Total synthesis of bryostatin 7 via C-C bond-forming hydrogenation

Article abstract of DOI:10.1021/ja205673e

The marine macrolide bryostatin 7 is prepared in 20 steps (longest linear sequence) and 36 total steps with five C-C bonds formed using hydrogenative methods. This approach represents the most concise synthesis of any bryostatin reported, to date.

Full text of DOI:10.1021/ja205673e

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pubs.acs.org/JACS
Total Synthesis of Bryostatin 7 via CÀC Bond-Forming Hydrogenation
Yu Lu, Sang Kook Woo, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712, United States
S Supporting Information
b
ABSTRACT: The marine macrolide bryostatin 7 is pre-
pared in 20 steps (longest linear sequence) and 36 total
steps with five CÀC bonds formed using hydrogenative
methods. This approach represents the most concise synthe-
sis of any bryostatin reported, to date.
he bryostatins are a family of 20 marine natural products
T
originally isolated from the bryozoan Bugula neritina1 that
possess a polyacetate backbone and differ largely on the basis of
substitution at C7 and C20 (Figure 1).2 The bryostatins display
diverse biological effects, including antineoplastic activity, im-
munopotentiating activity, restoration of apoptotic function, and
the ability to act synergistically with other chemotherapeutic
agents.3 Neurological effects also are evident, including activity
against Alzheimer’s disease,4 neural growth and repair, and the
reversal of stroke damage,5 as well as memory enhancement.6
As their natural abundance is insufficient to advance clinical
studies, the bryostatins have emerged as a vibrant testing ground
for polyketide construction. To date, total syntheses of bryosta-
tins 1,7a 2,7b,c 3,7d,e 7,7f 9,7g and 167h have been reported. A formal
synthesis of bryostatin 78a and total syntheses of C20-epi-
bryostatin 78b and C20-deoxybryostatin8c have been disclosed.
Simplified bryostatin analogues that retain high potency have
been identified.9À11
Figure 1. Bryostatins 1À17 and prior total syntheses. See SI for a
graphical summary of prior syntheses.
quantities of material. Conversion of 3 to the enol silane followed by
addition of LiAlH4 to the reaction mixture directly provides the
allylic alcohol 4.19 Treatment of crude 4 with tert-butyldimethylsilyl
chloride followed by N-bromosuccinimide provides the R-bromo-
ketone 5 in 84% yield over the 2-step sequence from R,β-
unsaturated ester 3. Finally, Kornblum oxidation of R-bromo-
ketone 5 delivers the glyoxal 6 (Scheme 2).20
Preparation of the 1,3-enyne 9 begins with Sharpless asym-
metric dihydroxylation of crotononitrile 7, which provides the
diol in 86% enantiomeric excess.21 The diol is converted to the
acetonide and exposed to diisobutylaluminum hydride to provide
the aldehyde 8, which is a known compound previously prepared
using a six-step sequence.22 Chelation-controlled propargylzinc
addition converts 8 to the homopropargylic alcohol, which is
formed as a 5:1 mixture of diastereomers.22 As described in the
SI, the minor isomer is easily converted to the desired epimer by
Mitsunobu inversion. Conversion of the homopropargylic alco-
hol to the TBDPS ether followed by Sonogashira coupling
delivers 9 (Scheme 2).
Given the challenges associated with defining concise routes
to the bryostatins, these products were deemed an ideal vehicle to
benchmark the utility of the CÀC bond-forming hydrogenations
developed in our laboratory.12 Retrosynthetically, a convergent
assembly of the bryostatin 7 core from Fragments A and B employ-
ing the KeckÀYu pyran annulation13,14 and Yamaguchi macro-
lactonization15 was envisioned. For the synthesis of Fragment A,
hydrogen-mediated reductive coupling ofglyoxal6 and 1,3-enyne 9
appeared strategic, as the key C20ÀC21 bond would be formed
with control of the C20 carbinol stereochemistry and C21 olefin
geometry.16 The planned synthesis of Fragment B, which incorpo-
rates the A-ring, takes advantage of three transfer hydrogenative
processes: enantioselective double allylation of 1,3-propanediol
to form the C2-symmetric diol 11,17a subsequent aldehyde tert-
prenylation17b to establish the C7 carbinol stereochemistry and
install the C8 gem-dimethyl moiety, and finally, allylation17c,d at C9
to introduce the C11 aldehyde. The feasibility of these syntheses has
been established in model systems (Scheme 1).16,17e
To complete the synthesis of Fragment A, 6 and 9 are sub-
jected to hydrogen-mediated reductive coupling to furnish the
R-hydroxyketone in 77% yield as a 7:1 mixture of diastereomers.16
The synthesis of Fragment A begins with the hydroxymethyla-
tion of 3-methyl-2-butanone 1 to furnish the aldol product.18
MoffattÀSwern oxidation of the aldol product provides keto-
aldehyde 2, which upon HornerÀWadworthÀEmmons olefination
delivers the R,β-unsaturated ester 3. All compounds up to this
point are isolated by vacuum distillation, expediting access to large
Received: June 18, 2011
Published: July 22, 2011
r
2011 American Chemical Society
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|

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COMMUNICATION
Notably, although the coupling product incorporates multiple
points of unsaturation, over-reduction is not observed under the
conditions of hydrogenative coupling. Exposure of R-hydroxy-
ketone to acetic anhydride provides the acetate. Selective deprotec-
tion of the allylic TBS ether in the presence of the TBDPS ether,
which is accomplished using HF-pyridine, provides the allylic
alcohol. Finally, oxidation of allylic alcohol delivers the enal,
Fragment A, in a total of 10 steps from 3-methyl-2-butanone 1 or
crotononitrile 7 (Scheme 2).
Efforts toward Fragment B begin with allyl acetate-mediated
double allylation of 1,3-propanediol 1017a,e to form C2-symmetric
diol 11. This process employs an iridium catalyst generated in situ
from [Ir(cod)Cl]2, allyl acetate, 4-chloro-3-nitrobenzoic acid, and
(S)-Cl,MeO-BIPHEP. Because the minor enantiomer of the mono-
allylated intermediate is converted to the meso-diastereomer, 11 is
obtained as a single enantiomer, as determined by chiral stationary
phase HPLC analysis. Previously, the mono-TBS ether of 11 was
prepared in 7 steps from 1,3-propanediol through iterative use of
Brown’s reagent for carbonyl allylation.23a Alternatively, a 4-step
protocol for the preparation of 11 from acetylacetone is described.23b
Ozonolysis of 11 delivers an unstable lactol, which is protected
in situ as the bis-TBS ether to provide aldehyde 12 as a single isomer.
Transfer hydrogenation of 12 in the presence of 1,1-dimethylallene
promotes tert-prenylation17b to form neopentyl alcohol-13. In this
process, the discrete iridium complex derived from [Ir(cod)Cl]2,
allyl acetate, m-nitrobenzoic acid, and (S)-SEGPHOS is used as
catalyst. Complete levels of catalyst-directed diastereoselectiv-
ity are observed. Exposure of 13 to acetic anhydride followed by
ozonolysis provides β-acetoxy aldehyde 14. Reductive coupling
of 14 and allyl acetate under transfer hydrogenation conditions
results in the formation of homoallylic alcohol 15. As the
stereochemistry of this addition is irrelevant, an achiral iridium
complex is employed as catalyst. Selective removal of the
glycosidic silyl ether followed by concomitant DessÀMartin
oxidation of the lactol and homoallylic alcohols provides
β,γ-enone 16. Treatment of a methanolic solution of 16 to
pyridinium p-toluenesulfonate triggers sequential lactone ring-
opening followed by formation of the cyclic ketal 17a. Ozono-
lysis of 17a provides Fragment B in a total of 10 steps from 10
(Scheme 3).
Scheme 1. Retrosynthetic Analysis of Bryostatin 7 Illustrat-
ing CÀC Bonds Formed via Hydrogenative Coupling
The union of Fragments A and B is achieved through KeckÀYu
annulation to form the B-ring pyran.13,14 The desired adduct 18a
is accompanied by the elimination product 18b; however, both
compounds participate in acidic methanolysis to form triol 19b.
Chemoselective hydrolysis of the C1 methyl ester in the presence
of the C7 and C20 acetates employing trimethyltin hydroxide24
followed by selective TES-protection of the triol reveals a hydroxy
acid, which upon macrolactonization15 provides tetraene 20.
Concomitant oxidative cleavage25 of the olefinic termini of 20 in
the presence of the neopentyl olefin at C16ÀC17 installs both the
B-ring ketone and C-ring enal. Whereas CoreyÀGilman oxidation
Scheme 2. Synthesis of Fragment A via Hydrogen-Mediated Reductive Coupling of Glyoxal 6 and 1,3-Enyne 9a
a Indicated yields are of material isolated by silica gel chromatography or distillation. See SI for experimental details.
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Scheme 3. Synthesis of Fragment B Employing Multiple Transfer Hydrogenative CÀC Bond Formationsa
a Indicated yields are of material isolated by silica gel chromatography. See SI for experimental details.
Scheme 4. Union of Fragment A and Fragment B and Total Synthesis of Bryostatin 7a
a Indicated yields are of material isolated by silica gel chromatography. See SI for experimental details.
of enal failed,26 the corresponding N-heterocyclic carbene-
promoted process provides the desired methyl ester 21 in good
isolated yield.27 Finally, as practiced in prior syntheses,7aÀd,g
asymmetric olefination of the B-ring ketone using Fuji’s chiral
phosphonate28 followed by global deprotection using HF-pyr-
idine provides bryostatin 7 (Scheme 4).
The present synthesis of bryostatin 7 is accomplished in 20
linear and 36 total steps, representing the most concise route to
any bryostatin reported, to date. The step economy associated with
this approach can be attributed to the rapid assembly of Fragments
A and B through CÀC bond-forming hydrogenations developed in
our laboratory,12 a technology that has enabled dramatic simplifica-
tion in the synthesis of other polyketide natural products.29 This
work serves as a prelude to even shorter syntheses of bryostatins and
their analogues. More broadly, the merged redoxÀconstruction
events central to this study speak to an emerging retrosynthetic
paradigm, wherein CÀC bond construction is accompanied by
withdrawal of hydrogen.30,31
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’ ASSOCIATED CONTENT
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’ AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
’ ACKNOWLEDGMENT
The Welch Foundation (F-0038) and the NIH-NIGMS
(RO1-GM093905) are acknowledged for financial support.
Max Hansmann and Dr. Jin Haek Yang are acknowledged for
skillful technical assistance.
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