Diastereoselective temporary silicon-tethered ring-closing-metathesis reactions with prochiral alcohols: A new approach to long-range asymmetric induction

Article abstract of DOI:10.1002/anie.200250486

A useful approach to 1,4-, 1,5-, and 1,6-stereocontrol, diastereoselective ring-closing-metathesis reactions that utilize temporary silicon tethers represent a new strategy for long-range asymmetric induction. This method facilitates the construction of c

Full text of DOI:10.1002/anie.200250486

Communications
Si-Tethered Asymmetric Induction
Diastereoselective Temporary Silicon-Tethered
Ring-Closing-Metathesis Reactions with Prochiral
Alcohols: A New Approach to Long-Range
Asymmetric Induction**
P. Andrew Evans,* Jian Cui, and Gerald P. Buffone
The ability to control stereochemistry in substrates where the
reactive elements are distal represents a fundamentally
important area of investigation that is commonly referred to
as long-range asymmetric induction.[1,2] Although there are
numerous examples of this phenomenon, a significant limi-
tation with this type of process is the ability to predict the
manner in which the chiral group attains proximity to the
reactive site in order to translate stereochemical information.
The inherent challenge associated with this requirement
provided the incentive for the development of a new process
where the elements of stereocontrol could be conserved in a
predictable manner.[1,2] Herein, we describe a new approach
to long-range asymmetric induction using the diastereoselec-
tive temporary silicon-tethered (TST) ring-closing-metathesis
(RCM) reaction of mixed bisalkoxy silanes 1, derived from an
allylic and prochiral alcohol, for the construction of cis-1,4-
silaketals 2 (Scheme 1; n = 0). This methodology was also
extended to higher homologues (where n = 1–4), which
resulted in the formation of the opposite trans diastereo-
isomer.[3–8]
( )n
O
( )n
O
( )n
O
R
R
R
LnM=CH2
vs
O
O
O
n = 0-4
Si
Si
Si
R' R'
R' R'
R' R'
2
3
1
Scheme 1. General approach to the diastereoselective TST-RCM reac-
tions with alkenyl and prochiral alcohols.
[*] Dr. P. A. Evans, Dr. J. Cui
Department of Chemistry
Indiana University
Bloomington, IN 47405 (USA)
Fax: (+1)812-855-8300
E-mail: paevans@indiana.edu
G. P. Buffone
Department of Chemistry and Biochemistry
University of Delaware
Newark, DE19716 (USA)
[**] We sincerely thank the National Institutes of Health (GM54623) for
generous financial support. We also thank Johnson and Johnson for
a Focused Giving Award, Pfizer Pharmaceuticals for the Creativity in
Organic Chemistry Award, and Novartis Pharmaceuticals for an
Academic Achievement Award. The Camille and Henry Dreyfus
Foundation is thanked for a Camille Dreyfus Teacher-Scholar Award
(P.A.E.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200250486
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Angewandte
Chemie
N
N
Ar
Ar
Cl
PCy
Ru
NAr
Mo
Ph
3Ph
Cl
Cl
(CF3)2MeCO
(CF3)2MeCO
Me
Me
Ru
Cl
Ph
PCy3
PCy3
Cy = Cyclohexyl Ar = 2,4,6-Trimethylbenzene Ar = 2,6-Diisopropylbenzene
10
11
12
Grubbs' Catalyst
Carbene Catalyst
Schrock's Catalyst
Figure 1. Proposed transition states for 1,4-stereocontrol in the TST-
RCM reaction of an allylic alcohol.
Table 1: Optimization of the diastereoselective TST-RCM reaction with
silicon tether 7a (R=Np).
Entry
7a; R’=
Catalyst[a]
8a:9a[b,c]
Yield of 8aþ9a [%]
41
70
75
31[d]
23[e]
We envisioned that the TST-RCM of the mixed bisalkoxy
silane 1 (Scheme 1; n = 0) should proceed through the favored
transition state illustrated in Figure 1. The basis for this
hypothesis was the assumption that the substituents (R’) on
silicon would result in nonbonding interactions with the
pseudoaxial propenyl moiety in the disfavored transition
state, and thereby prefer the formation of the cis-1,4-silaketal
2. The potential advantage of this approach is that the reactive
elements involved in diastereoselection are conserved irre-
spective of ring size, which should translate into a convenient
stereochemical relay, provided the relative orientation of the
substituents is maintained in the medium rings. Moreover, the
ability for ring-closing metathesis to facilitate the formation
of medium and large rings should allow the application of this
concept to higher homologues.
1
2
3
4
5
Me
Ph
iPr
iPr
iPr
10
10
10
11
12
23:1
15:1
ꢀ99:1
6:1
14:1
[a] All reactions (0.1 mmol) were carried out using 10 mol% of the
catalyst in dichloromethane (0.05m) at 408C except for entry 5. [b] Ratios
of diastereoisomers were determined by capillary GLC on aliquots of the
crude reaction mixture. [c] Authentic standards were prepared inde-
pendently from the corresponding 1,4-diols. [d] The more reactive
second-generation catalyst proved less selective in furnishing significant
amounts of polymeric and recovered starting material (30%). [e] This
reaction was carried out using 10 mol% catalyst in benzene (0.04m) at
room temperature.
Preliminary studies examined the feasibility of this
hypothesis for 1,4-stereocontrol (Scheme 2) through the
examination of various substituents on silicon[9,10] and metal
Table 2: Scope of the diastereoselective TST-RCM reaction (Scheme 2;
R’=iPr).
Entry 4; R=
Yield of 7 [%][a] 8:9[b,c,d] Yield of 8þ9 [%]
1
2
3
4
5
6
7
8
9
Np (1a)
Ph (1b)
nPr (1c)
c-Hex (1d)
iBu (1e)
PhCH2 (1 f)
Ph(CH2)2 (1g)
BnOCH2 (1h)
BnO2CCH2 (1i)
88
76
71
85
77
86
85
72
72
ꢀ99:1 75
ꢀ99:1 90
29:1 66
22:1 54
34:1 73
20:1 82
32:1 66
41:1 61
40:1 73
R
Imidazole
R
R
LnM=CH2
O
O
O
O
O
O
5
+
Si
Si
Si
OH
R' R'
R' R'
R' R'
R'2SiCl2 (xs)
Imidazole
6
8
9
7
d.r. 20 : 1
R
4
OH
[a] The bisalkoxy silanes were prepared on a 0.5 mmol reaction scale
using diisopropyldichlorosilane (10 equiv) and imidazole. [b] The meta-
thesis reactions were carried out on a 0.05–0.1 mmol reaction scale
(0.05m) using 10–15 mol% of Grubbs' catalyst 10 in dichloromethane at
408C. [c] Ratios of diastereoisomers were determined by capillary GLC
on aliquots of the crude reaction mixture. [d] The major stereoisomer
was confirmed by nOe experiments in each case.[12]
Scheme 2. Preparation of bisalkoxy silanes 7 and the resulting diaster-
eoselective TST-RCM reaction to form the cis-1,4-silaketals.
alkylidene catalysts,[11] as outlined in Table 1. Initial studies
determined that the steric nature of the substituents on the
silicon tether were indeed crucial in terms of silaketal
construction, overall efficiency, and the level of diastereose-
lection, in which the diisopropylsilane proved optimal
(Table 1; entry 3 versus 1 and 2). Treatment of the triene 7a
(R = 2-naphthyl (Np), R’ = iPr) with Grubbs' catalyst 10 at
reflux in dichloromethane furnished the silaketals 8a and 9a
in 75% yield, with ꢀ 99:1 diastereoselectivity favoring 8a
(Table 1; entry 3).[12] Additional studies explored the effects
of more reactive metal alkylidene catalysts, in which the
second-generation Grubbs catalyst 11 and the molybdenum-
based Schrock catalyst 12 proved significantly inferior for this
particular transformation (Table 1; entries 4 and 5).[11]
the requisite allylic alcohol 4, through treatment with excess
diisopropyldichlorosilane, to afford the monoalkoxychlorosi-
lane 5, followed by the removal of the excess silylating agent
and addition of the prochiral alcohol 6 (Scheme 2). The
diastereoselective TST-RCM proved remarkably tolerant to a
range of aryl, linear, and branched alkyl substituents (Table 2;
entries 1–7), albeit with lower conversion for the a-branched
allylic alcohol derivatives (Table 2; entry 4). Moreover, in
nearly all cases the bisalkoxy silanes 7a–i were recovered and
could be resubmitted to the reaction conditions. This trans-
formation is also tolerant of both benzyloxymethyl and
carboalkoxy substituents (Table 2; entries 8–9).[13]
Table 2 summarizes the scope of the TST-RCM, under the
optimized reaction conditions (Table 1, entry 3). The con-
struction of the mixed bisalkoxy silane 7 was achieved from
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We envisioned that the application of diastereoselective
TST-RCM to higher homologues would extend this concept,
and provide a general method for long-range asymmetric
induction. Table 3 summarizes the results of this study.
Treatment of the trienes 13a–d with the second-generation
Grubbs catalyst 11 in refluxing dichloromethane furnished,
after hydrogenation, the saturated silaketal intermediates 14/
15a–d, with the trans isomers 15a–d favored (Table 3;
entries 1–4).[14] The unsaturated silaketals were reduced in
Table 3: Diastereoselective TST-RCM reactions with homologated
alkenyl alcohols.
1. cat. 11
( )n
O
( )n
O
( )n
O
Figure 3. Plot of diastereoselectivity with time for the TST-RCM reac-
tions of 15a–c at min. 95% conversion. All aliquots were quenched
with DMSO and directly hydrogenated prior to GLC analysis.
Bn
CH2Cl2, ∆
nPr
Bn
Bn
nPr
+
O
O
O
2. 10% Pd/C
H2, PhH, RT
Si
Si
Si
iPr iPr
iPr iPr
iPr iPr
13
14
15
reaction revealed that the diastereoselectivity for 15a and
15b decreases and increases respectively with time at 95%
conversion.[15] Hence, the level of stereocontrol in these
reactions may be optimized accordingly. For example, the
diastereoselectivity for the formation of 15a can be improved
to approximately 18:1, provided the reaction is quenched
after about 10 min at room temperature.
In conclusion, diastereoselective TST-RCM provides a
useful approach to 1,4-, 1,5-, and 1,6-stereocontrol, and thus
represents a new strategy for long-range asymmetric induc-
tion. This method facilitates the construction of cis-1,4-
silaketals 8a–i (Scheme 1; d.r. ꢀ 20:1), whereas the extension
of this concept to homologated alkenyl alcohols (Table 3; n =
1–4), results in reversal in diastereoselectivity favoring the
trans isomers 15a–d. The ability to systematically examine
medium-ring stereocontrol in this manner should provide a
greater understanding of the conformational factors that
control diastereoselection in these systems.
Entry Ring size n= Yield of 13 [%][a] 14:15[b–d] Yield of 14þ15 [%]
1
2
3
4
1 (13a)
2 (13b)
3 (13c)
4 (13d)
92
68
75
87
1:11
1:27
1:3
90
92
75
73
1:3
[a] The bisalkoxy silanes were prepared on an analogous reaction scale to
those in Table 2. [b] The RCM reactions (0.1 mmol) were carried out
using new Grubbs catalyst 11 (6 mol%) in dichloromethane (0.003m) at
408C.[14] [c] Ratios of diastereoisomers were determined by capillary GLC
on the saturated silaketals 14 and 15 after hydrogenation. [d] The major
isomer was assigned by analogy to an independently prepared authentic
sample.
this particular case to remove the E and Z isomers and
simplify the stereochemical analysis. The origin of diaster-
eoselectivity is consistent with the previous model, albeit with
the caveat that the pseudoaxial/equatorial positions are
reversed in the medium rings (Figure 2). Hence, the preferred
transition state in the medium rings also places both
substituents in pseudoequatorial positions, thus avoiding the
steric interaction derived from the axial isopropyl group on
the silicon tether.
Additional studies demonstrated that the RCM is con-
sistent with a kinetic reaction that affords the more thermo-
dynamically stable product. Although there is evidence for
reversibility in the formation of 15a and 15b, the trans isomer
appears to be the major product throughout the course of the
reaction, as outlined in Figure 3. Periodic analysis of the
Received: November 6, 2002 [Z50486]
Keywords: cyclization · diastereoselectivity · medium-sized
.
rings · metathesis · silicon
[1] For recent reviews on long-range asymmetric induction, see:
a) H. Sailes, A. Whiting, J. Chem. Soc. Perkin Trans. 1 2000,
1785 – 1805; b) K. Mikami, M. Shimizu, H.-C. Zhang, B. E.
Maryanoff, Tetrahedron 2001, 57, 2917 – 2951, and references
therein.
[2] For recent examples of long-range asymmetric induction, see:
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Miyano, J. Chem. Soc. Perkin Trans. 1 2001, 645 – 653;
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references therein.
Figure 2. Proposed transition states for 1,n-stereocontrol in the TST-
RCM reaction of homologated alkenyl alcohols (where n=1–4).
[3] For recent reviews on ring-closing metathesis, see: a) R. H.
Grubbs, S. Chang, Tetrahedron 1998, 54, 4413 – 4450; b) U. K.
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Angewandte
Chemie
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[14] Although Grubbs' catalyst 10 was not optimal for the larger
rings, it also furnished 15 as the major diastereoisomer, which
confirmed that the catalyst was not responsible for the reversal
in selectivity.
[15] The diastereoselectivities in Figure 3, refer to crude product
ratios, whereas the selectivities in Table 3 are for the purified
silaketals 14a–d and 15a–d.
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[12] The major stereoisomer was confirmed from nOe experiments in
each case (8a–i). Details are available in the Supporting
Information.
NOE
Ha
O
Hb
R
O
Si
8
iPr iPr
[13] The silyl tether can be readily removed in each case to afford the
corresponding diol. For example, treatment of 8 f with 5%
aqueous HFat room temperature furnished the bisallylic 1,4-diol
16 in 99% yield.
5% aq. HF
Ph
Ph
MeCN/CH2Cl2
O
O
OH
OH
Si
iPr iPr
RT, 2 h
99%
8f
16
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