Total synthesis of (+)-trienomycins A and F via C-C bond-forming hydrogenation and transfer hydrogenation

Article abstract of DOI:10.1021/ja4061273

The triene-containing C17-benzene ansamycins trienomycins A and F were prepared in 16 steps (longest linear sequence, LLS) and 28 total steps. The C11-C13 stereotriad was generated via enantioselective Ru-catalyzed alcohol CH syn crotylation followed by chelation-controlled carbonyl dienylation. Enantioselective Rh-catalyzed acetylene-aldehyde reductive coupling mediated by gaseous H₂ was used to form a diene that ultimately was subjected to diene-diene ring closing metathesis to form the macrocycle. The present approach is 14 steps shorter (LLS) than the prior syntheses of trienomycins A and F, and 8 steps shorter than any prior synthesis of a triene-containing C17-benzene ansamycin.

Full text of DOI:10.1021/ja4061273

Communication
pubs.acs.org/JACS
Total Synthesis of (+)-Trienomycins A and F via C−C Bond-Forming
Hydrogenation and Transfer Hydrogenation
David J. Del Valle and Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The triene-containing C17-benzene ansa-
mycins trienomycins A and F were prepared in 16 steps
(longest linear sequence, LLS) and 28 total steps. The
C11−C13 stereotriad was generated via enantioselective
Ru-catalyzed alcohol CH syn crotylation followed by
chelation-controlled carbonyl dienylation. Enantioselective
Rh-catalyzed acetylene−aldehyde reductive coupling medi-
ated by gaseous H2 was used to form a diene that
ultimately was subjected to diene−diene ring closing
metathesis to form the macrocycle. The present approach
is 14 steps shorter (LLS) than the prior syntheses of
trienomycins A and F, and 8 steps shorter than any prior
synthesis of a triene-containing C17-benzene ansamycin.
oughly 20% of the top-selling small-molecule drugs are
1,2 and it is estimated
Rpolyketides derived from soil bacteria,
that polyketides are 5 times more likely to possess drug activity
compared to other classes of natural products.3 Despite the
significance of polyketides, less than 5% of the soil bacteria from
which they derive are amenable to culture.4 Hence, as methods
for bacterial culture improve, it is anticipated that polyketides will
become even more important to human medicine. Among
polyketides, the ansamycins have emerged as important
antibiotic and anti-neoplastic agents.5 The first ansamycins, the
rifamycins, were discovered in the late 1950s in soil samples
taken from the south of France.6 These compounds were largely
responsible for vanquishing drug-resistant tuberculosis in the
1960s and were forerunners of what is now a broad class of
medicinally relevant compounds.5 An important ansamycin
subclass includes the triene-containing C17-benzene ansamycins
or “ansatrienins”.7−9 This subclass emanates from different
Streptomyces and Bacillus species and encompasses the
mycotrienins/mycotrienols,7 the trienomycins,8 and the cyto-
Figure 1. Triene-containing C17-benzene ansamycins and prior total
trienins (Figure 1).9 While the mycotrienins display antifungal
syntheses. For graphical summaries of prior total syntheses, see the
properties,7d,e the trienomycins and cytotrienins exhibit anti-
Supporting Information (SI). For total syntheses of other ansamycin
neoplastic activity.8a,9b,10 Elegant studies conducted in the Smith
laboratory led to the stereochemical assignment of the
trienomycins and mycotrienins11 as well as total syntheses of
trienomycins A and F and thiazinotrienomycin E.12a−d
Subsequently, Panek reported total syntheses of mycotrienol I
and mycotrienin I,12e,f and Hayashi reported a total synthesis of
cytotrienin A.12g Syntheses of the ansatrienol and cytotrienin
cores were reported by Kirschning,13a Panek,13b and the present
author.13c Here, using hydrogen mediated C−C couplings
developed in our laboratory,14 we report total syntheses of the
triene-containing C17-benzene ansamycins, trienomycins A and
family members, see the review literature.5 LLS = longest linear
sequence; TS = total steps.
F. This approach represents the most concise route to any triene-
containing C17-benzene ansamycin.
Our retrosynthetic analysis of trienomycins A and F invokes a
convergent assembly of fragments A and B wherein (E)-
Received: June 18, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4061273 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
trimethyl-2,4-pentadienylsilane15 serves as a linchpin through
chelation-controlled aldehyde addition16 followed by diene−
diene ring closing metathesis (RCM) (Scheme 1).13b Fragment
Scheme 2. Synthesis of Fragment A via Ru-Catalyzed syn-
Crotylation Employing Silyl-Substituted Diene 5
a
Scheme 1. Retrosynthetic Analysis of Trienomycins A and F
A is itself prepared using an enantio- and syn-diastereoselective
Ru-catalyzed crotylation developed in our laboratory,17 which
enables direct C−C coupling of the Z-configured trisubstituted
allylic alcohol obtained via Suzuki reaction of (Z)-3-iodo-2-
methyl-1-propenol and the indicated vinyl arene 2. Fragment B is
prepared in accordance with our previously described procedure
involving C−C bond-forming hydrogenation of acetylene in the
presence of the p-toluenesulfonate of hydroxyacetaldehyde.13c,18
The present syntheses of trienomycins A and F overcomes
limitations evident in our prior work on the cytotrienin core
pertaining to formation of the C11−C13 stereotriad, introduc-
tion of the side chain at C11, and late-stage protecting group
cleavage.13c
a
Indicated yields are of materials isolated by silica gel chromatography.
See the SI for experimental details.
Scheme 3. Synthesis of Fragment B via Rh-Catalyzed
Reductive C−C Coupling of Acetylene
a
The synthesis of fragment A begins with successive Suzuki
cross-couplings to form the C17−C18 and C15−C16 bonds
(Scheme 2). First, Suzuki−Molander coupling of 3-bromo-5-
nitrophenol (1) with potassium ethenyltrifluoroborate19 pro-
vides vinyl arene 2 after methoxymethyl (MOM) protection.
Second, in a one-pot procedure, regioselective hydroboration of
2 using 9-borabicyclo[3.3.1]nonane (9-BBN) followed by B-
alkyl Suzuki cross-coupling20,21 with (Z)-3-iodo-2-methyl-1-
propenol tert-butyldimethylsilyl (TBS) ether (3)22 provides (Z)-
allylic alcohol 4 as a single olefin stereoisomer. Direct redox-
triggered syn-crotylation of 4 using silyl-substituted diene 5 as a
crotyl donor17a enables enantio- and diastereoselective formation
of homoallylic alcohol 6. Protection of the C13 alcohol as the p-
methoxybenzyl (PMB) ether followed by oxidative cleavage of
the terminal olefin using a modification of the Johnson−Lemieux
protocol23 provides aldehyde Fragment A in only seven steps
from 1.
The carboxylic acid, Fragment B, was prepared previously in
12 steps in 16% overall yield.12g Our approach to fragment B is
accomplished in seven steps from allyl alcohol in 32% overall
yield.13c The synthesis begins with enantioselective H2-mediated
C−C coupling of acetylene to acetaldehyde derivative 7 to form
the Z-butadienylation product,18 which upon treatment with
Meerwein’s reagent provides methyl ether 8 (Scheme 3). Pd-
catalyzed diene isomerization24 followed by substitution of the p-
a
Indicated yields are of materials isolated by silica gel chromatography.
See the SI for experimental details.
toluenesulfonate by cyanide and, finally, peroxide-assisted
hydrolysis of the resulting nitrile delivers fragment B. A
remarkable feature of this sequence relates to the ability to
engage aldehyde 7 in carbonyl Z-butadienylation without
inducing epoxide formation through displacement of the vicinal
p-toluenesulfonate.
To complete the syntheses of trienomycins A and F, fragment
A is exposed to (E)-trimethyl-2,4-pentadienylsilane15 in the
B
dx.doi.org/10.1021/ja4061273 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 4. Union of Fragments A and B and Total Synthesis of Trienomycins A and F
a
Indicated yields are of materials isolated by silica gel chromatography. See the SI for experimental details.
presence of AlMe2Cl to generate the product of chelation-
controlled pentadienylation,16 which is followed by acylation
with the symmetrical anhydride of N-Fmoc-D-alanine to provide
9 (Scheme 4). It was found that the major syn diastereomer of
fragment A reacts more quickly than the corresponding anti-
diastereomer, allowing the stereotriad of 9 to form as a single
isomer as determined by 1H NMR analysis.25 Because different
acyl moieties can be introduced at C11, 9 serves as a common
intermediate in the syntheses of trienomycins A and F and
potentially other triene-containing C17-benzene ansamycins.
Treatment of 9 with piperidine followed by the indicated acids
permits formation of amides 10a and 10f. Cleavage of the PMB
ethers of 10a and 10f in the presence of the 1,3-diene moieties
requires special conditions.26 Subsequent reduction of the C20
nitro moieties and acylation of the resulting anilines with
fragment B provides tetraenes 11a and 11f, respectively. Finally,
diene−diene RCM to form the triene was explored.13b,c With
Grubbs’ first- and second-generation catalysts and the Grubbs−
Hoveyda-II catalyst, RCM occurs to form substantial quantities
of undesired diene products (30−40%). The indenylidene
analogue of the first-generation Grubbs metathesis catalyst27 is
more selective for triene formation, although modest yields are
obtained, perhaps due to the lack of a conformational-biasing
element in the form of a C19 substituent. Triene formation in
this manner followed by removal of the MOM protecting group
completes the total syntheses of trienomycins A and F in 16 steps
(LLS). This sequence is 14 steps (LLS) shorter than the prior
syntheses of trienomycins A and F,12a,b and 8 steps shorter than
any prior synthesis of a triene-containing C17-benzene
ansamycin.
cyanolide A29d as well as formal syntheses of rifamycin S and
scytophycin C,29e applications of our technology have availed the
most concise routes to any member of these natural product
families. Future studies will focus on the development of related
catalytic processes that streamline syntheses by merging redox
and C−C bond construction events.30,31
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
mkrische@mail.utexas.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH
NIGMS (R01-GM093905) are acknowledged for partial support
of this research. D.J.D. received partial support from an NIH
NRSA Fellowship to promote diversity in health related research.
Dr. Michael Rossle is acknowledged for preliminary studies (ref
̈
13c). Dr. Raul R. Rodriguez is acknowledged for skillful technical
assistance.
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D
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