A Convenient One-Pot Procedure to Afford Bicyclic Molecules by Stereospecific Iron Carbonyl Mediated [6 + 2] Ene-Type Cyclization: A Possible Approach to Gelsemine

Article abstract of DOI:10.1021/ja030407e

A convenient one-pot procedure to prepare angularly substituted bicyclic and tricyclic molecules with excellent diastereoselectivity in good yield was developed, by Fe(CO)₅ promoted cyclization. Three transformations (complexation, isomerizatio

Full text of DOI:10.1021/ja030407e

Published on Web 10/09/2003
A Convenient One-Pot Procedure to Afford Bicyclic Molecules by
Stereospecific Iron Carbonyl Mediated [6 + 2] Ene-Type Cyclization: A
Possible Approach to Gelsemine
Anthony J. Pearson* and Xiaolong Wang
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106
Received July 8, 2003; E-mail: ajp4@cwru.edu
Iron has been widely used in organic synthesis.1 Fe(0) is known
Scheme 3
to promote isomerization of monoolefins2 and cycloaddition of
conjugated dienes.3 For several years, we have been developing
an intramolecular coupling reaction between cyclohexadiene-Fe-
(CO)3 complexes and pendant olefins, which cyclize to give
spirocyclic molecules.4 By tandem double cyclization, a complex
tricyclic molecule can be prepared in a single step with complete
diastereoselectivity (Scheme 1).4d
Scheme 1
atmosphere for 6 h gave only traces of 5. The major products were
enamide 3 and five-membered lactam 4. Extension of the reaction
time led to decomposition. Varying the substrate concentration
indicated an autocatalysis phenomenon. We concluded that six-
membered lactam formation was not favored, and instead the
Looking only at the second cyclization suggests that a bicyclic
structure might be formed in the absence of the lactam ring. If
substrates (B) similar to the double cyclization intermediate (A)
can be made (eq 1), this methodology may be extended to produce
a variety of bicyclic molecules.
reaction proceeded via isomerization (catalyzed by a diene-Fe-
(CO)2 residue), also observed in our previous work,4c followed by
cyclization. Since it is known that Fe(CO)5 catalyzes double bond
migration,2 we added 1-1.5 equiv of Fe(CO)5, whereupon the
isomerization-cyclization proceeded cleanly in 6 h to give 4 in
91% yield as the sole product! Direct cyclization of enamine iron
complex 7 (preparation shown in Scheme 2) to afford 8, without
the ismerization step, was also realized.
Compounds 4 and 8 have a bicyclic framework and stereochem-
istry identical to that in gelsemine, a hexacyclic natural product
which has attracted much attention from the synthetic community
because of its unique cage structure.6 If proper functionality could
be introduced onto 4, this reaction might provide a potential pathway
to gelsemine via intermediate D or its equivalent.
To generate a possible approach to the gelsemine structure, a
substituent is required at C(7a) (structure 12, Scheme 3). Investiga-
tion of our protocol showed that this was problematic. If the R
group (for example Me) is introduced before step c, the ester 9
cannot be hydrolyzed due to steric hindrance.7 Similar difficulties
are anticipated for direct conversion of 10 to 11 (R * H). Attempts
on alkylation (step e) of 2 were disappointing. Similar problems
exist for alkylation of 4 to give 12 (R * H).
The cyclization reaction proceeds via coordination of a pendant
double bond to Fe,4a which should therefore be cis to Fe(CO)3 in
B. With this in mind, we began with amide complex 2, which was
prepared from known acid 15 and N-benzyl allylamine (Scheme
2). Our initial plan was to make six-membered lactam 5. To our
surprise, refluxing 2 in di-n-butyl ether (0.02 mol/L) under CO
Scheme 2
This dilemma prompted us to devise an alternate strategy. Careful
examination of Scheme 3 showed that preparation of the iron
complex (step b) and cyclization (step f) share the same reaction
conditions. We argued that these two steps might be combined,
making the organic framework first, which is then treated with Fe-
(CO)5 in refluxing di-n-butyl ether as the last step (Scheme 4). This
last step would require selective complexation of Fe(CO)3 to the
cyclohexadiene, and isomerization of the pendant double bond,
followed by cyclization. Using our new one-pot protocol, only three
operations are required to obtain the angularly substituted bicyclic
lactam with stereochemistry matching the possible intermediate D
toward gelsemine.
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J. AM. CHEM. SOC. 2003, 125, 13326-13327
10.1021/ja030407e CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 5
combined yield (eq 2). Here, four transformations are realized in a
single operation, but there is little or no regiocontrol during the
hydrosilation reaction (19:20/1.1:1).
Table 1. One-Step Cyclization of 14 to Produce Bicycles 15a
1
2
3
4
reactant
R , R , R , R
product
yield
14a
14b
14c
14d
14e
14f
R1 + R2 ) CH2, R3 ) H, R4 ) Bn
R1 + R2 ) CH2CH2, R3 ) H, R4 ) Bn
R1 ) Ph, R2 ) H, R3 ) Me, R4 ) Bn
R1 ) Me, R2 ) R3 ) H, R4 ) Bn
R1 ) R2 ) R3 ) H, R4 ) Bn
R1 + R2 ) CH2, R3 ) H, R4 )
CH2CH2OTBDPS
15a
15b
15c
15d
15e
15f
92
85
81b
82c
20
68
14g
R1 ) Me, R2 ) DMPS, R3 ) H, R4 )
CH2CH2OTBDPS
15g
63
In conclusion, we have successfully developed a convenient one-
pot (complexation, isomerization, and cyclization) procedure to
construct angularly substituted bicyclic and tricyclic molecules with
excellent diastereoselectivity. Further studies on this reaction
including combination of the in situ hydrosilation of alkyne (eq 2)
are underway. Synthetic approaches to gelsemine using this
methodology are under consideration.
a Reaction times for cyclization step range from 24 to 36 h, see
Supporting Information. b Including another isomer, where iron is on the
other face of the cyclohexadiene ring.11 c Including 21% demetalated
product.
To our delight, the transformations worked as expected. Alky-
lation of 1,4-dihydrobenzoic acid8 followed by amidation delivered
N-allylamides 14a-g, substrates that were subjected to the Fe-
mediated one-pot cyclization reaction. When trienes 14 were
refluxed in di-n-butyl ether (0.02 mol/L) under CO atmosphere in
the presence of Fe(CO)5, a single product 15 was obtained in good
yield for all of the substrates except 14e (Table 1). Tricyclic
products were formed for 15a, b, and f. In 15f and 15g, a vinyl
equivalent (CH2CH2OTBDPS) was introduced at the angular
position instead of a simple benzyl group (but note that phenyl
group can be converted to carboxylic acid9). 15g is especially
noteworthy, where the organic part matches D, not only in terms
of skeleton and stereochemistry, but also functionality, since
dimethylphenylsilyl is a latent hydroxyl and TBDPS-protected
hydroxyethyl is a potential vinyl group. It also showed that a
vinylsilane is compatible with the reaction conditions. 15g was
chosen to demonstrate the demetalation of these diene-Fe(CO)3
complexes,4c yielding the corresponding diene 16 quantitatively.
With known chemistry to selectively functionalize conjugated
cyclohexadienes,10 we have good reason to envision compound 16
as a potential gelsemine intermediate.
Acknowledgment. We thank the National Science Foundation
for financial support (CHE-0131043).
Supporting Information Available: Experimental procedures and
Figures giving NMR spectra (1H, 13C) of all new compounds (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Hegedus, L. S. In Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; Universtiy Science Books: Sausalito,
California, 1999. (b) Pearson, A. J. Iron Compounds in Organic synthesis;
Academic Press: San Diego, 1994.
(2) (a) Stille, J. K.; Becker, Y. J. Org. Chem. 1980, 45, 2139. (b) Uma, R.;
Crevisy, C. Gre´e, R. Chem. ReV. 2003, 103, 27.
(3) Dieck, H. T.; Dietrich, J.; Wilke, G. Angew. Chem. 1985, 97, 795.
(4) (a) Pearson, A. J.; Zettler, M. J. Am. Chem. Soc. 1989, 111, 3908. (b)
Pearson, A. J.; Dorange, I. B. J. Org. Chem. 2001, 66, 3140. (c) Pearson,
A. J.; Wang, X. Tetrahedron Lett. 2002, 43, 7513. (d) Pearson, A. J.;
Wang, X. J. Am. Chem. Soc. 2003, 125, 638. For other metal catalyzed
[6 + 2] cyclizations, see for example: (e) Rigby, J. H.; Kondratenko, M.
A.; Fiedler, C. Org. Lett. 2000, 2, 3917. (f) Schmidt, T.; Bienewald, F.;
Goddard, R. Chem. Commun. 1994, 16, 1857.
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(6) See for example: (a) Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem.
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(11) Fe(CO)3 disengaged from the diene due to steric hindrance of the isopropyl
and recoordinated to the diene on the other face during the reaction.
(12) Bandara, B. M. R.; Birch, A. J.; Chauncy, B.; Kelly, L. F. J. Organomet.
Chem. 1981, 208, 332.
Scheme 5 explains the diastereoselectivity of this reaction. The
amide carbonyl directs Fe(CO)3 to coordinate the diene on the same
side,12 followed by rearrangement of the allyl amide to enamide
(steps a and b, Scheme 5) or vice versa (steps c and d) to give the
intermediate 17, which then readily cyclizes to give the final product
15. Intermediate 17f was isolated and fully identified. It should be
mentioned that enamide 17 is difficult to make by conventional
organic chemistry.
Interestingly, when N-propargylamide 18 was subjected to the
above cyclization conditions in the presence of 3 equiv of
triethylsilane, 19 and 20 were produced in 53% (unoptimized)
JA030407E
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