
tre, CCDC 226046.
(()-(3S,4S,5S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-4,5-ep -
oxycycloh ex-1-en e (14). To a solution of 13 (655 mg, 5.84
mmol) in CH2Cl2 (30 mL) was added DIPEA (1.43 mL, 8.17
mmol), TBDMSCl (1.06 g, 7.59 mmol), and DMAP (71.0 mg,
0.584 mmol) at 0 °C. The solution was stirred for 5 h at room
temperature. Water was added, and the product was extracted
with CH2Cl2, dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by flash chromatog-
raphy (EtOAc/n-heptane, 1/10) to yield 14 (1.12 g, 85%) as a
colorless oil. Rf 0.6 (EtOAc/n-heptane, 1/3). IR υmax film: 2952,
2927, 2856, 1254, 1068, 837 cm-1. 1H NMR (CDCl3, 400 MHz,
ppm): δ 5.58-5.49 (m, 2H, 2CH), 4.49 (br s, 1H, CH), 3.30 (br
s, 1H, CH), 3.15 (br s, 1H, CH), 2.54 (br s, 2H, CH2), 0.92 (s,
9H, t-Bu), 0.14 (s, 3H, Me), 0.12 (s, 3H, Me). 13C NMR (CDCl3,
100 MHz, ppm): δ 125.1, 123.2, 63.7, 54.1, 50.7, 25.9, 24.9,
18.3, -4.5, -4.6. HRMS (EI) m/z calcd for C12H22O2Si (M)+
226.1389, found 226.1381.HRMS (EI) m/z calcd for C11H19O2-
Si (M - Me) 211.1154, found 211.1152.
(()-(1S,2S,6R)-6-Azid o-2-[(ter t-bu tyld im eth ylsilyl)oxy]-
cycloh ex-3-en -1-ol (15). To a solution of 14 (3.05 g, 13.5
mmol) in MeOH (50 mL) was added NaN3 (1.75 g, 26.9 mmol)
and NH4Cl (1.29 g, 24.1 mmol). The reaction was stirred under
reflux for 40 h. MeOH was evaporated, CH2Cl2 was added, and
the solution was washed with brine and dried (Na2SO4). The
solvent was evaporated and the crude product was purified
by flash chromatography (EtOAc/n-heptane, 1/10) to obtain 15
as a colorless oil (4.2 g, 85%). IR υmax film: 2109, 1253, 1088,
837, 779 cm-1. 1H NMR (CDCl3, 400 MHz, ppm): δ 5.59-5.55
(m, 1H, CH), 5.50 (d, J ) 10.1 Hz, 1H, CH), 4.22-4.20 (m,
1H, CH), 3.60-3.57 (m, 2H, 2CH), 2.50-2.44 (m, 1H, CH), 2.46
(s, 1H, OH, disappears with a drop of D2O), 2.14-2.07 (m, 1H,
CH), 0.91 (s, 9H, t-Bu), 0.13 (s, 3H, MeSi), 0.12 (s, 3H, MeSi).
13C NMR (CDCl3, 100 MHz, ppm): δ 130.0, 124.1, 76.9, 73.9,
60.7, 31.0, 25.8, 18.1, -4.5. MS(CI): 270 (M + H). HRMS (EI)
m/z calcd for C12H23O2SiN3 (M)+ 269.1559, found 269.1551.
(()-(1S,2R,3R,4R,6R)-6-Azid o-2-[(ter t-bu tyld im eth ylsi-
lyl)oxy]-3,4-ep oxycycloh exa n -1-ol (16). To a solution of 15
(3.61 g, 13.4 mmol) in CH2Cl2 (180 mL) at room temperature
was added m-CPBA (5.76 g, 33.4 mmol). After being stirred
overnight the suspension was diluted with CH2Cl2, filtered,
and washed with water and twice with a phosphate buffer (pH
7.5) to get rid of the excess benzoic acid. The crude product
was dried (Na2SO4), concentrated under reduced pressure, and
purified by flash chromatography (EtOAc/n-heptane, 1/5) to
give 2.74 g (72%) of compound 16 as a colorless crystalline
solid. Rf 0.4 (EtOAc/n-heptane, 1/5). IR υmax film: 2956, 2927,
2860, 2110, 1709, 841 cm-1. 1H NMR (CDCl3, 400 MHz, ppm):
δ 3.82 (d, 1H, 3, J ) 7.16 Hz, CH), 3.42-3.32 (m, 3H, CH),
3.01 (d, 1H, J ) 3.66 Hz, CH), 2.53 (ddd, J ) 1.9, 3.1, 6.9 Hz,
1H, CH2), 2.40 (d, J ) 2.64 Hz, 1H, OH), 1.79 (ddd, J ) 1.32,
10.41, 11.87 Hz, 1H, CH2), 0.93 (s, 9H, t-Bu), 0.18 (s, 3H, MeSi),
0.16 (s, 1H, MeSi). 13C NMR (CDCl3, 100 MHz, ppm): δ 73.2,
57.4, 56.4, 53.1, 28.9, 25.9, 18.2, -4.5, -4.6. HRMS (CI) m/z
calcd for C12H24O3SiN3 (M + H)+ 286.1587, found 286.1577.
(1R,2r ,3S,4R,6S)-4,6-Dia zid o-2-[(ter t-bu tyld im eth ylsi-
lyl)oxy]cycloh exa n e-1,3-d iol (17). A solution of the starting
epoxide (16) (448 mg, 1.66 mmol) in 22 mL of toluene is added
(1R,2r ,3S,4R,6S)-4,6-Diazidocycloh exan etr iol (20). Com-
pound 17 (30 mg, 0.093 mmol) was dissolved in a 1 N HCl
solution in MeOH (1 mL). The reaction mixture was stirred
at room temperature overnight. EtOAc was added and the
reaction mixture was washed with NaHCO3 and dried (Na2-
SO4), to give after flash chromatography (EtOAc) the 4,6-
diazidocyclohexanetriol (quant.). Rf 0.4 (EtOAc). IR υmax film:
3369, 2923, 2100, 1359, 1260, 1113, 1080, 1023, 668, 616, 556
1
cm-1. H NMR (CD3OD, 400 MHz, ppm): δ 3.38 (m, 2H, CH),
3.18-3.27 (m, 3H, CH), 2.09 (dt, J ) 4.4 Hz, 1H, CH2), 1.25
(q, J ) 12.6 Hz, 1H, CH2); in agreement with literature.27
2-Deoxystr ep ta m in e. To a solution of 4,6-diazidocyclohex-
anetriol 20 (20 mg, 0.093 mmol) in MeOH was added Pd/C
(spatula). After the mixture had been stirred for 14 h under 3
bar of H2, Pd/C was filtered off and the filtrate was concen-
trated to yield 2-deoxystreptamine (14 mg, 95%). IR υmax film:
1
3345, 2917, 2362, 2094, 1559, 1541, 1095, 988 cm-1. H NMR
(CD3OD, 400 MHz, ppm): δ 3.13 (m, 1H, CH), 3.02 (t, J ) 9.5
Hz, 2H, CH), 2.68-2.54 (m, 2H, 2CH), 1.98 (dt, J ) 4.3, 4.1
Hz, 1H, CH2) 1.16 (q, J ) 12.1 Hz, 1H, CH2).28
Ack n ow led gm en t. The authors thank Dr. A. J . H.
Klunder (University of Nijmegen, The Netherlands) for
helpful discussions and advice on the flash vacuum
thermolysis methodology and Dr. H. Borkent (Univer-
sity of Nijmegen, The Netherlands) for AM1 calculations
and quantum mechanics. The work described here was
financially supported by the Council for Chemical
Sciences of The Netherlands Organization for Scientific
Research (NWO).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization, and X-ray analysis data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O049788K
(27) Ku¨hlmeyer, R.; Keller, R.; Schwesinger, R.; Netscher, T.; Fritz,
H.; Prinzbach, H. Chem. Ber. 1984, 117, 1765-1800.
(28) Koch, K. F.; Rhoades, J . A.; Hagaman, E. W.; Wenkert, E. J .
Am. Chem. Soc. 1974, 96, 3300-3305.
J . Org. Chem, Vol. 69, No. 13, 2004 4481