Silylene-mediated ring contraction of homoallylic ethers to form allylic silanes

Article abstract of DOI:10.1021/jo901111j

(Chemical Equation Presented) (-)-Isopulegol derivatives undergo a ring contraction under silylene-mediated conditions to provide cyclopentane products. Silylene transfer to other homoallylic ethers did not provide the ring contraction products. Allylic s

Full text of DOI:10.1021/jo901111j

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leads to compounds not easily accessed by other syntheses.13
Silylene-Mediated Ring Contraction of Homoallylic
Ethers To Form Allylic Silanes
In this paper, we report the ring contraction of six-membered
carbocyclic homoallylic ethers to form five-membered carbo-
cyclic allylic silanes by treatment with silylene intermediates.
As part of our investigations into silylene transfer reac-
tions to homoallylic ethers,14 we examined the reaction of
(-)-isopulegol derivative 1 under the optimized reaction
conditions. Subjection of benzyl ether 1 to cyclohexene
silacyclopropane 2 and AgO2CCF3 did not provide the
expected silylmethyl allylic silane product. Instead, the
five-membered ring allylic silane product 3 was isolated as
a single stereoisomer (eq 1).
Laura E. Bourque, Pamela A. Haile, and K. A. Woerpel*
Department of Chemistry, University of California, Irvine,
California 92697-2025
kwoerpel@uci.edu
Received May 26, 2009
Alteration of the protecting group on the homoallylic
ether provided similar ring contraction products. When alkyl
ether 4 was treated to the reaction conditions, allylic silane 5
was observed (eq 2). Treatment of silyl ether 6 to the reaction
conditions provided allylic silane 7 (eq 2). Both allylic silanes
were found to be predominantly one stereoisomer, as in-
dicated by 1H NMR and 13C NMR spectroscopy.15,16
(-)-Isopulegol derivatives undergo a ring contraction
under silylene-mediated conditions to provide cyclopen-
tane products. Silylene transfer to other homoallylic
ethers did not provide the ring contraction products.
Allylic silane products were elaborated to determine the
stereochemical course of the ring contraction reaction. A
mechanism for the transformation is proposed.
Cyclopentane units are found in many natural and non-
natural products, including alkaloids, steroids, prostaglan-
dins, triquinanes, and guaianes.1-6 The ring contraction of a
six-membered carbocyclic compound is an efficient way to
assemble a cyclopentane because the reorganization of the
bonds can occur with high selectivity.7-12 This reorganization
A variety of homoallylic ethers were subjected to the
reaction conditions, but they did not undergo rearrangement.
epi-Isopulegol derivative 8 underwent silylene transfer to the
alkene17 to form silacyclopropane 9 as a mixture of diaster-
eomers that was not stable to purification (eq 3). The product
did not undergo further transformations upon heating. The
same result was observed with both five-membered ring ether
10 and seven-membered ring ether 12 (eq 4). The lack of ring
contraction of the five-membered ring silacyclopropane 11
(eq 4) may be the result of too much ring strain involved
in contraction to the four-membered ring.18 Differences in
conformational preferences and flexibility between six- and
seven-membered rings may cause the seven-membered ring
(1) For examples of total synthesis, see: Corey, E. J.; Cheng, X.-M. The
Logic of Chemical Synthesis; Wiley: New York, 1989.
(2) For examples of marine natural products, see: Faulkner, D. J. Nat.
Prod. Rep. 2002, 19, 1–48.
(3) For examples of sesquiterpenoids, see: Fraga, B. M. Nat. Prod. Rep.
2001, 18, 650–673.
(4) For examples of monoterpenoids, see: Grayson, D. H. Nat. Prod.
Rep. 2000, 17, 385–419.
(5) For examples of diterpenoids, see: Hanson, J. R. Nat. Prod. Rep.
2002, 19, 125–132.
(6) For examples of triterpenoids, see: Connolly, J. D.; Hill, R. A. Nat.
Prod. Rep. 2001, 18, 560–578.
(7) For a review concerning Wagner-Meerwein rearrangements, see:
Hanson, J. R. Wagner-Meerwein Rearrangements; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 3.
(8) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746–
1757.
(9) Guijarro, D.; Yus, M. Curr. Org. Chem. 2005, 9, 1713–1735.
(10) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.,
Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman: Lon-
don, 1989.
(11) Ferraz, H. M. C.; Silva, L. F., Jr. Tetrahedron Lett. 1997, 38, 1899–
1902.
(12) Mathew, F.; Myrboh, B. Synth. Commun. 1996, 26, 1097–1101.
(13) For a review concerning ring contractions, see: Silva, L. F., Jr.
Tetrahedron 2002, 58, 9137-9161.
(14) Cleary, P. A.; Woerpel, K. A. Org. Lett. 2005, 7, 5531–5533.
(15) The relative configurations of 5 and 7 were assigned based on
comparisons of their 1H NMR and 13C NMR spectra to those of allylic
silane 3.
(16) Allylic silane 7 was difficult to purify, so we have not been able to
identify minor components of the reaction mixture.
(17) Driver, T. G.; Woerpel, K. A. J. Am. Chem. Soc. 2004, 126, 9993–
10002.
(18) Wiberg, K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312–322.
7180 J. Org. Chem. 2009, 74, 7180–7182
Published on Web 08/14/2009
DOI: 10.1021/jo901111j
r
2009 American Chemical Society

Bourque et al.
JOCNote
system of silacyclopropane 13 to align orbitals differently,19
thus preventing ring contraction.
SCHEME 1. Proposed Mechanism for the Formation of Allylic
Silane 3
The structure and relative stereochemistry of allylic silane3was
determined by X-ray crystallography of a derivative. Allylic silane
3 underwent hydroboration, followed by oxidation, to form
oxasilacyclopentane 14 as a single isomer (eq 5).20 Oxasilacyclo-
pentane 14 was then subjected to modified Tamao-Fleming
oxidation conditions21-23 to remove the di-tert-butylsilylene
moiety, providing diol 15 (eq 6). The stereochemistry and connec-
tivity of diol 15 was established by X-ray crystallography.24
favored trans-fused ring system 17.27,28 The analogous
structure for the cis-fused ring system (20) derived from alkene
8 appears to encounter steric hindrance due to a t-Bu group
being forced over the cyclohexane ring (Figure 1).29 The ring-
contracting step forms silacyclopropylcarbinyl cation 18
with inversion of configuration. Carbocation 18 undergoes
silacyclopropylcarbinyl cation rearrangement30,31 to form
ylide 19. The nucleophilic pentavalent silicon atom can then
reform the terminal alkene, providing allylic silane 3.30,31
FIGURE 1. Proposed conformation of ylide 20.
A stepwise mechanism is proposed to account for the
contraction of the original six-membered ring to form the
five-membered ring (Scheme 1). Silylene transfer to the
double bond of 1 would form silacyclopropane adduct 16
as one diastereomer.25 The oxygen atom can then complex to
the Lewis-acidic silicon atom26 to form the conformationally
In summary, silylene transfer to (-)-isopulegol derivatives
provided allylic silanes by a ring contraction. Similar five-
and seven-membered ring systems underwent silylene trans-
fer to the alkene but did not provide ring contraction
products. A mechanism for the transformation was pro-
posed utilizing a silylene ylide intermediate and a silacyclo-
propylcarbinyl rearrangement.
(19) Huffman, J. W.; Engle, J. E. J. Org. Chem. 1959, 24, 1844–1847.
(20) Fleming, I. J. Chem. Soc., Perkin Trans. 1 1992, 3363–3369.
(21) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044–6046.
(22) Driver, T. G.; Franz, A. K.; Woerpel, K. A. J. Am. Chem. Soc. 2002,
124, 6524–6525.
(23) For reviews of C-Si bond oxidation, see: (a) Tamao, K. In Advances
in Silicon Chemistry; Larson, G. L., Ed.; JAI: Greenwich, CT, 1996; Vol. 3, pp 1-
62. (b) Fleming, I. Chemtracts-Org. Chem. 1996, 9, 1–64. (c) Jones, G. R.;
Landais, Y. Tetrahedron 1996, 52, 7599–7662.
Experimental Section
Allylic Silane 3. To a solution of homoallylic ether 1 (0.394 g,
1.60 mmol) in 8.0 mL of toluene was added cyclohexene
silacyclopropane 2 (0.470 g, 2.09 mmol). AgO2CCF3 (0.004 g,
ꢀ
€
(28) Belzner, J.; Dehnert, U.; Ihmels, H.; Hubner, M.; Muller, P.; Uson, I.
€
(24) The details of the crystallographic studies are provided as Supporting
Information.
(25) A similar substrate gave this stereoselectivity using t-Bu2SiCl2 and
Li0 to generate the silylene (reference 22).
(26) Sullivan, S. A.; DePuy, C. H.; Damrauer, R. J. Am. Chem. Soc. 1981,
103, 480–481.
(27) tert-Butyldimethylsilyl ethers, whose basicities are comparable to
that of analogous dialkyl ethers, should be capable of complexation: Blake,
J. F.; Jorgensen, W. L. J. Org. Chem. 1991, 56, 6052–6059.
Chem.-Eur. J. 1998, 4, 852–863.
(29) Both stereoisomers of silacyclopropane 20 encounter steric hin-
drance. The conformer drawn places the ring methyl group equatorial to
avoid 1,3-diaxial interactions.
(30) Tamao, K.; Nakajima, T.; Kumada, M. Organometallics 1984, 3,
1655–1660.
(31) Robinson, L. R.; Burns, G. T.; Barton, T. J. J. Am. Chem. Soc. 1985,
107, 3935–3941.
J. Org. Chem. Vol. 74, No. 18, 2009 7181

Bourque et al.
JOCNote
0.02 mmol) was then added. The brown solution was then placed
under an Ar atmosphere and allowed to stir for 1 h at 50 °C, at
which point the mixture was concentrated in vacuo. Purification
by flash chromatography (hexanes) provided 0.402 g (65%) of 3
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.28-7.35 (m,
4H), 7.19-7.23 (m, 1H), 4.91-5.01 (m, 2H), 4.74-4.76 (m, 2H),
2.22-2.32 (m, 1H), 2.01-2.07 (m, 2H), 1.80-1.93 (m, 1H),
1.61-1.77 (m, 5H), 1.02-1.29 (m, 20H), 0.89 (d, J=6.6, 3H),
0.71-0.79 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 147.7, 142.1,
128.3, 126.8, 126.2, 113.2, 66.6, 44.7, 43.7, 41.1, 34.3, 32.4, 32.3,
30.1, 29.8, 25.0, 23.8, 23.2, 21.5; IR (thin film) 2951, 2860, 2360,
1112, 820, 726 cm-1; HRMS (ESI) m/z calcd for C25H42OSiNa
(M þ Na)þ 409.2903, found 409.2910.
Oxasilacyclopentane 14. To a 0 °C solution of allylic silane 3
(0.440 g, 1.10 mmol) in 3.8 mL of THF was added 9-BBN
(6.8 mL of a 0.5 M solution in THF, 3.3 mmol) dropwise. The
reaction mixture was allowed to warm to room temperature for
8 h. After the solution was cooled to 0 °C, 1.5 mL of NaOH (3 N)
and 1.5 mL of 30% H2O2 were added. The heterogeneous
mixture was warmed to room temperature and stirred for an
additional 3 h. The mixture was then saturated with K2CO3 and
diluted with 5 mL of CH2Cl2. The layers were separated, and the
organic layer was washed with 5 mL of brine. The organic layer
was dried over Na2SO4 and concentrated in vacuo. Purifica-
tion by flash chromatography (95:5 hexanes/EtOAc) provided
1
0.250 g (75%) of 14 as a colorless oil: H NMR (500 MHz,
Homoallylic Ether 4. To a 0 °C solution of sodium hydride
(0.710 g, 29.6 mmol) in 50 mL of THF was added (-)-isopulegol
(2.50 mL, 14.8 mmol) dropwise followed by methyl iodide (1.01
mL, 16.3 mmol). The reaction mixture was warmed to room
temperature and stirred for 12 h. The solution was then cooled
to 0 °C and diluted with 20 mL of H2O. The aqueous layer was
extracted twice with 20 mL of EtOAc. The combined organic
layers were washed with 20 mL of brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography
(95:5 hexanes/EtOAc) provided 2.35 g (95%) of 4 as a colorless
oil: 1H NMR (500 MHz, CDCl3) δ 4.77-4.79 (m, 2H), 3.33 (s,
3H), 3.08-3.13 (m, 1H), 2.15-2.17 (m, 1H), 1.98-2.03 (m, 1H),
1.73 (s, 3H), 1.61-1.67 (m, 3H), 1.33-1.44 (m, 2H), 0.93-0.96
(m, 3H), 0.82-0.89 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
148.2, 110.9, 80.7, 56.1, 51.9, 39.2, 34.6, 31.6, 31.3, 22.4, 19.6; IR
(thin film) 2923, 2869, 1454, 1371, 1106, 885 cm-1; HRMS (ESI)
m/z calcd for C11H20ONa (M þ Na)þ 191.1412, found 191.1419.
Allylic Silane 5. To a solution of homoallylic ether 4 (0.017 g,
0.01 mmol) in 0.7 mL of benzene-d6 was added cyclohexene
silacyclopropane 2 (0.029 g, 0.13 mmol). AgO2CCF3 (0.001 g,
0.005 mmol) was then added. The brown solution was then
heated for 1 h at 50 °C, at which point the mixture was
concentrated in vacuo. Purification by flash chromatography
(hexanes) provided 0.022 g (71%) of 5 as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 4.72-4.77 (m, 2H), 3.62 (s,
3H), 2.26-2.29 (m, 1H), 2.09-2.12 (m, 1H), 1.93-2.00 (m, 2H),
1.82 (s, 3H), 1.67-1.75 (m, 2H), 1.14-1.20 (m, 3H), 1.10 (s, 9H),
1.09 (s, 9H), 0.98-1.07 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
147.6, 113.1, 53.1, 44.3, 43.4, 41.3, 34.4, 32.5, 32.2, 30.1, 29.6,
27.1, 24.9, 23.1, 21.7; IR (thin film) 2948, 2859, 1469, 1189, 1116,
819 cm-1; HRMS (ESI) m/z calcd for C19H37OSi (M - H)þ
309.2614, found 309.2623.
CDCl3) δ 3.82-3.86 (m, 1H), 3.70-3.72 (m, 1H), 2.23-2.31 (m,
1H), 2.04-2.13 (m, 1H), 1.86-1.97 (m, 3H), 1.72-1.82 (m, 1H),
1.35-1.37 (m, 1H), 1.16-1.26 (m, 2H), 1.11 (s, 9H), 1.00-1.05
(m, 15H), 0.83-0.90 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 73.9, 45.4, 38.8, 37.0, 36.0, 34.6, 33.7, 33.3, 29.6, 29.0, 22.3,
21.3, 21.1, 17.0; IR (thin film) 2948, 2859, 1377, 1080, 985,
822 cm-1; HRMS (ESI) m/z calcd for C18H37OSi (M þ H)þ
297.2614, found 297.2613. Anal. Calcd for C18H36OSi: C, 72.60;
H, 12.24. Found: C, 72.84; H, 12.30.
Diol 15. To a solution of KH (0.120 g, 2.90 mmol) in 1.5 mL of
THF was added 18-crown-6 (0.780 g, 2.90 mmol). The solution
was cooled to 0 °C, and cumene hydroperoxide (88%, 0.49 mL,
2.9 mmol) was added dropwise. The cooling bath was removed,
and oxasilacyclopentane 14 (0.150 g, 0.490 mmol) was added by
way of cannula in 0.5 mL of THF. The reaction mixture was
heated to 50 °C for 2 h, and Bu4NF (1.47 mL of a 1.00 M
solution in THF, 1.47 mmol) was added. After 12 h, the mixture
was cooled room temperature, and the solution was diluted with
2 mL of saturated sodium thiosulfate and 5 mL of CH2Cl2. The
layers were separated, and the organic layer was washed with
5 mL of brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. Purification by flash chromatography
(70:30 hexanes/EtOAc) provided 0.480 g (57%) of diol 15 as a
white solid: mp 97 °C; 1H NMR (500 MHz, CDCl3) δ 3.72-3.75
(m, 1H), 3.64-3.68 (m, 1H), 3.56-3.59 (m, 1H), 1.89-2.33 (m,
4H), 1.69-1.81 (m, 2H), 1.56-1.66 (m, 1H), 1.10-1.29 (m, 3H),
0.84-1.04 (m, 7H); 13C NMR (125 MHz, CDCl3) δ 79.9, 68.1,
44.4, 40.3, 37.7, 34.8, 33.8, 28.1, 21.0, 9.3; IR (thin film) 3307,
2917, 2861, 1454, 1029, 820 cm-1; HRMS (ESI) m/z calcd for
C10H20O2Na (M þ Na)þ 195.1361, found 195.1366. Anal. Calcd
for C10H20O2: C, 69.72; H, 11.70. Found: C, 69.49; H, 11.83.
Allylic Silane 7. To a solution of homoallylic ether 6 (0.027 g,
0.01 mmol) and cyclohexene silacyclopropane 2 (0.029 g, 0.13
mmol) in 0.7 mL of benzene-d6 was added AgO2CCF3 (0.001 g,
0.005 mmol). The brown solution was then heated for 1 h at
50 °C, at which point the mixture was concentrated in vacuo.
Purification by flash chromatography (hexanes) provided 0.034
g (82%) of 7 as a colorless oil: 1H NMR (400 MHz, CDCl3) δ
4.68-4.80 (m, 2H), 2.26-2.32 (m, 1H), 1.91-1.96 (m, 2H), 1.82
(s, 3H), 1.69-1.72 (m, 2H), 1.08 (s, 18H), 1.02-1.06 (m, 5H),
0.97-0.98 (m, 2H), 0.94 (s, 9H), 0.15 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 13C NMR (125 MHz, CDCl3) δ 123.2, 114.8,
44.7, 40.7, 33.7, 33.0, 31.3, 30.1, 29.6, 29.2, 28.2, 27.5, 27.1,
21.5, -1.3, -1.4; IR (thin film) 2952, 2859, 1469, 1253, 1043,
833 cm-1; HRMS (ESI) m/z calcd for C24H50OSi2Na (M þ
Na)þ 433.3298, found 433.3295.
Acknowledgment. This research was supported by
the National Institute of General Medical Sciences of the
National Institutes of Health (GM-54909). L.E.B. thanks
the Department of Education (GAANN) for a predoctoral
fellowship. K.A.W. thanks Amgen and Lilly for awards to
support research. We thank Dr. Phil Dennison (UCI) for
assistance with NMR spectroscopy, Dr. Joseph W. Ziller
(UCI) for X-ray crystallography, and Dr. John Greaves and
Ms. Shirin Sorooshian (UCI) for mass spectrometry.
Supporting Information Available: Complete experimental
procedures, X-ray data, and product characterization. This
material is available free of charge via the Internet at http://
pubs.acs.org.
7182 J. Org. Chem. Vol. 74, No. 18, 2009