A new strategy towards the total synthesis of phenanthridone alkaloids synthesis of (+)-2,7-dideoxypancratistatin as a model study

Article abstract of DOI:10.1039/b200624c

A new strategy towards the synthesis of phenanthridone alkaloids has been reported through the synthesis of (+)-2,7-dideoxypancratistatin from D-(-)-quinic acid employing PET initiated carbocyclization of an electron rich aromatics by silylenol ether as a

Full text of DOI:10.1039/b200624c

A new strategy towards the total synthesis of phenanthridone alkaloids:
synthesis of (+)-2,7-dideoxypancratistatin as a model study
Ganesh Pandey,* Andiappan Murugan and Madhesan Balakrishnan
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune-411008, India.
E-mail: pandey@ems.ncl.res.in; Fax: +91-20-5893153
Received (in Cambridge, UK) 17th January 2002, Accepted 12th February 2002
First published as an Advance Article on the web 22nd February 2002
A new strategy towards the synthesis of phenanthridone
alkaloids has been reported through the synthesis of
induced electron transfer (PET) initiated cyclization of silylenol
ether to an electron rich aromatic ring (ca. 4 to 3) and also
(+)-2,7-dideoxypancratistatin from
D-(2)-quinic acid em-
making use of naturally abundant -(2)-quinic acid (7) as chiral
D
ploying PET initiated carbocyclization of an electron rich
aromatics by silylenol ether as a key step.
source to build the highly oxygenated C-ring system. This
strategy was designed keeping in view the requirement for 1 in
significant yield for mapping biological and pharmaceutical
profiles. To evaluate the efficacy of the strategy, we have
synthesized (+)-2,7-dideoxypancratistatin (8) as a model study
and report the results in this communication.
The potent cytotoxic and antiviral1 properties associated with
(+)-pancratistatin (1a) coupled with its limited availability from
natural resources2 have prompted significant efforts for the total
synthesis of this deceptively simple looking molecular struc-
ture. Despite commendable efforts expended by numerous
research groups over many years for the synthesis of 1a3 and its
congeners 7-deoxypancratistatin (1b),4 narciclasine (2a)5 and
lycoricidine (2b),6 the members of this family of alkaloids
remain particularly formidable targets for organic synthesis.
The main challenge towards designing any synthetic strategy
for 1 lies into the control of the trans fused BC-ring junction
(4a,10b) and with the stereocontrolled installation of continuous
hydroxy functionalities located around the perimeter of the C-
ring moiety.
The synthesis began with the preparation of 9 from
D-
(2)-quinic acid (7) according to the literature procedure
(Scheme 2).8 To avoid any unforeseen complication in the later
part of the synthesis, the cyclohexylidene moiety of 9 was
replaced with the corresponding TBS ether 10. Sodium
We viewed a new synthetic approach for 1 through the
retrosynthetic route as outlined in Scheme 1. The key features of
our synthetic plan involved the utilization of the crucial C–C
bond formation step, developed earlier by our group7 via photo
Scheme 2 Reagents and conditions: a, NaH, BnCl, DMF, 85%; b, HOAc–
H2O, 50 °C, 10 h, 95%; c, TBSCl, ImH, DMAP, DMF, 24 h, 80%; d, H2–Pd/
C, EtOH, quant.; e, NaIO4, EtOH, 95%; f, MsCl, TEA, 0 °C, DCM,
95%.
Scheme 1
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CHEM. COMMUN., 2002, 624–625

Scheme 3 Reagents and conditions: a, n-BuLi, HMPA, THF, 278 °C, TBSCl, 95%; b, hn, DCN, CH3CN, H2O, 68%; c, NaBH4, iPrOH; d, TBSCl, ImH,
DMAP, DCM, 85% over two steps; e, RuO2, NaIO4, EtOAc, H2O, 90%; f, NaOMe, MeOH, reflux; g, TBAF, THF, 90% over two steps.
3 (a) S. Danishefsky and J. Y. Lee, J. Am. Chem. Soc., 1989, 111, 4829;
metaperiodate oxidation of 10 gave 11 in good yield. b-
(b) X. Tian, T. Hudlicky and K. Königsberger, J. Am. Chem. Soc., 1995,
Hydroxy elimination of 11 by treating with MsCl and TEA at 0
117, 3643; (c) B. M. Trost and S. R. Pulley, J. Am. Chem. Soc., 1995,
°C gave 12 in 95% yield.
117, 10143; (d) T. J. Doyle, M. M. Hendrix, D. Van Der Veer, S.
Conjugate addition of N-lithiated piperonylamine carbamate,
Jaanmard and J. Haseltine, Tetrahedron, 1997, 53, 11153; (e) P. Magnus
and I. K. Sebhat, J. Am. Chem. Soc., 1998, 120, 5341; (f) J. H. Rigby, U.
S. M. Maharoof and M. E. Mateo, J. Am. Chem. Soc., 2000, 122, 6624;
prepared by the treatment of 13 with n-BuLi in THF–HMPA at
278 °C followed by trapping the resultant enolate as TBS ether
by quenching with TBSCl, afforded 14 in 95% yield (Scheme
3). PET cyclization by irradiating (pyrex filter, > 280 nm, 450
W Hanovia medium pressure lamp, 6 h) a mixture of 14 (0.8 g,
1.18 mmol) and 1,4-dicyanonaphthalene (DCN, 0.05 g, 0.028
mmol) in 250 mL of CH3CN–H2O (24+1) and usual work up
and chromatographic purification of the crude photolysate gave
cyclized product 15 in 68% yield as a single diastereomer.
Compound 15 was fully characterized by spectroscopic meth-
ods. Sodium borohydride reduction of 15 followed by the
protection of the resultant alcohol moiety as TBS ether gave 16
in 85% yield as a single diastereomer.
(g) G. R. Pettit, N. Melody and D. L. Herald, J. Org. Chem., 2001, 66,
2583.
4 (a) H. Paulsen and M. Stubbe, Liebigs Ann. Chem., 1983, 535; (b) T.
Hudlicky, X. Tian and K. Königsberger, Synlett, 1995, 1125; (c) G. E.
Keck, S. F. McHardy and J. A. Murry, J. Am. Chem. Soc., 1995, 117,
7289; (d) T. Hudlicky, X. Tian, K. Königsberger, R. Maurya, J. Rouden
and B. Fan, J. Am. Chem. Soc., 1996, 118, 10752; (e) G. E. Keck, T. T.
Wager and S. F. McHardy, J. Org. Chem., 1998, 63, 9164; (f) G. E.
Keck, J. A. Murry and S. F. McHardy, J. Org. Chem., 1999, 64, 4465;
(g) J. L. Acena, O. Arjona, M. L. Leon and J. Plumet, Org. Lett., 2000,
2, 3683.
5 (a) J. H. Rigby and M. E. Mateo, J. Am. Chem. Soc., 1997, 119, 12655;
(b) G. E. Keck, T. T. Wager and J. F. D. Rodriquez, J. Am. Chem. Soc.,
1999, 121, 5176.
The 1H NMR spectrum of 169 showed a characteristic
doublet of doublet for H10b at d 2.9 (J = 10.3, 6.3 Hz)
confirming the syn relationship between H10b and H1 (J = 6.3
Hz) and anti relationship between H10b and H4a (J = 10.3
Hz).
6 (a) S. Ohta and S. Kimoto, Tetrahedron Lett., 1975, 2279; (b) S. Ohta
and S. Kimoto, Chem. Pharm. Bull., 1976, 24, 2969; (c) S. Ohta and S.
Kimoto, Chem. Pharm. Bull., 1976, 24, 2977; (d) H. Paulsen and M.
Stubbe, Liebigs Ann. Chem., 1983, 535; (e) S. Ogawa, M. Ohtsuka and
N. Chida, Tetrahedron Lett., 1991, 32, 4525; (f) T. Hudlicky and H. R.
Olivo, J. Am. Chem. Soc., 1992, 114, 9694; (g) S. F. Martin and H. H.
Tso, Heterocycles, 1993, 35, 85; (h) S. Ogawa, M. Ohtsuka and N.
Chida, J. Org. Chem., 1993, 58, 4441; (i) T. Hudlicky, H. F. Olivo and
B. McKibben, J. Am . Chem. Soc., 1994, 116, 5108.
7 (a) G. Pandey, A. Krishna, K. Girija and M. Karthikeyan, Tetrahedron
Lett., 1993, 34, 6631; (b) G. Pandey, M. Karthikeyan and A. Murugan,
J. Org. Chem., 1998, 63, 2867.
8 D. Mercier, J. Leboul, J. Cleophax and S. D. Gero, Carbohyd. Res.,
1971, 20, 299.
Benzylic oxidation of 16 by utilizing a catalytic amount of
RuO2 and NaIO4,10 followed by carbamate and silyl deprotec-
tion gave 8, [a]25 +90.91(c 0.055, MeOH), in overall 23%
D
yield. The final product 8 was also fully characterized by all
spectroscopic11 means.
In conclusion, we have demonstrated a new strategy which
could be useful for the synthesis of all of the phenanthridone
class of alkaloids utilizing a methodology developed from our
group for the key C–C bond formation step. Total syntheses of
(+)-pancratistatin and 7-deoxypancratistatin are in progress and
will be disclosed appropriately in due course.
We are thankful to DST, New Delhi for the financial support.
One of us (AM) thanks CSIR, New Delhi for the award of
research fellowship.
9 Spectral data for 16: 1H NMR (200 MHz, CDCL3) d 6.73 (s, 1H), 6.65
(s, 1H), 5.91 (s, 2H), 5.00 (d, J = 15.4 Hz 1H), 3.92 (d, J = 15.4 Hz),
3.72 (m, 7H), 2.95 (dd, J = 10.3, 6.3 Hz, 1H), 2.10 (dd, J = 23.2, 11.7
Hz, 1H), 1.72 (m, 1H), 0.94 (s, 9H), 0.91 (s, 9H), 0.80 (s, 9H), 0.13 (s,
3H), 0.12 (s, 3H), 0.07 (s, 6H), 20.25 (s, 3H), 20.47 (s, 3H). 13C NMR
(125 MHz, CDCl3) d 156.8, 146.3, 145.9, 131.0, 127.8, 111.0, 106.5,
100.5, 72.2, 70.3, 68.5, 58.1, 52.4, 45.8, 43.9, 36.2, 25.8, 25.6, 18.1,
17.9, 17.6, 24.8, 25.0, 25.1, 25.2, 25.4, 25.9.
Notes and references
1 (a) G. R. Pettit, V. Gaddamidi, D. L. Herald, S. B. Singh, G. M. Gragg
and J. M. Schmidt, J. Nat. Prod., 1986, 46, 995; (b) B. Gabrielson, T. P.
Monath, J. W. Huggins, J. J. Kirsi, M. Hollingshead, W. M. Shannon
and G. R. Pettit, Natural products as Antiviral Agents, ed. C. K. Chu, H.
G. Cutler, Plenum, New York, 1992, p. 121.
2 G. R. Pettit, G. R. Pettit III, G. Groszek, R. A. Backhaus, D. L. Doubek,
R. J. Barr and A. W. Meerow, J. Nat. Prod., 1995, 58, 756.
10 A. B. Smith III and R. M. Scarborough Jr, Syn. Commun., 1980, 10,
205.
11 Spectral data for 8: 1H NMR (200 MHz, CD3OD) 7.34 (s, 1H), 6.82 (s,
1H), 6.01 (bs, 2H), 3.91 (m, 3H), 3.57 (m, 1H), 2.74 (dd, J = 10.2, 3.9
Hz, 1H), 1.91 (m, 2H); 13C NMR (125 MHz, CD3OD) d 166.3, 150.53,
147.1, 136.7, 121.3, 109.3, 106.3, 101.4, 69, 68.4, 66.4, 55.6, 42.3,
35.7.
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