Total synthesis of (+)-lepadin B: Stereoselective synthesis of nonracemic polysubstituted hydroquinolines using an RC-ROM process

Article abstract of DOI:10.1021/ja8068215

This communication describes a new tandem metathesis reaction for which an RC-ROM mechanism was experimentally supported. This process was successfully applied to the synthesis of cis-fused polyhydroquinolines enabling a short stereoselective total synthe

Full text of DOI:10.1021/ja8068215

Published on Web 09/27/2008
Total Synthesis of (+)-Lepadin B: Stereoselective Synthesis of Nonracemic
Polysubstituted Hydroquinolines Using an RC-ROM Process
Guillaume Barbe and Andre´ B. Charette*
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received August 28, 2008; E-mail: andre.charette@umontreal.ca
Scheme 1. Retrosynthetic Analysis for Lepadin B
Lepadins are members of a growing family of natural products
possessing a cis-fused decahydroquinoline subunit in which five
stereogenic centers are included.1 Lepadin A (1) and B (2), which
were isolated from the tunicate of ClaVelina lepadiformis,1a, have
been shown to exhibit significant in Vitro cytotoxicity against several
human cancer cell lines.1 In addition, Tsuneki et al. recently
identified lepadin B as a potent blocker of neuronal nicotinic
acetylcholine receptors (nAChR’s) R4ꢀ2 and R7.2 As nAChR’s
have been implicated in several neurological disorders including
nicotinic addiction, epilepsy, and Parkinson’s and Alzheimer’s
diseases, lepadin B could represent a new lead for the development
of nicotinic-based therapies. These structural and biological features
motivated research groups worldwide to address the synthetic
question of lepadin B, culminating to date in three asymmetric total
syntheses based on enzymatic3a,b and chiron3c-f approaches.3g
stage diastereoselective incorporation of the diene side chain.
Retrosynthetic modification of enone 4, including an enone trans-
position and a stereospecific Baeyer-Villiger oxidation at C-3
position, revealed polyhydroquinoline 5 containing all structural
requirements for a tandem metathesis product.7 Therefore, metath-
esis precursor 6 was a key synthon that could be rapidly accessed
by applying our recently developed Diels-Alder based strategy.8f
It is interesting to note that all atoms included in the lepadin B
skeleton originate from inexpensive commodities, i.e. ring-opened
pyridine 7, readily available allyl Grignard reagent 8 as well as
methyl acrylate 9 (Scheme 1).
Over the past decade, alkene metathesis has emerged as a
powerful tool in organic synthesis for the rapid access of structural
complexity.4 Particularly, alkene metathesis-induced molecular
rearrangements have been widely explored and successfully applied
as atom economic strategies5 for natural product syntheses.4c
Among these, ring-opening/ring-closing metathesis (ROM-RCM)
processes involving bicyclo[2.2.1]heptenes were extensively studied
for the synthesis of all-carbon6a-g and heteroatom-containing
[n.3.0]bicyclic systems.6h-n More recently, Phillips showed that
the analogous bicyclo[2.2.2]octene can participate in such a
metathesis sequence to produce [n.4.0] bicyclic systems including
the cis-fused decaline structure.7
As part of our research program directed toward the stereose-
lective synthesis of polysubstituted piperidines,8 we became
interested in the hydroquinoline scaffold and elected to explore a
new tandem metathesis as an atom economic strategy5 for the
formation of the cis-fused decahydroquinoline structures. Recogniz-
ing lepadin B as a valuable target to challenge our approach (Vide
supra), we embarked in the design of a synthetic strategy containing
tandem metathesis chemistry as a key feature. Herein, we detail a
stereoselective synthesis of chiral nonracemic cis-fused polysub-
stituted hydroquinolines and describe a new stereoselective total
synthesis of ent-Lepadin B.
The synthesis begins with our regio- and diastereoselective, chiral
auxiliary-based pyridine8a dearomatization. An endo-selective
Diels-Alder cycloaddition then afforded azabicyclo[2.2.2]octene
12 (Scheme 2).8f,9 It is noteworthy that these two steps positioned
four of the five stereogenic centers included in lepadin B (Scheme
1). Alane reduction of the ester and amidine8d moieties, with in
situ protection of the secondary amine, provided compound 13 in
47% yield for the three steps (92:8 er). This highly crystalline
compound was easily recrystallized from EtOAc affording 13 in
gram quantities with >99:1 er.9 Finally, a three-step sequence from
alcohol 13 provided the metathesis precursor 6 in 81% yield.
With diene 6 in hand, we began our exploration of the metathesis
sequence. After extensive optimization (Table 1), we were delighted
to find that submitting 6 to 2 mol % of Grubbs’ catalyst second
generation (16)10 at 80 °C for 2 min afforded the desired rearranged
product 5 in 79% yield (entry 6). It is noteworthy that no rigorous
exclusion of air and moisture were required for this process,
although such precautions gave a slight increase in the reaction
yield (entry 12). In addition, performing the reaction under an
ethylene atmosphere improved the catalyst’s stability and prevented
the formation of dimeric material11 but significantly decreased the
reaction rate (entry 13). Finally, we found that adding the catalyst
portionwise was beneficial (entry 14) and particularly crucial for
Our retrosynthetic analysis of lepadin B is outlined in Scheme
1. We identified enone 4 as a suitable Michael acceptor for late
9
10.1021/ja8068215 CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 13873–13875 13873

C O M M U N I C A T I O N S
Scheme 2. Synthesis of Metathesis Precursorsa
Figure 1. Relative stereochemistry: X-ray analysis of 5-S.
Scheme 3. Possible Mechanistic Pathways
a Reagents and conditions: (a) (i) N-Bz-O-Me-L-valinol, 7, Tf2O, DCM,
-78 °C f 0 °C; (ii) MeMgBr, -78 °C; (b) 9, BF3-Et2O, toluene, 50 °C;
(c) (i) LiAlH4, AlCl3, Et2O/DCM, 0 °C f rt; (ii) BzCl, NaOH 2.5 N, 47%
from 7 (3 steps); (d) 13, (COCl)2, DMSO, TEA, DCM, -78 °C; (e)
AllylMgBr, DCM, -78 °C f rt; (f) BnBr, NaH, TBAI, DMF, rt, 98% for
14, 81% for 6 (3 steps).
Table 1. Metathesis Reaction Optimizationa
Scheme 4. Proximal Hydroxyl Protecting Group Effect
16
(mol %)
[6]
(M)
T
(°C)
time
(min)
yieldf
(%)
entry
1
2
3
4
1.0
1.0
1.0
1.0
5.0
2.0
2.0
0.50
0.25
2.0
2.0
1.0
1.0
1.0
2.5
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.05
0.10
0.01
0.01
0.01
0.01
rt
24 h
6
2
2
2
2
4
2
4
2
2
2
2.5 h
4
30
72
74
74
74
77
79
79
51
29
71
65
79
62
77
75
60
80
reflux
80
80
80
80
80
80
80
80
80
80
80
Scheme 5. Competitive Study
5
6
7b
8
9b
10
11
12c
13d
14b
15e
a 16 is added at reported temperature to a solution of 6 (1 mmol) in
commercially available toluene under an argon atmosphere. b Catalyst
added in two portions. c Reaction performed under anhydrous conditions
with degassed toluene (Ar atm). d Reaction performed under anhydrous
conditions with degassed toluene (H2CdCH2 atm). e Reaction performed
on 15 mmol of 6 with addition of catalyst 16 in three portions. f Mixture
of diastereoisomers at C-5.
formed. Surprisingly, none of the conditions studied afforded any
ring-opened products and all starting materials were completely
recovered. This virtually absent reactivity of the internal alkene
can be explained by a large steric demand on both faces of the π
system, hence inhibiting catalyst approach. However, these results
alone cannot entirely rule out mechanism A, since bicyclic com-
pounds 13 and 14 may represent thermodynamic products in these
conditions.12
reliability on a multigram scale (entry 15). Relative stereochemistry
of 5 was secured by X-ray analysis (Figure 1).
We, therefore, decided to probe the first step of mechanism B,
i.e. the formation of a ruthenium carbene on the endo side chain.
First, we examined the effect of the protecting group on the
proximal secondary alcohol and rapidly realized that such protection
was crucial to attain any conversion (Scheme 4). Then, we
synthesized bis-allyl analogues 20 and 23, hypothesizing that a five-
member ring formation could compete with the expected rearrange-
ment in the second step of mechanism B (RCM) (Scheme 5). Not
surprisingly, free alcohol 20 failed in producing the desired
rearranged product 21 (Vide supra). However, the presence of the
Two general mechanistic pathways could explain the formation
of 5 from 6, i.e., (A) ring-opening of the bicyclic system and ring-
closure with the pending alkene (ROM-RCM) or (B) cross-
metathesis of the ruthenium catalyst with the terminal alkene
followed by a ring-closing/ring-opening metathesis sequence (RC-
ROM) (Scheme 3). To gain insight into the main operative pathway,
we submitted compounds 13 and 14, both lacking their terminal
alkene, to a wide range of metathesis conditions. We anticipated
that, in the event of ROM being the first step of the catalytic cycle
(mechanism A), various amounts of polymeric materials would be
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C O M M U N I C A T I O N S
Scheme 6. Total Synthesis of ent-Lepadin Ba
of other biologically interesting hydroquinolines. These results will
be reported in due course.
Acknowledgment. This work was supported by NSERC, the
Canada Research Chairs Program, the Canadian Foundation for
Innovation, and the Universite´ de Montre´al. G.B. thanks NSERC
and Boehringer Ingelheim for postgraduate fellowships.
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) For isolation, see: Lepadin A: (a) Steffan, B. Tetrahedron 1991, 47, 8729.
Lepadin A and B: (b) Kubanek, J.; Williams, D. E.; de Solva, E. D.; Allen,
T.; Andersen, R. J. Tetrahedron Lett. 1995, 36, 6189–6192. Lepadin D-
F: (c) Wright, A. D.; Goclik, E.; Konig, G. M.; Kaminsky, R. J. Med.
Chem. 2002, 45, 3067. Lepadin F-H: (d) Davis, R. A.; Carroll, A. R.;
Quinn, R. J. J. Nat. Prod. 2002, 65, 454.
(2) Tsuneki, H.; You, Y.; Toyooka, N.; Sasaoka, T.; Nemoto, H.; Dani, J. A.;
Kimura, I. Biol. Pharm. Bull. 2005, 28, 611–614.
a Reagents and conditions: (a) (i) Hg(TFA)2, NaTFA, THF/H2O (4:1), rt,
2 h; (ii) NaBH4, NaOH 4.5 M; (b) Jones’ reagent, acetone, rt, 1 h, 74% (2
steps); (c) H2 (1 atm), Pd/C, MeOH, rt, 24 h; (d) TFAA, UHP, DCM, rt, 2 h,
69%; (e) IBX, toluene/DMSO (2:1), 80 °C, 15 h, 75%; (f) H2O2, KOH, THF/
H2O, rt, 2.5 min; (g) H2N-NH2, AcOH, MeOH, rt 2 h, 51% (2 steps); (h)
TPAP, NMO, DCM, rt, 2 h, 75%; (i) 10, Cp2Zr(H)Cl, CuI-DMS, THF, 40
°C, 2 h, 76%; (j) TsNHNH2; NaBH3CN, ZnCl2, MeOH, reflux, 2 h, 70%; (k)
Me3OBF4, Na2HPO4, MeCN; NaHCO3 aq.; K2CO3, MeOH, rt, 61%.
(3) (a) Toyooka, N.; Okumura, M.; Takahata, H.; Nemoto, H. Tetrahedron Lett.
1999, 55, 10673–10684. (b) Toyooka, N.; Okumura, M.; Takahata, H. J. Org.
Chem. 1999, 64, 2182–2183. (c) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org.
Lett. 2000, 2, 2955–2958. (d) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org.
Chem. 2001, 66, 3338–3347. (e) Pu, X.; Ma, D. Angew. Chem., Int. Ed.
2004, 43, 4222. (f) Pu, X.; Ma, D. J. Org. Chem. 2006, 71, 6562–6572. For
a formal total synthesis of racemic lepadin B, see: (g) Kala¨ı, C.; Tate, E.;
Zard, S. C. Chem. Commun. 2002, 1430–1431.
(4) For reviews on alkene metathesis, see: (a) Grubbs, R. H. Tetrahedron 2004,
60, 7117. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199. (c)
For applications in total synthesis, see: Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
(5) Trost, B. M. Science 1991, 254, 1471.
hydroxyl group did not impair the formation of a ruthenium carbene
(6) For seminal application in total synthesis, see: (a) Stille, J. R.; Grubbs, R. H.
J. Am. Chem. Soc. 1986, 108, 855. For all-carbon systems, see: (b) Hart,
A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 1094. (c) Holtsclaw, J.;
Koreeda, M. Org. Lett. 2004, 6, 3719. (d) Wrobleski, A.; Sahasrabudhe, K.;
Aube´, J. J. Am. Chem. Soc. 2004, 126, 5475. (e) Hagiwara, H.; Katsumi, T.;
Endou, S.; Hoshi, T.; Suzuki, T. Tetrahedron 2002, 58, 6651. (f) Funel, J.;
Prunet, J. Synlett 2005, 235. (g) Stragies, R.; Blechert, S. Synlett 1998, 159.
For oxygen-containing systems, see: (h) Weatherhead, G. S.; Ford, J. G.;
Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 1828. (i) Arjona, O.; Csaky, A. G.; Murcia, M. C.; Plumet, J. Tetrahedron
Lett. 2000, 41, 9777. (j) Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am.
Chem. Soc. 1996, 118, 6634. For nitrogen-containing systems, see: (k)
Maechling, S.; Norman, S. E.; McKendrick, J. E.; Basra, S.; Koppner, K.;
Blechert, S. Tetrahedron Lett. 2006, 47, 189. (l) Liu, Z.; Rainier, J. D. Org.
Lett. 2006, 8, 459–462. (m) Arjona, O.; Csaky, A. G.; Medel, R.; Plumet, J.
J. Org. Chem. 2002, 67, 1380. (n) Buchert, M.; Meinke, S.; Prenzel,
A. H. G. P.; Deppermann, N.; Maison, W. Org. Lett. 2006, 8, 5553.
(7) (a) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–
5335. (b) Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43, 5357–
5359.
(8) (a) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel, J. J. Am.
Chem. Soc. 2001, 123, 11829. (b) Lemire, A.; Grenon, M.; Pourashraf, M.;
Charette, A. B. Org. Lett. 2004, 6, 3517. (c) Lemire, A.; Charette, A. B.
Org. Lett. 2005, 7, 2747. (d) Lemire, A.; Beaudoin, D.; Grenon, M.; Charette,
A. B. J. Org. Chem. 2005, 70, 2368. (e) Charette, A. B.; Mathieu, S.; Martel,
J. Org. Lett. 2005, 7, 5401. (f) Sales, M.; Charette, A. B. Org. Lett. 2005, 7,
5773. (g) Focken, T.; Charette, A. B. Org. Lett. 2006, 8, 2985. (h) Larivee,
A.; Charette, A. B. Org. Lett. 2006, 8, 3955.
(9) See Supporting Information for more details.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 6, 953–
956.
(11) (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082.
(b) Kinoshita, A.; Sakakibara, N.; Mori, M. J. Am. Chem. Soc. 1997, 119,
12388.
(12) Moisan, L.; Thue´ry, P.; Nicolas, M.; Doris, E.; Rousseau, B. Angew. Chem.,
Int. Ed. 2006, 45, 5334.
(13) Further mechanistic studies are in progress and will be reported elsewhere.
(14) It is interesting to note that diastereoisomer 6-S reacts faster than its 6-R
isomer. See ref 13.
(15) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett 1990,
533–535.
(16) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000,
122, 7596–7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong,
Y.-L. J. Am. Chem. Soc. 2002, 124, 2245–2258.
as cyclopentene 22 was obtained in 86% yield.
When compound 23 was treated under the same reaction con-
ditions, cyclopentene 25 was isolated as the main product (87%
yield), accompanied by 11% of the corresponding rearranged
product 24. The latter results are suggestive of a common ruthenium
carbene involved in both mechanistic sequences leading to com-
pounds 24 and 25. Taken altogether, the absence of reactivity of
compounds 13 and 14 and the large influence of the proximal
hydroxyl group on the terminal alkene reactivity (Scheme 4), as
well as the kinetically competitive cyclopentene formation over the
expected rearrangement (Scheme 5), all support mechanism B as
the main pathway for the formation of 5.13,14
To complete the synthesis of ent-lepadin B, we turned our
attention to the introduction of the oxygen at the C-3 position and
sought a stereospecific Baeyer-Villiger oxidation as the obvious
choice (Scheme 6). After extensive survey of reaction conditions,
the required methylketone was obtained via a chemoselective
oximercuration/reduction of the terminal alkene followed by the
oxidation of the resulting alcohol using a Jones reagent. Hydrogena-
tion of the remaining alkene concomitantly with hydrogenolysis
of the benzyl ether provided ketone 26. Cooper’s conditions then
produced the C-3 oxygenated, conveniently bis-protected compound
27.15 The free secondary alcohol was then oxidized to the
corresponding enone16 which was transposed following the Wharton
three-step procedure (4).17 The trans,trans-dienyl moiety was then
introduced using Bergdhal’s modification of the Lipshutz methodol-
ogy with enyne 10 yielding 76% of 28 as a single stereoisomer.18
Finally, a Wolff-Kishner reduction19 and full deprotection20
concluded an 18-step synthesis of ent-Lepadin B from pyridine 5.
(17) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615.
(18) (a) El-Batta, A.; Hage, R. T.; Plotkin, S.; Bergdahl, M. Org. Lett. 2004, 6,
107. (b) Lipshutz, B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112,
7440–7441.
In conclusion, a new tandem metathesis reaction was presented
for which an RC-ROM mechanism was experimentally supported.
This process was successfully applied to the synthesis of cis-fused
polyhydroquinolines enabling a new stereoselective total synthesis
of lepadin B. We are further exploring the mechanism of the
metathesis sequence and applying this methodology to the synthesis
(19) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem. 1985,
50, 1927.
(20) Keck, G. E.; McLaws, M. D.; Wager, T. T. Tetrahedron 2000, 56, 9875.
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