Synthetic Studies Towards Phorboxazole B: Stereoselective Synthesis of the C3-C19 Bis-oxane Oxazole Fragment

Article abstract of DOI:10.1055/s-2003-41462

A convergent and enantioselective synthesis of the C3-C19 bis-oxane oxazole fragment of phorboxazole B has been described. This work features highly efficient substrate-controlled reductions to construct the functionalised cis-oxane and a Mukaiyama aldol

Full text of DOI:10.1055/s-2003-41462

LETTER
1817
Synthetic Studies Towards Phorboxazole B: Stereoselective Synthesis of
the C3–C19 Bis-oxane Oxazole Fragment
Dong-hui Zhang, Wei-shan Zhou*
Shanghai Institute of Organic Chemistry, 354 Fenglin Rd, Shanghai 200032, P. R. China
Fax +86(21)64166128; E-mail: zhws@mail.sioc.ac.cn.
Received 15 July 2003
tumor cell lines (mean GI50 < 1.6 × 10–9 M).2 The unprec-
edented structural features and extraordinary potency of 1
have inspired wide interest in the organic synthetic com-
munity,3,4 and several outstanding achievements of total
Abstract: A convergent and enantioselective synthesis of the C3–
C19 bis-oxane oxazole fragment of phorboxazole B has been de-
scribed. This work features highly efficient substrate-controlled re-
ductions to construct the functionalised cis-oxane and a Mukaiyama
aldol reaction followed by an intramolecular Williamson reaction synthesis have been reported.5
leading to a trans-oxane.
Our retrosynthetic analysis of phorboxazole B (1b) in-
Key words: enantioselective synthesis, phorboxazole, reduction,
Mukaiyama reaction, Williamson reaction
volved disconnections of the structure at the C2–C3, the
C19–C20 and the C27–C28 bonds, which led to the key
building blocks 2–4. The stereoselective synthesis of
C21–C27 fragment 3 has been reported in a previous
publication.4b Herein, we describe our synthesis of the
C3–C19 bis-oxane oxazole portion 4 of phorboxazole B.
The phorboxazoles (1a and 1b) (see Figure 1), which
were isolated from the Indian Ocean sponge Phorbas sp.,
are unique macrolides accommodating four heavily func-
tionalised oxanes and two 2,4-disubstituted oxazoles.1
These metabolites have ranked among the most potent an-
tibiotic agents discovered to date, displaying exceptional
cytostatic activity throughout the panel of 60 NCI human
The strategy for constructing the bis-oxane 4 is retrosyn-
thetically outlined in Scheme 1. Disconnection of the
structure at the C5–O ether bond followed by sequentially
functional group transformations afforded the b-hydroxyl
R1
R2
O
19
N
O
20
OMe
O
O
O
28
OMe
N
O
27
Br
3
O
O
2
46
H
OH
OH
OMe
O
OTBS
1a R1 = H, R2 = OH
1b R1 = OH, R2 = H
O
19
OTBS
N
OBz
O
PMBO
28
21
OMe
N
O
O
Br
O
O
46
H
OMe
OAc
OTIPS
27
4
2
3
BPSO
3
Figure 1 Phorboxazole A (1a) and phorboxazole B (1b).
SYNLETT 2003, No. 12, pp 1817–1821
2
9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41462; Art ID: U13703ST
© Georg Thieme Verlag Stuttgart · New York

1818
D.-h. Zhang, W.-s. Zhou
LETTER
OTBS
O
OTBS
O
O
OPMB
TBSO
OTBS
13
15
15
N
OH
9
O
OBPS
11
OTBS
O
N
O
8
9
N
O
O
H
15
O
TBSO
O
4
16
BPSO
14
5
OPMB
BPSO
3
O
N
O
O
11
PMBO
TBSO
Scheme 1 Retrosynthetic analysis of 4.
ketone 16. An aldol disconnection at the C8–C9 bond of removing the two TBS protecting group in 9. Indeed, ex-
compound 16 then let to methyl ketone 156 and aldehyde posure of 9 to 5% solution of HF acid in CH3CN at room
14. The aldehyde 14 could be synthesised from 2H-pyra- temperature smoothly led to the cyclodehydrated product
none 11 and the stereochemistry of C13 and C15 was 10 in an excellent yield (90%). The primary hydroxyl of
expected to be established via Luche reduction7 of ketone 10 was reprotected with TBS group to afford 2H-pyra-
carbonyl of 11 followed by hydrogenation8 of the double none 11 in 97% yield.
bond.
With a quantity of 11 in hand, we focused our attention on
The synthesis of 2H-pyranone 11 was described in the construction of C13 and C15 stereogenic centers (see
Scheme 2. Wacker oxidation9 of the chiral building block Scheme 3). Thus, a stereoselective Luche reduction7 of
55d gave rise to the methyl ketone 6 in 89% yield. Treat- pyranone 11 in methanol at –78 °C provided 2H-pyrane
ment of the lithium enolate of 6 with aldehyde 710 in THF 12 in 95% yield as a single isomer. The next step involved
at –78 °C let to the b-hydroxy ketone 8 in 81% yield as a the creation of cis-(C11/C15) oxane ring through a stereo-
mixture of two C15 epimeric isomers. These diastereoiso- selectively substrate-controlled hydrogenation of the
meric substances were used directly in the next step with- C14–C15 double bond.8 In the presence of a catalytic
out separation. Thus, oxidation of the mixture of 8 with amount of palladium on charcoal, compound 12 was
Dess–Martin periodinane11 afforded the corresponding b- smoothly hydrogenated to the cis-oxane 13 in 95% yield
diketone 9 in 90% yield, which was showed to exist com- as a single isomer.13 To our surprise, direct hydrogenation
pletely in the form of enol-ketone by NMR spectrum. In of 11 in EtOAc also delivered compound 13 although the
the following step, it was anticipated that HF acid12 would yield was very low. After a lot of trials, it was found
immediately catalyse the cyclodehydration reaction after that yield was increased to 65% when the reaction was
O
N
H
OH
15
O
OTBS
O
OTBS
TBSO
O
OTBS
7
a
N
O
b
OPMB
OPMB
OPMB
6
5
8
TBSO
O
O
OH
O
OTBS
N
O
N
O
d
c
OPMB
OPMB
9
TBSO
10 R=H
11 R=TBS
RO
e
Scheme 2 a) catalyst PdCl2, CuCl, O2, DMF–H2O, r.t., 6 h, 89%; b) LDA, 7, –78 °C, THF, 81%; c) Dess–Martin periodinane, CH2Cl2, r.t.,
90%; d) 5% HF in CH3CN, r.t., 12 h, 90%; e) TBSCl, imidazole, DMF, r.t., 97%.
Synlett 2003, No. 12, 1817–1821 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of the C3–C19 Bis-oxane Fragment
1819
OH
13
O
15
c
N
O
N
O
O
OPMB
O
OPMB
13
11
OH
O
TBSO
TBSO
b
a
N
OPMB
O
TBSO
12
Scheme 3 a) NaBH4, CeCl3, MeOH, –78 °C, 95%; b) H2, 10% Pd/C, EtOAc, 8 h, 95%; c) H2, 5% Pd/C, EtOAc-buffer solution (pH = 1),
8 h, 65%.
OTBS
OTBS
O
OPMB
d
OH
9
15
OBPS
O
N
O
a,b, c
O
e
13
N
O
O
H
TBSO
O
16
14
TBSO
BPSO
OBz
OPMB
OTBS
O
OTBS
O
OBz
N
O
g, h, i
f
N
TBSO
O
TBSO
O
18
BPSO
OPMB
17
BPSO
OPMB
OTBS
19(C9 epimeric isomer)
+
OMs
N
j
O
4
O
TBSO
20
BPSO
OH
Scheme 4 a) TBSCl, imidazole, DMF, r.t., 96%; b) DDQ, CH2Cl2–H2O, r.t., 93%; c) Dess–Martin periodinane, CH2Cl2, r.t., 92%;
d) 1) LHDMS, TMSCl, THF, –78 °C; 2) 14, TiCl4, –78 °C, 68%; e) BzCl, py, r.t., 90%; f) Nysted reagent, TiCl4, r.t., 30 min, then 17, 74%;
g) DIBAL-H, CH2Cl2, –78 °C; h) MsCl, Et3N, CH2Cl2, 0 °C; i) DDQ, CH2Cl2–H2O, 68% for three steps; j) Et3N, CH3CN, reflux, 83%.
conducted in a mild acidic condition. It is particularly the b-hydroxyl ketone 16 as the major component of an
noteworthy that the highly stereoselective introduction of inseparable mixture of C9 epimeric isomers (7.8:1).15 Al-
the C13 and C15 stereogenic centers together with the though it was more convenient to separate these isomers
cis-oxane ring required only conventional manipulations in later step, the mixture were used without difficulties in
using easily available reagents.
the ensuing steps. Unfortunately, methylenation of the ke-
tone carbonyl group of 16 did not result in the desired
product but a dehydrate one under many conditions, such
as Lombardo’s condition,16 Takai’s condition,17 and Peta-
sis’s condition.18 To suppress this undesirable side reac-
tion, the hydroxyl group of 16 was shielded with benzoyl
group to provide ketone 17, which was smoothly methyl-
enated with Nysted reagent {cyclo-dibromodi-m-methyl-
ene [m-(tetrahydrofuran)] trizinc}19 to give product 18 in
The final completion of this synthesis is described in
Scheme 4. Protection of the C13 hydroxy of compound 13
and subsequent removal of the PMB protecting group fol-
lowed by oxidation of the resulting primary hydroxy af-
forded the corresponding aldehyde 14 in 82% yield for
three steps. Aldol reaction of aldehyde 14 with the silyl
enol ether of 156 in the Mukaiyama condition14 produced
Synlett 2003, No. 12, 1817–1821 © Thieme Stuttgart · New York

1820
D.-h. Zhang, W.-s. Zhou
LETTER
2000, 39, 2533. (w) Evans, D. A.; Fitch, D. M. Angew.
Chem. Int. Ed. 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.
66% yield and 19 in 8% yield. Two isomers were conve-
niently separated by flash column chromatography on sil-
ica gel. With compound 18 in hand, it required only a few
steps to complete the synthesis of 4. Thus, removal of the
benzoyl protecting group and subsequent mesylation of
the resulting hydroxyl followed by cleavage of the p-
methoxybenzyl protecting group provided 20 in 68%
yield for three steps. According to Forsyth’s condition,3b
finally, when a solution of compound 20 in CH3CN was
treated with excess Et3N and heated to reflux for 12 hours,
the bis-oxane 4 was smoothly produced in 83% yield.20
(4) (a) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44,
3749. (b) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003, 44,
4933. (c) Haustedt, L. O.; Hartung, I. V.; Hoffmann, H. M.
R. Angew. Chem. Int. Ed. 2003, 42, 2711.
(5) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 120, 5597. (b) Evans, D. A.; Smith, T. E.;
Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033. (c) Smith,
A. B.; Verhoest, P. R.; Minbiole, K. P.; Schelhaas, M. J. Am.
Chem. Soc. 2001, 123, 4834. (d) Smith, A. B. I. I. I.;
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. 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. 2003, 42, 1258.
(6) (a) The methyl ketone 15 was conveniently prepared from
1-(tert-butyl-diphenyl-silanyloxy)-hex-5-en-3R-ol, see:
Smith, A. B. III; Lin, Q.; Nakayama, K.; Boldi, A. M.;
Brook, C. S.; McBriar, M. D.; Moser, W. H.; Sobukawa, M.;
Zhuang, L. Tetrahedron Lett. 1997, 38, 8675. (b)Protection
of 1-(tert-butyl-diphenyl-silanyloxy)-hex-5-en-3R-ol with
PMB protecting group [Cl3C(NH)OPMB, 0.03 equiv
BF3·OEt2, CH2Cl2–cyclohexane, 0 °C, 87%) followed by
Wacker oxidation of the resulting substance (catalyst PdCl2,
CuCl, O2, DMF–H2O, r.t., 12 h, 86%) provided 6.
In summary, we have described a convergent and enantio-
selective synthesis of the bis-oxane oxazole fragment of
phorboxazole B. This work features a remarkably effi-
cient strategy for construction of the functionalised cis-
oxane using stereoselectively substrate-controlled hydro-
genation chemistry.
Acknowledgment
We thank Professor Wu Hou-ming and Mr. Wang Zhong-hua for
the NOE measurements of compound 13. We also thank Professor
Xia Li-jun and Miss Lin Lin for performing the HPLC analysis.
References
(7) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(8) (a) Sato, M.; Kuroda, H.; Kaneko, C.; Furuya, T. J. Chem.
Soc., Chem. Commun. 1994, 6, 687. (b) Uesato, S.; Takeda,
Y.; Hashimoto, T.; Uobe, K.; Inouye, H.; Taguchi, H.; Endo,
T. Helv. Chim. Acta 1984, 67, 2111.
(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. 1998, 37, 7879.
(c) Searle, P. A.; Molinski, T. F.; Brzeainski, L. J.; Leahy, J.
W. J. Am. Chem. Soc. 1996, 118, 9422.
(9) For a review on Wacker oxidation, see: Tsuji, J. Synthesis
1984, 369.
(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) 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.
(10) The aldehyde 7 was constructed from the known ethyl 2-
hydroxymethyl-oxazole-4-carboxylate, via silylation of the
primary hydroxyl (TBSCl, imidazole, DMF, r.t., 96%)
followed by partial reduction of the ester (DIBAL-H,
CH2Cl2, –78 °C, 85%), see: Panek, J. S.; Beresis, R. T. J.
Org. Chem. 1996, 61, 6496.
(11) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(12) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D.
R.; Roberts, S. M. Tetrahedron Lett. 1979, 20, 3981.
(13) The configuration of 13 was confirmed by NOE
measurements. Compound 13: 1H NMR (600 MHz, CDCl3)
d = 7.51 (s, 1 H), 7.14 (d, J = 8.7 Hz, 2 H), 6.75 (d, J = 8.7
Hz, 2 H), 4.73 (s, 2 H), 4.42 (s, 2 H), 4.36 (d, J = 10.5 Hz, 1
H), 3.85–3.90 (m, 1 H), 3.80 (s, 3 H), 3.64–3.67 (m, 1 H),
3.60–3.62 (m, 1 H), 3.53–3.56 (m, 1 H), 2.28 (dt, J = 12.6,
2.4 Hz, 1 H), 2.01 (dt, J = 12.3, 2.4 Hz, 1H), 1.88–1.93 (m,
1 H), 1.78–1.83 (m, 1 H), 1.34 (app q, J = 11.7 Hz, 1 H), 1.28
Tetrahedron Lett. 1999, 40, 2287. (h) Williams, D. R.;
Clark, M. P. Tetrahedron Lett. 1999, 40, 2291. (i) Wolbers,
P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett.
1999, 40, 4527. (j) Wolbers, P.; Hoffmann, H. M. R.
Tetrahedron 1999, 55, 1905. (k) Misske, A. M.; Hoffmann,
H. M. R. Tetrahedron 1999, 55, 4315. (l) Wolbers, P.;
Hoffmann, H. M. R. Synthesis 1999, 2291. (m) Evans, D.
A.; Cee, V. J.; Smith, T. E.; Santiaga, K. J. Org. Lett. 1999,
1, 87. (n) Smith, A. B. III; Verhoest, P. R.; Minbiole, K. P.;
Lim, J. J. Org. Lett. 1999, 1, 909. (o) Smith, A. B.;
Minbiole, K. P.; Verhoest, P. R.; Beauchamp, T. J. Org. Lett.
1999, 1, 913. (p) Wolbers, P.; Hoffmann, H. M. R.; Sasse, F.
Synlett 1999, 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) Rychnovsky, 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.
(app q, J = 10.5 Hz, 1 H), 0.92 (s, 9 H), 0.10 (s, 6 H). 13
C
NMR (75 MHz, CDCl3): d = 162.5, 159.1, 141.2, 135.2,
130.5 129.2, 113.7, 73.1, 72.5, 71.0, 67.8, 66.1, 58.3, 55.2,
40.9, 40.0, 36.0, 25.7, 18.3, –5.4.
(14) (a) Mukaiyama, T.; Banno, K.; Naraska, K. J. Am. Chem.
Soc. 1974, 96, 7503. (b) For 1,3-asymmetric induction in
diastereoselective Mukaiyama aldol addition reaction, see:
Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322. (c) Also see: Reetz, M. T.;
Jung, A. J. Am. Chem. Soc. 1983, 105, 4833.
(15) The diastereoselective ratio was measured by HPLC
analysis.
Synlett 2003, No. 12, 1817–1821 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of the C3–C19 Bis-oxane Fragment
1821
(16) Lombardo, L. Org. Synth. 1987, 65, 81.
(17) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org.
Chem. 1994, 59, 2668.
(18) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392.
(19) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313.
(20) The relative stereochemistry between C5 and C9 of 4 was
confirmed by NOE experiments. Compound 4: Colorless oil,
[a]D25 = –14.2 (c 0.35, CHCl3). 1H NMR (400 MHz, CDCl3)
d = 7.65–7.68 (m, 4 H), 7.47 (s, 1 H), 7.37–7.40 (m, 6 H),
4.72 (d, J = 5.4 Hz, 2 H), 4.72 (s, 2 H), 4.27 (d, J = 10.8 Hz,
1 H), 4.02 (app q, J = 6.0 Hz, 1 H), 3.93 (app q, J = 6.0 Hz,
1 H), 3.67–3.83 (m, 3 H), 3.49–3.55 (m, 1 H), 2.36 (br s, 1
H), 2.35 (br s, 1 H), 2.12–2.16 (m, 1 H), 1.95–2.07 (m, 3 H),
1.88–1.92 (m, 1 H), 1.79–1.85 (m, 1 H), 1.62–1.70 (m, 1 H),
1.48–1.54 (m, 2 H), 1.20–1.33 (m, 1 H), 1.04 (s, 9 H), 0.89
(s, 9 H), 0.86 (s, 9 H), 0.09 (s, 6 H), 0.034 (s, 3 H), 0.028 (s,
3 H). 13C NMR (100 MHz, CDCl3): d 162.4, 142.2, 141.8,
135.7, 135.2, 135.0, 134.0, 129.7, 127.8, 127.7, 110.4, 73.0,
71.4, 69.0, 68.7, 68.6, 60.7, 58.5, 41.2, 40.8, 40.0, 39.6, 39.6,
39.4, 36.5, 27.0, 26.7, 25.9, 19.3 (3 C), 18.5 (3 C), 18.1 (3
C), –4.4 (2 C), –5.3 (2 C). IR (cm–1): 3073, 1655, 1093,
1112. HRMS (ESI) calcd for C46H73O6NSi3Na (M + Na)+:
842.4633, found: 842.4638.
Synlett 2003, No. 12, 1817–1821 © Thieme Stuttgart · New York