Gram-Scale Synthesis of the (?)-Sparteine Surrogate and (?)-Sparteine

Article abstract of DOI:10.1002/anie.201710261

An 8-step, gram-scale synthesis of the (?)-sparteine surrogate (22 % yield, with just 3 chromatographic purifications) and a 10-step, gram-scale synthesis of (?)-sparteine (31 % yield) are reported. Both syntheses proceed with complete diastereocontrol and allow access to either antipode. Since the syntheses do not rely on natural product extraction, our work addresses long-term supply issues relating to these widely used chiral ligands.

Full text of DOI:10.1002/anie.201710261

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Accepted Article
Title: Gram-Scale Synthesis of the (-)-Sparteine Surrogate and (-)-
Sparteine
Authors: James D Firth, Steven J Canipa, Peter O'Brien, and Leigh
Ferris
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10.1002/anie.201710261
Angewandte Chemie International Edition
COMMUNICATION
Gram-Scale Synthesis of the (–)-Sparteine Surrogate and (–)-
Sparteine
James D. Firth,[a] Steven J. Canipa,[a] Leigh Ferris[b] and Peter O’Brien*[a]
Abstract: An 8-step, gram-scale synthesis of the (–)-sparteine
surrogate (22% yield, with just 3 chromatographic purifications) and a
10-step, gram-scale synthesis of (–)-sparteine (31% yield) are
reported. Both syntheses proceed with complete diastereocontrol and
allow access to either antipode. Since the syntheses do not rely on
natural product extraction, our work addresses long-term supply
issues relating to these widely used chiral ligands.
to a greatly enhanced reactivity of the s-BuLi/sparteine surrogate
complex. For example, the high reactivity of the s-BuLi/sparteine
surrogate complex was required for one of the steps in Aggarwal’s
recently completed total synthesis of (–)-stemaphylline[12] and was
crucial for the high yielding lithiation-trapping of N-Boc
piperidine.[13]
Over the years, our group[10,14] and others[15] have explored
synthetic approaches to enantiopure (+)- and (–)-sparteine
surrogate. However, all approaches are either inconveniently long,
lack diastereo- and/or regioselectivity, only allow access to one
enantiomer and/or proceed with overall low yields. These
limitations have thus far precluded the synthesis of enantiopure
(+)- and (–)-sparteine surrogate on a gram-scale and addressing
this is the primary topic of this paper. In addition, in designing our
new approach to the sparteine surrogate, we also recognized that
it could also be adapted to deliver a new resolution-reconnection
strategy for the gram-scale synthesis of (–)-sparteine. Despite
numerous syntheses of racemic sparteine over 65 years,[16] there
are only two enantioselective syntheses (by Aubé[17] and our
group[18]) which delivered ~50 mg quantities of (+)- or (–)-
sparteine over long or low yielding approaches.
Our retrosynthetic analyses and design concepts are shown
in Scheme 1. We envisaged that the (–)-sparteine surrogate
would be derived from quinolizidine 3 via reduction and N-
methylation; the quinolizidine ring would be constructed from 2 by
deprotection and conjugate addition of the amine to the ,-
unsaturated nitrile, where we predicted that axial protonation of
the intermediate nitrile anion would set the required cis relative
stereochemistry for bispidine formation. Diastereoselective
alkylation (precedented with other electrophiles[19]) of piperidine
(R)-1 obtained by enzymatic resolution[20] would deliver nitrile 2.
The natural product sparteine and its structurally related
cousin, the sparteine surrogate (Scheme 1) developed in our
laboratory,[1] are widely used chiral ligands in asymmetric
synthesis. In particular, these diamines are the “go-to” chiral
ligands for organolithium bases such as s-BuLi[2] for use in
reactions pioneered in the 1990s by Hoppe[3] and Beak.[4] The
more recent work from the Aggarwal group on programmable
assembly-line synthesis[5] using chiral boron reagents (generated
from s-BuLi/chiral diamine-mediated asymmetric lithiations) has
significantly expanded the synthetic potential offered by sparteine
and the sparteine surrogate.
Both (–)- and (+)-sparteine are naturally occurring[6] and are
thus commercially available, although the availability of each
antipode has varied over the last 20 years![7] They can also be
obtained from the alkaloid lupanine via a resolution procedure,[8]
recently patented by Maulide et al.[9] In contrast, only the (+)-
sparteine surrogate is commercially available but, due to its high
price, it is best obtained by our group’s gram-scale synthesis from
the natural product (–)-cytisine.[10] The main issue with all of these
sources of sparteine/sparteine surrogate is that they rely on
natural product extractions and this can lead to supply issues (as
observed for (–)- and (+)-sparteine over the last few years).[7]
Indeed, during the development of the hepatitis C drug, Telaprevir,
researchers at Vertex rejected a process-scale route that used
the (+)-sparteine surrogate since “inquiries about long-term, high-
volume supply of (–)-cytisine had been met with concerns about
production variability, due mainly to reliance on (–)-cytisine
isolation from natural sources”.[11]
The lack of adoption of the (+)-sparteine surrogate by process
chemists at Vertex re-ignited our desire to develop a new
synthesis of the sparteine surrogate that would allow access to
both antipodes on a gram-scale. Furthermore, the sparteine
surrogate has a much broader synthetic scope than sparteine due
[a]
[b]
Dr. J. D. Firth, Dr. S. J. Canipa, Prof. P. O’Brien
Department of Chemistry
University of York
Heslington, York, YO10 5DD, UK
E-mail: peter.obrien@york.ac.uk
Dr. L. Ferris
AstraZeneca UK
Macclesfield, Cheshire, SK10 2NA, UK
Scheme 1. Retrosynthetic analysis of (–)-sparteine surrogate and (–)-sparteine.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201710261
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For (–)-sparteine, we realized that the two resolved
enantiomers of 1 could, if they were recombined, make up the
entire (–)-sparteine skeleton except for the bridging methylene
group. Therefore, separation and recombination of 1, with
methylene incorporation, would lead to a highly connective
synthesis of enantiopure (–)-sparteine from a simple racemic
starting material that had been resolved into its two enantiomers.
We anticipated that this resolution-recombination strategy should
improve the efficiency of our earlier (–)-sparteine synthesis which
proceeded via the same strategy.[18] In our planned route, (–)-
sparteine would be derived from bis-ester 5 by N-deprotection,
amide formation and reduction. A Michael reaction of the enolate
of (R)-1 and -unsaturated ester (S)-4 (itself crafted from (S)-1
with the extra methylene unit) would give bis-ester 5. The relative
stereochemistry in 5 would be assured if the reaction (enolate
Michael addition and enolate protonation) followed the same
diastereoselectivity as in enolate alkylations.[18,19]
relative stereochemistry of 2 was assigned based on Knight’s
precedent.[19] Subsequent Boc cleavage followed by an
intramolecular conjugate addition reaction between the resulting
amine and ,-unsaturated nitrile gave key quinolizidine 3 in 84%
yield (after chromatography) as a single diastereomer. The
relative
stereochemistry
was
identified
by
X-ray
crystallography.[21] Interestingly, quinolizidine 3 adopts a cis-
decalin conformation with the ester and nitrile substituents
adopting equatorial positions. Assuming that the nitrile anion
formed after conjugate addition adopts a conformation similar to
this X-ray structure, then axial protonation on the less sterically
hindered top face would account for the observed
diastereoselectivity.
With all three stereocentres set, we then formed the bispidine
framework of the (–)-sparteine surrogate. Selective reduction of
the nitrile of quinolizidine 3, with in situ generated nickel boride,
and concomitant lactamisation gave 8.[15c] The structure of 8 was
confirmed by single crystal X-ray diffraction[21] and clearly showed
the trans-decalin framework. Thus, ring flipping via nitrogen
inversion can allow the aminomethyl and ester groups to adopt
the required axial positions for cyclisation (compare with the X-ray
structure of 3). Next, methylation of lactam 8 with NaH and MeI
proceeded well, giving 9 in 72% (after chromatography) over 2
steps and completing the skeleton of the (–)-sparteine surrogate.
The optimized synthesis of the (–)-sparteine surrogate is
shown in Scheme 2. Using a known method,[14b,c] racemic ester
rac-1 was synthesised by pyridine hydrogenation and Boc
protection in 90% yield over 2 steps on a 30 g scale (no
chromatography, see SI for details). Using conditions optimized
from a related literature protocol,[20] treatment of ~10 g batches of
racemic 1 with lipase from Burkholderia cepacia, in a mixture of
THF and phosphate buffer (pH 7.0) at 35 °C, resulted in the
isolation (after simple filtration and aqueous work-up, no
chromatography) of acid (S)-6 (49%, 98:2 er) and enantiopure
ester (R)-1 (46%, >99:1 er).
Reduction of the lactam 9 initially proved problematic, with the use
[14a]
of LiAlH4
or borane[22] giving complex mixtures. Gratifyingly,
the use of DIBAL-H resulted in clean reduction of the lactam,
giving 3.5 g of the (–)-sparteine surrogate in 93% yield after
distillation. The optical rotation ([α]D –29.2 (c 1.0, EtOH)) mirrored
that of semi-synthetic (+)-sparteine surrogate ([α]D +29.7 (c 1.1,
EtOH)[10]). Of note, this gram-scale, fully diastereocontrolled
synthesis proceeded in 22% overall yield over 8 steps[23] from
commercially available materials, with only 3 chromatographic
separations and one distillation utilised.
With significant quantities of (R)-1 in hand, attention turned to
construction of the full carbon skeleton of the (–)-sparteine
surrogate. We initially explored the use of a bis-ester analogue of
3 but the end-game was less efficient than that via 3 (see SI for
details). Installation of the acrylonitrile and the accompanying
stereocentre was achieved through alkylation of the lithium
enolate derived from (R)-1 with 2-bromomethylacrylonitrile 7,[15c]
giving 2 in 93% yield (after chromatography) as a single
diastereomer, without any reduction in er. At this stage, the
Scheme 2. Multigram synthesis of the (–)-sparteine surrogate.
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10.1002/anie.201710261
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COMMUNICATION
Scheme 3. Total synthesis of (–)-sparteine.
diastereocontrolled synthesis of (–)-sparteine was completed in
10 steps (longest linear sequence[23]) in 31% yield.
We also used piperidines (S)-6 and (R)-1 in a total synthesis
of (–)-sparteine (Scheme 3); in this case, all intermediates except
5 were purified by chromatography. Acid (S)-6 was re-esterified
under Steglich conditions, giving (S)-1 in 94% yield. Next,
installation of the requisite methylene group was achieved
through the use of Eschenmoser’s salt. Enolization with LiHMDS
followed by trapping gave amine 10 as a single diastereomer in
92% yield. The relative stereochemistry in 10 has not been proven
but is likely to be as shown based on related alkylations (vide
infra). Methylation and DBU-mediated elimination gave ,-
unsaturated ester (S)-4 in 92% yield, with no racemization.
Disappointingly, all attempts to add an enolate derived from Boc-
protected (R)-1 to (S)-4 resulted in the generation of complex
mixtures of products. Therefore, we resorted to switching the
protecting groups. Benzyl protected piperidines (S)-11 and (R)-12
were obtained in 97% and 91% yields from (S)-1 and (R)-1
respectively. Gratifyingly, using conditions based on a related
example from the literature,[22] treatment of (R)-12 with LDA at –
78 °C before addition of ,-unsaturated ester (S)-11 led to a
successful Michael addition to give 5, with complete control over
the two newly-formed stereocentres. The stereoselectivity
presumably arises due to the Michael addition and protonation of
the intermediate enolate following the same sense of induction as
previously reported enolate alkylations.[18,19] Debenzylation of 13
under transfer hydrogenolysis conditions, was followed by in situ
bis-lactamisation (upon addition of K2CO3), giving lactam 13 as a
single diastereomer in 69% over 2 steps, on a gram-scale. The
relative stereochemistry was confirmed by single crystal X-ray
diffraction.[21] Amide reduction completed the synthesis of (–)-
sparteine, which was isolated as the bisulfate salt,[24] after
recrystallization, in 67% yield.[25] The optical rotation (of the free
base, [α]D –20.4 (c 1.0, EtOH)(lit.,[17] ([α]D –20.7 (c 1.8, EtOH))
confirmed that (–)-sparteine had been synthesied. Overall, this
In summary, we have presented a unified strategy for the
gram-scale synthesis of the (–)-sparteine surrogate and the lupin
alkaloid (–)-sparteine, with full control over relative and absolute
stereochemistry. The modular nature of the routes facilitates the
synthesis of either antipode of the sparteine surrogate and
sparteine and thus addresses any long-term supply issues
relating to these synthetically useful chiral ligands.
Acknowledgements
This work was supported by EPSRC (DTA), AstraZeneca and F.
Hoffmann-La Roche. We thank Adrian Whitwood and Sam Hart
for X-ray crystallography.
Keywords: Total synthesis • Alkaloids • Asymmetric synthesis •
N-ligands • Kinetic resolution
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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James D Firth, Steven J. Canipa, Leigh
Ferris, Peter O’Brien*
Page No. – Page No.
Gram-Scale Synthesis of the (–)-
Sparteine Surrogate and (–)-Sparteine
Supply and demand: The first gram-scale synthesis of the (–)-sparteine surrogate
and (–)-sparteine has been achieved. A convergent approach to the two diamines is
reported with (–)-sparteine being obtained through a resolution/recombination
strategy. This work addresses long-term supply issues relating to these widely used
chiral ligands.
This article is protected by copyright. All rights reserved.