Memory of chirality in the transannular cyclization of cyclodecenyl radicals

Article abstract of DOI:10.1021/ol049038x

The transannular cyclization of an enantioenriched cyclodecenyl radical proceeds in a 5-exo fashion to produce scalemic bicyclo[5.3.0]-decanes. This cyclization is notable because it demonstrates chirality transfer through conformational memory of an unst

Full text of DOI:10.1021/ol049038x

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2713-2716
Memory of Chirality in the Transannular
Cyclization of Cyclodecenyl Radicals
Jackline E. Dalgard and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697
srychnoV@uci.edu
Received May 24, 2004
ABSTRACT
The transannular cyclization of an enantioenriched cyclodecenyl radical proceeds in a 5-exo fashion to produce scalemic bicyclo[5.3.0]-
decanes. This cyclization is notable because it demonstrates chirality transfer through conformational memory of an unstabilized secondary
radical.
The field of stereoselective radical reactions has rapidly
advanced with the emergence of both chiral auxiliary based
and chiral Lewis acid based approaches.1 More recently,
“memory of chirality”2,3 has emerged as another strategy for
enantioselective radical reactions.4 Previous work in our
laboratory has demonstrated memory of chirality in the
hydrogen abstraction of an anomeric-stabilized tetrahydro-
pyranyl radical (Scheme 1).5 We hoped to extend this
cyclodecenyl radical system was chosen on the basis of its
rigidity and potential to undergo a transannular cyclization6
faster than a conformational change that would result in
racemization. In addition, the potential for cyclodecenes to
provide 5,7-fused ring systems and the presence of these
hydroazulene skeletons in natural products makes cyclo-
decenes an attractive target for radical reactions.
To investigate chirality transfer in the transannular cy-
clization, we chose cyclodecene 4 as our test substrate
(Scheme 2). Radical deoxygenation of 4 via its mixed oxalate
generates a cyclodecenyl radical that cyclizes in a 5-exo
fashion to produce 5,7-fused bicycle 5. The potential for the
chiral radical precursor 4 to undergo an enantioselective
cyclization is dependent upon the rate of the transannular
cyclization. If a radical generated from optically pure mixed
Scheme 1. Memory of Chirality in Hydrogen Abstraction of a
Tetrahydropyranyl Radical
(2) Kawabata, T.; Fuji, K. Top. Stereochem. 2003, 23, 175-205.
(3) In alkylations: (a) Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P.
C.-H. J. Am. Chem. Soc. 2003, 125, 11482-11483. (b) Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708-2748.
(4) (a) Curran, D. P.; Liu, W.; Chen, C. H.-T. J. Am. Chem. Soc. 1999,
121, 11012-11013. (b) Giese, B.; Wettstein, P.; Stahelin, C.; Barbosa, F.;
Neuburger, M.; Zehnder, M.; Wessig, P. Angew. Chem., Int. Ed. 1999, 38,
2586-2587. (c) Sauer, S.; Schumacher, A.; Barbosa, F.; Giese, B.
Tetrahedron Lett. 1998, 39, 3685-3688.
(5) (a) Buckmelter, A. J.; Kim, A. I.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2000, 122, 9386-9390. (b) Buckmelter, A. J.; Powers, J. P.;
Rychnovsky, S. D. J. Am. Chem. Soc. 1998, 120, 5589-5590.
(6) Beckwith, A. L. J.; Bowry, V. W.; Schiesser, C. H. Tetrahedron 1991,
47, 121-130.
methodology to include an unstabilized secondary radical
in the transannular cyclization of a cyclodecenyl radical. The
(1) (a) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163-171.
(b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions; VCH: New York, 1996.
10.1021/ol049038x CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/09/2004

Scheme 2. Radical Cyclization via Deoxygenation
Scheme 3. Synthesis of Radical Precursora
oxalate 6 underwent a transannular cyclization (path a) before
conformational interconversion (path b), enantioenriched
products would be obtained (Figure 1).
a Reaction conditions: (a) 1-tert-butylthio-1-(trimethylsilyl) oxo-
ethene, (R)-BINOL, Ti(OiPr)4, 4 Å MS, ether, -35 °C, 89%, 89%
ee. (b) TBSOTf, 2,6-lutidine, CH2Cl2, 100%. (c) DIBALH, CH2Cl2,
-25 °C, 93%. (d) I2, PPh3, CH2Cl2, imidazole, 0 °C, 94%. (e) NaH,
allyl dibenzylmalonate, THF, 0 °C to rt, 96%. (f) 20 mol % 16,
CH2Cl2, 1 mM, 40 °C, 16 h, 88%. (g) TBAF, THF, 0 °C to rt,
95%.
such as those developed by Grubbs.7 Initial studies employing
15 as a catalyst (1 mM, CH2Cl2, 40 °C) did not provide the
desired 10-membered carbocycle; instead, only acyclic dimer
products were observed. However, it was found that Grubbs’
second-generation catalyst 16 was effective in forming the
strained ring in good yield (88%) under high dilution
conditions (1 mM in substrate).
The ring-closing metathesis product was isolated as a
mixture of alkene products (ca. 1:1.7), initially assigned as
the E- and Z-cyclodecenes. This result was expected since
ring-closing metathesis in the synthesis of large rings
generally gives mixtures of olefin isomers.7b,8 However,
attempts to separate the alkene products, both as the silyl
ethers and the deprotected alcohols, were unsuccessful by a
variety of chromatographic methods. This result and the
inability to enrich one isomer over the other by chemical
means9 led us to consider the alkene products were not olefin
isomers but rather conformational isomers. Variable tem-
perature NMR studies were conducted to confirm the
presence of two different conformers. 1H NMR experiments
carried out from -30 to 100 °C in toluene-d8 showed
coalescence of the doubled peaks at temperatures at and
above 37 °C (Figure 2). This coalescence temperature
corresponds to an interconversion barrier of ca. 15.5 kcal/
Figure 1. Racemization pathway.
Racemization would occur through a disfavored chair/boat
interconversion. This is an example of memory of chirality
because the chiral information is held by the conformation
of the radical intermediate and not the radical center.
We set out to synthesize the radical precursor 4 through a
ring-closing metathesis of the bisolefin 14 (Scheme 3). The
synthesis of bisolefin 14 began with Mukaiyama-Keck aldol
condensation of 5-hexenal with the trimethylsilyl ketene
acetal derived from tert-butyl thioacetate to afford thioester
11 in 89% yield and 89% ee. Silyl ether formation followed
by reduction of the ester provided alcohol 12 in 93% over
two steps. Conversion of the resultant alcohol to the iodide
13 and coupling with anionic allyl dibenzylmalonate fur-
nished the requisite bisolefin 14 (90%, 2 steps).
(7) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (c) Grubbs, R. H.; Kirkland, T. A. J. Org. Chem. 1997, 62, 7310-
7318.
(8) (a) Lee, C. W.; Grubbs, R. H. Org. Lett. 2000, 2, 2145-2147. (b)
Furstner, A.; Muller, T. Synlett 1997, 1010-1011. (b) Furstner, A.;
Langemann, K. Synthesis 1997, 792-803.
(9) Selective dihydroxylation with R-AD-mix (60% conversion) returned
the starting cyclodecene of the same isomeric ratio.
With the cyclization precursor 14 in hand, we investigated
the ring-closing metathesis utilizing ruthenium alkylidenes,
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Org. Lett., Vol. 6, No. 16, 2004

transannular cyclization proceeded with significant chirality
transfer. At room temperature, the 5,7-fused product 5 was
obtained in 63:37 er from the 94:6 er of the starting material
(Table 1, entry 1). Higher levels of enantioselectivity were
reached by lowering the temperature to 0 °C to obtain
products of 79:21 er. Interestingly, the same er (84:16) was
obtained at both -15 and -35 °C, suggesting a limit in the
enantioselectivity observed. The yields ranged from 43% to
88%, and products were accompanied with significant
amounts of the monodecarboxylated and trapped side product
17, demonstrating that the fragmentation is a stepwise process
(Scheme 4).
Scheme 4. Stepwise Fragmentation Leads to Side Product 17
1
Figure 2. Variable-temperature H NMR studies: 5.6-2.5 ppm.
The variation in enantioselectivity observed may be due
to the presence of two conformers in the starting substrate.
Energy minimization calculations of the cyclodecenol methyl
ester using MacroModel (MM2 force field) strongly suggests
two boat-chair-boat conformers, BCB-1 and BCB-2, as the
lowest energy conformers present (Figure 3). Further analysis
mol. Thus, the ring-closing metathesis provided a single
alkene isomer, determined to be the Z-cyclodecene by NOE
measurements, as a 1:1.7 mixture of conformational iso-
mers.10
Our attention was then turned to the radical cyclization.
Cyclodecene 4 was treated with oxalyl chloride, followed
by N-hydroxy pyridine thione and catalytic DMAP to
generate mixed oxalate 6 in situ. Photolysis of the reaction
mixture led to bicyclo[5.3.0]decane 5, demonstrating that the
cyclodecenyl radical, from deoxygenation of 4, cyclized in
a 5-exo fashion to generate the bicyclo[5.3.0]decane 5.
Table 1. Radical Cyclization Results
entrya
temp (°C)
yield (%)
erb
1
2
3
4
23
0
-15
-35
88
67
51
43
63:37
79:21
84:16
84:16
Figure 3. Low-energy conformers of cyclodecenol methyl ester.
a Reaction mixtures were photolyzed with a 500-W tungsten lamp.
b Enantiomeric ratio determined by chiral HPLC analysis (Diacel OD-H
column), 90:10 hexanes/IPA, 0.9 mL/min.
reveals direct cyclization of BCB-2 leads to the cis-fused
product, whereas direct cyclization of BCB-1 leads to the
trans-fused product (Figure 4). The trans-fused product is
not observed, so the major conformer may undergo a
conformational change prior to cyclization to provide the
cis-fused product, potentially leading to an erosion in the
enantioselectivity.
Trapping of the intermediate carbon radical with the thiopy-
ridyl group occurred from the convex face of the bicycle,
providing 5 as a single diastereomer (NOE). Notably, the
1
(10) Isomeric ratio was determined by H NMR at -30 °C and varied
The presence of two distinct conformers was not antici-
pated and may have a deleterious effect on the selectivity of
slightly at different temperatures: 1:1.71 (-30 °C), 1:1.66 (-20 °C), 1:1.60
(-10 °C).
Org. Lett., Vol. 6, No. 16, 2004
2715

quence to the enantioselectivity; however, the major com-
putational conformer must undergo a conformational change
to provide the observed product. Furthermore, the increase
in enantioselectivity and decrease in yield may be a
consequence of the minor conformer cyclizing faster than
the major conformer. Despite the presence of these two
conformers, we have shown that the cyclization of cyclo-
decenyl radicals proceeds with 90% chirality transfer at -15
and -35 °C, thus demonstrating memory of chirality in the
transannular cyclization of an unstabilized secondary radical.
Acknowledgment. The National Institutes of Health (GM
65338) provided financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 4, 5, and 10-14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 4. Fate of conformers of cyclodecenol 4.
the reaction. The minor computational conformer can directly
cyclize to provide the observed product with little conse-
OL049038X
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Org. Lett., Vol. 6, No. 16, 2004