Rh(I)-catalyzed ring opening of an IMDAF-derived oxabicyclo cycloadduct as the key step in the synthesis of (±)-epi-zephyranthine

Article abstract of DOI:10.1021/ol049348f

A new strategy for epi-zephyranthine has been developed that is based in part on an extraordinarily facile intramolecular Diels-Alder reaction of a 2-imido-substituted furan. By using a Rh(I)-catalyzed ring opening of the resulting oxabicyclic adduct, the

Full text of DOI:10.1021/ol049348f

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2189-2192
Rh(I)-Catalyzed Ring Opening of an
IMDAF-Derived Oxabicyclo Cycloadduct
as the Key Step in the Synthesis of
(±)-epi-Zephyranthine
Qiu Wang and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received April 9, 2004
ABSTRACT
A new strategy for epi-zephyranthine has been developed that is based in part on an extraordinarily facile intramolecular Diels−Alder reaction
of a 2-imido-substituted furan. By using a Rh(I)-catalyzed ring opening of the resulting oxabicyclic adduct, the cis-diol stereochemistry of
epi-zephyranthine was established.
The alkaloids of the Amaryllidaceae family are composed
of over 100 architecturally interesting natural bases and have
been classified into various skeletally homogeneous sub-
groups.1 The lycorine-type group2 constitutes one of the eight
classes within this large family of natural products and has
captured the interest among a number of synthetic groups
as targets for total synthesis due to the challenging tetracyclic
galanthan skeleton.3-5 The lycorine alkaloids display useful
biological properties including antiviral, insect antifeedant,
and antineoplastic activity, as well as other pharmacological
properties.6 Lycorine (1) was the first alkaloid of this group
to be isolated7 and was studied for its antitumor properties
long before the more oxygenated congeners were identified.8
The structurally related amaryllidaceae constituents dihy-
drolycorine (2),9 lycoricidine (3), pancratistatin (4), and
zephyranthine (5)10 have also been isolated,11 screened for
biological activity,12 and synthesized by several research
Figure 1. Lycorine-type alkaloids.
(1) (a) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1987; Vol. 30, p 251. (b) Polt, R. In Organic Synthesis: Theory
and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich CTt, 1998; Vol.
groups.3-5 In contrast to other members of the lycorine
family, only a limited number of syntheses of zephyranthine
(5) have been carried out10 and there are no reports dealing
with the synthesis of the stereoisomeric epi-zephyranthine
3, pp 109-148.
(2) (a) Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: New York, 1998; Vol. 51, pp 323-424. (b) Lewis, J. R. Nat. Prod.
Rep. 1998, 107-110.
10.1021/ol049348f CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/19/2004

6. The work reported herein derives from a general program
underway in our laboratories that is designed to exploit the
[4+2]-cycloaddition chemistry of readily available 2-amid-
ofurans for natural product synthesis.13 Our approach toward
epi-zephyranthine 6 employs two novel synthetic steps: (1)
an imidofuran Diels-Alder reaction that occurs at room
temperature and (2) a Rh(I)-catalyzed ring opening of the
resulting 7-oxa-bicyclo[2.2.1]hept-2-ene cycloadduct, which
sets the cis-diol stereochemistry of 6 with complete diaste-
reoselectivity. The approach takes advantage of some related
chemistry developed by Lautens and co-workers where an
oxabicyclo[2.2.1]heptane undergoes a Rh(I)-catalyzed nu-
cleophilic ring opening reaction.14
provided the expected imidofuran 10, which rapidly reacted
at room temperature to deliver the Diels-Alder cycloadduct
9 in 55% isolated yield. Intrigued by the ease with which
imidofuran 10 underwent cycloaddition, we investigated
several other systems containing related tethers as illustrated
in Scheme 2. The mixed anhydrides 14-15 were subjected
Scheme 2
Our retrosynthetic analysis was based on our earlier report
describing the intramolecular [4+2]-cycloaddition of amid-
ofurans (IMDAF).13 The desired tetracyclic galanthan core
of 6 was envisioned to arise from a radical-induced cycliza-
tion of 7,15 which in turn may be derived from lactam 8.
We anticipated that the hexahydroindolinone unit of 8 would
be formed by a Rh(I)-catalyzed alcoholysis of cycloadduct
916 acquired by an IMDAF reaction of furan 10 (Scheme
1).
Scheme 1
to the acylation protocol and provided the desired imid-
ofurans 18-19 which also underwent cycloaddition at 25
(4) For total syntheses of pancratistatin see: (a) Danishefsky, S.; Lee, J.
Y. J. Am. Chem. Soc. 1989, 111, 4829. (b) Tian, X. R.; Hudlicky, T.;
Ko¨nigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643. (c) Trost, B. M.;
Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (d) Keck, G. E.;
McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (e)
Hudlicky, T.; Tian, X. R.; Ko¨nigsberger, K.; Maurya, R.; Rouden, J.; Fan,
B. J. Am. Chem. Soc. 1996, 118, 10752. (f) Chida, N.; Jitsuoka, M.;
Yamamoto, Y.; Ohtsuka, M.; Ogawa, S. Heterocycles 1996, 43, 1385. (g)
Doyle, T. J.; Hendrix, M.; VanDerveer, D.; Javanmard, S.; Haseltine, J.
Tetrahedron 1997, 53, 11153. (h) Magnus, P.; Sebhat, I. K. Tetrahedron
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Pharm. Bull. 1976, 24, 2977. (b) Paulsen, H.; Stubbe, M. Tetrahedron Lett.
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Initially, we had envisioned imidofuran 10 arising from
the simple acylation of furanyl carbamate 11 with the acid
chloride derived from 3-butenoic acid. However, under a
variety of conditions 11 proved to be remarkably resistant
toward acylation. After some experimentation, we found that
the addition of lithium carbamate 12, formed by the action
of n-BuLi on 11, to a solution of the mixed anhydride 13
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Org. Lett., Vol. 6, No. 13, 2004

°C (12 h) to furnish the oxabridged cycloadducts 22-23.
When the more highly activated anhydride 16 was used,
imidofuran 20 could not be observed because the [4+2]-
cycloaddition occurred too rapidly to preclude its detection,
even at 0 °C. In contrast, the more sterically congested
anhydride 17 furnished imidofuran 21, which required
heating at 90 °C to give cycloadduct 25. The increase in
reactivity of these 2-imido-substituted furans (0-90 °C)
when compared to the related furanyl carbamates13 (>150
°C) is clearly related to the placement of the carbonyl center
within the dienophilic tether. Dramatic effects on the rate of
the Diels-Alder reaction were previously noted to occur
when an amido group was used to anchor the diene and
dienophile.17 Our ability to isolate the highly labile oxabi-
cyclic adducts (9; 22-25) is presumably a result of the lower
reaction temperatures employed as well as the presence of
the extra carbonyl group, which diminishes the basicity of
the nitrogen atom thereby retarding the ring cleavage/
rearrangement reaction generally encountered with these
systems.13 When exposed to more forcing conditions (i.e.,
>100 °C), the oxabridged cycloadducts 22-25 were smoothly
transformed (>90%) into the corresponding hexahydroin-
dolinone systems 26-29.
compounds is highly regioselective, giving rise to products
derived from the attack of the nucleophile distal to the
bridgehead substituent.16,19 Our first set of experiments were
carried out with oxabicyclics 9 and 22 using Lauten’s
conditions16 ([Rh(COD)Cl]2, DPPF). Phenol and N-methyl-
aniline were employed as the nucleophilic reagents. This led
to the ring-opened alcohols 30-33 in excellent yield (Scheme
3). An X-ray crystal structure (i.e. 31) of the major
Scheme 3
7-Oxabicyclo[2.2.1]heptanes have been employed as valu-
able intermediates for the synthesis of a variety of natural
products.18 The large number of selective transformations
possible with the oxabicyclic system endow this nucleus with
impressive versatility. A crucial synthetic transformation
employing these intermediates involves cleavage of the
oxygen bridge to provide functionalized cyclohexane deriva-
tives.19 In earlier reports, Lautens and co-workers demon-
strated that the ring opening of unsymmetrical oxabicyclic
diastereomer formed (5:1 for 30/31; 20:1 for 32/33) un-
equivocally established the cis relationship between the
nucleophile and hydroxyl groups in the ring-opened products.
Interestingly, the stereochemical outcome of this reaction was
exactly opposite to that reported by Lautens for the Rh(I)-
catalyzed alcoholysis and aminolysis of oxabenzonorborna-
diene.16 Subsequent experiments revealed that the reaction
of 9 with the Rh(I)-catalyst in the presence of various
ammonium carboxylates16c generated the dienyl alcohol 34
in 75% isolated yield as the exclusive product. Reaction of
5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane (35) with oxabi-
cyclics 9 and 22, using 5 mol % of the Rh(I) catalyst and
2.0 equiv of Cs2CO3 (5 M in H2O) in THF at 65 °C, led to
the ring-opened alcohols 36 and 37 in 70-80% yield. The
cis isomer was formed exclusively and parallels the results
observed with the alcoholysis and aminolysis experiments.
When the Rh(I)-catalyzed reaction was carried out with
phenyl boronic acid16d and without added base, the ring-
opened boronates 38 and 39 were obtained in excellent yield
(>95%). Both boronates were cleaved to the corresponding
diols20 which were subsequently transformed into dioxolanes
40 and 41 by reaction with 2,2-dimethoxypropane. It was
also possible to prepare the same 1,3-dioxolanes (>90%)
by treating oxabicyclic adducts 9 and 22 with catalytic
anhydrous SnCl2 in acetone.21
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Lautens, M. Top. Curr. Chem. 1997, 190, 1.
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Org. Lett., Vol. 6, No. 13, 2004
2191

The proposed mechanism for the Rh(I)-catalyzed reaction
of the oxabicyclic adduct is outlined in Scheme 4. Coordina-
Scheme 5
Scheme 4
tion of Rh(I) to the alkenyl π-bond followed by nitrogen-
assisted cleavage of the carbon-oxygen bond occurs to
furnish the π-allyl rhodium(III) species 42. A subsequent
nucleophilic addition occurs from the least hindered terminus
of 42 and on the side opposite the rhodium complex. Proton
exchange of intermediate 43 followed by rhodium decom-
plexation ultimately leads to the cis diastereomers 30-33.
In the presence of the basic ammonium carboxylate, inter-
mediate 42 (R ) H) undergoes preferential deprotonation
and subsequent loss of Rh(I) to generate a transient diene
that isomerizes to give 34. The formation of 36 (or 37) from
the reaction with phenyl boronic ester 35 can best be
rationalized as proceeding by an initial transmetalation of
the boronate to rhodium(I) chloride or hydroxide in the
presence of Cs2CO3. The resulting species will then undergo
an exo-selective carborhodation at the oxabicyclic olefin to
generate intermediate 44. Chelation of the olefin and oxygen
atom of the oxabicycle with the rhodium metal accounts for
the high exo selectivity. â-Elimination of oxygen, assisted
by the nitrogen lone pair, furnishes intermediate 45, which
eventually leads to the ring-opened alcohols 36 and 37.
We are now in a position to apply the experience gained
from our model studies to the synthesis of epi-zephyranthine
(6). To this end, dioxolane 40 was easily converted to the
corresponding benzamide 46 in 81% yield by first removing
the t-Boc group, using MgClO4 in CH3CN followed by
benzoylation with the acid chloride of 6-iodobenzo[1,3]-
dioxazole-5-carboxylic acid (Scheme 5). Exposure of 46 to
n-Bu3SnH in benzene at reflux in the presence of AIBN
afforded the anticipated tetracyclic product 47 in 55% yield.
The trans-B,C- and cis-C,D-ring fusion of the cyclized
product was unambiguously assigned by an X-ray crystal
structure of compound 47. SYBYL force field calculations
suggest that this stereochemistry corresponds to the most
stable isomer, and is also in agreement with the earlier reports
of Rigby15a and Schultz.15b Reduction of 47 with BH3‚THF
followed by hydrolysis of the 1,3-dioxolane furnished (65%)
epi-zephyranthine in an overall yield of 14.5% for the 7-step
sequence starting from tert-butyl furanyl carbamate 11.
In summary, a new strategy for the synthesis of the
amaryllidaceae alkaloid family has been developed, which
is based in part on an extraordinarily facile intramolecular
Diels-Alder reaction of a 2-imido-substituted furan for
construction of the hexahydroindolinone core. By using a
Rh(I)-catalyzed ring opening of the oxabicyclic adduct, the
cis diol stereochemistry of epi-zephyranthine was established.
The application of this approach to other natural product
targets is currently under investigation, the results of which
will be disclosed in due course.
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (Grant No.
CHE-0132651). We thank our colleague, Dr. Kenneth
Hardcastle, for his assistance with the X-ray crystallographic
studies, Dr. Stephen M. Lynch for some experimental
assistance in the early stages of the project, and Professor
Tomas Hudlicky for some helpful comments.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds together with an Ortep drawing for compounds
31 and 47. This material is available free of charge via the
Internet at http://pubs.acs.org.
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