A convergent synthesis of the C31-C46 fragment of phorboxazoles

Article abstract of DOI:10.1055/s-2004-829572

A convergent synthesis of the C31-C46 fragment of phorboxazoles has been achieved. This involved the preparation of a C31-C39 aldehyde and a C40-C46 benzothiazole secondary sulfone followed by their coupling, employing modified Julia olefination as a key

Full text of DOI:10.1055/s-2004-829572

LETTER
1743
A Convergent Synthesis of the C31-C46 Fragment of Phorboxazoles1
A
C
onverg
.
ent Synthesi
S
s
of the C31-C
.
46 Fragmen
Y
t
of Phorboxazole
a
s
dav,* G. Rajaiah
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadav@iict.ap.nic.in
Received 31 December 2003
The impressive biological activity and the unique struc-
ture of phorboxazoles have led to efforts directed towards
the synthesis of these compounds. The first total synthesis
of phorboxazole A was reported in 1998 by Forsyth and
co-workers.8a Synthetic studies towards the total synthesis
of phorboxazoles have also been published by several
groups.8
Abstract: A convergent synthesis of the C31-C46 fragment of
phorboxazoles has been achieved. This involved the preparation of
a C31-C39 aldehyde and a C40-C46 benzothiazole secondary
sulfone followed by their coupling, employing modified Julia ole-
fination as a key reaction.
Key words: phorboxazole, Julia olefination, secondary sulfone,
sodium formate
We made the disconnections to reveal the segments, re-
presenting C1-C19 (1), C20-C30 (2) and C31-C46 (3) as
depicted in Scheme 1. Our route to the C31-C46 fragment
3 in phorboxazoles was based on a convergent approach
using an E-selective Julia olefination9 reaction between
the secondary sulfone 4 and the aldehyde 5 as a key step.
Therefore, we planned to synthesise the sulphone 4 and
the aldehyde 5 from the chiral precursors (R)-p-methoxy-
phenylmethyl (MPM) glycidol 6 and (S)-MPM protected
homoallylalcohol epoxide 12, respectively. The synthesis
of sulfone 4 started with the metallation of acetylene (n-
BuLi, THF, –78 °C)10 followed by the addition of
BF3·OEt2 and (R)-MPM protected glycidol 613 to provide
secondary alcohol in 71% yield. Methylation of the free
hydroxyl group with NaH and MeI in THF, at 0 °C yield-
ed 7 in 98%. The terminal alkyne in 7 was hydrostannated
under standard conditions (n-Bu3SnH, AIBN, benzene,
Searle and Molinski reported the isolation of phorbox-
azoles A and B, C-13 epimeric oxazole-containing mac-
rolides, from an Indian Ocean sponge Phorbas sp. in 1995
(Scheme 1).2 Complete structural assignments for phor-
boxazoles have resulted from the extensive NMR studies.3
The phorboxazoles were reported to be extremely cyto-
static towards the National Cancer Institute’s panel of 60
tumor cell lines, and to have potent in vitro antifungal ac-
tivity against C. albicans and S. carlsbergensis.3a Togeth-
er with the altohyrtins4 and the bryostatins,5 they are
amongst the antitumor natural products as they inhibit
growth of tumor cells at sub-nanomolar concentrations in
vitro (mean GI50 1.58·10–9M).3b Unlike antimitotic natural
products such as Paclitaxel6 or the epothilones,7 the phor-
boxazoles arrest the cell cycle during S-phase.
Scheme 1
SYNLETT 2004, No. 10, pp 1743–1746
0
9
.0
8
.2
0
0
4
Advanced online publication: 28.07.2004
DOI: 10.1055/s-2004-829572; Art ID: D30503ST
© Georg Thieme Verlag Stuttgart · New York

1744
J. S. Yadav, G. Rajaiah
LETTER
80 °C, 48 h) to give the vinyl stannane in 70% yield as a THP protected propargyl alcohol with epoxide 1214 fol-
5:1 (E:Z) mixture of geometric isomers, which were sep- lowing the Yamaguchi protocol afforded the desired
arated by flash column chromatography. Facile tin-bro- alcohol 13 in 76% yield.11
mine exchange reaction using NBS in acetonitrile at 0 °C
Quantitative methylation of alcohol 13 with NaH and MeI
in THF at 0 °C and deprotection of THP gave the propar-
gylic alcohol 14 in 94% yield. Compound 15 was access-
ed by sequential reduction with LAH followed by
provided vinylic bromide 8 quantitatively. Chiral key in-
termediate 98d was obtained by treatment with DDQ
(CH2Cl2:H2O = 7:3; r.t.; 10 min) in 95% yield. Alcohol 9
was converted into a,b-unsaturated ketone by employing
treatment of the resulting allyl alcohol with TPP in CCl4
Swern oxidation followed by Wittig olefination with 1-
in 86% overall yield. Sharpless asymmetric dihydroxyla-
triphenyl-phosphoranylidene-2-propanone to yield 10 in
tion reaction conditions using AD-mix b on allylic chloro
72%. The carbonyl functionality in 10 was quantitatively
compound 15 afforded diol 16 in 78% (de 94%) yield.12
reduced to vinyl carbinol 11 with NaBH4 in MeOH at 0 °C
The protection of vicinal diol as isopropylidene with 2,2-
DMP and the deprotection of p-methoxybenzyl group
in 15 minutes. The target sulfone 4 was accessed in two
steps from the alcohol 11 (Scheme 2). First, compound 11
with DDQ resulted in the chiral alcohol 17 in 86% yield
was converted to thioether under Mitsunobu reaction11
(in two steps). Alcohol 17 was quantitatively oxidised to
the aldehyde with IBX, and treated with pre a-metallated
CH3COOEt (LiHMDS, THF; –78 °C; 15 min) to give 18
conditions in 89% yield, which was subsequently oxidised
to give the target sulfone 4 in 87% yield.
Aldehyde 5 was also prepared in a similarly straightfor- in 79% yield. The epimeric mixture 18 was oxidised with
ward manner as indicated in Scheme 3. Condensation of PDC in DCM to b-keto ester 19 in 80% yield.
Scheme 2 Reagents and conditions: a) BuLi, BF3·OEt2, –78 °C; b) NaH, MeI, THF, 0 °C, 1 h; c) n-Bu3SnH, AIBN (cat.), benzene, 80 °C, 48
h; d) NBS, MeCN, 0 °C; e) DDQ, CH2Cl2:H2O (7:3); f) Swern oxidation; g) CH3COCH=PPh3, benzene; h) NaBH4, MeOH, 0 °C; i) 2-mercap-
tobenzothiazole, DEAD, TPP, THF; j) oxone, MeOH:H2O:THF (1:1:2), r.t.
Scheme 3 Reagents and conditions: a) n-BuLi, BF3·OEt2, –78 °C; b) NaH, MeI, THF; c) p-TSA, MeOH; d) LAH, THF, reflux, 2 h; e) TPP,
CCl4, reflux, 12 h; f) AD-mix b, 0 °C, 48 h; g) 2,2-DMP, p-TSA, acetone; h) DDQ, CH2Cl2:H2O (7:3); i) IBX; j) LiHMDS; CH3COOEt, –78 °C;
k) PDC; l) PPTS, MeOH, 36 h; m) MOMCl, DIPEA; n) HCOONa, NaI, DMF, 80 °C, 3 d; o) NaBH4, MeOH, 0 °C; p) Dess–Martin periodinane
oxidation.
Synlett 2004, No. 10, 1743–1746 © Thieme Stuttgart · New York

LETTER
A Convergent Synthesis of the C31-C46 Fragment of Phorboxazoles
1745
(8) (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 120, 5597. (b) Smith, A. B. III; Verhoest,
P. R.; Minbiole, K. P.; Schelhaas, M. J. Am. Chem. Soc.
2001, 123, 4834. (c) Smith, A. B. III; Minbiole, K. P.;
Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123,
10942. (d) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V.
J. J. Am. Chem. Soc. 2000, 122, 10033. (e) Evans, D. A.;
Cee, V. J.; Smith, T. E.; Fitch, D. M.; Cho, P. S. Angew.
Chem. Int. Ed. 2000, 39, 2533. (f) Evans, D. A.; Fitch, D.
M. Angew. Chem. Int. Ed. 2000, 39, 2536. (g) Gonzalez, M.
A.; Pattenden, G. Angew. Chem. Int. Ed. 2003, 42, 1255.
(h) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M.
P.; Berliner, M. A.; Reeves, J. T. Angew. Chem. Int. Ed.
2003, 42, 1258; and references cited therein.
(9) (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. (c) Review on modified Julia olefination:
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(10) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(11) Mitsunobu, O. Synthesis 1981, 1.
The substrate 19 was sonicated for 36 hours using PPTS
as the catalyst in MeOH, during which deprotection of the
isopropylidene group as well as the cyclisation occurred
to yield a single diastereomer of the cyclic acetal methyl
ether 20 in 50%. The free alcohol was protected with
methoxymethyl chloride and DIPEA in CH2Cl2 (in 94%
yield), and the chloro functionality was converted to for-
mate 21 with sodium formate in DMF at 80 °C for three
days in 70% yield.
Deformylation with NaBH4 in MeOH furnished primary
alcohol 23 in 96% yield. The Dess–Martin periodinane
oxidation afforded the aldehyde 5 in quatitative yield.
Coupling of the secondary sulfone 4 and the aldehyde 5
under the modified Julia olefination conditions gave an in-
separable mixture of E:Z geometrical isomers in 70%
yield in a ratio of 1:1 (Scheme 4).
(12) Vanhessche, K. P. M.; Wang, Z. M.; Sharpless, K. B.
Tetrahedron Lett. 1994, 35, 3469.
(13) i) Epichlorohydrin, MPMOH, NaH; ii) Jacobsen
resolution.15
(14) i) Homoallyl alcohol, MPMBr, NaH; ii) m-CPBA; iii)
Jacobsen resolution15 and related work reported by our
group. See: Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C.
Tetrahedron Lett. 2001, 42, 4907.
Scheme 4
(15) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936.
In conclusion, the practical synthesis of the highly func-
tionalised C31-C46 fragment, achieved in 17 steps (in the
longest linear sequence) from MPM protected (S)-ho-
moallyl alcohol epoxide 12,16 is described. Modified Julia
olefination between secondary benzothiazole sulfone 4
and the aldehyde 5 was achieved. Efforts towards the
synthesis of the other fragments 1 and 2 and the total syn-
thesis of phorboxazoles are under progress.
(16) Spectral data for the key fragments: Compound 3 (E:Z
mixture): 1H NMR (200 MHz, CDCl3): d = 6.61 (d, J = 17.3
Hz, 1 H), 6.27–6.02 (m, 5 H), 5.61–5.42 (m, 2 H), 5.37–5.24
(m, 2 H), 4.58–4.36 (m, 6 H), 4.14 (q, J = 14.1 Hz, 4 H),
3.72–3.45 (m, 6 H), 3.34 (s, 6 H), 3.31 (s, 6 H), 3.24 (s, 6 H),
3.23 (s, 6 H), 2.66 (dd, J = 14.1 Hz, 4.6 Hz, 4 H), 2.44–2.22
(m, 6 H), 1.90 (s, 3 H), 1.83 (s, 3 H), 1.69–1.55 (m, 2 H),
1.41–1.19 (m, 10 H). IR (neat): 2926, 1736, 1619, 1418,
1376, 1207, 1146, 1089, 1033 cm–1. FAB-MS: m/z = 536
[M + 1].
[a]D = –19.8 (c 0.5, CHCl3).
Acknowledgment
Compound 4 (mixture of diastereomers): 1H NMR (200
MHz, CDCl3): d = 8.22–8.18 (m, 2 H), 8.02–7.96 (m, 2 H),
7.67–7.53 (m, 4 H), 6.02–5.44 (m, 8 H), 4.36–4.23 (m, 2 H),
3.56–3.46 (m, 2 H), 3.16 (s, 3 H), 3.02 (s, 3 H), 2.14–1.95
(m, 4 H), 1.64–1.56 (m, 6 H). IR (neat): 2926, 1701, 1469,
1325, 1145, 1093 cm–1. FAB-MS: m/z = 418 [M + 2].
[a]D = –8.20 (c 0.8, CHCl3).
G. R. thanks CSIR, New Delhi for financial assistance.
References
(1) IICT Communication No. 030704.
(2) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117,
8126.
(3) (a) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J.
W. J. Am. Chem. Soc. 1996, 118, 9422. (b) Molinski, T. F.
Tetrahedron Lett. 1996, 37, 7879.
(4) Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.;
Stevens, K. L.; Guo, J.; Kishi, Y. Angew. Chem. Int. Ed.
1998, 37, 192; and references cited therein.
(5) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.;
Charette, A. B.; Lautens, M. Angew. Chem. Int. Ed. 1998,
37, 2354; and references cited therein.
(6) Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 15.
Compound 6: 1H NMR (200 MHz, CDCl3): d = 7.25 (d,
J = 8.8 Hz, 2 H), 6.81 (d, J = 8.8 Hz, 2 H), 4.45 (Abq,
J = 12.3 Hz, 2 H), 3.81 (s, 3 H), 3.69–3.63 (dd, J = 12.5, 6.0
Hz, 1 H), 3.45–3.34 (dd, J = 12.5, 6.0 Hz, 1 H), 3.23–3.18
(m, 1 H), 2.76–2.69 (dd, J = 12.3, 5.9 Hz, 1 H), 2.57–2.54
(dd, J = 12.3, 5.9 Hz, 1 H). IR (neat): 2922, 1512, 1245
cm–1. MS (EI): m/z = 194 [M+].
[a]D = +3.1 (c 1.5, CHCl3).
Compound 10: 1H NMR (200 MHz, CDCl3): d = 6.64–6.49
(m, 1 H), 6.32–6.08 (m, 3 H), 3.93–3.70 (m, 1 H), 3.29 (s,
3 H), 2.58–2.46 (m, 1 H), 2.38–2.26 (m, 1 H), 2.22 (s, 3 H).
IR (neat): 2932, 1735, 1612, 1310 cm–1. MS (EI): m/z = 233
[M+].
(7) Nicolaou, K. C.; Roschanger, F.; Vourloumis, D. Angew.
Chem. Int. Ed. 1998, 37, 2014; and references cited therein.
[a]D = +2.9 (c 0.6, CHCl3).
Compound 12: 1H NMR (200 MHz, CDCl3): d = 7.18 (d,
J = 8.8 Hz, 2 H), 6.84 (d, J = 8.8 Hz, 2 H), 4.40 (s, 2 H), 3.81
(s, 3 H), 3.58–3.53 (m, 2 H), 3.06–2.96 (m, 1 H), 2.76–2.72
(m, 1 H), 2.50–2.43 (m, 1 H), 1.89–1.78 (m, 1 H), 1.72–1.60
Synlett 2004, No. 10, 1743–1746 © Thieme Stuttgart · New York

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J. S. Yadav, G. Rajaiah
LETTER
Compound 20: 1H NMR (200 MHz, CDCl3): d = 4.17 (q,
J = 6.7 Hz, 2 H), 3.98–3.88 (m, 1 H), 3.75–3.58 (m, 4 H),
3.38 (s, 3 H), 3.28 (s, 3 H), 2.68 (s, 2 H), 2.55–2.48 (m, 1 H),
2.38–2.15 (m, 2 H), 2.05–1.92 (m, 2 H), 1.28 (t, J = 6.7 Hz,
3 H). IR (neat): 3447, 2949, 1731, 1319, 1228 cm–1.
FAB-MS: m/z = 279 [M – OMe].
(m, 1 H). IR (neat): 2845, 1612, 1513 cm–1. MS (EI): m/z =
208 [M+].
[a]D = +14.4 (c 1.0, CHCl3).
Compound 15: 1H NMR (200 MHz, CDCl3): d = 7.22 (d,
J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 5.80–5.57 (m, 2
H), 4.40 (s, 2 H), 4.00 (d, J = 7.2 Hz, 2 H), 3.79 (s, 3 H),
3.55–3.45 (m, 2 H), 3.40–3.36 (m, 1 H), 3.31 (s, 3 H), 2.34–
2.18 (m, 2 H), 1.74–1.68 (m, 2 H). IR (neat): 2935, 1608,
1513, 1252 cm–1. FAB-MS: m/z = 298 [M + 1].
[a]D = –17.6 (c 0.75, CHCl3).
[a]D = –78.6 (c 1.0, CHCl3).
Compound 23: 1H NMR (200 MHz, CDCl3): d = 4.71 (Abq,
J = 10.4 Hz, 2 H), 4.13 (q, J = 6.7 Hz, 2 H), 3.79–3.48 (m, 5
H), 3.41 (s, 3 H), 3.32 (s, 3 H), 3.21 (s, 3 H), 2.63 (Abq,
J = 14.1 Hz, 2 H), 2.38–2.28 (m, 1 H), 1.98–1.88 (m, 1 H),
1.49–1.31 (m, 2 H), 1.27 (t, J = 6.7 Hz, 3 H). IR (neat): 3443,
2925, 1733, 1036 cm–1. MS (EI): m/z = 336 [M+].
[a]D = –19.2 (c 1.1, CHCl3).
Compound 17: 1H NMR (200 MHz, CDCl3): d = 4.09–3.93
(m, 1 H), 3.88–3.71 (m, 3 H), 3.66–3.55 (m, 3 H), 3.41 (s, 3
H), 1.96–1.94 (m, 2 H), 1.77–1.63 (m, 2 H), 1.40 (s, 6 H).
IR (neat): 3482, 2921, 1462 cm–1. MS (EI): m/z = 252 [M+].
[a]D = +12.2 (c 2.0, CHCl3).
Synlett 2004, No. 10, 1743–1746 © Thieme Stuttgart · New York