Lasonolide A: Structural revision and synthesis of the unnatural (-)-enantiomer

Article abstract of DOI:10.1021/ja017265d

Total synthesis of the unnatural (-)-enantiomer of lasonolide A was achieved starting from ethyl l-malate. The two tetrahydropyranyl fragments were prepared stereoselectively via radical cyclization reactions of β-alkoxyacrylates. The full structure of na

Full text of DOI:10.1021/ja017265d

Published on Web 12/28/2001
Lasonolide A: Structural Revision and Synthesis of the Unnatural
(-)-Enantiomer
Eun Lee,* Ho Young Song, Jung Won Kang, Dae-Shik Kim, Cheol-Kyu Jung, and Jung Min Joo
School of Chemistry and Molecular Engineering, Seoul National UniVersity, Seoul 151-747, Korea
Received October 9, 2001
Scheme 1a
Lasonolide A (proposed structure: 1 or 2) is a novel macrolide
isolated from the shallow water Caribbean marine sponge, Forcepia
sp.1 It is a potent cytotoxin against the A-549 human lung carcinoma
and P388 murine leukemia cell lines, and inhibits cell adhesion in
the EL-4.IL-2 cell line. We synthesized compounds 1 and 2,2 and
a 1) 1.03 equiv BH3‚SMe2, 0.05 equiv NaBH4, THF, rt 1 h; 2) 1.0 equiv
Bu2SnO, benzene, reflux (-H2O), 16 h; 2.0 equiv BnBr, 1.0 equiv TBAI,
reflux, 4 h; 3) 3.0 equiv MeNH(OMe)‚HCl, 3.0 equiv Me3Al, THF, 0 °C
to rt 5 h; 4) 3.0 equiv H2CC(Me)MgBr, THF, rt 5 h; 5) 1.1 equiv Et3B, 1.1
equiv NaBH4, THF-MeOH (4:1), -78 °C, 5 h; 6) 2.5 equiv (p-
MeO)PhCH(OMe)2, 0.05 equiv CSA, DCM, rt 1 h; 7) 2.5 equiv DIBAL,
found that neither corresponded with the structure of the natural
product. Herein we wish to report a synthesis3 of the compound 3,
the unnatural enantiomer of lasonolide A.
DCM, rt 5 h; 8) 1.5 equiv HCCCO2Et, 0.2 equiv NMM, MeCN, rt 2 d; 9)
1.1 equiv DDQ, DCM-H2O, rt 1 h; 10) 1.2 equiv BrCH2SiMe2Cl, 1.4 equiv
TEA, 0.05 equiv DMAP, benzene, rt 30 min; 11) 1.5 equiv Bu3SnH, 0.2
equiv AIBN, benzene (0.02 M), reflux, 5 h (syringe pump, 4 h).
Preparation of the first tetrahydropyran fragment started with
ethyl L-malate (4), which was converted into the enone 6 via the
Weinreb amide derivative of the ester 5. Stereoselective reduction4
of 6 provided the syn diol, and regioselective reduction of the cyclic
PMB acetal yielded the triol derivative 7. The â-alkoxyacrylate 8
was obtained from 7 via reaction with ethyl propiolate and PMB-
deprotection. Radical cyclization reaction5 of the bromomethyl-
(dimethyl)silyl derivative 9 proceeded smoothly and the bicyclic
product 10 was obtained as a single product6 (Scheme 1).
Reduction of the ester group and reaction with pivaloyl chloride
provided the pivaloate derivative of 10, which was converted into
the diol 11 via Tamao oxidation.7 Selective deprotection of the bis-
(TBS) derivative of 11 yielded the primary alcohol 12. Conversion
of 12 into the lower homologue 13 required selenide substitution/
selenoxide elimination, osmium tetroxide dihydroxylation/sodium
periodate cleavage, and sodium borohydride reduction. The alde-
hyde 14 was synthesized via TBS deprotection of 13, acetonide
protection, benzyl ether deprotection, and oxidation with sulfur
trioxide-pyridine complex. The aldehyde 14 was converted to the
trans olefin 16 via Kocienski-Julia reaction8 with the sulfone 15.
The sulfone 18 was then obtained after TBDPS deprotection,
Mitsunobu-type substitution with 2-mercaptobenzothiazole (17), and
selective oxidation9 (Scheme 2).
The Evans chiral imide 19 served as the starting material for
the synthesis of the second tetrahydropyran fragment. The aldol
product from the reaction of the (Z)-boron enolate of 19 and
benzyloxyacetaldehyde was converted into the hydroxy enone 20
via vinyl Grignard reaction of the corresponding Weinreb amide.10
After stereoselective reduction of 20, the product syn diol was
converted into the dibenzyl ether 21 via regioselective reduction
of the corresponding benzylidene acetal. Osmium tetroxide dihy-
droxylation/sodium periodate cleavage followed by sodium boro-
hydride reduction provided a primary alcohol, from which the TBS
ether 22 was obtained via selective silylation. Reaction of 22 with
ethyl propiolate provided the corresponding â-alkoxyacrylate, which
was converted into the bromide 23 via TBS deprotection and
Scheme 2a
a 1) 1.0 equiv LiBH4, ether, rt 6 h; 2) 1.5 equiv PivCl, 0.05 equiv DMAP,
2.0 equiv pyridine, DCM, rt 8 h; 3) ex. 30% H2O2, 3.0 equiv KF, 4.0 equiv
KHCO3, THF-MeOH (1:1), rt 36 h; 4) 3.0 equiv TBSOTf, 5.0 equiv 2,6-
lutidine, DCM, rt 8 h; 5) 0.2 equiv CSA, MeOH, 0 °C, 90 min; 6) 1.3
equiv (o-NO2)PhSeCN, 1.3 equiv Bu3P, THF, rt 2 h; ex. 30% H2O2, rt 5 h;
7) 0.05 equiv OsO4, 3.0 equiv NMO, acetone-H2O (3:1), rt 2 d; 3.0 equiv
NaIO4, rt 5 h; 8) 2.0 equiv NaBH4, EtOH, 0 °C, 10 min; 9) concd HCl,
MeOH, rt 5 h; 10) 1.5 equiv Me2C(OMe)2, 0.05 equiv PPTS, acetone, rt 2
h; 11) H2, Pd/C, MeOH, rt 2 h; 12) 5.0 equiv SO3‚pyridine, 10 equiv TEA,
DMSO-DCM (1:1), 0 °C, 1 h; 13) 1.8 equiv 15, 1.8 equiv LHMDS, THF-
HMPA (5:1), -78 °C; 1.0 equiv 14, -78 °C to rt 12 h; 14) 1.5 equiv TBAF,
THF, rt 3 h; 15) 1.5 equiv Ph3P, 1.5 equiv DIAD, 1.5 equiv 17, THF, 0 °C,
1 h; 16) 2.0 equiv (NH4)6Mo7O24, 30 equiv H2O2, EtOH, 0 °C, 2 h.
bromide substitution. Radical cyclization of 23 proceeded unevent-
fully to give the tetrahydropyranyl intermediate 24 in high yield.
Benzyl deprotection via hydrogenolysis and silylation provided the
bis(TBS) ether analogue of 24, which was converted into the
corresponding aldehyde via lithium borohydride reduction and
oxidation with sulfur trioxide-pyridine complex. The trans-
iodovinyl derivative 25 was obtained by adopting the Takai
protocol.11 Generation of the primary hydroxy group via selective
TBS deprotection and oxidation with sulfur trioxide-pyridine led
to the production of the corresponding aldehyde in good yield, from
9
384 VOL. 124, NO. 3, 2002 J. AM. CHEM. SOC.
10.1021/ja017265d CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3a
Scheme 5a
a 1) 1.1 equiv n-Bu2BOTf, 1.2 equiv TEA, DCM, 0 °C, 30 min; 1.2
equiv BnOCH2CHO, -78 to 0 °C, 2 h; 2) 3.5 equiv MeNH(OMe)‚HCl,
3.5 equiv Me3Al, THF, 0 °C to rt 8 h; 3) 3.0 equiv H2CCHMgBr, THF, rt
3 h; 4) 1.2 equiv Et3B, 1.2 equiv NaBH4, THF-MeOH (2.5:1), -78 °C, 5
h; 5) 1.5 equiv, PhCH(OMe)2, 0.05 equiv CSA, DCM, rt 1 h; 6) 2.5 equiv
DIBAL, DCM, rt 1 h; 7) 0.05 equiv OsO4, 3.0 equiv NMO, acetone-H2O
(3:1), rt 16 h; 2.0 equiv NaIO4, rt 1 h; 8) 1.5 equiv NaBH4, EtOH, 0 °C, 30
min; 9) 1.1 equiv TBSCl, 1.3 equiv imidazole, DCM, 0 °C, 1 h; 10) 1.5
equiv HCCCO2Et, 0.2 equiv NMM, MeCN, rt 2 d; 11) concd HCl, MeOH,
0 °C, 90 min; 12) 1.5 equiv CBr4, 1.4 equiv Ph3P, 3.0 equiv pyridine, DCM,
0 °C to rt 2 h; 13) 1.5 equiv Bu3SnH, 0.2 equiv AIBN, benzene (0.02 M),
reflux, 4 h (syringe pump, 3 h); 14) H2, Pd/C, MeOH, rt 3 h; 15) 3.0 equiv
TBSOTf, 5.0 equiv 2,6-lutidine, DCM, rt 3 h; 16) 1.2 equiv LiBH4, ether,
rt 12 h; 17) 4.0 equiv SO3‚pyridine, 8.0 equiv TEA, DMSO-DCM (1:1),
0 °C, 1 h; 18) 7.5 equiv CrCl2, 2.0 equiv CHI3, dioxane-THF (6:1), rt 10
h; 19) 0.2 equiv CSA, MeOH, rt 1 h; 20) 4.0 equiv SO3‚pyridine, 8.0 equiv
TEA, DMSO-DCM (1:1), 0 °C, 1 h; 21) 1.5 equiv MeO2C(Me)CHPO-
(OCH2CF3)2, 1.5 equiv KHMDS, 2.0 equiv 18-c-6, THF, -78 °C, 1 h; 22)
2.5 equiv DIBAL, DCM, -78 °C, 1 h; 23) 20 equiv MnO2, DCM, rt 12 h.
a 1) 1.2 equiv LDA, THF, -78 °C; 1.3 equiv 27, THF, -78 °C to rt 10
h; 2) 0.005 M CSA, MeOH, 50 equiv (HOCH2)2, rt 8 h; 3) 3.0 equiv TBSCl,
5.0 equiv imidazole, DCM, rt 2 h; 4) 3.0 equiv 34, 4.0 equiv DIC, 2.5
equiv DMAP, DCM, rt 20 h; 5) 0.1 equiv Pd2dba3, 10 equiv DIPEA, NMP
(0.004 M), rt 16 h; 6) 5.0 equiv LiEt3BH, THF, -78 °C, 1 h; 7) 5.0 equiv
SO3‚pyridine, 10 equiv TEA, DMSO-DCM (1:1), 0 °C, 2 h; 8) 6.0 equiv
32, 5.5 equiv KHMDS, THF, -78 °C, 1.0 equiv 37, 5 min; -78 °C to rt
10 h; 9) ex. HF‚pyridine, ex. pyridine, THF, rt 16 h.
Comparison of the NMR spectra revealed that 3 represented the
correct structure of lasonolide A except the specific rotation, which
was opposite to the reported value for the natural product.13 In the
present studies, an excellent stereocontrol was achieved in the
introduction of the quaternary center at C-22 via 6-endo, 6-exo
tandem radical cyclization reactions of a â-alkoxyacrylate.
Acknowledgment. We thank the Ministry of Science and
Technology, Republic of Korea, and Korea Institute of Science and
Technology Evaluation and Planning for a National Research
Laboratory Grant (1999). Brain Korea 21 graduate fellowship grants
to H.Y.S. and C.K.J. are gratefully acknowledged.
Scheme 4a
Supporting Information Available: Selected experimental pro-
cedures and spectral data for 1, 2, 3, and other isomers, and further
schemes and references (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
a 1) 1.0 equiv cyclohexanone, 1.5 equiv BF3‚OEt2, ether, 0 °C to rt 20
h; 2) 3.0 equiv BH3‚DMS, 3.0 equiv B(OMe)3, THF, 0 °C to rt 8 h; 3) 1.2
equiv TBSCl, 1.5 equiv imidazole, DCM, rt 1 h; 4) 3.0 equiv 30, 1.0 equiv
NaH, THF, rt 1 h; 5) 1.3 equiv TBSCl, 1.5 equiv imidazole, 0.05 equiv
DMAP, DCM, rt 12 h; 6) HF‚pyridine, pyridine, THF, rt 1 h; 7) 1.5 equiv
Ph3P, 1.5 equiv I2, 3.0 equiv imidazole, THF, rt 1 h; 8) 2.0 equiv Ph3P,
MeCN, reflux, 16 h.
References
(1) Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J. Am.
Chem. Soc. 1994, 116, 6015-6016.
(2) See the Supporting Information.
(3) For synthetic studies in the literature, see: (a) Beck, H.; Hoffmann, H.
M. R. Eur. J. Org. Chem. 1999, 2991-2995. (b) Nowakowski, M.;
Hoffmann, H. M. R. Tetrahedron Lett. 1997, 38, 1001-1004. (c) Gurjar,
M. K.; Chakrabarti, A.; Venkateswara Rao, B.; Kumar, P. Tetrahedron
Lett. 1997, 38, 6885-6888. (d) Gurjar, M. K.; Kumar, P.; Venkateswara
Rao, B. Tetrahedron Lett. 1996, 37, 8617-8620.
which the (Z)-enoate 26 was prepared following the Still proce-
dure.12 The aldehyde 27 was in turn obtained from 26 (Scheme 3).
Synthesis of the side chain fragment started from D-malic acid
(28), which was converted into the ketal 29 after selective ketal
formation, borane reduction, and TBS protection. After reaction
of 29 with the alcohol 30, the primary alcohol 31 was obtained via
TBS protection and selective TBS deprotection. The phosphonium
salt 32 was prepared from the alcohol 31 via iodide substitution
(Scheme 4).
Julia-Julia reaction between the sulfone 18 and the aldehyde
27 generated the trans double bond producing the intermediate 33.
Careful acetonide deprotection and selective silylation led to the
formation of the corresponding secondary alcohol, and esterification
with the acid 34 led to the preparation of the trans-â-stannylacrylate
35: the undesired cis-â-stannylacrylate isomer was easily separated
and recycled under basic conditions. Intramolecular Stille coupling
reaction of 35 proceeded uneventfully to provide the macrolactone
36, which was converted into the aldehyde 37. Wittig reaction
between the ylide prepared from 32 and the aldehyde 37 led to the
product 3 after subsequent TBS deprotection (Scheme 5).
(4) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.; Repic,
O.; Shapiro, M. J. Chem. Lett. 1987, 1923-1926.
(5) For selected examples of â-alkoxyacrylate radical cyclizations, see: (a)
Lee, E.; Park, C. M.; Yun, J. S. J. Am. Chem. Soc. 1995, 117, 8017-
8018. (b) Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K. J.
Am. Chem. Soc. 2001, 123, 10131-10132. (c) For further references,
see: Lee, E. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Applications, Vol. 2; Wiley-VCH: Weinheim, 2001; pp 303-333.
(6) For selected examples of similar 6-endo cyclization reactions, see: (a)
Wilt, J. W. J. Am. Chem. Soc. 1981, 103, 5251-5253. (b) Koreeda, M.;
George, I. A. J. Am. Chem. Soc. 1986, 108, 8098-8100.
(7) Tamao, K.; Kakui, T.; Akita, M.; Iwahara, T.; Kanatani, R.; Yoshida, J.;
Kumada, M. Tetrahedron 1983, 39, 983-990.
(8) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26-28.
(9) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999,
121, 4924-4925.
(10) For similar reaction sequences, see: Evans, D. A.; Kaldor, S. W.; Jones,
T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001-7031.
(11) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408-
7410.
(12) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(13) The reported value1 for natural lasonolide A: [R]D +24.4 (c 0.045, CDCl3).
The value obtained for 3: [R]20 D -24.1 (c 0.055, CDCl3). The unnatural
enantiomer 3 was obtained in 0.68% total yield from ethyl L-malate (4)
in 36 steps in the longest sequence.
JA017265D
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