An Asymmetric Synthesis of Hamigeran B via a Pd Asymmetric Allylic Alkylation for Enantiodiscrimination

Article abstract of DOI:10.1021/ja0497025

A protocol for the asymmetric allylic alkylation of a five-membered ring ketone derivative that employs the lithium enolate in the presence of lithium alkoxides gave high yields and enantioselectivities. This product serves as a versatile intermediate as demonstrated in a convergent total synthesis of the antiviral agent hamigeran B. The sequence involves two unusual observations. In the intramolecular Heck reaction which establishes the complete ring sytem, the β-H elimination step occurs both endocyclic (as expected) and exocyclic, the latter most surprising since it creates an exocylic tetrasubstituted double bond. In the catalytic hydrogenation, use of Pd/C gives complete selectivity for net delivery of hydrogen to the most hindered face of the substrate, whereas use of Ir black gives complete selectivity for delivery of hydrogen to the least hindered face. Such unusual behavior speaks to the unusual chemical properties associated with hamigeran B which may be relevant to its biological activity. Copyright

Full text of DOI:10.1021/ja0497025

Published on Web 03/18/2004
An Asymmetric Synthesis of Hamigeran B via a Pd Asymmetric Allylic
Alkylation for Enantiodiscrimination
Barry M. Trost,* Carole Pissot-Soldermann, Irwin Chen, and Gretchen M. Schroeder
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received January 16, 2004; E-mail: Bmtrost@stanford.edu
Table 1. Pd AAA of Enol Ether 4a
Hamigeran B (1), a metabolite isolated from the poecilosclerid
sponge Hamigera tarangaensis Bergquist and Fromont, exhibits
entry
t-butanol
temp (°C)
yield (%)
ee (%)
1
00% virus inhibition against both herpes and polio viruses with
1
2
3
4
5
none
none
1 equiv
3 equiv
7 equiv
7 equiv
0
-60
rt
rt
rt
rt
93
80
85
86
87
83
12
29
15
79
91
95
1
only slight cytotoxicity throughout the host cells. Its structural motif
combined with the biological activity stimulates the development
of a practical synthesis that can facilitate exploration of the chemical
biology of such structural types represented by these scarce natural
products. Nicolaou reported the first as well as asymmetric synthesis
utilizing a novel [4 + 2] photocycloaddition from N-tert-butyl-2-
methoxy-p-toluamide. During the course of our studies, Clive
reported a racemic and an asymmetric synthesis, the latter from
R-butyrolactone and 2-bromo-6-methoxy-p-tolualdehyde. Our in-
b
6
a
All reactions were performed with 1.1 equiv of allyl acetate
5a, 1 equiv of trimethyltin chloride, 2 equiv of LDA, 2.5 mol % of
2
3
b
3
[η -C3H5PdCl]2, and 5 mol % (S,S)-ligand. For this run, 1 mol %
3
[
η -C3H5PdCl]2 and 2 mol % (S,S)-ligand were used.
4
terest stemmed from the question of whether setting the stereo-
chemistry of the quaternary center from which all the remaining
stereocenters may evolve might be achievable by a Pd-catalyzed
asymmetric allylic alkylation (AAA) of a ketone enolate derived
from 4 (see Scheme 1). In this communication, we report the results
effect (entry 3), addition of 3 equiv quickly put the reaction back
into the range of the first results (entry 4). Increasing the amount
to 7 equiv returned the ee to >90% (entry 5). Interestingly,
decreasing the catalyst loading saw a further increase in the ee (entry
5
6). This last set of conditions is very robust and scales up nicely.
Scheme 1. Retrosynthetic Analysis
With asymmetric alkylation resolved, attention turned to imple-
menting a synthesis of hamigeran B (Scheme 2). To obtain the
Scheme 2. Synthesis of Substrate 2 for Heck Reactiona
of this latter study which then led to an effective convergent
approach to hamigeran B. During the course of this study, we
uncovered a most unusual dependence of diastereoselectivity in a
heterogeneous catalytic hydrogenation.
6
Alkylation of the lithium enolate of 4 was examined under
conditions developed earlier for six-membered ring ketones (eq 1).7
a
(
a) As in Table 1, entry 6, 77%, 93% ee. (b) (CH3)2CuLi, ether, -20
°
C, 89%. (c) LDA, PhN(SO2CF3)2, THF, 87%. (d) cat. OsO4, NMO, THF,
H2O then add NaIO4. (e) i. DME, -55 °C. ii. Dess-Martin periodinane,
NaHCO3, CH2Cl2, rt, 75% from 7. (f) BCl3, CH2Cl2, -20°, 86%. (g) 10
mol % Pd(OAc)2, 20 mol % dppf, HCO2H, (C2H5)3N, DMF, 70°, 94%. (h)
(CF SO ) O, CH Cl , pyridine, 0 °C, 94%.
Initially, the results were very encouraging. At room temperature,
the reaction gave the alkylated product 6 in 61% yield and 64%
ee. At -20 °C, the ee rose to an astonishing 92-96%. However,
upon switching to a fresh bottle of n-butyllithium to generate LDA,
repetition of the reactions led to ee’s of 5-12% (Table 1, entry 1).
Lowering the temperature increased the ee somewhat (entry 2) but
still far from the earlier results. Speculating that the earlier bottles
of n-butylithium had higher levels of lithium alkoxide led to the
addition of tert-butyl alcohol, which should form a relatively non-
nucleophilic alkoxide. While 1 equiv of tert-butyl alcohol had little
3
2 2
2
2
stereochemistry assigned to hamigeran B, the mirror image alkyla-
tion was performed simply by changing the chirality of the ligand.
The versatility of the alkoxymethylene group is illustrated by its
direct conversion to the isopropyl compound 7 upon treatment with
8
lithium dimethylcuprate. While, in principle, quenching with a
triflating agent should allow direct formation of the vinyl triflate
8, the isolated ketone was converted to the vinyl triflate in a separate
4480
9
J. AM. CHEM. SOC. 2004, 126, 4480-4481
10.1021/ja0497025 CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
step. Oxidative cleavage of the double bond completes the synthesis
of one-half of hamigeran B.
selenium dioxide and bromination completes the sequence (eq 4).
Comparison of the data to that previously reported1 confirmed
their identity.
-4
Direct reaction with lithiated dimethyl orcinol 9 followed by
oxidation with the Dess-Martin periodinane gave the full carbon
count of the target. With the vision that the last C-C bond would
9
be formed by an intramolecular Heck reaction, the vinyl triflate
was reductively cleaved to alkene 12 and the aryl ether was
converted to the requisite aryl triflate 2. The Heck reaction produced
two isomeric alkenes, 14 and 15, in addition to the expected alkene
1
3, surprisingly, since it involves a highly strained tetrasubstituted
In summary, a new class of nucleophiles allows asymmetric
allylation of five-membered rings in high yield and enantioselec-
tivity. The importance of the nature of the nucleophile on the
enantioselectivity is highlighted by the critical dependence on the
presence of lithium alkoxides, which presumably affects the nature
of the enolate clusters. The virtue of this class is revealed by a
double bond exocyclic to the ring. Use of carbonate rather than
tertiary amine bases minimizes the problem of simple hydrogenoly-
sis of the triflate. With either dppe or dppp as ligands,1 the desired
alkene 13 was isolated in 42-48% yield, which increased to 58%
with dppb.11
0
15-step asymmetric synthesis of hamigeran B from 2-methylcy-
clopentanone in 10% overall yield. The unusual nature of the
structure is highlighted by two abnormal reactivities: first, the
formation of an exocyclic tetrasubstituted double bond during the
Heck studies and second, the high propensity to give net reduction
of the trisubstituted double bond of 13a from the more hindered
face. The orthogonality between the thermodynamic and kinetic
control in hydrogenation by choice of catalyst is noteworthy.
Hydrogenation from the least hindered face (see Figure 1) to
give the desired stereochemistry of C-6 seemed to be straightfor-
ward. To avoid reduction of the carbonyl group, the free phenol
Acknowledgment. We thank the National Institutes of Health
(GM-13598) and the National Science Foundation for their generous
support of our programs. Dr. Carole Pissot-Soldermann thanks the
Swiss National Science Foundation and La Soci e´ t e´ de Secours des
Amis des Sciences, and Mr. Irwin Chen and Dr. Gretchen M.
Schroeder thank the U. S. National Science Foundation for
fellowships. We thank Prof. D. Clive for experimental details
regarding the bromination step.
Supporting Information Available: Full experimental procedures
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 1. Conformational Depiction of Phenol 13a.
3 2 2
was liberated with BBr (CH Cl , -78 °C). Upon hydrogenation
over Pd/C, a single diastereomer did result. X-ray crystallography,
however, revealed the product 16 to have exclusively the C-6 epi
configuration (eq 3, path a).
References
(
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(
(
(
(
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(
6) Derived in one pot from reaction of 2-methylcyclopentanone with ethyl
4 9
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4
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(
(
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11) After completion of our work, Mehta reported a strategy similar to ours
that resulted in a synthesis of 6-epi-hamigeran B. In his intramolecular
Heck reaction, he reports a 2:1 mixture of 13 and the simple hydrogenoly-
sis product in a total 55-60% yield but does not report the tetrasubstituted
olefin. See: Mehta, G.; Shinde, H. M. Tetrahedron Lett. 2003, 44, 7049.
12) (a) Nishimura, S.; Mochizuki, F.; Kobayakawa, S. Bull. Chem. Soc. Jpn.
(
Hypothesizing that this product must arise by an equilibration
in the semihydrogenation intermediate because the final reductive
(
(
elimination step is too slow, attention turned to iridium since it is
1
970, 43, 1919. (b) Nishimura, S.; Sakamoto, H.; Ozawa, T. Chem. Lett.
known to minimize such equilibrations.1
2,13
Gratifyingly, hydro-
1973, 855.
13) Mehta and Shinde report that variation of catalyst did not resolve the
unfavorable diastereoselectivity of the hydrogenation but fail to record
what catalysts were tried.
genation once again proceeded with complete diastereoselectivity
eq 3, path b). X-ray crystallography confirmed the correct
stereochemistry as in structure 17 for all centers. Oxidation with
(
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