Stereoflexible total synthesis of (-)-epiquinamide

Article abstract of DOI:10.1016/j.tetlet.2009.02.051

Hydroxy propiolate rearrangement to conjugated diene, Sharpless asymmetric dihydroxylation and one-pot quinolizine construction have been used as key steps in the total synthesis of (-)-epiquinamide.

Full text of DOI:10.1016/j.tetlet.2009.02.051

Tetrahedron Letters 50 (2009) 3294–3295
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoflexible total synthesis of (ꢀ)-epiquinamide
*
S. Chandrasekhar , Bibhuti Bhusan Parida, Ch. Rambabu
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydroxy propiolate rearrangement to conjugated diene, Sharpless asymmetric dihydroxylation and one-
pot quinolizine construction have been used as key steps in the total synthesis of (ꢀ)-epiquinamide.
Ó 2009 Published by Elsevier Ltd.
Received 12 January 2009
Revised 2 February 2009
Accepted 9 February 2009
Available online 12 February 2009
Keywords:
Epiquinamide
Sharpless asymmetric dihydroxylation
Quinolizidine alkaloid
Alkaloidsisolatedfromtheamphibianskinhaveshowninteresting
biological profiles especially relevant to neurology.1 The skin of the
EcuadorianfrogEpipedobatestricolorhasprovidednovelquinolizidine
O
N3
N
TBSO
1a
O
alkaloidepiquinamide1, albeit inminutequantities (240 lg from 183
3
2
frogs) representing a new class of nicotinic agonists in CNS disorders
(Fig.1).2 Thescarcityofthisnaturalproduct didnot permitresearchers
to identify the absolute configuration and thus total synthesis was
warranted.3 Neither the absolute configuration nor optical rotation
was reported by the group which isolated this natural product. The
total synthesis of either enantiomer did not provide any lead on the
absolute configuration. However, more recently, the Gallagher group
synthesized the racemate and found no nicotinic activity.4
O
OH
CO2Et
HO
OH
TBSO
4
4
5
Scheme 1. Retrosynthesis of (ꢀ)-epiquinamide.
As part of a programme aimed at building a natural product li-
brary with alkaloid scaffolds as the back bone, we desired an effi-
cient route to larger quantities of key natural products and also
their intermediates.5 Herein, we disclose a practical synthesis of
(ꢀ)-epiquinamide 1a following the retrosynthetic planning shown
in Scheme 1. We have devised the plan in such a way that by
changing the chiral reagents while following the same synthetic
route we will be able to synthesize both the enantiomers. The
key steps included the propargyl alcohol rearrangement to all trans
diene ester 4,6 Sharpless asymmetric dihydroxylation7 (involving
(i) TBSCl, Imidazole, CH2Cl2
30 min, 0 oC, 75%
CO2Et, LiHMDS
THF, -78 oC, 30 min
CHO
5
TBSO
4
77%
(ii) BAIB, TEMPO, CH2Cl2
0 oC to rt, 2 h, 92%
6
OH
PPh3, benzene
rt, 3 h, 84 %
TBSO
4
CO2Et
7
CH3SO2NH2,
H
tBuOH : H2O (1 : 1)
N
Cl
N
N
N
0 oC, 48 h, 80%
AD mix α
OH
AD mix β
NHAc
(-)-Epiquinamide, 1a
NHAc
(+)-Epiquinamide, 1b
Epibatidine 1c
OH
CO2Et
CO2Et
Figure 1. Neurologically relevant alkaloids from Epipedobates.
TBSO
TBSO
OH
OH
8
8a
* Corresponding author. Tel.: +91 4027193210; fax: +91 4027160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.02.051

S. Chandrasekhar et al. / Tetrahedron Letters 50 (2009) 3294–3295
3295
(i) TsCl, Et3N, DMAP
CH2Cl2, 0 oC - rt, 12 h
OH
N3
Pd-C/H2, EtOAc, rt, 6 h
8
TBSO
N3
TBSO
(ii) NaN3, DMF, 68 oC, 4 h
80% for two steps
then K2CO3, THF, reflux
10 h,75%
O
O
9
3
O
O
N3
p-TSA, MeOH
MsCl, Et3N, CH2Cl2,
-10 oC, 15 min, 94%
Pd-C/H2, EtOH, 10 h
HO
MsO
rt, 30 min, 81 %
then K2CO3, EtOH
reflux, 6 h, 55 %
O
O
11
10
O
O
O
N
(i) MsCl, Et3N, CH2Cl2, -10 oC, 15 min
N
(ii) NaN3, DMF, 65 oC, 36 h
(iii) LiAlH4, THF, reflux then Ac2O
NaOH (1 N) (30% for three steps)
NHAc
OH
(-)-Epiquinamide, 1a
2
Scheme 3.
2. Fitch, R. W.; Garraffo, H. M.; Spande, T. F.; Yeh, H. J. C.; Daly, J. W. J. Nat. Prod.
2003, 66, 1345.
both ADmix
lactamization.
a and ADmix b as reagents) and one-pot reduction-
3. (a) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker, H. E.; Rutjes, F.
P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005; (b) Suyama, T. L.; Gerwick, W. H.
Org. Lett. 2006, 8, 4541; (c) Huang, P.-Q.; Guo, Z.-Q.; Ruan, Y.-P. Org. Lett. 2006, 8,
1435; (d) Tong, S. T.; Barker, D. Tetrahedron Lett. 2006, 47, 5017; (e) Voituriez, A.;
Ferreira, F.; Perez-luna, A.; Chemla, F. Org. Lett. 2007, 9, 4705; (f) Wijdeven, M.
A.; Wijtmans, R.; Van den Berg, R. J. F.; Noorduin, W.; Schoemaker, H. E.; Sonke,
T.; Van Delft, F. L.; Blaauw, R. H.; Fitch, R. W.; Spande, T. F.; Daly, J. W.; Rutjes, F.
P. J. T. Org. Lett. 2008, 10, 4001.
Thus, the forward synthesis was initiated with the commercially
available 1,6-hexane-diol 5 as the starting material. The selective
monosilylation of diol 5 followed by oxidation of alcohol using
bis(acetoxy)iodobenzene (BAIB) and 2,2,6,6-tetramethylpiperidi-
nyloxy (TEMPO) afforded aldehyde 6. Aldehyde 6 was subjected to
the next crucial step to append the ethyl propiolate group (Scheme
2). The lithiated ethyl propiolate was added to aldehyde 6 at
ꢀ78 °C to yield the hydroxy ethyl propiolate 7 which is ready for
an ‘allene’-type rearrangement in the presence of PPh3. Hydroxy
ethyl propiolate 7 was thus stirred in benzene in the presence of
PPh3 to yield the (E,E)-diene ester 4 in 84% yield, this being the com-
monprecursorforthesynthesisof boththeenantiomersof thetarget
molecule. The diene ester 4 was subjected to the enantio- and regio-
4. Kanakubo, A.; Gray, D.; Innocent, N.; Wonnacott, S.; Gallagher, T. Bioorg. Med.
Chem. Lett. 2006, 16, 4648.
5. (a) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. J. Org. Chem. 2008, 73, 7826; (b)
Chandrasekhar, S.; Vijaykumar, B. V. D.; Pratap, T. V. Tetrahedron: Asymmetry
2008, 19, 746; (c) Chandrasekhar, S.; Sultana, S. S.; Kiranmai, N.; Narsihmulu, Ch.
Tetrahedron Lett. 2007, 48, 2373; (d) Chandrasekhar, S.; Chandrasekhar, G.;
Vijeender, K.; Sarma, G. D. Tetrahedron: Asymmetry 2006, 17, 2864; (e)
Chandrasekhar, S.; Jagadeshwar, V.; Jaya Prakash, S. Tetrahedron Lett. 2005, 46,
3127.
6. Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 394.
selective Sharpless asymmetric dihydroxylation using ADmix
a and
7. Xu, D.; Crispino, G.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, . 7570.
8. Spectral data of selected compounds: (4S,5S,E)-Ethyl 9-(tert-butyldimethylsilyloxy)-
also ADmix b to yield the diols 8 and 8a in over 80% yield and 98%
enantioselectivity. One of the enantiomers, 8, has been successfully
transformed to target (ꢀ)-epiquinamide (vide infra). Thus 8 was
subjected to hydrogenation using Pd-C in EtOAc at room tempera-
ture and atmospheric pressure for 6 h. This following filtration and
evaporation was further refluxed in THF in the presence of K2CO3,
which only yielded the butyrolactone 9 in 75% yield for two steps.
The secondary hydroxyl group was transformed to the azido group
via tosylate to realize azide 3 in 80% yield (two steps). As the stage
is set for building the quinolizine framework, the silyl ether group
in 3 was transformed to mesyl ester 11 via alcohol 10 in 76% yield
(for two steps). The mesylate 11 was subjected to one-pot reduc-
tion–double cyclization involving azide reduction to amine which
underwent intramolecular cyclization displacing mesylate. Another
facile lactamization opened up the butyrolactone ring to furnish the
hydroxyl quinolizinone 2 in 55% yield. The acetamino group in 2 was
introduced following the literature procedure to realize the (ꢀ)-
epiquinamide 1a whose spectral data was in full agreement with
the literature data3c,e (Scheme 3).8
4,5-dihydroxynon-2-enoate (8): ½a D27
ꢁ
ꢀ15.8 (c 1.0, CHCl3); IR (KBr): mmax 3425,
2932, 2858, 1717, 1655, 1465, 1254 cmꢀ1
;
1H NMR (CDCl3, 200 MHz): d 6.88 (dd,
J = 15.6, 5.4 Hz, 1H), 6.10 (dd, J = 15.6, 1.5 Hz, 1H), 4.19 (q, J = 7.0 Hz, 2H), 4.12–
4.02 (m, 1H), 3.68–3.57 (m, 2H), 3.56–3.47 (m, 1H), 2.55 (d, J = 5.4 Hz, 1H), 2.40
(d, J = 3.9 Hz, 1H), 1.64–1.36 (m, 6H), 1.30 (t, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.04 (s,
6H); 13C NMR (CDCl3, 75 MHz): d 166.4, 146.9, 122.3, 74.0, 73.9, 63.0, 60.5, 32.6,
32.4, 25.9, 21.9, 18.3, 14.1, ꢀ5.3; ESIMS: m/z 347 (M+H)+; HRMS: calcd for
C17H34O5NaSi (M+Na)+: 369.2073, found: 369.2079. (4R,5R,E)-Ethyl 9-(tert-
butyldimethylsilyloxy)-4,5-dihydroxynon-2-enoate (8a):
½
a 2D7
ꢁ
+17.0 (c 1.5,
CHCl3); IR (KBr): mmax 3430, 2931, 2858, 1718, 1656, 1466, 1254 cmꢀ1
;
1H
NMR (CDCl3, 300 MHz): d 6.88 (dd, J = 15.8, 5.2 Hz, 1H), 6.10 (dd, J = 15.8, 1.5 Hz,
1H), 4.19 (q, J = 6.7 Hz, 2H), 4.12–4.02 (m, 1H), 3.68–3.57 (m, 2H), 3.56–3.47 (m,
1H), 2.46–2.38 (m, 1H), 2.30–2.21 (m, 1H), 1.64–1.36 (m, 6H), 1.30 (t, J = 6.7 Hz,
3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3, 75 MHz): d 166.4, 146.9, 122.3,
74.0, 73.9, 63.0, 60.5, 32.6, 32.4, 25.9, 21.9, 18.3, 14.1, ꢀ5.3; ESIMS: m/z 347
(M+H)+; HRMS: calcd for C17H34O5NaSi (M+Na)+: 369.2073, found: 369.2077.
(S)-5-((S)-5-(tert-Butyldimethylsilyloxy)-1-hydroxypentyl)-dihydrofuran-2(3H)-
one (9): ½a 2D7
+15.0 (c 1.4, CHCl3); IR (KBr): mmax 3446, 2931, 2858, 1773, 1466,
ꢁ
1631, 1466, 1254 cmꢀ1; d 4.36 (td, J = 10.9, 7.0 Hz, 1H), 3.63–3.56 (m, 2H), 3.55–
3.45 (br m, 1H), 2.65–2.41 (m, 2H), 2.36 (br m, 1H), 2.27–2.04 (m, 2H), 1.61–1.45
(m, 6H), 0.87 (s, 9H), 0.02 (s, 6H); 13C NMR (CDCl3, 75 MHz): d 177.3, 83.1, 73.8,
63.1, 32.8, 32.6, 28.8, 25.9, 24.2, 22.1, 18.5, ꢀ5.2; ESIMS: m/z 325 (M+Na)+;
HRMS: calcd for C15H30O4NaSi (M+Na)+: 325.1811, found: 325.1806. (1S,9aR)-1-
Hydroxy-hexahydro-1H-quinolizin-4(6H)-one (2): ½a D27
ꢀ8.0 (c 1.0, CHCl3); IR
ꢁ
(KBr): mmax 3424, 2922, 2853, 1616, 1462 cmꢀ1 1H NMR (CDCl3, 500 MHz): d
;
In conclusion, a strategy devised to synthesize either of the
enantiomers has been developed and successfully demonstrated
for the synthesis of (ꢀ)-isomer in good yields amenable to analog-
ing and derivatization.
4.77–4.69 (m, 1H), 3.77–3.69 (m, 1H), 3.14 (ddd, J = 12.0, 4.6, 2.7 Hz, 1H), 2.57
(ddd, J = 17.5, 7.4, 5.5 Hz, 1H), 2.41 (dt, J = 12.9, 2.7 Hz, 1H), 2.34 (ddd, J = 17.5,
8.3, 5.5 Hz, 1H), 2.02–1.79 (m, 4H), 1.67 (br d, J = 12.9, 1H), 1.54–1.42 (m, 1H),
1.42–1.33 (m, 1H), 1.27–1.16 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 168.4, 69.8,
63.7, 42.9, 31.6, 28.5, 27.0, 25.2, 24.4; ESIMS: m/z 170 (M+H)+; HRMS: calcd for
C9H15NO2Na (M+Na)+: 192.1000, found: 192.1002. Opposite enantiomer of
compound 2: (1R,9a S)-1-Hydroxy-hexahydro-1H-quinolizin-4(6H)-one: ½a D27
ꢁ
+7.8
Acknowledgement
(c 1.0, CHCl3); IR (KBr): m ;
max 3430, 2920, 2851, 1616, 1462 cmꢀ1 1H NMR (CDCl3,
400 MHz): d 4.77–4.69 (m, 1H), 3.77–3.69 (m, 1H), 3.16 (ddd, J = 11.7, 4.4,
2.9 Hz, 1H), 2.57 (ddd, J = 17.5, 8.0, 5.8 Hz, 1H), 2.41 (dt, J = 13.1, 2.9 Hz, 1H),
2.33 (ddd, J = 16.8, 8.0, 5.8 Hz, 1H), 2.03–1.79 (m, 4H), 1.67 (br, d, J = 13.0,
1H), 1.54–1.42 (m, 1H), 1.42–1.33 (m, 1H), 1.27–1.16 (m, 1H); 13C NMR
(CDCl3, 50 MHz): d 168.4, 69.6, 63.7, 42.9, 31.5, 28.4, 26.9, 25.2, 24.4; ESIMS:
m/z 170 (M+H)+; HRMS: calcd for C9H15NO2Na (M+Na)+: 192.1000, found:
192.1003.
B.B.P. and C.R. thank CSIR, New Delhi, for the award of research
fellowships.
References and notes
1. Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556.