Intramolecular [1 + 4 + 1] cycloaddition: Establishment of the method

Article abstract of DOI:10.1021/ja103551x

Structurally complex and physiologically active natural products often include bicyclic and polycyclic ring systems having defined relative and absolute configuration. Approaches that allow the construction of more than one carbocyclic ring at a time have proven valuable, in particular those that allow at the same time the control of an array of new stereogenic centers. One of the most general and most widely used protocols has been the intramolecular Diels-Alder [4 + 2] cycloaddition, in which a single stereogenic center between the diene and the dienophile can control the relative and absolute configuration of the product. We report a two-step [1 + 4 + 1] procedure for bicyclic and polycyclic construction, based on the cyclization of an ω-dienyl ketone. This is complementary to, and will likely be as useful as, the intramolecular Diels-Alder cycloaddition.

Full text of DOI:10.1021/ja103551x

Published on Web 07/23/2010
Intramolecular [1 + 4 + 1] Cycloaddition: Establishment of
the Method
Douglass F. Taber,* Pengfei Guo, and Na Guo
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received April 26, 2010; E-mail: taberdf@udel.edu
Abstract: Structurally complex and physiologically active natural products often include bicyclic and
polycyclic ring systems having defined relative and absolute configuration. Approaches that allow the
construction of more than one carbocyclic ring at a time have proven valuable, in particular those that
allow at the same time the control of an array of new stereogenic centers. One of the most general and
most widely used protocols has been the intramolecular Diels-Alder [4 + 2] cycloaddition, in which a
single stereogenic center between the diene and the dienophile can control the relative and absolute
configuration of the product. We report a two-step [1 + 4 + 1] procedure for bicyclic and polycyclic
construction, based on the cyclization of an ω-dienyl ketone. This is complementary to, and will likely be
as useful as, the intramolecular Diels-Alder cycloaddition.
Introduction
condensation of the dienophile onto the diene directed by a
single stereogenic center can generate simultaneously up to four
Carbocycles, as exemplified by calcitriol and taxol, can be
potent drugs. Although computationally driven lead generation
often suggests potential new drug candidates that are polycar-
bocyclic, such candidates are usually not pursued, because of
the assumption that a carbocyclic drug would be impractical to
manufacture.1 We report a simple two-step route (eq 1) to the
enantiomerically pure carbobicyclic scaffold 3a from the acyclic
ketone 1a (eq 1).2
new stereogenic centers in a highly steroselective and often
predictable fashion.4 Seeking a complementary protocol, we
anticipated that cyclization of an acyclic diene ketone 1a
followed by Fe-mediated cyclocarbonylation of the resulting
alkenyl cyclopropane 2a could efficiently deliver the bicyclic
enone 3a with high diastereocontrol.
There were three concerns with this strategy. The first and
most important question was whether we could develop a
method for the cyclization of a dienyl ketone such as 1a to the
alkenyl cyclopropane 2a. The second question was whether a
substituent on the bridge between the ketone and the diene could
direct the new stereogenic centers as they formed. The last
question was whether Fe-mediated cyclocarbonylation would
work with such congested alkenyl cyclopropanes.
The construction of carbobicylic 5,6- or 6,6-systems is of
great importance in the preparation of structurally complex and
biologically intriguing natural products.3 Among those ring
forming strategies, intramolecular Diels-Alder (IDA) cycload-
dition has received intensive attention for decades because
Results and Discussion
Novel Metal-Free Synthesis of Bicyclic and Tricyclic Alk-
enyl Cyclopropanes. We had reported (Scheme 1) that heating
the tosylhydrazone of an ω-alkenyl ketone 4 or aldehyde to
reflux in toluene in the presence of K2CO3 delivered the bicyclic
diazene 5 and that irradiation of the diazene converted it to the
cyclopropane 6.5 In consideration of the high reaction temper-
ature (130 °C), we envisioned that activation of the diazene 7
by an additional alkenyl substituent might enable spontaneous
extrusion of N2. The diradical intermediate 8 so generated could
cyclize to the alkenyl cyclopropane 2b or to the cyclopentene
(1) (a) For an overview of synthetic strategies for polycarbocyclic natural
products, see. Taber, D. F.; Sheth, R. B.; Tian, W. J. Org. Chem.
2009, 74, 2433. For more recent examples, see. (b) Chandler, C. L.;
List, B. J. Am. Chem. Soc. 2008, 130, 6737. (c) Surendra, K.; Corey,
E. J. J. Am. Chem. Soc. 2008, 130, 8865. (d) Trost, B. M.; Ferreira,
E. M.; Gutierrez, A. C. J. Am. Chem. Soc. 2008, 130, 16176. (e)
Pardeshi, S. G.; Ward, D. E. J. Org. Chem. 2008, 73, 1071. (f) Li, L.;
McDonald, R.; West, F. G. Org. Lett. 2008, 10, 3733. (g) Sethofer,
S. G.; Staben, S. T.; Hung, O. Y.; Toste, F. D. Org. Lett. 2008, 10,
4315. (h) Maity, P.; Lepore, S. D. J. Am. Chem. Soc. 2009, 131, 4196.
(i) Chung, W. K.; Lam, S. K.; Lo, B.; Liu, L. L.; Wong, W.-T.; Chiu,
P. J. Am. Chem. Soc. 2009, 131, 4556.
(4) (a) Taber, D. F.; Gunn, B. P. J. Am. Chem. Soc. 1979, 3992. (b) Taber,
D. F.; Saleh, S. A. J. Am. Chem. Soc. 1980, 5085. (c) Takao, K.;
Munakata, R.; Tadano, K. Chem. ReV. 2005, 4779–4807. (d) Craig,
D. Chem. Soc. ReV. 1987, 187–238.
(2) For a previous example of intramolecular cyclopropanation followed
by Fe-mediated cyclocarbonylation, see ref 1a.
(3) (a) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 10264–
10266. (b) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am.
Chem. Soc. 2002, 4552–4553. (c) Taber, D. F.; Nakajima, K.; Xu,
M.; Rheingold, A. L. J. Org. Chem. 2002, 4501–4504. (d) Johnson,
T. W.; Corey, E. J. J. Am. Chem. Soc. 2001, 4475–4479. (e) Boger,
D. L.; Ichikawa, S.; Jiang, H. J. Am. Chem. Soc. 2000, 12169–12173.
(f) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 7411–7419.
(5) (a) Taber, D. F.; Guo, P. J. Org. Chem. 2008, 73, 9479. For earlier
accounts of this sort of cyclization, see. (b) Padwa, A.; Ku, H. J. Org.
Chem. 1980, 45, 3756. (c) Brinker, U. H.; Schrievers, T.; Xu, L. J. Am.
Chem. Soc. 1990, 112, 8609. (d) Ashby, E. C.; Park, B.; Patil, G. S.;
Gadru, K.; Gurumurthy, R. J. Org. Chem. 1993, 58, 424. (e) Jung,
M. E.; Huang, A. Org. Lett. 2000, 2, 2659.
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A R T I C L E S
Taber et al.
Scheme 1
Table 1. Cyclization of ω-Dienyl Ketones
9. To explore this hypothesis, the diene ketone 1b was exposed
to our standard conditions. We were pleased to find that the
reaction proceeded smoothly to provide the vinyl cyclopropane
2b directly. Notably, neither the diazene intermediate 7 nor the
cyclopentene 9 derived from rearrangement was observed.
We briefly examined the scope of this cyclization. Alkyl
substituents at all positions of the diene were well tolerated.
The formation of the fused 6,3-system was also successful
(Table 1, Entry 5). Even the ketone 1g cyclized smoothly to
the strained tricyclic vinyl cyclopropane 2g (Table 1, Entry 6).
To our knowledge, this is the first direct protocol for the
preparation of such alkenyl cyclopropanes.
Fe-Mediated Cyclocarbonylation. With the bicyclic alkenyl
cyclopropanes readily available, we were prepared to explore
the Fe-mediated cyclocarbonylation. Previous studies in our
laboratory (Scheme 2) showed that the Fe(CO)5-mediated
cyclocarbonylation of alkenyl cyclopropanes was a general
method for the construction of 5-alkyl cyclohexenones.7 The
organometallic cleavage of alkenyl cyclopropane 10 preferen-
tially proceeded via the metallacycle 12, leading to the cyclo-
hexenone 14. In consideration of the complexity of alkenyl
cyclopropane 2c, there are still two uncertainties for cyclocar-
bonylation. The first is whether this cyclocarbonylation would
work with the much more sterically hindered substrate 2c. The
other factor to consider is whether the Fe(CO)5-mediated
carbonylation of bicyclic alkenyl cyclopropane 2c could follow
the same rule to give bicyclic cyclohexenone 3c via metallacycle
16 with a more stable secondary carbon-metal bond or take a
a The tosylhydrazone cyclizations were run at 130 °C, unless otherwise
noted. For the preparation of the precursor diene iodides, see ref 4. b Yields
are for pure chromatographed products. The cyclopropanes were ∼1:1
mixtures of diastereomers. c Yields are based on the starting ketone.
d Cyclization was run at 140 °C.
different route to deliver the bicyclic cyclohexenone 17 via a
metallacycle 15 with the tertiary carbon-metal bond.
In practice we were pleased to observe that the Fe catalyzed
reaction of 2c proceeded smoothly to yield 3c as the sole
product. We have made a preliminary investigation (Table 2)
of this reaction, which appears to be general. The reaction gave
carbobicyclic 5,6-systems with good regiocontrol. Alkyl sub-
stituents at all positions of the alkenyl cyclopropane were again
well tolerated. The formation of a 6,6-system was also successful
(Entry 5). Cyclocarbonylation of 2g even delivered the more
complex tricyclic compound 3g (Entry 6). Although in general
the product cyclohexenones were conjugated, equilibration of
3e delivered predominantly the nonconjugated enone, as il-
lustrated. We note that Fe(CO)5 is relatively innocuous (LD50
) 25 mg/kg) and certainly inexpensive (three cents/mmol).
Diastereocontrol in the Cycloaddition. We had earlier ob-
served that the intramolecular dipolar cycloaddition to form the
cyclic diazene could proceed with substantial diastereocontrol.
(6) For the preparation of the precursor diene iodides, see (a) Miller, C. A.;
Batey, R. A. Org. Lett. 2004, 699. (b) Page, P. C. B.; Vahedi, H.;
Batchelor, K. J.; Hindley, S. J.; Edgar, M.; Beswick, P. Synlett 2003,
1022. (c) Wang, I.; Dobson, G. R.; Jones, P. R. Organometallics 1990,
9, 2510. (d) Taber, D. F.; Saleh, S. A. J. Am. Chem. Soc. 1980, 102,
5085. (e) Elias, C. A.; Mihou, A. P. Tetrahedron Lett. 1999, 4861.
(7) For the development of Fe-mediated cyclocarbonylation, see: (a)
Victor, R.; Ben-Shoshan, R.; Sarel, S. J. Org. Chem. 1978, 43, 4971.
(b) Taber, D. F.; Kanai, K.; Jiang, Q.; Bui, G. J. Am. Chem. Soc.
2000, 122, 6807. (c) Taber, D. F.; Bui, G.; Chen, B. J. Org. Chem.
2001, 66, 3423. (d) Taber, D. F.; Joshi, P. V.; Kanai, K. J. Org. Chem.
2004, 69, 2268. (e) Taber, D. F.; Sheth, R. B. J. Org. Chem. 2008,
73, 8030.
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Intramolecular [1 + 4 + 1] Cycloaddition
A R T I C L E S
Scheme 2
To understand the diastereoselectivity of the intramolecular 1,3-
dipolar cycloaddition of diazoalkanes, computational analysis
of the possible transition states (TS) was performed to compare
Figure 1. Calculation of the transition states.
their relative stability (Figure 1). For the calculation, a simplified
model structure 18 (Scheme 3) was used. There are four
competing transion states (TS-A-D) which lead to four diazene
diastereomers (20-A-D). To assess the relative energies of these
transition states, we employed B3LYP density functional theory
(DFT) calculations, using the 6-31+G(d,p) basis set as imple-
mented in the Gaussian 03 program.8 Computational results
indicated that TS-A was more stable by 1.51 kcal/mol compared
with its nearest competitor TS-C. Therefore 20-A would be the
kinetically favored product. We also observed that, for these
two more stable TS, the C-C atom distance was about 2.25 Å
and the C-N atom distance was about 2.3 Å. The diazo dipole
was bent at 142°. These results are similar to those calculated
for the intramolecular dipolar cycloaddition of a nitrile oxide.9
Encouraged by these calculations, we prepared the acyclic
ketone 1a from the commerical enantiomerically pure ester 21.10
Alkylation of 21 followed by protection of the alcohol provided
Table 2. Fe-Mediated Cyclocarbonylation
Scheme 3
a Yields are for pure chromatographed material. b Reactions were run to
52-82% conversion. Yields are based on starting material not recovered.
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A R T I C L E S
Taber et al.
several research groups.12 Direct construction of alkenyl cy-
clopropanes usually involves metal carbene chemistry.13 Based
on the intramolecular 1,3-dipolar cycloaddition of an in situ
generated diazoalkane, we have uncovered an efficient metal-
free synthesis of bicyclic alkenyl cyclopropanes that proceeds
with substantial diastereocontrol. The diastereomer preferentially
formed was consistent with our computational analysis of the
competing transition states. We expect that the same compu-
tational approach will make it possible to design other dienyl
ketones that will cyclize with high diastereocontrol.
Scheme 4
The two-step [1 + 4 + 1] protocol for the rapid stereocon-
trolled assembly of carbobicyclic and carbotricyclic scaffolds
outlined here should make such polycyclic intermediates readily
available. We expect that this short and environmentally benign
protocol will have many applications in target-directed synthesis.
Acknowledgment. We thank Dr. John Dykins for mass spectro-
metric measurements, supported by the NSF (0541775), Dr. Glenn
Yap for the X-ray analysis, and the NIH (GM42056) for financial
support. We also thank Professor Douglas J. Doren for helpful
discussions.
Supporting Information Available: Experimental procedures,
details of the X-ray analysis, and 1H and 13C NMR spectra for
all new compounds, and a complete ref 8. This material is
available free of charge via the Internet at http://pubs.acs.org.
the ester 24. Reduction followed by mesylation and SN2
substitution gave the nitrile 25. Exposure of the nitrile to methyl
lithium completed the assembly of the enantiomerically pure
acyclic substrate 1a. Application of the two-step [1 + 4 + 1]
protocol delivered 3a as a 6:1 mixture of diastereomers (Scheme
4). The structure of the major diastereomer, as illustrated, was
confirmed by X-ray analysis. These results are consistent with
the prediction based on the computationally based estimate of
the differences in energy of the competing transition states for
the intramolecular dipolar cycloaddition of 19.
JA103551X
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Alkenyl cyclopropanes are versatile building blocks for
organic synthesis.11 Their unique structural and electronic
properties give rise to an array of interesting and characteristic
transformations, which have been extensively developed by
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