On the use of the modified Julia olefination for bryostatin synthesis

Article abstract of DOI:10.1016/j.tetlet.2008.08.075

Modified Julia olefination reactions using aldehyde 27 and the benzothiazol-2-yl sulfones 13 and 39 provide efficient syntheses of alkenes 28 and 42, which are advanced intermediates for syntheses of bryostatins.

Full text of DOI:10.1016/j.tetlet.2008.08.075

Tetrahedron Letters 49 (2008) 6352–6355
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Tetrahedron Letters
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On the use of the modified Julia olefination for bryostatin synthesis
Joanne V. Allen a, Anthony P. Green b, Simon Hardy b, Nicola M. Heron a, Alan T. L. Lee b, Eric J. Thomas b,
*
a AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
b The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Modified Julia olefination reactions using aldehyde 27 and the benzothiazol-2-yl sulfones 13 and 39
provide efficient syntheses of alkenes 28 and 42, which are advanced intermediates for syntheses
of bryostatins.
Received 17 July 2008
Revised 14 August 2008
Accepted 21 August 2008
Available online 27 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The bryostatins, for example, bryostatin 1 (1), are important
marine macrolides with the potential for development as anti-can-
cer chemotherapeutic agents.1 Three total syntheses2 of bryosta-
tins and one formal total synthesis3 have been reported to date,
and many other synthetic approaches have been described.1 In
addition, interesting, biologically active analogues with a cyclic
acetal in place of the B-ring have been synthesized,4 and other
macrocyclic analogues have been prepared using ring-closing
metathesis.5,6 Nevertheless, there remains a need for improved
synthetic access to bryostatins for further studies of structure–
activity relationships. We here report studies on the use of the
modified Julia olefination for the assembly of advanced intermedi-
ates to be used in the synthesis of bryostatin 11 (2), a bryostatin
which lacks the acyloxy substituent at C(20).
reactions, for example, between aldehydes 4 and sulfone 5, were
investigated first for the synthesis of the open-chain C(10)–C(19)
fragment 3.
P'O
10
S(O)2Ph
P'O
H
OP
H
OP
CHO
Me
Me
16
+
17
Me
Me
19
5
3
4
In the event, preliminary studies of the Julia olefination involv-
ing aldehyde 68 and the phenyl sulfone 79 were unsuccessful. The
addition step gave a mixture of diastereoisomeric adducts 8, see
Scheme 1, but these could not be activated towards elimination
by acylation and reductive elimination using samarium di-iodide
gave complex mixtures of products. However, the one-pot, modi-
fied, Julia olefination10 using the benzothiazol-2-yl sulfone 911
was more successful and gave the alkene 10 in a 60% yield, albeit
as 75:25 mixture of (E)- and (Z)-isomers.
Me
Me
H
HO
O
Me
MeO2C
H
B O
16
O
O
1
OH
H
O
17
OH
H
O
O
Me
Me
20
27
X
Me
OH
H
S(O)2Ph
OPMB
CO2Me
OTES
SO2Ph
TBDPSO
i
H
+
1 X = n-PrCH=CH-CH=CH-CO2
2 X = H
Me
Me
OTES
TBDPSO
HO
Me
CHO
S(O)2BT
OPMB
In each of the three total syntheses of bryostatins reported to
date,2 the key assembly step involved formation of the 16,17-dou-
ble-bond by classical Julia olefination, although only moderate
yields were obtained in some cases. Thus, when planning the syn-
thesis of bryostatin 11 (2), the use of Julia olefinations was consid-
ered for the synthesis of intermediates possessing the 16,17-
double-bond. Since the B-ring can be formed by conjugate addition
6
7
8
Me
OPMB
+
H
OTES
TBDPSO
ii
Me
Me
Me
Me
9
10
OPMB
(BT = benzothiazol-2-yl)
of a hydroxyl group at C(15) to an
a
b-unsaturated ketone,7 Julia
Scheme 1. Reagents and conditions: (i) 7, n-BuLi, THF, 10 min, À78 °C; add 6,
À78 °C (ca. 60%); (ii) 9, LiHMDS, THF, 20 min, À78 °C, add 6, À78 °C to rt (60%;
E:Z = 75:25).
* Corresponding author. Tel.: +44 161 275 4614; fax: +44 161 275 4939.
E-mail address: e.j.thomas@manchester.ac.uk (E. J. Thomas).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.075

J. V. Allen et al. / Tetrahedron Letters 49 (2008) 6352–6355
6353
With a view to incorporating the C(20)–C(27) fragment using an
OBOM
OTES
MeO2C
MeO2C
acyl carbanion equivalent at C(19),12 the dithianylalkyl benzo-
thiazol-2-yl sulfone 13 was prepared from the monoprotected diol
11,13 see Scheme 2. Conversion into the hydroxyalkyl sulfone 12
was achieved using a Mitsunobu reaction, sulfide oxidation14 and
oxidative removal of the p-methoxybenzyl group. Following oxida-
tion to the corresponding aldehyde, treatment with propane-1,3-
dithiol15 gave the dithianylalkyl sulfone 13. Deprotonation of this
sulfone using lithium hexamethyldisilazide and reaction with alde-
hyde 6 gave alkene 14 with excellent stereoselectivity in favour of
the (E)-isomer. However, the strongly basic conditions required to
deprotonate dithiane 14 led to the formation of complex mixtures
of products. To enhance the acidity of the dithiane moiety, dithiane
14 was oxidized to the monosulfoxide 1516 which was isolated as a
mixture of diastereoisomers. Deprotonation could now be achieved
using LDA, and the lithiated species was alkylated using (E)-crotyl
bromide to give the 2,2-dialkyldithiane monoxides 16 in a reason-
able yield. However, attempts to reduce these dialkylated dithiane
i - iii
OTES
OPMB
17
18
OPMB
iv - vii
TIPSO
OBOM
OTES
TIPSO
OBOM
OTES
CHO
viii
S
Me
Me
19
20
S
TIPSO
OBOM
ix
OTES
TIPSO
OBOM
OTES
S
x, xi
Me
Me
O
S
S
17
Me
Me
monoxides 16 back to the corresponding dithiane using P2I4 in
S
the presence of triethylamine were unsuccessful, and complex
mixtures of products were obtained.
21
22
Me
To check whether the difficulties in manipulating the dithiane
14 and the derived monosulfoxides were due to the skipped diene,
the sequence of a modified Julia reaction using the sulfonyl-dithi-
ane 13 and subsequent alkylation was repeated using the aldehyde
19, see Scheme 3. This aldehyde was prepared from the dienyl es-
ter 178 by regioselective hydroxylation using osmium tetroxide,
followed by cleavage using sodium periodate with reduction of
the aldehyde so obtained using sodium borohydride. Protection
gave the benzyloxymethyl (BOM) ether 18, and reduction of the es-
ter with protection of the primary alcohol as its tri-isopropylsilyl
ether followed by oxidative removal of the p-methoxybenzyl ether
gave aldehyde 19 after a Dess–Martin oxidation. Reaction of this
aldehyde with the lithiated dithiane 13 was very efficient, and gave
the (E)-alkene 20 in excellent yield (95% from 19) with only the (E)-
isomer of the alkene being isolated. Unlike dithiane 14, dithiane 20
could be deprotonated directly and was alkylated using (E)-crotyl
bromide to give the 2,2-dialkyldithiane 22, albeit only in a modest
35% yield. Alternatively, oxidation of dithiane 20 using m-chloro-
peroxybenzoic acid to the dithiane monoxides 21 followed by
alkylation using (E)-crotyl bromide and reduction using P2I4 gave
the 2,2-dialkyldithiane 22 in a slightly better overall yield. Dithiane
Scheme 3. Reagents and conditions; (i) OsO4 (8 mol %, NMO, acetone, H2O, t-BuOH,
rt, 4 h (76%); (ii) NaIO4, MeOH, THF, H2O, 0 °C, 1 h, then NaBH4, 0 °C, 1 h (76%); (iii)
BOMCl, TBAI, i-Pr2NEt, THF, 0 °C, 16 h (93%); (iv) DIBAL-H, tol., À78 °C, 45 min
(88%); (v) TIPSCl, imid., CH2Cl2, rt, 16 h (98%); (vi) DDQ, pH 7, phosphate buffer,
CH2Cl2, 0 °C, 1 h then rt 2 h (71%); (vii) Dess–Martin periodinane, py., CH2Cl2, rt,
45 min; (viii) 13-Li, THF, À78 °C to rt, 1 h (95%, two steps); (ix) MCPBA, CH2Cl2, 0 °C,
5 min (95%); (x) LDA, THF, À78 °C to À60 °C, 30 min then (E)-crotyl bromide, À78 °C
to rt, 40 min (87%); (xi) P2I4 (0.55 mol equiv), Et3N, CH2Cl2, 0 °C, 40 min in the dark
(70%).
22 corresponds to the C(10)–C(21) fragment of
a
20-
deoxybryostatin.
As the modified Julia olefination between sulfone 13 and the
aldehyde 19 was very efficient, it was decided to see whether an
aldehyde attached to the fully developed C(1)–C(15) fragment
would also react usefully with this sulfone. The 4-(tri-isopropyl-
silyloxyethylidene)tetrahydropyran 25 was prepared from aldehyde
23 and ketophosphonate 24 using chemistry reported earlier,3,7 see
Scheme 4, and an excellent yield obtained for the conversion of the
ketone 25 into the cyclic acetal 26 using PPTS as catalyst. The free
hydroxyl group was then protected as its tert-butyldimethylsilyl
ether and the p-methoxybenzyl group removed using DDQ under
buffered conditions although some reacetalization was necessary
before oxidation to the aldehyde 27. However, the stereoselectivity
of the Julia reaction of this aldehyde with the dithianylalkyl sulfone
13 varied with the reaction conditions. Better yields, up to 78%,
were obtained if the reaction mixture was allowed to warm from
À78 °C to room temperature immediately after addition of the alde-
hyde to the lithiated sulfone, but the stereoselectivity was only 2:1
in favour of the (E)-isomer. In contrast, the (E)-alkene 28 was the
only product obtained if the reaction mixture was stirred for
20 min after the addition of the aldehyde at À78 °C before being
allowed to warm up, but the isolated yield was only ca. 50%
(Scheme 4).
Nevertheless, these successful alkene syntheses suggested that
the modified Julia olefination might be applicable to a convergent
bryostatin assembly involving aldehyde 27 and an intact C(17)–
C(27) benzothiazol-2-yl sulfone containing fragment. To investi-
gate this possibility, alcohol 2912 was converted into the aldehyde
34 by protection, selective removal of the O-benzyl group, substi-
tution of the primary alcohol via bromide 32 to give nitrile 33
and reduction to the aldehyde 34. Aldol addition of lithiated
methyl 2-methylpropanoate to this aldehyde gave a 1:1 mixture
of epimers 35, which were protected as their triethylsilyl ethers
36. Reduction of the methoxycarbonyl group then gave alcohol
Me Me
Me Me
Me Me
iv, v
i - iii
S
OH OPMB
BTS(O)2 OH
BTS(O)2
S
11
12
13
(BT = benzothiazol-2-yl)
(BT = benzothiazol-2-yl)
vi
H
H
OTES
TBDPSO
OTES
TBDPSO
vii
S
Me
S
Me
Me
Me
S
O
R
S
15 R = H
16 R = CH3CH=CHCH2-
14
viii
Scheme 2. Reagents and conditions: (i) 2-mercaptobenzothiazole, Ph3P, DIAD, THF,
rt; (ii) Mo7O24(NH4)8Á4H2O, H2O2, EtOH, H2O (80% from 11); (iii) DDQ, pH 7,
phosphate buffer, CH2Cl2, rt, 45 min (ca. 100%); (iv) (COCl)2, DMSO, CH2Cl2, À78 °C,
then Et3N (94%); (v) propane-1,3-dithiol, BF3ÁEt2O, CH2Cl2, 0 °C to rt (79%); (vi)
LiHMDS, THF, À78 °C, 30 min, add 6, À78 °C to rt, 1.5 h (60%); (vii) MCPBA, CH2Cl2,
0 °C, 5 min (78%); (viii) LDA, HMPA, THF, À78 °C to À60 °C, 30 min, (E)-crotyl
bromide, À78 °C to rt, 40 min (67%).

6354
J. V. Allen et al. / Tetrahedron Letters 49 (2008) 6352–6355
Me Me
TIPSO
Me Me
H
O
CHO
OTES
see ref. 7
TIPSO
(MeO)2P(O)
+
H
O
OBn
O
O
OTBDPS
O
OBn
O
O
OTBDPS
Me Me
OPMB
Me Me
25
23
OPMB
24
i
Me Me
MeO
H
O
Me Me
MeO
Me Me
MeO
TIPSO
OBn
H
O
H
O
TIPSO
OBn
TIPSO
OBn
H
H
ii - iv
v
O
S
H
H
H
H
O
O
OTBDPS
OTBDPS
OTBDPS
CHO
OPMB
OTBS
Me
Me
OTBS
OH
28
27
26
S
Scheme 4. Reagents and conditions: (i) PPTS, HC(OMe)3, MeOH, CH2Cl2, THF (88%); (ii) TBSOTf, 2,6-lutidine, CH2Cl2, À78 °C, 2 h (86%); (iii) DDQ, pH 7, phosphate buffer, rt,
1 h, then PPTS, HC(OMe)3, MeOH, CH2Cl2 (60%); (iv) TPAP, NMO, 4 Å sieves, CH2Cl2, rt, 1 h (60%); (v) 13-Li, THF, À78 °C, 20 min, to rt, 2 h [51%: (E)-only] or À78 °C to rt, 16 h
[78%; (E):(Z) = 2:1].
MeO2C
OTBS
Me
OR OTBS
Me
OSEM
OTBS
RO
OSEM
OTBS
TBSO
OSEM
OTBS
OSEM
OTBS
OHC
Me
Me
ii - iv
v
vi, vii
BnO
Me
X
Me
OTIPS
OTIPS
OTIPS
OTIPS
29 R = H
30 R = TBS
31 X = OH
32 X = Br
33 X = CN
35 R = H
36 R = TES
i
34
Me Me
MeO
Me Me
H
H
O
MeO
viii - x
TIPSO
OBn
TIPSO
OBn
H
H
H
H
X
O
O
O
OTESOTBS
Me
OTBS
OTBS
OSEM
OTBS
OTBDPS
OSEM
OTBDPS
Me
Me
xi, xii
xiii
OTBS
OR OTBS
Me
O
OSEM
OTBS
Me
Me
Me
Me
Me
OTBS
OTIPS
OTIPS
OTIPS
37 X = OH,
40 R = TES
41 R = H
42
38 X = BTS-
39 X = BTS(O)2-
(BT = benzothiazol-2-yl)
Scheme 5. Reagents and conditions: (i) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C to rt (89%); (ii) Li, naphthalene, THF, À20 °C (88%); (iii), CBr4, Ph3P, CH2Cl2, 0 °C (94%); (iv) NaCN,
DMF, 0 °C, 2.5 h (75%); (v) DIBAL-H, CH2Cl2, À78 °C, 45 min then satd aq NH4Cl, À78 °C to rt, 30 min; (vi) methyl 2-methylpropanoate, LDA, THF, À78 °C, 70 min, add 34, THF,
À78 °C, 30 min, rt 30 min (50% from 33); (vii) TESCl, imid., DMF, 0 °C to rt, 16 h (79%); (viii) DIBAL-H, tol., À78 °C, 1 h (82%); (ix) 2-mercaptobenzothiazole, Ph3P, DIAD, THF, rt,
24 h (95%); (x) Mo7O24(NH4)8Á4H2O, H2O2, H2O, EtOH, i-PrOH (39, 41%; sulfoxides, 50%); (xi) 39, LiHMDS, THF, À78 °C to À60 °C, 30 min, add 27, THF, À78 °C, 20 min, rt,
30 min (70%); (xii) PPTS, HC(OMe)3, MeOH, rt, 3 d (64%); (xiii) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt, 30 min (85%).
37, which was converted into the benzothiazol-2-yl sulfone 39 via
a Mitsunobu reaction using 2-mercaptobenzothiazole followed by
oxidation (Scheme 5).
This work has explored the application of the modified, one-pot,
Julia olefination using benzothiazol-2-yl sulfones for the stereose-
lective assembly of the C(16)–C(17) double-bond in advanced
intermediates for incorporation into syntheses of bryostatins. Both
the dithiane 28, which corresponds to the C(1)–C(19) component
of bryostatins, and ketone 42, which has the intact bryostatin skel-
eton, may be useful for the syntheses of bryostatins and their ana-
logues. Of general interest is the use of the benzothiazol-2-yl
dithianylalkyl sulfone 13 which may have a wider application in
synthesis. The present work is concerned with applying this chem-
istry to complete total syntheses of naturally occurring bryostatins
and their analogues.
Deprotonation of the sulfone 39 was achieved using lithium
hexamethyldisilazide and addition of the aldehyde 27 at À78 °C
with warming to room temperature after 20 min gave the (E)-
alkene 40, with excellent stereoselectivity, no (Z)-isomer being
isolated, in a reasonable yield (71% from aldehyde 27). Alkene 40
was isolated as a mixture of epimers at C(19) (bryostatin number-
ing), these being derived from the mixture of epimers at the
corresponding carbon in sulfone 39. However, the 1:1 mixture of
epimers in the sulfone was replaced by an apparent 2:1 mixture
in alkene 40 suggesting a small degree of kinetic resolution in
the Julia reaction. That the two products were the two C(19)
epimers was established by selective removal of the triethylsilyl
group using PPTS and oxidation of the epimeric mixture of
alcohols 41 using the Dess–Martin periodinane to give the corre-
Acknowledgements
We thank Dr. R. Dumeunier for preliminary studies of the Julia
reactions of aldehyde 6, the EPSRC for the support (to A.T.L.L.) and a
studentship (to A.G.), and AstraZeneca for support (to S.H.) through
the CASE scheme.
sponding ketone 42 which was characterized as
a single
compound.

J. V. Allen et al. / Tetrahedron Letters 49 (2008) 6352–6355
7. O’Brien, M.; Taylor, N. H.; Thomas, E. J. Tetrahedron Lett. 2002, 43, 5491.
6355
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