Total synthesis of a 20-deoxybryostatin

Article abstract of DOI:10.1039/c1cc12332g

The 20-deoxybryostatin 40 has been prepared using a modified Julia olefination to form the 16,17-double-bond, followed by macrolactonisation, selective deprotection and oxidation. This is the first total synthesis of a 20-deoxybryostatin.

Full text of DOI:10.1039/c1cc12332g

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 7200–7202
www.rsc.org/chemcomm
COMMUNICATION
Total synthesis of a 20-deoxybryostatinw
Anthony P. Green, Alan T. L. Lee and Eric J. Thomas*
Received 21st April 2011, Accepted 27th April 2011
DOI: 10.1039/c1cc12332g
The 20-deoxybryostatin 40 has been prepared using a modified
Julia olefination to form the 16,17-double-bond, followed by
macrolactonisation, selective deprotection and oxidation. This is
the first total synthesis of a 20-deoxybryostatin.
sub-group of the bryostatins that has yet to succumb to total
synthesis, using the modified Julia approach.
At this stage, it was necessary to modify the protecting
group strategy and to develop an improved synthesis of
sulfone 4. Thus, the hydroxydecylphosphonate 8, prepared
by desilylation of silyl ether 7,12 was condensed with aldehyde
6 using barium hydroxide as the base to give the (E)-enone 9,
see Scheme 1. Selective removal of the triethylsilyl protecting
group using the hydrogen fluoride-pyridine complex gave the
secondary alcohol 10 that was cyclised immediately using
potassium tert-butoxide in tetrahydrofuran to give the
2,5-cis-disubstituted tetrahydropyran 11 stereoselectively.
Oxidation of the primary alcohol gave the corresponding acid
and alkylation under basic conditions using prop-2-enyl
bromide gave the allyl ester 12. Treatment with pyridinium toluene
p-sulfonate in methanol containing trimethyl orthoformate then
initiated methanolysis of the acetonide with formation of the
methoxy acetal 13 and silylation of the C(3)-alcohol gave the fully
protected ester-acetal 14. Finally, oxidative removal of the
p-methoxybenzyl group delivered the alcohol 15 that corresponds
to the C(1)–C(16) fragment of the bryostatins.
The bryostatins are macrocyclic natural products with potent
anti-cancer activity due in part to protein kinase C inhibition.1
They also show a range of other biological activities including
cognition enhancement. Representative examples include the
widely studied bryostatin 1 (1) and bryostatin 10 (2)2 which
lacks an oxygen function at C(20). Five total syntheses of
bryostatins have been described to date,3 together with a
formal synthesis,4 syntheses of close analogues5–7 and many
partial syntheses.1a,8 Moreover, analogues with simplified
C(1)–C(16) fragments have been prepared with improved
biological activity.9 However the isolation of bryostatins from
natural sources is difficult and only limited quantities are
available for SAR studies.2b,10 For these reasons the synthesis
of bryostatins and analogues is still of interest.8
Convergent syntheses of bryostatins can be envisaged with
assembly of the 16,17-double-bond as a key step. Indeed, the
early total syntheses of bryostatins used classical Julia
reactions to form this bond.3 However, formation of the
16,17-double-bond using ring-closing metathesis was successful
only for a ring-expanded derivative6 and for analogues which
lacked the geminal dimethyl groups at C(18).7 The (E)-alkene 5
was recently prepared from the aldehyde 3 and sulfone 4 using a
modified Julia olefination.11,12 We now report the synthesis
of a benzyl ether of a 20-deoxybryostatin, a biologically active
In the original synthesis of sulfone 4 the final step involved
oxidation of the corresponding sulfide and was complicated by
competing oxidation of the alkene.12 A more efficient synthesis
of sulfone 4 was required.
The alcohol 1613 was converted to the bromide 19 by
protection of the secondary alcohol as its triethylsilyl (TES)
ether 17, debenzylation and conversion of the allylic alcohol 18
into the bromide 19, see Scheme 2. Selective removal of the
TES ether and acylation of the resulting alcohol 20 using
acryloyl chloride then gave the bromoalkenyl acrylate 21.
If an organometallic reagent derived from bromide 21 could
be reacted with aldehyde 22,13 ring-closing metathesis, reduction
and protection would give the required sulfone directly. However,
such organometallic reagents were expected to be unstable due to
the possibility of competing intramolecular reactions with the
School of Chemistry, University of Manchester, Manchester,
M13 9PL, UK. E-mail: e.j.thomas@manchester.ac.uk;
Fax: 00 44 (0)161 275 4939; Tel: 00 44 (0)161 275 4614
w Electronic supplementary information (ESI) available: full experi-
mental details and spectra of key compounds. See DOI: 10.1039/
c1cc12332g
c
7200 Chem. Commun., 2011, 47, 7200–7202
This journal is The Royal Society of Chemistry 2011

View Article Online
Scheme 1 Synthesis of the C(1)-C(16) fragment 15: Reagents and conditions: (i) TBAF, THF, r.t., 16 h (ca. 100%); (ii) Ba(OH)2, THF, H2O, 0 1C -
t
r.t., 16 h; (iii) HF.py, THF, 0 1C, 25 min; (iv) BuOK, THF, r.t., 5 min (49% of 11 based on 8); (v) (a) DMP, py, DCM, r.t., 1 h; (b) NaClO2,
NaH2PO4, 2-methylbut-2-ene, THF, tBuOH, H2O, r.t., 1 h; (c) allyl bromide, NaHCO3, DMF, 70 1C, 16 h (70% of 12 based on 11); is (vi) PPTS,
MeOH, HC(OMe)3, DCM, r.t., 1 h (66%); (vii) TBSOTf, 2,6-lut., DCM, À78 1C, 1 h (84%); (viii) DDQ, MeOH, DCM, r.t. 2 h (72%).
acrylate. Indeed, preliminary studies of indium mediated addition
of bromide 21 to the aldehyde 22 gave complex mixtures of
products. However, it was thought that for an organobismuth
species generated from the bromoalkenyl acrylate 21 and
bismuth(0) in situ,14,15 an intermolecular reaction with an
aldehyde might be able to compete with any intramolecular
reaction with the acrylate. Indeed, the bismuth(0) mediated
reaction of bromide 21 with aldehyde 22 followed by silylation
of the resulting alcohols 23 gave a 60% yield of the silyl ethers
24. Ring-closing metathesis13 then gave the lactone 25 which
was reduced to the diol 26 using Luche’s conditions. Protection
of the primary and secondary alcohols gave the sulfone 4 which
was converted into the trimethylsilyl ether 29.
toluene p-sulfonate in methanol containing trimethyl ortho-
formate selectively removed the triethylsilyl group to give the
19-alcohol 35 which was characterised as the ketone 36.
Removal of the triisopropylsilyl groups from alcohol 35 using
tetrabutylammonium fluoride in acetic acid then gave the triol
37. Stepwise oxidation of the exocyclic allylic hydroxyl groups
using manganese dioxide and a Pinnick oxidation followed by
esterification using trimethylsilyl diazomethane gave the bis-
methyl ester 38 which on oxidation using the Dess–Martin
periodinane was converted into the sensitive ketone 39. Finally,
desilylation using hydrogen fluoride in pyridine—tetrahydrofuran
gave the 20-deoxybryostatin 40 which corresponds to bryostatin
10 2 except for the presence of the benzyloxy group at C(7).
20-Deoxybryostatins are known to dehydrate to give the
19,20-enol ethers2 and analogous dehydrations had been
observed during model studies. However, extensive NMR
studies confirmed the desilylated product was the 20-deoxy-
bryostatin 40 rather than the analogous enol ether 41. In
particular, no carbon was seen at ca. d150 in its 13C NMR
spectrum, cf. C(19) of brysotatin 16 42.16 Moreover neither of
the two peaks at ca. d102 in the 13C NMR spectrum of the
The modified Julia reaction of the aldehyde 30, prepared
by oxidation of the alcohol 15, and the sulfone 29 gave the
(E)-alkene 31, see Scheme 3. Methanolysis of the trimethylsilyl
ether gave the alcohol 32 and cleavage of the allyl ester
provided the seco-acid 33 that was cyclised under Yamaguchi
conditions to the macrolide 34.
Conversion of the macrolide 34 into 7-des-O-pivolyl-7-O-
benzylbryostatin 10 40 is outlined in Scheme 3. Pyridinium
Scheme 2 Synthesis of sulfone 29: Reagents and conditions: (i) TESCl, imid., DCM, r.t., 1 h (98%); (ii) Li, naph., THF, À25 1C (97%); (iii) CBr4,
Ph3P, NEt3, DCM, 0 1C, 20 min (95%); (iv) PPTS, MeOH, CH(OMe)3, THF, r.t., 3 h (95%); (v) acryloyl chloride, iPr2NEt, DCM, 0 1C, 40 min
(97%); (vi) (a) BiI3, Zn, THF, then add 21 and 22, THF, reflux, 4.5 h; (b) TESCl, imid., DCM, r.t., 90 min (61% of 24 from 21); (vii) Grubbs’ 2 cat.,
(5 mol%), syringe pump, 20 h, 1,2-DCE, reflux (90%); (viii) NaBH4, CeCl3, MeOH, THF, 0 1C to r.t., 7.5 h (75%); (ix) TIPSCl, imid., DCM, r.t.,
12 h (86%); (x) TBSOTf, 2,6-lut., DCM, r.t., 2 h (93%); (xi) nBuSH, MgBr2ÁEt2O, K2CO3, Et2O, r.t., 1 h (96%); (xii) TMSCl, Et3N, DCM, 0 1C to
r.t., 3 h (100%).
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 7200–7202 7201

View Article Online
Scheme 3 Synthesis of a 20-deoxybryostatin: Reagents and conditions: (i) (a) SO3.py, DMSO, iPr2NEt, DCM, r.t., 1 h; (ii) (a) 29, LiHMDS, THF,
À60 1C, 30 min then add 30, À78 1C, 1 h to r.t., 20 min; (b) PPTS, MeOH, CH(OMe)3, DCM. r.t., 1 h (60% of 32 from 30); (iii) Pd(Ph3P)4,
morpholine, THF, r.t., 16 h; (iv) 2,4,6 Cl3C6H2COCl, Et3N, THF, r.t., 16 h, toluene, DMAP, 40 1C, 14 h (85% of 34 from 32); (v) PPTS, MeOH,
CH(OMe)3, DCM, r.t., 48 h (54%); (vi) TPAP, NMO, 4 A sieves, DCM, r.t., 6 h (50%); (vii) TBAF, AcOH, r.t., 40 h (53%); (viii) (a) MnO2,
DCM, r.t., 1 h (b) NaOCl2, 2-methylbut-2-ene, tBuOH, r.t., 1 h (c) TMSCHN2, MeOH, tol., 0 1C, 1 h (40% of 38 from 37); (ix) DMP, py., DCM,
r.t., 2 h; (x) HF, py., THF, r.t., 24 h, py. and HFÁH2O, added, r.t. 24 h (50% of 40 from 38).
product correlated with a hydrogen and so were assigned to
the hemi-acetal carbons C(9) and C(19). In the 1H NMR
spectrum of the product 40, the methylene protons at C(20)
and the 19-hydroxyl group were observed at ca. d2.1 and as a
singlet at d5.3, as would be expected.2bw
3 (a) M. Kageyama, T. Tamura, M. H. Nantz, J. C. Roberts,
P. Somfrai, D. C. Whritenour and S. Masamune, J. Am. Chem.
Soc., 1990, 112, 7407; (b) D. A. Evans, P. H. Carter,
E. M. Carreira, A. B. Charette, J. A. Prunet and M. Lautens,
J. Am. Chem. Soc., 1999, 121, 7540; (c) K. Ohmori, Y. Ogawa,
T. Obitsu, Y. Ishikawa, S. Nishiyama and S. Yamamura, Angew.
Chem., Int. Ed., 2000, 39, 2290; (d) B. M. Trost and G. Dong,
J. Am. Chem. Soc., 2010, 132, 16403; (e) G. E. Keck, Y. B. Poudel,
T. J. Cummins, A. Rudra and J. A. Covel, J. Am. Chem. Soc.,
2011, 133, 744.
4 S. Manaviazar, M. Frigerio, G. S. Bhatia, M. G. Hummerstone,
A. E. Aliev and K. Hale, Org. Lett., 2006, 8, 4477.
5 G. E. Keck, Y. B. Poudel, D. S. Welch, M. B. Kraft, A. P. Truong,
J. C. Stephens, N. Kedei, N. E. Lewin and P. M. Blumberg, Org.
Lett., 2009, 11, 593.
6 B. M. Trost, H. Yang, O. R. Thiel, A. J. Frontier and C. S. Brindle,
J. Am. Chem. Soc., 2007, 129, 2206.
7 B. Bradshaw, M. Ball, R. Dumeunier, T. J. Gregson,
S. MacCormick and E. J. Thomas, Tetrahedron Lett., 2006, 47,
2223.
8 (a) K. J. Hale and S. Manaviazar, Chem.–Asian J., 2010, 5, 704;
(b) A. P Green, S. Hardy, A. T. L. Lee and E. J. Thomas,
Phytochem. Rev., 2010, 9, 501.
9 (a) P. A. Wender, B. A. DeChristopher and A. J. Schrier, J. Am.
Chem. Soc., 2008, 130, 6658; (b) P. A. Wender, J. C. Horan and
V. A. Verma, Org. Lett., 2006, 8, 5299; (c) P. A. Wender and
J. C. Horan, Org. Lett., 2006, 8, 4581; (d) P. A. Wender and
V. A. Verma, Org. Lett., 2008, 10, 3331.
The synthesis of the bryostatin 10 analogue 40 amounts to
the first total synthesis of a 20-deoxybryostatin. The reliability
of the modified Julia reaction for the stereoselective assembly
of the 16,17-(E)-double-bond and the use of organobismuth
chemistry for assembly of the metathesis precursor 24 together
with the selective late-stage desilylation reactions and isolation
of the 20-hemiacetal 40 are of interest.
10 D. E. Schaufelberger, et al., J. Nat. Prod., 1991, 54, 1265.
11 C. Aissa, Eur. J. Org. Chem., 2009, 1831.
We thank the EPSRC for support.
12 J. Allen, A. P. Green, A. Hardy, N. Heron, A. T. L. Lee and
E. J. Thomas, Tetrahedron Lett., 2008, 49, 6352.
Notes and references
1 (a) K. J. Hale, M. G. Hummersone, S. Manaviazar and
M. Frigerio, Nat. Prod. Rep., 2002, 19, 413; (b) J. H. Sharp,
M. K. Winson and J. S. Porter, Nat. Prod. Rep., 2007, 24, 659.
2 (a) G. R. Pettit, Y. Kamano and C. L. Herald, J. Org. Chem., 1987,
52, 2848; (b) Y. Kamano, H.-p. Zhang, A. Hino, M. Yoshida,
G. R. Pettit, C. L. Herald and H. Itokawa, J. Nat. Prod., 1995, 58,
1868; (c) Y. Kamano, H.-p. Zhang, H. Morita, H. Itokawa,
O. Shirota, G. R. Pettit, D. L. Herald and C. L. Herald, Tetra-
hedron, 1996, 52, 2369.
13 A. P. Green, S. Hardy and E. J. Thomas, Synlett, 2008, 2103.
14 (a) S. Donnelly, M. Fielding and E. J. Thomas, Tetrahedron Lett.,
2004, 45, 6779; (b) N. Bazar, S. Donnelly, H. Liu and
E. J. Thomas, Synlett, 2010, 575.
15 M. Wada, H. Ohki and K.-Y. Akiba, Bull. Chem. Soc. Jpn., 1990,
63, 1738.
16 G. R. Pettit, F. Gao, P. M. Blumberg, C. L. Herald, J. C. Coll,
Y. Kamano, N. E. Lewin, J. M. Schmidt and J.-C. Chapuis, J. Nat.
Prod., 1996, 59, 286.
c
7202 Chem. Commun., 2011, 47, 7200–7202
This journal is The Royal Society of Chemistry 2011