Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: Formal synthesis of quinine

Article abstract of DOI:10.1039/c1ob05219e

Stereocontrolled Mn-mediated radical addition of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond disconnection of chiral amines. This strategy was examined in the context of a total synthesis of quinine, generating new findings of functional group compatibility leading to a revised strategy. Completion of a formal synthesis of quinine is presented, validating the application of Mn-mediated radical addition as a useful new C-C bond construction method for alkaloid synthesis. The Mn-mediated addition generates the chiral amine substructure of quinine with complete stereocontrol. Subsequent elaboration includes two successive ring closures to forge the azabicyclo[2.2.2]octane ring system of quincorine, linked to quinine through two known reactions.

Full text of DOI:10.1039/c1ob05219e

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Intermolecular radical addition to N-acylhydrazones as a stereocontrol
strategy for alkaloid synthesis: formal synthesis of quinine†‡
Gregory K. Friestad,* An Ji, Chandra Sekhar Korapala§ and Jun Qin¶
Received 10th February 2011, Accepted 8th March 2011
DOI: 10.1039/c1ob05219e
Stereocontrolled Mn-mediated radical addition of alkyl io-
dides to chiral N-acylhydrazones enables strategic C–C bond
disconnection of chiral amines. This strategy was examined
in the context of a total synthesis of quinine, generating new
findings of functional group compatibility leading to a revised
strategy. Completion of a formal synthesis of quinine is
presented, validating the application of Mn-mediated radical
addition as a useful new C–C bond construction method
for alkaloid synthesis. The Mn-mediated addition generates
the chiral amine substructure of quinine with complete
stereocontrol. Subsequent elaboration includes two succes-
sive ring closures to forge the azabicyclo[2.2.2]octane ring
system of quincorine, linked to quinine through two known
reactions.
Fig. 1 Structures of quinine, quinidine, and quinotoxine.
acylhydrazones A13 (Fig. 2b) and their use in a variety of
addition reactions under mild conditions,14,15 including additions
of carbon-centered radicals.16 In general, intermolecular radical
additions to imino compounds are attractive complements to polar
addition reactions for reasons of functional group compatibility.
Despite seminal work by Naito17 and Bertrand18 and others19
to develop such reactions, their strategic use for stereocontrol
in total synthesis of multifunctional natural product targets
is rare;20 such applications have been slow to emerge because
methods exhibiting versatility with respect to both radical and
acceptor are limited. On the other hand, the emergence of
Mn-mediated intermolecular radical additions has significantly
expanded the scope, enabling effective use of primary iodides
and precursors bearing electrophilic functionality in either of the
coupling components.21 Still, the intermolecular radical addition
to imino compounds has yet to be validated as a stereocontrol
strategy en route to a complex synthetic target. As an alkaloid
of some complexity and synthetic challenge, quinine presented
a worthy adversary against which to test the limits of this
reaction in a multifunctional molecular setting in natural product
synthesis.22
Our initial approach to quinine focused upon strategic appli-
cation of Mn-mediated hybrid radical–ionic annulation, a type
of radical–polar crossover reaction23 which we have reported
as an entry to piperidine and pyrrolidine synthesis.21a,21b,21e This
would entail intermolecular Mn-mediated radical addition (with
stereocontrol as indicated in Fig. 2c) using multifunctional iodide
B as the radical precursor for addition to hydrazone 1 (Scheme 1),
bearing the 6-methoxyquinoline group characteristic of quinine.
The piperidine annulation would then be completed via SN2-type
cyclization employing a suitable leaving group X. The alkene
would serve as a handle for a late-stage oxidative cleavage to unveil
a two-carbon bridge needed for construction of the quinuclidine
ring system.
The long-established antimalarial properties of quinine (Fig. 1)
fueled great interest in its synthesis since the very early days
of natural product chemistry, endowing quinine with special
historical importance in the field.1,2 Successful syntheses are high-
lighted by the Woodward–Doering formal synthesis of quinine in
1944,3 practical approaches to quinine and quinidine (Fig. 1) by
Uskokovic, Taylor, and Gates in the 1970s,4 and the first asym-
metric total synthesis of quinine as reported by Stork in 2001.5
More recently, syntheses by Jacobsen,6 Kobayashi,7 Williams (7-
hydroxyquinine),8 Krische,9 and Aggarwal10 have highlighted a
variety of strategies for construction of the azabicyclo[2.2.2]octane
ring system of quinine.
Quinine attracted our interest in the course of a program
to develop new C–C bond construction approaches to chiral
amines.11 While numerous indirect methods involving C–N bond
construction are available, an attractive alternative is a C–C
bond construction via addition to the C N bond of carbonyl
imino derivatives (Fig. 2a).12 We introduced novel chiral N-
Department of Chemistry, University of Iowa, Iowa City, Iowa, 52242.
E-mail: gregory-friestad@uiowa.edu
† Dedicated with gratitude to Professor Athel Beckwith for his seminal
contributions to understanding stereocontrol in free radical reactions.
‡ Electronic supplementary information (ESI) available: Characteriza-
tion data and selected experimental procedures (PDF). See DOI:
10.1039/c1ob05219e
§ Current Address: Syngene International, Bangalore, India
¶ Current Address: Merck-Kenilworth, Kenilworth, NJ, USA
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Fig. 2 Asymmetric radical addition in chiral amine synthesis. (a) Strategic
C–C bond disconnection. (b) The Mn-mediated radical addition to chiral
N-acyl hydrazones. (c) Stereocontrol model for radical addition to chiral
N-acyl hydrazones.
Scheme 2
to photolysis (Rayonet, 300 nm) in the presence of InCl3, but to
our dismay no coupling product was observed.
The anomalous failure of the Mn-mediated coupling of 1
and 5a led us to consider which structural features of the
chiral N-acyl hydrazone partner might be interfering with the
reaction. Mn-mediated radical additions of iodides containing
the silyl ether moiety had previously been successful in various
contexts,21b–e so we turned our attention to the functionalized
aryl unit. Its compatibility was addressed by a series of control
experiments with hydrazones 6a–6c and iodide 7 (Scheme 3).27
Successful Mn-mediated radical addition was observed with
hydrazones 6a and 6b, leading to the expected products 8a and
8b in moderate yield (ca. 40%). However, hydrazone 6c, now
containing the pyridyl unit, failed to undergo the Mn-mediated
Scheme 1
Testing this approach required the N-acylhydrazone of ho-
moquininaldehyde, prepared via homologation of quininalde-
hyde (3), which in turn was available from 6-methoxy-4-
methylquinoline (2).24 Oxidation of 2 according to Minisci
et al.25 afforded 3 in 77% yield (Scheme 2a). Wittig reaction with
(methoxymethyl)triphenylphosphorane and condensation with N-
aminooxazolidinone 4 delivered hydrazone 1 in low yield (22%, 2
steps). A more efficient route to 1 (Scheme 2b) was achieved via
sequential condensations of 6-methoxy-4-methylquinoline with
Bredereck’s reagent26 and N-aminooxazolidinone 4, furnishing
hydrazone 1 in 62% yield for two steps. Its proposed coupling part-
ner, radical precursor 5a, was prepared as previously described.22
The stage was set to attempt the key Mn-mediated coupling. A
mixture of hydrazone 1, iodide 5a, and Mn2(CO)10 was subjected
Scheme 3
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coupling reaction at all, consistent with the observations on
hydrazone 1. This indicated that the heteroaromatic nitrogen of the
quinoline substructure interfered with the Mn-mediated coupling
reaction.
some experimentation, it was found that cleavage of the N–N
bond prior to piperidine ring construction led to an efficient
overall process (Scheme 5). Successive treatment of 11 with n-BuLi,
TFAA, and SmI2 cleaved the N–N bond; Mitsunobu conditions
then completed the annulation sequence in an efficient manner,
albeit stepwise, furnishing piperidine 12 on 1.1 mmol scale. Next,
in preparation to forge the bicyclic quinuclidine ring system char-
acteristic of the cinchona alkaloids, hydrogenative debenzylation
of 12 (Scheme 5) afforded the corresponding vicinal diol; exposure
to sodium periodate and hydride reduction furnished diol 13 in
excellent yield.
The findings above, taken together with a separate series of
experiments demonstrating the detrimental effect of the alkene
functionality on yield,22 led to a revision of the strategy which en-
tailed two main changes (Scheme 4). First, the 6-methoxyquinoline
would need to be introduced during a later stage in the synthesis,
perhaps using an organometallic reagent prepared from 4-bromo-
6-methoxyquinoline,28 Second, the original late-stage C6–C7 bond
cleavage tactic (e.g., alkene ozonolysis) was changed to oxidative
cleavage of a vicinal diol, which would require oxidation of the
C6–C7 alkene prior to the radical addition.
(1)
To access the azabicyclic quinuclidine ring system, a group
selective cyclization of 13, possessing two nearly equivalent
hydroxyethyl substituents, was attempted. The diiodide 15 was
procured from diol 13 by a standard method (PPh3/I2), but when
cyclization was attempted in methanolic ammonia, the result was
a mixture of bicyclic tertiary amines 16 (eqn (1)) favoring an
undesired [3.2.1] bicyclic structure 16b.
Prior differentiation of the two hydroxyethyl groups would
be needed as a consequence of the undesirable selectivity in
cyclization of the diiodide. To this end, when diol 13 was exposed to
vinyl acetate in the presence of Candida antarctica lipase (Scheme
5), a 64% yield of a mixture of regioisomeric monoacetates 14a
and 14b was obtained in a 1 : 1.2 ratio, along with 32% of starting
material (94% yield based on conversion).
Scheme 4
Synthesis according to this revised plan required diastereoselec-
tive preparation of iodide 5b (Scheme 5), accomplished in seven
steps from enantiopure diester 9. As previously reported, the key
Mn-mediated coupling of 5b and 10 was achieved in 93% yield
using only a slight excess of the iodide radical precursor.22 This
prior result was a very attractive way to access adduct 11, but its
synthetic utility remained to be realized.
To convincingly demonstrate the utility of the foregoing Mn-
mediated coupling, conversion of adduct 11 to quinine (or a
known precursor to quinine) would be required. First, the radical–
ionic annulation was completed in a stepwise fashion. The SN2-
type cyclization of a tosylate derived from 11 proceeded to a
piperidine structure analogous to 12,22 but that material could
not be advanced due to difficulties in N–N bond cleavage. After
A regio-convergent approach was then adopted as a practical
way to make use of both monoacetates 14a and 14b; these were
both processed with the same set of standard transformations
(Scheme 6), converting both to the same bicyclic quinuclidine
Scheme 5
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free hydroxyl group to the corresponding iodide, cyclization
in methanolic ammonia, acetate saponification, and selenoxide
elimination to generate the vinyl group, producing 17 in 76%
overall yield. For 14b, essentially the same tactics were applied
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desilylation (TBAF), the material obtained from both sequences
was found to match an authentic sample of quincorine (18). Two
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to quinine, and this route therefore constitutes a formal synthesis.
In conclusion, a Mn-mediated radical–ionic annulation strategy
was validated as a synthetic route to quinine. Structural features
which interfere with the Mn-mediated radical addition were
uncovered via a series of control experiments, which guided
revision of the synthetic strategy. After completing the radical–
ionic annulation in a stepwise fashion, a problematic group-
selectivity issue was surmounted by a regio-convergent process
for assembling the quinuclidine ring system, completing a formal
synthesis of quinine. This synthesis of quinine offers the first
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Acknowledgements
We thank NIH (R01-GM67187), NSF (CHE-0749850) and the
University of Iowa for generous support of this work.
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