Application of Two Direct C(sp3)-H Functionalizations for Total Synthesis of (+)-Lactacystin

Article abstract of DOI:10.1021/ol503291s

(Figure Presented). Herein, we report a new synthetic route from (S)-pyroglutaminol to (+)-lactacystin, a potent inhibitor of the 20S proteasome. The photoinduced intermolecular C(sp³)-H alkynylation and intramolecular C(sp³)-H acylation chemo- and stereoselectively constructed the tetra- and trisubstituted carbon centers, respectively. The obtained bicycle was transformed into the target compound in a concise manner. The present total synthesis demonstrates the power of the direct C(sp³)-H functionalizations for the assembly of multiple functionalized structures of natural products.

Full text of DOI:10.1021/ol503291s

Letter
pubs.acs.org/OrgLett
Application of Two Direct C(sp3)−H Functionalizations for Total
Synthesis of (+)-Lactacystin
Shun Yoshioka, Masanori Nagatomo, and Masayuki Inoue*
Graduate School of Pharmaceutical Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Herein, we report a new synthetic route from (S)-pyroglutaminol to (+)-lactacystin, a potent inhibitor of the 20S
proteasome. The photoinduced intermolecular C(sp3)−H alkynylation and intramolecular C(sp3)−H acylation chemo- and
stereoselectively constructed the tetra- and trisubstituted carbon centers, respectively. The obtained bicycle was transformed into
the target compound in a concise manner. The present total synthesis demonstrates the power of the direct C(sp3)−H
functionalizations for the assembly of multiple functionalized structures of natural products.
(+)-Lactacystin (1, Scheme 1), isolated from Streptomyces sp.
OM-6519,1 possesses neurite outgrowth activity in the murine
neuroblastoma cell line Neuro-2a. A detailed investigation of the
mode of biological action revealed that 1 irreversibly inhibits
the proteolytic activity of the 20S proteasome.2 Since the
proteasome machinery plays an essential role in cell cycle
control, differentiation, apoptosis, antigen processing, and
immune response, proteasome inhibitors have emerged as
important candidates for the development of pharmaceuticals3
and new biological tools for the study of proteasome functions.4
Accordingly, 1 has attracted significant attention as a synthetic
target, and a number of total syntheses have been reported to
date.5−7
Scheme 1. Synthetic Plan of (+)-Lactacystin
Direct transformation of C(sp3)−H bonds to C(sp3)−C
bonds eliminates the need for preactivation steps and thus
permits the design of simpler synthetic schemes.8 Recently, we
developed photochemically induced intra- and intermolecular
C(sp3)−H functionalizations and established their chemo-
selectivities (Scheme 1).9−11 While the intermolecular C−H
alkynylation employs Ph2CO and 1-tosyl-2-(trimethylsilyl)-
acetylene (I → II),9e the intramolecular C−H acylation consists
of the Norrish−Yang cyclization12 of a 1,2-diketone (III → IV)
and subsequent oxidative ring-opening reaction (IV → V).9a
In both reactions, the electrophilic oxyl radical photochemically
generated from the carbonyl group chemoselectively cleaves the
most electron-rich bond in the molecule (nitrogen-substituted →
oxygen-substituted → aliphatic carbons), and the resultant carbon
radical forms a new C−C bond. The mildness, simplicity, and
predictability are highly advantageous features of these protocols
for development of novel routes to complex natural products.
Herein we describe construction of the multiply substituted
structure of (+)-lactacystin (1) by combined use of these two
powerful C(sp3)−H functionalizations.
Received: November 13, 2014
© XXXX American Chemical Society
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Letter
In planning the total synthesis, we correlated the C5−9 core
skeleton of 1 to the structure of commercially available (S)-
pyroglutaminol (2, Scheme 1). The chemo- and stereoselective
C(sp3)−H alkynylation of bicyclic lactam 3, prepared from 2,
was expected to occur at the most electron-rich N-substituted
C5-carbon to produce 4. Alkyne 4 would be converted to
1,2-diketone 5. Transfer of the two carbon unit of 5 to the most
electron-rich O-substituted C9-carbon would be attained by
utilizing the intramolecular C(sp3)−H acylation, leading to 6.
In this way, both the C5- and C9-functional groups would be
efficiently introduced by the C(sp3)−H functionalizations at
the correct oxidation levels. Once the highly substituted 6 is
obtained, the targeted 1 would be synthesized through standard
functional group manipulations at C4, 6, 7, and 10.
by changing the substrate from 3a to 3b, but the stereoselectivity
was moderate (dr at C5 = 4:1). To affect the stereochemical
outcome, one more stereocenter was introduced to 3b via base-
promoted methylation to produce 3c. When 3c was irradiated
by a mercury lamp in the presence of 1-tosyl-2-(trimethylsilyl)-
acetylene (1.5 equiv) and Ph2CO (0.5 equiv) in t-BuOH,
the C5-tetrasubstituted carbon of 4c was stereoselectively
constructed, and the subsequent desilylation of 4c gave rise to
terminal alkyne 7c in 54% yield over two steps. Therefore, the
stereochemical information at C5 that was once lost upon radical
formation was effectively regenerated by influence of the two
proximal stereocenters.15 The higher requisite stereoselectivity
from 3c than from 3b would be rationalized by considering the
two equilibrating conformers of the resultant tertiary radicals A
and A′. Since the unfavorable steric interaction between A′ and
the acetylene would be enhanced by the additional C7-methyl
group of 3c (R1 = Me), 4c is exclusively generated via the less
shielded radical A.
To realize the challenging chemo- and stereoselective C5-
alkynylation, the three bicyclic structures 3a−c were prepared
(Scheme 2). First, formation of the benzylidene acetal from
To prepare for the next stereoselective C(sp3)−H function-
alization, diketone 5c was synthesized from 7c (Scheme 3).
Scheme 2. Stereoselective C(sp3)−H Alkynylation
Scheme 3. Synthesis of the Key Intermediate 6c
Methylation of terminal alkyne 7c using LiN(SiMe3)2 and
MeOTf afforded 8. Internal alkyne 8 was then oxidized to
1,2-diketone 5c by the action of catalytic RuO2 and
stoichiometric NaIO4.16 Compound 5c was next irradiated
with a mercury lamp for the Norrish−Yang cyclization. However,
the reaction resulted in a complex mixture, presumably due to
undesired reaction pathways associated with concomitant
photoexcitation of monoketone 9 with UV light (<360 nm).
For selective photoactivation of the diketone moiety (λmax
=
(S)-pyroglutaminol (2) afforded 3a13 as a single stereoisomer.
The mixture of 3a, 1-tosyl-2-(trimethylsilyl)acetylene, and
Ph2CO was subjected to photoirradiation. Although the
alkynylated adduct 4a was indeed obtained, the yield was low
(7a, 12%) after removal of the Me3Si group. Not only the
electron-rich N-substituted methine but also the N,O-acetal
methine appeared to react with the photoexcited Ph2CO.
Therefore, the alternative substrate 3b with no acetal methine
was prepared through the acid-induced trans-acetalization
between 2 and acetophenone dimethyl acetal.14 The same
photoinduced alkynylation conditions transformed 3b into 4b in
62% yield. Thus, the chemoselectivity was significantly improved
433 nm) of 5c,17 a blue LED was alternatively applied because it
emits light of longer wavelength (approximately 460 nm) than
the mercury lamp. Consequently, compound 5c was smoothly
transformed into the cis-fused cyclobutanone 9 in a chemo- and
stereoselective manner. The site-selective H-abstraction of B at
C9 over C6 in this reaction reflected the more electron-rich
nature of the ethereal C(sp3)−H bond in comparison to the
aliphatic C−H bond. Finally, the oxidative ring-opening reaction
of 9 using Pb(OAc)4 and Na2CO3 resulted in ketoester 6c as
a single isomer in 66% yield over two steps.18 Hence, stereo-
selective introductions of the two vicinal C5- and C9-centers
were realized by the two C−H bond functionalizations.
B
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The highly branched structure of 6c was converted to
(+)-lactacystin (1) through homologation at C10, construction
of C6,7-stereocenters, and attachment of the cysteine moiety
(Scheme 4). Thus, olefination of the C10-ketone in 6c with
IR, and [α]D) were in complete agreement with those previously
reported.1b,5
In conclusion, a novel route to (+)-lactacystin (1) from (S)-
pyroglutaminol (2) has been established by judicious applica-
tion of intermolecular C−H alkynylation (3c → 4c) and intra-
molecular C−H acylation (5c → 6c). These reactions realized
unique C−C bond formations, which were otherwise difficult to
attain, and simplified the assembly of the branched carboskeleton
of 6c, which was efficiently derivatized into the targeted 1.
The present total synthesis demonstrates the high applicability
of the two C(sp3)−H functionalizations to form the complex
intermediates and the high predictability of their chemo-
selectivities (N-substituted > O-substituted > aliphatic carbons).
Further applications of these and other direct reactions9 for
construction of diverse structures of natural products and
pharmaceuticals are currently underway in our laboratory.
Scheme 4. Total Synthesis of (+)-Lactacystin
ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data for all new compounds and experimental
procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: inoue@mol.f.u-tokyo.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the Funding Program
for Next Generation World-Leading Researchers (JSPS), a
Grant-in-Aid for Scientific Research (A) and Nagase Science and
Technology Foundation to M.I., and a Grant-in-Aid for Young
Scientists (B) (JSPS) to M.N. A fellowship from JSPS to S.Y. is
gratefully acknowledged.
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