Synthesis of (4S,5S)-4,5-O-isopropylidene-cyclopent-2-ene-1-one via the intramolecular Reformatsky reaction

Article abstract of DOI:10.1016/j.tetlet.2008.08.017

Isomeric mixtures of bromo- and iodohydrins produced via bromohydroxylation and iodohydroxylation of exo-methylene derivative 2 undergo an intramolecular aldol cyclization-dehydration sequence under Reformatsky reaction conditions to give cyclopentenone 1

Full text of DOI:10.1016/j.tetlet.2008.08.017

Tetrahedron Letters 49 (2008) 6179–6181
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (4S,5S)-4,5-O-isopropylidene-cyclopent-2-ene-1-one via the
intramolecular Reformatsky reaction
*
Nadezhda A. Ivanova, Zuleykha R. Valiullina, Natal’ya P. Akhmetdinova, Mansur S. Miftakhov
Institute of Organic Chemistry, Ufa Scientific Centre of the Russian Academy of Sciences, 450054, Prosp. Octyabrya, 71, Ufa, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Isomeric mixtures of bromo- and iodohydrins produced via bromohydroxylation and iodohydroxylation
of exo-methylene derivative 2 undergo an intramolecular aldol cyclization–dehydration sequence under
Reformatsky reaction conditions to give cyclopentenone 1.
Received 7 June 2008
Revised 26 July 2008
Accepted 5 August 2008
Available online 8 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
D-Ribose
Bromohydrins
Iodohydrins
Reformatsky reaction
Cyclopentenones
Chiral cyclopentenone 1, its enantiomer, and related structures
are used widely in the synthesis of cyclopentenone antibiotics,1
prostaglandins,2 carbanucleosides,3 etc.4 A number of methods have
been reported for the synthesis of compound 1, for example, early
approaches using cyclopentadiene5 via ( )-1 with further optical
resolution using Johnson’s sulfoximine method,6 Hudlicky’s micro-
biological approach7 involving toluene oxidation to afford the chiral
cis-toluenediol. The most effective approaches to 1, employing nat-
ural chiral pool compounds, were based on the reaction of ribono-
lactone and its derivatives with dimethylmethylphosphonate
anions,8,9 LiAlH(OBu)3,10 etc.11 An extremely convenient and practi-
cal approach to 1 and related structures is based on intramolecular
The formation of minor bicyclic compound 522 in this reaction is
probably the result of a Williamson type of intramolecular ether-
formation of an acyclic form of hemiacetal 3 followed by HBr elim-
ination. The same carbacyclization of separated 3 also led to a mix-
ture of 1 and 5 in the ratio 1.4:1 (HPLC). Under the same conditions
4 gave cyclopentenone 1 only, in a yield of 43%. Attempts to use
CrCl2 and SmI2 instead of Zn in this reaction were unsuccessful.
The preparation of iodo derivatives 6 and 7 considerably im-
proved the transformation of 2?1. Iodohydrins 6 and 7 (Scheme
2) were generated from 2 using 1.5 equiv of I2 in THF–H2O (3:1).
The reaction proceeded rapidly and in quantitative yield. The mix-
ture of 6 and 7 was subjected to the Reformatsky reaction with Zn
in refluxing benzene.23 When all of the iodohydrins 6 and 7 had re-
acted (TLC) the reaction was worked up and the residue was puri-
fied by column chromatography on SiO2. Compounds 1 and 8 were
obtained in yields of 50% and 8%, respectively.
cyclization of the corresponding a,x-diolefins derived from sugars.
The cyclization was promoted with Grubbs’12–16 and Schrock17
catalysts (RCM).
Herewith we report a new and practical method for the synthe-
sis of cyclopentenone 1. The approach is based on the use of an
intramolecular Reformatsky aldol cyclization–dehydration proce-
A possible mechanism for the formation of 8 involves cross-
aldol condensation between ketol 10, a precursor of enone 1, and
lactol 7 followed by elimination of H2O. The structure of 8 was
identified from NOE and COSY studies of acetate 9,24 obtained by
acylation of 8 (Ac2O, Py). The location of the cyclic furanyl frag-
dure of 1,4-dioxo compounds derived from
D-ribose. The initial
exo-methylene derivative 2, easily prepared from
D-ribose, was
transformed via bromohydroxylation (NBS–H2O) to a mixture of
isomeric bromohydrins 3 and 4.18 Treatment of this mixture with
NaI and Zn powder led to a mixture of cyclopentenone 119 and
methoxypyranoside 5 in the ratio 3.2:1 (HPLC) (Scheme 1).20 The
yield of the target product 121 was 40% (calculated based on 2).
ment at C-2 of the enone unit in 8 and 9 was confirmed by the cou-
4
pling constant J3,1 = 1.9 Hz between olefin protons H-3 and H-10.
0
3
0
0
The vicinal constant J1 2 = 4.0 Hz indicates on the cis-orientation
of protons H-10 and H-20 and consequently on the cis-orientation
of cyclic fragments. The observed NOE between protons H-10 and
H-20 (
g
= 4.3%) also confirms their cis-orientation. The arrangement
of the CH2I- and AcO-groups was proposed in accordance with the
NOE ( = 1.9%) observed between the methylene protons of the
* Corresponding author. Tel.: +7 3472 355847; fax: +7 3472 356066.
E-mail address: bioreg@anrb.ru (M. S. Miftakhov).
g
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.017

6180
N. A. Ivanova et al. / Tetrahedron Letters 49 (2008) 6179–6181
O
O
O
OH
OMe
OMe
Br
Br
a
HO
HO
O
O
O
O
O
O
2
4
3
O
O
b
O
OMe
+
O
O
O
O
1
5
Scheme 1. Synthesis of cyclopentenone 1 via bromohydrins 3 and 4. Reagents and conditions: (a) 1.2 equiv NBS, THF–H2O (3:1), 20 °C, 5 min (98%); (b) 1.3 equiv NaI,
2.3 equiv Zn, THF,
D
, 2 h (40% from 2).
O
O
OH
OMe
I
I
a
HO
HO
2
O
O
O
O
7
6
O
O
O
O
I
O
O
O
b
OR
1
+
O
O
Ac2O,
Py
OH
10
8, R=H, 8% from 2
9, R=OAc, 50%
Scheme 2. Synthesis of cyclopentenone 1 via iodohydrins 6 and 7. Reagents and conditions: (a) 1.5 equiv I2, THF–H2O (3:1), 20 °C, 5 min (quant.); (b) 2.3 equiv Zn, C6H6,
3 h (50% from 2).
D,
CH2I- group and proton H-30. The NOE of 9 revealed the interac-
tions as shown in Figure 1, which clearly confirmed the assigned
structure.
toxic organo-phosphorous compounds. In addition, the by-prod-
ucts 5 and 8 are of interest as novel chiral synthetic blocks.
The principal advantages of using 2 as starting material (easily
Acknowledgments
prepared in three steps from D
-ribose18) were the use of inexpen-
sive and available reagents, and mild and simple reaction condi-
tions for the transformation to 1. The synthetic protocol avoids
the use of any explosive and inflammable materials (such as n-BuLi
and O3), as well as expensive organometallics (Ru-catalysts) or
This work was financially supported by the state contract with
Rosnaukoj No. 02.512.12.2015. The authors thank Dr. A. A. Fatyk-
hov, Dr. E. G. Galkin, and Dr. E. M. Vyrupaev for assistance with
spectral studies.
NOE 1.9%
NOE 4.3%
References and notes
1. Ferrier, R. J. Chem. Rev. 1993, 93, 2779.
2. Donaldson, R. E.; Saddler, J. C.; Byrn, S.; McKenzie, A. T.; Fuchs, P. L. J. Org. Chem.
1983, 48, 2167.
O
O
H
H
H
H
I
,
,
O
3. Moon, H. R.; Choi, W. J.; Kim, H. O. Tetrahedron: Asymmetry 2002, 13, 1189.
4. Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99, 779.
5. Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1986, 108, 5655.
6. Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1988, 110, 4726.
7. Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am. Chem. Soc. 1988, 110,
4735.
3
2
,
H
,
,
4
1
5
1
5
4
O
2
O
OAc
3
O
8. Ali, S. M.; Ramesh, K.; Borchardt, R. T. Tetrahedron Lett. 1990, 31, 1509.
9. Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T. J. Org. Chem. 1987, 52, 5457.
10. Belanger, P.; Prasit, P. Tetrahedron Lett. 1988, 29, 5521.
Figure 1. NOE correlations in 9.

N. A. Ivanova et al. / Tetrahedron Letters 49 (2008) 6179–6181
6181
11. Petrignet, J.; Prathap, I.; Chandrasekhar, S.; Sing Vadav, J.; Jrec, R. Angew. Chem.,
Int. Ed. 2007, 46, 6297.
12. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
13. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 425.
(C6), 75.27 (C2), 77.57 (C3), 99.93 (C4), 111.9 (C), 203.2 (C1); MS m/z: M+ (not
observed), 187 (21%, MꢁCH3)+, 171 (3%, MꢁOCH2I)+, 144 (32%,
MꢁCH3ꢁCOCH3)+,
113
[100%,
MꢁOC(CH3)2ꢁCH3],
85
[72%,
MꢁOC(CH3)2ꢁOCOCH3], 59 (21%, CH3OCO), 43 (91%, CH3CO). Anal. Calcd for
14. Lee, K.; Cass, C.; Jacobson, K. A. Org. Lett. 2001, 3, 597.
C9H14O5: C, 53.46; H, 6.98%. Found: C, 53.38; H, 7.09%.
15. Crimmins, M. T.; Tabet, E. A. J. Org. Chem. 2001, 66, 4012.
16. Jin, Y. H.; Chu, C. K. Tetrahedron Lett. 2002, 43, 4141.
17. Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748.
18. Ivanova, N. A.; Valiullina, Z. R.; Shitikova, O. V.; Miftakhov, M. S. Zh. Org. Khim.
(Russ. J. Org. Chem.) 2007, 43, 745.
19. Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.; Chum, M. W.; Moon, H.;
Jung, Y. H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490.
23. Preparation of compound 1 by intramolecular cyclization of iodohydrins 6 and 7:
(a) To a stirred solution of enol-ether 2 (0.20 g, 1.07 mmol) in a mixture of
THF–H2O (3:1, 8 mL) was added iodine (0.35 g, 1.40 mmol). The mixture was
stirred for 5 min (TLC), then the solvent was removed under vacuum and the
product was extracted with CH2Cl2. The combined organic extracts were
washed with a saturated solution of Na2S2O3, brine, dried over Na2SO4, and
concentrated. Flash chromatography of the residue on silica gel column using
petroleum ether–ethyl acetate (95:5?7:3) as a eluent gave a mixture of
methoxy- and oxy-iodohydrins 6 and 7 (0.29 g). (b) To a stirred solution of a
mixture of iodohydrins 6 and 7 (0.29 g) in dry benzene (8 mL) was added Zn
powder (0.17 g, 2.61 mmol) under an argon atmosphere. The reaction mixture
20. Preparation of compound 1 by intramolecular cyclization of bromohydrins 3 and 4:
To a stirred solution of bromohydrins 3 and 4 (0.085 g) in dry THF (8 mL) was
added NaI (0.057 g, 0.39 mmol) under an argon atmosphere. The mixture was
stirred for 10 min, and then Zn powder (0.046 g, 0.69 mmol) was added. The
mixture was stirred under reflux for 2 h, then filtered and concentrated. The
residue was separated by column chromatography on silica gel using
petroleum ether–ethyl acetate (95:5) as the eluent to give cyclopentenone 1
(0.019 g, 40% from 2) and methoxypyranoside 5 (0.011 g, 13% from 2).
was stirred for 2.5
h under reflux, then filtered and the filtrate was
concentrated under vacuum. The product was purified by column
chromatography on silica gel (CH2Cl2) to give cyclopentenone 1 (0.083 g, 50%
from 2) and dimeric compound 8 (0.038 g, 8% from 2).
21. Compound 1: White crystal; mp 66–67 °C (lit.19 68.5–69.5 °C); ½a 2D0
ꢀ
+66.3 (c 1.0,
;
24. Compound 9: ½a 2D0 1730, 1724 cmꢁ1 1H NMR
ꢁ59.9 (1.0, CHCl3); IR (Nujol) m ;
ꢀ
CHCl3) [lit.19 +69.1 (c 1.98, CHCl3)]; IR (Nujol)
m
1720, 1595 cmꢁ1
1H NMR
(300 MHz, CDCl3), d 1.25 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.39 (s,
3H, CH3), 2.10 (s, 3H, CH3), 3.90 (d, 2J = 11.1 Hz, 1H, CH2I), 3.97 (d, 2J = 11.1 Hz,
3
(300 MHz, CDCl3), d 1.42 (s, 6H, CH3), 4.48 (d, J5,4 = 5.5 Hz, 1H, H5), 5.27 (dd,
3
3
3J4,3 = 2.2, J4,5 = 5.5 Hz, 1H, H4), 6.22 (d, J2,3 = 5.9 Hz, 1H, H2), 7.10 (dd,
3J3,4 = 2.2, 3J3,2 = 5.9 Hz, 1H, H3); 13C (75 MHz, CDCl3), d 26.33 (Me), 27.59 (Me),
76.69 (C2), 78.78 (C3), 115.69 (C), 134.49 (C5), 159.83 (C4), 203.17 (C1). Anal.
Calcd for C8H10O3: C, 62.33; H, 6.54%. Found: C, 62.28; H, 6.59%.
1H, CH2I), 4.54 (d, 3J5,4 = 5.4 Hz, 1H, H5), 4.90 (m, 1H, H4), 4.93 (d, 3J3 ,2 = 5.8 Hz,
0
0
0
0
0
1H, H3 ), 5.11 (dd, 3J2 ,3 = 5.8, 3J2 ,1 = 4.1 Hz, 1H, H2 ), 5.25 (m, 1H, H1 ), 7.53 (br
0
0
0
0
s, 1H3); 13C (75 MHz, CDCl3), d 14.17 (CH2I), 21.69 (CH3), 24.610 (CH3), 25.04
0
(CH3), 27.11 (CH3), 27.66 (CH3), 76.95 (C4), 77.35 (C3 ), 80.17 (C2 ), 83.75 (C5),
0
22. Compound 5: Colorless oil; ½a D20
ꢀ
ꢁ3.94 (0.9, CHCl3); IR (Nujol)
m
1743 cmꢁ1
;
1H
109.14 (C1 ), 113.62 (C), 115.55 (C), 141.78 (C2), 155.44 (C3), 169.26 (C@O),
NMR (300 MHz, CDCl3), d 1.38 (s, 3H, CH3), 1.52 (s, 3H, CH3), 3.47 (s, 3H, OCH3),
4.11 (d, 2J = 16.8 Hz, 1H, CH2O), 4.20 (d, 2J = 16.8 Hz, 1H, CH2O), 4.41 (m 2H),
4.78 (br s, 1H); 13C (75 MHz, CDCl3), d 25.3 (CH3), 26.6 (CH3), 56.1 (OCH3), 65.7
200.96 (C1); MS m/z: M+ (not observed), 479 (68.5%, MꢁCH3)+, 434 (100%,
MꢁAcOH)+, 367 (72%, MꢁI)+. Anal. Calcd for C18H23IO8: C, 43.74; H, 4.69; I,
25.67%. Found: C, 43.59; H, 4.80; I, 25.81%.