Toward the synthesis of tetrodecamycin: Asymmetric synthesis of a direct precursor of the C6-C18 trans-decalin portion

Article abstract of DOI:10.1016/S0040-4039(03)00339-3

We report the asymmetric synthesis of a direct precursor of the C6-C18 trans-decalin portion of tetrodecamycin utilising an asymmetric intramolecular Diels-Alder (IMDA) reaction as the key step.

Full text of DOI:10.1016/S0040-4039(03)00339-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2549–2552
Toward the synthesis of tetrodecamycin: asymmetric synthesis of
a direct precursor of the C6ꢀC18 trans-decalin portion
Franz F. Paintner,* Gerd Bauschke and Kurt Polborn
Department Pharmazie-Zentrum fu¨r Pharmaforschung, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstraße 5-13,
Haus C, D-81377 Mu¨nchen, Germany
Received 9 January 2003; accepted 30 January 2003
Abstract—We report the asymmetric synthesis of a direct precursor of the C6ꢀC18 trans-decalin portion of tetrodecamycin
utilising an asymmetric intramolecular Diels–Alder (IMDA) reaction as the key step. © 2003 Elsevier Science Ltd. All rights
reserved.
Tetrodecamycin 1 is a novel a-(g-hydroxyacyl) tetronic
acid based polyketide antibiotic isolated from the cul-
ture broth of Streptomyces nashvillensis in 1994 by
Takeuchi and co-workers.1 It shows distinct activity
against Gram-positive bacteria including methicillin-
resistant Staphylococcus aureus (MRSA) as well as
Bacillus anthracis. The unique ring skeleton and abso-
lute configuration of compound 1 were fully elucidated
by 2D NMR and X-ray crystallography.2 However, no
total synthesis of this interesting antibiotic has been
reported so far.
imide 6, where the simultaneous generation of the four
stereogenic centres at C1, C2, C4a and C8a of the
resulting octahydronaphthalene ring skeleton was to be
directed by Evan’s chiral 4-benzyl-2-oxazolidinone aux-
iliary,5 and (b) the stereoselective transformation of
acid 7 into lactone 8, suitably functionalised for conver-
sion into target molecule 3 (Scheme 2).
The synthesis of cyclisation precursor 6 was begun by
Li2CuCl4-catalysed cross coupling6 between the Grig-
nard reagent 10, prepared from 2-(3-bromopropyl)-1,3-
dioxolane,7 and commercially available (2E,4E)-
2,4-hexadien-1-yl acetate (9) to yield (6E,8E)-deca-6,8-
dienal (12)8 after hydrolysis of the corresponding acetal
11 with aqueous acetic acid (61% from 9) (Scheme 3).9
Our approach to tetrodecamycin 1 is based on key
intermediate 2, which is envisioned to arise from alde-
hyde 3 and 4-methoxy-5-methyl-5H-furan-2-one (4),3
involving disconnections of the tetracyclic structure at
the C2ꢀC6 and the C3ꢀO or C15ꢀO bonds (Scheme 1).
In a recent publication we have disclosed an efficient
approach to the core structure 5 of tetrodecamycin,
starting from 4 and an appropriate aldehyde, which
represents a close model of aldehyde 3 (bold type in
Scheme 1).4
In this letter we report the asymmetric synthesis of key
building block 3, which contains four of the six stereo-
genic centres inherent in the target molecule 1.
Our strategy is founded on: (a) the asymmetric
intramolecular Diels–Alder (IMDA) reaction of trien-
Keywords: tetrodecamycin; antibiotics; asymmetric synthesis; Diels–
Alder reactions; lactonisation.
* Corresponding author. Fax: +49 089 2180 77247; e-mail:
franz.paintner@cup.uni-muenchen.de
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00339-3

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F. F. Paintner et al. / Tetrahedron Letters 44 (2003) 2549–2552
ment of
a dilute solution of the triene 6 in
dichloromethane with dimethylaluminium chloride (1.4
equiv.) at −30°C for 21 h provided the desired cycload-
duct 14 with high diastereoselectivity [d.s. (endo)]98:2;
ꢀendo:ꢀexo]50:1] and in excellent yield (92%). The
relative configuration of C1, C2, C4a and C8a in 1412
1
was determined on the basis of the H–1H J-coupling
values and NOE studies. The absolute configuration
assigned for 14 was confirmed by X-ray diffraction
analysis of the dibromo derivative 1513 (Fig. 1), which
was obtained in 66% yield from 14 on treatment with
bromine (CH2Cl2, 0°C).
To introduce the missing C1 methyl group by alkyla-
tion of an appropriate enolate, the N-acyloxazolidinone
14 was transformed into the methyl ester 17 (Scheme 4).
Since removal of the chiral auxiliary by hydrolysis with
lithium hydroperoxide (2.0 equiv. LiOH, 8.0 equiv.
H2O2, THF/H2O, 0°C to rt)14 failed, due to competing
endocyclic cleavage of the N-acyloxazolidinone,15 the
cycloadduct 14 was first converted into the thioester 16
by Damon’s lithio mercaptide method16 (96% yield;
92% recovery of the chiral auxiliary). Subsequent
hydrolysis of the thioester 16 led to the acid 7, which
was converted to the methyl ester 17 in 90% overall
yield (ꢀ4:1 mixture of diastereomers due to partial
epimerisation in the course of alkaline hydrolysis).
Scheme 2.
Stereoselective methylation at C1 was achieved by con-
verting the methyl ester 17 first into the corresponding
lithio enolate (1.25 equiv. LDA, THF, −78°C to rt) and
Scheme 3. Reagents and conditions: (a) Li2CuCl4 (cat.), THF,
−20°C (69%); (b) AcOH, H2O, THF, 80°C (88%); (c) LiCl,
i-Pr2NEt, CH3CN, rt (91%); (d) Me2AlCl (1.4 equiv.),
CH2Cl2, −30°C (92%); (e) Br2, CH2Cl2, 0°C (66%).
Figure 1. ORTEP plot of 15.
Scheme 4. Reagents and conditions: (a) PrSLi, PrSH, THF,
0°C (96%); (b) 2 M aq NaOH, MeOH, 120°C; (c) trimethyl-
oxonium tetrafluoroborate, i-Pr2NEt, CH2Cl2, rt (90% from
16); (d) (i) LDA, THF, −78°C to rt; (ii) CH3I, −90°C to rt
(84%); (e) 3 M NaOH aq., MeOH, 125°C (91%); (f) PhSeCl,
CH2Cl2, −78°C to rt; (g) MMPP/SiO2, CH2Cl2, rt (90% from
19); (h) DIBAL, CH2Cl2, −78°C (74%); (i) TBDMSOTf,
i-Pr2NEt, CH2Cl2, 0°C (65%).
Modified Horner–Wadsworth–Emmons reaction10 of
aldehyde 12 with the chiral phosphonate 1311 selectively
led to the triene 6 in 91% yield (E:Z]95:5). With the
chiral triene 6 in hand, asymmetric intramolecular
Diels–Alder (IMDA) reaction was performed following
the reaction conditions reported by Evans.5 Thus treat-

F. F. Paintner et al. / Tetrahedron Letters 44 (2003) 2549–2552
2551
then by reacting it with methyl iodide (−90°C to rt) to
form 18 as the major isomer of a separable 88:12
mixture of diastereomers in 84% yield. The relative
configuration of 18 was assigned on the basis of NOE
experiments. Thus irradiation of the CH3 group at C1
gave rise to a significant NO effect for 2-H.
8. Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107,
1768–1769.
9. All new compounds were characterized by 1H and 13C
NMR spectra and gave satisfactory elemental analyses.
10. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A.
P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183–2186.
Hydrolysis of the methyl ester 18 had to be run under
forced conditions (3 M NaOH aq., MeOH, 125°C, 10
h) to obtain acid 19 in good yield (91%). The stereospe-
cific transformation of the g,d-unsaturated acid 19 into
lactone 8 was achieved by phenylselenolactonisation17
(PhSeCl, CH2Cl2, −78°C to rt, 7d) and subsequent
oxidative removal (MMPP/SiO2, CH2Cl2, rt) of the
phenylselenanyl substituent to establish the crucial
C4ꢀC4a double bond. Thus the unsaturated lactone 8
was obtained in high overall yield (90%). Finally con-
version of 8 into TBDMS-protected g-hydroxy alde-
hyde 3 was accomplished by a two-step protocol. First
lactone 8 was reduced to the corresponding lactol 20
(3.0 equiv. DIBAL, CH2Cl2, −90°C) in 79% yield,
which provided the building block 318 in 65% yield on
treatment with TBDMSOTf (i-Pr2NEt, CH2Cl2, 0°C).19
11. Broka, C. A.; Ehrler, J. Tetrahedron Lett. 1991, 32,
5907–5910.
12. 14: [h]2D0 −185° (c 0.96, CH2Cl2). IR (KBr): 3012, 2923,
1
1780, 1696, 1508, 1386, 1196 cm−1. H NMR (500 MHz,
CDCl3) l=0.87 (m, 1H, 8-Hax), 0.96 (d, 3H, J=7.2 Hz,
CH3), 1.12 (m, 1H, 5-Hax), 1.25–1.45 (m, 2H, 6-Hax and
7-Hax), 1.60 (m, 1H, 8a-H), 1.73–1.81 (m, 4H, 4a-H,
5-Heq, 6-Heq and 7-Heq), 1.91 (m, 1H, 8-Heq), 2.63 (dd,
1H, J=10.6, 13.1 Hz, CH2Ph), 2.81 (m, 1H, 2-H), 3.42
(dd, 1H, J=3.3, 13.1 Hz, CH2Ph), 3.82 (dd, 1H, J=5.9,
11.3 Hz, 1-H), 4.12–4.19 (m, 2H, OCH2), 4.72 (ddd, 1H,
J=3.4, 7.0, 13.9 Hz, NCH), 5.41 (br d, 1H, J=9.9 Hz,
4-H), 5.58 (ddd, 1H, J=2.6, 4.6, 9.9 Hz, 3-H), 7.23–7.31
(m, 3H, Harom), 7.32–7.37 (m, 2H, Harom). 13C NMR (500
MHz, CDCl3) l=17.77 (CH3), 26.59, 26.70 (C-6 and
C-7), 30.09 (C-8), 30.92 (C-2), 33.17 (C-5), 36.59 (C-8a),
38.29 (CH2Ph), 41.89 (C-4a), 47.67 (C-1), 55.36 (NCH),
66.02 (OCH2), 127.31, 128.99, 129.34 (C6H5), 130.70,
130.83 (C-3 and C-4), 135.52 (C6H5), 153.05 (NCꢁOO),
173.61 (NCꢁO). MS (CI, CH5+): m/z (%)=354 (100)
[M+H+], 177 (60). Anal. calcd for C22H27NO3 (353.5): C,
74.76; H, 7.70; N, 3.96. Found: C, 74.53; H, 7.73; N,
3.87%.
In conclusion, we have developed an efficient synthetic
pathway to a direct precursor of the C6ꢀC18 trans-
decalin portion of tetrodecamycin (1). Further synthetic
studies toward 1 starting from key building block 3 are
now in progress and will be reported in due course.
13. Crystallographic data (excluding structure factors) for
structure 15 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC199999. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail:deposit@ccdc.cam.ac.uk].
Acknowledgements
We are greatly indebted to Professor Dr. Klaus Th.
Wanner for his generous support.
14. Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron
Lett. 1987, 28, 6141–6144.
15. The carboxylic acid 7 and the chiral auxiliary were
obtained only in low yield (12 and 10%, respectively) in
addition to the cleavage product i, which was formed in
85% yield.
References
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18. 3: Colorless oil; [h]2D0=−124° (c 1.2, CH2Cl2). IR (film):
1
2930, 1722, 1675, 1462, 1256 cm−1. H NMR (500 MHz;
CD2Cl2) l=0.04 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3),
0.86 [s, 9H, C(CH3)3], 0.89 (br d, 3H, Jꢀ6.5 Hz,
CHCH3), 0.97 (s, 3H, CH3), 1.09 (m, 1H, 8-Hax), 1.21 (m,
1H, 6-Hax), 1.44 (m, 1H, 7-Hax), 1.68 (m, 1H, 8-Heq),
1.77–1.86 (m, 2H, 6-Heq and 7-Heq), 1.92 (ddd, 1H,
J=4.1, 7.1, 14.2 Hz, 2-H), 2.03 (m, 1H, 5-Hax), 2.22
(dquin, 1H, J=2.1, 12.8 Hz, 5-Heq), 2.27 (m, 1H, 8a-H),

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F. F. Paintner et al. / Tetrahedron Letters 44 (2003) 2549–2552
(CHO). MS (CI, CH5+): m/z (%)=323 (7) [M+H+], 207
4.13 (br s, 1H, 3-H), 5.30 (br s, 1H, 4-H), 9.58 (s, 1H,
CHO). 13C NMR (500 MHz, CD2Cl2) l=−5.23 (SiCH3),
−4.57 (SiCH3), 10.10 (CHCH3), 16.90 (CH3), 18.01
[C(CH3)3], 25.57 [C(CH3)3], 26.69 (C-7), 28.49 (C-6), 29.75
(C-8), 36.01 (C-5), 39.13 (C-2),), 47.30 (C-8a), 68.25 (C-1),
68.37 (C-3), 121.15 (CꢁCH), 135.66 (CꢁCH), 204.47
(100). HRMS: m/z calcd for C19H34O2Si (M+): 322.2328.
Found: 322.2332.
19. The remaining material was the corresponding TBDMS-
protected lactol, which after chromatographic separation
and deprotection (HF, acetonitrile, 0°C) could be recycled.