Total synthesis of 6-deoxyerythronolide B via C-C bond-forming transfer hydrogenation

Article abstract of DOI:10.1021/ja4008722

The 14-membered macrolide 6-deoxyerythronolide B is prepared in 14 steps (longest linear sequence) and 20 total steps. Two different methods for alcohol CH-crotylation via transfer hydrogenation are deployed for the first time in target-oriented synthesis

Full text of DOI:10.1021/ja4008722

Communication
pubs.acs.org/JACS
Total Synthesis of 6‑Deoxyerythronolide B via C−C Bond-Forming
Transfer Hydrogenation
Xin Gao,† Sang Kook Woo,†,‡ and Michael J. Krische*,†
†Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
‡Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea
S
* Supporting Information
ABSTRACT: The 14-membered macrolide 6-deoxy-
erythronolide B is prepared in 14 steps (longest linear
sequence) and 20 total steps. Two different methods for
alcohol CH-crotylation via transfer hydrogenation are
deployed for the first time in target-oriented synthesis.
Enyne metathesis is used to form the 14-membered ring.
The present approach represents the most concise
construction of any erythronolide reported, to date.
n 1952, the pharmaceutical company Eli Lily commercialized
I
the first macrolide antibiotic, erythromycin A.1 Beyond its
impact on human medicine, the challenges in chemical synthesis
posed by erythromycin A and related polyketides propelled
advances in acyclic stereocontrol via carbonyl addition, especially
aldol bond constructions2d and crotylation methods.3 Perhaps
fueled further by Woodward’s dim assessment of the prospect of
accessing erythromycin A through chemical synthesis,4 the
erythromycins have become inextricably tied to the evolution of
synthetic organic chemistry, and their total syntheses are widely
regarded as benchmarks for the state of the art.9f As illustrated in
total syntheses of erythromycin A5 and B,6 erythronolide A7 and
B,8 (9S)-dihydroerythronolide A,9 and their biogenic precursor
6-deoxyerythronolide B,10 tremendous strides have been made
over the past 30 years. However, all reported syntheses remain
well over 20 steps in length, suggesting the influence of the
erythromycins on chemical synthesis will persist into the future
(Figure 1).
In the course of exploring C−C bond-forming hydrogenations
and transfer hydrogenations beyond hydroformylation,11 our
laboratory developed a suite of methods for stereoselective
polyketide construction, including methods for carbonyl crotyl-
ation via redox-triggered C−C coupling of primary alcohols and
α-methyl allyl acetate (5) or butadiene using Ir12 and Ru13
catalysts, respectively. These studies evoked an exceptionally
powerful transformation that has no counterpart in conventional
allylmetal chemistry:3 the anti-diastereo- and enantioselective Ir-
catalyzed double crotylation of 2-methyl-1,3-propanediol (6) to
form polypropionate stereoquintets.12c To benchmark the utility
Figure 1. Erythromycin A and B, erythronolide A and B, and 6-
deoxyerythronolide A and B and prior total syntheses. For graphical
summaries of prior total syntheses, see Supporting Information. For
total syntheses of other erythromycin family members and their seco-
acids, see ref 2. LLS, longest linear sequence; TS, total steps.
the 14-membered macrolide.14 Fragment A is prepared in six
steps from n-propanol (1) through successive introduction of
propionate subunits via Ru-catalyzed, butadiene-mediated syn-
crotylation13d followed by substrate-directed syn-aldol addition15
to form thiol ester 3, which incorporates the four contiguous
stereogenic centers spanning C10−C13. Fragment B, which
incorporates the five contiguous stereogenic centers spanning
C2−C6, is prepared in eight steps from 6 via Ir-catalyzed double
̀
of this method vis-a-vis polyketide construction, it was applied to
the preparation of 6-deoxyerythronolide B. This undertaking has
resulted in the most concise route to any erythronolide reported,
to date.2,5−10
Retrosynthetically, a convergent assembly of 6-deoxyerythro-
nolide B from fragments A and B was envisioned through
esterification followed by ring-closing enyne metathesis to form
Received: January 25, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4008722 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 1. Retrosynthetic Analysis of Deoxyerythronolide B,
Highlighting C−C Bonds Formed via Hydrogenative
Coupling
Scheme 3. Synthesis of Fragment B via Ir-Catalyzed Double-
anti-Crotylation of 2-Methyl-1,3-propanediol (6)
a
Scheme 2. Synthesis of Fragment A via Ru-Catalyzed syn-
a
Crotylation of n-Propanol (1)
a
Indicated yields are of material isolated by silica gel chromatography.
See Supporting Information for experimental details.
formation of the TBS ether 2 are added to the reaction mixture
after the C−C coupling is complete, enabling direct acquisition
of 2 from 1 in 59% isolated yield with 5:1 syn-diastereoselectivity
and 98% enantiomeric excess.13d,16 Oxidative cleavage of the
terminal olefin followed by treatment of the resulting aldehyde
with the (E)-boron enolate derived from S-phenyl propane-
thioate delivers the product of syn-aldol addition 3, with only
1
trace quantities of the anti-diastereomer detected by H NMR
analysis.15 The thiol ester 3 is converted to the β-hydroxy
aldehyde,17 which is exposed to the Ohira−Bestmann reagent to
form the homopropargyl alcohol 4 without protection of the
hydroxyl moiety.18b Finally, benzylation of 4 accompanied by
acidic hydrolysis of the TBS ether in the course of isolation
provides fragment A. An even more concise route to fragment A
potentially involves 1,3-enyne hydrohydroxyalkylation to form
the C10−C11 bond with concomitant installation of the alkyne;
however, this chemistry has not yet been adapted to the use of
chiral β-stereogenic alcohols (Scheme 2).19
The synthesis of fragment B begins with the anti-diastereo-
and enantioselective Ir-catalyzed double crotylation of 6 to
furnish the pseudo-C2-symmetric diol 7 (Scheme 3).12c The diol
7 is produced as a single enantiomer as determined by HPLC, as
the minor enantiomer of the mono-adduct is converted to the
pseudo-meso-diastereomer.20 Iodoetherification of 7, which
differentiates the alkene termini and diol moieties and defines
the nonstereogenic chirotopic center at C4, followed by
benzylation delivers pyran 8. Os-catalyzed oxidative cleavage of
the olefin to form the carboxylic acid,21 followed by Zn-mediated
reductive cleavage of the iodoether, provides the β-hydroxy acid
9, which is prone to epimerization. To convert 9 to fragment B,
a
Indicated yields are of material isolated by silica gel chromatography.
See Supporting Information for experimental details.
crotylation followed by iodoetherification and alkene oxidative
cleavage to form the carboxylic acid (Scheme 1).12c
The synthesis of fragment A begins with the hydro-
hydroxyalkylation of butadiene employing n-propanol 1 to
form the product of syn-crotylation (Scheme 2).13d As the
resulting secondary alcohol is quite volatile, reagents promoting
B
dx.doi.org/10.1021/ja4008722 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 4. Union of Fragment A and Fragment B and Total Synthesis of 6-Deoxyerythronolide B
a
Indicated yields are of material isolated by silica gel chromatography. See Supporting Information for experimental details.
an inversion in stereochemistry at C3 is required. To this end,
conversion of 9 to the β-lactone 10 was attempted under
Mitsunobu conditions; however, decarboxylative Grob-type
elimination to form the cis-alkene occurred, in over 70%
yield.22 Treatment of the dianion of 9 with methanesulfonyl
chloride23 delivers 10 in 15−20% yield along with recovered 9,
suggesting a more electrophilic sulfonyl chloride is required.
Indeed, use of chloromethanesulfonyl chloride leads to the
formation of 10 in 72% yield. It was our hope to directly exploit
10 in the acylation of fragment A. However, although related β-
lactone ring openings are known,24a as we learned, cis-
disubstituted β-lactones are recalcitrant acylating agents,24b and
so 10 was converted to the carboxylic acid fragment B (Scheme
3).
The convergent assembly of fragments A and B is achieved
through esterification under Yamaguchi’s conditions to form the
tethered enyne 11 (Scheme 4).25 Initial attempts at ring-closing
enyne metathesis14 in the absence of ethylene led to isomer-
ization of the terminal olefin. Under an atmosphere of ethylene at
80 °C, the terminal alkyne is converted to the conjugated diene in
nearly quantitative yield, but macrocyclization is not observed.
Hence, upon complete conversion to the conjugated diene at 80
°C, the reaction vessel is purged with nitrogen and the reaction
temperature increased to 110 °C, which induces formation of the
14-membered macrolide 12 as a single regioisomer in a
remarkable 89% yield. Os-catalyzed oxidative cleavage of the
C9 methylidene residue provides the conjugated enone 13.21
Reductive methylation of 13 to form ketone 14 under the
conditions of dissolving metal reduction26a,b or through the
agency of arene anion radicals26c,d was explored. Although
efficient reductive alkylation was achieved in a model system
(4,4-dimethylcyclohexenone), 13 underwent benzyl cleavage or
decomposed upon exposure to dissolving metal conditions and,
upon treatment with arene anion radicals, 13 was converted to
the product of enone 1,2-reduction. Consequently, the
conversion of 13 to 14 was accomplished by Ni-catalyzed
conjugate reduction27 followed by conventional enolate methyl-
ation. Interestingly, highly variable levels of diastereoselectivity
were associated with the newly formed C8-stereocenter of 14,
suggesting facile epimerization at this position. Indeed,
irrespective of the diastereomeric ratio at C8, exposure of 14
to the slightly acidic conditions of Pd-catalyzed homogeneous
hydrogenation provides 6-deoxyerythronolide B in 93% isolated
yield as a single diastereomer. Thus, 6-deoxyerythronlide B is
prepared in 14 steps (longest linear sequence) and 20 total steps,
representing the most concise route to any erythromycin family
member reported, to date.
New reactivity is the principal basis of new functional group
interconversions and new strategies that can shift the
retrosynthetic paradigm, ultimately simplifying longstanding
challenges in chemical synthesis. As illustrated in the present
total synthesis of 6-deoxyerythronolide B and recent total
syntheses of the macrolides roxaticin28a and bryostatin 7,28b
alcohol C−H functionalization via transfer hydrogenation
augments synthetic efficiency by opening novel routes to
polyketide natural products that bypass stoichiometric use of
chiral auxiliaries, premetalated C-nucleophiles, and discrete
alcohol-to-aldehyde redox reactions. As organic molecules are
defined as compounds composed of C and H, the reactivity
embodied by such processes where C−C bond formation is
accompanied by H redistribution evokes numerous possibilities
in terms of related transformations, including imine addition
from the amine oxidation and the direct C−C coupling of
alcohols to α-olefins. These and other topics are currently under
investigation in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
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 (RO1-GM093905) are acknowledged for partial
support of this research.
C
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Journal of the American Chemical Society
Communication
C.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 1636. (c) Evans, D. A.; Kim,
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