Studies on the synthesis of phorboxazole B: Stereoselective synthesis of the C28-C46 segment

Article abstract of DOI:10.1016/j.tetlet.2003.09.141

A stereoselective synthesis of C28-C46 segment of phorboxazole B is described. Key features of the synthetic route involved the use of 1,3-asymmetric induction of Mukaiyama aldol reaction to construct the stereogenic center at C35, and the employment of m

Full text of DOI:10.1016/j.tetlet.2003.09.141

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8729–8732
Studies on the synthesis of phorboxazole B: stereoselective
synthesis of the C28–C46 segment
De Run Li,a,b Yong Qiang Tu,b Guo-Qiang Lina,* and Wei-Shan Zhoua
aShanghai Institute of Organic Chemistry, 354 Fenglin Road, Shanghai 200032, PR China
bDepartment of Chemistry and State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
PR China
Received 25 July 2003; revised 8 September 2003; accepted 12 September 2003
Abstract—A stereoselective synthesis of C28–C46 segment of phorboxazole B is described. Key features of the synthetic route
involved the use of 1,3-asymmetric induction of Mukaiyama aldol reaction to construct the stereogenic center at C35, and the
employment of metalated oxazole chemistry to prepare the ketal 6.
© 2003 Elsevier Ltd. All rights reserved.
Phorboxazoles 1 (Fig. 1), which were isolated from the
Indian Ocean sponge Phorbas sp., are novel 21-mem-
bered macrolides accommodating four heavily function-
alized oxanes and two 2,4-disubstituted oxazoles.1
These metabolites have ranked among the most cyto-
static natural products known, and exhibit extraordi-
nary potency (mean GI50<1.6×10−9 M) while bioassayed
for the 60 human tumor cell strains at the National
Cancer Institute (NCI).2 The unprecedented structural
features and remarkable antitumor activity of 1 have
inspired wide interest in the synthetic community,3 and
several excellent achievements of total synthesis have
been reported.4 Our retrosynthetic analysis of phorbox-
azole B (1b, Figure 1) released the disconnections of the
structure at the C2–C3, the C19–C20 and the C27–C28
double bonds, which led to the key building blocks 2, 3
Figure 1. Phorboxazole A (1a) and phorboxazole B (1b).
Keywords: phorboxazole B; synthesis; Mukaiyama aldol reaction; oxazole.
* Corresponding author. Tel.: +86-21-64163223; e-mail: lingq@mail.sioc.ac.cn
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.141

8730
D. R. Li et al. / Tetrahedron Letters 44 (2003) 8729–8732
Scheme 1. Retrosynthetic analysis of the segment 2.
reported in a previous publication.3bb Herein, we wish
to describe our stereoselective synthesis of the C28–C46
oxane–oxazole segment 2 of phorboxazole B.
DIBAL-H and acylation of the resultant C41 hydroxyl
group.13 Hydrolysis of TBS ether of 19 and oxidation
of the alcohol under Dess–Martin condition14 yielded
20, which was a -OPMB protected aldehyde and suit-
able for 1,3-anti Mukaiyama aldol reaction.
From the retrosynthetic perspective (Scheme 1), discon-
nection of C41–C42 double bond separate the unit 2
into the known sulfone 54b,e,f and oxane–oxazole 6. We
envisaged that coupling the lactone 7 with oxazole 8 by
using metalated oxazole chemistry3m would lead to
formation of 6.
The aldol coupling of 1-ethoxy-1-[(trimethylsilyl)-
oxy]ethane 2115 with the aldehyde 20 was found to
afford 22 in modest stereoselectivity under standard
conditions (BF3·OEt2, MgBr2·OEt2) and neither did the
strong Lewis acid such as TiCl4 promote a clean reac-
tion, while the use of the mixed titanium species
TiCl2(Oi-Pr)2 (toluene, −78°C) delivered a high-yield-
ing, stereoselective reaction (87%, 4:1 dr)8 to afford
22,16 which is consistent with the result reported by
Evans et al.17 The orientation of C35 hydroxyl was
assigned to be on the basis of 2D NOSEY spectroscopy
of the succeeding lactone 24. Several methylation meth-
ods to protect the free hydroxyl of 22 were proved to be
unsuccessful, including NaH/CH3I18 and catalyzed di-
azomethane procedure.19 Finally, treatment of 22 with
Sulfone 5 was conveniently prepared from the known
optically active bis-3C building block 9 (Scheme 2).5
Ring opening of 9 by lithium TMS acetylide in the
presence of BF3·OEt2 gave diol 10, which was followed
by transformation to methyl ether 11 by methylation
with Meerwein’s salt (Me3OBF4).4b Removal of
hydroquinone from 11 by treatment with CAN5 pro-
duced 2 equiv. of the known alcohol 12.4d Displacement
of the primary alcohol of 12 with 2-mercaptobenzothia-
zole and desilylation of the TMS group furnished the
alkyne 13. Thus, introduction of the vinyl bromide via
hydrozirconation of the alkyne and subsequent treat-
ment with NBS,6 followed by oxidation of the sulfide
with ammonium molybdate4b afforded the desired sul-
fone 5.
As shown in Scheme 3, monosilylation of 14 and the
subsequent oxidation of the alcohol by PCC, followed
by olefination of the resultant aldehyde gave the unsat-
urated ester 157 as a almost single E isomer (E:Z>
95:5).8 15 was subjected to Sharpless asymmetric
dihydroxylation to afford the diol 16 in 87% yield (86%
ee by chiral GC analysis).9 Thus, the stereogenic centers
at C37 and C38 were smoothly constructed. Protection
of hydroxyl groups of 16 by p-methoxybenzyl
trichloroacetimidiate in the presence of BF3·OEt2,10 fol-
lowed by reduction afforded the alcohol 17. The
hydroxyl moieties at C37 and C38 were protected with
PMB ether due to the fact that PMB ether gave the best
1,3-stereoinduction of Mukaiyama aldol reaction
according to the literature.11 Swern oxidation12 of
hydroxyl group of 17 and Wittig olefination of the
resulting aldehyde with CH3C(PPh3)CO2Et incorpo-
rated the E-unsaturated ester 18.3c Ester 18 was conve-
niently transferred to acetate 19 by reduction with
Scheme 2. Reagents and conditions: (a) TMSCꢀCH, BuLi,
BF3·OEt2, THF, −78°C, 81%; (b) Me3OBF4, Proton Sponge,
CH2Cl2, rt, 87%; (c) CAN, CH3CN/H2O, rt, 91%; (d) 2-mer-
captobenzothiazole, PPh3, DEAD, THF, 0°C, 81%; (e)
TBAF, THF, rt, 99%; (f) Cp2ZrHCl, THF, then NBS; (g)
(NH4)6Mo7O24·4H2O, 30% H2O2, EtOH, 56%, 2 steps.

D. R. Li et al. / Tetrahedron Letters 44 (2003) 8729–8732
8731
Scheme 3. Reagents and conditions: (a) NaH, TBSCl, THF, 0°C; (b) PCC, CH2Cl2, rt; (c) Ph3PꢁCHCO2Et, benzene, reflux, 51%,
3 steps; (d) AD-mix , t-BuOH/H2O, rt, 87%; (e) PMBOC(ꢁNH)CCl3, cyclohexane/CH2Cl2, BF3·OEt2, 0°C; (f) LiAlH4, Et2O, rt,
71%, 2 steps; (g) (COCl)2, DMSO, CH2Cl2, −78°C, then Et3N; (h) CH3C(PPh3)CO2Et, CH2Cl2, reflux, 84%, 2 steps; (i) DIBAL-H,
CH2Cl2, −78°C, 95%; (j) Ac2O, Et3N, CH2Cl2, rt, 95%; (k) Bu4NF, THF, rt, 96%; (l) Dess–Martin periodinane, CH2Cl2, 91%; (m)
TiCl2(Oi-Pr)2, toluene, −78°C, then 1-ethoxy-1-[(trimethylsilyl)-oxy]ethane 21, 87%, 4:1 dr; (n) Me3OBF4, Proton Sponge, CH2Cl2,
rt, 86%; (o) CF3CO2H, CH2Cl2, rt, 95%; (p) TIPSCl, imidazole, cat. DMAP, DMF, rt, 78%; (q) 8, LiNEt2, THF, −78°C, then 7;
(r) pTSA, MeOH, rt, 44%, 2 steps; (s) Dess–Martin periodinane, pyridine, CH2Cl2, rt; (t) 5, NaHMDS, THF, −78°C, then
aldehyde from 6, 46%, 2 steps.
Meerwein’s salt (Me3OBF4)4b and 1,8-bis(dimethyl-
amino)-naphthalene (Proton Sponge) gave the desired
compound 23 in 86% yield. Due to the existence of two
vicinal PMB ethers, deprotection of the PMB ethers
became an obstacle under oxidation procedure,20 such
as DDQ21 and CAN.22 Fortunately, when compound
23 was treated with 10% CF3CO2H in CH2Cl2,23 the
PMB ethers were smoothly removed and the resultant
diol was spontaneously cyclized to afford lactone 24 in
excellent yield (95%). Protection of C38 free hydroxyl
as its triisopropylsilyl ether furnished lactone 7.24
In summary, an efficient and enantioselective synthesis
of C28–C46 unit 2 of phorboxazole B was described.
Key features of the synthetic route involved 1,3-induc-
tion of Mukaiyama aldol reaction to stereoselectively
construct the stereocenter at C35, and the synthesis of
the ketal 6 by utilizing metalated oxazole chemistry.
Progress toward the completion of phorboxazole B is
now underway.
Acknowledgements
Now it is time to set up the condition for the coupling
of 4-(4-methoxy-benzyloxymethyl)-2-methyl-oxazole 825
with lactone 7. To our delight, when oxazole 8 was
deprotonated with lithium diethylamide at −78°C, and
treated with lactone 7, the desired methyl ketal 6 was
obtained after methylation (pTSA, CH3OH).4d,26 It was
noteworthy that the acetoxyl moiety in lactone 7 was
also removed in the metalation procedure. Careful oxi-
dation of the allylic primary alcohol of 6 with Dess–
Martin periodinane,14 followed by Julia olefination of
the resultant aldehyde with sulfone 5, according to the
similar condition reported by Williams et al.,4f fur-
nished the desired E, E segment 2 (46%, 2 steps; >95:5
E:Z).8,27
We thank Professor Wu Hou-ming and Mr. Wang
Zhong-hua for the NOE measurements.
References
1. Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126.
2. (a) Molinski, T. F.; Antonio, J. J. Nat. Prod. 1993, 56,
54; (b) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879;
(c) Searle, P. A.; Molinski, T. F.; Brzeainski, L. J.; Leahy,
J. W. J. Am. Chem. Soc. 1996, 118, 9422.
3. (a) Lee, C. S.; Forsyth, C. J. Tetrahedron Lett. 1996, 37,
6449; (b) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997,

8732
D. R. Li et al. / Tetrahedron Letters 44 (2003) 8729–8732
13. Ho¨fle, G.; Steglich, W.; Vorbru¨gen, H. Angew. Chem.,
62, 5672; (c) Pattenden, G.; Plowright, A. T.; Tornos, J.
A.; Ye, T. Tetrahedron Lett. 1998, 39, 6099; (d) Ahmed,
F.; Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183; (e) Ye,
T.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319; (f)
Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39,
7185; (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) Wol-
bers, P.; Misske, A. M.; Hoffman, H. R. Tetrahedron
Lett. 1999, 40, 4527; (j) Wolber, P.; Hoffman, H. M. R.
Tetrahedron 1999, 55, 1905; (k) Misske, A. M.; Hoffman,
H. M. R. Tetrahedron 1999, 55, 4315; (l) Wolbers, P.;
Hoffman, H. M. R. Synthesis 1999, 40, 2291; (m) Evans,
D. A.; Cee, V. J.; Smith, T. E.; Santiaga, K. J. Org. Lett.
1999, 1, 87; (n) Smith, A. R., III; Verhoest, P. R.;
Minbiole, K. P.; Lim, J. J. Org. Lett. 1999, 1, 909; (o)
Smith, A. R., III; Minbiole, K. P.; Verhoest, P. R.;
Beauchamp, T. J. Org. Lett. 1999, 1, 913; (p) Wolbers, P.;
Hoffman, H. M. R.; Sasse, F. Synlett 1999, 11, 1808; (q)
Pattenden, G.; Plowright, A. T. Tetrahedron Lett. 2000,
41, 983; (r) Greer, P. B.; Donaldson, W. A. Tetrahedron
Lett. 2000, 41, 3801; (s) Rychovsky, S. D.; Thomas, C. R.
Org. Lett. 2000, 2, 1217; (t) Williams, D. R.; Clark, M.
P.; Emde, V.; Berliner, M. A. Org. Lett. 2000, 2, 3023; (u)
Schaus, J. V.; Panek, J. S. Org. Lett. 2000, 2, 469; (v)
Evans, D. A.; Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho,
P. S. Angew. Chem., Int. Ed. Engl. 2000, 39, 2533; (w)
Evans, D. A.; Fitch, D. M. Angew. Chem., Int. Ed. Engl.
2000, 39, 2536; (x) Huang, H.; Panek, J. S. Org. Lett.
2001, 3, 1693; (y) White, J. D.; Kranemann, C. L.;
Kuntiyong, P. Org. Lett. 2001, 3, 4003; (z) Greer, P. B.;
Donaldson, W. A. Tetrahedron 2002, 58, 6009–6018; (aa)
Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44,
3749; (bb) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003,
44, 4933.
Int. Ed. Engl. 1978, 17, 569.
14. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
15. Mikami, K.; Matsumoto, S.; Ishika, A.; Takamuku, S.;
Suenobu, T.; Fukuzumi, S. J. Am. Chem. Soc. 1995, 117,
11134.
16. 22 was isolated in 61% yield as the major diastereomer.
17. Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A.
B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999,
121, 7540.
18. Jung, M. E.; Kaas, S. M. Tetrahedron Lett. 1989, 30, 641.
19. Ohno, K.; Nishiyama, H.; Nagase Tetrahedron Lett.
1979, 20, 4405.
20. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 889.
21. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885.
22. Johansson, R.; Samuelsson, B. J. Chem. Soc., Perkin
Trans. 1 1984, 2371.
23. Yan, L.; Kahne, D. Synlett 1995, 523.
24. Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797.
25. Oxazole 8 was conveniently prepared from methyl 2-
methyloxazole-4-carboxylate in two operations: (a)
DIBAL-H, CH2Cl2, −78°C, 68%; (b) PMBCl, NaH,
THF, rt, 91%. For the preparation of methyl 2-methylox-
azole-4-carboxylate see: Cornforth, J. W.; Cornforth, R.
H. J. Chem. Soc. 1947, 96.
26. The stereochemistry of C33 in methyl ketal 6 was con-
firmed by the NOE effect among C33 methoxyl group,
H35 and H37 of the compound 2. That the methyl ketal
6 was obtained as a single diastereoisomer is presumably
due to anomeric effects; see: Juaristi, E.; Cuevas, G.
Tetrahedron 1992, 48, 5019.
4. (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J.
Am. Chem. Soc. 1998, 120, 5597; (b) Evans, D. A.; Fitch,
D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000,
122, 10033; (c) Smith, A. B., III; Verhoest, P. R.; Minbi-
ole, K. P.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123,
4834; (d) Smith, A. B., III; Minbiole, K. P.; Verhoest, P.
R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942; (e)
Gonzalez, M. A.; Pattenden, G. Angew. Chem., Int. Ed.
Engl. 2003, 42, 1255; (f) Williams, D. R.; Kiryanov, A.
A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T.
Angew. Chem., Int. Ed. Engl. 2003, 42, 1258.
5. Wang, Z.-M.; Shen, M. J. Org. Chem. 1998, 63, 1414.
6. Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
7. Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39,
4421.
27. The NOE effect between H42 and H47 and the coupling
constant between H41 and H42 (J41,42=15.7 Hz) con-
firmed E configuration of C41–C42 double bond. Physi-
cal and spectroscopic data for 2: colorless oil. [h]2D5=
−21.7 (c 0.12, CHCl3). 1H NMR (400 MHz, CDCl3) l
7.51 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz,
2H), 6.20–6.07 (m, 3H), 5.43 (dd, J=15.7 Hz, 7.7 Hz,
1H), 5.42 (d, J=9.0 Hz, 1H), 4.61 (dd, J=8.8 Hz, 6.2 Hz,
1H), 4.53 (s, 2H), 4.41 (s, 2H), 3.80 (s, 3H), 3.66–3.53 (m,
3H), 3.33 (s, 3H), 3.30 (d, J=15.0 Hz, 1H), 3.28 (s, 3H),
3.26 (s, 3H), 2.96 (d, J=15.0 Hz, 1H), 2.38–2.20 (m, 3H),
1.97 (ddd, J=12.0, 2.2, 2.1 Hz, 1H), 1.76 (s, 3H), 1.37
(dd, J=12.0, 12.0 Hz, 1H), 1.12–1.04 (m, 22H). 13C
NMR (100 MHz, CDCl3): l 160.3, 159.3, 138.1, 137.3,
136.4, 133.9, 133.8, 133.1, 130.0, 129.5 (2C), 127.9, 113.8
(2C), 106.3, 99.9, 81.2, 73.9, 73.5, 72.3, 71.7, 63.7, 56.3,
55.5, 55.3, 47.9, 39.2, 39.1, 35.7, 32.1, 18.0 (3C), 17.9
(3C), 13.6, 12.4 (3C). IR (film) 2942, 2867, 1614, 1572,
1515 cm−1. HRMS (ESI) calcd for C40H62O8SiNBrNa
(M+Na)+: 814.3320, found: 814.3332.
8. Product ratio determined by 1H NMR spectral analysis
(300 MHz).
9. Column: Rt-bDEXCST™, 30 meter, 0.25 mm ID, 25 m
df.
10. Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738.
11. (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron
Lett. 1994, 35, 8537; (b) Evans, D. A.; Dart, M. J.;
Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118,
4322.
12. Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem.
1978, 43, 2480.