Studies into the stereoselectivity of tartrate-derived dienophiles

Article abstract of DOI:10.1021/ol050105c

(Chemical Equation Presented) Diels-Alder reactions of 1-(tert- butyldimethylsiloxy)-1,3-butadiene (3) with three C2 symmetric dienophiles derived from tartaric acid have been examined. Complementary diastereoselectivity is observed depending on the natur

Full text of DOI:10.1021/ol050105c

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1687-1689
Studies into the Stereoselectivity of
Tartrate-Derived Dienophiles
Wei-Der Lee, Kwangho Kim, and Gary A. Sulikowski*
Department of Chemistry, Vanderbilt UniVersity, NashVille, Tennessee 37235
gary.a.sulikowski@Vanderbilt.edu
Received January 18, 2005
ABSTRACT
Diels−Alder reactions of 1-(tert-butyldimethylsiloxy)-1,3-butadiene (3) with three C2 symmetric dienophiles derived from tartaric acid have
been examined. Complementary diastereoselectivity is observed depending on the nature of the 1,2-diol protecting group incorporated in
these dienophiles.
The Diels-Alder reaction has enjoyed immense popularity
as a synthetic method since its discovery over 75 years ago.1
A major reason for this extraordinary level of interest from
the synthetic community is the seemingly endless possibilities
of inter- and intramolecular variations of this reaction in
addition to the high levels of stereoselectivity often achieved
in this reaction.2 Even relatively remote stereocenters have
been shown to induce high levels of stereoselectivity.3
Despite extensive investigations into this reaction process,
unexpected and/or unpredictable cases of Diels-Alder ste-
reoselectivity have been occasionally encountered due to
seemingly subtle balances of steric and electronic effects
dictating overall stereoselectively. In this communication,
we describe a study of such a Diels-Alder cycloaddition in
connection with our ongoing efforts toward the total synthesis
of members of the hibarimicin group of antitumor antibiotics.
During the course of designing a synthetic approach
toward the AB and GH ring systems of hibarimicin and
congeners such as HMP-Y1 (1), we proposed a stereose-
lective intermolecular Diels-Alder reaction between tartrate-
derived dienophile 4 and 1-(tert-butyldimethylsiloxy)-1,3-
butadiene (3)4 as the key ring-forming step.5 In this cy-
cloaddition process we required bond formation to occur with
good stereocontrol leading to the desired relative stereo-
chemistry between C(9) and C(11) as indicated in cis Decalin
2. Examination of molecular models shows enedione 4 to
be locked in a half-chair conformation with the two hy-
drogens located at the ring fusion of the bicyclic system
occupying axial positions (4, Figure 2). The Diels-Alder
(1) Reviews: (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis Angew. Chem., Int. Ed. 2002, 41, 1668-1698. (b) Corey,
E. J Angew. Chem., Int. Ed. 2002, 41, 1650-1667.
(2) (a) Intramolecular Diels-Alder reactions: Roush, W. R. In Com-
prehensiVe Organic Synthesis; Trost B. E., Ed.; Pergamon Press: Elmsford,
NY, 1991; Vol. 5, pp 513-550. (b) Intermolecular Diels-Alder reactions:
Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost B. E., Ed.;
Pergamon Press: Elmsford, NY, 1991; Vol. 5, pp 316-399.
(3) (a) Angell, E. C., Fringuelli, F.; Minuti, L.; Pizzo, F.; Porter, B.;
Taticchi, A.; Wenkert, E. J. Org. Chem. 1985, 50, 4686-4690. (b) Angell,
E. C., Fringuelli, F.; Pizzo, F.; Porter, B.; Taticchi, A.; Wenkert, E. J. Org.
Chem. 1986, 51, 2642-2649.
Figure 1. Retrosynthetic analysis of the AB/GH ring system of
HMP-Y1 (1).
10.1021/ol050105c CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/30/2005

chromatography and could be stored at -20 °C for several
months without any sign of isomerization to 10 ob-
served.
The Diels-Alder reaction of enedione 4 with 1-(tert-
butyldimethylsiloxy)-1,3-butadiene (3) was examined using
several different solvent and temperature conditions. Optimal
conditions reacted enedione 4 with 1.5 equiv of diene 3 in
dichloromethane at 40 °C for 3 days to afford a single (>95:
5) crystalline (mp 185-187°) cycloadduct in 60-68% yield.
The stereochemistry of this adduct was unambiguously
assigned by single-crystal X-ray analysis and much to our
surprise proved to be the unanticipated diastereomer 6
(Scheme 2). It was later determined that microwave irradia-
Figure 2. Stereochemical analysis of Diels-Alder reaction between
3 and 4.
Scheme 1
cycloaddition between 3 and 4 may proceed by way of four
different transition state structures, two endo and two exo
structures. Initially, we considered only the endo approach
to be viable, and our rationale leading to the prediction that
diastereomer 2 would be the major reaction product was as
follows. First, on the basis of considerations of frontier
molecular orbitals, we anticipated that the transition-state
structure leading to the cycloaddition product would be
asynchronous with bond a further developed relative to bond
b (cf. 5).6 Next, we anticipated, on the basis of stereoelec-
tronic considerations, that the first formed bond (bond a)
would favor a pseudoaxial approach, leading us to predict
formation of the desired cycloadduct (2) instead of the
diastereomeric product 6.7 A second major concern was the
questionable stability of diketone 4 since tautomerization
could readily lead to the corresponding, thermodynamically
more stable dihydroquinone.8
tion (100 W) of a neat mixture of enedione 4 and siloxydiene
3 (4 equiv) heated to 70 °C reduced the reaction time to 10
h and increased the chemical yield to 84%.12
Following the procedure of Fu¨rstner and co-workers, we
converted dimethyl tartrate (-)-7 to diol 8 starting with a
one-pot reduction/vinyl Grignard addition to afford diol 8
in 77% yield.9 As reported earlier, diol 8 underwent a ring-
closing metathesis reaction mediated by Grubbs second-
generation catalyst to afford cyclohexene 9 in 90-95% yield.
Next, we examined the oxidation of 9 to enedione 4 under
Swern oxidation conditions.10 In this case, we were disap-
pointed to observe exclusive production of hydroquinone 10
(45% yield). Fortunately, oxidation of 9 with Dess-Martin
periodinane proceeded smoothly to give enedione 4 in 84%
yield.11 Enedione 4 proved to be stable to silica gel
Scheme 2
The [4 + 2] cycloaddition of diene 3 and dienophile 4
proceeded with anticipated endo selectivity; however, the
observed facial selectivity was the reverse of that anticipated
on the basis of our earlier discussion of stereoelectronic
control (Figure 2) and required for the synthesis of the AB/
GH ring system of the hibarimicins. We therefore elected to
examine alternate diol protecting groups in hope of altering
the course of the facial selectivity of the Diels-Alder
reaction. Toward this end, we prepared dienophiles 11 and
14,13 where the diol was protected as a bis-TBS ether and
(4) Trost, B. M.; Chupak, L. S.; Lubbers, T. J. Org. Chem. 1997, 62,
736-736.
(5) For an earlier approach to this ring system, see: Kim, K.; Maharoof,
U. S. M.; Raushel, J.; Sulikowski, G. A. Org. Lett. 2003, 5, 2777-2780.
(6) Dewar, M. J. S. J. Am. Chem. Soc. 1984, 106, 209-215.
(7) (a) Capaccio, C. A. I.; Varela, O. J. Org. Chem. 2002, 67, 7839-
7846. (b) Primeau, J. L.; Anderson, R. C.; Fraser-Reid, B. J. Am. Chem.
Soc. 1983, 105, 5874-5879.
(8) Guo, Z. X., Haines, A. H.; Pyke, S. M.; Pyke, S. G.; Taylor, R. J. K
Carbohydr. Res. 1994, 264, 147-153.
(9) (a) Ackermann, L.; El Tom, D.; Fu¨rstner, A. Tetrahedron 2000, 56,
2195-2202. (b) Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett.
2002, 4, 1359-1361.
(10) Mancuso, A. J.; Swern, D. Tetrahedron 1981, 165-185.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(12) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250-6284.
Org. Lett., Vol. 7, No. 9, 2005
1688

tion for the differences in stereoselectivity of the two
dienophiles we examined molecular models. Dienophile 4
is a rigid bicyclic system, and assuming a highly asynchro-
nous transition state we arrived at two possible diastereomeric
transition-state structures (20 and 21, Figure 3). Transition
Scheme 3
bis-pivaloate, respectively (Scheme 3). Reaction of enedione
11 with diene 3 resulted in a 71:29 ratio of Diels-Alder
adducts 12 and 13, again favoring production of the undesired
relative stereochemistry between C9 and C11 (12). In
contrast, heating a solution of enedione 14 and diene 3 in
dichloromethane for 5 h produced a 33:67 mixture of
diastereomers, now faVoring the desired stereoisomer 16.
The stereochemistry of cycloadducts 12 and 15 was assigned
by chemical correlation with Diels-Alder adduct 6. The
second Diels-Alder adduct produced in each reaction (i.e.,
adducts 13 and 16) was assumed to be the diastereomeric
endo. While there existed a probability that the second isomer
may be one of two exo adducts, we discounted this possibility
on the basis of the observed propensity for endo addition of
cyclopentadiene to all three dienophiles 4, 11, and 14
(Scheme 4).14
Figure 3. Transition-state structures.
state 20 (leading to the minor adduct 2) apparently suffers,
due to the asymmetry of bond formation, from a steric
interaction between the C2 diene carbon and ring fusion
hydrogen. In the case of transition state 21, the asymmetry
of bond formation matches the chirality of the C2 dienophile
resulting in reduction of steric interactions relative to
structure 20. Dienophile 14 may favor the two-ester groups
occupying axial positions, as this conformation reduces
gauche interactions.15 Then, following an analysis parallel
to transition states 20 and 21, we may conclude that structure
23 is favored leading to cycloadduct 16 as the major product.
In summary, we have observed complementary facial
selectivity in the addition of diene 3 to C2 symmetric
dienophiles 4 and 14. Capitalizing on these results, progress
on the total synthesis of HMP-Y1 (1) will be reported in
due course.
Scheme 4
Acknowledgment. We thank the National Institutes of
Health (CA59515-10) and The Robert A. Welch Foundation
(A-1230) for support of this research. Wei-Der Lee gratefully
acknowledges the National Science Council (Republic of
China) for partial financial support. We also thank Joseph
Reibenspies (Center for Chemical Characterization and
Analysis, Texas A&M University) for determining the X-ray
crystal structure of 6.
Supporting Information Available: Full characterization
data and select experimental procedures for 4, 6, 8, 9, and
11-19. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL050105C
The observed reversal of stereoselectivity of dienophiles
4 (Scheme 2) and 14 (Scheme 3) led to a unique solution to
the stereochemical problem of establishing the correct relative
stereochemistry between C9 and C11 posed by HMP-Y1
(1) and the hibarimicins (Figure 1). To arrive at an explana-
(13) Preparation of 11 and 14 starting from enedione 4 is described in
Supporting Information.
(14) Stereochemical assignments of 17-19 based on NOESY analysis.
(15) Hosoya, T.; Ohashi, Y.; Matumoto, T.; Suzuki, K. Tetrahedron Lett.
1996, 37, 663-666.
Org. Lett., Vol. 7, No. 9, 2005
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