Total synthesis of (+)-tubelactomicin A. 1. Stereoselective synthesis of the lower-half segment by an intramolecular Diels-Alder approach

Article abstract of DOI:10.1021/ol0507625

(Chemical Equation Presented) Starting from diethyl (R)-malate, synthesis of the lower-half segment of (+)-tubelactomicin A, a 16-membered macrolide antibiotic, has been achieved. The synthesis involved the highly endo- and π-facial selective intramolecul

Full text of DOI:10.1021/ol0507625

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2261-2264
Total Synthesis of (+)-Tubelactomicin
A. 1. Stereoselective Synthesis of the
Lower-Half Segment by an
Intramolecular Diels−Alder Approach
Toru Motozaki, Kiyoto Sawamura, Akari Suzuki, Keigo Yoshida, Tatsuo Ueki,
Aiko Ohara, Ryosuke Munakata, Ken-ichi Takao, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio UniVersity, Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
tadano@applc.keio.ac.jp
Received April 8, 2005
ABSTRACT
Starting from diethyl (R)-malate, synthesis of the lower-half segment of (
+)-tubelactomicin A, a 16-membered macrolide antibiotic, has been
achieved. The synthesis involved the highly endo- and -facial selective intramolecular Diels
π
−Alder reaction achieved using a trisubstituted
methacrolein derivative tethering a 10-carbon dienyne unit at the
â
-carbon, which in turn was prepared from a known allylated malic acid
derivative.
(+)-Tubelactomicin A (1) was isolated from the culture broth
of an actinomycete strain designated MK703-102F1, a
member of Nacardia, which showed potent antimicrobial
activity against acid-fast bacteria, including drug-resistant
strains.1a The structure of 1 was elucidated by extensive NMR
analysis and confirmed by a single-crystal X-ray analysis of
the carboxamide derivative with L-phenylalanine methyl
ester; therefore, the absolute stereochemistry was established
as shown in Scheme 1.1b The structure of 1 is characterized
by a trans-fused octahydronaphthalene moiety possessing six
contiguous stereogenic centers and a 16-membered macro-
lactone incorporating an (E,E)-conjugate diene and an R,â-
disubstituted (Z)-acrylic acid moiety. So far, a number of
macrolides, which consist of tricyclic structures similar to
1, have been isolated as biologically intriguing natural
products. In addition, synthetic studies directed at these
octahydronaphthalene-fused macrolides have been explored
by many research groups in the past 2 decades.2 The focus
of our research has been the total synthsis of 1, which was
recently completed.
In retrosynthetic consideration of the target natural product
shown in Scheme 1, 1 was divided into two segment, 2 and
3, i.e., an (E)-vinylstannane incorporating a C14-C24 chain
as the upper-half segment and an octahydronaphthalene
(2) For the total synthesis of (-)-chlorothricolide, see: (a) Roush, W.
R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457-6458. (b) Roush, W.
R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411-7419. For the total
synthesis of (()-24-O-methylchlorothricolide, see: (c) Takeda, K.; Igarashi,
Y.; Okazaki, K.; Yoshii, E.; Yamaguchi, K. J. Org. Chem. 1990, 55, 3431-
3434. For the total synthesis of (+)-tetronolide, see: (d) Takeda, K.;
Kawanishi, E.; Nakamura, H.; Yoshii, E. Tetrahedron Lett. 1991, 32, 4925-
4928. For the formal synthesis of (+)-tetronolide, see: (e) Roush, W. R.;
Reilly, M. L.; Koyama. K.; Brown, B. B. J. Org. Chem. 1997, 62, 8708-
8721. For synthetic studies of superstolide A, see: (f) Roush, W. R.;
Champoux, J. A.; Peterson, B. C. Tetrahedron Lett. 1996, 37, 8989-8992.
(g) Yu, W.; Zhang, Y.; Jin Z. Org. Lett. 2001, 3, 1447-1450. (h) Zampella,
A.; D’Auria, M. V. Tetrahedron: Asymmetry 2001, 12, 1543-1545. (i)
Roush, W. R.; Hertel, L.; Schnaderbeck, M. J.; Yakelis, N. A. Tetrahedron
Lett. 2002, 43, 4885-4887. (j) Yakelis, N. A.; Roush, W. R. J. Org. Chem.
2003, 68, 3838-3843.
(1) (a) Igarashi, M.; Hayashi, C.; Homma, Y.; Hattori, S.; Kinoshita,
N.; Hamada, M.; Takeuchi, T. J. Antibiot. 2000, 53, 1096-1101. (b)
Igarashi, M.; Nakamura H.; Naganawa, H.; Takeuchi, T. J. Antibiot. 2000,
53, 1102-1107.
10.1021/ol0507625 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/29/2005

Scheme 1. Structure of (+)-Tubelactomicin A (1) and
Scheme 2. Synthesis of the Upper-Half Segment (Part 1)
Retrosynthetic Analysis
carboxylic acid carrying an (E)-vinyl iodide as the lower-
half (C1-C13) segment, respectively. These two segments
could be connected sequentially in later synthetic stages by
(1) sp2-sp2 Stille coupling to form a carbon-carbon bond
between C13 and C14 and (2) intramolecular esterification
at the C1 carboxylic acid and the C23 hydroxyl group to
form the 16-membered macrolactone structure. The highly
functionalized trans-fused octahydronaphthalene 3 could be
synthesized through the endo- and π-facial selective intramo-
lecular Diels-Alder (IMDA) reaction of a â-substituted (E)-
methacrolein derivative 4 possessing a 10-carbon tether
incorporating an (E,E)-dienyne terminal. One of the key
issues for the total synthesis was the stereoselectivity of the
IMDA reaction3 using substrate 4. In this Letter, we report
a highly stereoselective synthesis of the lower-half segment
3, starting with diethyl (R)-malate (5)4 along this synthetic
plan. The synthesis of the upper-half segment 2 and the
completion of the total synthesis of 1 are described in the
following paper.5
Synthesis of the lower-half segment 3 is outlined in
Schemes 2 and 3. According to Seebach’s precedent,6 regio-
and diastereoselective allylation of the lithium enolate
generated from 5 predominantly provided the anti-allylated
product 6 (8:1 diastereomeric ratio). Hydride reduction of
(3) For reviews on IMDA reactions, see: (a) Roush, W. R. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L.
A., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 153-550. (b) Fallis,
A. G. Acc. Chem. Res. 1999, 32, 464-474. (c) Bear, B. R.; Sparks, S. M.;
Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820-849. (d) Marsault, E.;
Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243-
4260.
the diester 6, followed by regioselective acetalization of the
resulting triol 77 with benzaldehyde dimethylacetal, provided
8.8 Temporary protection of the primary hydroxyl group in
(4) Wipf, P.; Uto, Y.; Yoshimura, S. Chem. Eur. J. 2002, 8, 1670-
1681.
(5) Motozaki, T.; Sawamura, K.; Suzuki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.-i.; Tadano, K.-i. Org. Lett. 2005, 7,
2265-2268.
(6) (a) Seebach, D,; Wasmuth, D. HelV. Chim. Acta 1980, 63, 197-
200. (b) Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1984, 63, 109-
120.
(7) Owing to its highly polar nature, the reduction product was once
acetylated. The peracetate was purified on silica gel and then deacetylated
with a catalytic amount of NaOMe.
(8) For the synthesis of enantiomeric 8, see: Morimoto, Y.; Mikami,
A.; Kuwabe, S.; Shirahama, H. Tetrahedron: Asymmetry 1996, 7, 3371-
3390.
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Org. Lett., Vol. 7, No. 11, 2005

8 as the MPM (methoxy-phenylmethyl) ether provided 9.
Regioselective hydroboration of 9, followed by oxidative
treatment, produced 10. Silylation of the resulting primary
hydroxyl group and deprotection of the MPM group provided
11. Dess-Martin oxidation9 of the liberated hydroxyl group,
followed by the E-selective Horner-Emmons olefination of
the resulting aldehyde 12 with phosphonate 13,10 predomi-
nantly provided (E,E)-conjugated dienyne 14. Acidic depro-
tection of the TBS group in 14 provided 15. Installation of
the dienophile part into 15 was achieved through a Wittig
olefination reaction of the aldehyde prepared from 15 by
Dess-Martin oxidation, followed by a two-step reduction/
oxidation protocol of the resulting R,â-unsaturated ester 16,
which eventually provided the unsaturated aldehyde 4, the
substrate for the aimed IMDA reaction.
states (endo-TS and exo-TS) were conformationally locked
by the presence of the trans-oriented benzylidene acetal. In
the two TSs, a severe nonbonded interaction occurred
between the methyl substituent in the diene part and the
dienophile terminal, apparently making the exo-TS unfavor-
able. Therefore, the IMDA reaction proceeds through the
endo-TS, leading to the predominant formation of the desired
17-endo. It is apparent that the existence of the benzylidene
acetal plays a critical role in the IMDA reaction.
The NaClO2 oxidation of the aldehyde functionalities in
the diastereomeric mixture 17-endo/exo, followed by desi-
lylation of the resulting 18,12 provided 19 (Scheme 3). Acid
Scheme 3. Synthesis of the Upper-Half Segment (Part 2)
The thermal IMDA reaction of 4 in toluene at 80 °C for
24 h proceeded stereoselectively to provide the desired trans-
fused cycloadduct 17-endo11 with an 8:1 endo:exo ratio (1H
NMR analysis) in a combined yield of 93%. As a result, the
IMDA reaction of 4 proceeded with complete π-facial
Figure 1. Plausible transition states for the IMDA of 4.
selectivity. As shown in Figure 1, two chairlike transition
(9) (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. (c) Frigerio,
M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537-4538.
(10) Phosphonate 13 was prepared from the known (E)-2-methyl-5-
(trimethylsilyl)pent-2-en-4-yn-1-ol 26, which in turn was prepared from
diethyl methylmalonate (24) via 25.
hydrolytic removal of the benzylidene acetal provided 20.
After protection of the carboxylic acid in 20 as the 2-(tri-
methylsilyl)ethoxymethyl (SEM) ester, the primary hydroxyl
group of the resulting 21 was selectively sulfonylated,
providing the tosyl ester 22. The NaBH4-reduction of the
tosyloxy group in 22 in hot DMSO provided deoxygenated
derivative 23. The acetylene terminal was then hydrostan-
nylated regio- and stereoselectively. The resulting (E)-
vinylstannane was treated with iodine to provide the lower-
half segment 3.
In conclusion, we have achieved a stereoselective synthesis
of the lower-half segement 3 for the total synthesis of 1.
Access to 3 features (1) the stereoselective IMDA of 4 for
efficient construction of the highly functionalized trans-fused
octahydronaphthalene derivative 17-endo and (2) regio- and
stereoselective hydrostannylation followed by iodination for
For preparation of 25, see: Baker, R.; Castro, J. L. J. Chem. Soc., Perkin
Trans. 1 1990, 47-65. For preparation of 26, see: de Lera, A. R.; Iglesias,
B.; Rodriguez, J.; Alvarez, R.; Lopez, S.; Villanueva, X.; Padros, E. J. Am.
Chem. Soc. 1995, 117, 8220-8231.
(11) The structure of the major adduct 17-endo was confirmed on the
(12) At this stage, the compound (not shown) derived from the minor
exo-adduct of the IMDA reaction could be removed.
1
basis of extensive H NMR analysis.
Org. Lett., Vol. 7, No. 11, 2005
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the conversion of the acetylenic part in 23 into the trans-
vinyl iodide part.
Supporting Information Available: Experimental pro-
cedures and characterization data, including 1H and 13C NMR
spectra for all new synthetic compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by Grants-
in-Aid for the 21st Century COE program “Keio LCC” from
the Ministry of Education, Culture, Sports, Science, and
Technology of Japan.
OL0507625
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