A convergent route to the galbulimima alkaloids (-)-GB 13 and (+)-GB 16

Article abstract of DOI:10.1002/anie.201002299

Alkaloids all round: A 19-step total synthesis of the galbulimima alkaloid (-)-CB 13 starting from commercially available starting material and the first total synthesis of'the galbulimima alkaloid (+)-GB 16 have been achieved (see scheme; Boc = tert-butoxycarbonyl). (Figure Presented)

Full text of DOI:10.1002/anie.201002299

Angewandte
Chemie
DOI: 10.1002/anie.201002299
Natural Products
A Convergent Route to the Galbulimima Alkaloids (À)-GB 13 and
(+)-GB 16**
Weiwei Zi, Shouyun Yu, and Dawei Ma*
GB alkaloids are a growing family of natural products that
were isolated from the bark of Galbulimima belgraveana,
which include himbacine (1),[1] (À)-GB 13, (2),[2] himgaline
(3),[2] himandrine (4)[2] and (+)-GB 16 (5)[3] (Scheme 1).
convergent and efficient routes to these alkaloids are still
required to facilitate their SAR studies.
In the previous reports, formation of the D ring,[6a]
B ring,[6b,d,e] or A ring[6c] was set up at a late stage to complete
the total synthesis of GB 13. Apparently, if formation of the
C-ring of GB 13 could be conducted at the late stage, this
molecule would be disconnected into two equally complex
fragments, thereby offering a more convergent approach to
the natural product. With this idea in mind, we started our
retrosynthetic analysis for (À)-GB 13 (2). As shown in
Scheme 2, we envisioned that the C ring of 2 could be
Scheme 1. Structures of galbulimima alkaloids and their analogue.
These alkaloids have received much attention from the
pharmaceutical industry, mainly because the Galbulimima
belgraveana bark has been used as a medicinal substance and
himbacine (1) displays potent muscarinic antagonist activity.[4]
Based on intensive structure-activity relationship (SAR)
studies of himbacine, an exceptionally potent series of
thrombin receptor antagonists have been discovered. One
of these compounds (SCH 530348, 6) is now in phase III
clinical trials for treatment of acute coronary syndrome.[4a]
Meanwhile, the fascinating structures of these alkaloids have
attracted much interest in the orgainc synthesis community.
As a consequence a number of total syntheses of himbacine,[5]
five of GB 13,[6] two of himgaline[6c,d] and one of himandrine[7]
Scheme 2. Retrosynthetic analysis for (À)-GB 13 and (+)-GB 16.
Boc=tert-butoxycarbonyl.
installed by a carbonyl–alkene reductive coupling of inter-
mediate 7 mediated by SmI2[8,9]. If this transformation worked
well we would be able to disconnect the pentacyclic skeleton
of 2 into two less complicated bicyclic intermediates 9 and 10,
which could be connected to each other by a Mukaiyama–
Michael addition.[10] This approach could also provide an
opportunity to synthesize (+)-GB 16 (5) because it would be
possible to convert the lactone 8 into 1,3-diketone 11, which
could undergo an intramolecular condensation between its
secondary amine moiety and its 1,3-diketone to set up the
C ring of (+)-GB 16. In the following investigations, we
realized that our strategy offered a very convergent synthesis
of (À)-GB 13 and (+)-GB 16, allowing for a 19-step total
synthesis of the former alkaloid beginning from commercially
available material, and the first total synthesis of the latter
alkaloid. Herein, we disclose our results.
have been disclosed.
A biomimetic transformation of
(À)-GB 13 into (+)-GB 16 was reported.[3] However, more
[*] W. Zi, S. Yu, Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
Fax: (+86)21-6416-6128
E-mail: madw@mail.sioc.ac.cn
[**] We are grateful to the National Basic Research Program of China
(973 Program, grant no. 2010CB833200), the Chinese Academy of
Sciences, the National Natural Science Foundation of China (grant
no. 20632050 and 20921091) for their financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002299.
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Our synthesis started from the preparation of the two
required partners for the Mukaiyama–Michael addition. As
shown in Scheme 3, condensation of commercially available
Scheme 3. Reagents and conditions: a) 1,3-cyclohexanedione, M.S.
(4 ꢀ), THF, reflux; b) CBr4, Ph3P, CH3CN, RT; then iPrNEt2, reflux;
c) Pt/C, H2 (80 atm), AcOH, 408C; d) (Boc)2O, NaOH, benzene/THF/
H2O (2:1:1), reflux; e) IBX, DMSO, 658C; f) (S)-1-phenylethylamine,
M.S. (4 ꢀ), MgSO4, THF, RT; g) KOH, MeOH, reflux, acid workup;
then CH2N2, Et2O, 91% ee; h) NaBH4, MeOH, À788C; i) TsOH·H2O,
CH2Cl2, reflux. DMSO=dimethyl sulfoxide, IBX=2-iodoxybenzoic acid,
M.S.=molecular seives, THF=tetrahydrofuran, Ts=4-toluenesulfonyl.
Scheme 4. Reagents and conditions: a) LDA, TMSCl, THF, À788C;
b) 9, TiCl4, CH2Cl2, À788C; c) IBX, DMSO, 708C; d) DBU, CH2Cl2, RT;
e) Pd/C, H2, iPrOH; f) DMP, NaHCO3, CH2Cl2. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DMP=Dess–Martin periodinane, LDA=lithium
diisopropylamide, TMS=trimethylsilyl.
(S)-3-aminobutan-1-ol (12) with 1,3-cyclohexanedione fol-
lowed by treatment with CBr4/Ph3P and substitutive cycliza-
tion mediated by Et3N afforded bicyclic enamine 13.[11] The
=
next step was a stereoselective hydrogenation of the C C
oxidation, we were able to obtain the ketone 8 in 80%
combined yield after two cycles.
bond of 13. On the basis of our previous observations,[11a] we
anticipated that the methyl group would shield the a face of
the enamine 13, thus directing the hydrogenation to the
desired b face to form the reduction product 14. Accordingly,
hydrogenation of 13 catalyzed by Pt/C was conducted in
HOAc at 408C and afforded 14 in 72% yield, together with its
trans isomer in 14% yield. Protection of 14 with (Boc)2O and
subsequent oxidation with IBX[12] delivered the desired enone
9. In a parallel procedure, g-keto ester 16 was assembled from
olefin 15[13a] by applying a known method.[13] Diastereoselec-
tive reduction of the keto moiety in 16 with NaBH4 at À788C
and subsequent cyclization under acidic conditions provided
the lactone 10.
The addition of silyl enol ether generated from the lactone
10 onto the enone 9 was achieved under TiCl4 catalysis at
À788C,[10] and afforded Michael adducts 17 as a diastereo-
meric mixture in a ratio of about 3.5:1 (Scheme 4). As
predicted, the nucleophilic agent favored addition on the
enone 9 from the Re face to give the products with
R configuration at the newly generated stereocenter at C8,
which was confirmed by X-ray crystal structural analysis of
17b.[14] Because this configuration was not matching the one
of the target molecule, we planned to invert it through an
oxidation/reduction approach.
Next, we turned our attention to the transformation of the
lactone moiety in 8 into the desired enone unit. Protection of
the ketone 8 with ethylene glycol and subsequent LAH
reduction gave rise to diol 20 in 91% yield (Scheme 5). For
obtaining the required b-hydroxy ketone 21 via oxidation of
the diol 20 and subsequent intramolecular aldol reaction, we
initially utilized Dess–Martin periodinane as the oxidating
agent. In this case 21 was isolated in 35–50% yield, but
lactone 22 was formed as a side product. Changing the
oxidating agent to PCC or TPAP/NMO gave similar results.
The lactone 22 is probably formed through a cascade
oxidation/hemiketalization/oxidation process.[15] Inspired by
work of Boger et al.,[16] we found that if DBU was used as a
base instead TEA or DIPEA, Swern oxidation of diol 20
provided 21 with 85% yield without any traces of 22. This
result further demonstrated that the cascade oxidation/hemi-
ketalization/oxidation process could be inhibited by using
DBU as a base in Swern oxidation. Dehydration of 21 through
its trifluoroacetyl ester afforded an enone, which was treated
with PTSA in wet acetone to selectively remove the ketal
protecting group, thus producing the desired enone 7 in 74%
yield.
With the enone 7 in hand, the stage was set for the crucial
carbonyl–alkene reductive coupling mediated by SmI2. To our
surprise, the initial attempts under the typical reaction
conditions (SmI2/HMPA/tBuOH,[17a] SmI2/HMPA,[17b] or
SmI2/MeOH,[17c] À78-08C) all failed to give any desired
cyclization products and only simple reduction products were
isolated. After careful screening various reaction conditions,
we were pleased to discover that by adding the enone 7 slowly
to a solution of SmI2 in THF at reflux in the absence of any
Accordingly, exposure of the mixture of 17a and 17b to
IBX in DMSO at 708C produced a mixture of enone 18a and
its C9 epimer 18b. Treatment of this mixture with DBU in
methylene chloride gave the thermodynamically more stable
18a as a single product with 84% yield. Hydrogenation of 18a
afforded the reduced ketone 8 that has the desired config-
uration at both the C8- and C9-position together with alcohol
19. Because 19 could be transferred into 18a by Dess–Martin
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(2) in 71% yield. Owing to the known balance between GB 13
and 16-oxahimgaline (25), our synthetic 2 contained about
25% 16-oxohimgaline in C6D6, which is consistent with the
observation of Evans[6d] (containing 10% of 16-oxohimgaline)
and Sarpong[6e] (containing 30% of 16-oxohimgaline). To
further confirm our synthetic result, we converted this
mixture into (À)-himgaline (3) by treatment with acetic acid
and subsequent reduction with NaBH(OAc)3. The analytical
data for synthetic 3 were in agreement with those of natural
himgaline.
To synthesize (+)-GB 16, we initially employed b-hydroxy
ketone 21 as an advanced intermediate. However, after its
oxidation to the corresponding 1,3-diketone, cleavage of the
ketal protecting group was found to be quite difficult. This
problem led us to continue our synthesis using lactone 8. At
this stage we decided to reduce the ketone group of 8 and then
protect the resulting hydroxy group with an easily removable
silyl ether. Consequently, reduction of 8 with NaBH4 at
À788C and subsequent treatment with TBSCl in DMF
provided 26 in 76% yield (Scheme 7). Reduction with LAH
Scheme 5. Reagents and conditions: a) glycol, TsOH·H2O, toluene,
Dean–Stark; b) LiAlH4, THF, 08C to RT; c) (CF3CO)2O, DMSO, DBU,
CH2Cl2, À788C to RT; d) (CF3CO)2O, Et3N, CH2Cl2, RT; e) TsOH·H2O,
acetone, H2O, reflux, 4 days; f) SmI2, THF, reflux, then Dess–Martin
oxidation; g) IBX, DMSO, 708C; h) CF3CO2H, CH2Cl2; then NaOH;
i) HOAc, CH3CN; then NaBH(OAc)3.
additives,[18] the desired reductive coupling product 23 could
be isolated in 45–65% yields, together with the over-reduced
product 24. Further attempts revealed that a satisfactory yield
(75%) for 23 could be obtained by reductive cyclization
mediated by SmI2 and subsequent oxidation of the mixture of
the cyclization products with Dess–Martin periodinane.
Our reductive cyclization results could be rationalized by
conformation analysis as shown in Scheme 6. During this
process, a [3.2.1]bicyclic core structure is created. Among the
three possibilities to form a [3.2.1]bicyclic core, only a 1,3-
diaxial connection is favored. Thus, only conformation B is
suitable for carbonyl–alkene reductive coupling mediated by
SmI2. Consequently, heating the reaction mixture was
required to obtain the thermodynamically less stable con-
formation B.
Scheme 7. Reagents and conditions: a) NaBH4, MeOH/THF (1:1),
À788C; b) TBSCl, imidazole, DMAP, DMF, RT; c) LiAlH4, THF, RT;
d) (CF3CO)2O, DMSO, DBU, CH2Cl2, À788C to RT; e) HF, CH3CN,
À208C; f) PCC, CH2Cl2, RT; g) CF3CO2H, CH2Cl2, RT; h) toluene,
NaOAc, Dean–Stark. DMF=N,N-dimethylformamide, PCC=pyridi-
nium chlorochromate.
of the lactone 26 to the corresponding diol, which was
subjected to Swern oxidation and subsequent intramolecular
aldol reaction provided b-hydroxy ketone 27a in 71% yield.
Treatment of 27a with aqueous HF in acetonitrile afforded
diol 27b, which was then oxidazed with PCC and provided
ketone 11. Removal of the Boc group with TFA and
subsequent heating of the free amine in toluene delivered
(+)-GB 16 (5) in 87% yield. The analytical data of synthetic 5
are identical with those reported for natural (+)-GB 16.[3] Its
structure was further confirmed by X-ray crystal structure
analysis.[14]
Dehydrogenation of the ketone 23 with IBX afforded
N-Boc-protected (À)-GB 13, which was treated with TFA and
then subjected to aqueous workup and provided (À)-GB 13
In conclusion, we have developed a novel and convergent
route for the asymmetric synthesis of alkaloid (À)-GB 13.
This protocol allows for the assembly of the target molecule in
19 linear steps (overall yield of 6.1%) from commercially
available starting material. The key steps include the con-
nection of two bicyclic parts through a Mukaiyama–Michael
Scheme 6. The favored conformation for carbonyl–alkene reductive
coupling of the enone 7.
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Communications
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addition and formation of the C ring by a carbonyl–alkene
reductive coupling mediated by SmI2. Using an advanced
intermediate from our (À)-GB 13 synthesis as a starting
material, we achieved the first total synthesis of (+)-GB 16—
a newly isolated member of the gabulimima alkaloid family.
The synthesis of other galbulimima alkaloids based on this
strategy and SAR studies of these compounds are currently
under way.
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Received: April 19, 2010
Published online: July 13, 2010
Keywords: alkaloids · Michael addition · natural products ·
.
reductive coupling · total synthesis
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