Total synthesis of bryostatin 9

Article abstract of DOI:10.1021/ja203034k

The total synthesis of bryostatin 9 was accomplished using a uniquely step-economical and convergent Prins-driven macrocyclization strategy. At 25 linear and 42 total steps, this is currently the most concise and convergent synthesis of a potent bryostatin.

Full text of DOI:10.1021/ja203034k

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Total Synthesis of Bryostatin 9
Paul A. Wender* and Adam J. Schrier
Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, California 94305-5080, United States
S Supporting Information
b
ABSTRACT: The total synthesis of bryostatin 9 was
accomplished using a uniquely step-economical and con-
vergent Prins-driven macrocyclization strategy. At 25 linear
and 42 total steps, this is currently the most concise and
convergent synthesis of a potent bryostatin.
he bryostatins are a family of 20 structurally complex natural
T
products1 putatively produced by a bacterial symbiont2 of
the marine bryozoan Bugula neritina. In 1968, Pettit and co-
workers3 found that extracts of this organism have potent anti-
cancer activity, but it was not until 1981 that the structure of
bryostatin 1, the prototypical member of this family, was elucidated
(Figure 1).4 Structurally characterized by a 20-membered macro-
lactone core containing three densely functionalized pyran rings,
members of this family differ primarily in the identity (or absence)
of acyloxy substituents at positions 7 and 20. Additional diversity is
observed in the C ring: bryostatins 16 and 17 contain a dihydropy-
ran C ring in lieu of the more common tetrahydropyran, and
bryostatins 3, 19, and 20 possess a C22 oxygen that engages the C21
exocyclic enoate as a butenolide.
Figure 1. Bryostatins that have been prepared by total synthesis.
(Ki < 10 nM21). Each congener contains a C-ring tetrahydropy-
ran motif with attendant C19 hemiketal and C20 acyloxy groups.
Bryostatin 16, which lacks these structural elements, is much less
active (PKCR Ki = 118 nM). While the early syntheses reported
by Masamune, Evans, and Yamamura provided a starting point
for accessing the potent bryostatins (42-45 linear, >75 total
steps), further development of these routes has not been
reported. In addition, the points of convergence of these
syntheses necessitate a further 14ꢀ21 linear steps to elaborate
each target following assembly of their respective pyran-contain-
ing backbones, thus limiting step-economical access to diverse
analogues.
Keck’s synthesis of bryostatin 1, which requires 31 linear and
an estimated 57 total steps, is a notable advance.18 This strategy
utilized an intermolecular Prins cyclization to anneal the B ring,
which was then followed by 11 additional steps to elaborate the
macrocycle (via lactonization) and other peripheral functionality.
In 1988, in collaboration with the groups of Pettit and Blum-
berg, we advanced a computer-based structureꢀfunction hypoth-
esis in which the northern A/B-ring architecture of bryostatin is
proposed to conformationally restrict the southern-fragment
functionality required for effective recognition by PKC.22 This
analysis guided our design of the first simplified functional
analogues of bryostatin,23 exemplified by 1 (Figure 2),24 which
demonstrated that bryostatin-like potency can be achieved and
even exceeded with great simplification of the northern-fragment
The bryostatins exhibit a uniquely rich and diverse portfolio of
biological activities. Bryostatin 1, the most thoroughly investi-
gated congener, has been found to restore apoptotic function in
cancer cells, stimulate the immune system,5 and reverse multi-
drug resistance.1 In anticancer clinical trials,6 bryostatin 1 has
demonstrated the ability to enhance the activities of known
oncolytic agents at remarkably low doses (∼50 μg/m2).7 Of
further significance, bryostatin 1 has been shown to induce the
formation of synapses,8 improve memory and learning in animal
models,9 and enhance the R-secretase processing of amyloid
precursor protein,10 suggesting its possible use as a novel
Alzheimer’s disease11 or poststroke12 therapeutic. These activ-
ities are believed to result in part from bryostatin’s extraordinary
affinity for protein kinase C (PKC) and other C1-domain-
containing proteins.13
Impressive total syntheses of five bryostatins have been
reported (Figure 1): bryostatin 7 in 1990 by Masamune and
co-workers,14 bryostatin 2 in 1998 by Evans and co-workers
(a formal synthesis of bryostatin 1),15 bryostatin 3 in 2000 by
Yamamura and co-workers,16 bryostatin 16 in 2008 by Trost and
Dong,17 and, most recently, bryostatin 1 by Keck and co-workers.18
Additionally, a formal total synthesis of bryostatin 7 was reported
by Hale and colleagues in 2006.19 Several additional groups have
contributed significantly to this field, including those of Thomas,
Vandewalle, Roy, Burke, Krische, Hoffmann, Yadav, and others.20
Of those bryostatins that have been prepared by total synth-
esis, bryostatins 1, 2, 3, and 7 are highly potent ligands for PKC
Received: April 3, 2011
Published: May 27, 2011
r
2011 American Chemical Society
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Prins macrocyclizations have also been described by the groups
of Scheidt, Lee, Rychnovsky, and Yadav.30
With this disconnection approach, the synthesis of bryostatin
9 was simplified to accessing hydroxyallylsilane-containing north-
ern fragment 4 and aldehyde-containing southern fragment 5.
The synthesis of 4 commenced with the benzylation of C1ꢀC9
lactone 6 (Scheme 1A), a versatile A-ring intermediate available
in seven steps from acrolein that we had previously disclosed for
the synthesis of several A-ring bryologues.27b The C10ꢀC13
carbon fragment was installed by addition of the ethyl acetoace-
tate dienolate, and equilibration of the resulting C9 lactol
epimers to the anomeric methyl ketal was accomplished using
PPTS in MeOH. Reduction of C11 with NaBH4 favored hy-
droxyester 8 (78:22 dr), which was isolated in 61% yield.
Silylation and double nucleophilic addition31 of TMSCH2MgCl
mediated by CeCl3 2LiCl32 provided alcohol 10. Knochel’s
3
Figure 2. Representative bryostatin analogues 1, 2, and 3 and strategies
for their synthesis.
soluble cerium salt provided the optimal yield (65%) for this
challenging reaction; conventionally dried anhydrous CeCl3
(from its heptahydrate) gave poorer yields (∼45%). Peterson
olefination of 10 with NaHMDS furnished the corresponding
allylsilane.
Debenzylation was cleanly effected using lithium naphthale-
nide to provide C1,C7 diol 11 in 87% yield, and the C1 hydroxyl
group was oxidized using a combined TEMPO/PhI(OAc)2/
NaClO2 system. Acetylation followed by alkaline aqueous work-
up provided the fully elaborated northern fragment 4 in 57%
yield over two steps and in ∼2% overall yield over a 17-step
sequence.
The preparation of bryostatin 9 southern fragment 5(Scheme1B)
began with olefin 12,24 an intermediate available in eight steps
from 2,2-dimethyl-1,3-propanediol. Ozonolysis provided the
corresponding ketoaldehyde, which was then chemoselectively
olefinated using Takai’s protocol33 to provide a 93:7 mixture of
(E)- and (Z)-ethylidene isomers 13. Although these isomers
were not separable via chromatography at this or subsequent
stages, the undesired Z component was ultimately removed in
the dihydroxylation step (see below).
functionality. Strategically, a design element common to this and
numerous related bioactive analogues25 was the incorporation of a
dioxane B ring as a pyran surrogate, which enabled assembly of
the macrocycle by esterification and subsequent macroacetaliza-
tion of a diolꢀacid northern fragment with an aldehyde-contain-
ing southern fragment to produce in sequence the ester (lactone)
and B-ring dioxane (Figure 2A). This mild sequence tolerates
fully functionalized coupling partners, thereby enabling excellent
overall convergence (e.g., 1 was accessed in one step following
fragment coupling).
We recently reported that this B-ring annulation strategy
accommodates a Prins-driven macrocyclization (Figure 2B) to
provide the corresponding B-ring tetrahydropyran architecture,
as exemplified by analogues 2 and 3.26 Like the macroacetaliza-
tion precedent, this mild macrocyclization tolerates sensitive
C-ring functionality, thereby enabling the synthesis of 2 in only
three steps following esterification of a hydroxyallylsilane-con-
taining northern piece with the same southern-fragment alde-
hyde employed in the synthesis of 1.
While the excellent PKC affinity and bioactivity of 1ꢀ3 and
related analogues support a scaffolding role of bryostatin’s northern
A/B-ring motif, recent work by us and Keck’s group has shown
additional structureꢀfunction relationships associated with this
region. For example, we found that A/B-ring structural variation
influences PKC isoform selectivity,27 and Keck, Blumberg, and
co-workers found that modifications of the A ring influence
activity against certain cancer cell lines.28
Prompted by the importance of elucidating these structureꢀ
functionꢀselectivity relationships, the therapeutic potential of
these agents, and the scarcity of the natural products, we sought a
facile, maximally convergent route to variably and systematically
functionalized northern-fragment analogues. Our designed ana-
logues included those possessing the full complement of func-
tionality present in the natural product family, an area that has
been largely unexplored because of scarce supply. Toward this
end, we report herein the first total synthesis of bryostatin 9. This
natural product has excellent affinity for PKC (Ki = 1.3 nM) and
was first isolated in 198629 by Pettit and co-workers in 0.000027%
yield. Our synthesis proceeds in 25 linear steps using a Prins-
driven macrocyclization strategy. This is the most step-economic-
al and convergent total synthesis of a potent bryostatin (PKC Ki <
10 nM), underscoring the strategic value of this functionality-
tolerant macrocyclization reaction. Recent notable examples of
Aldol condensation of 13 with methyl glyoxylate installed the
C21 enoate motif in 81% yield, and Luche reduction followed by
butanoylation provided ester 14 in 91% yield. Desilylation with
3HF Et3N followed by DessꢀMartin oxidation then gave a C17
3
aldehyde that was homologated in one step to unsaturated
aldehyde 15 using the dimethylzincate reagent derived from
(Z)-2-lithio-1-ethoxyethylene.
At this stage, the C25/C26 (R,R)-diol subunit was installed
with 83:17 dr in 78% combined yield via Sharpless’ dihydroxyla-
tion. The undesired C25/C26 (Z)-olefin carried through to this
point (∼8 mol %) was less reactive under these conditions, and
the recovered starting material was enriched in this isomer.34 The
mixture of (R,R)- and (S,S)-glycols was then subjected to
aqueous p-TsOH to hydrolyze the C19 methyl ketal, and selective
silylation of the C26 hydroxyl group provided recognition domain
5 as a single diastereomer in 64% yield over two steps. This
domain was thereby accessed in ∼2% yield over a 19-step longest
linear sequence. Esterification of 5 with 1 equiv of northern
fragment 4 proceeded in 82% yield using Yamaguchi’s protocol
(Scheme 2), thus setting the stage for the Prins macrocyclization.
In our previous report detailing the syntheses of 2 and 3,26 the
triethylsilyl-protected macrocyclization precursor analogous to
17 was desilylated and the corresponding hydroxyallylsilane
cyclized using TMSOTf in Et2O.35 However, for functionalized
A-ring substrates more closely related to 17, those conditions
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Scheme 1. Synthesis of the Bryostatin 9 Northern and Southern Fragment Coupling Partnersa
a Reagents and conditions in (A): (a) BnBr, NaHMDS, 5:1 THF/DMF, 0 °C, 90%. (b) Ethyl acetoacetate (2.5 equiv), LDA (5.0 equiv), THF, ꢀ78 °C.
(c) PPTS, MeOH, 40 °C, 84% over three steps. (d) NaBH4, EtOH, ꢀ15 °C, 78:22 dr, 61% isolated 8. (e) TESCl, imidazole, CH2Cl2, rt, 97%. (f)
CeCl3 2LiCl, TMSCH2MgCl, THF, rt, 65%. (g) NaHMDS, THF, 0 °C, 91%. (h) Lithium naphthalenide, THF, ꢀ30 f ꢀ10 °C, 87%. (i) TEMPO
3
(30 mol %), PhI(OAc)2 (3 equiv), 4:1 MeCN/H2O; then NaH2PO4, NaClO2, 2-methyl-2-butene, 0 °C. (j) Ac2O, DMAP, CH2Cl2, 0 °C; then
NaHCO3(aq), 57% over two steps. Reagents and conditions in (B): (a) O3, CH2Cl2, ꢀ78 °C; then PPh3, rt, 98%. (b) I2CHCH3, CrCl2, DMF, THF,
0 °C, 76%, 93:7 E:Z. (c) K2CO3, methyl glyoxylate, THF/MeOH, rt, 81%. (d) NaBH4, CeCl3 7H2O, MeOH, ꢀ49 °C. (e) Butyric anhydride, DMAP,
3
CH2Cl2, rt, 91% over two steps. (f) 3HF Et3N, THF, rt. (g) DessꢀMartin periodinane, CH2Cl2, rt. (h) (Z)-1-Bromo-2-ethoxyethylene, t-BuLi, Me2Zn,
3
Et2O, ꢀ78 °C; then H3Oþ, 64% over three steps. (i) K2OsO4 2H2O (∼0.5 mol %), DHQD2PYR (1.5 mol %), K2CO3, K3Fe(CN)6, 4 °C, 78%, 83:17
3
(R,R):(S,S). (j) p-TsOH, 4:1 MeCN/H2O, rt. (k) TBSCl, imidazole, CH2Cl2, 64% over two steps as a single diastereomer.
Scheme 2. Completion of Bryostatin 9a
yielded a significant amount of a spirocyclic byproduct that
resulted from activation of the methyl ketal at C9.36 We therefore
investigated alternative reaction conditions and found that treat-
ment of 17 with catalytic PPTS in anhydrous MeOH provided
macrocyclization product 18 in a single step (65% yield). Notably,
these mild conditions obviated the need for a separate C11 desilyla-
tion step, as the reactive hydroxyallylsilane was revealed in situ.
The exocyclic B-ring enoate was then installed in two steps:
oxidative cleavage of the C13 methylidene with stoichiometric
ozone (72% yield) and olefination of the resulting ketone with
phosphonoacetate 19 (82% yield, 79:21 Z:E).37 The selectivity of
this olefination is in good accord with that observed by Evans,
Yamamura, and Keck. The reaction with trimethyl phosphonoace-
tate lacked appreciable selectivity (48:52 Z:E).
Global desilylation and C9 ketal hydrolysis was accomplished
in two steps and 76% combined yield by treatment of enoate
mixture 20 with HF pyridine followed by aqueous PPTS,38
3
thereby providing pure bryostatin 9 in 52% yield.
We conclusively established the identity of our synthetic
a Reagents and conditions: (a) 2,4,6-Trichlorobenzoyl chloride, Et3N,
material by comparison with an authentic sample kindly provided
PhCH3; then alcohol 5, DMAP, 82%. (b) PPTS (20 mol %), MeOH,
by Prof. G. R. Pettit. All analytical data for the synthetic sample
were found to be in agreement with published or observed data
for the natural product (see the Supporting Information).
[17] = 0.02 M, rt, 22 h, 65%. (c) O3, CH2Cl2, ꢀ78 °C; then thiourea, 1:1
CH2Cl2/MeOH, rt, 72%. (d) 19, NaHMDS, THF, ꢀ78 f 4 °C, 79:21
Z:E, 82%. (e) HF py, THF, rt. (f) PPTS, 20% H2O in THF, rt, 76%
3
This synthesis provided bryostatin 9 in 25 linear and 42 total
steps. Significantly, the fragment syntheses can be readily scaled to
produce gram quantities of the advanced intermediates, which,
because of the potency of these agents, have clinical supply
potential. This approach enables access to the complete and highly
functionalized bryostatin oxycarbocyclic ring system (e.g., 18) in
only two steps from similarly complex northern fragment 4 and
southern fragment 5. More generally, the macro-Prins and macro-
acetalization strategies provide potentially general and functional-
group-tolerant approaches to natural or unnatural pyran-contain-
ing macrocycles and their dioxane analogues. The flexibility,
convergence, scalability, and step economy of these strategies
combined yield, 80:20 Z:E, 52% isolated bryostatin 9.
enable access to natural and designed bryostatin analogues that
are critically needed for ongoing mode-of-action, structural, and
preclinical studies.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
9230
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’ AUTHOR INFORMATION
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Corresponding Author
wenderp@stanford.edu
’ ACKNOWLEDGMENT
Financial support of this work provided by the NIH
(CA31845) is gratefully acknowledged. A.J.S. was supported by
an Eli Lilly Graduate Fellowship. We thank Dr. G. R. Pettit for
providing an authentic sample of bryostatin 9 for analytical
purposes.
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(b) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189.
(36) Analogous reactivity was also observed by Keck and co-workers
for similar substrates in an intermolecular Prins approach (see ref 18).
(37) (a) Tanaka, K.; Ohta, Y.; Fuji, K. Terahedron Lett. 1993,
34, 4071. (b) Also see refs 15, 16, and 18.
(38) The latter step was required to hydrolyze C9 fluoride products.
For a related example, see: Costello, B. J.; Driver, M. J.; MacLachlan,
W. S.; Taylor, A. W. J. Chem. Soc., Perkin. Trans. 1 1993, 1829.
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