Synthesis of a new 2,3-diaminoconduritol with conduritol F structure

Article abstract of DOI:10.1002/ejoc.201200582

A new 2,3-diaminoconduritol derivative with the conduritol F structure was prepared starting from cyclohexa-1,4-diene. Initially, a lactam, prepared by the cycloaddition of chlorosulfonyl isocyanate (CSI) to cyclohexa-1,4-diene, was converted into an amino acid. The conversion of the acid functionality into an isocyanate resulted in the formation of an imidazolidinone derivative, formed by an intramolecular cyclization. In the second part of this work, the known anhydride, 3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione was successfully converted into the desired bis(carbamate). The bromination of the double bond in the six-membered ring followed by a DBU-induced (DBU = 1,8-diazabicyclo[5.4.0] undec-7-ene) HBr elimination furnished the symmetrical diene. The photooxygenation of the diene unit afforded the bicyclic endoperoxide. The reaction of the endoperoxide with thiourea followed by acetylation resulted in the formation of a syn-configured diacetate. The deprotection of the urethane and acetate groups gave the new 2,3-diaminoconduritol with the conduritol F structure. A new 2,3-diaminoconduritol with the conduritol F structure was prepared starting from the known anhydride 3a,4,7,7a-tetrahydroisobenzofuran-1, 3-dione, which was successfully converted into the desired diene with bis(carbamate) functional groups. The photooxygenation of the diene followed by cleavage of the peroxide linkage and removal of the protecting groups gave the new 2,3-diaminoconduritol. Copyright

Full text of DOI:10.1002/ejoc.201200582

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DOI: 10.1002/ejoc.201200582
Synthesis of a New 2,3-Diaminoconduritol with Conduritol F Structure
Zeynep Ekmekci[a,b] and Metin Balci*[a]
Keywords: Natural products / Total synthesis / Configuration determination / Rearrangement / Oxygenation
A new 2,3-diaminoconduritol derivative with the conduritol F
structure was prepared starting from cyclohexa-1,4-diene.
Initially, a lactam, prepared by the cycloaddition of chloro-
sulfonyl isocyanate (CSI) to cyclohexa-1,4-diene, was con-
verted into an amino acid. The conversion of the acid func-
tionality into an isocyanate resulted in the formation of an
imidazolidinone derivative, formed by an intramolecular cy-
clization. In the second part of this work, the known anhy-
dride, 3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione was suc-
cessfully converted into the desired bis(carbamate). The bro-
mination of the double bond in the six-membered ring fol-
lowed by a DBU-induced (DBU = 1,8-diazabicyclo[5.4.0]un-
dec-7-ene) HBr elimination furnished the symmetrical diene.
The photooxygenation of the diene unit afforded the bicyclic
endoperoxide. The reaction of the endoperoxide with thio-
urea followed by acetylation resulted in the formation of a
syn-configured diacetate. The deprotection of the urethane
and acetate groups gave the new 2,3-diaminoconduritol with
the conduritol F structure.
Furthermore, they are potent inhibitors of human immuno-
deficiency virus (HIV).[5]
Introduction
Conduritol (1) is a cyclohexenetetrol (see Figure 1). The
presence of four stereogenic centers allows it to exist in six
different configurations, that is, the two meso forms A and
D and the four compounds B, C, E, and F, which can exist
as enantiomeric pairs.[1] The two isomers conduritol A and
conduritol F were found in nature. Conduritol A[1] was first
isolated from the bark of the vine Marsdenia condurango.[2]
The conduritol derivatives have remarkable biological prop-
erties,[3] namely, they act as glycosidase inhibitors.[4]
Conduramine analogues are aminocyclohexenetriols 2
derived from the conduritols, in which one of the hydroxy
groups is replaced by an amino group. One of the most
important conduramines is valienamine (3),[6] which was
isolated from the microbial degradation of validoxyl-
amine A. Valienamine occurs widely as a building block in
several aminoglycoside antibiotics such as narciclasine (4)
and lycoricidine (5).[7]
Diaminoconduritols are also derived from the conduritol
derivatives, in which two of the hydroxy groups are replaced
by amino groups (see Figure 2). There are four consti-
tutional isomers of the diaminoconduritols, namely, 1,2-,[8]
1,3-,[9] 1,4-,[10] 2,3-diaminoconduritols[11] 6–9, and their
stereoisomers.
Figure 2. Constitutional isomers of 1,2-, 1,3-, 1,4-, and 2,3-di-
aminoconduritols 6–9.
Figure 1. Representative compounds containing conduritol skel-
eton.
The diaminoconduritols also show interesting biological
activities such as the inhibition of α- and β-glycosidases.[10a]
Furthermore, they are used in the syntheses of diaminoin-
ositol derivatives and some antibiotics[12] as well as cyto-
static platinum complexes.[13]
1,2-Diaminoconduritol 6 and 1,3-diaminoconduritol 7
are unknown in free form. However, some derivatives have
been reported. In 1984, Kresze et al. synthesized protected
[a] Middle East Technical University, Department of Chemistry,
06800 Ankara, Turkey
Fax: +90-312-210-3200
Homepage: www.metu.edu.tr/~mbalci
[b] Süleyman Demirel University, Department of Chemistry,
32260 Isparta, Turkey
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200582.
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1,2- and 1,3-diaminoconduritol in five steps starting from
benzene oxide.[9] Vogel et al. described the first synthesis of
a meso-1,4-diaminoconduritol by treating syn-benzene di-
oxide with NaN3 followed by a reduction.[10c] The applica-
tion of the same methodology to anti-benzene dioxide gave
various substituted 1,4-diaminoconduritol derivatives.[10b]
Cerè et al. developed an elegant route for the synthesis of
2,3-diaminoconduritol 13, which has the same configura-
tion as conduritol B, starting with thiepane derivative 10
derived from d-mannitol (Scheme 1).[11a,14] The thiepane
derivative 10 was first converted into a diazido derivative,
which was then oxidized to 11, after the protection of the
hydroxy groups. The ring contraction and incorporation of
the double bond was achieved through the Ramberg–Back-
lund reaction. The reduction of the azide functions followed
by deprotection resulted in the formation of enantiomer-
ically pure 2,3-diaminoconduritol 13. Savoia et al. synthe-
sized 2,3-diaminoconduritol derivatives through ruthenium-
catalyzed ring-closing metathesis starting from the appro-
priate substrates.[15]
Scheme 2. Retrosynthetic analysis of 2,3-diaminoconduritol 14.
The cleavage of the azetidin-2-one ring in 15 followed by
a Curtius rearrangement of the ester functional group
would provide the key intermediate, a derivative of cy-
clohexa-3,5-diene-1,2-diamine. This intermediate can also
be synthesized from anhydride 16. The photooxygenation
of the diene followed by cleavage of the peroxide linkage
would provide the desired compound 14.
Initially, we focused on the synthesis of lactam 15, which
was prepared by the cycloaddition of chlorosulfonyl isocy-
anate (CSI) to cyclohexa-1,4-diene, as described in the lit-
erature.[17] The 1,2-dipolar cycloaddition of CSI took place
stereoselectively to form the cis-configured lactam 15. The
removal of the sulfonyl chloride group was accomplished
by treatment with NaOH. The cleavage of the lactam ring
was achieved by treating with concentrated HCl and heat-
ing at reflux temperature to form amino acid 17 (Scheme 3).
One of the general and versatile methods for the synthe-
ses of acyl azides involves the reaction of an anhydride with
sodium azide. Therefore, the salt of amino acid 17 was first
treated with NaOH and then with ethyl chloroformate to
give anhydride 18. The reaction of anhydride 18 with so-
dium azide in a mixture of acetone and water gave the ex-
pected acyl azide 19 in 69% yield. Upon heating 19 at the
reflux temperature of benzene, isocyanate 20 was formed as
an intermediate. However, it was not possible to isolate 20.
Instead, the imidazolidinone derivative 21 was formed by
an intramolecular attack of the nitrogen atom’s lone pair of
electrons on the carbonyl carbon of the isocyanate. To pre-
vent this intramolecular cyclization reaction, acyl azide 19
was dissolved in ethanol and heated at reflux temperature.
Unfortunately, the cyclization product, imidazolidinone 21,
Scheme 1. Synthesis of diaminoconduritol starting from a carbo-
hydrate using the Ramberg–Backlund rearrangement.
In this paper, we describe the synthesis of a new di-
aminoconduritol, namely, (1R*,4S*,5R*,6R*)-5,6-diamino-
cyclohex-2-ene-1,4-diol (14).
Results and Discussion
Upon examination of the possible synthetic approaches was formed again as the sole product. At this stage, we de-
to the conduritol and various cyclitol derivatives, we de- cided to change our synthetic strategy and apply the second
cided to adapt a pathway previously used in our laboratory, approach, as described in Scheme 2.
that is, the photooxygenation of diene systems, to construct
As an alternate method, the previously known diester
a number of conduritol and cyclitol derivatives.[16] Accord- 22[18] was synthesized by the addition of maleic anhydride
ing to the retrosynthetic analysis shown in Scheme 2, com- to the in situ generated butadiene to give anhydride 16.[19]
pound 14 can be obtained by using two concise approaches Treatment of 16 with methanol in the presence of a catalytic
starting from either 7-azabicyclo[4.2.0]oct-3-en-8-one (15) amount of HCl afforded diester 22, which was successfully
or anhydride 16.
converted into the desired dihydrazide 23 by treatment with
2
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Synthesis of a New 2,3-Diaminoconduritol
Scheme 3. Synthesis of lactam 15 and its conversion to imidazolidinone derivative 21.
hydrazine in methanol (Scheme 4). The resulting compound anol at room temperature. Imidazolidinone derivative 27
23 was treated with NaNO2 and HCl at low temperature to was formed as the sole product. We assume that the initially
give the corresponding diazide 24.[20] Heating 24 in re- formed urethane group blocks the attack of ethanol on the
fluxing benzene gave diisocyanate 25, which was carried isocyanate group. When the reaction was carried out with
onto the next step. Heating a solution of 25 in ethanol at methanol at room temperature, again the cyclization prod-
reflux temperature afforded the two products 26 and 27 in uct 29 was formed as the sole product. In contrast to eth-
57% and 40% yields, respectively. The configuration of the anol, methanol reacted smoothly with diisocyanate 25 at
substituents in 27 was trans and inverted from the cis con- high temperatures, and the desired addition product 28 was
figuration of starting diester 22. The comparison of the formed as the single product. We assume that the pKa val-
NMR spectroscopic data for 27 with those of 21 clearly ues of MeOH (pKa = 15.5) and EtOH (pKa = 15.9) are
indicated that product 27 was a stereoisomer of 21. We as- responsible for the product distribution, as MeOH is more
sume that hydrazine can also act as a base during the hydra- reactive than EtOH.
zination reaction and cause an α-epimerization to occur
For chemical proof of the configuration, bis(urethane)
during the conversion of 22 into 23. The products 26 and derivative 28 was treated with m-CPBA (meta-chloroper-
27 were separated by column chromatography, and their oxybenzoic acid) in dichloromethane at room temperature
structures were determined unambiguously by NMR spec- to give 30 as a single isomer with an unsymmetrical struc-
troscopic data. However, the NMR spectroscopic studies ture (Scheme 5). This indicated the isomeric configuration
did not reveal the exact configuration of the urethane of the urethane substituents. In the case of the substituents
groups in 26. To check the effect of temperature on the in 28 having the cis configuration, two isomeric epoxides
product distribution, diisocyanate 25 was treated with eth- with symmetrical structures would be formed. The most
Scheme 4. Syntheses of bis(urethane) derivatives 26 and 28 and imidazolidinones 27 and 29.
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1
conspicuous features in the H NMR spectrum of 30 are afforded the bicyclic endoperoxide 33 in 82% yield. The
the resonances of the epoxide protons. They appear at δ = diene unit in 32 is symmetric and can be attacked from both
3.16 ppm as a multiplet and 3.08 as a triplet (J = 4.3 Hz). sides to form a single isomer. However, the ten-line 13C
1
The COSY spectrum of 30 shows a strong correlation be- NMR spectrum as well as the H NMR spectrum shows
tween the epoxide protons, clearly indicating that these ep- that the formed compound is not symmetric because of the
oxide resonances arise from a single isomer.
trans configuration of the urethane groups.
Unsaturated bicyclic endoperoxides can easily be con-
verted into the corresponding diols upon treatment with
thiourea under very mild conditions.[22,23] The reaction of
the endoperoxide 33 with thiourea in methanol gave diol
35. The acetylation of the diol in pyridine with acetic anhy-
dride at room temperature afforded diacetate 36 with the
syn configuration (Scheme 7). Finally, 2,3-diaminoconduri-
Scheme 5. Epoxidation of bis(urethane) 28.
After the successful synthesis of bis(carbamate) 28, the tol 37 with all groups deprotected was obtained by hydroly-
next step was the introduction of hydroxy groups to the C- sis of 36 with NaOH followed by treatment with HCl. The
1
2 and C-5 positions in 28. One of the best methods to intro- six-line 13C NMR spectrum as well as the H NMR spec-
duce oxygen functionalities in the cis configuration is trum was in agreement with the proposed structure.
through a photooxygenation reaction of the appropriate
dienes.[22] To synthesize the diene moiety, the double bond
in 28 was brominated at 0 °C to give a single isomer 31
(Scheme 6). The symmetrical structure, confirmed by the
five-line 13C NMR spectrum, was in agreement with the
trans addition of bromine to the double bond in 28. The
bromine can approach the double bond from either the top
or bottom, and there is no differentiation between those
approaches. However, the formed bromonium ion can be
opened in two ways. The bromide anion can attack either
of the two carbon atoms to give an isomeric mixture con-
sisting of 31 and 34 (see Figure 3).
Scheme 7. Synthesis of 2,3-diaminoconduritol 37.
Conclusions
The synthesis of 2,3-diaminoconduritol 37 with the con-
duritol F structure was achieved starting from anhydride
16. The nitrogen functionalities were introduced by the
Curtius rearrangement of the corresponding acyl azides,
Scheme 6. Synthesis of diene 32 and its photooxygenation reaction.
whereas the cis-configured oxygen functionalities were at-
tached to C-1 and C-4 by a photooxygenation of the diene
unit. The cleavage of the oxygen–oxygen bond followed by
hydrolysis of the urethane groups provided 2,3-diaminocon-
duritol 37.
Figure 3. Possible bromine addition products 31 and 34.
Experimental Section
General Methods: Infrared spectra were obtained from solution
We assume that the bromide anion attacks the initially
formed bromonium ion from the less-hindered side to form
31 as the sole product. A DBU-induced (DBU = 1,8-diaza-
(CHCl3) in a cell (0.1 mm) or from KBr pellets using a FT-IR
1
Bruker Vertex 70 instrument. The H and 13C NMR spectroscopic
data were recorded with a Bruker-Biospin (DPX-400) instrument.
The apparent splitting is given in all cases. Column chromatog-
raphy was performed with silica gel (60-mesh, Merck), and TLC
bicyclo[5.4.0]undec-7-ene) HBr elimination furnished sym-
metrical diene 32 in 34% yield. The photooxygenation[22] of
32 in dichloromethane (500 W, projection lamp) at room
temperature using tetraphenylporphyrine as the sensitizer aluminum plates.
was carried out with Merck 0.2 mm silica gel 60 F254 analytical
4
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Synthesis of a New 2,3-Diaminoconduritol
(1R*,6S*)-7-Azabicyclo[4.2.0]oct-3-en-8-one (15): The lactam deriv-
ative 15 was synthesized as described in the literature; m.p. 118–
120 °C (CHCl3, colorless crystals); ref.[17] m.p. 121.5–122.5. 1H
(1S*,2S*)-Cyclohex-4-ene-1,2-dicarbohydrazide (23): Hydrazine
monohydrate (38.22 g, 0.76 mol) was added to a stirred solution of
diester 22[18] (43.22 g, 0.22 mol) in MeOH (75 mL), and the re-
NMR (400 MHz, CDCl3): δ = 6.44 (br. s, 1 H, NH), 5.82–5.75 (m, sulting solution was heated at reflux temperature for 12 h. The sol-
1 H, 4-H), 5.70–5.61 (m, 1 H, 3-H), 3.91 (t, J = 4.8 Hz, 1 H, 6-H), vent was removed in vacuo. The residue was filtered and was
3.29 (t, J = 4.8 Hz, 1 H, 1-H), 2.42–2.22 (m, 2 H, 5-H), 2.15–2.01
(m, 2 H, 2-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.9, 126.0,
124.3, 47.9, 46.9, 27.1, 21.2 ppm.
washed with dichloromethane to give dihydrazide 23 (26.0 g, 59%)
as a white solid; m.p. 230–233 °C (THF); ref.[21] m.p. 236–238 °C.
1H NMR (400 MHz, DMSO): δ = 8.98 (br. s, 2 H, NH), 5.65 (br.
s, 2 H, 4-H and 5-H), 3.8–3.2 (br. s, 4 H, NH2), 2.60–2.44 (m, 2 H,
1-H and 2-H), 2.20–1.95 (m, 4 H, 6-H and 3-H) ppm. 13C NMR
(100 MHz, DMSO): δ = 174.4, 126.3, 45.5, 29.9 ppm.
(1R*,6S*)-6-Aminocyclohex-3-ene-1-carboxylic Acid·HCl (17):
Compound 17 (white solid) was synthesized as described in the
literature.[17c] 1H NMR [400 MHz, DMSO (dimethyl sulfoxide)]: δ
= 8.17 (br. s, 3 H, NH3Cl), 5.70–5.50 (m, 2 H, 3-H and 4-H), 3.58–
3.48 (m, 1 H, 6-H), 3.06–2.97 (m, 1 H, 1-H), 2.44–2.22 (m, 4 H, 2-
H and 5-H) ppm. 13C NMR (100 MHz, DMSO): δ = 173.6, 125.4,
123.0, 45.9, 39.1, 27.5, 24.9 ppm.
(1S*,2S*)-Cyclohex-4-ene-1,2-dicarbonyl Diazide (24): Dihydrazide
23 (6.2 g, 31 mmol) was dissolved in HCl (1 m solution, 100 mL),
and the resulting solution was cooled to 0 °C. To this was added
dropwise at 0–5 °C a solution of NaNO2 (4.3 g, 62 mmol) dissolved
in water (10 mL). The mixture was stirred at this temperature range
for 1 h and then was extracted with diethyl ether (3ϫ75 mL). The
combined ether layers were washed with saturated NaHCO3
(2ϫ50 mL) and brine (50 mL). The organic layer was dried with
MgSO4, and the solvent was evaporated, keeping the temperature
under 30 °C, to give diacyl azide 24 (5.2 g, 24 mmol, 77%) as a
light yellow liquid.[21] 1H NMR (400 MHz, CDCl3): δ = 5.72–5.64
(m, 2 H, 4-H and 5-H), 2.88–2.78 (m, 2 H, 1-H and 2-H), 2.50–
2.38 (br. d, J = 17.9 Hz, 2 H, 3-H and 6-H), 2.20–2.06 (m, 2 H, 3Ј-
H and 6Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 181.7, 124.6,
42.9, 27.7 ppm.
Synthesis of {(1R*,6S*)-6-[(Ethoxycarbonyl)amino]cyclohex-3-en-1-
yl}carbonyl Ethyl Carbonate (18): To a solution of aminocarboxylic
acid 17 (1.16 g, 6.53 mmol) in THF (tetrahydrofuran, 40 mL) and
water (2 mL) was added dropwise a cooled solution of NaOH
(1.04 g, 26.00 mmol) dissolved in minimum amount of water. After
30 min, a cold (0 °C) solution of ethyl chloroformate (4.24 g,
39.07 mmol) in THF (10 mL) was added dropwise over a period of
10 min, and then the reaction mixture was stirred for 4 h in an ice
bath. The reaction mixture was diluted with EtOAc (50 mL), and
the resulting solution was washed with a 10% HCl solution
(3ϫ30 mL). The organic layer was washed with brine (2ϫ20 mL),
dried with MgSO4, and concentrated in vacuo. The residue was
purified by chromatography on a silica gel column (CH2Cl2) to
afford anhydride 18 (1.28 g, 4.48 mmol, 69%) as a white solid; m.p.
132–133 °C (EtOAc/hexane, 4:1). 1H NMR (400 MHz, CDCl3): δ
= 5.63 (apparent t, 2 H, 3-H and 4-H), 5.16 (d, J = 6.3 Hz, 1 H,
NH), 4.40–4.14 (m, 4 H, OCH2), 3.01–2.89 (m, 1 H, 1-H), 2.62–
2.13 (m, 4 H, 2-H, and 5-H), 1.32 (t, J = 7.2 Hz, 3 H, CH3), 1.26
(t, J = 6.5 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
166.2, 154.9, 147.7, 124.0, 123.2, 64.7, 59.9, 45.2, 41.6, 29.3, 24.3,
(4S*,5S*)-4,5-Diisocyanatocyclohexene (25): Diacyl azide 24 (5.2 g,
24 mmol) was dissolved in dry benzene (75 mL), and the resulting
solution was heated to reflux temperature for 90 min. Evaporation
of solvent gave the rearranged product, diisocyanate 25, as light
yellow liquid. The compound was used in the next step without
1
further purification. H NMR (400 MHz, CDCl3): δ = 5.64 (m, 2
H, 1-H and 2-H), 3.73–3.66 (m, 2 H, 4-H and 5-H), 2.63–2.52 (br.
d, A part of AB system, J = 17.5 Hz, 2 H, 3-H and 6-H), 2.28–
2.17 (br. ddd, B part of AB system, J = 17.5, 5.3, and 3.5 Hz, 2 H,
3Ј-H and 6Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 123.7,
55.3, 32.62 ppm.
13.5, 12.9 ppm. IR [ATR (attenuated total reflectance)]: ν = 3340,
˜
3325, 2982, 2934, 1815, 1716, 1514, 1239, 1084, 986 cm–1.
C13H19NO6 (285.29): calcd. C 54.73, H 6.71, N 4.91; found C
54.40, H 7.08, N 4.65.
Reaction of (4S*,5S*)-4,5-Diisocyanatocyclohexene (25) with EtOH
at Reflux Temperature: Diisocyanate 25, obtained from diacyl azide
24 (5.2 g, 23.6 mmol), was dissolved in EtOH (75 mL), and the re-
sulting solution was heated to reflux temperature. After 6 h, the
solvent was evaporated. The crude residue was a mixture of 26
and 27, which were separated by silica gel column chromatography
(CH2Cl2).
Ethyl
(3aR*,7aS*)-2-Oxo-2,3,3a,4,7,7a-hexahydro-1H-benzimid-
azole-1-carboxylate (21): To a solution of anhydride 18 (0.32 g,
1.1 mmol) in acetone (30 mL) at 0 °C was added a solution of so-
dium azide (0.11 g, 1.65 mmol) in water (10 mL). After completion
of the addition, the resulting mixture was stirred for 1 h. Ethyl acet-
ate (30 mL) was added, and the organic phase was separated. The
organic phase was washed with water (2ϫ30 mL) and dried with
MgSO4. After removal of the solvent under reduced pressure, the
residue was dissolved in dry benzene (30 mL), and the resulting
solution was heated at reflux temperature for 2 h. Evaporation of
the solvent yielded imidazolidinone 21 (157 mg, 67%) as a white
solid; m.p. 135–136 °C (hexane/dichloromethane, 7:3). 1H NMR
(400 MHz, CDCl3): δ = 6.83 (s, 1 H, NH), 5.83–5.71 (m, 2 H, 5-H
and 6-H), 4.30–4.14 (m, 3 H, 7a-H and OCH2), 3.93 (q, J = 4.8 Hz,
1 H, 3a-H), 2.36 (dt, A part of AB system, J = 15.6, 5.2 Hz, 1 H,
7-H), 2.28 (dt, B part of AB system, J = 15.6, 5.1 Hz, 1 H, 7Ј-H),
2.24 (dt, A part of AB system, J = 15.3, 5.0 Hz, 1 H, 4-H), 2.14
Diethyl [(1S*,6S*)-Cyclohex-3-ene-1,6-diyl]dicarbamate (26): Com-
pound 26 (white powder, 3.43 g, 13.4 mmol, 57%) was isolated in
the first fraction; m.p. 126–127 °C (EtOAc); ref.[21] m.p. 135–
137 °C. 1H NMR (400 MHz, CDCl3): δ = 5.55 (br. s, 2 H, 3-H and
4-H), 5.20 (br. s, 2 H, NH), 4.04 (q, J = 7.0 Hz, 4 H, OCH2), 3.92
(q, J = 5.8 Hz, 2 H, 1-H and 6-H), 2.47 (br. d, A part of AB system,
J = 16.2 Hz, 2 H, 2-H and 5-H), 1.96 (dd, B part of AB system, J
= 16.3, 5.6 Hz, 2 H, 2Ј-H and 5Ј-H), 1.17 (t, J = 7.0 Hz, 6 H,
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.1, 124.9, 60.9,
51.7, 32.6, 14.6 ppm.
Ethyl
(3aS*,7aS*)-2-Oxo-2,3,3a,4,7,7a-hexahydro-1H-benzimid-
(dt, B part of AB system, J = 15.9, 4.4 Hz, 1 H, 4Ј-H), 1.38 (t, J azole-1-carboxylate (27): Compound 27 (white solid, 1.99 g,
= 7.0 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.4, 9.45 mmol, 40%) was isolated in the second fraction; m.p. 136–
151.9, 127.0, 126.7, 62.2, 54.1, 47.5, 28.5, 26.9, 14.4 ppm. IR
138 °C (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 5.74 (br. s, 1
H, NH), 5.68–5.58 (m, 2 H, 5-H and 6-H), 4.23 (q, J = 7.2 Hz, 2
H, OCH2), 3.56 (dt, J = 10.8, 4.7 Hz, 7a-H), 3.31 (dt, J = 10.9,
5.0 Hz, 1 H, 3a-H), 2.94–2.82 (m, 1 H), 2.44–2.34 (m, 1 H), 2.22–
(ATR): ν = 3307, 3029, 2980, 2909, 1778, 1714, 1318, 1285, 1138,
˜
1099, 778 cm–1. C10H14N2O3 (210.23): calcd. C 57.13, H 6.71, N
13.33; found C 57.12, H 6.42, N 13.38.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Z. Ekmekci, M. Balci
2.02 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR MgSO4. Removal of the solvent gave the crude product, which was
FULL PAPER
(100 MHz, CDCl3): δ = 158.2, 152.9, 125.9, 124.7, 62.7, 59.7, 53.8,
washed with cold EtOAc to give adduct 31 (27.3 g, 81 mmol, 95%)
31.3, 30.9, 14.6 ppm. IR (KBr): ν = 3298, 3022, 2860, 1771, 1687,
as a white solid; m.p. 197–198 °C (EtOH). 1H NMR (400 MHz,
˜
1351, 1321, 1289, 1142, 1152, 1013, 680 cm–1. HRMS (EI): calcd. DMSO): δ = 7.18 (br. s, 2 H NH), 4.56 (br. s, 2 H, 4-H and 5-H),
for C10H14N2O5 [M + H]+ 211.1077; found 211.1085.
3.80–3.68 (br. s, 2 H, 1-H and 2-H), 3.20 (s, 6 H, OCH3), 2.50–2.44
(m, 2 H), 2.03 (br. d, J = 14.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
Dimethyl (1S*,6S*)-Cyclohex-3-ene-1,6-diyldicarbamate (28): Di-
isocyanate 25, obtained from diacyl azide 24 (17.8 g, 81 mmol), was
dissolved in MeOH (150 mL), and the resulting solution was heated
to reflux temperature for 6 h. After evaporation of solvent, the resi-
due was purified (in small portions) by column chromatography
(CH2Cl2) to give bis(urethane) 28 (17.4 g, 87%) as a white solid;
DMSO): δ = 155.8, 50.6, 49.6, 49.3, 33.2 ppm. IR (ATR): ν = 3333,
˜
2943, 1694, 1533, 1288, 1244, 1049, 777 cm–1. HRMS: calcd. for
C10H16Br2N2O4 [M + Na]+ 408.9369; found 408.9335.
Dimethyl [(1R*,2R*)-Cyclohexa-3,5-diene-1,2-diyl]dicarbamate
(32): To a solution of dibromide 31 (3.0 g, 7.73 mmol) in dry benz-
ene (100 mL) was added a solution of 1,8-diazabicyclo[5.4.0]undec-
7-ene (4.73 g, 31.08 mmol) at room temperature. The reaction mix-
ture was heated at reflux for 6 h and then cooled to room tempera-
ture. The solid was removed by filtration, and the solvent was evap-
orated. The residue was dissolved in EtOAc (100 mL), and the re-
sulting solution was extracted with aqueous sodium hydrogen car-
bonate (2ϫ50 mL). The organic phase was dried with MgSO4, and
the solvent was evaporated. The residue was separated by silica gel
column chromatography (EtOAc/CH2Cl2/hexane, 1:2:0.5). The first
fraction was methyl phenylcarbamate[24] (colorless crystals, 109 mg,
9%). The second fraction was identified as diene 32 (colorless crys-
tals, 594 mg, 34%); m.p. 162–163 °C (EtOAc). 1H NMR (400 MHz,
CDCl3): δ = 5.90 (apparent d, A part of AAЈBBЈ system, J =
8.4 Hz, 2 H, 3-H and 4-H), 5.71 (apparent d, B part of AAЈBBЈ
system, J = 8.7 Hz, 2 H, 2-H and 5-H), 5.00 (br. s, 2 H, NH), 4.40
(br. s, 2 H, 1-H and 6-H), 3.61 (s, 6 H, OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.2, 128.7, 125.1, 53.0, 52.3 ppm. IR
1
m.p. 175–176 °C (CH2Cl2). H NMR (400 MHz, CDCl3): δ = 5.53
(br. s, 2 H, 3-H and 4-H), 4.92 (br. s, 2 H, NH), 3.66–3.55 (m, 2
H, 1-H and 6-H), 3.51 (s, 6 H, CH3), 2.52–2.40 (br. d, A part of
AB system, J = 17.3 Hz, 2 H, 2-H and 5-H), 2.03–1.88 (m, B part
of AB system, 2 H, 2Ј-H and 5Ј-H) ppm. 13C NMR (100 MHz,
CDCl ): δ = 157.5, 124.9, 52.2, 51.8, 32.6 ppm. IR (ATR): ν =
˜
3
3305, 2951, 2921, 2843, 1679, 1540, 1281, 1249, 1085, 1059,
669 cm–1. HRMS (EI): calcd. for C10H16N2O4 [M + H]+ 229.1183;
found 229.1185.
Methyl-(3aS*,7aS*)-2-Oxo-2,3,3a,4,7,7a-hexahydro-1H-benz-
imidazole-1-carboxylate (29): Diisocyanate 25, obtained from di-
acyl azide 24 (2.04 g, 9.3 mmol), was dissolved in MeOH (50 mL),
and the resulting solution was stirred at room temperature for 6 h.
After evaporation of solvent, the residue was purified by
chromatography on a silica gel column (CH2Cl2) to give imid-
azolidinone 29 (1.7 g, 8.6 mmol, 93%) as a white solid; m.p. 172–
1
(ATR): ν = 3291, 2991, 1688, 1537, 1263, 1026, 685 cm–1. HRMS:
174 °C (CH2Cl2). H NMR (400 MHz, CDCl3): δ = 5.70–5.58 (m,
˜
calcd. for C10H14N2O4 [M + Na]+ 249.0846; found 249.0828.
2 H, 5-H and 6-H), 5.49 (br. s, 1 H, NH), 3.79 (s, 3 H, OCH3),
3.57 (dt, J = 10.9, 4.9 Hz, 1 H, 7a-H), 3.32 (dt, J = 10.9, 4.9 Hz, 1
H, 3a-H), 2.96–2.86 (m, 1 H, 7-H), 2.43–2.33 (m, 1 H, 7Ј-H), 2.22–
2.05 (m, 2 H, 4-H and 4Ј-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 157.9, 153.4, 125.7, 124.4, 59.6, 53.6, 53.4, 30.9, 30.6 ppm. IR
Dimethyl [(1R*,4R*,5R*,6S*)-2,3-Dioxabicyclo[2.2.2]oct-7-ene-5,6-
diyl]dicarbamate (33): To a stirred solution of 32 (390 mg,
1.72 mmol) in CH2Cl2 (30 mL) was added tetraphenylporphyrine
(TPP, 20 mg). The resulting mixture was irradiated with a lamp
(500 W), as oxygen was passed through the solution. The reaction
mixture was stirred at room temperature for 24 h. After evapora-
tion of solvent (30 °C, 20 Torr), the residue was washed with cold
CH2Cl2 to give endoperoxide 33 (364 mg, 82%) as colorless crys-
(ATR): ν = 3329, 3232, 3029, 2913, 2854, 2246, 1740, 1682, 1318,
˜
1289, 1142, 723 cm–1. HRMS: calcd. for C9H12N2O3 [M + Na]+
219.07401; found 219.0769.
Dimethyl [(1R*,3R*,4R*,6S*)-7-Oxabicyclo[4.1.0]heptane-3,4-diyl]-
dicarbamate (30): To a stirred solution of 28 (500 mg, 2.19 mmol)
in CH2Cl2 (30 mL) was added m-CPBA (60%, 818 mg, 4.38 mmol).
The reaction mixture was stirred at room temperature for 12 h. The
solid matter was removed by filtration, and the filtrate was washed
with saturated NaHCO3 (2ϫ50 mL) and water (50 mL) and then
dried with MgSO4. Removal of the solvent under reduced pressure
gave epoxide 30 (374 mg, 70%) as a white solid; m.p. 192–193 °C
1
tals; m.p. 153–155 °C (EtOH). H NMR (400 MHz, DMSO): δ =
7.93 (d, J = 6.8 Hz, 1 H, NH), 7.40 (d, J = 6.6 Hz, 1 H, NH), 6.82
(t, J = 6.9 Hz, 1 H, 7-H), 6.64 (t, J = 6.4 Hz, 1 H, 8-H), 4.69 (br.
t, J = 4.0 Hz, 1 H, 1-H or 4-H), 4.65 (br. d, J = 6.0 Hz, 1-H or 4-
H) 3.96–3.88 (m, 1 H, 5-H), 3.61 (s, 3 H, OCH3), 3.59 (s, 3 H,
OCH3), 3.56–3.48 (m, 1 H, 6-H) ppm. 13C NMR (100 MHz,
DMSO, ppm): δ = 156.6, 156.1, 132.4, 130.7, 74.7, 71.2, 52.7, 51.4
1
(EtOAc/hexane, 2:1). H NMR (400 MHz, CCl3): δ = 5.01 (br. s, 1
(2 C), 49.0 ppm. IR (ATR): ν = 3328, 2955, 1682, 1526, 1291, 1229,
˜
1033, 941 cm–1. HRMS: calcd. for C10H14N2O6 [M + Na]+
281.0741; found 281.0803.
H, NH), 4.76 (br. s, 1 H, NH) 3.70 (s, 6 H, OCH3), 3.16–3.18 (m,
1-H or 6-H), 3.07 (t, J = 4.3 Hz, 1 H, 1-H or 6-H), 2.54–2.33 (m,
2 H, 5-H), 1.88–1.61 (m, 2 H, 2-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 157.3 (2 C), 52.7, 52.2, 50.9, 50.7, 48.4, 48.3, 31.5,
(1R*,4S*,5S*,6S*)-5,6-Bis[(methoxycarbonyl)amino]cyclohex-2-
ene-1,4-diyl Diacetate (36): To a solution of endoperoxide 33
(364 mg, 1.41 mmol) in MeOH (50 mL) stirred by a magnetic stir
bar was added thiourea (215 mg, 2.82 mmol) at room temperature.
The mixture was stirred at room temperature for 3 h, and the solids
30.9 ppm. IR (ATR): ν = 3301, 2990, 2951, 1681, 1543, 1465, 1312,
˜
1285, 1248, 1090, 652 cm–1. HRMS: calcd. for C10H16N2O5 [M +
H]+ 215.0914; found 215.0950.
Dimethyl [(1S*,2R*,4S*,5S*)-4,5-Dibromocyclohexane-1,2-diyl]- were removed by filtration. Pyridine (10 mL) and Ac2O (3 mL)
dicarbamate (31): To a magnetically stirred solution of 28 (19.5 g,
85.5 mmol) in CH2Cl2 (150 mL) at 0 °C was added dropwise a solu-
tion of bromine (14.4 g, 90 mmol) in CH2Cl2 (25 mL) over a period
of 1 h. The reaction mixture was stirred at room temperature for
an additional 2 h. After completion of the reaction, a saturated
solution of sodium metabisulfite was slowly added to the homogen-
eous mixture at 0 °C to reduce the excess amount of bromine. The
organic phase was separated, washed with water, and dried with
were added to the viscous liquid residue followed by stirring at
room temperature for 12 h. The residue was then quenched with
ice-cold HCl (30 mL), and after stirring for 5 min, the mixture was
extracted with diethyl ether (3ϫ50 mL). The combined organic
phases were washed with a NaHCO3 solution and water and then
dried with MgSO4. After evaporation of solvent, the residue was
purified by silica gel column chromatography (EtOAc/n-hexane,
2:1) to give diacetate 36 (305 mg, 63%) as colorless crystals; m.p.
6
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Synthesis of a New 2,3-Diaminoconduritol
1
Berchtold, A. G. Braun, J. Org. Chem. 1989, 54, 2787–2793; e)
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1955–1977.
180–182 °C (EtOAc/n-hexane, 2:1). H NMR (400 MHz, CDCl3):
δ = 6.08 (ddd, A part of AB system, J = 10.1, 5.0, and 1.7 Hz, 1
H, 2-H), 5.82 (dd, B part of AB system, J = 10.1, 2.0 Hz, 1 H, 3-
H), 5.43 (br. d, J = 9.2 Hz, 1 H, 4-H), 5.32–5.27 (m, 2 H, 1-H and
NH), 5.17 (br. d, 1 H, NH), 4.17 (q, J = 9.5 Hz, 1 H, 5-H), 3.99
(ddd, J = 12.8, 9.5, and 3.7 Hz, 1 H, 6-H), 3.69 (s, 6 H, OCH3), 2.13
(s, 3 H, COCH3), 2.12 (s, 3 H, COCH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.1, 170.0, 158.0, 157.2, 131.6, 126.1, 71.7, 68.4,
[6]
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10050–10067; b) C. Ramstadius, O. Hekmat, L. Eriksson, H.
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52.5, 52.4, 52.3, 52.2, 20.9 (2 C) ppm. IR (ATR): ν = 3327, 2950,
˜
1732, 1694, 1532, 1234, 1040, 920 cm–1. HRMS: calcd. for
C14H20N2O8 [M + Na]+ 367.1119; found 367.1177.
(1R*,4S*,5R*,6R*)-5,6-Diaminocyclohex-2-ene-1,4-diol Dihydro-
chloride (37): To a solution of compound 36 (148 mg, 0.43 mmol)
in MeOH (10 mL) stirred by a magnetic stir bar was added NaOH
(2 m solution, 2 mL) at room temperature. The mixture was stirred
for 12 h. The solid was removed by filtration, and the pH of the
solution was adjusted to pH = 1 by adding HCl (1 m solution).
After the addition of water (10 mL), the aqueous phase was ex-
tracted with EtOAc (3ϫ20 mL). The water phase was evaporated,
and the residue was washed with hot ethanol to give compound 37
1
(39 mg, 42%) as a white solid; m.p. Ͼ 210 °C dec (hot EtOH). H
NMR (400 MHz, D2O): δ = 6.04–5.94 (m, 2 H, 2-H and 3-H), 4.52
(t, J = 4.2 Hz, 1 H, 4-H), 4.45–4.39 (br. d, J = 8.6 Hz, 1 H, 1-H),
3.87 (dd, J = 11.6, 4.2 Hz, 1 H, 5-H), 3.59 (dd, J = 11.6, 8.6 Hz, 1
H, 6-H) ppm. 13C NMR (100 MHz, D2O): δ = 131.5, 126.6, 67.6,
[8]
62.9, 52.3, 50.9 ppm. IR (ATR): ν = 3339, 2845, 1620, 1556, 1514,
˜
1004, 927 cm–1. HRMS: calcd. for C6H13N2O2 [M]+ 145.0972;
found 145.1010.
Supporting Information (see footnote on the first page of this arti-
cle): H and 13C NMR spectra of all new compounds.
1
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We are indebted to the Scientific and Technological Research
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Department of Chemistry at Middle East Technical University, and
the Turkish Academy of Sciences (TUBA) for their financial sup-
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7

Job/Unit: O20582
/KAP1
Date: 25-07-12 10:44:51
Pages: 9
Z. Ekmekci, M. Balci
FULL PAPER
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Received: May 2, 2012
Published Online: ᭿
65, 5973–5976.
8
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/KAP1
Date: 25-07-12 10:44:51
Pages: 9
Synthesis of a New 2,3-Diaminoconduritol
Diaminoconduritol
A new 2,3-diaminoconduritol with the con-
duritol F structure was prepared starting
from the known anhydride 3a,4,7,7a-tetra-
hydroisobenzofuran-1,3-dione, which was
successfully converted into the desired di-
ene with bis(carbamate) functional groups.
The photooxygenation of the diene fol-
lowed by cleavage of the peroxide linkage
and removal of the protecting groups gave
the new 2,3-diaminoconduritol.
Z. Ekmekci, M. Balci* ..................... 1–9
Synthesis of a New 2,3-Diaminoconduritol
with Conduritol F Structure
Keywords: Natural products / Total syn-
thesis / Configuration determination / Re-
arrangement / Oxygenation
Eur. J. Org. Chem. 0000, 0–0
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