A synthesis of the C(17)-C(27) fragment of bryostatin 1

Article abstract of DOI:10.1055/s-2008-1078015

An approach to the C(17)-C(27) fragment of bryostatin 1, based on forming the C(19)-C(20) bond by reaction of an acyl carbanion equivalent at C(19) with an aldehyde, is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078015

LETTER
2103
A Synthesis of the C(17)–C(27) Fragment of Bryostatin 1
Synthesis of the
C
(
n
17)–C(27)
F
t
ragmen
h
t
of Bryosta
o
tin 1 ny P. Green, Simon Hardy, Eric J. Thomas*
The School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Fax +44(161)2754939; E-mail: e.j.thomas@manchester.ac.uk
Received 8 July 2008
Dedicated to Jack Baldwin on the occasion of his 70th birthday
Me
HO
Me
Abstract: An approach to the C(17)–C(27) fragment of bryostatin
1, based on forming the C(19)–C(20) bond by reaction of an acyl
carbanion equivalent at C(19) with an aldehyde, is described.
H
O
O
Me
O
MeO2C
H
H
H
O
O
O
16
17
OH
Key words: acetals, metathesis, natural products, stereoselective
synthesis, total synthesis
OH
O
Me
Me
20
X
Me
CO2Me
OH
The bryostatins are a group of marine natural products
with potentially important anticancer activity whose total
synthesis is of considerable interest at present.1 Three to-
tal syntheses and a formal total synthesis have been com-
pleted to date2 and many other synthetic approaches have
been described.1 Biologically interesting acetal-contain-
ing analogues3 have been prepared and macrocyclic ana-
logues have been obtained by ring-closing metathesis.4
Nevertheless, there is still a need for improved synthetic
access to both the natural products and their analogues for
fuller investigations of structure–activity relationships in
this area. The lead natural product is bryostatin 1 (1,
Figure 1), but other members of the group, for example,
bryostatin 11 (2), which lack the acyloxy substituent at
C(20), are also of interest.
In the three syntheses of bryostatins completed to date,2
the macrocyclic ring was assembled by formation of the
C16–C17 double bond using a Julia reaction followed by
macrolactonisation. These syntheses required an efficient
synthesis of the C(17)–C(27) fragment. We here report a
new synthesis of this fragment,5 in particular of acetal 3,
using the reaction between dithiane 4, an acyl carbanion
equivalent, and the aldehyde 5, as the key assembly step,
together with observations on the stereoselectivity of cy-
clic acetal formation in this series (Scheme 1).
1 X = n-PrCH=CH-CH=CH-CO2
2 X = H
Figure 1
benzyloxy-2-bromomethylpropene7 to the aldehyde 6
gave a mixture4a of the epimeric adducts 7 and 8 which
were separable by flash chromatography, and the unwant-
ed epimer 7 was converted into the required isomer 8 via
a Mitsunobu inversion and hydrolysis. O-Acylation of the
alcohol 8 using acryloyl chloride gave the acrylate 9
which was converted into the lactone 10 by ring-closing
metathesis using the Grubbs second-generation catalyst.8
Reduction of the lactone under Luche conditions9 then
gave diol 11 which was selectively protected and deben-
zylated using lithium naphthalenide10 to give the alcohol
12. This was oxidised using the Dess–Martin
periodinane11 to give the required aldehyde 5 which cor-
responds to the C(20)–C(27) fragment of bryostatin 1 (1).
Deprotonation of dithiane 4, prepared from 3-benzyloxy-
2,2-dimethylpropanal12 using propane-1,3-dithiol and bo-
ron trifluoride diethyl etherate,13 was carried out using n-
butyllithium and the lithiated dithiane added to the alde-
hyde 5 to give alcohols 13 and 15 with isolated yields of
53% and 26%, respectively (Scheme 3). The major prod-
uct 13 corresponds to that required for incorporation into
Aldehyde 5 was prepared from the known aldehyde 64a as
outlined in Scheme 2. Indium-mediated addition6 of 3-
BnO
TESO
OHC
OSEM
OTBS
OMe
O
19
H
BnO
Me
OSEM
OTBS
Me
Me
S
Me
+
TBSO
Me
Me
S
OTIPS
OTIPS
3
4
5
Scheme 1
SYNLETT 2008, No. 14, pp 2103–2106
2
2
.0
8
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078015; Art ID: D25708ST
© Georg Thieme Verlag Stuttgart · New York

2104
A. P. Green et al.
LETTER
ii, iii
HO
OSEM
RO
OSEM
OTBS
OSEM
i
OHC
+
BnO
Me
OTBS
BnO
Me
Me
OTBS
7
6
8 R = H
9 R = CH2=CH⋅CO
iv
v
HO
OSEM
OTBS
H
OSEM
BnO
vi
BnO
Me
O
Me
OTBS
O
11
OH
10
vii–ix
TESO
OHC
OSEM
TESO
OSEM
OTBS
x
Me
OTBS
HO
Me
OTIPS
OTIPS
12
5
Scheme 2 Reagents and conditions: i) 3-benzyloxy-2-bromomethylpropene, In, THF, H2O, r.t. (7, 43%; 8, 45%); ii) 4-O2NC6H4CO2H, Ph3P,
DIAD, THF (92%); iii) K2CO3, MeOH, 0 °C (90%); iv) CH2=CH·COCl, DIPEA, CH2Cl2, 0 °C (94%); v) Grubbs II (5 mol%) added over 22
h, DCE, reflux (80%); vi) NaBH4, CeCl3, MeOH, 0 °C (ca. 100%); vii) TIPSCl, imidazole, CH2Cl2, r.t. (93%); viii) TESCl, imidazole, CH2Cl2
(93%); ix) Li, naphthalene, THF, –30 °C (83%); x) Dess–Martin periodinane, pyridine, CH2Cl2, r.t. (ca. 100%).
RO
OH
RO
OH
OSEM
OTBS
OSEM
OTBS
BnO
Me
Me Me
S
Me Me
S
i
BnO
BnO
S
+
Me
Me
S
S
Me
S
4
OTIPS
OTIPS
13 R = TES
15 R = TES
ii
ii
14 R = H
16 R = H
iii
iii
BnO
BnO
Me
BnO
Me
BnO
MeO
OMe
OMe
OMe
H
H
H
H
OSEM
OSEM
OTBS
OSEM
OTBS
OSEM
OTBS
O
O
O
O
Me
Me
Me
Me
6
2
6
2
6
2
2
6
Me
Me
+
+
4
4
4
4
HO
Me
OTBS
HO
Me
HO
Me
HO
Me
ii
18
19
OTIPS
OTIPS
OTIPS
OTIPS
17
20
BnO
Me
BnO
OMe
H
OMe
H
OSEM
O
O
OSEM
OTBS
Me
Me
iv
iv
2
6
6
2
Me
17, 20
18, 19
4
4
O
Me
OTBS
O
Me
OTIPS
OTIPS
22
21
Scheme 3 Reagents and conditions: i) n-BuLi, r.t., 5 min, –78 °C, add 5 (13, 53%; 15, 26%); ii) PPTS, MeOH, THF, CH(OMe)3 (14, 85%;
16, 80%); iii) Hg(ClO4)2·3H2O, lutidine, MeOH, THF, –10 °C (17, 37%; 18, 25%; 19, 45%; 20, 15%); iv) Dess–Martin periodinane, pyridine,
CH2Cl2 (21, 55% from 17; 22, 61% from 19).
a bryostatin synthesis. Its configuration is that expected addition reaction. Instead, acetal formation from the diols
on the basis of chelation control, but no attempts were 14 and 16, prepared by selective removal of the triethyl-
made at this stage to optimise the stereoselectivity of the silyl groups from alcohols 13 and 15, was investigated. It
Synlett 2008, No. 14, 2103–2106 © Thieme Stuttgart · New York

LETTER
Synthesis of the C(17)–C(27) Fragment of Bryostatin 1
2105
was found that, on treatment with mercuric perchlorate in
buffered methanol,14 two acetals were isolated from each
of the diols with the anomers 17 and 18 being obtained
from the diol 14, and the anomers 19 and 20 from diol 16,
in isolated yields of 37%, 25%, 45%, and 15%, respec-
tively.
HO
OTBS
OSEM
Me Me
S
BnO
i, ii
Me
OTBS
13
S
OTIPS
23
The structures of the alcohols 13 and 15 and the cyclic ac-
etals 17–20 derived from them were established by chem-
ical correlation and by 1H NMR NOE and chemical shift
studies. It was found that oxidation of the major hydroxy-
acetal prepared from diol 14 gave the same ketone, later
shown to be 21, as that prepared by oxidation of the minor
hydroxyacetal prepared from diol 16, showing that these
diols had the same configuration at the anomeric carbon.
Similarly, oxidation of the minor hydroxyacetal prepared
from diol 14 gave the same ketone, later shown to be 22,
as that prepared from the major hydroxyacetal prepared
from diol 16. Significant NOEs were observed for H-6 on
irradiation of the methoxy groups of the major acetal de-
rived from the minor aldehyde adduct and the ketone pre-
pared from it showing that the 2-methoxy substituent and
6-H were cis as indicated in structures 19 and 22. There-
fore in ketone 21 the 2-methoxy and 6-H must be trans
and this must also be the case for the alcohols which gave
this ketone on oxidation. The configuration at C(3) in the
major acetal derived from the major aldehyde adduct was
shown to be as depicted in structure 17 by an NOE ob-
served for 3-H on irradiation of 6-H and complementary
NOEs were observed for the major acetal from the minor
aldehyde adduct involving 5-H2 consistent with structure
19.
iii
BnO
OMe
O
H
OSEM
OTBS
Me
Me
TBSO
Me
OTIPS
3
Scheme 4 Reagents and conditions: i) TBDMSOTf, 2,6-lutidine,
CH2Cl2, r.t. (94%); ii) PPTS, MeOH, THF, CH(OMe)3 (93%); iii)
Hg(ClO4)2, lutidine, MeOH, THF, 0 °C to r.t. (88%).
HO
OR
H
OSEM
OTBS
i
O
Me
Me
3
TBSO
Me
OTIPS
24 R = Me
25 R = H
ii
Me
OMe
O
H
Me
The formation of the hydroxyacetals 17–20 from diols 14
and 16 is interesting in that the major products in each
case, 17 and 19, have the 2-methoxy and 3-hydroxy
groups cis to each other, and this preference, presumably
due to a degree of kinetic control, overrules the anomeric
effect in acetal formation from diol 14 under our condi-
tions. However, from the point of view of the synthesis of
bryostatins, a more stereoselective cyclic acetal formation
was required.
OSEM
OTBS
O
Me
H
OTIPS
26
Scheme 5 Reagents and conditions: i) Pd/C, H2, H-cube, EtOAc,
MeOH (24, 50%; 25, 40%); ii) 2-mercaptobenzothiazole, Ph3P,
DIAD, 0 °C to r.t. (79%).
Since it was possible that the hydroxyl group next to the
diathiane was playing a role in acetal formation from diols
14 and 16, it was decided to protect this substituent before
dithiane cleavage and cyclisation. Protection of alcohol 13
as its tert-butyldimethylsilyl ether followed by selective
methanolysis of the triethylsilyl group gave alcohol 23
which was converted into a cyclic acetal using mercuric
perchlorate under the usual conditions.14 In this case a sin-
gle acetal was obtained which was identified as isomer 3,
with the methoxy substituent at C(2) in the axial position,
on the basis of NOE experiments (Scheme 4).15
was obtained, see Scheme 5. However, attempts to con-
vert alcohol 24 into a thioether using 2-mercaptobenzothi-
azole under Mitsunobu conditions were unsuccessful with
tetrahydrofuran 26 being isolated in a good yield.
This work has resulted in a synthesis of acetal 3 in 17 lin-
ear steps from commercially available starting materials.
Of interest was the formation of mixtures of isomers on
acetal formation from the hydroxydithianes 14 and 16,
which shows that anomeric configurations cannot be as-
signed to cyclic acetals in this system simply on the basis
of an assumed anomeric effect. Present work is concerned
with further development of this chemistry and the incor-
poration of the C(17)–C(27) fragments into syntheses of
bryostatins.
During preliminary studies into the elaboration of acetal
3, hydrogenolysis of the benzyl goup was achieved using
10% palladium on carbon as the catalyst with no compet-
ing hydrogenation of the double bond although partial hy-
drolysis of the acetal was observed, and a mixture of the
hydroxyacetal 24 and the corresponding hemiacetal 25
Synlett 2008, No. 14, 2103–2106 © Thieme Stuttgart · New York

2106
A. P. Green et al.
LETTER
(12) Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts,
J. C.; Somfrai, P.; Whritenour, D. C.; Masamune, S. J. Org.
Chem. 1989, 54, 2817.
Acknowledgment
We thank the EPSRC for a studentship (to A.P.G.) and the School
of Chemistry in Manchester and AstraZeneca for a studentship (to
S.H.).
(13) Sugiyama, H.; Yokokawa, F.; Shiori, T. Tetrahedron 2003,
59, 6579.
(14) Smith, A. B.; Doughty, V. A.; Lin, Q.; Zhuang, L.; McBriar,
M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama,
K.; Sobukawa, M. Angew. Chem. Int. Ed. 2001, 40, 191.
(15) To a solution of dithiane 23 (341 mg, 0.34 mmol) in THF
(5.5 mL) and MeOH (5.5 mL) at 0 °C was added 2,6-lutidine
(0.27 mL, 2.3 mmol) and mercury(II) perchlorate trihydrate
(273 mg, 0.68 mmol). After stirring at 0 °C for 10 min, the
reaction mixture was allowed to warm to r.t. and was stirred
for 8 h. The resulting white suspension was filtered through
Celite and partitioned between ether and sat. aq NaHCO3.
After separation of the organic layer, the aqueous phase was
extracted with Et2O. The combined organic extracts were
dried (MgSO4), filtered, and concentrated under reduced
pressure. Flash chromatography of the residue using Et2O
(2%) in light PE as eluent afforded the acetal 3 (277 mg,
88%) as a colourless oil, Rf = 0.34 (light PE–Et2O, 15:1);
[a]D24 –32 (c 0.5, CH2Cl2). IR: nmax = 2954, 2894, 2864,
1471, 1463, 1380, 1361, 1251, 1148, 1102, 1058, 939, 883,
859, 835, 775 cm–1. 1H NMR (500 MHz, C6D6): d = 0.00 [9
H, s, Si(CH3)3], 0.15, 0.16, 0.17, 0.23 [each 3 H, s, Si(CH3)],
0.96 [2 H, m, CH2Si(CH3)3], 1.01, 1.03 [each 9 H, s,
SiC(CH3)3], 1.05–1.15 {21 H, m, Si[CH(CH3)2]3}, 1.31 (3
H, d, J = 6.0 Hz, 4¢¢¢-H3), 1.52 (6 H, s, 2 × 1¢-CH3), 1.68 (1
H, t, J = 12.5 Hz, 1¢¢¢-H), 2.13 (1 H, dd, J = 10.5, 13.0 Hz,
1¢¢¢-H¢), 2.26 (1 H, dd, J = 3.0, 13.5 Hz, 5-H), 2.33 (1 H, t,
J = 12.5 Hz, 5-H¢), 3.38 (3 H, s, OCH3), 3.47 (1 H, m,
OCHHCH2Si), 3.75 (1 H, br. s, 2¢-H), 3.82 (1 H, m,
OCHHCH2Si), 4.03–4.21 (3 H, m, 6-H, 2¢-H¢ and 2¢¢¢-H),
4.28 (1 H, dd, J = 5.5, 12.5 Hz, 2¢¢-H), 4.30–4.38 (3 H, m, 3-
H, 2¢¢-H¢ and 3¢¢¢-H), 4.60, 4.63 (each 1 H, d, J = 12.5 Hz,
CHHPh), 4.74 (1 H, d, J = 7.0 Hz, OCHHO), 4.91 (1 H, br
d, J = 7.0 Hz, OCHHO), 5.75 (1 H, m, 1¢¢-H), 7.10 (1 H, t,
J = 7.4 Hz, ArH), 7.21 (2 H, t, J = 7.5 Hz, ArH), 7.44 (2 H,
d, J = 7.5 Hz, ArH). 13C NMR (75 MHz, C6D6): d = –4.4,
–4.2, –4.0, –3.4, –0.9, 12.7, 17.6, 18.7, 18.7, 18.8, 19.0, 21.9,
22.5, 26.6, 26.7, 31.9, 36.3, 46.7, 52.3, 60.1, 65.9, 68.7, 69.8,
73.9, 76.3, 76.9, 80.1, 97.2, 104.2, 127.8, 127.9, 128.9,
137.2, 140.4. MS (ES+): m/z (%) = 962 (100) [M + 23], 963
(70), 964 (38), 965 (13).
References and Notes
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Synlett 2008, No. 14, 2103–2106 © Thieme Stuttgart · New York

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