A stereoselective synthesis of the C(1)-C(16) fragment of the bryostatins

Article abstract of DOI:10.1016/j.tetlet.2004.09.124

A synthesis of the C(1)-C(16) fragment of the brysostatins has been developed. Key steps are the stereoselective copper(I) catalysed addition of allylmagnesium bromide to an alkynyl ester, a condensation of a βγ-unsaturated aldehyde with a ketophosphonate

Full text of DOI:10.1016/j.tetlet.2004.09.124

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8737–8740
A stereoselective synthesis of the C(1)–C(16)
fragment of the bryostatins
Matthew Ball, Anne Baron, Benjamin Bradshaw, Hiroki Omori,
Somhairle MacCormick and Eric J. Thomas*
Department of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Received 11 August 2004; accepted 17 September 2004
Available online 5 October 2004
Abstract—A synthesis of the C(1)–C(16) fragment of the brysostatins has been developed. Key steps are the stereoselective copper(I)
catalysed addition of allylmagnesium bromide to an alkynyl ester, a condensation of a bc-unsaturated aldehyde with a ketophos-
phonate, and the formation of the B-ring under mild conditions by stereoselective intramolecular conjugate addition.
Ó 2004 Elsevier Ltd. All rights reserved.
The bryostatins are an important group of complex
macrocyclic natural products isolated from the marine
filter feeder Bugula neritina. They have potent antineo-
plastic activity and are candidates for the treatment of
cancer in conjunction with other chemotherapies.1 This
biological activity is based on their ability to modulate
various protein kinase Cꢀs and has led to substantial
interest into bryostatin synthesis with three total synthe-
ses reported to date.2–4 Recent developments in aquacul-
ture techniques are able to provide 100g quantities of
bryostatin 1( 1) per annum for clinical trials, and several
complex acetal-containing analogues have been pre-
pared and their biological activities investigated.5 How-
ever, there remains a need for better synthetic access to
the bryostatins to provide additional analogues for bio-
logical evaluation. We identified the 20-deoxybryosta-
tins, for example, bryostatin 11 (2), as our initial
targets as they have not yet succumbed to total
synthesis.6
In the three total syntheses of bryostatins reported to
date, the macrolide was assembled by using a Julia reac-
tion to prepare the 16,17-double-bond followed by
macrolactonisation. Other strategies, for example, form-
ation of the macrolide by metathesis, have yet to be
evaluated. We now report a scalable synthesis of the
C(1)–C(16) fragment, which should allow fuller evalua-
tion of assembly strategies.
Conjugate addition reactions have been used to assem-
ble ring B of the bryostatins with the exocyclic, trisubsti-
tuted, double-bond introduced after the cyclisation step,
but with only modest stereoselectivity.7,8 An alternative
approach would be to introduce this double-bond before
ring B formation, hopefully with better stereochemical
control. Our initial target was therefore identified as
an enone 4, which would provide the C(8)–C(16) frag-
ment 3 after cyclisation and oxidation–esterification.
Aldehydes 5 and ketophosphonates 6 were identified
as precursors of enones 4.
Me Me
H
O
HO
OAc
MeO2C
A
B
O
Me Me
Me Me
R
H
OH
1
O
17
OH
8
MeO2C
R
16
H
H
H
O
O
PO
OH
OP
O
O
O
Me
Me
16
C
27
Me
OP
3
4
X
HO
CO2Me
1 X = PrCH=CH.CH=CH.CO2
2 X = H
Me Me
R
CHO
H
(P = protecting
groups)
+
(MeO)2P(O)
PO
OP
O
*
Corresponding author. Tel.: +44 161 275 4614; fax: +44 161 275
4939; e-mail: e.j.thomas@man.ac.uk
5
6
OP
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.124

8738
M. Ball et al. / Tetrahedron Letters 45 (2004) 8737–8740
CO2Me
Me
O
Me
H
O
O
MeO2C
i
ii
H
OBn
OH
OR
OH
19 R = H
20 R = TBDPS
OPMB
i, ii
OPMB
7
8
9
OPMB
18
+
OPMB
iii
Me
Me
H
iii
H
O
OBn
OR
O
CHO
iv
H
21 R = H
22 R = TBDPS
TBSO
OTBS
TBSO
10
OTBS
OPMB
OPMB
11
OPMB
Scheme 3. Reagents and conditions: (i) 5% v/v concd aq HCl in
MeOH, 40°C, 15min; (ii) TBDPSCl, imid. (20, 63%; mixed 19%); (iii)
KOt-Bu, THF, 10min (20, a further 12%, 75% combined yield of 20
based on 18).
Scheme 1. Reagents and conditions: (i) methyl propiolate, n-BuLi,
BF3ÆTHF (94%); (ii) CuI, LiCl, 2molequiv allylmagnesium bromide,
À78°C; (iii) (a) DIBAL-H, THF, (b) TBSOTf, 2,6-lutidine (85% from
8); (iv) (a) ADmix b, n-BuOH, H2O, 5mol% OsO4 (70%), (b) NaIO4,
MeOH (ca. 100%).
Condensation of the phosphonate 17 with the aldehyde
11 using lithium chloride in acetonitrile then gave the
required enone 18 in a 73% yield.
The aldehyde 11 was prepared as outlined in Scheme 1.
Reaction of the protected hydroxyepoxide 7 with lithi-
ated methyl propiolate is known to give the hydroxy
ester 8.9 Copper(I) catalysed conjugate addition of
allylmagnesium bromide to this ester gave the (Z)-ab-
unsaturated ester 9 with excellent stereoselectivity, and
reduction followed by protection gave the bis-tert-but-
yldimethylsilyl ether 10 in an excellent, 85%, overall
yield. Regioselective oxidation of the terminal double-
bond to give the aldehyde 11 was best achieved by
hydroxylation using ADmix b followed by cleavage of
the intermediate vicinal diol using sodium periodate in
methanol.
Earlier studies on the formation of ring B by conjugate
addition had indicated that useful stereoselectivity
required thermodynamic control.7 Fairly vigorous and
prolonged reaction conditions, incompatible with many
protecting groups, were therefore used to effect simulta-
neous 15-hydroxyl deprotectionꢁ and conjugate addi-
tion.7 In the present work, milder reaction conditions
were investigated for these transformations.
Removal of the tert-butyldimethylsilyl groups from
enone 18 using hydrochloric acid in methanol, 15min,
rt, was accompanied by cyclisation to give a 72% yield
of a mixture of the 2,6-cis- and 2,6-trans-tetrahydropy-
rans 19 and 21, ratio 80:20 in favour of the required
cis-isomer 19 (Scheme 3). Following silylation of this
mixture,10 the silyl ethers 20 and 22 were separated by
flash column chromatography and fractions enriched
in the minor 2,6-trans-isomer 22 were treated with
potassium tert-butoxide11 in THF, 10min, rt to effect
cis:trans equilibration giving more of the required cis-
isomer 20. Overall, the required 2,6-cis-isomer 20 was
isolated in yields of 75% based on the enone 18.
The ketophosphonate 17 was prepared as outlined in
Scheme 2. Alcohol 12 is available in three steps (ca.
60% overall yield) from (R)-pantolactone7 and was pro-
tected as its tert-butyldimethylsilyl ether 13. Hydrobor-
ation–oxidation gave the primary alcohol 14, which
was converted into the alkene 15 by oxidation to the
corresponding aldehyde followed by a Wittig condensa-
tion. Removal of the tert-butyldimethylsilyl group gave
the alcohol 16, which was taken through to the keto-
phosphonate 17 by oxidation, addition of lithiated di-
methyl methylphosphonate and further oxidation.
Having achieved the formation of ring B by conjugate
addition under mild conditions, it was necessary12
to synthesise an enone with the C(1)–C(9) fragment pre-
sent before attempting to synthesise the intact C(1)–
C(16) fragment of the bryostatins. The ketophosphonate
31 was therefore prepared as outlined in Scheme 4. Pro-
tection of the alcohol 12 as its p-methoxybenzyl ether 23
and hydroboration–oxidation gave the alcohol 24,
which was oxidised to the aldehyde 25. The aldol
condensation of this aldehyde with the lithium enolate
of the methyl ketone 26 was subject to chelation con-
trol13 and gave the 1,3-anti-adduct 27. Reduction to
the anti-diol 28 was achieved using lithium tris-tert-but-
oxyaluminium hydride and the diol was protected as its
acetonide 29. Oxidative removal of the p-methoxybenzyl
ether then gave the primary alcohol 30, which was taken
through to the ketophosphonate 31 by oxidation to the
Me
OR
Me
Me
Me
Me
OR
Me
ii
iii
OBn
OTBS OBn OH
OBn
12 R = H
13 R = TBS
15 R = TBS
16 R = H
14
i
iv
v
Me
O
Me
Me
Me
vi
H
(MeO)2P(O)
OBn
TBSO
OTBS
O
OBn
OPMB
18
17
Scheme 2. Reagents and conditions: (i) TBSCl, imid., DMAP (91%);
(ii) BH3ÆTHF, 3h, then NaOH, aq H2O2 (72%); (iii) (a) (COCl)2,
DMSO, then Et3N, (b) Ph3PMeBr, t-BuOK (58% from 14); (iv) TBAF
(ca. 100%); (v) (a) (COCl)2, DMSO, then Et3N, (b) (MeO)2P(O)Me, n-
BuLi, (c) Dess–Martin periodinane (83% from 16); (vi) LiCl, 11,
MeCN then i-Pr2NEt (73%).
ꢁ Bryostatin numbering.

M. Ball et al. / Tetrahedron Letters 45 (2004) 8737–8740
8739
Me
Me
Me
Me
Condensation of aldehyde 35 with the phosphonate 31
was carried out using barium hydroxide as the base
and the crude product was immediately treated with
HFÆpyridine complex, 30s, 0°C, to effect removal of
the trimethylsilyl group. This gave the hydroxyenone
36, which was isolated, after flash column chromatogra-
phy, in a 65% yield based on the phosphonate 31, see
Scheme 6. Stereoselective cyclisation of the free alcohol
was accomplished using potassium tert-butoxide, 5min,
Me
OR
Me
ii
iii
CHO
OPMBOBn
OPMBOBn OH
OBn
12 R = H
23 R = PMB
24
25
i
iv
Me
Me
Me
v
Me
OPMBOBn OH
OH
OTBDPS
OTBDPS
OPMBOBn OH
O
OTBDPS
OTBDPS
27
28
vi
Me
Me
Me
Me
vii
Me
O
Me
OH
OBn
O
O
OPMBOBn
O
O
i
Me Me
Me Me
29
35
TBDPSO
OH
OBn
O
O
OTBDPS
30
viii
Me Me
Me Me
OPMB
H
36
Me
ii
(MeO)2P(O)
O
OTBDPS
Me
Me
O
OBn
31
O
O
OTBDPS
26
Me Me
H
TBDPSO
O
O
OBn
O
O
OTBDPS
Scheme 4. Reagents and conditions: (i) NaH, PMBCl, DMF, TBAI
(88%); (ii) BH3ÆTHF, then NaOH, H2O2 (72%); (iii) (COCl)2, DMSO,
then Et3N (92%); (iv) 26ÆLDA, THF, À78°C (76%); (v) Li(t-
BuO)3AlH, LiI; (vi) 2,2-dimethoxypropane, TsOHÆH2O (91% from
27); (vii) DDQ, pH7 buffer (63%); (viii) (a) (COCl)2, DMSO, then
Et3N, (b) (MeO)2P(O)Me, nBuLi, (c) Dess–Martin periodinane (80%
from 30).
Me Me
OPMB
iii
37
Me Me
H
O
MeO
OBn
H
H
TBDPSO
O
OR
38 R = H
39 R = SEM
OPMB
iv
OTBDPS
aldehyde, addition of lithiated dimethyl methylphospho-
nate, and further oxidation.
Scheme 6. Reagents and conditions: (i) (a) 31, Ba(OH)2, THF, 18h, (b)
HFÆpy, 30s (65% from 31); (ii) KOt-Bu, THF, 5min; (iii) (MeO)3CH,
MeOH, PPTS (cat.), MeOH, 19h, rt (60% from 36); (iv) SEMCl, i-
Pr2NEt, DCM (85%).
Since the acidic conditions used for the removal of the
tert-butyldimethylsilyl groups from the cyclisation pre-
cursor 18, see Scheme 3, would be incompatible with
the acetonide protecting group derived from the phos-
phonate 31, it was necessary to protect the 15-hydroxyl
group using a more labile protecting group. Therefore,
after protection of the primary hydroxyl group of diol
32, obtained by reduction of the ester 9, as its tert-but-
yldiphenylsilyl ether, the secondary hydroxyl was con-
verted into its trimethylsilyl derivative to give
intermediate 33 (Scheme 5). This was hydroxylated
using ADmix b to give diol 34 and the vicinal diol oxid-
atively cleaved to the aldehyde 35 using lead(IV) acetate,
as the trimethylsilyl group was hydrolysed by aqueous
sodium periodate.
Me Me
H
MeO
OBn
i
H
H
39
TBDPSO
O
O
OSEM
OH
ii
40
OTBDPS
Me Me
H
H
MeO
OBn
H
OR
O
X
O
OSEM
OR
41 X = O R = TBDPS
42 X = CH2 R = TBDPS
43 X = CH2 R = H
iii
iv
i
ii
v
9
OH
OH
TBDPSO
OTMS
OPMB
Me Me
H
O
MeO
33
OPMB
32
OBn
MeO2C
iii
H
H
OH
O
iv
CHO
OH
OSEM
TBDPSO
OTMS
TBDPSO
OTMS
OPMB
44
OH
35
OPMB
34
Scheme 7. Reagents and conditions: (i) DDQ, DCM then (MeO)3CH,
MeOH, PPTS (71%); (ii) Dess–Martin periodinane; (iii) Ph3PMeBr,
KOt-Bu (71% from 40); (iv) TBAF (76%); (v) MnO2, then add KCN,
MeOH, AcOH (40%).
Scheme 5. Reagents and conditions: (i) DIBAL-H, THF; (ii) (a)
TBDPSCl, imid. (93% from 9), (b) TMSCl, Et3N (91%); (iii) ADmix b,
5% OsO4, n-BuOH (70%); (iv) Pb(OAc)4, py (ca. 100%).

8740
M. Ball et al. / Tetrahedron Letters 45 (2004) 8737–8740
rt, and gave the tetrahydropyran 37 essentially as a sin-
gle diastereoisomer, equilibration occurring under the
basic reaction conditions. Without purification, this
intermediate was treated with trimethyl orthoformate
in methanol under acidic conditions, which removed
the acetonide group and induced cyclisation to give
the acetal 38. Finally, the 3-hydroxyl group was pro-
tected as its trimethylsilylethoxymethyl (SEM) ether to
give the fully protected C(1)–C(16) fragment 39.
References and notes
1. (a) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8,
1841; (b) Hale, K. J.; Hummersone, M. G.; Manaviazar,
S.; Frigero, M. Nat. Prod. Rep. 2002, 19, 413.
2. (a) Masamune, S. Pure Appl. Chem. 1988, 60, 1587; (b)
Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.;
Somfrai, P.; Whritenour, D. C.; Masamune, S. J. Am.
Chem. Soc. 1990, 112, 7407.
3. Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.;
Charette, A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998,
37, 2354; Evans, D. A.; Carter, P. H.; Carreira, E. M.;
Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem.
Soc. 1999, 121, 7540.
4. Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.;
Nishiyama, S.; Yamamura, S. Angew. Chem., Int. Ed.
2000, 39, 2290.
This synthesis of the acetal 39 can provide multigramme
quantities for investigation of different assembly strate-
gies. For example, the advanced metathesis precursor
44 was prepared as outlined in Scheme 7.
Selective removal of the p-methoxybenzyl ether to give
the alcohol 40 was effected using DDQ. In this reac-
tion, although buffered conditions were used, partial
acetal hydrolysis was observed and so the crude prod-
uct had to be resubjected to the acetal forming condi-
tions to give the required alcohol 40 in 71% overall
yield. Oxidation then gave aldehyde 41, which was con-
densed with methylenetriphenylphosphorane to give the
alkene 42. Selective removal of the two tert-butyldiphen-
ylsilyl groups using TBAF gave the diol 43 and prelim-
inary studies indicated the viability of selective
oxidation of the exocyclic allylic primary hydroxyl
group through to the methyl ester 44 via the corre-
5. Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez,
J.-M.; Koehler, M. F. T.; Lippa, B.; Park, C.-M.;
Shiozaki, M. J. Am. Chem. Soc. 1998, 120, 4534; Wender,
P. A.; De Brabander, J.; Harran, P. G.; Hinkle, K. W.;
Lippa, B.; Pettit, G. R. Tetrahedron Lett. 1998, 39, 8625;
Wender, P. A.; Lippa, B. Tetrahedron Lett. 2000, 41, 1007.
6. Almendros, P.; Rae, A.; Thomas, E. J. Tetrahedron Lett.
2000, 41, 9565; Gracia, J.; Thomas, E. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 2865; Maguire, R. J.; Munt, S. P.;
Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1998, 2853.
7. OꢀBrien, M.; Taylor, N. H.; Thomas, E. J. Tetrahedron
Lett. 2002, 43, 5491.
8. Yadav, J. S.; Bandyopadhyay, A.; Kunwar, A. C. Tetra-
hedron Lett. 2001, 42, 4907.
9. Munt, S. P.; Thomas, E. J. J. Chem. Soc., Chem. Commun.
1989, 480.
sponding aldehyde in
a
one-pot process.14 The
aldehyde 41 may also be incorporated into a Julia
assembly of the bryostatins.
10. The ratio of a mixture of the free alcohols 19 and 21 was
not changed on treatment with potassium tert-butoxide at
0°C. It appears that the free primary alcohol interferes
with the equilibration process (see Ref. 11).
11. For examples, of the control of the stereoselectivity of
intramolecular addition of an alcohol to an enone using
base, see: Bhattacharjee, A.; Soltani, O.; De Brabander, J.
K. Org. Lett. 2002, 4, 481; Evans, D. A.; Ripin, D. H. B.;
Halstead, D. P.; Campos, K. R. J. Am. Chem. Soc. 1999,
121, 6816.
12. Problems were encountered during preliminary attempts
to hydroxylate the terminal double bond of 20 with
starting material being recovered under standard condi-
tions and prolonged reaction times leading to
decomposition.
This work has developed a scalable procedure for the
synthesis of the C(1)–C(16) fragment of bryostatins.
Key steps are the stereoselective conjugate addition of
allylmagnesium bromide to an alkynyl ester and the form-
ation of ring B by an intramolecular conjugate addition
under mild conditions. Present work is concerned with
evaluating different procedures for assembly of the
macrocycle.
Acknowledgements
13. De Brabander, J.; Vandewalle, M. Synthesis 1994, 855.
14. A small amount of (E)/(Z)-isomerisation of the exocyclic
double bond was observed during the oxidation of the
alcohol 43 to ester 44 but this will be avoided using
different oxidation conditions.
We thank the EPSRC for support (to A.B. and B.B.)
and for studentships (to M.B. and S.McC.). We are also
grateful to Fujisawa for support (for H.O.) and to Dr.
D. Gill for helpful preliminary studies.