A concise synthesis of harzialactone A from D-glucose and revision of absolute stereochemistry

Article abstract of DOI:10.1016/S0957-4166(99)00245-1

Synthesis of 2 by a chiron approach is described starting from monoacetone-D-glucose 4. Absolute stereochemistry of natural harzialactone A 1 (2S,4S) is revised to 2 (2R,4R).

Full text of DOI:10.1016/S0957-4166(99)00245-1

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2305–2306
A concise synthesis of harzialactone A from D-glucose and
revision of absolute stereochemistry
Hari Babu Mereyala ∗ and Rajendrakumar Reddy Gadikota
Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 1 April 1999; accepted 7 June 1999
Abstract
Synthesis of 2 by a chiron approach is described starting from monoacetone-D-glucose 4. Absolute stereochem-
istry of natural harzialactone A 1 (2S,4S) is revised to 2 (2R,4R). © 1999 Elsevier Science Ltd. All rights reserved.
Marine organisms have been a useful source of bioactive metabolites with antitumor activity.1 Thus,
among the new antitumor metabolites inhabiting the marine environment harzialactone A 1 was isolated
from a strain of Trichoderma harzianium OUPS-N 115 and characterized.2 Compound 1 was shown
to exhibit weak cytotoxic activity against P 388 lymphocytic leukemia test system in cell culture. In
the course of our long-term program towards the design and synthesis of oxygenated lactones3 with
anticancer activity we targeted the synthesis of (2R,4R)-2 which is an antipode of (2S,4S)-1. We intended
to develop a general synthetic route to prepare 2 and its analogs for studying the structure–activity
relationship starting from easily available homochiral sugars.
Retrosynthetic analysis of the hydroxy furanolactone 2 (Scheme 1) indicated that it could be derived
from diol 3 by regioselective oxidation. Diol 3 in turn could be derived from commercially available
monoacetone-D-glucose 4.
Scheme 1.
Compound 4 was reacted with NaIO4 in CH2Cl2/MeOH/saturated aqueous NaHCO3 solution at room
temperature for 2 h to obtain the aldehyde4 that without purification was immediately reacted with
∗
Corresponding author. E-mail: haribabu@iict.ap.nic.in
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00245-1

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H. B. Mereyala, R. R. Gadikota / Tetrahedron: Asymmetry 10 (1999) 2305–2306
phenylmagnesium bromide at 0°C to obtain a diastereomeric mixture of diol (3:1) 55 in 73% yield
(Scheme 2). Compound 5 was reacted with NaH/CS2/MeI to obtain the methyl xanthate derivative 6 that
was characterized from the 1H NMR spectrum from the appearance of methylthio protons at δ 2.5 (s, 3H)
and δ 2.6 (s, 3H). Compound 6 was reacted with Bu3SnH6 at reflux temperature in toluene containing
a catalytic amount of AIBN for 6 h to obtain dideoxy derivative 7 in 76% yield and was characterized
from the appearance of H-3 at δ 1.6 (m, 1H), δ 2.0 (dd, 1H, Jgem 13.8, J2,3 3.5) and H-5 at δ 2.8 (dd, 1H,
0
Jgem 14.4, J4,5 5.2) and 3.02 (dd, 1H, J4,5 5.3). Compound 7 was treated with 60% aqueous HOAc/cat.
H2SO4 at 45°C for 6 h to obtain diol 3 in 79% yield as a crystalline solid, mp 91–93°C.
Scheme 2. Reagents and conditions: (a) NaIO4, CH2Cl2:MeOH:aq. satd. NaHCO3, 0°C–rt, 2 h; PhMgBr, THF, 0°C–rt, 8 h; (b)
NaH, CS2, MeI, THF, 0°C–rt, 1 h; (c) Bu3SnH, cat. AIBN, toluene, reflux, 6 h; (d) 60% aq. HOAc, cat. H2SO4, 45°C, 6 h; (e)
Ag2CO3/Celite, benzene:DMF, reflux, 1 h
Oxidation of 3 with pyridinium dichromate (PDC) in CH2Cl2 at reflux for 1 h resulted in the formation
of 2 (10%) along with the undesired diketo compound 8 (45%). However, regioselective oxidation of
the C-1 hydroxyl group of 3 was achieved using Ag2CO3/Celite7 to obtain the hydroxy lactone 2 as a
1
crystalline solid, mp 78–79°C (lit. 82–84°C)2 in 71% yield along with 8 in 11% yield. H, 13C NMR,
IR (1769 cm−1) spectroscopic8 data of (2R,4R)-2 were in complete agreement with the reported data of
1, except that it exhibited a positive specific rotation of +38.0 (c 0.3, CHCl3) instead of the expected
negative rotation. We designed the synthesis for the optical antipode of (2S,4S)-1. Compound 1 has been
reported to possess a specific rotation of +33.50 (c 0.3, CHCl3).2 Hence, the natural compound 1 should
have the revised structure 2 based on the chiron approach followed to derive it.
In conclusion, synthesis of harzialactone 2 by a chiron approach has been achieved. The usefulness
of the chiron approach is evident in the assignment of the correct absolute stereochemistry for natural
harzialactone 1. Thus, the stereochemistry of (2S,4S)-1 has been revised to (2R,4R)-2.
Acknowledgements
R.R.G. thanks U.G.C. (New Delhi) for financial assistance.
References
1. Sims, J. J.; Rose, A. F.; Izac, R. R. Mar. Nat. Prod., Chem. Biol. Perspect.; Scheuer, P. J., Ed.; Academic Press: New York,
1978; Vol. 2, p. 297.
2. Amagata, T.; Usami, Y.; Minoura, K.; Ito, T.; Numata, A. J. Antibiot. 1998, 51, 33–40.
3. Mereyala, H. B.; Gadikota, R. R.; Krishnan, R. J. Chem. Soc., Perkin Trans. 1 1997, 3567–3571.
4. Inch, T. D. Carbohydr. Res. 1967, 5, 45–52; Lichtenthaler, F. W.; Jarglis, P.; Lorenz, K. Synthesis 1988, 709–712.
5. Gracza, T.; Jager, V. Synthesis 1994, 1359–1368.
6. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585.
7. McKillop, A.; Young, D. W. Synthesis 1979, 401–422; Trost, B. M.; Klun, T. P. J. Am. Chem. Soc. 1981, 103, 1864–1865.
8. All new compounds gave satisfactory elemental analysis.