A new method for the construction of the hydroxylated tropane skeleton: Enantioselective synthesis of (-)-Bao Gong Teng A

Article abstract of DOI:10.1039/c0cc04371k

An efficient and highly diastereoselective method for the construction of the hydroxylated tropane skeleton is described. The method features a new intramolecular reductive coupling reaction of N-acyl N,O-acetal with aldehyde, cooperatively mediated by BF

Full text of DOI:10.1039/c0cc04371k

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A new method for the construction of the hydroxylated tropane skeleton:
enantioselective synthesis of (À)-Bao Gong Teng Aw
Geng-Jie Lin,a Xiao Zhenga and Pei-Qiang Huang*ab
Received 12th October 2010, Accepted 8th November 2010
DOI: 10.1039/c0cc04371k
An efficient and highly diastereoselective method for the
construction of the hydroxylated tropane skeleton is described.
The method features a new intramolecular reductive coupling
reaction of N-acyl N,O-acetal with aldehyde, cooperatively
mediated by BF3ÁOEt2 and SmI2. On the basis of this method,
a new enantioselective total synthesis of (À)-Bao Gong Teng A
has been accomplished.
natural products,14 we recently reported a method for
the one-pot cross-coupling of N-acyl N,O-acetals with a,b-
unsaturated compounds.15 We now report an extension of this
methodology and its application to the asymmetric total
synthesis of (À)-Bao Gong Teng A.
The basic synthetic strategy was to extend our intermolecular
cross-coupling method (N-acyl N,O-acetals with a,b-unsaturated
compounds)15 to intramolecular N-acyl N,O-acetal–aldehyde
coupling, and merge it to our cyclic imide chiron-based
synthetic methodology.13 On the basis of this concept, our
retrosynthetic analysis of (À)-Bao Gong Teng A is displayed in
Scheme 1, in which the intramolecular reductive coupling of
N,O-acetal with aldehyde (4) is the key step.
Tropane alkaloids are a class of alkaloids possessing an
8-azabicyclo[3.2.l]octane skeleton, which have been known
for more than 170 years.1 Because of their remarkable
medicinal significance, tropane alkaloids have received a
great deal of attention of medicinal, natural product, and
synthetic organic chemists.2 The members of tropane
alkaloids have been significantly expanded with the discovery
of a number of hydroxylated tropane alkaloids, such as Bao
Gong Teng A (1),3 (+)-2a,7b-dihydroxynortropane (2),4
(À)-vaccinine B (3),5 and more generally calystegines (Fig. 1).6
Bao Gong Teng A (1) is a tropane alkaloid isolated from
the stem of Chinese medicinal plant Baogongteng (Erycibe
obtusifolia Benth).3 It exhibits hypertensive and miotic
activities. Being more effective and having fewer side effects
than pilocarpine and physostigmine in curing glaucoma, this
alkaloid is used as a miotic agent to treat glaucoma in clinics.7
In addition, Bao Gong Teng A (1) is also the first naturally
occurring tropane alkaloid acting as muscarinic acetylcholine
receptor (mAChR) agonist.8 However, due to scarcity of the
herbs, the clinical use of this eyedrop has been severely limited.
Consequently, Bao Gong Teng A has become an attractive
synthetic target.8–12 Because of the challenges in the construc-
tion of the unique hydroxylated 8-azabicyclo[3.2.l]octane
skeleton, only one racemic10 and two enantioselective11,12 total
syntheses of Bao Gong Teng A have been reported so far. As a
continuation of our interest in the development of efficient
synthetic methodologies13 for the asymmetric synthesis of
The synthesis started from the known building block 6.14f
Stepwise reductive alkylation of 6 was accomplished by
treatment of 6 with Grignard reagent 7 (THF/CH2Cl2, 0 1C,
8
h) followed by BF3ÁOEt2-mediated dehydroxylative
reduction of the resulting diastereomeric mixture of N,O-
acetals with Et3SiH (À50 1C, overnight; rt, 2 days), giving
regioselectively the concomitant desilylated 4,5-trans-lactam 8
in 82% overall yield (Scheme 2). The stereoselectivity
was >98 : 2 as determined by 1H NMR spectroscopy at
400 MHz and the trans-stereochemistry of the product was
deduced from the observed coupling constant between the
protons H-4 and H-5 (J4,5 = 2.0 Hz).16 N-Deallylation of 8
was achieved by RhCl3ÁxH2O-catalyzed double bond
migration17 (EtOH, refl., 6 h) followed by acid-catalyzed
hydrolysis (AcOH/H2O, refl., 2 days; then HCl/EtOH, rt,
1 day), affording lactam 9 in 75% yield. O-Protection
(TBSCl, DMAP, imid., CH2Cl2, rt, overnight) of 9 afforded
compound 10 in 85% yield. Treatment of lactam 10 with
Fig. 1 Some hydroxylated tropane alkaloids.
a Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China
b The State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, P.R. China.
E-mail: pqhuang@xmu.edu.cn; Fax: +86 592 2186400;
Tel: +86 592 2180992
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c0cc04371k
Scheme 1 Retrosynthetic analysis of (À)-Bao Gong Teng A.
Chem. Commun., 2011, 47, 1545–1547 1545
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Scheme 4 BF3ÁOEt2 and SmI2-mediated intramolecular reductive
coupling of compound 4 (N,O-acetal–aldehyde).
trifluoride etherate, and a solution of SmI2/t-BuOH/THF15
at À50 1C produced the desired intramolecular coupling
product 13 and its diastereomer 14 in 56% and 5% yield,
respectively, along with 11% of the reduced product 15
(Scheme 4).
Scheme 2 Reductive alkylation of chiron 6.
Although we were unable to determine the stereochemistry
of the diastereomers 13 and 14 at this stage due to rotamerism
(rotameric ratio of 13 was 63 : 37 as determined by 1H NMR),
they were deduced as shown in Scheme 4 on the basis of the
mechanistic considerations, and confirmed by the subsequent
transformations (cf. vide infra). Considering two plausible
biradical intermediates B and C, intermediate B is favored
over C due to electronic effects (Fig. 2).
di-tert-butyl dicarbonate (TEA, DMAP (cat.), CH2Cl2)
afforded the activated amide 11 in 94% yield.
O-Debenzylation (H2, 1 atm, 10% Pd/C, EtOH, rt) of com-
pound 11 gave amido alcohol 5 in 95% yield (Scheme 3).
Controlled partial reduction of the activated amide 5 with
NaBH4 in MeOH produced the hemiaminal as a diastereomeric
mixture, which without separation, was treated with Ac2O/py in
CH2Cl2 to yield the bis-acetate. Treatment of the crude labile
bis-acetate with iodine in MeOH18 gave chemoselectively
desilylated and transacetylated product N,O-acetal 12 in 68%
yield over three steps. Dess–Martin oxidation19 of the
diastereomeric mixture 12 provided the key precursor 4 as a
1 : 1 diastereomeric mixture (determined by 1H NMR) in
73% yield.
Oxidation of the major diastereomer 13 with Dess–Martin
periodinane (Scheme 5) followed by reduction of the resulting
ketone 16 with L-selectride12 afforded compound 14 (14 : 13 >
1
98 : 2 as determined by H NMR at 400 MHz on the crude
product) in 84% yield. It is worthy mentioning that reduction
with superhydride (LiBEt3H) gave 13 and 14 in a ratio of 1 : 2,
while the reduction with LiAl(Ot-Bu)3H gave 13 as the major
diastereomer (13 : 14 = 1.5 : 1).
After securing the access to the key N,O-acetal/aldehyde 4,
we turned to investigate its intramolecular reductive coupling
reaction. In this regard, we have recently established the
conditions for the one-pot cross-coupling of N-acyl N,O-
acetals with a,b-unsaturated compounds.15 Prior to this, the
homo-coupling of acetals20 and intramolecular coupling of
benzylic acetals with benzylic aldehydes21 had been reported. It
was envisioned that the conditions we developed for the
coupling of N-acyl N,O-acetals with a,b-unsaturated
compounds would also be applicable to intramolecular
coupling of N,O-acetal/aldehyde 4. Indeed, successive
treatment of a THF solution of N,O-acetal 4 with boron
Fig. 2 Plausible electronic effects in the highly diastereoselective
SmI2-mediated intramolecular coupling of compound 4.
Scheme 3 Synthesis of the N-acyl N,O-acetal/aldehyde 4.
1546 Chem. Commun., 2011, 47, 1545–1547
Scheme 5 Synthesis of (À)-Bao Gong Teng A.
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Finally, chemoselective cleavage of the Boc group in
compound 14 was achieved by treatment of compound 14
with TMSOTf/2,6-lutidine,22 and the concomitantly formed
TMS ether was desilylated with TBAF in THF, which afforded
(À)-Bao Gong Teng A (1) in 72% yield from 14. Our synthetic
product exhibited the same physical and spectral properties as
those reported {colorless crystalline solid, mp 75–76 1C
(CH2Cl2/PE); lit.12 colorless crystalline solid: mp 76–78 1C;
B. T. Fan, Z. N. Chen and Y. Lu, Bioorg. Med. Chem. Lett., 2005,
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24
25
[a]D –31.6 (c 0.59 in EtOH); lit.12 [a]D –29.6 (c 0.97 in
EtOH)}.
In summary, we have demonstrated that by cooperative
action of BF3ÁOEt2 and SmI2, the intramolecular reductive
coupling reaction of N-acyl N,O-acetal with aldehyde could
be achieved efficiently and highly diastereoselectively.23 This
established a novel approach to hydroxylated tropane skeleton.
On the basis of this method, a new enantioselective total
synthesis of (À)-Bao Gong Teng A (1) was accomplished in
14 steps with 7.58% overall yield from the malimide chiron 6.
Application of this strategy to the synthesis of other N-containing
hydroxylated heterocycles, in particular hydroxylated tropanoids
such as (+)-2a,7b-dihydroxynortropane (2) and (À)-vaccinine B
(3), is in progress.
13 For an account on the methodologies, see: P.-Q. Huang, Synlett,
2006, 1133–1149.
14 For recent examples, see: (a) H.-Q. Lan, Y.-P. Ruan and
P.-Q. Huang, Chem. Commun., 2010, 46, 5319–5321; (b) Y. Du,
J.-F. Zheng, Z.-G. Wang, L.-J. Jiang, Y.-P. Ruan and P.-Q. Huang,
J. Org. Chem., 2010, 75, 4619–4622; (c) R. Fu, J.-L. Ye, X.-J. Dai,
Y.-P. Ruan and P.-Q. Huang, J. Org. Chem., 2010, 75, 4230–4243;
(d) G. Liu, T.-J. Wu, Y.-P. Ruan and P.-Q. Huang, Chem.–Eur. J.,
2010, 16, 5755–5768; (e) W.-J. Liu, J.-L. Ye and P.-Q. Huang, Org.
Biomol. Chem., 2010, 8, 2085–2091; (f) J.-M. Luo, C.-F. Dai,
S.-Y. Lin and P.-Q. Huang, Chem.–Asian. J., 2009, 4, 328–335.
15 Y.-G. Xiang, X.-W. Wang, X. Zheng, Y.-P. Ruan and
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The authors are grateful to the NSF of China (20832005,
21072160), and the National Basic Research Program (973
Program) of China (Grant No. 2010CB833200) for financial
support.
Notes and references
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Chem. Commun., 2011, 47, 1545–1547 1547