Temporary restraints to overcome steric obstacles: An efficient strategy for the synthesis of mycalamideB

Article abstract of DOI:10.1002/anie.201003361

Restrain and release: A one-pot MukaiyamaMichael/epoxidation sequence introduced three stereocenters, an intramolecular isocyanate trapping produced a rigid 10-membered cyclic carbamate, and the selective opening of the cyclic carbamate was used to reveal

Full text of DOI:10.1002/anie.201003361

Communications
DOI: 10.1002/anie.201003361
Natural Products Synthesis
Temporary Restraints To Overcome Steric Obstacles: An Efficient
Strategy for the Synthesis of Mycalamide B**
John C. Jewett and Viresh H. Rawal*
In memory of Michael P. Cava
A fundamental concept in synthesis planning is
that of convergence. Rather than the incremen-
tal, step-by-step assembly of a linear synthesis, a
convergent route involves the assembly of two or
more advanced fragments of a molecule in a key
step, thereby reducing the arduousness of the
exercise. While desirable in principle, a conver-
gent path does not guarantee success. The steric
bulk associated with advanced fragments can
frustrate established reactions and thwart the
coupling step. Herein, we describe a convergent
synthesis of mycalamide B, wherein steric hur-
dles are overcome through the use of “chemical
handcuffs” to temporarily restrain portions of a
molecule, thereby enabling a coupling reaction
Scheme 1. Previous coupling approaches to mycalamide B. Bz=benzoyl.
that would otherwise fail.[1] We also demonstrate the success-
ful extension of our route to pederamine, the right-hand part
of pederin, to the more-oxygenated mycalamine system.
Sponges of the genus Mycale have yielded a diverse group
of intricate bioactive natural products.[2] Noteworthy among
these are the mycalamides, highly cytotoxic substances that
are members of the pederin family of compounds.[3] For
example, mycalamide B displays 0.6 nm and 1.3 nm antipro-
liferative activity against A549 and P388 cancer cell lines,
respectively.[4,5] Given their potent anticancer activities,
research groups from around the world have pursued the
chemical synthesis of the mycalamides and their related
natural products, and impressive successes have been
recorded.[6–8] Although creative routes have been developed
for the synthesis of the two halves of these molecules—the
pederic acid and the trioxadecalin parts—no solution has yet
been developed for the stereocontrolled coupling of the two
fully elaborated halves of mycalamides. At the heart of the
problem is that free mycalamine (3) readily epimerizes under
acidic, basic, and neutral conditions, eroding the stereochem-
ical information at the C10 position (Scheme 1), such that
acylation of a free mycalamine component with a pederic acid
derivative proceeds with modest selectivity at best.[9] On the
other hand, acylation of a carbamate-protected mycalamine
unit (e.g., 4) has been accomplished in a stereocontrolled
manner, but only with simpler electrophiles, not with the fully
elaborated pederic acid unit.[10] A solution to this coupling
difficulty would allow a truly convergent synthesis of the
natural product and open up the possibility of concise,
stereocontrolled syntheses of many members of the family,
as well as their analogues.
The route we envisioned for the synthesis of mycal-
amide B hinged on two key transformations: 1) the conver-
sion of dihydropyranone 7 into the highly functionalized
trioxadecalin framework of the mycalamine unit (Scheme 2)
and 2) the stereocontrolled coupling of mycalamine unit 4, or
a derivative thereof, with a pederic acid component (2;
Scheme 1). The successful realization of these two trans-
formations was expected to provide a route to mycalamide B
that would be significantly shorter than those reported
previously. A solution to the first of these processes was
incorporated in the design of our pederin synthesis, but that
for the second process was not evident at the outset.[8c]
Specifically, the Mukaiyama–Michael reaction of an appro-
priately substituted ketene-acetal with dihydropyranone 7
[*] J. C. Jewett, Prof. Dr. V. H. Rawal
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: vrawal@uchicago.edu
Homepage: http://rawalgroup.uchicago.edu
[**] Generous financial support from the National Cancer Institute of
the NIH (R01 CA101438) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003361.
Scheme 2. Retrosynthetic analysis of the mycalamine unit. MOM=
methoxymethyl, TBS=tert-butyldimethylsilyl.
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was expected to give silylenol ether 6, the epoxidation and
further elaboration of which would pave the way to mycal-
amine unit 5. An efficient strategy to 5 was expected to
provide ample material for overcoming the acylative-coupling
hurdle.
The required dihydropyranone was synthesized in five
steps from commercially available benzyl-(S)-glycidyl ether
(8; Scheme 3). Vinyl-cuprate addition to 8, protection of the
free hydroxy group with TIPSCl, and a Johnson–Lemieux
Scheme 4. Synthesis of the trioxadecalin core. m-CPBA=meta-chloro-
perbenzoic acid.
introduced stereocenters relative to the enantiomerically
pure starting material, 8.[15,16]
The next hurdle that had to be crossed before arriving at
the coupling precursor was reduction and methylation of the
C13 ketone. Selective reduction of the ketone was expected to
be challenging, based on consideration of the steric and
electronic factors in the two interconverting chair–chair
conformations of 14. Indeed, borohydride reduction pro-
ceeded with complete selectivity for the undesired dia-
stereomer. On the other hand, Meerwein–Ponndorf–Verley
(MPV) reduction, carried out by gently heating the reaction
mixture, gave the desired alcohol as the only diastereomer,
albeit as the isopropyl ester (Scheme 5).[17] Methylation of the
alcohol had to be carried out under neutral conditions using
silver oxide in methyl iodide to avoid epimerization of the
C10 stereocenter.[18] In preparation for the key coupling step,
the ester was hydrolyzed and the resulting acid was trans-
formed by the Curtius rearrangement and trapping to give the
Teoc-protected mycalamine unit 16. Disappointingly, but in
accord with earlier reports,[6c] all attempts to acylate 16 with
pederic acid chloride (2b) were unsuccessful. The failure of
this acylation step stands in contrast to the analogous
acylation used successfully in our synthesis of pederin.[8c]
Scheme 3. Synthesis of dihydropyranone 11. Bn=benzyl, HMDS=
hexamethyldisilazide, THF=tetrahydrofuran, TIPS=triisopropylsilyl,
Tf =trifluoromethanesulfonyl, TMS=trimethylsilyl.
oxidative cleavage of the vinyl unit provided aldehyde 9. The
formal hetero-Diels–Alder reaction between aldehyde 9 and
Danishefsky-type diene 10 was promoted using Yamamotoꢀs
MAD Lewis acid in conjunction with TMSOTf and afforded
the expected dihydropyranone in good yield and with high
diastereoselectivity.[11–13] Quenching the reaction mixture with
aqueous acid gave the free alcohol directly, which was
methylated in a separate step to furnish dihydropyranone 11.
Further elaboration of dihydropyranone 11 to the densely
functionalized mycalamine core was achieved in a highly
efficient manner and with good diastereoselectivity. Initial
studies showed that the Mukaiyama–Michael reaction of
MOM-protected silylketene acetal 12[14] with dihydropyra-
none 11 proceeded in 5 minutes at À788C using TBSOTf as a
catalyst. However, the expected silylenol ether product (cf. 6)
was accompanied by significant amounts of the corresponding
ketone. After some experimentation, it was found that rather
than isolating the intermediate enol ether, it could be
epoxidized in situ to afford silyl epoxide 13 in good yield
and high diastereoselectivity (Scheme 4). Interestingly, the
epoxide was sufficiently stable so as to allow its purification
by chromatography. This one synthetic operation set four new
stereocenters, three of which are retained in the final product,
and installed most of the required parts of mycalamine. Silyl
epoxide 13 was treated with P2O5 in dimethoxymethane and
acetonitrile to arrive at trioxadecalin 14, the X-ray structure
of which confirmed the arrangement of all the newly
Scheme 5. Synthesis of mycalamine unit and attempted coupling.
Teoc=2-(trimethylsilyl)ethoxycarbonyl, DPPA=diphenylphosphoryl
azide.
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hypothesis that the cyclic carbamate would over-
come the steric issues encountered by us and
others and, for the first time, allowed access to the
full mycalamide framework with complete control
of the aminal stereocenter. Although the coupling
reaction was an important step towards the natural
product, the selective hydrolytic cleavage of the
carbamate unit over the amide was critical to
completing the synthesis. Hydrolysis of the latter
would separate the two units that had been so
painstakingly assembled. Consideration of known
reactivity patterns did not provide clear direction
on the relative electrophilicity of the two carbonyl
groups toward nucleophiles, although the amide
carbonyl group was expected to be more reactive.
For example, N-acyloxazolidinones are known to
react primarily at the amide carbonyl, although the
steric environment around the amide carbonyl can
reverse the expected chemoselectivity.[22] Exami-
nation of the molecular model of 19 showed the
carbamate carbonyl to be constrained and steri-
cally more-accessible to nucleophilic attack than
Scheme 6. The handcuff solution for overcoming steric obstacles.
Our analysis of the above problem and a possible solution
are illustrated in Scheme 6. In both pederamine and mycal-
amine, the dialkoxypropyl “arm” is expected to be oriented
toward the pyran oxygen, so as to avoid the gem-dimethyl
group. However, whereas the deprotonated nitrogen atom in
pederamine can freely rotate away from the blocking arm into
an orientation that allows acylation, the mycalamine nitrogen
is locked by the dioxane ring. Conceptually, if the arm could
be constrained—or handcuffed—to the amine, then the
nitrogen would be forced to point outwards, making it
accessible to the acylating agent. The plan was to tie the
nitrogen to the interfering propyl side chain through a 10-
membered cyclic carbamate linkage. In addition to restraining
the molecule, the cyclic carbamate would protect both the
amine and the alcohol, and increase the acidity of the former
for the acylation step.[19] Not only are such cyclic carbamates
uncommon, but the desired compound is also quite rigid and,
ignoring the dioxane ring, represents an example of a system
having “inside-outside” stereoisomerism.[20]
The above concerns notwithstanding, synthesis of the
cyclic carbamate was straightforward (Scheme 7). Hydro-
genolysis over palladium hydroxide on carbon cleanly
removed the benzyl group from the C18 hydroxy group.
Saponification of the ester followed by treatment with
diphenylphosphoryl azide (DPPA) and triethylamine pro-
vided the acyl azide, which underwent the Curtius rearrange-
ment upon heating.[21] The resulting isocyanate, 18, was
intercepted intramolecularly by the primary alcohol to
cleanly provide the sought-after cyclic carbamate. To the
best of our knowledge, this is the first 10-membered cyclic
carbamate employed in an organic synthesis exercise.
With tricycle 17 in hand, we turned our attention to its
coupling with pederic acid. We were delighted to find that
deprotonation of 17 with LiHMDS followed by acylation with
pederic acid chloride 2b gave the desired product (19,
Scheme 7). The success of the acylation confirmed our
Scheme 7. Coupling and synthesis of mycalamide B. DMAP=4-(dimethyl-
amino)pyridine.
the amide carbonyl. In addition, the C7 hydroxy group that
resulted from hydrolysis of the benzoate group was expected
to favor the desired pathway through intramolecular addition
and transacylation to the carbamate carbonyl. Indeed, we
found that removal of the benzoyl group and opening of the
carbamate occurred upon treatment with lithium hydroxide in
the presence of lithium chloride in methanol, thus giving us
mycalamide B (1) with a small amount of recovered 17.[23]
To summarize, we have developed a stereocontrolled
synthesis of mycalamide B, the cornerstone of which is the use
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[7] The only previously reported total syntheses of mycalamide B
of temporary restraints to enable coupling of the fully
elaborated mycalamine and pederic acid units. The total
synthesis requires 14 steps from commercially available
starting materials in the longest linear sequence and proceeds
in 2.6% overall yield. In addition, the synthetic route features
1) a one-pot Mukaiyama-Michael/epoxidation sequence to
introduce three new stereocenters found in the natural
product, 2) the intramolecular trapping of the isocyanate
from a Curtius rearrangement to produce a rigid, bridged 10-
membered cyclic carbamate, and 3) the selective opening of
the cyclic carbamate over hydrolysis of the amide linkage.
This strategy is expected to enable the synthesis of other
members of this large family of highly cytotoxic natural
products well as provide rapid access to significant quantities
of these compounds for biological and target identification
studies.
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Received: June 3, 2010
Published online: October 7, 2010
[9] For examples of this coupling strategy for the trioxadecalin core
see, Refs. [6a,b,d], and [8a,b,d].
[10] For examples of this coupling strategy for the trioxadecalin core,
see Refs. [6c,e], [7a,b], and [8f].
Keywords: amides · Diels–Alder reaction · Mukaiyama–
Michael reaction · mycalamide B · natural products
.
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[15] For a similar acetal formation, see Ref. [7a] and the references
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