Asymmetric total synthesis of (+)-merobatzelladine B

Article abstract of DOI:10.1002/anie.201201001

Putting the syn in synthesis: The first total synthesis of (+)-merobatzelladineB was accomplished using an iterative sequence of stereoselective palladium-catalyzed alkene carboamination reactions for formation of two of the three rings. This represents a new strategy for the generation of polycyclic guanidine natural products, and provides access to compounds with a synrelationship between the C6 hydrogen atom and the C8 alkyl group. Copyright

Full text of DOI:10.1002/anie.201201001

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Angewandte
Communications
DOI: 10.1002/anie.201201001
Alkaloid Synthesis
Asymmetric Total Synthesis of (+)-Merobatzelladine B**
Nicholas R. Babij and John P. Wolfe*
Polycyclic guanidine natural products, such as batzelladi-
nes A, E, and F, exhibit a rich and diverse array of interesting
biological activities (Figure 1).[1,2] Some polycyclic guanidine
alkaloids have been shown to inhibit protein–protein inter-
actions, including the binding of HIV gp120 to CD4 on human
T-cells. Furthermore, many polycyclic guanidines display
potent antiviral, antimalarial, and immunosuppressive prop-
erties.
that differs from other members in this family. The C8 alkyl
substituents in merobatzelladines A and B are positioned in
a syn relationship with the C6 hydrogen atoms, whereas other
related natural products, such as batzelladines A, E, or F (1–
3), have these groups positioned in an anti relationship.
Merobatzelladines A and B exhibit moderate antimicrobial
activity against Vibrio anguillarum, and also show inhibitory
activity against the K1 strain of Plasmodium falciparum
(IC50 = 0.48 mgmLꢀ1 and 0.97 mgmLꢀ1, respectively). Given
the rich biological activity of the related batzelladine
alkaloids, it is possible that merobatzelladines A and B may
exhibit additional useful properties that have yet to be
reported.
Because of the importance of polycyclic guanidine
alkaloids, several different approaches have been employed
for the synthesis of these compounds. The most widely
utilized routes typically generate the fused ring system
through condensation reactions,[4] cycloaddition reactions,[5]
radical cyclizations,[6] or substitution reactions.[7] Although
these routes have proven highly useful, none provide a means
ꢀ
for the generation of a C C bond adjacent to the ring (such as
the C8’-C4H9 bond in 5) during the ring-closing event. Also,
none of these routes have been employed for the generation
of molecules with a syn relationship between the C8 alkyl
group and the C6 H atom, such as that found in merobatzel-
ladines A and B. Herein, we describe the first total synthesis
of merobatzelladine B (5) utilizing a new strategy for the
construction of polycyclic guanidine alkaloids that provides
the natural product as a single stereoisomer in high optical
purity.
Our approach to the synthesis of merobatzelladine B
centered on the use of Pd-catalyzed alkene carboamination
reactions for the formation of two of the three rings in the
natural product.[8] As shown in Scheme 1, we envisioned that
a Pd-catalyzed carboamination between vinyl bromide and an
Figure 1. Polycyclic guanidine natural products.
In 2009, Matsunaga et al. reported the isolation of
merobatzelladines A and B (4 and 5) from the marine
sponge Monanchora sp. (Figure 2).[3] These compounds are
members of a new subclass of the batzelladine alkaloids that
possess the signature tricyclic guanidine core common to all
batzelladines, but display a unique stereochemical feature
appropriately functionalized g-aminoalkene derivative
6
Figure 2. Merobatzelladine alkaloids.
[*] N. R. Babij, Prof. J. P. Wolfe
Department of Chemistry, University of Michigan
930 N. University Ave, Ann Arbor, MI 48109-1055 (USA)
E-mail: jpwolfe@umich.edu
[**] The authors acknowledge the NIH-NIGMS (GM 098314) and the
University of Michigan Associate Professor Support Fund for
financial support of this work. Additional funding was provided by
GlaxoSmithKline and Amgen.
Scheme 1. Iterative carboamination strategy for polycyclic guanidine
synthesis. LG= leaving group, R=p-methoxybenzyl (PMB) or
p-methoxyphenyl (PMP) protecting group.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201001.
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would generate cis disubstituted pyrrolidine 7 with high
stereocontrol. A second carboamination reaction between
allylpyrrolidine derivative 8 and 1-bromo-1-butene would
afford bicyclic product 9, which could then be transformed
into the polycyclic guanidine natural product 5 through
functional group interconversion and ring-closure by an
intramolecular SN2 reaction.
Our prior studies on Pd-catalyzed alkene carboamination
reactions have illustrated that the conversion of N-Boc-g-
aminoalkenes (Boc = tert-butoxycarbonyl) to 2,5-disubsti-
tuted pyrrolidines typically proceeds in good yield with
greater than 20:1 diastereoselectivity favoring the
cis isomer.[8,9] As such, the transformation of 6 to 7 appeared
quite feasible; however, the likelihood of success in the
planned Pd-catalyzed carboamination between 8 and an
alkenyl halide was less clear. The generation of six-membered
rings by Pd-catalyzed carboamination is considerably more
difficult than the formation of five-membered rings,[10] and
this has not previously been accomplished with an unsatu-
rated urea substrate.[11] To test the feasibility of this key
transformation, we examined the Pd-catalyzed carboamina-
tion of 2-allylpyrrolidine-derived urea 11 with simple aryl and
alkenyl halides. After optimization of conditions, we found
that a catalyst consisting of [Pd2(dba)3] and PCy3 (Cy =
cyclohexyl) provided satisfactory results in these reactions
(Scheme 2). The bicyclic urea products 12a and 12b were
Scheme 3. Synthesis of g-aminoalkene 19. Bn=benzyl, Boc=tert-
butoxycarbonyl, KHMDS=potassium hexamethyldisilazide.
lenging,[14] and after examining many different reducing
agents we found that the combination of NaBH4 and CeCl3
led to formation of 18 with 3:1 diastereoselectivity. However,
the two diastereomers were separable by column chromatog-
raphy, and 18 was isolated as a single stereoisomer in 63%
yield. Protection of the alcohol as a benzyl ether, followed by
exchange of the sulfinyl group for a Boc group provided 19
with 99% ee in 91% yield over three steps.
With intermediate 19 in hand, the key sequence of
carboamination reactions was undertaken (Scheme 4). The
Scheme 4. Carboamination reaction sequence for bicyclic urea con-
struction. TFA=trifluoroacetic acid, TMS=trimethylsilyl.
Scheme 2. Synthesis of bicyclic ureas by Pd-catalyzed carboamination.
Cy =cyclohexyl, dba=dibenzylideneacetone.
obtained in good yield and high diastereoselectivity, which
may arise from cyclization through a boat-like transition state
13.[10b,c,12] The alternative boat-like transition state 14, which
leads to the minor diastereomer, appears to suffer from
significant steric interactions between the alkene and the
pyrrolidinyl ring. Moreover, cyclization through a chair-like
Pd/P(2-furyl)3-catalyzed carboamination of 19 with E-2-
bromovinyltrimethylsilane provided pyrrolidine 20 in 68%
yield and with excellent stereocontrol (> 20:1 d.r.).[15] Treat-
ment of 20 with trifluoroacetic acid (TFA) led to cleavage of
the Boc group and protodesilylation of the alkene. The
resulting pyrrolidine was coupled with p-methoxybenzyliso-
cyanate to generate pyrrolidinyl urea 21 in 72% yield over
two steps.[16] The Pd/PCy3-catalyzed carboamination of 21
with (Z)-1-bromo-1-butene proceeded smoothly to yield
bicyclic urea 22 in 91% yield and greater than 20:1 d.r.
Bicyclic urea 22 was converted into guanidinium salt 23 in
89% yield by treatment with POCl3 followed by addition of
ammonia (Scheme 5).[17] The tetrafluoroborate counterion
was introduced during the workup procedure by washing
a dichloromethane solution of the crude guanidine product
with aqueous NaBF4. This anion exchange was essential to
transition state appears to be less accessible because of poor
[10b,c]
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overlap between the alkene p system and the Pd N bond.
Having illustrated the feasibility of our approach to the
generation of fused bicyclic ureas, we undertook the synthesis
of merobatzelladine B by constructing an appropriately
functionalized g-aminoalkene derivative for the pyrrolidine-
forming carboamination. As shown in Scheme 3, the amine-
bearing stereocenter was generated by a highly efficient
asymmetric Mannich reaction of sulfinyl imine 16.[13] The
stereocontrolled reduction of ketone 17 proved quite chal-
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Scheme 5. Completion of the synthesis. DIAD=diisopropyl azodicar-
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avoid complications during the subsequent ring-closing
step.[18] Guanidinium salt 23 was then transformed into the
natural product 5 in a three-step sequence involving initial
hydrogenation with Pd/C to reduce the alkene followed by
cleavage of the benzyl ether protecting group. Ring closure
was achieved through an intramolecular Mitsunobu reac-
tion.[7a] Subsequent removal of the p-methoxybenzyl (PMB)
group provided merobatzelladine B (5) in 41% yield over
three steps from 23. The synthetic alkaloid was obtained in an
23
enantiopure form (½aꢁD ¼ + 40.1 (c = 0.7, MeOH); Ref. [3]:
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23
½aꢁD ¼ + 27 (c = 0.15 MeOH)), and NMR spectra of 5 were
identical to the data previously reported for the natural
product.[3]
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In summary, we have developed the first asymmetric total
synthesis of (+)-merobatzelladine B (5), which confirms the
structural and stereochemical assignments of the natural
product. Our route afforded the desired alkaloid in 15 steps
and 6.7% overall yield from commercially available pent-4-
enal (15). The results described above represent a fundamen-
tally new strategy for the stereocontrolled synthesis of
polycyclic guanidine natural products. This new approach
allows for formation of a carbon–carbon bond during the ring-
closing event, and is the first route shown to provide access to
alkaloids with a syn relationship between the C6 hydrogen
atom and the C8 alkyl group. This strategy could potentially
be employed to access other guanidine alkaloids that contain
this stereochemical feature, and could also be used for the
generation of novel analogs of the batzelladine alkaloids.
Furthermore, this work also illustrates the feasibility of
forming 5,6-fused bicyclic urea ring systems through Pd-
catalyzed carboamination, which could be of value for the
preparation of other interesting biologically active hetero-
cycles.
[15] 2-Bromovinyltrimethylsilane was used in place of vinyl bromide
because of the volatility of the latter compound.
[16] The p-methoxybenzyl (PMB) protecting group was employed
because it is relatively easy to remove, as compared to the
p-methoxyphenyl (PMP) group used in the model study.
[17] This transformation must be conducted under rigorously anhy-
drous conditions to avoid HCl-mediated side reactions.
[18] Use of the analogous guanidinium chloride salt in the ring-
closing Mitsunobu reaction led to the formation of a chlorinated
side product resulting from the substitution of chloride for
hydroxide. A diastereomeric side product resulting from double
inversion at C1 was also formed. Use of the BF4 salt prevented
the formation of these side products.
Received: February 7, 2012
Published online: March 16, 2012
Keywords: alkaloids · asymmetric synthesis · natural products ·
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palladium · total synthesis
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