Synthetic studies toward galbulimima alkaloid (-)-GB 13 and (+)-GB 16 and (-)-himgaline

Article abstract of DOI:10.1002/asia.201000556

Condensation of (S)-3-aminobutan-1-ol with 1,3-cyclohexane-dione followed by an intramolecular alkylation afforded bicyclic enamine 32, which was converted into enone 35 through a diastereoselective hydrogenation. Mukaiyama-Michael addition of a bicyclic

Full text of DOI:10.1002/asia.201000556

DOI: 10.1002/asia.201000556
Synthetic Studies toward Galbulimima Alkaloid (À)-GB 13 and (+)-GB 16
and (À)-Himgaline
Weiwei Zi, Shouyun Yu, and Dawei Ma*[a]
Dedicated to Professor Eiichi Nakamura on the occasion of his 60th birthday
Abstract: Condensation of (S)-3-ami-
nobutan-1-ol with 1,3-cyclohexane-
dione followed by an intramolecular al-
kylation afforded bicyclic enamine 32,
which was converted into enone 35
through a diastereoselective hydroge-
nation. Mukaiyama–Michael addition
of a bicyclic silyl enol ether to 35 and
subsequent stereochemistry inversion
by means of an oxidation/reduction
strategy provided lactone 41. After re-
duction of lactone 41 with LAH, Swern
oxidation was carried out to give enone
46 upon a spontaneous intramolecular
aldol reaction and cleavage of the ketal
protecting group. SmI2-mediated car-
bonyl–alkene reductive coupling of 46
proceeded smoothly in refluxing tetra-
hydrofuran to deliver pentacyclic inter-
mediate 49, which was oxidized with 2-
iodoxybenzoic acid and then treated
with trifluoroacetic acid to furnish (À)-
GB 13. The overall yield was 6.1%
over 19 linear steps. By following the
known procedure, our synthetic (À)-
GB 13 was converted into himgaline.
In addition, by starting from lactone
41, the first total synthesis of (+)-GB
16, a newly isolated member of the ga-
bulimima alkaloid family, was ach-
ieved. This synthesis features an intra-
molecular condensation between an
amine and a 1,3-diketone moiety.
Keywords: alkaloids
·
condensa-
tion · Michael addition · reductive
coupling · total synthesis
Introduction
Himbacine (1),[1] himandrine (2),[2] galbulimima alkaloid 13
((À)-GB 13, 3),[3] and himgaline (4)[4] represent class I–III
galbulimima alkaloids that were isolated from the bark of
Galbulimima belgraveana, a rain forest tree native to North-
ern Australia and Papua New Guinea. Recently, GB 16
(5),[5] a new member of this family, was discovered by
Mander and co-workers. These alkaloids have received great
attention from the pharmaceutical industry, mainly because
the Galbulimima belgraveana bark has been used as a me-
dicinal substance and himbacine (1) has shown potent mus-
carinic antagonist activity.[6] On the basis of a series of struc-
ture–activity relationship (SAR) studies by using himbacine
as a leading compound, a number of thrombin receptor an-
tagonists have been developed. Among them, SCH 530348
[a] W. Zi, Dr. S. Yu, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
(6) is now in phase III clinic trials for treatment of acute
coronary syndrome.[6a]
During the past decade, the fascinating structure of GB 13
has received considerable attention from synthetic chemists.
This campaign has led to a number of total syntheses of
354 Fenglin Lu, Shanghai 200032 (China)
Fax : (+86)21-64166128
E-mail: madw@mail.sioc.ac.cn
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Scheme 1. Previous studies on the total synthesis of GB 13. MOM=methoxymethyl, TBS=tert-butyldimethylsilyl, Bn=benzyl, TBDPS=tert-butyldiphe-
nylsilyl.
himbacine,[1b–d] five total syntheses of GB 13,[3a–e] two total
syntheses of himgaline,[3c,d] and one total synthesis of himan-
drine.[2d] For the synthesis of (Æ)-GB 13, Mander and McLa-
chlan used a Diels–Alder reaction of olefin 9 and diene 10
as the key step to set up the D-ring in the intermediate 8,
and then converted the aromatic ring into the required pi-
peridine ring (Scheme 1).[3a] Movassaghi and co-workers
achieved the first total synthesis and the assignment of the
absolute stereochemistry of natural (À)-GB 13 by forming
its B-ring (from 11) at the final stage by using a biomimeti-
cally inspired strategy. The requisite imino ketone 11 was as-
sembled by a vinyl radical cyclization of enol ether 12 that
was generated by condensation by iminium chloride 13 and
aldehyde 14.[3b] By constructing the A-ring (from 16 to 15)
at a late stage, Chackalamannil and co-workers accom-
plished the second total synthesis of (À)-GB 13. Their key
intermediate 17 was obtained by an intramolecular Diels–
Alder reaction of 18.[3c] Soon after that, Evans and Adams
disclosed their total synthesis towards (+)-GB 13, in which
the B-ring was conducted by an intramolecular enamine
aldol reaction of 19 at the final stage.[3d] The required enam-
ine ketone 19 was elaborated by an intramolecular Michael
addition of enone 20 and subsequent transformations,
whereas 20 was synthesized from Diels–Alder adduct 21.
Recently, Larson and Sarpong applied a rhodium(I)-cata-
lyzed ketone hydroarylation of 22 to achieve the total syn-
thesis of (Æ)-GB 13, in which the key intermediate 22 was
generated from the 1,2-addition of the lithioanion of bromo-
methoxypicoline to enone 23, a Diels–Alder reaction, and
subsequent retro-Diels–Alder reaction product from diene
10 and dienone 24.[3e]
Abstract in Chinese:
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Synthetic Studies toward Galbulimima Alkaloids
Upon studying the literature, we were surprised to find
that no one has reported a strategy to synthesize GB 13 by
introducing its C-ring at a late stage, as this would probably
provide a more-convergent approach to GB 13 because we
could disconnect it into two equally complex fragments. On
the basis of this analysis, we started our retrosynthetic analy-
sis for (À)-GB 13 (3). As depicted in Scheme 2, we envi-
sioned that the C-ring of (À)-GB 13 could be constructed by
Scheme 3. Reagents and conditions: a) 1,3-cyclohexanedione, 4 ꢁ MS,
THF, reflux; b) CBr4, Ph3P, CH3CN, RT; then DIPEA, reflux; c) Pt/C, H2
(80 atm.), AcOH, 458C, cis/trans 4:1; d) (Boc)2O, NaOH, benzene/THF/
H2O, reflux; e) IBX, DMSO, 658C.
the a face of the enamine 32, thus directing the hydrogena-
tion to the desired b face to form the reduction product
(34a). Accordingly, Pt/C-catalyzed hydrogenation of 32 was
carried out in acetic acid at 608C and 80 atm. After the re-
action, the desired 34a was isolated together with trans-
isomer 34b in a ratio of 1.8:1. We reasoned that the forma-
tion of 34b might result from partial epimerization of the
hydrogenation intermediate 33a, and therefore decided to
inhibit this side-reaction by reducing the reaction tempera-
ture. To our delight, a better ratio (4:1) was observed, when
the hydrogenation was conducted at 408C. Further reducing
of the reaction temperatures inhibited the hydrogenation.
The separated 34a was protected with (Boc)2O (Boc=tert-
butoxycarbonyl) and oxidized with 2-iodoxybenzoic acid
(IBX)[13] to deliver enone 35.
The preparation of O-silylated ketene acetal 38 is depict-
ed in Scheme 4. Intramolecular Michael addition of 36
under the action of (S)-1-phenylethylamine proceeded
smoothly to deliver g-keto ester 37, after KOH-mediated
isomerization and subsequent esterification.[14] Diastereose-
lective reduction of the keto moiety in 37 with NaBH4 at
À788C followed by cyclization under acidic conditions pro-
vided a lactone. Following deprotonation of this lactone
with lithium diisopropylamide (LDA), the resultant anion
was trapped with trimethylsilyl chloride to deliver an 89%
yield over four steps.
Scheme 2. Retrosynthetic analysis of (À)-GB 13 and (+)-GB 16.
a SmI2-mediated carbonyl–alkene reductive coupling reac-
tion[7,8] of enone 25. The enone 25 could be assembled from
lactone 26 by ring-opening and a subsequent intramolecular
aldol reaction. The bond disconnection of 26 would give two
less-complicated bicyclic intermediates 27 and 28, which
could be connected to each other by a Mukaiyama–Michael
addition.[9] Apparently, by starting from the lactone 26, 1,3-
diketone 29 could be assembled by ordinary transforma-
tions. This intermediate would in turn provide (+)-GB 16
through the intramolecular condensation between its secon-
dary amine moiety and its 1,3-diketone. Herein, we detail
our results.[10]
Results and Discussion
Our synthesis started from the preparation of the two re-
quired partners for the Mukaiyama–Michael addition. As
shown in Scheme 3, condensation of commercially available
(S)-3-aminobutan-1-ol (30) with 1,3-cyclohexanedione in re-
fluxing tetrahydrofuran gave enamine 31 in 87% yield.[11]
Treatment of 31 with CBr4/Ph3P followed by Et3N-mediated
substitutive cyclization afforded bicyclic enamine 32.[12a] The
next step was a stereoselective hydrogenation of the C=C
double bond of 32. On the basis of our previous observa-
tions,[12] we anticipated that the methyl group would shield
Scheme 4. Reagents and conditions: a) (S)-1-phenylethylamine, 4 ꢁ MS,
MgSO4, THF, RT; b) KOH, MeOH, reflux, acid workup then CH2N2,
Et2O; 75% yield for 2 steps; c) NaBH4, MeOH, À788C; d) PTSA·H2O,
CH2Cl2, reflux; e) LDA, then TMSCl, THF, À788C.
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The Michael addition of silyl enol ether 38 onto enone 35
was achieved under TiCl4 catalysis at À788C,[9] affording Mi-
chael adduct 39 as a diastereomeric mixture in a ratio of
about 3.5:1 (Scheme 5). As predicted, the nucleophilic agent
38 favored addition on enone 35 from the Re face to give
the products with an R configuration at the newly generated
C8 stereocenter. This result was further confirmed by single-
crystal X-ray analysis of 39b.[15]
Scheme 6. Reagents and conditions: a) glycol, PTSA·H2O, toluene,
Dean–Stark; b) LAH, THF, 08C to RT; c) TFAA/DMSO, DBU, CH2Cl2,
À788C–RT; d) TFAA, Et3N, CH2Cl2, RT; e) PTSA·H2O, acetone, H2O,
reflux, 4 days.
required b-hydroxy ketone 44 by oxidation of the diol 43
and a subsequent intramolecular aldol reaction. Initially,
Dess–Martin periodinane (DMP) was employed as the oxi-
dizing agent. This reaction afforded the desired product 44,
but the yield was not satisfactory owing to formation of lac-
tone 46. This side-product was probably generated through
a cascade oxidation–hemiketalization–oxidation[19] process
as indicated in Scheme 7. After the failed attempt of inhibit-
ing the formation of 46 by changing the oxidizing agent to
pyridinium chlorochromate (PCC)[17] or tetrapropylammoni-
um perruthenate (TPAP)/N-methylmorpholine-N-oxide
(NMO),[18] we were pleased to find that diol 43 could be
converted into 44 with 85% yield under modified Swern ox-
idation conditions (by using DBU but not triethylamine
Scheme 5. Reagents and conditions: a) TiCl4, CH2Cl2, À788C; b) IBX,
DMSO, 708C; c) DBU, CH2Cl2, RT; d) Pd/C, H2, iPrOH; e) DMP,
NaHCO3, CH2Cl2. DMSO=dimethyl sulfoxide.
As the stereochemistry at the C8-position in both 39a and
39b was not required for synthesizing the target molecule,
we decided to invert it by an oxidation/reduction approach.
Accordingly, oxidation of the mixture of 39a and 39b with
IBX produced a mixture of enone 40a and its C9 epimer
40b. It was found that, during column chromatography on
silica gel, 40b partially isomerized into 40a, which indicated
that the latter is the thermodynamically more-stable isomer.
Complete isomerization was achieved by treatment of the
mixture of 40a and 40b with 1,8-diazabicycloACTHNUGRTENUNG[5.4.0]undec-7-
ene (DBU), thereby giving 40a in an 84% yield. Hydroge-
nation of 40a afforded the reduced ketone 41 that has the
desired stereochemistry at both the C8- and C9-positions. In
this case, alcohol 42 was isolated in 41% yield as a side-
product. As 42 could be transformed into 40a by Dess–
Martin oxidation,[16] we were able to obtain ketone 42 in
80% combined yield after two cycles.
Our next task was transforming the lactone moiety in 41
into the desired enone part. As outlined in Scheme 6, treat-
ment of the ketone 41 with ethylene glycol followed by lithi-
um aluminum hydride (LAH) reduction afforded diol 43
with 91% yield. At this stage, we planned to synthesize the
Scheme 7. Possible pathway for the conversion of diol 43 into lactone 46.
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Synthetic Studies toward Galbulimima Alkaloids
Table 1. SmI2-mediated carbonyl–alkene reductive coupling reaction of the enone 25 under different conditions.
Entry
Conditions
Products (yield [%])
1
2
3
4
5
SmI2/HMPA/tBuOH, À78 to 08C
SmI2/HMPA, RT
SmI2/MeOH, RT
SmI2, reflux
SmI2, reflux, then Dess–Martin oxidation
47 (55)
47 (46)
47 (33)
49 (45–65)
48 (7)
48 (12)
48 (17)
50 (12–20)
49 (75)
(TEA) or N,N-diisopropylethylamine (DIPEA) as
a
ly, only conformation B is suitable for this transformation,
and therefore, heating the reaction mixture was required to
get the thermodynamically less-stable conformation B. As
such, only the conditions indicated in Table 1, entry 5 suc-
cessfully produced the desired cyclization products.
base).[20,21] In this case, no 46 was detected, which indicated
that the cascade oxidation–hemiketalization–oxidation pro-
cess could be blocked by using DBU as a base in the Swern
oxidation.[20] Next, treatment of 44 with trifluoroacetic anhy-
dride (TFAA) afforded elimination product 45. Selective re-
moval of the ketal protecting group in 45 without touching
the Boc-protecting group proved to be challenging. After
failure to cleave this group under mild conditions, such as
pyridinium para-toluenesulfonate (PPTS)/acetone/H2O,[22a]
InACHTUNGTRENNUNG
(OTf)3/acetone,[22b] and CeCl3·7H2O/NaI/CH3CN,[22c] we
were pleased to find that exposure of 45 to para-toluenesul-
fonic acid (PTSA) in wet acetone[22d] under reflux for four
days produced the desired enone 25 in 78% yield.
With the enone 25 in hand, SmI2-mediated carbonyl–
alkene reductive coupling was then attempted. Initially, we
treated 25 with SmI2/hexamethylphosphoramide (HMPA)/
tert-butanol,[23a] SmI2/HMPA,[23b] or SmI2/methanol,[23c] at re-
action temperatures ranging from À78 to 08C and observed
that these typical reductive coupling reaction conditions
only produced simple reduction products 47 and 48 (Table 1,
entries 1–3).[24] After careful screening of the existing reac-
tion conditions, we were pleased to discover that by adding
enone 25 slowly to a refluxing solution of SmI2 in tetrahy-
drofuran in the absence of any additives,[25] the desired re-
ductive coupling product 49 could be isolated in 45–65%
yields, together with the over-reduced product 50 with 12–
20% yields (Table 1, entry 4). Further attempts revealed
that a satisfactory yield for 49 could be obtained by SmI2-
mediated reductive cyclization and subsequent oxidation of
the mixture of the cyclization products with Dess–Martin
periodinane (Table 1, entry 5).
Scheme 8. Favored conformation for carbonyl–alkene reductive coupling
of 46.
The completion of the synthesis of (À)-GB 13 and its
transformation into (À)-himgaline are outlined in Scheme 9.
Dehydrogenation of the ketone 49 with IBX[3b,13] afforded
N-Boc-protected GB 13 51 with 75% yield. Removal of the
Boc group of 51 with TFA followed by an aqueous workup
provided target molecule 3 in 79% yield. Owing to the
known balance between GB 13 and 16-oxahimgaline, our
synthetic (À)-GB 13 contained about 25% 16-oxohimgaline
in C6D6, which is consistent with the observation of Evans
and Adams[3d] (containing 10% 16-oxohimgaline) and
Larson and Sarpong[3e] (containing 30% 16-oxohimgaline).
To further confirm our synthetic result, conversion of this
mixture into (À)-himgaline (4) was conducted through
HOAc treatment and subsequent reduction with NaBH-
During the course of the SmI2-mediated reductive cycliza-
tion, a [3.2.1] bicyclic core structure was created. Among the
three possibilities to form a [3.2.1] bicyclic core, as shown in
Scheme 8, only a 1,3-diaxial connection is favored. Obvious-
AHCTUNGTRENNUNG
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Scheme 11. Reagents and conditions: a) NaBH4, MeOH/THF, À788C;
b) TBSCl, imidazole, cat. DMAP, DMF, RT; c) LAH, THF, RT;
d) TFAA/DMSO, DBU, CH2Cl2, À788C to RT; e) PCC, CH2Cl2, RT;
f) TFA, CH2Cl2, RT; g) toluene, NaOAc, Dean–Stark; h) HF, CH3CN,
75% yield; or TBAF, THF, 82% yield. DMAP=4-dimethylaminopyri-
dine.
Scheme 9. Reagents and conditions: a) IBX, DMSO, 708C; b) TFA,
CH2Cl2, and then NaOH; c) HOAc, CH3CN; then NaBHACHTNUGTRENUNG(OAc)3.
We next moved our attention to the synthesis of (+)-
GB 16. Initially, b-hydroxy ketone 44 was chosen as an ad-
vanced intermediate. However, after its oxidation to 1,3-di-
ketone 52,[26] cleavage of the ketal protecting group gave
ketone 53 in only 35% yield owing to the formation of
some unidentified side products (Scheme 10). This result
tramolecular Michael addition product 58, presumably be-
cause the free hydroxyl group is close to the enone moiety.
To solve the intramolecular Michael addition problem, it
seemed reasonable to remove the TBS group before the for-
mation of the enone part. Thus, treatment 37 with aqueous
HF in acetonitrile afforded diol 59, which was then oxidized
with PCC to provide ketone 60 (Scheme 12). Deprotection
of the Boc group with TFA followed by heating the free
amine in toluene delivered (+)-GB 16 (6) in 87% yield. The
analytical data of synthetic 5 are identical with those report-
ed for natural (+)-GB 16. Its structure was further con-
firmed by X-ray crystal structure analysis,[15] as indicated in
Scheme 12.
Scheme 10. Reagents and conditions: a) PCC, CH2Cl2, RT; b) PTSA/ace-
tone/H2O, reflux.
made us want to continue our synthesis by using lactone 41.
At this stage, we decided to reduce the ketone group of 41
and then protect the resulting hydroxyl group with an easily
removable silyl ether. Consequently, reduction of 41 with
NaBH4 at À788C followed by treatment with TBSCl in N,N-
dimethylformamide provided 54 in 76% yield (Scheme 11).
LAH reduction of the lactone 54 to the corresponding diol,
which was subjected to Swern oxidation and subsequent in-
tramolecular aldol reaction provided b-hydroxy ketone 55 in
71% yield. PCC oxidation of 55 produced 1,3-diketone 56,
which was treated with TFA to remove the Boc group. The
liberated amine was heated in toluene to furnish condensa-
tion product 57. Unfortunately, desilylation of 57 under vari-
ous conditions (HF/CH3CN,[27a] HF/pyridine,[27b] PTSA/
MeOH,[27c] and tetrabutylammonium fluoride (TBAF)/
THF[27d]) did not provide the free alcohol, but gave the in-
Scheme 12. Reagents and conditions: a) HF, CH3CN, À208C; b) PCC,
CH2Cl2, RT; c) TFA, CH2Cl2, RT; d) toluene, NaOAc, Dean–Stark.
578
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Synthetic Studies toward Galbulimima Alkaloids
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[8] For some applications in the natural product synthesis of this
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[9] K. Narasaka, K. Soai, T. Mukaiyama, Chem. Lett. 1974, 1223.
[10] Part of this work has been disclosed in a previous communication,
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[11] Y. Aoyagi, T. Mizusaki, M. Shishikura, T. Komine, T. Yoshinaga, H.
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We have developed a novel and convergent route for the
asymmetric syntheses of alkaloids (À)-GB 13, (+)-GB-16,
and himgaline. The key transformations in our synthesis in-
clude: 1) the connection of two bicyclic parts by means of a
Mukaiyama–Michael addition, 2) the formation of the C-
ring by a SmI2-mediated carbonyl–alkene reductive coupling
(for alkaloid (À)-GB 13), and 3) the intramolecular conden-
sation between an amine and a 1,3-diketone moiety (for al-
kaloid (+)-GB 16). Our new strategy offers a more-conver-
gent approach for assembling these natural products and
their analogues, which will prompt the syntheses of other
galbulimima alkaloids and their SAR studies.
[13] K. C. Nicolaou, T. Montagnon, P. S. Baran. Y.-L. Zhong, J. Am.
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[15] CCDC 770766 (39b) and CCDC 770765 ((+)-GB 16) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif..
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Acknowledgements
The authors are grateful to the National Basic Research Program of
China (973 Program, grant no.2010CB833200), the Chinese Academy of
Sciences, and the National Natural Science Foundation of China (grant
nos. 20632050 and 20921091) for their financial support.
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Received: August 11, 2010
Published online: December 14, 2010
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