Total synthesis of (+)-korupensamine B via an atropselective intermolecular biaryl coupling

Article abstract of DOI:10.1021/ja1065202

The asymmetric total synthesis of nonracemic korupensamine B is reported. It includes a newly designed and highly trans-diastereoselective (>20:1 dr) route to the tetrahydroisoquinoline ring and an unprecedented atropdiastereoselective Suzuki-Miyaura coupling for construction of the fully fashioned naphthylisoquinoline framework that invokes π stacking as a possible source of stereocontrol.

Full text of DOI:10.1021/ja1065202

Published on Web 09/17/2010
Total Synthesis of (+)-Korupensamine B via an Atropselective Intermolecular
Biaryl Coupling
Shenlin Huang, Tue B. Petersen, and Bruce H. Lipshutz*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received July 23, 2010; E-mail: lipshutz@chem.ucsb.edu
Abstract: The asymmetric total synthesis of nonracemic koru-
pensamine B is reported. It includes a newly designed and highly
trans-diastereoselective (>20:1 dr) route to the tetrahydroiso-
quinoline ring and an unprecedented atropdiastereoselective
Suzuki-Miyaura coupling for construction of the fully fashioned
naphthylisoquinoline framework that invokes π stacking as a
possible source of stereocontrol.
Michellamine B (1), the heterodimerization product of atropdi-
astereomeric korupensamines A (2) and B (3), has received
considerable attention as a potent anti-HIV-1 and -2 agent (Figure
1).1 Korupensamines A and B, which were originally isolated
from the Cameroonian liana Ancistrocladus korupensis,2 have
Figure 1. Selected naphthyltetrahydroisoquinoline alkaloids.
a naphthyltetrahydroisoquinoline skeleton with axial chirality
between the naphthalene and tetrahydroisoquinoline (THIQ) rings
Scheme 1. Proposed Intermediate 7 in Biaryl Construction
and are presumed to be biosynthetic precursors to the michel-
lamines.3 Both 2 and 3 themselves exhibit good antimalarial
activities in vitro and in vivo.1,2a Although their antimalarial
properties are no longer being pursued, these targets nonetheless
represent a considerable synthetic challenge in stereocontrolled
intermolecular biaryl construction between highly functionalized
precursors. To date, stereoselective syntheses of either 2 or 3,
notably from the laboratories of Bringmann, Hoye, Kelly, and
Uemura, have been completed via indirect routes in which either
the naphthyl ring or the THIQ ring is installed after formation
of the biaryl bond.4 Alternatively, literature reports describing
the formation of the biaryl nucleus directly have led to dr’s in
the range of 1.5:1.4f-i In 1999, we reported a stereospecific,
intermolecular biaryl-coupling approach to the biaryl nucleus
in 2.5 In continued efforts directed toward this class of natural
products, we now report an asymmetric total synthesis of (+)-3
featuring a stereocontrolled biaryl coupling between the highly
functionalized naphthyl and THIQ subsections.
Our strategy for the synthesis of 3 was based on the potential
for intramolecular π-stacking interactions as a source of stereo-
control in the key Suzuki-Miyaura cross-coupling reaction
(Scheme 1). Such a phenomenon has been invoked previously
to potentially account for other types of highly stereoselective
transformations in asymmetric synthesis.6 In this case, it was
speculated that intramolecular π stacking between the electron-
rich THIQ and electron-deficient aryl ester of 5 would orient
one face of the THIQ ring as in 7, thereby positioning the bulky
triisopropylsilyl (TIPS) ether to avoid steric interactions with
ligands L in a square-planar array around the metal. The net
effect would be to encourage formation of biaryl 6 with M axial
chirality.
Bringmann toward a related naphthylboronic acid4a,7 (Scheme 2;
also see the Supporting Information).
Scheme 2. Synthesis of Naphthylboronic Acid 4a
The synthesis of THIQ 10 commenced with commercially
available 1-bromo-3,5-difluorobenzene (11). Nucleophilic aromatic
substitution provided bromobenzene 12 (Scheme 3). A copper-
catalyzed opening of known (R)-TIPS-glycidol8 with the Grignard
reagent derived from 12 led to alcohol 13. Mitsunobu inversion9
in 13 with phthalimide followed by hydrazinolysis furnished the
Naphthylboronic acid 4a was prepared from commercially
available 5-benzyloxy-2-bromobenzaldehyde (8) via the known
halonaphthol precursor 9,5 using a modification of a route by
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10.1021/ja1065202  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 14021–14023 14021

C O M M U N I C A T I O N S
Table 1. M:P Ratios from Suzuki-Miyaura Couplings of 4a with
nonracemic primary amine, which was further converted to for-
mamide 14. Bischler-Napieralski cyclization10 using POCl3 in
combination with 2-methylpyrazine11 afforded the corresponding
imine in 73% yield. Treatment of the imine with MeMgCl in Et2O
initially at low temperature delivered 15 in 85% isolated yield with
excellent trans diastereoselectivity (>20:1 dr). By contrast, the
alternative route used previously involving the corresponding
acetamide analogue of 14 and its subsequent reduction with LiAlH4/
AlMe3 or Ru-catalyzed hydrogenation led to poor trans:cis ratios
(e2:1 or <1:20, respectively). N-Sulfonylation and subsequent
regiospecific iodination were accomplished without incident. Desi-
lylation followed by esterification with 1-naphthoic acid provided
coupling partner 10. Other benzoic esters 17a-h were synthesized
in a similar fashion for cross-coupling studies (also see the
Supporting Information).
17a-ha b
,
Scheme 3. Synthesis of Tetrahydroisoquinoline 10a
a 4a, 17a-h, Pd(OAc)2, SPhos, K3PO4, rt. b M:P ratios were
determined by HPLC (Dupont Instruments Zorbax Sil 4.6 mm × 25
cm).
Scheme 4. Testing the Effect of π Stacking with Acetate 17i
a Conditions: (a) NaOBn, NMP, 100 °C, 91%; (b) Mg, THF, reflux; CuI
(cat.), (R)-triisopropylsilyl glycidyl ether, THF, 64%; (c) Ph3P, phthalimide,
DIAD, THF; NH2NH2 ·H2O, EtOH, reflux, 74%; (d) AcOH, HCO2Et, reflux,
quant.; (e) POCl3, 2-methylpyrazine, CH2Cl2, 0 °C to rt, 73%; (f) MeMgCl,
Et2O, -78 °C to rt, 85% (trans:cis >20:1); (g) TsCl, Et3N, DMAP, CH2Cl2,
88%; (h) CH(OMe)3, I2, PhI(O2CCF3)2, CH2Cl2, -10 to 0 °C, 2 h, 94%; (i)
TBAF, THF, 97%; (j) 1-naphthoic acid, EDCI, DMAP, Et3N, CH2Cl2, 92%.
Abbreviations: Bn ) benzyl, NMP ) 1-methyl-2-pyrrolidinone, DIAD )
diisopropyl azodicarboxylate, TsCl ) p-toluenesulfonyl chloride, DMAP
) 4-N,N-dimethylaminopyridine, TBAF ) tetra-n-butylammonium fluoride,
EDCI ) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
The effectiveness of the proposed Suzuki-Miyaura cross-
coupling reaction was examined using various aryl-containing esters
(R in 17a-h; Table 1) of model methyl ether analogues. These
were designed to test several potential factors [e.g., internal
hydrogen bonding (17a), steric effects (17c), and extended conjuga-
tion (17g, 17h)] in a variety of polar media. The atropdiastereo-
selectivity12 was highest for the bulkier 1-naphthyl ester 17g (vs
the 2-naphthyl case, 17h) in solvents such as n-BuOH (M:P ) 9:1)
and CH3NO2 (M:P ) 8:1), while alcohols either shorter (n-PrOH,
M:P ) 8:1) or longer than four carbons (1-hexanol, M:P ) 5:1)
did not offer any advantages. In nonpolar solvents, the ratios were
noticeably less pronounced (e.g., THF, M:P ) 3:1; toluene, M:P
) 2:1). Interactions of a π-stacking nature may account for the
observed selectivity. Coupling of the corresponding non-aromatic
acetate derivative 17i (R ) Me) with either boronic acid 4a or its
TBS (rather than TIPS) analogue 4b led to a 1:1 ratio of M and P
isomers under otherwise identical reaction conditions (Scheme 4).
The coupling of 4a and 10 as partners en route to korupensamine
B could be further optimized (Table 2). Although biaryl formation
proceeded smoothly using the conditions described by Buchwald
[Pd(OAc)2, SPhos, THF, rt],13 an initial screening gave a 1:1
mixture of M and P atropisomers (entry 1). The atropdiastereose-
lectivity was improved to M:P ) 9:1 when the reaction was run in
n-BuOH (entry 2). Eventually,14 the combination of PdI2/SPhos/
K3PO4 in n-BuOH was identified as the best (M:P ) 11:1; entry
3), leading to pure 19 in 72% isolated yield after chromatographic
separation. Other ligands (entry 4) or branching in the alcoholic
medium (s-BuOH; entry 5) led to low yields of product.
After the naphthylisoquinoline framework in 19, including all
of the stereocenters in the natural configuration, had been assembled,
the remaining transformations focused mainly on deoxygenation
of the two side chains and ultimately on removal of the N-tosyl
protecting group. Coupling product 19 was first transformed into
diol 20 via saponification and then desilylation (Scheme 5). After
hydroxyl-to-halogen exchange by treatment with (Cl2BrC)2/Ph3P,15,16
a two-step sequence involving debromination of 21 with Zn
(nanopowder) in acetic acid at 40 °C followed by removal of the
17
tosyl group with LiAlH4 led to tri-O-benzylated korupensamine
B (22).18 Hydrogenolysis of crude 22 afforded korupensamine B
(3), [R]2D3 ) +68.0 (c 0.182, MeOH; lit.2a +65, c 0.76, MeOH),
which was found to be identical in all respects to natural2 and
previously synthesized material.4
In summary, the asymmetric total synthesis of (+)-korupen-
samine B (3) has been completed in 7% overall yield, with a longest
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C O M M U N I C A T I O N S
Table 2. Optimization of Suzuki-Miyaura Coupling Between 4a
and 10a
Note Added after ASAP Publication. Table 2 footnote contained
an error in the version published ASAP September 17, 2010; the correct
version and an updated SI file were reposted September 22, 2010.
Supporting Information Available: Experimental procedures,
copies of spectral data, and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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entry
catalyst
solvent
M:Pb
yield (%)c
1
2
3
4
5
Pd(OAc)2, SPhos
Pd(OAc)2, SPhos
PdI2, SPhos
Pd(t-Bu3P)2
Pd(OAc)2, SPhos
THF
1:1
9:1
11:1
10:1
n.d.d
n.d.d
52
72
31
30
n-BuOH
n-BuOH
n-BuOH
s-BuOH
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Scheme 5. Completion of the Synthesis of Korupensamine B (3)a
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linear sequence of 18 steps from commercially available materials.
Prominent features of this route include (i) a two-step sequence
from formamide 14 to give tetrahydroisoquinoline 15 with note-
worthy trans diastereoselectivity (>20:1 dr) and (ii) an unprec-
edented atropdiastereoselective Suzuki-Miyaura biaryl coupling
(up to 11:1 dr) for construction of the naphthylisoquinoline
framework in polar media that invokes π-stacking interactions as
a potential source of stereocontrol.
(10) Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903–1908.
(11) The choice of base is crucial. A very low yield of the desired dihydroiso-
quinoline was obtained using 2,6-lutidine as the base.
(12) The diastereomers can be separated by chromatography in most cases, and
the stereochemistry can be assigned by saponification to the reported
compound. See the Supporting Information. Also see ref 5.
(13) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685–4696.
(14) Other solvents (CH3NO2, CH3CN, DME, and dioxane) were examined using
Pd(OAc)2/SPhos as the catalyst, but only traces of coupling product were
observed in each case.
(15) Bringmann, G.; Schneider, S. Synthesis 1983, 139–141.
(16) KOAc was added to avoid partial debenzylation.
(17) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999,
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Acknowledgment. Prof. Masahito Segi (Kanazawa University)
and Prof. Takashi Nishikata (Kyushu University) are thanked for
their contributions to this project. We are indebted to Prof. Gerhard
Bringmann (Wurzburg) for supplying reference spectra on natural
korupensamine B.
(18) The structure of tribenzylated korupensamine B (22) was confirmed by
transformation into the known tetrabenzylated korupensamine B: Hobbs,
P. D.; Upender, V.; Dawson, M. I. Synlett 1997, 965–967.
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