Diverging stereochemical pathways in an intramolecular Diels-Alder reaction determined by dienophile structure

Article abstract of DOI:10.1021/ol034823f

(Matrix presented) Intramolecular Diels-Alder cycloaddition of tolylsulfonyl alkynone 5a and vinyl ketone 19 led to single isomers with opposite diastereoselectivity. Decalin 20 incorporates the correct C(9)-C(11) stereochemical array for a projected synt

Full text of DOI:10.1021/ol034823f

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2777-2780
Diverging Stereochemical Pathways in
an Intramolecular Diels−Alder Reaction
Determined by Dienophile Structure
Kwangho Kim, Umar S. M. Maharoof, Jessica Raushel, and Gary A. Sulikowski*
Department of Chemistry, Texas A&M UniVersity, College Station, Texas 77842
sulikowski@mail.chem.tamu.edu
Received May 13, 2003
ABSTRACT
Intramolecular Diels−Alder cycloaddition of tolylsulfonyl alkynone 5a and vinyl ketone 19 led to single isomers with opposite diastereoselectivity.
Decalin 20 incorporates the correct C(9)−C(11) stereochemical array for a projected synthesis of HMP-Y1 (1).
Hibarimicins A, B, C, D, and G are among the most complex
aromatic polyketide dimeric microbial secondary metabolites
isolated (Figure 1).1,2 In addition to unique structural features,
the hibarimicins possess important biological activity, specif-
ically inhibiting protein tyrosine kinase activity with little
effect on protein kinases A and C. In an effort to elucidate
details of the biosynthetic pathway leading to the hiba-
rimicins, Kajiura and co-workers subjected the producing
strain, Microbispora rosea subsp. hibaria TP-A0121, to
random mutagenesis.3 Several of the resulting blocked
mutants were cultured and found to produce a series of novel
metabolites related to the biogenesis of the hibarimicins
(1) (a) The structure of Hibarimicin B is identical with that of angelmicin
B, see: Uehara, Y.; Li, P.-M.; Fukazawa, H.; Mizuno, S.; Nihei, Y.; Nishio,
M.; Hanada, M.; Yamamot, C.; Furumai, T.; Oki, T. J. Antibiot. 1993, 46,
1306-1308. (b) Hori, H.; Higashi, K.; Ishiyama, T.; Uramoto, M.; Uehara,
Y.; Oki, T. Tetrahedron Lett. 1996, 37, 2785-2788.
(2) (a) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51, 394-
401. (b) Hori, H.; Igarashi, Y.; Kajiura, T.; Furumai, T.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 1998, 51, 402-
417.
(3) (a) Kajiura, T.; Furumai, T.; Igarashi, Y.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 53-
60. (b) Igarashi, Y.; Kajiura, T.; Furumai, T.; Hori, H.; Higashi, K.;
Ishiyama, T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 61-
70. (c) Hori, H.; Kajiura, T.; Igarashi, Y.; Furumai, T.; Higashi, K.; Ishiyama,
T.; Uramoto, M.; Uehara, Y.; Oki, T. J. Antibiot. 2002, 55, 46-52.
Figure 1. Structure of hibarimicins and HMP-Y1 (1).
10.1021/ol034823f CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/08/2003

including the symmetrical aglycon HMP-Y1 (1) (hibarimicin-
mutant product Y1). A common structural feature shared by
HMP-Y1 (1) and the more complex hibarimicins is the highly
substituted AB and GH ring systems (Figure 1). In contem-
plating the development of a synthetic program directed
toward the hibarimicins and related metabolites such as
HMP-Y1 (1) we considered the development of a stereo-
controlled synthesis of the AB and GH ring systems a major
sub-goal. To this end, we have investigated the intramolecular
Diels-Alder cycloaddition of tolylsulfonyl alkynones 5a and
5b (Scheme 1). We anticipated that hydrolysis of cycloadduct
Scheme 2
Scheme 1
cis Decalin 9 with the desired sense of asymmetric induction
between the acetonide group and ring fusion hydrogen (cf.
C(9) and C(11) in 3 and 9). We also planned to evaluate the
effect of the configuration of the neighboring C(10) allylic
oxygen on the stereoselectivity of the cycloaddition process
(5a and 5b). An intramolecular Diels-Alder reaction re-
ported by Hirama and Uei leading to a substituted Decalin
en route to compactin showed that an allylic oxygen adjacent
to the diene component of the Diels-Alder reaction induced
the C(9)-C(10) relative stereochemistry shown in 4.6 We
thus anticipated that isomer 5a would constitute a matched
case and give higher selectivity for the desired cycloadduct
(4). Finally, our synthetic plan will also serve to evaluate
for the first time an arylsulfonyl alkynone as a dienophile in
a Diels-Alder reaction.7
Our route to arylsulfonyl alkynones 5a and 5b started with
aldehyde 10, which was prepared in four steps from L-tartaric
acid following a slight modification of a procedure reported
by Kibayashi.8 Addition of 1-lithio-1,3-butadiene9 to 10 gave
a 70:30 mixture of allylic alcohols 11 and 12, a ratio of
stereoisomers in accord with related aldehyde addition
reactions.10 We elected to first pursue the synthesis of
arylsulfonyl alkynone 5b, with the expectation that we would
observe the desired sense of asymmetric induction in the key
intramolecular Diels-Alder reaction based on the earlier
report from the Fallis group on a related Diels-Alder
substrate (6 f 7, Scheme 2). Allylic alcohol 11 was
converted to aldehyde 13 by a standard three-step procedure.
A key transformation was the addition of the ethynyl p-tolyl
sulfone anion to aldehyde 13. Ethynyl p-tolyl sulfone has
served as an excellent Michael acceptor and dienophile on
numerous occasions.11 However, there are no examples of
the derived anion adding to carbonyl compounds. We
4 would produce diketone 3, an intermediate that in principle
could be manipulated to ketone 2 based on earlier investiga-
tions on the hibarimicins reported from our group.4 An
important consideration in our proposed Diels-Alder cy-
cloaddition was the emergence of the C(9) stereocenter in
the configuration shown.
Among the factors to be taken into account to obtain
excellent stereoselectivity in intramolecular Diels-Alder
reactions are the incorporation of steric and rigidifying
structural features within the tether joining the diene and
dienophile. In earlier work Fallis demonstrated that the
incorporation of a trans isopropylidene acetal â to both the
diene and dienophiles serves to limit the flexibility of the
side chain. This added rigidity results in an enhancement of
the interaction between the reacting diene and dienophile
and induces excellent diastereoselectivity for the production
of substituted Decalins.5 For example, heating triene 6 in
refluxing dichloromethane resulted in exclusive production
of endo adduct 7 (Scheme 2). In this case A1,3 interaction
between the MOM ether and PMB carbinol ether groups may
contribute to the observed diastereoselectivity. Of greater
significance to our planned approach to the AB and GH ring
system of HMP-Y1 was the cycloaddition of triene 8 to give
(6) Hirama, M.; Uei, M. J. Am. Chem. Soc. 1982, 104, 4251-4253.
(7) Arylsulfonyl alkynoates: (a) Shen, M.; Schultz, A. G. Tetrahedron
Lett. 1981, 22, 3347-3350. (b) Corey, E. J.; Jardine, P. D.; Rohloff, J. C.
J. Am. Chem. Soc. 1988, 110, 3672-3673. (c) Pangka, V. R.; Morgan, A.
R.; Dolphin, D. J. Org. Chem. 1986, 51, 1094-1100.
(8) Iida, H.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1987, 52, 3337-
3342.
(4) Lee, C. S.; Audelo, M. Q.; Reibenspies, J.; Sulikowski, G. A.
Tetrahedron 2002, 58, 4403-4409.
(5) (a) Millan, D. S.; Pham, T. T.; Lavers, J. A.; Fallis, A. G. Tetrahedron
Lett. 1997, 38, 795-798. (b) Wong, T.; Wilson, P. D.; Woo, S.; Fallis, A.
G. Tetrahedron Lett. 1997, 38, 7045-7048. (c) Melekhov, A.; Forgione,
P.; Legoupy, S.; Fallis, A. G. Org. Lett. 2000, 2, 2793-2796.
(9) Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K.
Tetrahedron 1981, 37, 3967-3975.
(10) (a) Schneider, C.; Kazmaier, U. Synthesis 1998, 1314-1320. (b)
Martin, S. F.; Chen, H. J.; Lynch, V. M. J. Org. Chem. 1995, 60, 276-
278.
(11) Back, T. G. Tetrahedron 2001, 57, 5263-5301.
2778
Org. Lett., Vol. 5, No. 16, 2003

We next considered the possibility that the opposite C(10)
configuration may favor the desired cycloadduct stereoiso-
mer. To this end, we converted allylic alcohol 12 to alkynyl
sulfone 16 (Scheme 5) following a synthetic route identical
Scheme 3
Scheme 5
with the reaction sequence shown in Scheme 4. Oxidation
of 16 with Dess-Martin periodinane in dichloromethane led
to the production of a single Diels-Alder cycloadduct (17)
via arylsulfonyl alkynone 5a. The stereochemistry of 17 was
assigned based on an observed 10.5-Hz coupling constant
between H9 and H10. Thus, once again we observed exclusive
formation of the undesired configuration at C(9).
succeeded in adding the lithium salt derived from ethynyl
p-tolyl sulfone to several aldehydes; however, attempts to
add the corresponding anion to aldehyde 13 proceeded in
poor yield. In contrast, addition of trimethylsilylethynyl
p-tolyl sulfone12 to aldehyde 13 catalyzed by tetrabutylam-
monium fluoride (Kuwajima conditions) provided 14 in 50-
58% yield.13 Oxidation of 14 with Dess-Martin periodinane
in dichloromethane produced ketone 5b, which spontaneously
underwent Diels-Alder cycloaddition at room temperature
to afford a single cycloadduct 15 in 50-60% yield. The
stereochemistry of 15 was assigned following single-crystal
X-ray analysis and surprisingly proved to possess the
undesired C(9) stereochemical configuration.
Our results initially appeared to contradict the intramo-
lecular Diels-Alder cycloadditions reported by Fallis (Scheme
2). The two substrates we examined (5a and 5b) upon
oxidation led to a Diels-Alder cycloaddition in which the
C(9) and C(11) hydrogens emerged in a cis relationship. In
contrast, intramolecular cyclization of 6 and 8 led to the
corresponding trans isomer as the major product. The major
difference between substrates was the reacting dienophile.
To determine if simply changing the nature of the dienophile
did indeed lead to a reversal of diastereoselectivity we
prepared triene 19 (Scheme 6). Heating 19 at 90 °C in toluene
for 40 h led to the isolation of a single cycloadduct. Single-
crystal X-ray analysis revealed the cycloadduct indeed
possessed the trans relative stereochemistry between C(9)
and C(11) in accord with earlier results by Fallis.
Scheme 4
There have been many documented examples of cycload-
dition reactions reported in the literature in which the
dienophile activating group and/or substituents within the
connecting chain can have a major effect on the stereochem-
ical outcome of an intramolecular Diels-Alder reaction.14-16
For example, the position of the electron-withdrawing group
on the dienophile component can have a significant effect
on the stereoselectivity of an IMDA reaction (vis a´ vis
internal versus external activation) by inducing variation in
the asynchronicity of the reacting transition state.15 In the
case of Diels-Alder substrates 5a, 5b, and 19, the trans
(12) (a) Bhattach, S. N.; Josiah, B. M.; Walton, D. R. M. Organomet.
Chem. Synth. 1971, 1, 145-149. (b) Waykole, L.; Paquette, L. A. Org.
Synth. 1988, 67, 149-156.
(13) Kuwajima, I.; Nakamura, E.; Hashimoto, K. Tetrahedron 1983, 39,
975-982.
(14) (a) Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2297-
2300. (b) Boeckman, R. K.; Ko, S. S. J. Am. Chem. Soc. 1982, 104, 1033-
1041. (c) White, J. D.; Sheldon, B. G. J. Org. Chem. 1981, 46, 2273-
2280.
(15) (a) Taber, D. F.; Campbell, C.; Gunn, B. P.; Chiu, I. C. Tetrahedron
Lett. 1981, 22, 5141-5144. (b) Roush, W. R.; Peseckis, S. M. J. Am. Chem.
Soc. 1981, 103, 6696-6704.
(16) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915-930.
Org. Lett., Vol. 5, No. 16, 2003
2779

Scheme 6
Scheme 7
isomeric product. One cycloadduct (20) possesses an array
of four stereocenters common to the aglycon of hibarimicin
and various congeners. Finally, we also demonstrated the
excellent reactivity of arylsulfonyl alkynones as dienophiles.
Further progress on the total synthesis of hibarimicin and
related aromatic polyketide dimeric natural products will be
reported in due course.
acetonide group located within the connecting side chain
significantly restricts the number of possible transtion states
leading to the observed products. In the case of triene 19
the chair transition state 21 (Scheme 7) best accounts for
the observed stereoselectivity.5 In contrast, chair (22) and
boat (23 and 24) transition states can be proposed for the
cyclization of arylsulfonyl alkynones 5a and 5b to provide
cycloadducts 15 and 17. Inspection of molecular models
suggests a boat transition state provides optimal overlap of
the reacting diene and acetylenic dienophile.16 Furthermore,
boat transition state 23 should be favored over 24 based on
consideration of nonbonded interactions between C(8) and
C(11) hydrogens. Thus we conclude arylsulfonyl alkynones
5a and 5b favor boat transition state 23 and vinyl ketone 19
cyclizes by way of chair transition state 21 accounting for
the opposite stereoselectivity of these Diels-Alder substrates.
In conclusion we have observed opposite diastereoselec-
tivity for two Diels-Alder substrates that differ only in
dienophile structure. Notably, both substrates give a single
Acknowledgment. We thank the National Institutes of
Health (CA59515-06) and The Robert A. Welch Foundation
(A-1230) for support of this research. We also thank Joseph
Reibenspies for determining the X-ray crystal structure of
15 and 20.
Supporting Information Available: Full characterization
data for 10-20. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL034823F
2780
Org. Lett., Vol. 5, No. 16, 2003