Synthesis and absolute configuration of lactone II isolated from Streptomyces sp. Go 40/10

Article abstract of DOI:10.1039/b104920h

All four possible stereoisomers of lactone II isolated from Streptomyces sp. Go 40/10, an autoregulator, have been efficiently synthesized in a stereoselective manner starting from (S)-malic acid and sorbic acid, and the absolute configuration was determined to be 2S, 3S, 9R, 10S.

Full text of DOI:10.1039/b104920h

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Synthesis and absolute configuration of lactone II isolated from
Streptomyces sp. Go 40/10
Toshihiko Ueki, Yoshiki Morimoto and Takamasa Kinoshita*
Department of Chemistry, Graduate School of Science, Osaka City University, Sugimoto-cho,
Sumiyoshi-ku, Osaka 558-8585, Japan. E-mail: takamasa@sci.osaka-cu.ac.jp
Received (in Cambridge, UK) 5th June 2001, Accepted 8th August 2001
First published as an Advance Article on the web 3rd September 2001
All four possible stereoisomers of lactone II isolated from
Streptomyces sp. Go 40/10, an autoregulator, have been
efficiently synthesized in a stereoselective manner starting
from (S)-malic acid and sorbic acid, and the absolute
configuration was determined to be 2S, 3S, 9R, 10S.
Lactone II 1, which contains a highly oxidized g-butyrolactone
including a conjugated epoxy enone, was isolated1 from
Streptomyces sp. Go 40/10 in 1999 (Scheme 1). The ster-
eochemistry of the epoxide was proposed to be cis by
spectroscopic analysis; however, the relative, as well as the
absolute configurations of the four stereocenters remain
unknown. The synthesis of all four possible stereoisomers (1a,
1b, 2a and 2b) of lactone II was therefore undertaken to
determine the absolute configuration and to provide samples for
further biological assay. Our synthetic plan is illustrated in
Scheme 1. Lactone part A and epoxy acid part B were derived
from commercially available (S)-malic acid and sorbic acid,
respectively.
The synthesis of parts A and B are outlined in Schemes 2 and
3. (S)-Malic acid was converted into 3 according to the known
procedure.2 Reduction of the ester group with LiAlH4, followed
by acid hydrolysis and protection of the hydroxy group with p-
anisaldehyde gave an alcohol 5, which was submitted to the
Dess–Martin and sodium chlorite oxidation and subsequent
acid-catalyzed deprotection to afford the cis-g-butyrolactone 6a
(mp 85–86 °C; [a]2D9 +44.1 (c 1.0, CHCl3). By reductive
deoxygenation (via mesylate) of the hydroxy group, lactone 6a
was converted to the known compound 7 [overall 22.6% yield
from (S)-diethyl malate].3 THP protection4 of the hydroxy
Scheme 2 Reagents and conditions: i, LDA, ClCH2OCH2Ph, HMPA, THF,
group of (2S, 3S)-6a gave separable diastereomeric isomers 6b
(6+5). After separation an isomer was transformed into the
mixture of lactone alcohols 8a and 8b.5 The epoxy acid part was
efficiently prepared from methyl sorbate with AD-mix-a
according to the Sharpless method,6 the diol ester 9 was
converted by the usual procedure into 10b (Scheme 3).
Deprotection of the hydroxy groups with tetrabutylammonium
fluoride yield the epoxy ester 11. Successful hydrolysis of 11
with potassium trimethylsilanolate afforded (4R, 5S)-12a7
without complication.
278 °C to RT; ii, (a) LiAlH4, EtO2; (b) HCl, MeOH–H2O; iii, ZnCl2,
MeOC6H4CHO, Et2O, MS 4Å; iv, (a) Dess–Martin periodinane, CH2Cl2;
(b) NaCIO2, NaH2PO4, t-BuOH–H2O; (c) HCl, dioxane; v, (a) MsCl, Et3N,
CH2Cl2; (b) Zn, NaI, DME, 85 °C; vi, dihydropyran, CSA; vii, H2, Pd–C,
EtOH.
Esterification of 12a with the mixture of 8a and 8b was
achieved by the DCC method to provide 13 (67%) and 14 (13%)
Scheme 3 Reagents and conditions: i, AD-mix-a; ii, TBDMSCl, DMAP,
CH2Cl2, RT, 12 h; iii, MsCl, Et3N, CH2Cl2, RT, 17 h; iv, TBAF, THF, RT,
3 h; v, TMSOK, THF, RT 3 h.
Scheme 1
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Chem. Commun., 2001, 1820–1821
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b104920h

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In conclusion, we have completed the first synthesis of
lactone II (and its stereoisomers) from (S)-malic acid and sorbic
acid, and determined the absolute configuration of lactone II to
be 2S, 3S, 9R, 10S. Submitting these isomers to further
biological assay and total synthesis of analogous butalactin are
currently under investigation and will be reported in due
course.
Notes and references
† Data for synthetic 1a: mp 75 oC; 1H NMR (300 MHz, DMSO-d6): d 1.22
(d, 3H, J = 5.5 Hz, H-11), 2.86 (m, 1H, H-3), 3.33 (dq, 1H, J = 4.4, 5.5 Hz,
H-10), 3.61 (ddd, 1H, J = 0.7, 4.4, 7.1 Hz, H-9), 4.10–4.36 (m, 4H, H-4 and
H-5), 4.56 (dd, 1H, J = 6.0, 8.0 Hz, H-2), 6.12 (dd, 1H, J = 0.7, 15.5 Hz,
H-7), 6.13 (d, 1H, J = 5.9 Hz, 2-OH), 6.66 (dd, 1H, J = 7.1, 15.5 Hz, H-
8); 13C NMR (75 MHz, CDCl3): d 13.1, 38.9, 55.2, 55.5, 61.0, 67.6, 67.8,
124.2, 143.5, 165.2, 176.5.
For 1b: mp 95 oC; 1H NMR (300 MHz, DMSO-d6): d 1.23 (d, 3H, J =
5.4 Hz), 2.87 (m, 1H), 3.33 (dq, 1H, J = 4.4, 5.5 Hz), 3.61 (dd, 1H, J = 4.4,
7.1 Hz), 4.13-4.37 (m, 4H), 4.56 (dd, 1H, J = 5.7, 7.7 Hz), 6.12 (dd, 1H, J
= 0.7, 15.5 Hz), 6.13 (d, 1H, J = 5.7 Hz, OH), 6.66 (dd, 1H, J = 7.2, 15.5
Hz); 13C NMR (75 MHz, CDCl3): d 13.1, 38.9, 55.2, 55.5, 61.1, 67.5, 67.8,
124.3, 143.5, 165.1, 176.6.
For 2a: oil; [a]2D1 278.5 (c, 0.11, MeOH); 1H NMR (300 MHz, CDCl3):
d 1.30 (d, 3H, J = 5.5 Hz), 2.90 (m, 1H), 3.35 (dq, 1H, J = 4.4, 5.5 Hz),
3.55 (ddd, 1H, J = 0.9, 4.6, 5.5 Hz), 4.07 (t, 1H, J = 9.8 Hz), 4.32–4.50 (m,
4H), 6.15 (dd, 1H, J = 0.9, 15.7 Hz), 6.87 (dd, 1H, J = 6.3, 15.7 Hz); 13
NMR (75 MHz, CDCl3): d 13.0, 43.1, 55.1, 55.5, 61.9, 66.9, 68.8, 124.0,
143.4, 165.2, 176.7.
C
Scheme 4 Reagents and conditions: i, DCC, DMAP, CH2Cl2, RT, 24 h; ii,
AcOH, THF, H2O, 50 °C, 3 h.
For 2b: oil; [a]2D1 223.6 (c, 0.19, MeOH); 1H NMR (300 MHz, CDCl3):
d 1.30 (d, 3H, J = 5.4 Hz), 2.89 (m, 1H), 3.35 (dq, 1H, J = 4.6, 5.5 Hz),
3.54 (ddd, 1H, J = 0.9, 4.4, 5.3 Hz), 4.33 (d, 1H, J = 10.3 Hz), 4.32–4.50
(m, 4H), 6.15 (dd, 1H, J = 1.1, 15.6 Hz), 6.88 (dd, 1H, J = 6.2, 15.6 Hz);
13C NMR (75 MHz, CDCl3): d 13.1, 43.2, 55.1, 55.5, 61.8, 66.8, 68.9,
124.0, 143.6, 165.2, 173.6.
(Scheme 4).5 The stereochemistries of these compounds were
1
confirmed by H NMR analysis and NOE experiments. The
signals of H-2 appeared at d 4.63 (J = 7.7 Hz) in 13 and d 4.43
(J = 9.3 Hz) in 14, respectively. In 13, a NOE was observed
between H-2 and H-3, whereas a NOE was not observed in 14.
From these results, 13 and 14 are presumed to be 2,3-cis- and
2,3-trans-isomers, respectively. On treatment of 13 or 14 with
acetic acid in THF–H2O at 50 °C to remove THP protection, the
final products 1a and 2a were obtained in satisfactory yield,
respectively. Isomers 1b and 2b were synthesized from 8 and
(4S, 5R)-12b in the same manner.
1 H.-J. Schiewe and A. Zeeck, J. Antibiotics, 1999, 52, 635.
2 D. Seebach, J. Aebi and D. Wasmuth, Org. Synth. Coll. Vol. VII, 1990,
153.
3 Synthetic 7: [a]2D6 +34.6 (c 0.9, CHCl3). Cf. (a) [a]23 +32.5 (c 0.9,
CHCl3), 95% ee: K. Takabe, M. Tanaka, M. Sugimoto, TD. Yamada and H.
Yoda, Tetrahedron: Asymmetry, 1992, 3, 1385; (b) [a]1D9 236.8 (c 1.4,
CHCl3) for R-form: C. Mazzini, J. Lebreton, V. Alphand and R. Furstoss,
J. Org. Chem., 1997, 62, 5215.
By comparison8 of the 1H and 13C NMR results,† there was
little difference among natural, 1a and 1b, and also between 2a
and 2b. However, an obvious difference was observed between
1a and 2a, and also between 1b and 2b. Smaller coupling
constants of 1a (J = 8.0 Hz) and 1b (J = 7.7 Hz) than those of
2a (J = 9.8 Hz) and 2b (J = 10.3 Hz) and the observation of
NOE in 1a (no NOE in 2a) show that the stereochemistries of 1a
(and 1b) and 2a (and 2b) are presumed to be 2,3-cis and
2,3-trans configurations, respectively. The value of specific
rotation [natural: [a]D20 +32 (c, 0.1, MeOH); synthetic 1a: [a]2D1
+38.8 (c, 0.1, MeOH); synthetic 1b: [a]2D0 +121.0 (c, 0.12,
MeOH)] showed that 1a must be the natural product, i.e. lactone
II has the absolute configuration 2S, 3S, 9R, 10S.
4 THP protection was more successfully removed under mild conditions
than MOM (methoxymethyl) protection in the final step.
5 Hydrogenation with palladium on carbon yielded the inseparable mixture
2,3-cis 8a and 2,3-trans 8b; the ratio was approximately 6+1 by NMR.
The mixture arose solely from hydrogenolytic cleavage of the benzyl
group from 6b. It is probably that the cis 8a partly yielded the trans 8b
by intramolecular translactonization.
6 D. Xu, G. A. Crispino and K. B. Sharpless, J. Am. Chem. Soc., 1992, 114,
7570.
7 (4R, 5S)-12a: mp 94 °C (hygroscopic), [a]2D1 270.0 (c 0.5, CHCl3). By a
similar oxidation of methyl sorbate with AD-mix-b and a subsequent
series of reactions, the other isomer (4S, 5R)-12b was also obtained: mp
95 °C, [a]2D3 +77.8 (c 0.9, CHCl3).
Chem. Commun., 2001, 1820–1821
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