A stereoselective synthesis of the C20-C32 fragment of the phorboxazoles

Article abstract of DOI:10.1055/s-2007-982556

The C20-C32 fragment of the phorboxazoles was realized in a stereoconvergent manner utilizing a desymmetrization approach. This successful strategy involves epimerization and modified Julia olefination as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982556

LETTER
1577
A Stereoselective Synthesis of the C20–C32 Fragment of the Phorboxazoles
S
tereosele
.
ctive
S
ynthe
S
sis of
a
Phorbo
.
xazole Frag
Y
ment adav,*a M. Satyanarayana,a G. Srinivasulu,b A. C. Kunwarb
a
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
b
Centre for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)7160387; E-mail: yadavpub@iict.res.in
Received 6 October 2006
oxane ring. These are among the most cytostatic natural
products known, inhibiting the growth of tumor cells at
nanomolar concentrations with mean GI50 = 1.58 × 10–9
M against the NCI panel of 60 tumor cell lines. These
scarce natural products arrest cancer cell growth in the S
phase at low to subnanomolar concentrations, making
them promising candidates for therapeutic development.
The tremendous biological activity and the fascinating
molecular structure have stimulated synthetic efforts by a
number of research groups2 and seven elegant total
syntheses have been reported so far.3 The remarkable
biological activities associated with the phorboxazoles
make these compounds important leads for biotherapeutic
development.4 In this letter we describe the synthesis of
the C20–C32 fragment.
Abstract: The C20–C32 fragment of the phorboxazoles was
realized in a stereoconvergent manner utilizing a desymmetrization
approach. This successful strategy involves epimerization and
modified Julia olefination as key steps.
Keywords: phorboxazole, desymmetrization, epimerization, Julia
olefination
Phorboxazoles A (1) and B (2) are rare marine macrolides
isolated from the Indian Ocean sponge Phorbas sp. by
Searle and Molinski (Scheme 1).1 Both C13 epimers are
comprised of a 21-membered macrolide ring that embod-
ies three oxane rings, one oxazole and subtends a side-
chain that contains a second oxazole and a hemiketal
46
Br
MeO
R1
O
R2
15
19
N
O
11
20
OH
9
22
37
MeO
O
O
O
5
33
29
N
26
O
1
HO
32
O
O
(+)-phorboxazole A (1) R1 = H, R2 = OH
(+)-phorboxazole B (2) R1 = OH, R2 = H
OBn
OBn
O
S
OMe
N
+
N
S
N
O
BnO
O
BnO
O
O
O
O
O
3
4
5
6
O
N
O
OBn
7
Scheme 1
SYNLETT 2007, No. 10, pp 1577–1580
1
8
.0
6
.2
0
0
7
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982556; Art ID: D29306ST
© Georg Thieme Verlag Stuttgart · New York

1578
J. S. Yadav et al.
LETTER
O
O
O
b, c
a
HO
O
O
OBn
e, f
OBn
OBn
g
7
8
9
OBn
OBn
OBn
3
2
d
O
4
1
5
MeO
O
OMe
BnO
O
OH
BnO
O
OMe
10
11
12
OBn
OBn
O
OBn
O
h
i
j
BnO
O
O
BnO
O
BnO
OH
TMS
13
14
15
OBn
OBn
l
k
BnO
O
BnO
O
TMS
O
16
4
Scheme 2 Reagents and conditions: (a) (–)-Ipc2BH, THF, –23 °C, 24 h, NaOH (3 N), 30% H2O2, r.t., 6 h; (b) PCC, CH2Cl2, r.t., 3 h; (c) MCP-
BA, NaHCO3, CH2Cl2, r.t., 10 h; (d) H2SO4–MeOH, 0 °C→r.t., 12 h; (e) LiAlH4, THF, 0 °C→r.t., 6 h; (f) BnBr, NaH, THF, r.t., 12 h; (g) AcOH–
H2O (3:2), 55 °C, 15 h; (h) PCC (1.5 equiv), NaOAc (2 equiv), celite, r.t., 3 h; (i) DBU (1 equiv), THF, r.t., 12 h; (j) n-BuLi–trimethylsilyl-
acetylene (3 equiv each), THF, –78 °C, 1.5 h; (k) Et3SiH–BF3·Et2O (10 equiv each), MeCN–CH2Cl2 (1:1), –40 °C, 2 h; (l) HgO, H2SO4, acetone,
50 °C, 1 h.
We have depicted our strategy in Scheme 1, which shows yield by heating in acetic acid–water (3:2)6 at 55 °C, PCC
the disconnection approach. The convergent synthesis of oxidation of the lactol provided lactone 13 in quantitative
the C20–C32 oxazole–oxane 3 is envisaged to be yield. Epimerization7 of the C2-methyl of 13 was carried
achieved by coupling two subunits, the pentasubstituted out using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
oxane 4 and the oxazole sulfone 5 via a modified Julia tetrahydrofuran, which furnished epimer 14 in 95% yield
olefination. The tetrahydropyran moiety 4 is considered to and 100% conversion. Epimerization was also effected
be available by desymmetrization of the bicyclic pre- using catalytic sodium methoxide and catalytic ethanolic
cursor 7 (Scheme 2).
potassium hydroxide. This transformation was confirmed
by 1H NMR in which the C2-H of 14 resonated upfield (d
2.5 ppm) relative to the C2-H of 13 (d 2.8 ppm) and also
by the upfield chemical shift of the C3-H proton and mod-
ification of the multiplicity of the resonance (triplet to dd)
indicating an anti relationship between C2-H and C3-H.
We initiated our synthesis from precursor 7, which has
been previously utilized in the synthesis of rifamycin-S,5a
(+)-discodermolide,5b,c scytofycin C,5d prelactone B,5e
(+)-membrenone and its 7-epimer5f wherein we had
exploited the desymmetrization approach. Asymmetric
hydroboration of the olefin 7 using (–)-diisopinocam- Nucleophilic addition of lithiumtrimethylsilyl acetylide to
phenylborane was carried out to obtain 8 in high optical the resulting epi-lactone 14 at –78 °C in tetrahydrofuran
purity (96%). The alcohol 8 was converted into the provided an inseparable anomeric mixture of hemiketals
lactone 9 by a two-step sequence of pyridinium chloro- 15 in 90% yield.8 Reduction of the hemiketal to pyran was
chromate (PCC) oxidation followed by Baeyer–Villiger carried out using an excess of triethyl silane and boron
oxidation of the resulting ketone. The bicyclic lactone 9 trifluoride–diethyl ether complex in dichloromethane–
was then subjected to methanolysis in the presence of a acetonitrile (1:1) at –40 °C for one hour. This gave penta-
catalytic quantity of sulfuric acid in methanol to give ace- substituted pyran 16 exclusively in 85% yield in which the
tal ester 10 exclusively in 85% yield, in which three out of ether linkage between C1 and C5 is in a syn configuration
five stereocenters of the oxane ring are present. Our sub- (Scheme 2). The stereochemistry of the product was con-
sequent task was to obtain the two further stereocenters at firmed by 1H NMR and NOE analysis.9 Desilylation and
C1 and C2 of the tetrahydropyran unit. With that aim, hydration of the triple bond via oxy-mercuration10 in a
ester 10 was reduced to the alcohol in quantitative yield Markownikoff manner was effected in a single step using
using lithium aluminium hydride in tetrahydropyran and yellow mercury(II) oxide and aqueous sulfuric acid in re-
the product was protected as its benzyl ether. The dibenzyl fluxing acetone for two hours to give keto tetrahydropyran
methyl acetal 11 was hydrolyzed to give lactol 12 in 55% 4 in 70% yield.
Synlett 2007, No. 10, 1577–1580 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of a Phorboxazole Fragment
1579
Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905.
The oxazole unit 6 was synthesized following the pub-
lished procedure11 and was reduced to alcohol 17 using
DIBAL-H.12 Oxazole sulfone 5 was accessed in two steps
from the oxazole alcohol 17, which was converted into its
corresponding thioether under Mitsunobu reaction
conditions13 in 89% yield and subsequently oxidized with
oxone to give the sulfone 5 in 90% yield. Coupling of the
sulfone 5 and pentasubstituted tetrahydropyran 4 under
the modified Julia olefination conditions14 gave a separa-
ble mixture of E/Z geometrical isomers in a ratio of 9:1 in
70% yield based on the recovered starting material
(Scheme 4).15
(i) Misske, A. M.; Hoffmann, H. M. R. Tetrahedron 1999,
55, 4315. (j) Rychnovsky, S. D.; Thomas, C. R. Org. Lett.
2000, 2, 1217. (k) Donaldson, W. A.; Greer, P. B.
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Pattenden, G. Angew. Chem. Int. Ed. 2003, 42, 1255.
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3749. (o) Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J.
Tetrahedron 2003, 59, 8613.
(3) (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; Minbiole, K. P.; Verhoest, P. R.;
Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942.
(d) González, M. A.; Pattenden, G. Angew. Chem. Int. Ed.
2003, 42, 1255. (e) Williams, D. R.; Kiryanov, A. A.; Emde,
U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Angew Chem.
Int. Ed. 2003, 42, 1258. (f) Smith, A. B. III; Razler, T. M.;
Ciavarri, J. P.; Hirose, T.; Ishikawa, T. Org. Lett. 2005, 7,
4399. (g) Li, D. R.; Zhang, D. H.; Sun, C. Y.; Zhang, J. W.;
Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W. S.; Lin, G. Q.
Chemistry 2006, 12, 1185.
(4) (a) Forsyth, C. J.; Ying, L.; Chen, J.; La Clair, J. J. J. Am.
Chem. Soc. 2006, 128, 3858. (b) Uckun, F. M.; Forsyth, C.
J. Bioorg. Med. Chem. Lett. 2001, 11, 1181. (c) Chen, J.;
Ying, L.; Hansen, T. M.; Engler, M. M.; Lee, C. S.; La Clain,
J. J.; Forsyth, C. J. Bioorg. Med. Chem. Lett. 2006, 16, 901.
(d) Smith, A. B. III.; Razler, T. M.; Pettit, G. R.; Chapuis,
J.-C. Org. Lett. 2005, 7, 4403.
O
S
OMe
OH
N
S
N
a
b, c
N
N
O
O
O
O
O
6
17
5
Scheme 3 (a) DIBAL-H, CH2Cl2, –78 °C, 3 h, r.t., 1 h; (b) 2-mer-
captobenzothiazole, TPP, DEAD, THF, r.t., 12 h; (c) oxone, THF–
MeOH–H2O (2:1:1), 12 h.
OBn
NaHMDS, THF
4
+
5
(5) (a) Yadav, J. S.; Rao, C. S.; Chandrasekhar, S.; Ramarao, A.
V. Tetrahedron Lett. 1995, 36, 7717. (b) Yadav, J. S.;
Abraham, S.; Reddy, M. M.; Sabitha, G.; Sankar, A. R.;
Kunwar, A. C. Tetrahedron Lett. 2001, 42, 4713.
–78 °C to r.t., 4 h
BnO
O
3
O
N
(c) Yadav, J. S.; Abraham, S.; Reddy, M. M.; Sabitha, G.;
Sankar, A. R.; Kunwar, A. C. Tetrahedron Lett. 2002, 43,
3453. (d) Yadav, J. S.; Md. Ahmed, M. Tetrahedron Lett.
2002, 43, 7147. (e) Yadav, J. S.; Reddy, K. B.; Sabitha, G.
Tetrahedron Lett. 2004, 45, 6475. (f) Yadav, J. S.; Srinivas,
R.; Sathaiah, K. Tetrahedron Lett. 2006, 47, 1603.
(6) Snider, B. B.; Song, F. Org. Lett. 2001, 3, 1817.
(7) (a) Bernsmann, H.; Gruner, M.; Fröhlich, R.; Metz, P.
Tetrahedron Lett. 2001, 42, 5377. (b) Klotz, P.; Mann, A.
Tetrahedron Lett. 2003, 44, 1927.
Scheme 4
In summary, the practical synthesis of the central C20–
C32 pyran moiety has been developed using a convergent
strategy with key steps involving C-2 epimerization and
modified Julia olefination. Efforts are in progress to con-
struct the C20–C46 fragment of the phorboxazoles.
(8) Bolitt, V.; Mioskowski, C.; Kollah, R. O.; Manna, S.;
Rajapaksa, D.; Falck, J. R. J. Am. Chem. Soc. 1991, 113,
6320.
Acknowledgment
(9) The six-membered ring is in the chair form 5C2
conformation. C1-H, C3-H and C5-H have axial orientations
confirmed by NOE enhancement between C1-H/C5-H, C1-
H/C3-H and C3-H/C5-H and also between C4-Me/C2-H
(Figure 1). This arrangement is also strongly supported by
One of the authors, M.S.N., thanks CSIR, New Delhi for the award
of a fellowship.
References and Notes
the coupling constants JC1-H–C2-H = 10.57 Hz, JC3-H–C2-H
10.57 Hz and JC3-H–C4-H = 4.53 Hz.
=
(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.
H
H
(c) Molinski, T. F. Tetrahedron Lett. 1996, 37, 7879.
(2) (a) Ye, T.; Pattenden, G. Tetrahedron Lett. 1998, 39, 319.
(b) Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Tetrahedron Lett. 1998, 39, 6099. (c) Paterson, I.;Arnott, E.
A. Tetrahedron Lett. 1998, 39, 7185. (d) Williams, D. R.;
Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40,
2287. (e) Williams, D. R.; Clark, M. P. Tetrahedron Lett.
1999, 40, 2291. (f) Wolbers, P.; Misske, A. M.; Hoffmann,
H. M. R. Tetrahedron Lett. 1999, 40, 4527. (g) Wolbers, P.;
Hoffmann, H. M. R. Synthesis 1999, 797. (h) Wolbers, P.;
H
5
1
OBn
O
4
Me3Si
H
3
H3C
2
OBn
CH3
H
Figure 1
(10) Potman, R. P.; Janssen, N. J. M. L.; Scheeren, J. W.; Nivard,
R. J. F. J. Org. Chem. 1984, 49, 3628.
Synlett 2007, No. 10, 1577–1580 © Thieme Stuttgart · New York

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J. S. Yadav et al.
LETTER
(11) Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W.
J. Org. Chem. 2003, 68, 4215.
(12) Entwistle, D. A.; Jordon, S. I.; Montgomery, J.; Pattenden,
G. Synthesis 1998, 603.
8.64, 12.57, 32.41, 35.56, 39.46, 66.24, 73.19, 73.56, 76.26,
127.44, 127.73, 128.40, 137.78, 138.15, 174.34; MS (FAB):
m/z = 369 [M + H+].
Compound 14: colorless oil; [a]D +76.5 (c 1.00, CHCl3); 1H
NMR (200 MHz, CDCl3): d = 0.96 (d, J = 7.55, 3 H), 1.36
(d, J = 6.79 Hz, 3 H), 1.72–1.84 (m, 1 H), 1.96–2.08 (m 1 H),
2.24–2.32 (m, 1 H), 2.44–2.56 (m, 1 H), 3.48 (dd, J = 3.77,
9.82 Hz, 1 H), 3.54–3.60 (m, 2 H), 4.32–4.64 (m, 5 H), 7.24–
7.32 (m, 10 H); 13C NMR (75 MHz, CDCl3): d = 4.72, 14.61,
33.03, 38.31, 65.92, 70.56, 73.17, 76.15, 80.39, 127.61,
128.43, 137.59, 173.54; MS (FAB): m/z = 369 [M + H+].
Compound 16: colorless oil; [a]D +54.54 (c 0.01, CHCl3); IR
(KBr): 2961, 2926, 2179 cm–1; 1H NMR (400 MHz, CDCl3):
d = 0.17 (s, 9 H), 0.96 (d, J = 6.79 Hz, 3 H), 1.04 (d, J = 6.79
Hz, 3 H), 1.56–1.68 (m, 1 H), 1.76–2.04 (m, 3 H), 3.09 (dd,
J = 4.53, 10.57 Hz, 1 H), 3.46–3.60 (m, 2 H), 3.60–3.64 (d,
J = 10.57 Hz, 1 H), 4.10 (q, J = 7.55, 14.35 Hz, 1 H), 4.30 (d,
J = 11.33 Hz, 1 H), 4.49 (s, 2 H), 4.59 (d, J = 12.06 Hz, 1 H),
7.20–7.34 (m, 10 H); 13C NMR (50 MHz, CDCl3): d = 5.99,
14.19, 33.33, 34.47, 37.23, 67.02, 69.96, 73.71, 75.98,
83.05, 103.65, 127.74, 128.44, 138.59; LC–MS: m/z = 450
[M + H+].
(13) Mitsunobu, O. Synthesis 1981, 1.
(14) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 336. (b) Baudin, J. B.; Hareau, G.;
Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993,
130, 856. Review on modified Julia olefination:
(c) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563.
(15) Spectral Data: Compound 1 [a]D +28.26 (c 0.01, CHCl3); 1H
NMR (200 MHz, CDCl3): d = 0.82 (d, J = 6.07 Hz, 3 H),
0.96 (d, J = 6.96 Hz, 3 H), 1.60–2.16 (m, 4 H) 1.87 (s, 3 H),
2.42 (s, 3 H), 3.24 (dd, J = 5.20, 10.41 Hz, 1 H), 3.44–3.76
(m, 3 H), 4.30–4.68 (m, 5 H), 6.10 (s, 1 H), 7.20–7.34 (m, 10
H), 7.38 (s, 1 H); 13C NMR (50 MHz, CDCl3): d = 5.80,
13.23, 13.69, 18.72, 33.02, 33,38, 34.44, 67.03, 69.97,
72.95, 74.46, 76.28, 76.92, 77.56, 79.77, 83.99, 119.46,
127.44, 127.62, 128.26, 135.18, 137.24, 138.49, 138.67;
LC–MS: m/z = 476 [M + H+].
Compound 10: [a]D +57.29 (c 1.85, CHCl3); 1H NMR (200
MHz, CDCl3): d = 0.98 (d, J = 7.18 Hz, 3 H), 1.05 (d,
J = 7.81 Hz, 3 H), 2.0–2.20 (m, 2 H), 2.25–2.36 (dd, J = 3.9,
15.6 Hz, 1 H), 2.57–2.70 (m, 1 H), 3.30 (s, 3 H), 3.68 (s, 3
H), 3.84 (m, 1 H), 4.25–4.34 (m, 1 H), 4.47–4.50 (m, 3 H),
7.22–7.30 (m, 5 H); 13C NMR (50 MHz, CDCl3): d = 8.91,
12.89, 35.45, 36.60, 37.31, 51.53, 54.74, 67.34, 69.99,
75.36, 103.42, 127.03, 127.20, 128.14, 172.00; MS (FAB):
m/z = 291 [M+– OMe].
Compound 13: colorless oil; [a]D +50.5 (c 1.00, CHCl3); IR
(KBr): 3029, 2871, 1743 cm–1;1H NMR (200 MHz, CDCl3):
d = 1.00 (d, J = 7.23 Hz, 3 H), 1.32 (d, J = 7.23 Hz, 3 H),
1.72–2.12 (m, 2 H), 2.24–2.40 (m, 1 H), 2.72–2.88 (m, 1 H),
3.52–3.72 (m, 2 H), 3.88 (t, J = 5.78 Hz, 1 H), 4.44–4.56 (m,
5 H), 7.24–7.36 (m, 10 H); 13C NMR (50 MHz, CDCl3): d =
Compound 4: colorless oil; [a]D +90.0 (c 0.01, CHCl3); IR
(KBr): 2969, 2926, 2858, 1718 cm–1; 1H NMR (400 MHz,
CDCl3): d = 0.84–0.98 (m, 6 H), 1.60–2.20 (m, 4 H), 2.11 (s,
3 H) 3.18 (dd, J = 4.68, 10.93 Hz, 1 H), 3.32 (d, J = 10.93
Hz, 1 H), 3.44–3.64 (m, 3 H), 4.32–4.70 (m, 4 H), 7.28 (m,
10 H); 13C NMR (75 MHz, CDCl3): d = 6.98, 19.44, 26.51,
27.39, 28.40, 60.78, 64.133, 67.09, 69.16, 70.69, 71.11,
71.53, 77.26, 81.76, 121.69, 121.77, 122.44, 122.45, 132.39,
132.49, 201.15; LC–MS: m/z = 397 [M + H+].
Compound 5: IR (KBr): 3029, 2871, 1743 cm–1; 1H NMR
(400 MHz, CDCl3): d = 2.28 (s, 3 H), 4.71 (s, 2 H), 7.54–7.69
(m, 3 H), 7.99 (m, 1 H), 8.24 (m, 1 H); ESI-MS: m/z 295 [M
+ H+].
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