Synthetic studies towards phorboxazole A. Stereoselective synthesis of the C3-C19 bis-oxane oxazole portion of the phorboxazole macrolide

Article abstract of DOI:10.1016/S0040-4039(99)02187-5

A synthesis of the C3-C19 bis-oxane portion of phorboxazole A, involving an oxy anion intramolecular Michael reaction to produce a cis-oxane and an intramolecular Williamson reaction leading to a trans-oxane, is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02187-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 983–986
Synthetic studies towards phorboxazole A.
Stereoselective synthesis of the C3–C19 bis-oxane oxazole
portion of the phorboxazole macrolide
Gerald Pattenden ∗ and Alleyn T. Plowright
School of Chemistry, Nottingham University, Nottingham NG7 2RD, UK
Received 4 November 1999; accepted 24 November 1999
Abstract
A synthesis of the C3–C19 bis-oxane portion of phorboxazole A, involving an oxy anion intramolecular Michael
reaction to produce a cis-oxane and an intramolecular Williamson reaction leading to a trans-oxane, is described.
© 2000 Elsevier Science Ltd. All rights reserved.
The phorboxazoles 1 are unique oxane oxazole based macrolides isolated from an Indian Ocean sponge
Phorbas sp., which show profound cytostatic activity against human tumour cell lines.1 It is not surprising
therefore that the phorboxazoles have attracted wide interest among synthetic chemists2,3 and, indeed,
in 1998 Forsyth and his colleagues4 described the first total synthesis of phorboxazole A 1a. In recent
publications2 we have presented our retrosynthetic analysis of phorboxazole, involving disconnections of
the structure at the C2–C3, the C19–C20 and the C30–C31/C27–C28 bonds, leading to the key building
blocks 2, 3 and 4. In the same publications we described stereoselective syntheses of the C20–C27
pentasubstituted oxane ring unit 3 and also the C31–C46 polyene oxane-hemiacetal side chain 2. In
this letter we present a synthesis of the C3–C19 bis-oxane oxazole portion 4 of phorboxazole A, suitably
functionalised for connection to the oxane unit 3 en route to the natural product itself.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02187-5
tetl 16115

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Our synthesis of the C3–C19 bis-oxane oxazole 4 was based on: (i) conversion of the chiral oxazolidine
55 into the 7-hydroxy unsaturated ester 6 using successive Brown allylboration reactions;6 (ii) oxy anion
intramolecular Michael reaction of 6 leading to the cis-oxane 7;7 (iii) conversion of the oxazolidine unit
in 7 to the corresponding oxazole 8; (iv) introduction of the unsaturated polyol side chain producing 9;
and finally (v) intramolecular cyclisation of 9 to give the trans-oxane ring in 4 (Scheme 1).8
Scheme 1.
Thus, treatment of the homochiral aldehyde 5, derived from L-serine,5 with Brown’s (+)-allyl di-
isopinocampheylborane reagent first led to the homoallylic alcohol 10 in 80% yield and with >92%
diastereoselectivity (Scheme 2).9 After protection of the hydroxyl group in 10, ozonolysis to 11 followed
by a second allylboration reaction and hydroxy group protection led to the corresponding 1,3-dioxy
compound 12. Ozonolysis of the alkene 12 and a Wittig reaction between the resulting aldehyde and
(carboethoxymethylene)-triphenylphosphorane next led to 13, which was then selectively deprotected
in the presence of PPTS to reveal the 7-hydroxy unsaturated ester 6. Treatment of 6 with NaHMDS
at −78°C resulted in a selective intramolecular oxy anion Michael addition producing largely the
cis(C11/C15)-oxane 7 (ca. 14% of the corresponding trans-pyran was produced concurrently) in a
satisfying 88% yield. The oxazole ring in the target 4 was next elaborated from the oxazolidine 7
following deprotection and conversion of the resulting β-hydroxyamine to the amide 14. Oxidation of 14
to the corresponding aldehyde and cyclisation, under known literature conditions,10 produced the oxazole
15. NOE studies with 15 confirmed the cis(C11/C15)-stereochemistry in this oxane intermediate.
Introduction of the second (trans(C5/C9)) oxane ring in the target 4 was accomplished via the
protected triol 20, derived from addition of the cuprate reagent produced from the vinyl iodide 1911
to the epoxide intermediate 18. The oxane epoxide 18 was produced from the oxane ester 15 via vicinal
bis-hydroxylation of the alkene intermediate 16 (to 17) as a key step.12 Unfortunately we observed no
diastereoselectivity in the conversion of 16 into 17, although the oxazolidine oxane 22 related to the
oxazole oxane 16 led to the corresponding vicinal diol 23 with >80% diastereoselectivity.12 However,
addition of the cuprate reagent, produced from the iodide 19, to the epoxide 18 led to the coupled product

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Scheme 2. Reagents: i, (a) (+)-α-allyl diisopinocampheylborane, (b) Et3N,·H2O2, 80%; ii, TESCl, Et3N, DMAP, 90%; iii, (a)
O3, NaHCO3, (b) PPh3, 92%; iv, (a) (+)-α-allyl diisopinocampheylborane, (b) Et3N, H2O2, 76%; v, TIPSOTf, 2,6-lutidine, 92%;
vi, (a) O3, NaHCO3, (b) PPh3, 95%; vii, Ph3PCHCO2Et, 87%; viii, PPTS, 84%; ix, NaHMDS, −78°C, 88%; x, 4 M HCl, dioxane;
xi, PMBOCH2CO2H, EDC, HOBt, Et3N, 75% (two steps); xii, Dess–Martin periodinane; xiii, (a) 2,6-di-tbutylpyridine, PPh3,
C2Br2Cl4, (b) DBU, 73% (two steps); xiv, DIBAL-H, 87%; xv, Ph3PCH3Br, n-BuLi, 60%; xvi, (DHQD)2PYR, K2OsO2(OH)4,
K3Fe(CN)6, K2CO3, 95% (based on recovered SM); xvii, NaH, N-tosylimidazole, 76%; xviii, tBuLi, 2-Th-CuCNLi, 60% (based
on recovered SM); xix, MsCl, Et3N; xx, CSA, MeOH, 60% (two steps); xxi, Et3N, CH3CN, ∆, 78%
20, as a mixture of C9 epimers. Mesylation of 20 and acetonide deprotection gave rise to the penultimate
intermediate 21. Treatment of 21 with triethylamine in hot acetonitrile resulted in clean intramolecular
ether formation involving only the C5 hydroxyl group to produce the six-ring oxane 4 in 78% yield
as a 1:1 mixture of cis- and trans(C5/C9)-diastereoisomers. The diastereoisomers were separated by
chromatography to afford the target intermediate bis-oxane oxazole 4.13
Refinements to this strategy, especially to optimise the diastereoselectivity in the conversion of 15
into 18, either via an oxazole or oxazolidine based cis-oxane intermediate, are now in progress in our
laboratories.

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Acknowledgements
We thank Merck, Sharp and Dohme for a scholarship (to A.T.P.) to support this work, and we also
thank Dr. Luis Castro of MSD for his interest in this study.
References
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126; (b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.;
Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422; (c) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879.
2. (a) Pattenden, G.; Ye, T. Tetrahedron Lett. 1998, 39, 319; (b) Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T. Tetrahedron
Lett. 1998, 39, 6099.
3. (a) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37, 6449; (b) Cink, R. D. Forsyth, C. J. J. Org. Chem. 1997, 62, 5672;
(c) Ahmed, F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183; (d) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39,
7185; (e) Wolbers, P.; Hoffman, H. M. R. Tetrahedron 1999, 55, 1905; (f) Misske, A. M.; Hoffman, H. M. R. Tetrahedron
1999, 55, 4315; (g) Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287; (h) Williams, D. R.;
Clark, M. P. Tetrahedron Lett. 1999, 40, 2291; (i) Wolbers, P.; Hoffman, H. M. R. Synthesis 1999, 5, 797; (j) Wolbers, P.;
Misske, A. M.; Hoffman, H. M. R. Tetrahedron Lett. 1999, 40, 4527; (k) Dunkel, R.; Hoffman, H. M. R. Tetrahedron 1999,
55, 8385; (l) Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999, 1, 87; (m) Smith III, A. B.; Verhoest, P.
R.; Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909; (n) Smith III, A. B.; Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T.
J. Org. Lett. 1999, 1, 913.
4. Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597.
5. McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. Synthesis 1994, 31.
6. (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092; (b) Brown, H. C.; Ramachandran, P. V. J. Organomet.
Chem. 1995, 500, 1.
7. For some comparative examples, see: (a) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227; (b) Betancort, J.
M.; Martin, V. S.; Padron, J. M.; Palazon, J. M.; Ramirez, M. A.; Soler, M. A. J. Org. Chem. 1997, 62, 4570; (c) Micalizio,
G. C.; Roush, W. R. Tetrahedron Lett. 1999, 40, 3351.
8. For examples of conceptually similar approaches to oxane ring formation see Refs. 3b, g and Aicher, T. D.; Buszek, K. R.;
Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem.
Soc. 1992, 114, 3162.
9. The diastereoselectivity of each of the allylboration reactions was determined by analysis of the NMR spectra. All new
compounds showed satisfactory spectroscopic data together with mass spectrometry and/or combustion analysis. 1H NMR
data for compound 7 (360 MHz, C6D6, T=340K) δ 4.47–4.39 (1H, m), 4.24 (1H, bd, J∼8.5), 4.19 (1H, bs), 4.13 (1H, ddd,
J 10.8, 8.3, 2.0), 4.02–3.93 (1H, m), 3.98 (2H, q, J 7.1), 3.68 (1H, dd, J 8.6, 5.5), 2.51 (1H, dd, J 15.0, 7.3), 2.25 (1H,
dd, J 15.0, 6.1), 1.90–1.84 (1H, m), 1.75–1.68 (4H, m), 1.61–1.53 (4H, m), 1.44 (9H, s), 1.30 (1H, ddd, J 13.6, 11.6, 2.5),
1.17–1.03 (21H, m), 1.00 (3H, t).
10. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558.
11. The vinyl iodide 19 was prepared starting from L-malic acid, based on procedures described earlier, see: Kolb, H. C.;
Sharpless, K. B. Tetrahedron 1992, 48, 10515; Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391; Hara, S.; Dojo,
H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983, 24, 731.
12. Crispino, G. A.; Jeong, K. S.; Kolb, H. C.; Wang, Z. M.; Xu, D.; Sharpless, K. B. J. Org. Chem. 1993, 58, 3785.
1
13. The stereochemistry of the bis-oxane 4 was assigned using NOE experiments. H NMR data for 4 (360 MHz, CDCl3) δ
7.57 (1H, d, J 0.8), 7.27 (2H, d, J 8.7), 6.89 (2H, d, J 8.7), 4.91 (1H, dd, J 11.2, 3.2), 4.77 (1H, s), 4.72 (1H, s), 4.56 (2H, s),
4.55 (2H, s), 4.41–4.39 (1H, m), 4.18–4.04 (2H, m), 4.01–3.95 (1H, m), 3.81 (3H, s), 3.74–3.71 (2H, m), 2.76 (1H, bs), 2.41
(1H, dd, J 13.2, 4.8), 2.28 (1H, dd, J 13.2, 3.7), 2.08 (1H, bd, J∼14.0), 2.06 (1H, bd, J∼13.2), 1.98–1.80 (4H, m), 1.74–1.70
(2H, m), 1.66–1.60 (2H, m), 1.17–1.04 (21H, m).