Angewandte
Chemie
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]
ꢀ
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-
Angew. Chem. Int. Ed. 2012, 51, 4128 –4130
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4129