Synthesis of enantiomeric cyclosarcomycins

Article abstract of DOI:10.1016/j.mencom.2010.01.006

Based on chiral cyclopentene blocks 2 and 3, enantiomeric cyclosarcomycins 4 and 5 were obtained and characterised.

Full text of DOI:10.1016/j.mencom.2010.01.006

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 15–16
Synthesis of enantiomeric cyclosarcomycins
Airat M. Gimazetdinov,* Tat’yana V. Gimazetdinova and Mansur S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054 Ufa, Russian
Federation. Fax: + 7 347 235 6066; e-mail: airopet@yandex.ru
DOI: 10.1016/j.mencom.2010.01.006
Based on chiral cyclopentene blocks 2 and 3, enantiomeric cyclosarcomycins 4 and 5 were obtained and characterised.
Chiral cyclopentene blocks are important building templates at
O
the synthesis of cyclopentenone antibiotics, prostaglandins, carba-
nucleosides, etc.1–4 Earlier, we have developed a practical path-
way to produce diastereomeric cyclopentene 2 and 35 from
available bicycle 1 and (+)-α-methylbenzylamine. Here, we
consider the developed conversion of 2 and 3 into enantiomeric
cyclosarcomycins 4 and 5. Cyclosarcomycin 4 is a stable pre-
cursor of natural cyclopentanoid, sarcomycin A 6.
N
Ph
i, ii
H
2
H2B
Ph
O
A
O
O
iii
iv
N
H
(–)-4
O
O
O
O
HO
OH
HO
O
NH
OH
Ph
NH
OH
Ph
8
10
Cl
Cl
( )-1
2
3
N
Ph
O
O
O
i, ii
H
3
O
O
O
O
H2B
Ph
O
CO2H
B
O
O
O
O
4
5
6
7
iii
iv
N
(+)-5
Figure 1 Structures of basic initial and target compounds.
O
H
HO
OH
HO
Firstly, (–)-R-sarcomycin A 6 was isolated from soil micro-
organisms Streptomyces erythrochromogenes in 1954.6 It pos-
sesses antibiotic and antitumor properties and is used in Japan
for the chemotherapy of tumoral diseases.7
There are many publications on the synthesis of (–)- and
( )-6, esters, nor- and homoanalogues, cyclosarcomycin, dihydro-
sarcomycin, etc.8–13
The regioselective introduction of the oxo function into a
cyclopentene ring is a principal problem of the approaches to
cyclosarcomycins 4 and 5 from cyclopentenes 2 and 3. To
resolve this problem, we propose the hydroboration–oxidation
process directly with borane. In this case, the hydroxyl-directed14
intramolecular hydroboration becomes possible (Scheme 1).
Note that, for the similar synthesis of racemic 6 from lactone
7, Hudlicky also used the tandem reactions of hydroboration–
oxidation and oxidation by the Jones reagent to introduce the
oxo function.15 However, in this case, the regioselectivity of
hydroboration was low, and a significant amount of useless
regioisomeric ketone was formed in addition to product 6.
As it was expected, the hydroboration–oxidation reactions of
compounds 2 and 3 proceeded to form only diols 8 and 9.†,‡ The
acidic hydrolysis of compounds 8 and 9 gave hydroxylactones
10 and 11, respectively.§ The following oxidation by pyridinium
chlorochromate led to expected optically pure (–)- and (+)-cyclo-
9
11
Scheme 1 Synthesis of cyclosarcomycins 4 and 5. Reagents and condi-
tions: i, BH3·THF, THF, 1 h; ii, 20% NaOH, 35% H2O2, 3 h, 90–92%;
iii, 9 N H2SO4–dioxane (1:2), reflux, 4 h, 83–86%; iv, PCC, CH2Cl2, room
temperature, 4 h, 74–77%.
sarcomycins 4 and 5 (Scheme 1),¶ which can be transformed
into (–)- and (+)-sarcomycins 6 using known methods.
This work was supported by state contract no. 02.512.12.2015.
†
Typical procedure for the synthesis of amidodiols 8 and 9. Amido-
alcohol 2 (500 mg, 2 mmol) in 15 ml of dry THF was cooled to 0 °C
under argon and treated dropwise with 4 ml of a 1 M solution (2 equiv.)
of a borane–THF complex. The cooling bath was removed after the
addition (2 min), and the mixture was stirred at room temperature for
2 h, whereupon excess BH3 was decomposed by the addition of 1 ml of
H2O. The reaction mixture was cooled in ice, 1.2 ml of 3 M NaOH solu-
tion was added followed by 1 ml of 30% H2O2, and the entire mixture
was then heated at 50 °C for 1 h. The reaction mixture was cooled, acidified
with 2 ml of 3 M HCl, and stirred at room temperature for 0.5 h, then it
was partitioned between brine and diethyl ether and extracted. The organic
layers were combined, dried, and evaporated to give an oil, which was
chromatographed [15 g of silica, CHCl3:MeOH (10:1)] to give 480 mg
(92%) of amidodiol 8.
– 15 –
© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 15–16
4
5
6
7
8
(a) S. W. Li and R. A. Batey, Chem. Commun., 2007, 3759; (b) J. Toueg
and J. Prunet, Org. Lett., 2008, 10, 45.
A. M. Gimazetdinov, N. S. Vostrikov and M. S. Miftakhov, Tetrahedron:
Asymmetry, 2008, 19, 1094.
Antibiotics. Mechanism of Action, eds. D. Gottlieb and P. D. Shaw,
Springer-Verlag, New York, 1967, vol. 1, p. 156.
S. Kondo, H. Hakamura, Y. Ikeda, H. Haganawa, K. Maeda and
References
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‡
(1R,2S,3S)-3-Hydroxy-2-(hydroxymethyl)-N-(1-phenylethyl)cyclopent-
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anecarboxamide 8: yellow crystalline solid, yield 92%, mp 97–99 °C,
[a]1D6 +47.5 (c 1.25, CH2Cl2). IR (Nujol mull, n/cm–1): 3307, 2968, 2870,
1632, 1533, 1369, 1236, 1045, 696. 1H NMR (300 MHz, CDCl3) d: 1.45
(d, 3H, Me, J 7.1 Hz), 1.86–2.18 (m, 5H, 2-H, 4-H and 5-H), 2.89 (q,
1H, 1-H, J 8.3 Hz), 3.49 (d, 2H, OH and CH2–O, J 5.3 Hz), 3.54–3.63
(br. s, 2H, OH and CH2–O), 4.22 (q, 1H, 3-H, J 5.3 Hz), 5.05 (quint.,
1H, CH–Ph, J 7.1 Hz), 6.56 (d, 1H, N–H, J 7.1 Hz), 7.22–7.33 (m, 5H,
HPh). 13C NMR (75 MHz, CDCl3) d: 21.65 (Me), 26.83 (C-5), 33.63 (C-4),
46.25 (C-1), 48.96 (CHPh), 52.56 (C-2), 61.83 (CH2O), 75.69 (C-3), 126.10,
127.36, 128.63, 143.09 (Ph), 174.25 (C=O). MS (APCI), m/z (%): 264
[MH+] (100), 246 (98.5), 228 (8.6). Found (%): C, 68.27; H, 7.63; N, 5.09.
Calc. for C15H21NO3 (%): C, 68.44; H, 7.98; N, 5.32.
9
10 (a) J. N. Marx and G. Minaskanian, Tetrahedron Lett., 1979, 20, 4175;
(b) A. Misumi, K. Furuta and H. Yamamoto, Tetrahedron Lett., 1984,
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Chem., 1988, 53, 611.
(1S,2R,3R)-3-Hydroxy-2-(hydroxymethyl)-N-(1-phenylethyl)cyclopent-
anecarboxamide 9: white crystalline solid, yield 90%, mp 104–106 °C,
[a]1D6 +78.1 (c 0.965, CH2Cl2). IR (Nujol mull, n/cm–1): 3296, 2964, 2872,
1635, 1533, 1368, 1237, 1045, 693. 1H NMR (300 MHz, CDCl3) d: 1.45
(d, 3H, Me, J 6.9 Hz), 1.82–2.16 (m, 5H, 2-H, 4-H and 5-H), 2.89 (q,
1H, 1-H, J 8.5 Hz), 3.63 (d, 2H, OH and CH2–O, J 5.6 Hz), 3.78–3.98
(br. s, 2H, OH and CH2–O), 4.23 (q, 1H, 3-H, J 6.1 Hz), 5.04 (quint.,
1H, CH–Ph, J 6.9 Hz), 6.82 (d, 1H, N-H, J 6.9 Hz), 7.21–7.35 (m, 5H,
HPh). 13C NMR (75 MHz, CDCl3) d: 21.93 (Me), 26.64 (C-5), 33.57 (C-4),
46.11 (C-1), 49.00 (CHPh), 52.54 (C-2), 61.91 (CH2O), 75.51 (C-3),
126.14, 127.39, 128.72, 143.16 (Ph), 174.32 (C=O). MS (APCI), m/z
(%): 264 [MH+] (100), 246 (91.8), 228 (10.2). Found (%): C, 68.19; H,
7.74; N, 5.14. Calc. for C15H21NO3: C, 68.44; H, 7.98; N, 5.32.
11 (a) I. Ikeda and K. J. Kanematsu, J. Chem. Soc., Chem. Commun.,
1995, 453; (b) K. Königsberger and H. Griengl, Bioorg. Med. Chem.,
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R. Furstoss, Tetrahedron Lett., 1997, 38, 825; (d) G. Linz, J. Weetman,
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§
General procedure for the synthesis of compounds 10 and 11. 9 N solu-
tion of H2SO4 (1 ml) was added to a stirred solution of amidodiol 9
(100 mg, 0.4 mmol) in dioxane (2 ml) at room temperature. The mixture
was refluxed for 3 h and monitored by TLC (ethyl acetate–light petroleum,
1:1), cooled to room temperature, and concentrated in a vacuum. The
residue was diluted with water (4 ml) and extracted with diethyl ether
(3×7 ml). The combined extracts were washed with saturated brine, dried
over Na2SO4 and concentrated in a vacuum. Purification of the products
by column chromatography (ethyl acetate–light petroleum, 1:1) afforded
hydroxylactone 11 (45 mg, 83%) as a white crystalline solid.
Received: 2nd September 2009; Com. 09/3385
¶
General procedure for the synthesis of compounds 4 and 5. Solid
pyridinium chlorochromate (PCC) (604 mg, 2.8 mmol) was added to a
solution of hydroxylactone 11 (200 mg, 1.4 mmol) in CH2Cl2 (15 ml) at
room temperature. After stirring for 4 h, Et2O (20 ml) was added and the
reaction mixture was filtered on a pad of Celite, and concentrated. The
residue was purified by column chromatography on SiO2. Elution with
hexane–EtOAc (1:1) gave ketolactone 5 as a white crystalline solid.
(3aR,6aS)-Tetrahydro-1H-cyclopenta[c]furan-1,4(3H)-dione 5: yield 74%,
mp 58–60 °C, [a]1D6 +362.5 (c 1.17, CH2Cl2). IR (Nujol mull, v/cm–1):
2955, 2920, 2853, 1759, 1735, 1456, 1379, 1169, 1119, 1024, 952. 1H NMR
(300 MHz, CDCl3) d: 2.17–2.57 (m, 4H, 5-H and 6-H), 2.97–3.07 (m,
1H, 3a-H), 3.37–3.45 (m, 1H, 6a-H), 4.42 (dd, 1H, 3-H, J 7.5, 9.5 Hz),
4.48 (dd, 1H, 3-H, J 2.2, 9.5 Hz). 13C NMR (75 MHz, CDCl3) d: 23.60
(C-6), 36.51 (C-5), 41.45 (C-6a), 47.71 (C-3a), 68.67 (C-3), 178.27 (C-1),
216.92 (C-4). MS (APCI), m/z (%): 139 [MH+] (100). Found (%): C, 59.73;
H, 5.63. Calc. for C7H8O2 (%): C, 59.99; H, 5.75.
(3aR,4R,6aS)-4-Hydroxyhexahydro-1H-cyclopenta[c]furan-1-one 11:
yield 83%, mp 76–78 °C, [a]1D6 +81.0 (c 1.15, CH2Cl2). IR (Nujol mull,
n/cm–1): 3323, 2962, 2922, 2853, 1737, 1458, 1387, 1194, 1146, 1037,
1
962. H NMR (300 MHz, CDCl3) d: 1.62–1.87 (m, 2H, 5-H and 6-H),
2.01–2.12 (m, 1H, 5-H), 2.18–2.36 (m, 1H, 6-H), 2.82–2.93 (m, 1H, 3a-H),
2.94–3.04 (br. s, 1H, OH), 3.15 (td, 1H, 6a-H, J 2.3, 9.0 Hz), 4.03 (dd,
1H, 3-H, J 3.7, 9.5 Hz), 4.15–4.21 (m, 1H, 4-H), 4.49 (t, 1H, 3-H, J 9.5 Hz).
13C NMR (75 MHz, CDCl3) d: 27.86 (C-6), 34.05 (C-5), 43.03 (C-6a),
48.00 (C-3a), 70.62 (C-3), 79.05 (C-4), 180.82 (C=O). MS (APCI), m/z (%):
143 [MH+] (100), 125 (9.3). Found (%): C, 58.97; H, 6.93. Calc. for
C7H10O2 (%): C, 59.15; H, 7.04.
– 16 –