Stereoselective synthesis of the octahydronaphthalene unit of integramycin via an intramolecular Diels-Alder reaction

Article abstract of DOI:10.1021/ol050191g

(Chemical Equation Presented). The racemic cis-decalin core fragment 30 of integramycin was synthesized by a sequence involving a highly diastereoselective intramolecular Diels-Alder reaction of triene 24. A remarkable switch in stereoselectivity occurred

Full text of DOI:10.1021/ol050191g

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1355-1358
Stereoselective Synthesis of the
Octahydronaphthalene Unit of
Integramycin via an Intramolecular
Diels−Alder Reaction
Thomas A. Dineen and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received January 29, 2005
ABSTRACT
The racemic cis-decalin core fragment 30 of integramycin was synthesized by a sequence involving a highly diastereoselective intramolecular
Diels Alder reaction of triene 24. A remarkable switch in stereoselectivity occurred upon changing the dienophile unit of 24 from (Z)- to
−
(E)-geometry.
Integramycin (1, Scheme 1), a structurally novel HIV-1
integrase inhibitor (IC50 ) 4 µM), was isolated from
Actinoplanes extracts by Singh and co-workers in 2002.1
Integramycin contains a central cis-octahydronaphthalene unit
with acyl tetramic acid and spiroketal-containing side chains.
Thus far, the only synthetic effort directed toward integra-
mycin was published by Floreancig, who reported a synthesis
of the spiroketal fragment.2
Scheme 1. Integramycin and Proposed Biogenesis of the
cis-Decalin Core via an IMDA Reaction
It has been suggested3 that the biosynthesis of the cis-
octahydronaphthalene core unit of integramycin might arise
via an exo-selective intramolecular Diels-Alder reaction
(IMDA)3,4 of an appropriate triene, as in 2. However, our
analysis of this hypothesis indicated that such a transition
state (2) should be disfavored because of the axial orientation
of the hydroxyl and methyl substituents in the chairlike
conformation of the connecting chain. Therefore, a synthetic
approach relying on an IMDA reaction to form the octahy-
dronaphthalene core fragment would have to include ap-
propriate strategies for stereochemical control of this reaction.
We report herein a highly stereoselective synthesis of the
(1) Singh, S. B.; Zink, D. L.; Heimbach, B.; Genilloud, O.; Teran, A.;
Silverman, K. C.; Lingham, R. B.; Felock, P.; Hazuda, D. J. Org. Lett.
2002, 4, 1123.
(2) Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 569.
(3) Oikawa, H.; Tokiwano, T. Nat. Prod. Rep. 2004, 21, 321.
(4) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, 1992; Vol. 5, pp 513-550.
10.1021/ol050191g CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/09/2005

cis-fused octahydronaphthalene core unit of integramycin via
an IMDA reaction of trienone 24. We also present our
observations of the dependence of the cis vs trans selectivity
of IMDA reactions of 1,7,9-decatrien-3-ones on the stereo-
chemistry of the dienophilic double bond.
Scheme 3. Synthesis and IMDA Reaction of Triene 12
Our synthetic strategy is predicated on the expectation that
cis-fused octahydronaphthalenone 5 (Scheme 2) should be
Scheme 2. IMDA Transition State Analysis
a viable precursor to the targeted integramycin ring sys-
tem, 3. Further, we anticipated that intermediate 5 could be
accessed by the IMDA reaction of trienone 4 (Scheme 2).
Previous studies in this laboratory have implicated the
intervention of boatlike transition states in the IMDA
reactions of 1,7,9-decatrien-3-ones.5 Moreover, those studies
indicated that in the absence of overriding nonbonded
interactions, boatlike transition states should predominate in
the IMDA reactions of these substrates.4,5 We reasoned,
therefore, that the IMDA reaction of a trieneone 4, containing
the protected C(10)-OH group of integramycin, would
proceed through boatlike transition state A to give cis-decalin
5 (Scheme 2). The alternative chairlike transition state B
would lead to cis-decalin 6, with the incorrect stereochemistry
for integramycin.
We elected to synthesize racemic triene 12 to test this
hypothesis (Scheme 3). This synthesis began with the
thallium carbonate6 promoted Suzuki coupling7 of known
vinylboronic acid 78 and vinyl iodide 89 to give diene 9 in
60% yield. Treatment of 9 with KHMDS in THF at -78 °C
followed by addition of Davis’ oxaziridine (trans-2-(phen-
ylsulfonyl)-3-phenyloxzairidine)10,11 provided the R-hydroxy
methyl ester 10 in 73% yield. Treatment of the derived
TBDPS ether with dimethyl lithiomethylphosphonate gave
â-keto phosphonate 11 in 87% yield over two steps.
Subjection of 11 to a Horner-Wadsworth-Emmons olefi-
nation12 with ethyl glyoxylate, followed by addition of
2-mercaptopyridine to isomerize any (Z)-olefin formed,5
resulted in the generation and in situ cyclization of 12 to an
inseparable ca. 4:1 mixture of trans-fused bicycles 13 and
14. The isomeric cycloadducts were separated after depro-
tection of the PMB ethers. The stereochemistry of the two
adducts was then assigned on the basis of NOE and coupling
constant analysis (see Supporting Information).
The production of trans-fused cycloadducts 13 and 14 was
unexpected given the literature precedent for IMDA reactions
of similar substrates.4 To probe the possibility that the
dienophilic carboethoxy group might be responsible for the
trans selectivity, we examined the IMDA reaction of 15 with
a monoactivated dienophile.
Subjection of 11 to the HWE reaction12 with R-benzyloxy
acetaldehyde produced triene 15 in 82% yield (Scheme 4).
Treatment of 15 with 1.5 equiv of MeAlCl2 at -78 °C then
provided trans-fused cycloadduct 16 in 72% yield, along with
a small amount of another isomer that could not be purified
or identified. The stereochemistry of 16 was assigned by 1H
NOE and coupling constant analysis after deprotection of
the PMB ether (see Supporting Information).
At this point, we became concerned that the bulky C(10)-
OTBDPS group might be responsible for the exclusive
production of trans-fused products in the IMDA reaction.
To determine the selectivity of an IMDA substrate lacking
(5) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54, 915.
(6) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988,
61, 3008.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(8) Roush, W. R.; Warmus, J. S.; Works, A. B. Tetrahedron Lett. 1993,
34, 4427.
(9) Esumi, T.; Okamoto, N.; Hatekeyama, S. Chem. Commun. 2002,
3042.
(10) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M. J. Org. Chem.
1984, 49, 3241.
(11) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1744.
(12) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
1356
Org. Lett., Vol. 7, No. 7, 2005

Scheme 4. IMDA Reactions of Triene 15
Scheme 6. Synthesis and IMDA Reaction of Triene 24
this group, we synthesized triene 17 (Scheme 5). Treatment
of 17 with MeAlCl2 in CH2Cl2 at -78 °C gave two
cycloadducts in ca. 1:1 ratio. These products were identified
by oxidation of the derived primary alcohols to give trans-
Scheme 5. IMDA Reactions of Triene 17
yield with >95:5 diastereoselectiVity. The stereochemistry
of 25 could not be determined directly, so it was treated with
Tebbe reagent15 to give the diene 26 in 69% yield (Scheme
7). Acidic deprotection of the primary TBS ether, followed
by oxidation of the resulting alcohol with the Dess-Martin
Scheme 7. Elaboration of cis-Decalin 25 to the
Octahydronaphthalene Nucleus of Integramycina
fused 19 and cis-fused 20. The stereochemistry of 20 is
surprising because the C(7) substituent is trans to the
C(8)-H, a result that could arise either by epimerization of
C(8) under the IMDA reaction or from the IMDA reaction
of the (Z)-dienophile isomer of 17. Given that it seemed
unlikely that epimerization of C(8) occurred during the
IMDA reaction, we thought it possible that triene 17 partially
isomerized to a (Z)-dienophile in the presence of MeAlCl2,
and that the isomeric (Z)-triene underwent the IMDA reaction
to provide the cis-fused cycloadduct 20. If this analysis is
correct, then the IMDA reaction of triene 24 containing a
(Z)-dienophile would provide access to the targeted cis-fused
intermediate 25 (Scheme 6).
Accordingly, methyl ester 21 was treated with Me(OMe)-
NH‚HCl and iPrMgCl13 to give the Weinreb amide 22 in
83% yield. Addition of vinyllithium 2314 to 22 at -90 °C
provided triene 24 in 84% yield. To our delight, when 24
was treated with 0.6 equiV of MeAlCl2 in CH2Cl2 at -78 °C
for only 15 min, cis-fused decalin 25 was produced in 92%
(13) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(14) Araki, Y.; Konoike, T. J. Org. Chem. 1997, 62, 5299.
a NBSH ) o-nitrobenzenesulfonylhydrazide.
Org. Lett., Vol. 7, No. 7, 2005
1357

periodinane,16 furnished aldehyde 27 in 89% yield. Aldehyde
27 was suitable for stereochemical analysis and identified
as a cis-fused compound on the basis of J8,13 ) 6.6 Hz and
observation of 1H NOE between the ring fusion protons H(8)
and H(13). The stereochemistry of the critical C(10)-alkoxy
substituent was confirmed by an NOE interaction between
H(10) and the aldehyde C-H (see Supporting Information).
To complete the synthesis of the integramycin core
structure, aldehyde 27 was treated with K2CO3 in THF-
MeOH at 23 °C to provide the C(7) epimer 28 in quantitative
yield. The aldehyde was then oxidized to the carboxylic acid,
which after treatment with TMSCHN2 gave methyl ester 29
in 85% yield. Finally, reduction of the exo-methylene with
a large excess of diimide (generated in situ from o-nitro-
benzenesulfonylhydrazide17,18 and Et3N) provided 30 in
68% yield; approximately 10% of starting material 29 was
recovered. The C(9)-methyl stereochemistry was confirmed
by coupling constant analysis (J8,9 ) 3.7 Hz, J9,10 ) 10.3
Hz), as were the cis ring fusion (J8,13 ) 3.7 Hz) and
C(7)-CO2Me (J7,8 ) 10.7 Hz) configurations. Structure 30
therefore contains all of the stereochemical elements of the
cis-fused octahydronaphthalene core structure of integramy-
cin.
Modest differences in the cis vs trans ring fusion selectivity
of IMDA reactions of substituted 1,7,9-decatrien-3-ones
containing (E)- and (Z)-dienophiles have been noted previ-
ously.14 The complete reversal in ring fusion selectivity
that we observed upon switching from an (E)-dienophile (as
in 15, which provides trans-fused 16 exclusively) to a
(Z)-dienophile (as in 24, which provides cis-fused 25 with
20:1 selectivity), however, is quite remarkable. IMDA
reactions of 1,7,9-decatrien-3-ones are believed to proceed
via a concerted but nonsynchronous transition state in which
bonding at the C(1)-C(10) carbons (triene numbering) is
more advanced than at C(4)-C(9).4 This leads to a “skewing”
(or twisting) of the plane of the dienophile relative to the
diene in order to minimize steric repulsion between these
two units in the transition state.4,19 In the IMDA reaction
with an (E)-dienophile, transition state 31 (Figure 1) leading
Figure 1. Cis/Trans Selectivity in the IMDA Reaction.
to the cis-fused product 32 is disfavored because of a
near-eclipsing steric interaction between the -CH2OPG
unit and the R group of the diene. This interaction is less
severe in transition state 33, in which case the C(1)-C(10)
developing bond is nearly staggered, and as a result, 24 the
(Z)-dienophile substrate leads to the cis-fused product 34.
In summary, we have achieved an efficient synthesis of
the racemic cis-octahydronaphthalene unit 30 of integramycin
via a diastereoselective IMDA reaction of triene 24. We have
also described a remarkable switch in cis vs trans ring fusion
selectivity for trienes with an (E)- or (Z)-dienophile geometry.
Further studies toward the total synthesis of integramycin
will be reported in due course.
Acknowledgment. Financial support by the National
Institutes of Health (GM 26782) is gratefully acknowledged.
T.A.D. thanks Bristol-Myers Squibb for a graduate fellow-
ship.
Supporting Information Available: Experimental pro-
cedures and full characterization (1H NMR, 13C NMR, IR,
HRMS) for all new compounds and stereochemical deter-
minations for compounds 19, 20, 27, and 30 and derivatives
of compounds 13, 14, and 16. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(17) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7507.
OL050191G
(18) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771.
(19) Roush, W. R.; Peseckis, S. M. J. Am. Chem. Soc. 1981, 103, 6.
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