Synthesis of precursors of the agalacto (exo) fragment of the quartromicins via an auxiliary-controlled exo-selective Diels-Alder reaction

Article abstract of DOI:10.1021/ol0609208

A direct synthesis of the α-hydroxyaldehyde exo-5, a precursor of the exo-spirotetronate subunit of the quartromicins, was achieved through an exo-selective Lewis acid-catalyzed Diels-Alder reaction of dienophile 12a and diene 1.

Full text of DOI:10.1021/ol0609208

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2795-2798
Synthesis of Precursors of the Agalacto
(Exo) Fragment of the Quartromicins via
an Auxiliary-Controlled Exo-Selective
Diels−Alder Reaction
Jun Qi† and William R. Roush*,‡
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109, and
Department of Chemistry, Scripps-Florida, Jupiter, Florida 33458
roush@scripps.edu
Received April 15, 2006
ABSTRACT
A direct synthesis of the
an exo-selective Lewis acid-catalyzed Diels
r
-hydroxyaldehyde exo-5, a precursor of the exo-spirotetronate subunit of the quartromicins, was achieved through
Alder reaction of dienophile 12a and diene 1.
−
The quartromicins are a structurally unique group of
spirotetronate natural products isolated in 1991 by Oki and
co-workers.1 They display antiviral activity against herpes
simplex virus type 1 (HSV-1), the influenza virus, and the
human immunodeficiency virus (HIV).2,3 Oki and co-workers
demonstrated that the quartromicins possess a unique 32-
membered carbocyclic ring system containing two different
spirotetronic acid units connected in an alternating head to
1
tail manner. On the basis of published H NMR data,1
supporting synthetic studies in our group,4 and consideration
of possible biosynthetic precursors, we proposed 5 the relative
stereochemistry of quartromicins A3 and D3 depicted in
Figure 1. We refer to the two spirotetronate fragments as
endo (i.e., that bearing the galactose residue in quartromicin
† University of Michigan.
‡ Scripps-Florida.
(1) Kusumi, T.; Ichikawa, A.; Kakisawa, H.; Tsunakawa, M.; Konishi,
M.; Oki, T. J. Am. Chem. Soc. 1991, 113, 8947.
(2) Tsunakawa, M.; Tenmyo, O.; Tomita, K.; Naruse, N.; Kotake, C.;
Miyaki, T.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 180.
(3) Tanabe-Tochikura, A.; Nakashima, H.; Murakami, T.; Tenmyo, O.;
Oki, T.; Yamamoto, N. AntiViral Chem. Chemother. 1992, 3, 345.
(4) Roush, W. R.; Barda, D. A. Org. Lett. 2002, 4, 1539.
(5) Roush, W. R.; Barda, D. A.; Limberakis, C.; Kunz, R. K. Tetrahedron
2002, 58, 6433.
Figure 1. Structures of quartromicins A3 and D3.
A3) and exo (also referred to as the agalacto unit) by virtue
of the Diels-Alder chemistry that has been targeted for their
synthesis.5,6
10.1021/ol0609208 CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/23/2006

We have previously reported syntheses of the enantio-
merically pure monomeric endo- (6) and exo- (7) spirotetro-
nate units of the quartromicins via the Diels-Alder reaction
of (Z)-substituted diene 1 and the N-acryloyl sultam dieno-
phile 2 (Figure 2).5,6 The major (exo) product of this Diels-
Figure 3. Exo-selective Diels-Alder dienophiles.
However, dienophile 8 is not stable to the Lewis acidic
reaction conditions required for the Diels-Alder coupling
to the relatively unreactive (Z)-substituted diene 1.10 Although
the chiral imide dienophile 9 underwent a MeAlCl2-catalyzed
Diels-Alder reaction with 1 (data not shown), attempted
manipulation of the major Diels-Alder product proved
unproductive.11 In addition, attempts to effect Lewis acid-
mediated Diels-Alder reactions of 1 with R-substituted
dienophiles 10 and 11 were unsuccessful.5 The latter studies
are consistent with literature reports that methacryloyl
sultams adopt ground-state conformations with the dieno-
philic double bond out of conjugation with the methacrylate
carbonyl unit12 as well as with knowledge that the R-methyl
group of methacryloyl imide dienophiles destabilizes the
ground-state S-cis conformation,13 which causes these di-
enophiles to display poor Diels-Alder reactivity.
On the basis of these observations, we designed the
conformationally constrained dienophile 12 which we envis-
aged would undergo an exo-selective Lewis acid-mediated
Diels-Alder reaction with (Z)-diene 1 (Figure 4). It was
Figure 2. Previous syntheses of endo-6 and exo-7.
Alder reaction was converted to aldehyde exo-3, which was
further elaborated to endo-R-hydroxy aldehyde 4 via a
stereoselective two-step installation of the C-1 â-face hy-
droxyl group.5 However, installation of the hydroxyl group
on the hindered R-face of C-1, required for the synthesis of
exo-5, proved to be quite difficult and has been accomplished
only via multistep sequences.5,7 We therefore were interested
in developing a more straightforward strategy that would
allow the hydroxyl group of exo-5 to be installed in many
fewer steps, ideally during an exo-selective Diels-Alder
reaction.
Figure 4. Retrosynthetic analysis of dienophile 12.
anticipated that the R group in 12 would play a critical role
in inducing synthetically useful levels of diastereofacial
selectivity in the Diels-Alder reactions.
Syntheses of oxazolidinones 15a-c are outlined in Scheme
1. Conversion of L-valine (16a) to 5-oxazolidinone 17 as a
Conformationally restricted (S)-cis-enone and (S)-cis-
enoate dienophiles exhibit a striking preference for exo-
Diels-Alder cycloaddition.8 In previous studies, we have
demonstrated that chiral dienophiles 8 and 9 (Figure 3) give
excellent exo- and diastereofacial selectivity in thermal
Diels-Alder reactions with a range of (E,E)-dienes.8,9
(9) (a) Roush, W. R.; Essenfeld, A. P.; Warmus, J. S.; Brown, B. B.
Tetrahedron Lett. 1989, 30, 7305. (b) Roush, W. R.; Reilly, M. L.; Koyama,
K.; Brown, B. B. J. Org. Chem. 1997, 62, 8708. (c) Roush, W. R.; Sciotti,
R. J. J. Am. Chem. Soc. 1998, 120, 7411.
(10) Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402.
(11) Treatment of the exo cycloadduct deriving from Diels-Alder
reaction of 1 and 9 with a variety of nucleophilic reagents led to rapid
cleavage of the N-acetyl group, giving a very hindered lactam that could
not be further manipulated.
(12) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585.
(13) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238. (b) Boeckman, R. K.; Liu, Y. J. Org. Chem. 1996, 61,
6984.
(6) Roush, W. R.; Limberakis, C.; Kunz, R. K.; Barda, D. A. Org. Lett.
2002, 4, 1543.
(7) Trullinger, T. K.; Qi, J.; Roush, W. R. J. Org. Chem. 2006, 71, to be
submitted.
(8) Roush, W. R.; Brown, B. B. J. Org. Chem. 1992, 57, 3380.
2796
Org. Lett., Vol. 8, No. 13, 2006

Scheme 1. Synthesis of Oxazolidinones 15a-c
Scheme 2. Synthesis of Bicyclic Dienophiles 12a-c
single diastereomer proceeded via a three-step sequence.14
Alkylation of 17 with p-methoxybenzyloxymethyl chloride
(PMBMCl) followed by DDQ oxidative deprotection of the
PMB group provided primary alcohol 18.15 Treatment of 18
with sodium hydride induced a ring-closing event that
provided 15a in 90% yield.16 Oxazolidinones 15b,c were
readily synthesized in two steps from R-substituted serine
derivatives 16b,c.17
Synthesis of dienophiles 12a-c was initiated by protection
of racemic 218 as the TBS ether 14 (Scheme 2). The
corresponding acid chloride 22 was coupled with oxazoli-
dinones 15a-c using Evans’ procedure18 which provided
N-acyl oxazolidinones 23a-c in 80% yield. Deprotection
of the benzyl ester with titanium tetrachloride followed by
deprotection of the TBS group using HF produced hydroxy
acids 24a-c.19 Treatment of the hydroxy acids with pivaloyl
chloride provided lactones 13a-c in 60-75% yield. The
sulfide units of 13a-c were then oxidized to the correspond-
ing sulfoxides, subsequent thermal elimination of which
afforded the targeted dienophiles 12a-c in 40-70% yield.
Results of Diels-Alder reactions of dienophiles 12a-c
with (Z)-diene 1 are summarized in Scheme 3. The best
results were obtained using MeAlCl2 among the range of
Lewis acids tested.10 Treatment of 1 and dienophile 12a
(R ) i-Pr) with MeAlCl2 at -78 °C for 5 days provided a
5:1 mixture of cycloadducts 25a and 26a in 70% yield.
Reduction of this mixture with LiAlH4 and then oxidation
of the resulting diols using the Parikh-Doering procedure20
provided exo-hydroxy aldehyde 5 and the endo diastereomer
4 in 60% combined yield. The spectroscopic data for 4 and
5 matched those for samples obtained from previous synthetic
studies.5,7
These data demonstrate that dienophile 12a displays
excellent diastereofacial selectivity and synthetically useful
exo selectivity in the Diels-Alder reaction with (Z)-
substituted diene 1. Comparable selectivity was obtained
when dienophile 12b (R ) Me) was used, but the Diels-
Alder reaction was considerably less efficient in this case
owing to the poor solubility of 12b at -78 °C. Although
dienophile 12c (R ) CH2Ph) exhibited good solubility, it
displayed low reactivity and also was significantly less exo
selective in the Diels-Alder reaction with 1. Thus, a
Scheme 3. Diels-Alder Reactions of Dienophiles 12a-c and
Diene 1
(14) Seebach, D.; Fadel, A. HelV. Chim. Acta 1985, 68, 1243.
(15) Soli, E. D.; Manoso, A. S.; Patterson, M. C.; Deshong, P.; Favor,
D. A.; Hirschmann, R.; Smith, A. B. J. Org. Chem. 1999, 64, 3171.
(16) Avenoza, A.; Cativiela, C.; Corzama, F.; Peregrina, J. M.; Zurbano,
M. M. Tetrahedron: Asymmetry 2000, 11, 2195.
(17) (a) Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R. HelV.
Chim. Acta 1987, 70, 1194. (b) Xi, N.; Ciufolini, M. A. Tetrahedron Lett.
1995, 36, 6595.
(18) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238.
(19) (a) Tsuji, T.; Kataoka, T.; Yoshioka, M.; Sendo, Y.; Nishitani, Y.;
Hirai, S.; Maeda, T.; Nagata, W. Tetrahedron Lett. 1979, 20, 2793. (b)
Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.; Roberts, S.
M. Tetrahedron Lett. 1979, 20, 3981.
(20) Parikh, J. R.; von Doering, E. W. J. Am. Chem. Soc. 1967, 89, 5505.
Org. Lett., Vol. 8, No. 13, 2006
2797

preparatively useful three-step synthesis of R-hydroxy alde-
hyde exo-5 has been achieved by the exo-selective, MeAlCl2-
mediated Diels-Alder reaction of 12a. This synthesis is
considerably shorter than any of the previous routes to this
important quartromicin intermediate that we have examined
to date.5,7
Scheme 5. Diels-Alder Reactions of 12a with Other Dienes
The Diels-Alder reactions of 12a with several other
dienes were examined. The thermal Diels-Alder reaction
of 12a with cyclopentadiene at 23 °C provided a mixture of
three diastereomeric cycloadducts in 80% yield (Scheme 4).
Scheme 4. Diels-Alder Reactions of 12a with
Cyclopentadiene
Diels-Alder reaction of 12a and 2,4-dimethyl-1,3-pentadiene
gave only one diastereomeric product, 36. In all of the
reactions summarized in Scheme 5, near perfect diastereo-
facial selectivity was observed with respect to the dienophile
12a.
In summary, the new conformationally constrained chiral
dienophile 12a undergoes a preparatively useful Lewis acid-
catalyzed and exo-selective Diels-Alder reaction with (Z)-
trisubstituted diene 1, thereby paving the way for the
development of a direct and stepwise efficient synthesis of
R-hydroxy aldehyde exo-5 and the derived exo-spirotetronate
fragment of the quartromicins. Utilization of these intermedi-
ates in ongoing efforts to complete total syntheses of
quartromicins A3 and D3 are underway and will be reported
in due course.
LiAlH4 reduction of this mixture provided a 4:1 ratio of 30
(exo) and 31 (endo). This result indicated that the cycload-
ducts were formed with an exo/endo ratio of 4:1. Dienophile
1a also exhibited excellent diastereofacial selectivity at this
reaction condition (27/28 ) 19:1). Under Lewis acid-
catalyzed conditions (0.3 equiv of MeAlCl2 at -78 °C), the
exo/endo selectivity increased to 19:1 (entry 2). However,
the exo diastereofacial selectivity was significantly reduced
(27/28 ) 3:1). We do not understand the erosion of the
diastereofacial selectivity under these reaction conditions.
The Diels-Alder reactions of dienophile 12a with less-
reactive dienes such as 1,3-cyclohexadiene and trans-2-
methyl-1,3-pentadiene required higher reaction temperatures
than those with cyclopentadiene (Scheme 5). These reactions
gave two diastereomers under both thermal and Lewis acid-
catalyzed reaction conditions, with the exo cycloadduct
predominating under all conditions; stereochemical assign-
ments were made by 1H nOe analysis after reduction of the
cycloadducts to the diol derivatives 32-35. In contrast, the
Acknowledgment. Financial support from the National
Institute of Health (GM 26782) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0609208
2798
Org. Lett., Vol. 8, No. 13, 2006