The Hetero Diels-Alder reactions between D-mannose-derived halonitroso compounds and cyclopentadiene: Scope and limitations

Full text of DOI:10.1021/jo971696q

J . Org. Chem. 1998, 63, 885-888
885
dium-mediated reaction13-16 on the O-acetate of 4 will
facilitate the synthesis of 4-azacarbocyclic nucleoside
derivatives. Asymmetric synthesis of ent-4 or the related
4-amino-cyclopenten-1-ol system has also been reported15
in the context of synthesis of carbocyclic analogues of
“natural” D-nucleosides. However, recent studies showed
that several L-nucleosides possess activity comparable to
that of D-nucleosides.17 Asymmetric synthesis of 4 would
provide the appropriate intermediate for the synthesis
of carbocyclic L-nucleosides.
Th e Heter o Diels-Ald er Rea ction s betw een
D-Ma n n ose-Der ived Ha lon itr oso
Com p ou n d s a n d Cyclop en ta d ien e: Scop e
a n d Lim ita tion s
Deyi Zhang, Carsten Su¨ling, and Marvin J . Miller*
Department of Chemistry and Biochemistry, University of
Notre Dame, Notre Dame, Indiana 46556
Received September 11, 1997
Resu lts a n d Discu ssion
Hetero Diels-Alder reactions of nitroso compounds
with dienes have attracted great interest.18-20 Among
them, D-mannose-derived chloronitroso compound 5a has
been used in the synthesis of aminocyclitols21 and other
interesting molecules. In a typical case, highly diaste-
reoselective Diels-Alder reaction of 5a with cyclohexa-
diene generated hetero [2.2.2] bicyclic salt 6 in high
enantiomeric purity (eq 1).22-24 While reactions of 5a
In tr od u ction
Carbocyclic nucleosides have shown potential anti-
viral,1-4 antitumor,5,6 and other biological activities. For
example, carbocyclic nicotinamide analogue 17,8 displays
antibacterial and antifungal properties, whereas aris-
teromycin (2)9 and Carbovir (3)10 have potent antiviral
activity. Substantial efforts have been directed toward
the syntheses of carbocyclic nucleosides and related
areas, especially, the development of new methodology
for the synthesis of common intermediates used in
carbocyclic nucleoside syntheses.
with several other dienes were studied, cyclopentadiene
was not among those reported. We decided to explore
the possibility of utilizing this reaction with cyclopenta-
diene to provide an alternate route to 4.
Following literature procedures,25,26 hydroxyimino lac-
tone 7 was obtained in 70% overall yield from D-mannose.
Treatment of 7 with tert-butyl hypochlorite furnished
chloronitroso derivative 5a as a blue solid,22,23 whereas
treatment of 7 with N-bromosuccinimide afforded bro-
monitroso derivative 5b also as a blue solid (Scheme 1).26
With chloronitroso compound 5a in hand, a systematic
study of hetero Diels-Alder reactions with cyclopenta-
Recently, we reported the synthesis of racemic 411 and
ent-4,12 important precursors for the synthesis of many
carbocyclic nucleosides. Compounds 1-3 could be de-
rived from ent-4 by peripheral elaboration. Direct incor-
poration of purines and other bases using Trost’s palla-
(13) Trost, B. M.; Van Vranken, D. L. Chem. Rev. (Washington, D.C.)
1996, 96, 395.
(14) Trost, B. M.; Kuo, G.-H.; Benneche, T. J . Am. Chem. Soc. 1988,
110, 621.
(15) Trost, B. M.; Stenkamp, D.; Pulley, S. R. Chem. Eur. J . 1995,
1, 568.
(1) De Clercq, E. Nucleosides and Nucleotides 1994, 13, 1271.
(2) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1.
(3) Robins, R. K.; Revanker, G. R. in Antiviral Drug Development;
De Clercq, E., Walker, R. T., Eds.; Plenum: New York, 1988; p 11.
(4) Suhadolnik, R. J . Nucleosides as Biological Probe; Wiley: New
York, 1979; p 147.
(5) MacCoss, M.; Robins, M. J . In Chemistry of Antitumor Agents;
Wilman, D. E. V., Ed.; Blackie and Sons: U.K., 1990; p 261.
(6) Vince, R.; Brownell, J .; Daluge, S. J . Med. Chem. 1984, 27, 1358.
(7) Ikbal, M.; Cerceau, C.; Le Goffic, F.; Sicsic, S. Eur. J . Med. Chem.
1989, 24, 415.
(16) Frost, C. F.; Howarth, J .; William, J . M. J . Tetrahedron:
Asymmetry 1992, 3, 1089.
(17) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Zhu, Y.-L.; Gullen, E.;
Dutschman, G. E.; Cheng, Y.-C. J . Med. Chem. 1996, 39, 1757.
(18) Vogt, P. F.; Miller, M. J . Tetrahedron 1998, 54 in press and
references therein.
(19) Gouverneur, V.; Ghosez, L. Tetrahedron 1996, 52, 7585.
(20) Martin, S. F.; Hartmann, M.; J osey, J . A. Tetrahedron Lett.
1992, 33, 3583 and references therein.
(21) Werbitzky, O.; Klier, K.; Felber, H. Liebigs. Ann. Chem. 1990,
267.
(8) Sicsic, S.; Durand, P.; Langrene´, S.; Le Goffic, F. Eur. J . Biochem.
1986, 155, 403.
(9) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J . Am. Chem.
Soc. 1983, 105, 4049.
(22) Felber, H.; Kresze, G.; Braun, H.; Vasella, A. Tetrahedron Lett.
1984, 25, 5381.
(23) Felber, H.; Kresze, G.; Prewo, R.; Vasella, A. Helv. Chim. Acta
1986, 69, 1137.
(10) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17.
(11) Zhang, D.; Ghosh, A.; Su¨ling, C.; Miller, M. J . Tetrahedron Lett.
1996, 37, 3799.
(12) Vogt, P. F.; Hansel, J .-G.; Miller, M. J . Tetrahedron Lett. 1997,
38, 2803.
(24) Braun, H.; Charles, R.; Kresze, G.; Sabuni, M.; Winkler, J .
Liebigs. Ann. Chem. 1987, 1129.
(25) Basha, A.; Henry, R.; McLaughlin, M. A.; Ratajczyk, J . D.;
Wittenberger, S. J . J . Org. Chem. 1994, 59, 6103.
(26) Beer, D.; Vasella, A. Helv. Chim. Acta 1985, 68, 2254.
S0022-3263(97)01696-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

886 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
Sch em e 1
Ta ble 1. Asym m etr ic Heter o Diels-Ald er Rea ction s of 5
Diels-Alder adduct formed had no detrimental effect on
product formation. While solvent variation was found
to affect the diastereoselectivity of the Diels-Alder
reactions (entries 1 and 8), addition of various Lewis
acids had little influence on the diastereoselectivity.
D-Mannose-derived bromonitroso compound 5b was less
stable than its chloronitroso counterpart 5a , and its
Diels-Alder reaction had not been reported previously.
For comparison, the cycloaddition of 5b with cyclopen-
tadiene was also studied briefly (entries 15 and 16).
Interestingly, the diastereoselectivity of the Diels-Alder
reaction decreased with the addition of Lewis acid. Once
bicyclic compound 9 was obtained, reduction of the N-O
bond with Mo(CO)6 provided 4 in moderate yield.27,28
After several attempts, we found that addition of NaBH4
improved the yield of the reduction to 80% and also
simplified the workup.
The enantiomeric excess (ee) of 9 was measured
through chiral shift studies with chiral shift reagent Eu-
(hfc)3 using 1H NMR. The ee value derived from this
study was confirmed by measuring the diastereomeric
ratio of the Mosher esters29 of 4 using 19F NMR (for entry
8). The absolute stereochemistry of the product was
derived based on literature precedent.24 Under the scale
we tested (from 0.5 to 20 g of 5a ), the ee was satisfactory.
However, later, when we scaled up the reaction (50 g of
5a ) under conditions indicated in entry 8, we noticed a
significant drop in diastereoselectivity of the Diels-Alder
reaction as reflected by the low ee of isolated bicyclic
product (44% ee vs 76% measured for 9) under otherwise
similar conditions. The cause of this decrease is unclear
at this time and further investigation of this effect is
needed.
w ith Cyclop en ta d ien e
yield of 9
ee
entry
solvent
Et2O
Et2O
THF
Lewis acid (equiv)
none
ZnCl2 (0.6)
Et2AlCl (0.2)
TiCl4 (1.1)
TiCl4 (1.1)
none
Et2AlCl (0.2)
none
Et2AlCl (0.2)
Ti(OiPr)3Cl (0.3)
Ti(OiPr)4 (0.3)
Ti(OiPr)4/L-DETb (1.0)
Ti(OiPr)4/D-DETb (1.0)
none
from 5 (%) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
49
50
25
67
dec
8a
57
60
73
75
THF
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O/
89
93
76
84
78
76
70
75
74
12a
75
61
76
58
77
80
75
toluene (2:1)
15d toluene
16d toluene
none
Et2AlCl (0.2)
52
60
75
60
a
8 was separated and kept overnight at room temperature
before Boc2O protection. DET ) diethyl tartrate. c Diels-Alder
b
d
reaction temperature was -100 °C. Results from hetero Diels-
Alder reactions utilizing bromonitroso derivative 5b as the dieno-
phile.
diene was undertaken (Table 1). The cycloaddition was
studied under a range of conditions including changes
in reaction temperature, solvent systems, and addition
of Lewis acids as well as the method of product isolation.
As opposed to its [2.2.2] bicyclic counterpart 6, the
resulting [2.2.1] bicyclic salt 8 formed from the reaction
was not stable. Separation of salt 8 and overnight drying
at room temperature resulted in significant decomposi-
tion (entries 6 and 7). Thus, in most cases, the Diels-
Alder reaction product was further protected with Boc2O
to provide 9 which is stable and can be purified. Most of
the reactions were performed at -78 °C. The results
summarized in Table 1 indicate that, in general, the
enantiomeric excess of 9 formed from the reaction of 5
with cyclopentadiene is lower than that reported for the
formation of 6 from cyclohexadiene. Lowering the reac-
tion temperature to -100 °C did not improve the selec-
tivity (entry 14). In most cases, EtOH was added at the
beginning of the Diels-Alder reactions to facilitate
release of the chiral auxiliary. However, in a control
reaction, delayed addition of EtOH until after the initial
The significant difference in the diastereoselectivity
between the reaction of 5a with cyclopentadiene and
cyclohexadiene promoted us to further examine the latter
reaction. Following the literature procedure,22,23 com-
pound 6 was obtained in 71% yield and this salt was quite
stable. More importantly, one-pot protection with Boc2O
of the Diels-Alder adduct 6 without prior separation
(27) Cicchi, S.; Goti, A.; Brandi, A.; Guaran, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351.
(28) Ritter, A. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4602.
(29) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 887
1162 (br), 844 cm-1; HRMS [MH+] calcd for C10H16NO3 198.1130,
found 198.1135. Anal. Calcd for C10H15NO3: C, 60.90; H, 7.67;
N, 7.10. Found: C, 60.75; H, 7.84; N, 7.02.
Sch em e 2
(1R,4S)-4-(N-ter t-Bu tylcar bam oyl)-2-cyclopen ten -1-ol (4).
To a solution of 9 (570 mg, 2.89 mmol) in CH3CN-H2O (23 mL,
7:1) was added Mo(CO)6 (1.19 g, 4.5 mmol). After 10 min, NaBH4
(57 mg, 1.5 mmol) was added to the reaction mixture and the
mixture was refluxed for 2 h. The solid was filtered off. After
removal of all the solvent in vacuo, the black slurry was
chromatographed (EtOAc:hexanes 3:2) to give 4 (460 mg, 80%)
as a white solid: mp 64-65.5 °C; 1H NMR (CDCl3) δ 1.44 (s,
9H), 1.53 (m, 1H), 2.72 (dt, J ) 14.4, 7.8 Hz, 1H), 3.32 (br, 1H),
4.44 (m, 1H), 4.68 (m, 1H), 5.01 (d, J ) 8.4 Hz, 1H), 5.84 (m,
1H), 5.97 (dt, J ) 5.7, 1.8 Hz, 1H); 13C NMR (CDCl3) δ 28.37,
41.34, 54.81, 75.09, 79.53, 134.15, 136.00, 155.25; IR (KBr) 3330,
2985, 1680 (br), 1510 cm-1; HRMS [MH+] calcd for C10H18NO3
200.1287, found 200.1289. Anal. Calcd for C10H17NO3: C, 60.32;
H, 8.60; N, 7.03. Found: C, 60.29; H, 8.70; N, 7.04.
(1R,4S)-N-(ter t-Bu toxycar bon yl)-3-aza-2-oxabicyclo[2.2.2]-
oct-5-en e (10). Following the general procedure, compound 10
was obtained as a colorless oil: 1H NMR (CDCl3) δ 1.31-1.54
(m, 2H), 1.46 (s, 9H), 2.05-2.24 (m, 2H), 4.73 (m, 2H), 6.55 (m,
2H); 13C NMR (CDCl3) δ 20.47, 23.51, 28.09, 50.04, 70.57, 81.44,
131.48, 131.63, 157.61; IR (neat) 2968, 2940, 1737, 1696, 1370,
1162 cm-1; HRMS [MH+] calcd for C11H18NO3 212.1287, found
212.1279. Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63.
Found: 62.35; H, 7.96; N, 6.74.
provided the desired protected bicyclic derivative 10 in
very high yield (80%) as well as high ee (>90%) in either
toluene or chloroform as the Diels-Alder reaction sol-
vent. The only difference was that, at -78 °C, the
reaction in toluene proceeded much slower than that in
chloroform. These results independently confirmed the
previous report and further demonstrated that the dienes
used in this type of reaction significantly affect the
diastereoselectivity of the reactions. In a related study,
another chloronitroso analogue 14 with diols protected
as the cyclohexanone adducts was also synthesized from
1130,31 (Scheme 2). Unfortunately, its Diels-Alder reac-
tion with cyclopentadiene only afforded similarly moder-
ate diastereoselectivity (70% ee).
In conclusion, we explored novel hetero Diels-Alder
reactions between D-mannose-derived halonitroso com-
pounds and cyclopentadiene. Interestingly, the diaste-
reoselectivity of the hetero Diels-Alder reaction between
5a and cyclopentadiene is not as high as originally
expected on the basis of related studies with cyclohexa-
diene. However, this methodology provided an effective
and novel alternate route to 4, an important intermediate
for syntheses of carbocyclic nucleoside and other func-
tionally rich small molecules.
2,3:5,6-Di-O-cycloh exylid en e-D-m a n n ose Oxim e (12). A
250 mL round-bottom flask was charged with ethanol (60 mL),
lactol 1130,31 (7.48 g, 22 mmol), NH2OH‚HCl (2.45 g, 35.2 mmol),
and NaOAc (2.95 g, 36 mmol), and the reaction was stirred at
60 °C for 1.5 h. The ethanol was removed in vacuo and the
residue was partitioned between EtOAc and saturated aqueous
NaHCO3. The organic layer was separated, and the aqueous
layer was extracted with EtOAc once. The combined organic
layers were washed with saturated NaHCO3 and brine and dried
over Na2SO4. Filtration and concentration afforded a white
solid. Recrystalization (hexanes) afforded 12 (6.88 g, 88%) as
white crystals: mp 144-145.5 °C; 1H NMR (DMSO-d6) δ 1.33-
1.67 (m, 20 H), 3.14 (t, J ) 7.5 Hz, 1H), 3.84-3.93 (m, 3H), 4.50
(d, J ) 8.1 Hz, 1H), 4.61 (d, J ) 7.5 Hz, 1H), 5.16 (dd, J ) 4.0,
7.5 Hz, 1H), 6.92 (d, J ) 3.9 Hz, 1H), 11.11 (s, 1H); 13C NMR
(DMSO-d6) δ 23.44, 23.65, 23.70, 24.65, 24.73, 33.91, 34.60,
35.30, 36.28, 65.69, 69.46, 71.39, 75.23, 76.57, 108.62, 108.75,
149.93; IR (KBr) 3372, 1451 cm-1; HRMS [MH+] calcd for C18H30
-
NO6 356.2073, found 356.2047. Anal. Calcd for C18H29NO6: C,
60.83; H, 8.22; N, 3.94. Found: C, 60.85; H, 8.11; N, 4.02.
2,3:5,6-Di-O-cycloh exylid en e-1-C(h yd r oxyim in o)-D-m a n -
n ofu r a n ose (13). To a stirred solution of oxime 12 (5.80 g, 16.3
33
mmol) in methanol was added freshly made MnO2 (5.35 g, 61
mmol), and the reaction was stirred at rt. The mixture was
filtered through Celite, and the solvent was removed in vacuo.
The residue was dissolved in CH2Cl2 and washed with 1 M citric
acid aqueous solution and brine. The organic layer was stirred
at rt overnight. Concentration provided a white solid. Recrys-
talization (CH2Cl2-hexanes) afforded 13 (5.0 g, 89%) as a white
solid: mp 165-167 °C; 1H NMR (DMSO-d6) δ 1.33-1.55 (m,
20H), 3.85 (dd, J ) 5.1, 8.4 Hz, 1H), 4.03 (dd, J ) 6.3, 8.4 Hz,
1H), 4.33 (pseudo-q, J ) 5.8 Hz, 1H), 4.38 (dd J ) 3.6, 6.6 Hz,
1H), 4.75 (dd, J ) 3.3, 5.7 Hz, 1H), 5.12 (d, J ) 5.7 Hz, 1H),
9.80 (s, 1H); 13C NMR (DMSO-d6) δ 23.42, 23.45, 23.55, 23.63,
24.32, 24.59, 34.32, 34.85, 35.74, 35.98, 65.06, 72.34, 76.82, 77.01,
81.27, 108.80, 112.96, 155.45; IR (KBr) 3409, 1692 cm-1; HRMS
[MH+] calcd for C18H28NO6 354.1916, found 354.1904. Anal.
Calcd for C18H27NO6: C, 61.17; H, 7.70; N, 3.96. Found: C,
61.30; H, 7.58; N, 3.89.
2,3:5,6-Di-O-cycloh exyliden e-1-C-n itr oso-r-D-m an n ofu r a-
n osyl Ch lor id e (14). To a solution of 13 (4.23 g, 12 mmol) in
CH2Cl2 at -10 °C was added dropwise a solution of t-BuOCl in
CH2Cl2 in 20 min. The solution was stirred further for 40 min
at -10 °C. Concentration provided crude product as an oil.
Chromatography (EtOAc:hexanes 1:5) afforded 14 (4.56 g, 98%)
as a blue thick oil: 1H NMR (CDCl3) δ 1.22-1.67 (m, 20H), 4.05
Exp er im en ta l Section
Gen er a l m eth od s have been described previously.32
Gen er a l P r oced u r e for Diels-Ald er Rea ction . To a
solution of chloronitroso compound 5a 22,23 in toluene at -78 °C
were added cyclopentadiene (3 equiv), Lewis acid (if necessary),
and EtOH (10 equiv). The blue solution was stirred at -78 °C
until the color disappeared. The solution was adjusted to pH
8-9 using aqueous 1 M NaHCO3 and the reaction temperature
was allowed to raise to 0 °C. To this mixture was added the
solution of Boc2O (1.2 equiv) in THF, and the reaction was stirred
overnight at 0 °C. After removal of THF, the mixture was
extracted with EtOAc and the combined organic layers were
washed with brine and dried. Filtration and concentration in
vacuo gave the crude product. Flash chromatography (EtOAc:
hexanes 2:3) afforded 9 as a white solid: mp 47-49 °C; 1H NMR
(CDCl3) δ 1.47 (s, 9H), 1.73 (d, J ) 8.4 Hz, 1H), 1.99 (dt, J )
8.4, 2.0 Hz, 1H), 4.98 (br, 1H), 5.21 (m, 1H), 6.41 (m, 2H); 13C
NMR (CDCl3) δ 27.98, 47.96, 64.84, 81.81, 83.36, 132.76, 133.94,
158.37; IR (KBr) 2982, 1739 (br), 1700, 1370, 1332, 1286, 1252,
(30) Guthrie, R. D.; Honeyman, J . J . Chem. Soc. 1959, 853.
(31) Kasahara, K.; Iida, H.; Kibayashi, C. J . Org. Chem. 1989, 54,
2225.
(33) Attenburrow, J .; Cameron, A. F. B.; Chapman, J . H.; Evans,
R. M.; Hems, B. A.; J ansen, A. B. A.; Walker, T. J . Chem. Soc. 1952,
1094.
(32) Teng, M.; Miller, M. J . J . Am. Chem. Soc. 1993, 115, 548.

888 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
(dd, J ) 1.8, 9.0 Hz, 1H), 4.13 (dd, J ) 6.3, 9.0 Hz, 1H), 4.27
(dd, J ) 3.6, 7.5 Hz, 1H), 4.51-4.57 (m, 1H), 4.97 (dd, J ) 3.6,
5.4 Hz, 1H), 5.52 (d, J ) 5.4 Hz, 1H); 13C NMR (CDCl3) δ 23.51,
23.60, 23.84, 24.04, 24.72, 25.07, 34.35, 34.68, 35.03, 36.52, 66.16,
71.79, 78.79, 82.51, 84.49, 110.20, 115.80, 125.45; IR (neat) 1578,
1450 cm-1; HRMS [MH+] calcd for C18H27ClNO6 388.1527, found
388.1530.
facilities of the Lizzadro Magnetic Resonance Research
Center at the University of Notre Dame are appreciated.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 14 (2 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en ts. We gratefully acknowledge the
NIH and the Reilly Fellowship at the University of
Notre Dame (D.Z.) for support of this research. The
J O971696Q