Stereospecific route to 5,11-methanomorphanthridine alkaloids via intramolecular 1,3-dipolar cycloaddition of nonstabilized azomethine ylide: Formal total synthesis of (±)-pancracine

Article abstract of DOI:10.1021/ol051321o

(Chemical Equation Presented) The core structure of the complex pentacyclic 5,11-methanomorphanthridine alkaloids is constructed stereospecifically in one step employing an intramolecular [3 + 2]-cycloaddition of nonstabilized azomethine ylide as the key

Full text of DOI:10.1021/ol051321o

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3713-3716
Stereospecific Route to
5,11-Methanomorphanthridine Alkaloids
via Intramolecular 1,3-Dipolar
Cycloaddition of Nonstabilized
Azomethine Ylide: Formal Total
Synthesis of (±)-Pancracine
Ganesh Pandey,*,† Prabal Banerjee,† Ravindra Kumar,† and Vedavati G. Puranik‡
DiVision of Organic Chemistry (Synthesis) and Center for Material Characterization,
National Chemical Laboratory, Pune 411008, India
gp.pandey@ncl.res.in
Received June 7, 2005
ABSTRACT
The core structure of the complex pentacyclic 5,11-methanomorphanthridine alkaloids is constructed stereospecifically in one step employing
an intramolecular [3 2]-cycloaddition of nonstabilized azomethine ylide as the key step. The strategy is demonstrated by accomplishing the
formal total synthesis of ( )-pancracine.
+
±
The 5,11-methanomorphanthridine alkaloids, belonging to
the subclass Amaryllidaceae, were first isolated by Wildman
and co-workers in 1955.1 These natural products, produced
by various plant species such as Pancratium, Narcissus, and
BrunsVigia, have a unique pentacyclic framework. In general,
alkaloids of this group, (-)-pancracine (1), (-)-montanine
(2), (-)-coccinine (3), and (-)-brunsvigine (4), possess
identical structural features except for the oxygen substitu-
tions in the E-ring (methoxy vs hydroxyl)2 and stereochem-
istry at C-2 and C-3. Due to unique structural features and
important biological activities3 associated with these alka-
loids, considerable attention is directed from synthetic
chemists toward the total syntheses of these alkaloids.
† Division of Organic Chemistry (Synthesis).
‡ Center for Material Characterization.
Literature scrutiny revealed that methodologies pertaining
to the construction of the core pentacyclic 5,11-methano-
morphanthridine skeleton (5) have mainly been limited to
either Pictet-Spengler reaction from 6, intramolecular alkyl-
ation of 7, or intramolecular radical cyclization from 8.
(1) (a) Wildman, W. C.; Kaufman, C. J. J. Am. Chem. Soc. 1955, 77,
1249. (b) Dry, L. J.; Poynton, M. E.; Thompson, M. E.; Warren, F. L. J.
Chem. Soc. 1958, 4701. (c) Inubushi, Y.; Fales, H. M.; Warnhoff, E. W.;
Wildman, W. C. J. Org. Chem. 1960, 25, 2153. (d) Wildman, W. C.; Brown,
C. L. J. Am. Chem. Soc. 1968, 90, 6439.
(2) (a) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 51, pp 323. (b) Lewis, J. R. Nat. Prop. Rep.
1993, 10, 291. (c) Viladomat, F.; Bastida, J.; Codina, C.; Campbell, W. E.;
Mathee, S. Phytochemistry 1995, 40, 307.
(3) Southon, I. W.; Buckinghham, J. Dictionary of the Alkaloids;
Chapman & Hall; New York, 1989; pp 229, 735.
10.1021/ol051321o CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/21/2005

Figure 1. Summary of the reported strategies for assembling the 5,11-methanomorphanthridine class of alkaloids.
(Figure 1) However, in all these strategies, synthesis is
elaborated from a precursor having the proper stereochem-
istry at C-4a and C-11a and a relative disposition of the C-12
methylene group of 5 that involved their construction in a
stepwise manner. Hoshino and co-workers4 have accom-
plished the synthesis of 1-4 in racemic form from a
precursor of type 7, obtained from the Pictet-Spengler
reaction of a corresponding cyclohexane derivative. Weinreb
and Jin5 also utilized similar cyclization strategy from a
compound of type 7 in their synthesis of (-)-pancracine (1)
and (-)-coccinine (4). In another approach, Hoshino and co-
workers6 have used radical cyclization from a precursor of
type 8 to construct skeleton 5. Overman,7 Pearson,8 Ikeda,9
Sha,10 and Banwell11 have used a precursor of type 6 in their
respective elaborations of these alkaloids.
Figure 2. Empirical view of transition state 11 (hydrogens have
been omitted for simplicity).
the core 5,11-methanomorphanthridine CD-ring system in
one step. It may be mentioned that this concept originated
from our ongoing research activities in the area of alkaloid
syntheses12 involving a nonstabilized azomethine ylide
cycloaddition strategy, generated by sequential double desi-
lylation of R,R′-bis(trimethylsilylmethyl)alkylamines13 as the
key step. In this communication, we explore a conceptually
new route for the expedient construction of 9 toward the
total synthesis of (()-pancracine (1).
We viewed the synthesis of these alkaloids differently, as
depicted retrosynthetically in Scheme 1, employing an
Scheme 1. Retrosynthetic Analysis
An analysis of the steric repulsion present in A and B
indicated that endo attack (A) would be preferred over the
more encumbered exo alternative (B) (Figure 2). Such
cycloaddition was also envisaged to provide core 5,11-
methanomorphanthridine skeleton 10 with the stereochemical
dispositions required for assembling a suitably equipped
E-ring for further elaboration by intramolecular cycloalkyl-
ation reaction.
(4) (a) Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991, 32,
7079. (b) Ishizaki, M.; Hoshino, O. J. Org. Chem. 1992, 57, 7285.
(5) (a) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050. (b)
Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 5773.
(6) Ishizaki, M.; Kurihara, K.-I.; Tanazawa, E.; Hoshino, O. J. Chem.
Soc., Perkin Trans. 1 1993, 101.
(7) (a) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005. (b)
Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58, 4662.
(8) Pearson, W. H.; Lian, B. W. Angew. Chem., Int. Ed. 1998, 37, 1724.
(9) Ikeda, M.; Hamada, M.; Yamashita, T.; Ikegami, F.; Sato, T.;
Ishibashi, H. Synlett 1998, 1246.
(10) (a) Sha, C.-K.; Huang, C.-M.; Hong, A.-W.; T.-H. Pure Appl. Chem.
2000, 72, 1773. (b) Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001,
3, 2177.
intramolecular 1,3-dipolar cycloaddition strategy of a non-
stabilized azomethine ylide (AMY) for the construction of
3714
Org. Lett., Vol. 7, No. 17, 2005

Our synthetic journey began with the preparation of
principal precursor 12 in 70% yield by following the simple
steps as shown in Scheme 2.
lation using s-BuLi/TMEDA in THF at -78 °C and
quenching with TMSCl, gave 17 in 92% yield.17 Deprotection
of both N,O-acetal as well as N-Boc moieties using 1 N HCl
in refluxing dioxane produced corresponding free amine 18
in 87% yield, which upon alkylation with (iodomethyl)-
trimethylsilane in the presence of anhydrous K2CO3 in CH3-
CN gave 15 in 80% yield.
Scheme 2. Synthesis of 12
The crucial intramolecular cycloaddition reaction of the
azomethine ylide generated from 12, to our delight, gave 10
as a single diastereoisomer in 56% yield. The cycloaddition
reaction was performed by slow addition of 12 (1 equiv) to
a stirring heterogeneous mixture of the flame-dried Ag(I)F
(2.5 equiv) in dry CH3CN. The cycloadduct 10 was fully
characterized by 1H NMR, 13C NMR, and mass spectral data.
The stereochemical assignments, as shown in Scheme 4, are
Refluxing a mixture of 14 (1 equiv) and 15 (1.25 equiv)
in CH3CN in the presence of anhydrous K2CO3 gave the
corresponding coupled alcohol, which upon benzoylation
gave 13 in 81% yield. Our initial attempt of Heck coupling14
between 13 and methyl vinyl ketone (MVK) by following
usual reported procedures such as PdCl2(CH3CN)2 in THF15a
or Pd(OAc)2/n-Bu4NCl in DMF at room temperature,15b how-
ever, failed to provide 12 in satisfactory yield. Finally, with
little experimentation and optimization, we succeeded in ob-
taining 12 in 60% yield using Pd(OAc)2 as the catalyst and
with an increased amount of MVK (8 equiv). One of the
coupling components (14) used in this reaction was prepared
very easily from the commercially available piperonyl al-
cohol in 70% yield in two steps using known procedures.5b,16
The synthesis of another component (15) is shown in Scheme
3.
Scheme 4. Cycloaddition of 11
Scheme 3. Synthesis of 15
based on extensive COSY and NOESY NMR spectral
studies.
The N-Boc cyclic amine 16, synthesized easily in two steps
from commercially available 3-amino propanol, upon meta-
To proceed further from 10, we subjected it to the usual
debenzoylation reaction (LiOH/MeOH, rt), which, however,
provided unexpected epimerized alcohol 20 in 98% yield
(confirmed by X-ray crystallography).18 Although unepimer-
ized alcohol 19 could be obtained from 10 by stirring with
LiOH/MeOH at 0 °C (Scheme 4), we decided to continue
further with 20 itself, as the C11a stereochemistry at this
stage was irrelevant for final natural product synthesis.
Intramolecular cycloalkylation19 of the corresponding me-
(11) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Kemmler, M. J.
Chem. Soc., Perkin Trans. 1 2001, 1345.
(12) (a) Pandey, G.; Laha, J. K.; Lakshmaiah, G. Tetrahedron 2002, 58,
3525. (b) Pandey, G.; Sahoo, A. K.; Bagul, T. D. Org. Lett. 2000, 2, 2299.
(c) Pandey, G.; Laha, J. K.; Mohankrishnan, A. K. Tetrahedron Lett. 1999,
40, 6065. (d) Pandey, G.; Sahoo, A. K.; Gadre, S. R.; Bagul, T. D.; Phalgune,
U. D. J. Org. Chem. 1999, 64, 4990. (e) Pandey, G.; Bagul, T. D.; Sahoo,
A. K. J. Org. Chem. 1998, 63, 760. (f) Pandey, G.; Lakshmaiah, G.; Ghatak,
A. Tetrahedron Lett. 1993, 34, 7301.
(13) (a) Pandey, G.; Lakshmaiah, G.; Kumaraswamy, G. J. Chem. Soc.,
Chem. Commun. 1992, 1313. (b) Pandey, G.; Lakshmaiah, G. Tetrahedron
Lett. 1993, 34, 4861.
(14) For recent reviews of Heck reaction, see: (a) Bra¨se, S.; de Meijere,
A. In Metal-Catalysed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley: New York, 1998; Chapter 3. (b) Beletskaya, I. P.;
Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(15) (a) Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron
1981, 37, 4035 (b) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(16) (a) Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am. Chem.
Soc. 1990, 112, 6959. (b) Wilson, C. V.; Janseen, D. E. Organic Synthesis;
Wiley: New York, 1963; Collect. Vol. IV, pp 547.
(17) Beak, P.; Yum, E. K. J. Org Chem. 1993, 58, 823.
Org. Lett., Vol. 7, No. 17, 2005
3715

sylate derivative of 20 using LDA/THF at -78 °C very
surprisingly produced 24 in 65% yield, indicating the
involvement of a thermodynamic enolate 22 in this rear-
rangement (Scheme 5). Successful transformation of 20 to
23 (epi-9) was finally achieved in 58% yield involving kinetic
enolate20 21, generated from 20 in the presence of KHMDS/
THF at -78 °C. Involvement of an azetidinium salt-type
intermediate from 20 in the formation of 23 and 24, neither
can be supported nor ruled out at this stage.
Scheme 5. Formal Total Synthesis of (()-Pancracine 1
To demonstrate the significance of our strategy, we
decided to complete the formal total synthesis of (()-
pancracine 1. The pivotal ∆1,11a double bond from 23 leading
to the formation of 25 (71% yield) was created by the
reductive elimination of the corresponding enol triflate using
Pd(PPh3)4/Et3SiH in THF.21 The required enol triflate from
23 was generated by the reaction of the corresponding lithium
enolate of 23 with the Comins reagent.22 All spectral data
of 25 matched very well with the values reported by
Overman et al.,7 who have also elaborated 25 in a couple of
steps to (()-pancracine 1.
In conclusion, we have developed a short and conceptually
new route for the stereospecific construction of the core
structure of 5,11-methanomorphanthridine alkaloids in one
step. The success of this strategy is demonstrated by
accomplishing the formal total synthesis of (()-pancracine
1. The asymmetric version of this approach, along with an
alternative strategy for constructing the E-ring and synthesis
of some other important alkaloids of this class, is in progress
and will be revealed in a full paper shortly.
(18) X-ray analysis of 20: C16H19NO4, Mr ) 289.32, crystal dimensions
0.40 × 0.38 × 0.13, Bruker SMART APEX CCD diffractometer, Mo KR
radiation, multiscan data acquisition, a ) 5.7666(5), b ) 9.7162(8), c )
13.4268(11) Å, R ) 98.029(1), â ) 100.091(1), γ ) 97.602(1)°, V ) 723.8-
(1) Å3, Z ) 2, Dc ) 1.327 mg m-3, triclinic, space group P-1, µ (Mo KR)
) 0.095 mm-1, of 7005 reflections measured, 2539 unique [I > 2σ(I)], R
value 0.0441, wR2 ) 0.1167. All data were corrected for Lorentzian,
polarization, and absorption effects. SHELX-97 was used for structure
solution and full matrix least squares refinement on F2. Hydrogen atoms
were included in the refinement as per the riding model. Crystallographic
data (excluding structure factors) for the structure reported in this paper
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-271169.
(19) (a) Petrovic, G.; Cekovic, Z. Org. Lett. 2000, 2, 3769. (b) House,
H. O.; Phillips, W. V.; Sayer, T. S. B.; Yau, C. C. J. Org. Chem. 1978, 43,
700.
(20) Howard, M. H.; Sardina, F. J.; Rapoport, H. J. Org. Chem. 1990,
55, 2829.
(21) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(22) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
Acknowledgment. We are thankful to the Department
of Science and Technology, New Delhi, for financial support.
P.B. and R.K. thank CSIR, New Delhi, for the award of
Research Fellowships.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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