Enantio- and diastereoselective synthesis of cyclic β-hydroxy allylsilanes via sequential aldehyde γ-silylallylboration and ring-closing metathesis reactions

Article abstract of DOI:10.1021/ol034347t

(Matrix presented) Highly enantioenriched cyclic allylsilanes are prepared via stereoselective γ-silylallylboration reactions of β- or γ-unsaturated aldehydes followed by ring-closing metathesis.

Full text of DOI:10.1021/ol034347t

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1693-1696
Enantio- and Diastereoselective
Synthesis of Cyclic â-Hydroxy
Allylsilanes via Sequential Aldehyde
γ-Silylallylboration and Ring-Closing
Metathesis Reactions
Jung-Nyoung Heo, Glenn C. Micalizio, and William R. Roush*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received February 27, 2003
ABSTRACT
Highly enantioenriched cyclic allylsilanes are prepared via stereoselective γ-silylallylboration reactions of â- or γ-unsaturated aldehydes
followed by ring-closing metathesis.
Allylsilanes are important intermediates in organic synthesis.1
Allylsilanes react with a variety of electrophiles, including
carbonyl compounds, enones, and imines, to give products
with new C-C bonds with high levels of stereoselectivity.
The [3 + 2]-annulation reaction2-5 of allylsilanes with
aldehydes is of particular interest in our laboratory,6 as this
process provides facile and highly stereocontrolled access
to substituted tetrahydrofurans, which are the key structural
elements in a wide range of biologically active natural
products.7 While a number of strategies for synthesis of chiral
acyclic allylsilanes have been reported,1,2,8 relatively few
general methods for the synthesis of cyclic, nonracemic
allylsilanes are available.9 Accordingly, we have developed
and report herein a flexible strategy for synthesis of highly
enantiomerically enriched cyclic allylsilanes.
Previous reports from our laboratory have focused on the
asymmetric γ-silylallylboration reactions of aldehydes and
the tartrate ester-modified (E)-γ-silylallylboronates10 or the
more enantioselective B-diisopinocamphenyl-derived (E)-γ-
silylallylborane 3.8 It was readily apparent that the anti-â-
hydroxyallylsilane 2 could serve as a substrate for a ring-
closing metathesis (RCM) reaction,11 thereby providing
access to the syn-â-hydroxycyclohexenylsilane 1 (see Figure
1).12
(1) Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063, and
references cited therein.
(2) For review, see: Masse, C. E.; Panek, J. S. Chem. ReV. 1995, 95,
1293.
(3) (a) Panek, J. A.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. (b)
Panek, J. A.; Beresis, R. J. Org. Chem. 1993, 58, 809.
(4) (a) Akiyama, T.; Sugano, M.; Kagoshima, H. Tetrahedron Lett. 2001,
42, 3889. (b) Akiyama, T.; Yamanaka, M. Tetrahedron Lett. 1998, 39, 7885.
(c) Angle, S. R.; El-Said, N. A. J. Am. Chem. Soc. 2002, 124, 3608.
(5) (a) Roberson, C. W.; Woerpel. K. A. J. Am. Chem. Soc. 2002, 124,
11342. (b) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675. (c)
Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621. (d) Peng, Z.-H.;
Woerpel, K. A. Org. Lett. 2000, 2, 1379. (e) Roberson, C. W.; Woerpel,
K. A. J. Org. Chem. 1999, 64, 1434.
Figure 1. Strategy for Synthesis of Cyclic Allylsilane 1.
(6) (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461. (b)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949.
10.1021/ol034347t CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/15/2003

In the event, silylallylboration of 4-penten-1-al (4) using
γ-silylallylborane 3, prepared from (+)-Ipc2BOMe, at -78
°C gave anti-â-hydroxyallylsilane 2 with good enantio-
selectivity (94% ee)13 in 86% yield (Scheme 1). RCM of
cyclic allylsilanes, specifically allylsilanes such as 12 in
which the silicon substituent resides at a quaternary center.
On the basis of reports by Wang and co-workers,17 who
demonstrated that R-substituted syn-â-hydroxyallylsilanes (cf.
11) could be synthesized selectively via hydroboration of
allenylsilanes with 9-BBN-H or HB(Chx)2 followed by
addition of the resulting γ-substituted (Z)-γ-silylallyboranes
to aldehydes, we studied the reaction of allene 918 with
(Ipc)2BH. Thus, hydroboration of 9 with (-)-HB(Ipc)2,
prepared from (+)-R-pinene,19 followed by addition of
aldehyde 4, produced syn-11 as the major product via (Z)-
γ-silylallylborane 10a (Table 1). The ratio of â-hydroxy-
Scheme 1. Synthesis of Cyclic Allylsilanes 1 and 7
Table 1. Synthesis of â-Hydroxyallylsilanes 11
diene 2 using Grubbs’ second-generation catalyst 814 (5 mol
%) afforded cyclohexenylsilane 1 in excellent yield (94%).
This synthetic sequence was also applied to the synthesis of
five-membered cyclic allylsilane 7. In this case, silylallyl-
boration of 3-buten-1-al (5)15 with ent-3 provided anti-â-
hydroxyallylsilane 6 with 98% enantioselectivity.13 The RCM
cyclization of 6 using 10 mol % 8 at 80 °C then provided 7
in 73% yield.
hydroboration conditions
entry
temp
time
yield of 11
11 (syn:anti)a
1
2
3
4
66 °C
25 °C
-23 °C
-50 °C
6 h
6 h
6 h
76%
77%
79%
67%b
3:1
6:1
8:1
This two-step allylboration-ring closing metathesis se-
quence constitutes a highly efficient strategy for the synthesis
of cyclic cis-â-hydroxyallylsilanes. Previously, such inter-
mediates have been prepared by hydride reduction of 2-silyl-
substituted cyclohex-3-enones,5a which are prepared by
oxidation of trans-â-hydroxyallylsilanes deriving from the
reactions of cyclohexandienyl epoxides with an appropriate
silyllithium nucleophile.5a,16
14 h
10:1
a Determined by 1H NMR analysis. b Unreacted allenylsilane 9 was
recovered (5%).
allylsilane isomers (e.g., syn-11:anti-11) was dependent upon
the hydroboration reaction temperature; the best selectivity
was obtained when the hydroboration was performed at -50
°C, although the reaction was sluggish under these conditions
(entry 4). The kinetically formed (Z)-γ-silylallylborane 10a
presumably isomerizes to the thermodynamically more stable
(E)-isomer 10c via the boron allylic migration intermediate
10b, a process that is suppressed when the hydroboration is
performed at low temperatures.20 Interestingly, however, syn-
11 was obtained as the major product even when the
hydroboration of 9 was performed under reflux conditions
(entry 1). It is conceivable that, due to the steric bulk of the
(Ipc)2B- substituent, intermediate 10b is much less acces-
sible than in analogous reactions of less highly substituted
allylboranes and that the rate of isomerization (10a to 10c)
is relatively slow in the present case. Whether the ratio of
syn-11:anti-11 is reflective of kinetic control in the hydro-
boration step remains to be determined.
Having successfully demonstrated the synthesis of cyclic
cis-â-hydroxyallylsilanes 1 and 7, we turned our attention
toward the synthesis of an even more challenging group of
(7) (a) Elliot, M. C.; Williams, E. J. Chem. Soc., Perkin Trans. 1 2001,
2303. (b) Elliot, M. C. J. Chem. Soc., Perkin Trans. 1 2000, 1291.
(8) Roush, W. R.; Pinchuk, A. N.; Micalizio, G. C. Tetrahedron Lett.
2000, 41, 9413.
(9) (a) Fleming, I.; Higgins, D.; Lawrence, N. J.; Thomas, A. P. J. Chem.
Soc., Perkin Trans. 1 1992, 3331. (b) Landais, Y.; Zekri, E. Tetrahedron
Lett. 2001, 42, 6547.
(10) Roush, W. R.; Grover, P. T. Tetrahedron 1992, 48, 1981.
(11) For reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(12) For olefin metathesis reactions of allylsilanes: (a) Crowe, W. E.;
Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 2117. (b)
Engelhardt, F. C.; Schmitt, M. J.; Taylor, R. E. Org. Lett. 2001, 3, 2209.
(c) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J.; Yuan, H. J. Am. Chem.
Soc. 2001, 123, 2964.
(13) Enantioselectivity (% ee) of this reaction was determined by Mosher
ester analysis: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
(14) Prepared by the improved literature method: Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168. (b) For the original report: Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
(15) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675.
(17) (a) Gu, Y. G.; Wang, K. K. Tetrahedron Lett. 1991, 32, 3029. (b)
Wang, K. K.; Gu, Y. G.; Liu, C. J. Am. Chem. Soc. 1990, 112, 4424.
(18) Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A. Tetrahedron
1983, 39, 935.
(19) Brown, H. C.; Joshi, N. N. J. Org. Chem. 1988, 53, 4059.
(20) (a) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc.
1985, 107, 2564. (b) Roush, W. R. In ComprehensiVe Organic Synthesis;
Heathcock, C., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, p 1.
(16) For trans isomers, see ref 9b and: Clive, D. L. J.; Zhang, C.; Zhou,
Y.; Tao, Y. J. Organomet. Chem. 1995, 489, C35.
1694
Org. Lett., Vol. 5, No. 10, 2003

Because the mixture of the syn-11 and anti-11 allylsilane
diastereomers was inseparable by column chromatography,
a 10:1 mixture of syn-11 and anti-11 was subjected to RCM
cyclization. This provided an easily separable 10:1 mixture
of cyclohexenylsilanes 12a and 12b in 95-98% yield
(Scheme 2). The stereochemistry of cyclohexenylsilanes 12a
1). Diastereomers 15a (syn,syn) and 15b (syn,anti) arise from
the (Z)-silylallylborane 10a, while 15c (anti,syn) derives from
the (E)-isomer 10c. This result indicated that the selectivity
of the hydroboration step was ca. 7:1 (i.e., the ratio of (10a
+ 10b):10c), similar to that realized with the achiral aldehyde
4, but that the face selectivity of the reaction of 10a with 13
was 3.6:1 (i.e., the ratio of 15a:15b). When the hydroboration
reaction was performed at - 50 °C, the 10a:10c ratio
increased to 13:1, and the ratio of 15a:15b increased slightly
to 4.8:1 (entry 2). While 15b was easily separated from the
mixture by chromatography, isomers 15a and 15c were
inseparable. Analogously, the γ-silylallylboration of aldehyde
14 provided an 83:10:7 mixture of 16a-c (entry 3). Isomer
16b could be separated chromatographically, but 16a and
16c were obtained as a ca. 12:1 mixture.
Scheme 2. Synthesis of Cyclohexenylsilane 12a
Subsequent RCM of a 10:1 mixture of 15a and 15c
furnished the cyclohexenylsilane 17a in 88% yield (Scheme
3). A prolonged reaction period (3 days) was required in
and 12b was assigned via Peterson elimination21 (KHMDS,
THF, -78 °C). Only the cis-â-hydroxysilane 12b underwent
elimination to 2-propyl cyclohexadiene, while the trans
isomer 12a remained intact and was recovered as a single
isomer.
The scope of the γ-silylallylboration reactions of 10a was
expanded by using chiral aldehydes such as (2S,3R)-2,3-
dibenzyloxy-4-penten-1-al (13)22 and (S)-2-methyl-4-penten-
1-al (14)23 (see Table 2). Hydroboration of allenylsilane 9
Scheme 3. Synthesis of Cyclohexenylsilanes 17a and 18a
Table 2. γ-Silylallylboration of Aldehydes 13 and 14
this case due to the very hindered silyl-substituted quater-
nary center and the deactivating allylic benzyloxy sub-
stituent. RCM of a 12:1 mixture of 16a and 16c was
straightforward and provided cyclohexenylsilane 18a also
in excellent yield (81%).24 The stereochemistry of cyclo-
hexenylsilanes 17a and 18a (as well as the minor cyclo-
hexenylsilanes derived from 15c and 16c)24 was confirmed
hydroboration
temp
product
(yield)
ratio
(a:b:c)a
1
by H NOE experiments.
entry
RCHO
This route to highly substituted cyclohexenylsilanes was
developed in anticipation that these compounds would be
useful intermediates for C-C bond-forming reactions. Ac-
cordingly, in an initial test of this hypothesis, the hydroxyl
group of 12a was protected as the TES ether 19 under
standard conditions (Scheme 4). Treatment of 19 with
R-(benzyloxy)acetaldehyde in the presence of SnCl4 fur-
nished a 9:1 mixture of bicyclic ethers 20 and 21 in 71%
yield.25 The stereochemistry of epimers 20 and 21 was easily
1
2
3
13
13
14
-30 °C
-50 °C
-50 °C
15 (90%)
15 (79%)
16 (73%)b
69:19:12
77:16:7
83:10:7
a Determined by H NMR analysis. b Yield of 16a and 16c.
1
1
assigned by H NOE experiments (Scheme 4).
(23) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737. (b) Lin, N.-H.; Overman, L. E.; Rabinowitz, M. H.;
Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118,
9062.
(24) Cyclohexenylsilanes deriving from 15c and 16c were also obtained
(5-8% yield) but are not shown in Scheme 3.
(25) All attempts using other Lewis acids (BF3‚OEt2, TiCl4, ZnCl2, or
MgBr2) for this reaction failed to give [3 + 2]-annulation products, 20 or
21.
at -30 °C, followed by treatment of the in situ-generated
γ-silylallylborane 10a with 13 at -78 °C, provided a 69:
19:12 mixture of three diastereomeric products 15a-c (entry
(21) (a) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464.
(b) Koreeda, M.; Ciufolini, M. A. J. Am. Chem. Soc. 1982, 104, 2308.
(22) For synthesis of 13, see Supporting Information
Org. Lett., Vol. 5, No. 10, 2003
1695

by RCM. Applications of this methodology toward the
synthesis of representative conduritols and inositols are
presented in the accompanying paper.26 Additional applica-
tions of highly functionalized cyclohexenylsilanes in natural
product synthesis will be reported in due course.
Scheme 4. [3 + 2]-Annulation Reaction of
Cyclohexenylsilane 19
Acknowledgment. We thank the National Institutes of
Health (GM 38907) for generous financial support of this
research.
Supporting Information Available: Experimental details
and spectroscopic data for compounds 1, 3, 6, 7, 9, 11-13,
1
and 15-21 plus selected H NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL034347T
In summary, we have demonstrated that highly function-
alized cyclic allylsilanes can be prepared via γ-silylallyl-
boration reactions of â- or γ-unsaturated aldehydes followed
(26) Heo, J.-N.; Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697.
1696
Org. Lett., Vol. 5, No. 10, 2003