SmI2-mediated radical cyclizations directed by a C-Si bond

Article abstract of DOI:10.1021/ol102278c

The use of a silicon stereocontrol element in cyclobutanol and cyclopentanol-forming cyclizations mediated by SmI₂ results in excellent diastereocontrol. The C-Si bond in the products of cyclization provides a versatile handle for further manip

Full text of DOI:10.1021/ol102278c

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5446-5449
SmI2-Mediated Radical Cyclizations
Directed by a C-Si Bond
Hassan Y. Harb,† Karl D. Collins,† Jose V. Garcia Altur,† Sue Bowker,‡
Leonie Campbell,‡ and David J. Procter*,†
School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester, M13 9PL,
United Kingdom, and AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire,
SK10 4TG, United Kingdom
daVid.j.procter@manchester.ac.uk
Received September 22, 2010
ABSTRACT
The use of a silicon stereocontrol element in cyclobutanol and cyclopentanol-forming cyclizations mediated by SmI2 results in excellent
diastereocontrol. The C-Si bond in the products of cyclization provides a versatile handle for further manipulation. An asymmetric route to
cyclization substrates involving copper-catalyzed silyl transfer has also been developed.
Since its introduction by Kagan,1 samarium(II) iodide (SmI2)
has become one of the most important reducing agents in
organic synthesis.2 The versatile reagent has been used to
mediate many processes, ranging from functional group
interconversions to complex carbon-carbon bond-forming
sequences.2 Cyclization reactions are arguably the most
useful transformations mediated by SmI2, and these have
been used extensively in natural product synthesis.2b,d
We have developed a SmI2-mediated 4-exo-trig radical
cyclization3 to construct cyclobutanols and have employed
the transformation in an approach to the pestalotiopsin and
taedolidol natural products.4,5 Unfortunately, attempts to
† University of Manchester.
‡ AstraZeneca.
(1) (a) Namy, J. L.; Girard, P.; Kagan, H. B. NouV. J. Chim. 1977, 1, 5.
(b) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2693.
(3) (a) Weinges, K.; Schmidbauer, S. B.; Schick, H. Chem. Ber. 1994,
127, 1305. (b) Johnston, D.; McCusker, C. M.; Procter, D. J. Tetrahedron
Lett. 1999, 40, 4913. (c) Johnston, D.; McCusker, C. F.; Muir, K.; Procter,
D. J. J. Chem. Soc., Perkin Trans. 1 2000, 681. For discussions of other
radical 4-exo-trig cyclizations, see: (d) Walton, J. C. Top. Curr. Chem. 2006,
264, 163. (e) Friedrich, J.; Walczak, K.; Dolg, M.; Piestert, F.; Lauterbach,
T.; Worgull, D.; Gansa¨uer, A. J. Am. Chem. Soc. 2008, 130, 1788.
(4) (a) Johnston, D.; Francon, N.; Edmonds, D. J.; Procter, D. J. Org.
Lett. 2001, 3, 2001. (b) Johnston, D.; Couche´, E.; Edmonds, D. J.; Muir,
K. W.; Procter, D. J. Org. Biomol. Chem. 2003, 1, 328. (c) Edmonds, D. J.;
Muir, K. W.; Procter, D. J. J. Org. Chem. 2003, 68, 3190. (d) Baker, T. M.;
Edmonds, D. J.; Hamilton, D.; O’Brien, C. J.; Procter, D. J. Angew. Chem.,
(2) For recent reviews on the use of samarium(II) iodide: (a) Procter,
D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis using Samarium
Diiodide: A Practical Guide; RSC Publishing: Cambridge, 2010. (b)
Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48,
7140. (c) Gopalaiah, K.; Kagan, H. B. New J. Chem. 2008, 32, 607. (d)
Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. ReV. 2004, 104, 3371.
(e) Dahle´n, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393. (f) Kagan,
H. B. Tetrahedron 2003, 59, 10351. (g) Steel, P. G. J. Chem. Soc., Perkin
Trans. 1 2001, 2727. (h) Kagan, H.; Namy, J. L. In Lanthanides: Chemistry
and Use in Organic Synthesis; Kobayashi, S., Ed.; Springer: Berlin, 1999;
p 155. (i) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321.
Int. Ed. 2008, 47, 5631
.
10.1021/ol102278c  2010 American Chemical Society
Published on Web 11/04/2010

control facial selectivity in the SmI2-mediated 4-exo-trig
radical cyclization using a silyl ether stereocontrol element, as
in cyclization substrate 1, resulted in low diastereocontrol
(Scheme 1).4c Coordination to samarium(III) appears to com-
Scheme 3. Three-Step Synthesis of Cyclization Substrates
Scheme 1. Cyclization of a Silyl Ether Substrate
followed by quenching of the resultant enolate with aldehyde
43c gave aldol adducts 5 in good yield. Elimination of the
mixed aldol diastereoisomers 5a,b gave the required Z-
alkenes 6a,b as the major products (Scheme 3).8,9 Removal
of the thioacetal protection then gave the cyclization
substrates 3a,b. Thus, cyclization substrates 3 can be prepared
in three steps from simple starting materials.
Pleasingly, treatment of rac-3a with SmI2 in THF-MeOH
gave cyclobutanol 7a as the major product in high yield with
good diastereoselectivity (6:1 dr) (Scheme 4). Cyclization
promise the role of the silyl ether as a “blocking” group. In
addition, elimination of the silyloxy group from the intermediate
Sm(III)-enolate 2 proved problematic (Scheme 1).4c
Here we describe a revised approach that exploits silicon
connected to carbon as a stereocontrol element and in which
cyclizations proceed with high to complete diastereocontrol.
To our knowledge, this is the first example of a silicon
substituent directing the stereochemical course of a cycliza-
tion reaction mediated by SmI2.
Scheme 2. Proposed Cyclizations Directed by a C-Si Bond
Scheme 4. SmI2-Mediated Cyclizations Directed by a Silyl Group
We proposed that attaching the silyl group directly to carbon
in substrates 3 (cf. 1) would remove the possibility of unwanted
coordination to Sm(III) and elimination (see Scheme 1).
The silyl group would control the outcome of the reaction
by blocking one face of the alkene, resulting in radical
addition from the other. Furthermore, the synthetic equiva-
lence of the C-Si bond to a C-O bond6 would allow silicon-
free cyclic products to be obtained and could minimize the
use of hydroxyl protecting groups (Scheme 2).
The construction of the C-Si bond was used to facilitate
the assembly of racemic cyclization substrates (Scheme 3). The
one-pot conjugate addition of silyl cuprates7 to (2H)-furanone
of rac-3b bearing a more bulky silyl group gave 7b with
complete diastereocontrol.10 We were surprised to see that
(5) For other approaches to pestalotiopsin A, see: (a) Dong, S.; Parker,
G. D.; Tei, T.; Paquette, L. A. Org. Lett. 2006, 8, 2429. (b) Paquette, L. A.;
Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135. (c) Takao, K.;
Saegusa, H.; Tsujita, T.; Washizawa, T.; Tadano, K. Tetrahedron Lett. 2005,
46, 5815. (d) Takao, K.; Hayakawa, N.; Yamada, R.; Yamaguchi, T.; Morita,
U.; Kawasaki, S.; Tadano, K. Angew. Chem., Int. Ed. 2008, 47, 3426.
(6) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(7) (a) Fleming, I.; Newton, T. W.; Roessler, F. J. Chem. Soc., Perkin
Trans. 1 1981, 2527. (b) Ager, D. J.; Fleming, I. J. Chem. Soc., Chem.
Commun. 1978, 177. (c) Fleming, I.; Sarkar, A. K.; Doyle, M. J.; Raithby,
P. R. J. Chem. Soc., Perkin Trans. 1 1989, 2023
.
(8) The stereochemistry of the alkene isomers was assigned by
comparison of NMR data with those of the closely related “OTBS”
analogues. See ref 4c.
Org. Lett., Vol. 12, No. 23, 2010
5447

in all cases the intermediate Sm(III)-enolate11 is protonated
on the same face as the silicon group. This may arise from
protonation by MeOH bound to the Sm(III) center (see
Scheme 4). The relative stereochemistry in the cyclobutanol
products was confirmed by NOESY experiments12 and X-ray
crystallographic analysis of 7a.13
Scheme 6
.
Reductive-Aldol Cyclizations Directed by a Silyl
Group
We have also assessed the value of a silicon stereocontrol
element in SmI2-mediated reductive-aldol cyclizations de-
veloped in our group.14
The preparation of ketone cyclization substrates began with
conjugate addition of silyl cuprates to (2H)-furanone fol-
lowed by quenching of the resultant enolates with aldehyde
9.15 Adducts 10a,b underwent elimination to give alkenes
11a,b as inconsequential mixtures of isomers.16 Finally,
removal of the thioketal protection gave the cyclization
substrates 12a,b (Scheme 5).
Silyl lactone R-14 can be synthesized from vinylsilane 15
by Sharpless dihydroxylation17 and conversion of the diol
to unsaturated alcohol 17 (77% ee).18 Oxidative cyclization
of 17 then gave R-14 (Scheme 7).19
Scheme 5. Four-Step Synthesis of Cyclization Substrates
Scheme 7. Asymmetric Approach to Cyclization Substrates
Treatment of rac-12a,b with SmI2 in THF-MeOH gave
cyclopentanols 13a,b with complete diastereocontrol (Scheme
6). The stereochemistry of 13a and 13b was confirmed by
X-ray crystallographic analysis.13
The asymmetric synthesis of cyclization substrates is also
possible.
A more direct asymmetric approach to silyl lactone R-14
utilizes Hoveyda’s recently reported copper-catalyzed silyl
transfer reaction.20 Unfortunately, Hoveyda’s optimal
precatalyst system proved ineffective for silyl transfer to
(2H)-furanone.21 However, new precatalyst 18 was de-
signed22 and was found to give R-14 in 67% yield and
82% ee (Scheme 8).
(9) The alkene stereochemistry has a marked effect on the stereochemical
outcome of the cyclizations of 3a. See Supporting Information and also ref
4b.
(10) Surprisingly, the diphenylmethylsilyl analogue of rac-3a and rac-
3b underwent cyclization to give products analogous to rac-7a and rac-8a
in a 4:1 ratio, respectively (88% yield).
(11) For a review of the chemistry of samarium enolates, see: Rudkin,
I. M.; Miller, L. C.; Procter, D. J. Organomet. Chem. 2008, 34, 19.
(12) See Supporting Information.
(17) (a) Kolb, C. H.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) For the Sharpless dihydroxylation of vinylsilanes,
see: Vanhessche, K. P. M.; Sharpless, B. K. Chem.sEur. J. 1997, 3, 517.
Attempts to prepare silyl epoxides using Jacobsen’s hydrolytic kinetic
resolution were unsuccessful.
(13) See Supporting Information for X-ray structures and CCDC numbers.
(14) (a) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345.
(b) Hutton, T. K.; Muir, K. W.; Procter, D. J. Org. Lett. 2003, 5, 4811. (c)
Guazzelli, G.; Duffy, L. A.; Procter, D. J. Org. Lett. 2008, 10, 4291. (d)
Sloan, L. A.; Baker, T. M.; Macdonald, S. J. F.; Procter, D. J. Synlett 2007,
3155. (e) Baker, T. M.; Sloan, L. A.; Choudhury, L. H.; Murai, M.; Procter,
D. J. Tetrahedron: Asymmetry 2010, 21, 1246.
(18) (a) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
(b) Bassindale, A. R.; Taylor, P. G.; Xu, Y. Tetrahedron Lett. 1996, 37,
555.
(19) Schomaker, J. M.; Travis, B. R.; Borhan, B. Org. Lett. 2003, 5,
3089.
(20) Lee, K.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 2898.
(21) For an alternative approach to asymmetric silyl transfer, see: (a)
Walter, C.; Auer, G.; Oestreich, M. Angew. Chem., Int. Ed. 2006, 45, 5675.
(b) Walter, C.; Oestreich, M. Angew. Chem., Int. Ed. 2008, 47, 3818. (c)
Walter, C.; Fro¨hlich, R.; Oestreich, M. Tetrahedron 2009, 65, 5513. (d)
Hartmann, E.; Oestreich, M. Angew. Chem., Int. Ed. 2010, 49, 6195.
(15) Wilken, J.; Winter, M.; Stahl, I.; Martens, J. Tetrahedron: Asym-
metry 2000, 11, 1067.
(16) The alkene stereochemistry has no effect on the stereochemical
outcome of the cyclizations of 12a. See Supporting Information and also
ref 14b.
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Org. Lett., Vol. 12, No. 23, 2010

Scheme 8
.
Improved Asymmetric Approach to Cyclization
Substrates
Scheme 10
.
Manipulation of the C-Si Bond in Cyclization
Products
Enantiomerically enriched R-14 (70% ee) was then
converted to R-3a using the sequence outlined in Scheme 3:
aldol reaction with aldehyde 4, elimination and deprotection
gave R-3a in good overall yield. Subsequent treatment with
SmI2 in THF-MeOH gave enantiomerically enriched cy-
clobutanol (-)-7a (70% ee, HPLC) (Scheme 9).
the C-Si bond can be used as a precusor to alkenes in a
Peterson olefination:24 Reduction25 of 13a gave triol 20 which
underwent elimination under basic conditions to give 21
(Scheme 10).
In summary, we have shown the potential of a silicon
group bonded directly to carbon as a stereocontrol element
in SmI2-mediated cyclizations during which two or three new
stereocenters are formed. Preliminary studies show the value
of the C-Si bond in cyclization products as a synthetic
handle for further manipulation. A catalytic asymmetric route
to cyclization substrates has been developed.
Scheme 9
.
Cyclization of an Enantiomericaly Enriched
Substrate
Acknowledgment. We thank AstraZeneca (CASE awards
to H.Y.H. and K.D.C.), EPSRC (CPhD award, H.Y.H.) and
the University of Manchester.
Supporting Information Available: Additional experi-
ments, full experimental details, characterization data and
1H and 13C NMR spectra for all new compounds, chiral
HPLC analyses, X-ray crystal structures for 7a, 13a and 13b,
CCDC numbers and cif files. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL102278C
Finally, the C-Si bond in the products of directed cycliza-
tions can be oxidized stereospecifically.6 For example, oxidation
of cyclobutanol 7a under Fleming-Tamao conditions23 gave diol
19 in moderate, unoptimized yield (Scheme 10). Alternatively,
(23) (a) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson,
P. E. J. J. Chem. Soc., Perkin Trans. 1 1995, 317. (b) Wendeborn, S.; Binot,
G.; Nina, M.; Winkler, T. Synlett 2002, 10, 1683.
(24) Ager, D. J. Synthesis 1984, 5, 384.
(25) Attempts to convert 13a directly to triol 20 with hydride reducing
agents, including RedAl, led to decomposition. Partial reduction to the lactol
and reduction with SmI2-H2O gave the best result. Duffy, L. A.; Matsubara,
H.; Procter, D. J. J. Am. Chem. Soc. 2008, 130, 1136.
(22) We found that C2-Symmetrical precatalysts with more sterically
demanding substituents in the ortho-positions gave improved selectivity in
additions to (2H)-furanone.
Org. Lett., Vol. 12, No. 23, 2010
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