Total synthesis of the Galbulimima Alkaloid (-)-GB17

Article abstract of DOI:10.1002/anie.201108227

A tale of two Michaels: The first enantioselective total synthesis of (-)-GB17 is reported. Construction of this unique naphthoquinolizinone skeleton was achieved by two stereoselective intramolecular Michael additions, one under catalyst control and the other under substrate control. Copyright

Full text of DOI:10.1002/anie.201108227

Angewandte
Chemie
DOI: 10.1002/anie.201108227
Natural Product Synthesis
Total Synthesis of the Galbulimima Alkaloid (À)-GB17**
Reed T. Larson, Michael D. Clift, and Regan J. Thomson*
The Galbulimima alkaloids are isolated from the bark of
rainforest trees belonging to the Galbulimima genus that
grow in regions of Northern Australia, Papua New Guinea,
directed at preparing the more complex members of the
family. The first synthesis of GB13 (2) was reported by
Mander and MacLachlan in 2003, with subsequent reports
[6a]
[
1]
and Indonesia. Significant structural diversity exists within
from the groups of Movassaghi, Chackalamannil, Evans,
[
2]
[6b–f]
this alkaloid family, but common to all members is the
presence of a piperidine ring and a trans-decalin carbocylic
core (Scheme 1). Investigations into the biological activity of
the Galbulimima alkaloids have focused in large part on
himbacine (1): a potent muscarinic receptor antagonist that
might serve as a lead for the development of therapeutic
Sarpong, and Ma.
Himgaline (3) can be synthesized from
[
6c]
GB13 (2), as shown by the groups of both Chackalamannil
and Evans. Movassaghi and co-workers reported the only
synthesis of himandrine (4) in 2009, while the group of Ma
reported the only synthesis of GB16 (5) that same year. Our
interest was drawn to GB17 (6), which was one of 19 new
Galbulimima alkaloids whose isolation was reported by
[6d]
[7]
[
8]
[
3]
agents to treat Alzheimerꢀs disease. Himbacine-centered
research at Schering-Plough led to SCH 530348 (now Vor-
[
1a]
Taylor and co-workers in 1965.
At that time only an
[
4]
apaxar at Merck), a promising thrombin receptor agonist.
However, the clinical trial of SCH 530348 for the treatment of
acute coronary syndrome was halted in 2011 owing to adverse
side-effects.
elemental formula was reported; the structure of GB17 was
only revealed in 2009 when Mander and co-workers reported
[
2e]
an X-ray crystal structure. GB17 (6) possesses an unusual
naphthoquinolizinone ring system that is unique amongst the
family. We were drawn to the 1,4-dicarbonyl within 6 that we
[9]
hoped might be formed by oxidative enolate coupling.
Herein we report the first enantioselective total synthesis of
GB17 (6), through a concise and flexible strategy.
Our approach to GB17 (6) is outlined in retrosynthetic
format in Scheme 2. We envisioned the C8 ketone 7 as
a suitable precursor to 6 by way of carbonyl reduction and
Scheme 1. Selected Galbulimima alkaloids.
Scheme 2. Retrosynthetic analysis of (À)-GB17.
The combination of fascinating molecular structure and
significant therapeutic potential has made the Galbulimima
alkaloids attractive targets for total synthesis. While early
work focused on himbacine (1), most recent efforts have been
a late-stage oxidative enolate coupling to install the C17 2-
propanone substituent. This allowed for the retrosynthetic
clearing of several stereocenters and three of the compoundꢀs
four rings through application of two intramolecular Michael
additions. Thus, we arrived at aldehyde 10 as our first
subtarget on the way to GB17 (6).
[
5]
[*] R. T. Larson, M. D. Clift, Prof. R. J. Thomson
Department of Chemistry, Northwestern University
The conversion of aldehyde 10 into the desired trans-
cyclohexane 9 required the development of a stereoselective
catalyst-controlled intramolecular Michael addition. We
therefore conducted an initial model study utilizing readily
2145 Sheridan Rd, Evanston, IL 60208 (USA)
E-mail: r-thomson@northwestern.edu
[
**] This work was supported in part by Northwestern University (NU),
Amgen, and the National Institutes of Health (1R01GM085322). We
thank Prof. Lewis N. Mander (The Australian National University)
for providing an authentic sample of (À)-GB17.
[
10]
prepared aldehyde 12 (Scheme 3). Related catalytic intra-
molecular Michael additions had been reported for the
[
11]
analogous cyclopentanes by the groups of List and Hayashi.
A survey of several available organocatalysts revealed that
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108227.
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Scheme 3. Model study for the catalyst-controlled Michael addition.
a) Dimethyl 2-oxopropylphosphonate (1.3 equiv), LiCl (2.3 equiv),
iPr EtN (1.8 equiv), 91%; b) (COCl) (1.6 equiv), Me S(O) (4.2 equiv),
2
2
2
Et N (9.5 equiv), 89%; c) TsOH· H O (10 mol%), MgSO (2.6 equiv),
3
2
4
PhMe, 1008C, 91%. Ts=p-toluenesulfonyl, DCA=dichloroacetic acid,
TFA=trifluoroacetic acid.
Scheme 4. Synthesis of tetracyclic lactam 20. a) Dimethyl methyl-
phosphonate (2.1 equiv), n-BuLi (2.1 equiv); b) i. (Boc) O (3.0 equiv),
2
Et N (3.0 equiv), DMAP (9 mol%); ii. K CO (1.0 equiv), MeOH, 75%
3
2
3
[
12]
the diphenylprolinol derivative D
provided the highest
from 15; c) iPr EtN (2.0 equiv), LiCl (2.0 equiv), 11 (0.97 equiv), 99%;
2
levels of both diastereo and enantiocontrol for the synthesis
of cyclohexane 13 (20:1 d.r., 99% ee). We were able to
conduct this reaction on a 5 g scale using 5 mol% of D to
provide essentially quantitative yield of the carbocycle 13,
which could then be converted into the potentially useful
d) DMP (1.2 equiv), Py (7.0 equiv), 85%; e) cat. D (5 mol%), THF,
99%; f) methyl (triphenylphosphoranylidene)acetate (1.3 equiv), THF,
reflux, (91% from 10); g) KOtBu (15 mol%), MeOH, (80% of major
isomer); h) CF CO H; i) Cs CO (1.0 equiv), MeOH, reflux, 44% from
3
2
2
3
19. Boc=tert-butylcarbonyl, Py=pyridine, DMP=Dess–Martin period-
inane, TBS=tert-butyldimethylsilyl.
[13]
decalin synthon 14. Interestingly, very poor results were
obtained during attempts to carry out the intramolecular
Michael reaction without the dithiane present, an outcome we
interpret as arising from a lack of the favorable Thorpe–
by removal of the Boc group and cyclization using Cs CO in
2
3
[14]
[13]
Ingold effect that is present in dithiane 12. In contrast, the
methanol at reflux. X-ray analysis of a single crystal of 20
corresponding cyclopentane reactions reported by the groups
revealed that the Michael addition had proceeded with the
undesired sense of stereochemistry at C16 and that the C6
position of the piperidine had isomerized. 2D NMR studies
indicated that piperidine inversion occurred under the
lactamization conditions. Presumably, this isomerization pro-
ceeds through an E1cB elimination/conjugate addition
sequence of the b-disposed nitrogen; although this discovery
was potentially problematic for our synthesis, more pressing
was the issue of the C16 stereochemistry.
We had anticipated that the correct C16 stereochemistry
would be delivered from 18 by virtue of the enoate adopting
a pseudo equatorial conformation I (Scheme 5), but this leads
to unfavorable interactions with the piperidine ring, making
the axial conformer II more favorable. Based upon the model
proposed in Scheme 5, we hypothesized that the correspond-
ing cis-enoate might provide the desired C16 stereochemistry
via conformer III; the corresponding axial conformer IV
would now be significantly higher in energy because of severe
allylic strain. It also appeared that the carbamate protecting
group enforced a 1,3-diaxial relationship between the sub-
stituents of the piperidine ring, giving rise to unfavorable
steric interactions in the transition state leading to the desired
isomer of decalin 19. Therefore, it appeared to us that
[
11]
of List and Hayashi do not seem to require such an effect.
With this valuable insight into our proposed catalyst-
controlled cyclization, we began our GB17 (6) synthesis
(
Scheme 4). The enantioenriched phosphonate 16 was pre-
[
15]
pared from known cis-piperidine 15 in three steps. Con-
densation of 16 with the previously prepared aldehyde 11,
under Masamune–Roush conditions followed by oxidation,
delivered the desired aldehyde 10 and set the stage for the
first of our planned cyclization events. Exposure of aldehyde
[16]
1
0 to 5 mol% of organocatalyst D under our previously
developed conditions smoothly generated the desired trans-
substituted cyclohexane in excellent yield (99%). A Wittig
reaction of aldehyde 17 gave rise to the trans-enoate 18 in
high yield (91%) and with greater than 20:1 stereoselectivity.
This sequence (10 to 18) could be carried out in one pot with
no loss in yield or selectivity. At this juncture, we set out to
explore conditions to promote the second planned intra-
molecular Michael addition. Potassium tert-butoxide was
found to be effective for this reaction, affording the desired
decalin ring 19 in high yield and as a 16:2:1:1 mixture of
diastereomers. The major isomer could be readily separated
(
80% yield) and was converted into the tetracyclic lactam 20
2
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Scheme 5. Models for the intramolecular Michael addition.
a substrate possessing a cis-enoate and free piperidine
nitrogen would significantly favor the desired stereochemical
outcome.
Our modified approach commenced with a Still–Gennari
[
17]
olefination of aldehyde 17 to afford enoate 21 in 80% yield
after isolation (Scheme 6). Attempted cyclization of 21 using
potassium tert-butoxide gave rise to a mixture of stereoiso-
meric products, with the major product corresponding to the
same major isomer obtained from the cyclization of the trans-
enoate 18. This result confirmed our suspicions regarding the
impact of the Boc-group, and it was therefore removed by
treatment with TFA. While exposure of this free piperidine to
potassium tert-butoxide led to significant decomposition and
no desired cyclization products, the use of sodium methoxide
in methanol produced a remarkable transformation. Under
these conditions, the desired Michael addition proceeded
smoothly, and the intermediate ester 22 underwent lactam-
ization in situ to produce a product with the desired
tetracyclic framework (23). A combined yield of 70% of the
desired C16 isomers, differing only at C7, was obtained under
these conditions. X-ray crystallographic analysis established
Scheme 6. Synthesis of GB17. a) LiCl (2.0 equiv), iPr EtN (2.0 equiv),
methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]ethanoate (1.2 equiv),
2
8
0%; b) CF CO H; c) NaOMe (6.0 equiv), MeOH, 70% 23 and epi-23
3 2
from 21; d) NaHMDS (1.0 equiv), Tf NPh (1.1 equiv), 86%; e) Pd-
2
(OAc) (7 mol%), Ph P (14 mol%), HCO H (2.0 equiv), Bu N
2
3
2
3
(3.0 equiv), 99%; f) Selectfluor (2.5 equiv), 69%; g) NaBH
1.5 equiv); h) TBSCl (8.0 equiv), imidazole (16 equiv), DMF, 89%
over 2 steps; i) NaHMDS (4.5 equiv), 3-bromo-2-methylprop-1-ene
1.2 equiv), 75% 26 and 13% epi-26; j) Selectfluor (2.5 equiv), 66%;
k) NaBH (4.5 equiv), 99%; l) OsO (1.4 mol%), NMO (1.0 equiv);
4
(
(
4
4
NaIO (2.0 equiv), H O, 50%. HMDS=hexamethyldisilazide, Tf=tri-
4
2
fluoromethanesulfonyl, Selectfluor=1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), NMO=N-methyl-
morpholine N-oxide.
[
13]
the structure of 23, thereby unambiguously confirming the
stereochemistry of the Michael addition (Scheme 6). It there-
fore appeared that the C16 stereocenter of 23 was set via
conformer III (Scheme 5) as we had hypothesized, but also
that this stereochemistry allowed lactamization of 22 to
proceed without isomerization of the C6 piperidine stereo-
installation of the propanone substituent (61% from 24).
Disappointingly, our attempts to utilize oxidative enolate
coupling to install the propanone unit were met with
difficulties. We did not observe formation of the desired
[
18]
center.
Our endgame sequence called for conversion of the C8
7
,8
[21]
ketone within 23 and 7-epi-23 into the requisite D alkene.
This transformation was readily achieved by generation of the
corresponding enol triflate of 23 by the more thermodynami-
cally stable enolate, followed by palladium-catalyzed reduc-
adduct under a variety of conditions, and so made recourse
to an alternative strategy. We found alkylation of lactam 24
using NaHMDS and methallyl bromide provided the desired
product 26 in 75% yield, along with 13% of the undesired
axial epimer. Cleavage of the thioketal (66% yield), followed
by reduction using sodium borohydride, installed the requisite
equatorial C12 hydroxy group. Lastly, oxidative cleavage of
the methallyl group afforded synthetic GB17 (6), which was
[
19]
tion (80% yield of 24, two steps). Conversion of epi-23 into
the corresponding enol triflate was problematic. Fortunately,
we found that epi-23 could be equilibrated upon reexposure
to NaOMe to give a 3:2 mixture of 23 and epi-23, allowing for
easy recycling of material. From alkene 24, installation of the
equatorially disposed C12 hydroxy group proceeded first by
1
spectroscopically identical to a natural sample ( H NMR,
1
3
C NMR, and HRMS).
[20]
cleavage of the thioketal, then subsequent reduction of the
resulting ketone along the axial vector using sodium borohy-
dride. Protection of the hydroxy group as its tert-butyldime-
thylsilyl (TBS) ether 25 was carried out as a prelude to
Our stereoselective synthesis of the tetracyclic alkaloid
GB17 was executed through a route utilizing two intra-
molecular Michael additions to forge key stereochemical
elements. The development of the diphenylprolinol-catalyzed
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Communications
enantioselective intramolecular Michael addition was crucial
to the success of the synthesis, and will likely find further
applications for other natural product targets. The second
intramolecular Michael addition provided an example of the
profound effect enoate geometry can have during a substrate-
controlled conjugate addition. Future research on GB17
will focus on exploring its biological activity, which at this
time remains unknown.
[9] For recent examples of oxidative enolate coupling in natural
product synthesis, see: a) L. C. Konkol, F. Guo, A. A. Sarjeant,
R. J. Thomson, Angew. Chem. 2011, 123, 10105 – 10108; Angew.
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[
22]
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Received: November 22, 2011
Published online: January 27, 2012
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[
10] Prepared in three steps from dithiane; see the Supporting
Information for details.
Keywords: Galbulimima alkaloids · Michael addition ·
.
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1
1
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3
061 – 3064.
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9
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1
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2
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