A new reaction motif: "Homo-SN2′-like" direct nucleophilic addition to neutral η3-allylmolybdenum complexes. Total synthesis of the antimalarial (+)-isofebrifugine

Article abstract of DOI:10.1021/ja9056322

(Chemical Equation Presented) Charge neutral TpMo(CO)₂(5- acyloxy-η³-pyranyl) and TpMo(CO)₂(5-acyloxy- η³-pyridinyl) scaffolds undergo a novel intermolecular "homo-S_N2C-like" reaction with a variety o

Full text of DOI:10.1021/ja9056322

Published on Web 08/10/2009
A New Reaction Motif: “Homo-SN2′-Like” Direct Nucleophilic Addition to
Neutral η3-Allylmolybdenum Complexes. Total Synthesis of the Antimalarial
(+)-Isofebrifugine
Wenyong Chen and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory UniVersity, 1515 Dickey DriVe, Atlanta, Georgia 30322
Received July 8, 2009; E-mail: chemLL1@emory.edu
Enantiomerically pure, air- and moisture-stable TpMo(CO)2(η3-
Scheme 1. Nucleophilic Functionalization of Neutral
TpMo(CO)2(η3-pyranyl/pyridinyl) Complexes
pyranyl) and TpMo(CO)2(η3-pyridinyl) complexes, 1 and 2 (Scheme
1), are powerful scaffolds for the enantiocontrolled construction
of substituted heterocycles.1 Readily available in multigram
quantities,1m they not only provide new bond construction strategies
to access a variety of natural products but also constitute platforms
from which to explore novel reactivity. A survey of the literature
shows that a TpMo(CO)2-stabilized carbocation is a requisite
intermediate in almost all synthetic transformations of the
scaffolds.1a-i,k,l,n It was only recently that a new, noncationic
pathway taking place through the direct nucleophilic addition of
an internal enolate to a terminal π-carbon of a neutral 5-oxo-η3-
pyranyl (and pyridinyl) moiety was reported.1j,o This synthetically
useful 1,5-Michael-like functionalization mode was explained, in
part, by the tendency of TpMo(CO)2 systems to favor six-coordinate
over seven-coordinate structures2 and also because the nucleophilic
addition generates a characterizable anionic TpMo(CO)2 intermedi-
ate (5 in Scheme 1), which possesses three good π-back-bonding
ligands to delocalize the anionic charge: 2 terminal CO’s and the
η2-enone ligand. These observations led us to wonder if the
preference for six-coordinate over seven-coordinate structures alone
would be sufficient to enhance a more general nucleophilic addition
pathway by which TpMo(CO)2(η3-allyl) systems that are less-
activated than the 5-oxo-η3-pyranyl/pyridinyl complexes could be
functionalized. Following these considerations, we report herein
the first examples of the “homo-SN2′-like” intermolecular nucleo-
philic substitution of charge neutral TpMo(CO)2(5-acyloxy-η3-
pyranyl) and TpMo(CO)2(5-acyloxy-η3-pyridinyl) complexes (3 and
4,Scheme1).Thismechanisticallynewenantiocontrolledcarbon-carbon
bond forming reaction occurs enantiospecifically with excellent anti
stereoselectivity.
The homo-SN2′-like process does not appear to proceed by way
of an in situ generated Mo-stabilized carbocation that is then trapped
by the nucleophile. Exposure of 3a to TrPF6 generates the
molybdenum-stabilized carbocation 15, which upon treatment with
sodium dimethylmalonate and 15-crown-5-ether shows a different
reaction profile from the reactions in Table 1: only 18% of
nucleophilic addition compound 6 is produced (Scheme 2). The
reaction mostly forms the elimination product 16 in 55% yield.
Additional observations are consistent with the postulate of direct
attack of the nucleophile at the neutral η3-allylmolybdenum moiety:
(1) compound 3a is recovered unchanged after stirring overnight
in THF/Et3N; (2) the homo-SN2′-like substitution reaction proceeds
faster with less substituted substrates: both 3b and the acetate
corresponding to 3b (S2 in the Supporting Information) are faster
reacting than the more substituted 3a; and (3) most reactions are
significantly accelerated by the use of 15-crown-5 ether.
Table 1. “Homo SN2′-Like” Substitution Reactions
The requisite substrates 3a-c, 4a,b (Table 1) are prepared in
high yields from the readily available TpMo(CO)2(5-oxo-η3-
pyranyl) and TpMo(CO)2(5-oxo-η3-pyridinyl) complexes 1 and 2
through hydride or Grignard reagent addition to the carbonyl group
followed by acylation.3 Initial experiments were conducted on the
racemic forms of TpMo(CO)2(5-acetoxy-η3-pyranyl) and Tp-
Mo(CO)2(5-acetoxy-η3-pyridinyl) complexes. Treatment of
3a-c,4a,b with anionic carbon nucleophiles (pKa range ) 13.3-18.0
in DMSO)4 in the presence of catalytic 15-crown-5 ether afforded
substitution products 6-14 in good to excellent yields (Table 1).
Moreover, as indicated in entry 1, the use of the high enantiopurity
scaffold 3a led to the corresponding substitution product without
loss of enantiopurity. Reactions of carbanions generated from
precursors that are more acidic than dimethyl malonate benefited
from the use of acetonitrile rather than THF as solvent (compare
entry 2 and 3). When R on the scaffold is hydrogen, higher product
yields were obtained using p-nitrobenzoate rather than acetate as
the leaving group.
entry
reactant
NuH
solvent
% yield
1
2
3
4
5
6
7
8
9
10
3a
3a
3a
3a
3a
3b
3b
3c
4a
4b
CH2(COOMe)2
THF
ACN
THF
6, 99a
7, 69(99)b c
,
CH3COCH2COOMe
CH3COCH2COOMe
CH3CH(COOEt)2
CH3NO2
CH3COCH2COOMe
CH3COCH2COMe
CH2(COOMe)2
7, 31(99)b c
,
THF
8, 66(94)b
9, 80d
DMSO
ACN
ACN
THF
ACN
ACN
10, 94c
11, 68
12, 90
CH2(COOMe)2
CH3COCH2COOMe
13, 94
14, 91c
a 96% ee product from 96% ee starting material. The enantiopurity
was determined by chiral HPLC. b The number in the parentheses is the
yield based on the recovery of starting material. c An approximate 1.5:1
ratio of diastereomers was observed according to crude NMR. d No
15-crown-5-ether was added.
9
12546 J. AM. CHEM. SOC. 2009, 131, 12546–12547
10.1021/ja9056322 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Enantiocontrolled Synthesis of (+)-Isofebrifuginea
Scheme 2. Control Experiment: Reaction of
Molybdenum-Stabilized Carbocation 15 with Sodium Dimethyl
Malonate
An X-ray crystal structure of 8 (Table 1) unambiguously
established direct anti nucleophilic attack at the neutral η3-
allylmolybdenum (details are provided in the Supporting Informa-
tion). In contrast some Mo-catalyzed allylic alkylations occur
through a metal-centered attack,5 and Green has disclosed results
consistent with the direct attack of a nucleophile at the molybdenum
moiety of a neutral η3-lactonylmolybdenum complex.6
a (a) NaH, CH3COCH2SO2Ph, DMSO, rt, overnight then NaH, Cu(eth-
ylhexanoate)2, air, overnight. (b) (1) 10% Na/Hg,THF/MeOH, Na2HPO4,
-35 °C to rt; (2) HCl, acetone. (c) PtO2, H2. (d) TIPSCl, imidazole, DMF.
(e) (1) TMSOTf, TEA, DCM then NBS; (2) 4-hydroxyquinazoline, NaH,
THF, 15-C-5. (f) 6 M HCl, reflux, 90 min.
Acknowledgment. ThisworkwassupportedbyGrantGM043107,
awarded by National Institute of General Medical Sciences, DHHS.
We thank colleague Dr. Kenneth Hardcastle for his skilled and
efficient assistance with X-ray crystallography.
A represenative sampling of product molybdenum complexes
were cleanly converted to bicyclic annulation products in high yields
and with excellent stereoselectivity (Table 1). For example,
treatment of 7, 10, 11, and 14 with NaH in DMSO in the presence
of a catalytic amount of copper(II) 2-ethylhexanoate7 open to air
provided the annulation products 17-20 in 83-92% isolated yields
(Table 2). In earlier work, Pearson used different nonbasic
annulative demetalation reagents such as I28 or NOBF49 for related
transformations, but exposing our substrates to these reagents (as
well as prolonged standing in CDCl3) yielded only the undesired
elimination product (i.e., 16, Scheme 2) through ionization of the
carbon nucleophile10 and subsequent proton loss. Mechanistically,
we suggest that the reactions of Table 2 proceed through one-
electron oxidation of the stabilized enolate to a radical11 that then
reacts with the adjacent η3-allylmolybdenum moiety.
Note Added after ASAP Publication. Due to a production error
the graphics in Tables 1 and 2 were incorrect in the version published
ASAP August 10, 2009; the correct version was published ASAP
August 14, 2009.
Supporting Information Available: Experimental procedures,
synthesis and characterization of all new compounds and X-ray
crystallographic studies of 8, scanned copies of 1H and 13C NMR spectra
of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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The synthetic potential of this methodology was demonstrated
by an asymmetric synthesis of the antimalarial alkaloid (+)-
isofebrifugine (Scheme 3).12
Upon treatment of high enantiopurity (+)-4b3 in one pot with
phenyl sulfonyl acetone anion in DMSO followed by a copper-
catalyzed annulative demetalation, the bicyclic product (-)-21 was
obtained in good yield without loss of enantiopurity. Desulfony-
lation with 10% Na/Hg and an acidic workup afforded the hemiketal
(+)-22 in 86% yield. Hydrogenation on PtO2 yielded (+)-23 which
was subjected to standard TIPS protection conditions to furnish
(+)-24 selectively in 75% yield (along with the recovery of 20%
of the starting material). The ketone (+)-24 was monobrominated
by subjecting its in situ generated silyl enol ether to NBS. The
crude R-bromoketone was directly treated with 4-hydroxyquinazo-
line to afford (+)-25. Finally, deprotection with 6 M HCl delivered
20
(+)-isofebrifugine, 26, in 63% yield ([R]D ) +129, c ) 0.3,
CHCl3, Lit.12a [R]D ) +131, c ) 0.35, CHCl3).
20
(7) Other oxidants including CuCl2, Cu(acac)2, MnO2, Pb(OAc)4, and ceric
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entry
reactant
Z
EWG
R
% yield
1
2
3
4
7
O
O
O
COOMe
COOMe
COMe
Me
H
H
17, 85
18, 83
19, 92
20, 83
10
11
14
NCbz
COOMe
H
JA9056322
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J. AM. CHEM. SOC. VOL. 131, NO. 35, 2009 12547