Stereoselective synthesis of the C31-C39 unit of (+)-phorboxazoles from m-anisaldehyde

Article abstract of DOI:10.1016/j.tetlet.2006.12.105

A stereoselective route for the synthesis of the C31-C39 fragment of (+)-phorboxazoles is described. The route features Birch reduction, ozonolysis and acid-catalysed cyclisation of enantiopure precursors as key transformations to give the tetrahydropyran

Full text of DOI:10.1016/j.tetlet.2006.12.105

Tetrahedron Letters 48 (2007) 1391–1394
Stereoselective synthesis of the C31–C39 unit
of (+)-phorboxazoles from m-anisaldehydeI
S. Praveen Kumar and K. Nagaiah*
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 31 August 2006; revised 11 December 2006; accepted 19 December 2006
Available online 22 December 2006
Abstract—A stereoselective route for the synthesis of the C31–C39 fragment of (+)-phorboxazoles is described. The route features
Birch reduction, ozonolysis and acid-catalysed cyclisation of enantiopure precursors as key transformations to give the tetrahydro-
pyran ring, starting from m-anisaldehyde as a masked b-keto ester to obtain the pyran skeleton of compound 1.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Phorboxazole A and its C-13 epimer phorboxazole B,
isolated from a species of Indian Ocean sponge of the
genus Phorbas sp.1 are novel 21-membered macrolides
accommodating four heavily functionalised oxanes and
two 2,4-disubstituted oxazoles. Phorboxazoles A and B
exhibit an extraordinary cytotoxic activity (GI50 of
1.58 · 10ꢀ9 M) against the entire panel of 60 human
tumour cell lines held at the National Cancer Institute.
Together with the spongiastatins,2 the phorboxazoles are,
therefore, the most potent naturally occurring cytotoxic
agents yet discovered. Although their mechanism of ac-
tion remains to be established, phorboxazole A has been
shown to arrest the cell cycle in the S phase, whilst not
inhibiting tubulin polymerisation or interfering with
the integrity of microtubules, thereby suggesting a possi-
bly unique mechanism.1b Their novel structure and
potent biological activity have combined to make the
scarcely available phorboxazoles attractive synthetic tar-
gets.3 Forsyth et al.4 published the first total synthesis of
phorboxazole A in 1998; this was followed by a synthe-
sis of phorboxazole B by Evans et al. in 2000.5
groups have reported different strategies for the enantio-
selective assembly of this THP-hemiketal ring.6 The first
stereoselective approach to this fragment was published
by Molinski in 1996,1c wherein
a
derivative
(3R,5R,7R,8S)-1, bearing four stereogenic centres with
configuration identical to those present in the natural
phorboxazoles, was synthesised using malic acid as the
starting material. This synthesis of a model compound
and the use of different NMR techniques were pivotal
to the elucidation of the absolute configuration of 14
out of the 15 stereocentres in phorboxazoles1b (Fig. 1).
The most widely studied region of the phorboxazoles is
the C31–C39 tetrahydropyran ring system. This highly-
functionalised segment features four asymmetric centres
and has been a showcase for various methods of tetrahy-
dropyan synthesis. All approaches hitherto have been
dependent on stoichiometric amounts of a chiral source,
such as chiral starting materials, auxiliaries, or reagents.
In connection with our interest in utilizing a substituted
aromatic system as a masked, 1,3-dione or 1,3-diol and
1,5-dione in the synthesis of natural products, we report
here a facile synthesis of (ꢀ)-1. A retrosynthetic strategy
for constructing the pyran fragment is outlined in
Scheme 1.
The phorboxazole skeleton consists of two 2,4-disubsti-
tuted oxazoles, four tetrahydropyrans and 15 stereo-
genic centres organised into a macrolide (C1–C26) and
a side-chain substructure (C27–C46). Of the four THP
rings, only one, the C31–C39 fragment, possesses a hemi-
ketal functionality and three stereogenic centres. Several
Construction of pyran 1 began with the preparation of
allylic alcohol 3 from m-anisaldehyde (2) via a Wittig
reaction followed by reduction of the ester with DI-
BAL-H.7 Quantitative bromination of the allylic alcohol
with PBr3 in dry diethyl ether, furnished allyl bromide 4
which was coupled with propargyl alcohol using CuI/
NaI in n-heptanol and acetone (1:1) to give the aromatic
q IICT Communication No. 061115.
*
Corresponding author. Tel.: +91 40 27160387; fax: +91 40
27193275; e-mail: nagaiah@iict.res.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.105

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S. P. Kumar, K. Nagaiah / Tetrahedron Letters 48 (2007) 1391–1394
O
OH
15
19
21
N
O
11
Me
OMe
O
O
O
5
28
OMe
N
O
2
37
32
Br
Me
Me
O
O
46
H
OH
Me
OH
Phorboxazole A
Figure 1.
OMe
O
OTBS
O
OMe O
HO
O
OMe
H
OH
OH
OMe
12
1
OMe
O
OH
H
OH
OMe
OMe
OMe
OMe
5
9
2
Scheme 1.
propargyl alcohol 5.8 Protection of the primary alcohol
with DHP in THF furnished the THP protected alcohol
6 (Scheme 2).
rated by sequential reduction with LAH followed
by the treatment of the resulting allylic alcohol 98
with TBDMSCl in THF to furnish 10 in an 88% yield
(Scheme 3).
Sharpless asymmetric dihydroxylation using AD-mix b
on the protected alcohol afforded the diol in an 87%
yield and 95% de.9 Subsequent methylation with NaH
and MeI in THF yielded dimethoxy compound 7.10
Deprotection of the THP group led to the propargyl
alcohol 8 in an 85% yield. This compound was elabo-
Sharpless asymmetric dihydroxylation of protected allyl
alcohol 10 with AD-mix b afforded the corresponding
diol in a 90% yield and 94% de. Protection of the vicinal
diol as isopropylidene 11 was accomplished with 2,2-
DMP.11
O
Br
OH
c
a, b
H
OMe
OMe
OMe
4
2
3
OTHP
OH
d
e
OMe
OMe
6
5
Scheme 2. Reagents and conditions: (a) (carbethoxymethylene)triphenylphosphorane, toluene, 80 ꢁC, 82%; (b) DIBAL-H, dry DCM, ꢀ78 ꢁC, 90%;
(c) PBr3, dry diethyl ether, 0 ꢁC, 100%; (d) propargyl alcohol, CuI, NaI, K2CO3, n-heptane:acetone (1:1), rt, 62%; (e) DHP, dry THF, PTSA, 0 ꢁC,
3 h, 68%.

S. P. Kumar, K. Nagaiah / Tetrahedron Letters 48 (2007) 1391–1394
1393
OMe
OMe
OMe
OH
OH
a
OTHP
c
b
OMe
6
OMe
OMe
OMe
OMe
OMe
OMe
9
8
7
O
O
OMe
OTBS
OTBS
OTBS
d
f
e
MeO
O
OMe
O
OMe
OMe
OMe
OMe
11
10
12
OMe
O
O
g
OTBS
MeO
h
HO
O
O
OMe
O
O MeO
O
H
OH
H
1
13
Scheme 3. Reagents and conditions: (a) (i) AD-mix-b, MeSO2NH2, t-butanol:H2O (1:1), 0 ꢁC, 36 h, 87%; (ii) MeI, NaH, dry THF, 0 ꢁC, 1 h, 100%;
(b) cat. PTSA, MeOH + H2O, 0 ꢁC to rt, overnight, 85%; (c) LAH, dry THF, 0 ꢁC to reflux, 4 h, 95%; (d) TBDMSCl, imidazole, dry THF, 0 ꢁC to rt,
2 h, 88%; (e) (i) AD-mix-b, MeSO2NH2, t-butanol:H2O (1:1), 0 ꢁC, 40 h, 90%; (ii) 2,2-DMP, dry acetone, cat. PTSA, 5 h, 75%; (f) Li (80 equiv)/liq.
NH3, THF, t-butanol, ꢀ78 ꢁC, 45 min; (g) O3, CH2Cl2, Sudan-III, ꢀ78 ꢁC, Me2S, 2 h; (h) PPTS, methanol, 0 ꢁC to rt, 3 h (overall yield for three
steps, 20%).
118, 9422–9423; (c) Molinski, T. F. Tetrahedron Lett.
1996, 37, 7879–7880.
2. Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd,
M. R.; Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem.
1993, 58, 1302–1304.
The crucial intermediate, b-keto ester 13 was unveiled
via a Birch reduction–ozonolysis sequence.12 When 11
was treated with Li/liq. NH3, t-BuOH,13 the dihydroan-
isole intermediate 12 was produced. Ozonolytic cleavage
was performed on the unpurified Birch product to give
b-keto ester 13,14 which was carried to the next step
without purification. Treatment of b-keto ester 13 with
PPTS15 in methanol furnished the C31–C39 fragment
of phorboxazole (1) as a pale yellow semi-solid. The
1H NMR, 13C NMR and other spectral data of the syn-
thetic sample were consistent with those of the reported
product.
3. (a) Williams, D. R.; Clark, M. P. Tetrahedron Lett. 1999,
40, 2291–2294; (b) Williams, D. R.; Clark, M. P.; Berliner,
M. A. Tetrahedron Lett. 1999, 40, 2287–2290; (c) Williams,
D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org. Lett.
2000, 2, 3023–3026; (d) Rychnovsky, S. D.; Thomas, C. R.
Org. Lett. 2000, 2, 1217–1219; (e) Schaus, J. V.; Panek, J.
S. Org. Lett. 2000, 2, 469–471; (f) Huang, H.; Panek, J. S.
Org. Lett. 2001, 3, 1693–1696; (g) Wolbers, P.; Hoffmann,
H. M. R. Tetrahedron 1999, 55, 1905–1914; (h) Wolbers,
P.; Misske, A. M.; Hoffmann, H. M. R. Tetrahedron Lett.
1999, 40, 4527–4530; (i) Greer, P. B.; Donaldson, W. A.
Tetrahedron 2002, 58, 6009–6018; (j) White, J. D.; Krane-
mann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3, 4003–4006;
(k) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39,
7185–7188; (l) Paterson, I.; Luckhurst, C. A. Tetrahedron
Lett. 2003, 44, 3749–3754.
In conclusion, we have accomplished the synthesis of
the C31–C39 fragment of (+)-phorboxazoles using
asymmetric dihydroxylation and a Birch reduction–
ozonolysis sequence for generating the 3,5-disubstituted
5,6-dihydropyran unit. The use of m-anisaldehyde as a
masked b-ketoester is advantageous. Spectral data are
provided.16
4. Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 120, 5597–5598.
5. (a) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J.
Am. Chem. Soc. 2000, 122, 10033–10046; (b) Evans, D. A.;
Cee, V. J.; Smith, T. E.; Santiago, K. J. Org. Lett. 1999, 1,
87–90.
6. (a) Yasmin, B.; Carreno, M. C.; Antonio, U.; Colobert,
F.; Guy, S. Org. Lett. 2004, 6, 4335–4338; (b) Ahmed, F.;
Forsyth, C. J. Tetrahedron Lett. 1998, 39, 183–186; (c)
Pattenden, G.; Plowright, A. T.; Tornos, J. A.; Ye, T.
Tetrahedron Lett. 1998, 39, 6099–6102; (d) Wolbers, P.;
Hoffmann, H. M. R. Synthesis 1999, 797–802; (e) Wil-
liams, D. R.; Clark, M. P.; Emde, U.; Berliner, M. A. Org.
Lett. 2000, 2, 3023–3026; (f) Marshall, J. A.; Yanik, M. M.
Tetrahedron Lett. 2000, 41, 4717–4721; (g) Li, R. D.; Tu,
Acknowledgments
S.P.K. is thankful to the CSIR, New Delhi, for the
award of a fellowship, and to Dr. J. S. Yadav, Director
IICT, for his support and encouragement.
References and notes
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126–8131; (b) Searle, P. A.; Molinski, T. F.;
Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996,

1394
S. P. Kumar, K. Nagaiah / Tetrahedron Letters 48 (2007) 1391–1394
Y. Q.; Lin, G.-Q.; Zhou, W.-S. Tetrahedron Lett. 2003, 44,
58.7, 57.1, 55.2, 33.3; FABMS (relative intensity) m/z: 266
(M+, 15), 235 (10), 195 (13), 165 (10), 151 (55), 121 (20), 69
(70), 57 (100); Anal. Calcd for C15H22O4 (266.333): C,
67.64; H, 8.33; O, 24.03. Found: 266.228: C, 67.62; H,
8729–8732; (h) Yadav, J. S.; Rajaiah, G. Synlett 2004,
1743–1746; (i) Pradeep, K.; Vasudeva, N. S. J. Org. Chem.
2006, 71, 3935–3941.
25
7. Pradeep, K.; Vasudeva, N. S. J. Org. Chem. 2006, 71,
3935–3941.
8. Douglass, F. T.; Yongchun, P.; Xia, Z. J. Org. Chem.
2004, 69, 7234–7240.
8.30; O, 24.00. Compound 10: ½aꢁD ꢀ22.81 (c 0.035,
CHCl3); IR (KBr, neat): 2932, 2857, 1693, 1600, 1462,
1
1257, 1099; H NMR (CDCl3, 300 MHz) d: 7.20 (t, 1H,
J = 8.3), 6.80 (m, 3H), 5.53 (m, 2H), 4.07 (m, 3H), 3.79 (s,
3H), 3.38 (s, 3H), 3.28 (m, 1H), 3.23 (s, 3H), 2.14 (m, 1H),
1.95 (m, 1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3,
75 MHz) d: 159.6, 140.6, 131.7, 129.1, 126.7, 120.0, 113.3,
112.7, 85.1, 84.1, 63.7, 58.7, 57.0, 55.0, 33.3, 25.9 (3
carbons), 18.3, ꢀ5.13 (2 carbons); FABMS (relative
intensity) m/z: 380 (M+, 40), 349 (5), 323 (10), 249 (7),
195 (20), 151 (80), 121 (20), 89 (40), 73 (100); Anal. Calcd
for C21H36O4Si (380.594): C, 66.27; H, 9.53; O, 16.82.
Found: 380.487: C, 66.24; H, 9.49; O, 16.70. Compound
9. (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H.
L.; Morikawa, K.; Min Wang, Z. J. Org. Chem. 1992, 57,
2768–2771; (b) Pandey, S. K.; SubbaRao, V. K.; Pradeep,
K. Tetrahedron Lett. 2004, 45, 5877–5879; (c) Anjana, S.;
Santosh, C. S.; Subhash, C. S.; Keinan, E. J. Org. Chem.
1999, 64, 2381–2386.
10. (a) Park, S. H.; Lee, H. W.; Seung-Un, P. Bull. Korean
Chem. Soc. 2004, 25, 1613–1614; (b) Roush, R. W.;
Pfeifer, A. L. J. Org. Chem. 1998, 63, 2062–2063.
11. Subhash, C. S.; Ehud, K. J. Org. Chem. 1997, 62, 377–
386.
12. (a) Rao, B. V.; Rao, A. S. Synth. Commun. 1995, 1531–
1543; (b) Shashidhar, K. A.; Haritha, B.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 4261–4263; (c) Naveen, K. D.;
Rao, B. V. Tetrahedron Lett. 2004, 10, 2227–2229.
13. (a) Birch, A. J.; Fitton, P.; Smith, D. C. C.; Steere, D. E.;
Stelfox, A. R. J. Chem. Soc. 1963, 2209–2216; (b) Kirkeno,
C. L.; White, J. D. J. Org. Chem. 1985, 1316–1319; (c)
Bringmann, G. Liebigs Ann. Chem. 1985, 2105–2115; (d)
Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M.;
Charette, A. B. J. Org. Chem. 1991, 56, 741–750; For the
use of dyes in ozonolysis, see: (e) Veysoglu, T.; Mitscher,
L. A.; Swayze, J. K. Synthesis 1980, 807–810.
25
11: ½aꢁD ꢀ7.26 (c 0.011, CHCl3); IR (KBr, neat): 3443,
1
2930, 2857, 1603, 1463, 1362, 1315, 1257, 1100; H NMR
(CDCl3, 300 MHz) d: 7.20 (t, 1H, J = 8.5), 6.80 (m, 3H),
4.09 (d, 1H, J = 4.68), 3.94 (m, 1H), 3.80 (s, 3H), 3.64 (t,
1H, J = 5.2) 3.52 (m, 3H), 3.38 (s, 3H), 3.26 (s, 3H), 1.41
(m, 1H), 1.32 (s, 3H), 1.30 (s, 3H), 1.25 (m, 1H), 0.86 (s,
9H), 0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz) d: 159.6,
140.8, 129.0, 119.9, 113.2, 112.8, 85.9, 81.6, 81.4, 75.2,
63.4, 59.7, 57.2, 55.1, 35.6, 29.6, 27.3, 26.9, 25.8 (3
carbons), 14.1, ꢀ5.4 (2 carbons); FABMS (relative inten-
sity) m/z: 454 (M+, 20), 397 (10), 347 (10), 307 (10), 245
(20), 215 (22), 151 (70), 121 (20), 107 (10), 89 (50), 73
(100); Anal. Calcd for C24H42O6Si (454.672): C, 63.40; H,
9.51; O, 21.11. Found: 454.583: C, 63.36; H, 9.49; O,
25
21.08. Compound 1: ½aꢁD ꢀ52.35 (c 0.17, CHCl3); LCMS
14. Zvilichovsky, G.; Isra, G. H. Y. J. Org. Chem. 2004, 69,
5490–5493.
(relative intensity) m/z: 264.1 (M+, 98), 246.0 (65), 203.1
(100), 172.2 (13), 144.2 (12), 117.1 (22); Anal. Calcd for
C11H20O7 (264.273): C, 49.99; H, 7.63; O, 42.38. Found:
264.192: C, 49.97; H, 7.60; O, 42.34; 1H NMR (CDCl3,
300 MHz) d: 4.42 (s, 1H), 4.29 (m, 1H), 3.75 (s, 1H), 3.52
(s, 3H), 3.48 (m, 1H), 3.52 (m, 2H), 3.40 (s, 3H), 2.81 (s,
2H), 1.90 (m, 1H), 1.72 (m, 3H), 1.55 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d: 169.96, 98.5, 72.8, 72.0, 68.6, 58.2,
51.9, 48.0, 41.9, 38.7, 32.1.
15. Yadav, J. S.; Rajaiah, G. Synlett 2004, 1537–1540.
25
16. Compound 9: ½aꢁD ꢀ17.45 (c 0.021, CHCl3); 1H NMR
(CDCl3, 300 MHz) d: 7.22 (t, 1H, J = 8.3), 6.78 (m, 3H),
5.58 (m, 2H), 4.04 (m, 3H), 3.79 (s, 3H), 3.41 (s, 3H), 3.32
(q, 1H, J = 10.4, 5.9), 3.23 (s, 3H), 2.04 (m, 2H), 1.5
(br, 1H); 13C NMR (CDCl3, 75 MHz) d: 159.6, 140.6,
131.5, 129.2, 128.5, 120.1, 113.3, 112.9, 85.2, 83.9, 63.5,