The triisopropylsilyl effect: Exceptional Cram-type selectivity in Mukaiyama aldol reactions of a silyl ketene thioacetal

Article abstract of DOI:10.1039/a804153i

The level of 1,2-asymmetric induction in the BF₃·OEt₂-promoted addition of silyl ketene thioacetals to α-asymmetric aldehydes is affected by the bulk of the silyl group; unprecedented Cram-type selectivity is given by the triisopropylsilyl derivative 8a.

Full text of DOI:10.1039/a804153i

View Article Online / Journal Homepage / Table of Contents for this issue
The triisopropylsilyl effect: exceptional Cram-type selectivity in Mukaiyama
aldol reactions of a silyl ketene thioacetal
Anthony P. Davis,*† Stephen J. Plunkett and Jayne E. Muir
Department of Chemistry, Trinity College, Dublin 2, Ireland
The level of 1,2-asymmetric induction in the BF3·OEt2-
promoted addition of silyl ketene thioacetals to
a-asymmetric aldehydes is affected by the bulk of the silyl
group; unprecedented Cram-type selectivity is given by the
triisopropylsilyl derivative 8a.
SBut
R′
SBut
Ph
+
RO
R3SiO
O
O
SiPri3
8a R = Pri3Si
b R = ButMe2Si
7
9
The optimisation of 1,2-asymmetric induction in additions to
aldehydes 1 still presents challenges in stereoselective synthe-
employing BF3·OEt2 catalysis, and 3 as substrate, gave lower
selectivities (ca. 3:1) that did not depend substantially on the
bulk of the silyl group in the enolate.3f,6
R1
O
O
O
O
Ph
R2
Ph
The present work was aimed at extending the scope of our
earlier method, specifically by employing a nucleophile of more
general utility than 5. Silyl ketene thioacetals 8 seemed
especially attractive due to the versatility of the thioester groups
in aldol products 9.3e Accordingly, we prepared the triisopro-
pylsilyl derivative 8a and, for comparison, the tert-butyldime-
thylsilyl analogue 8b, by treatment of tert-butyl thioacetate with
LDA/THF/DMPU followed by Pri3SiOTf and ButMe2SiCl
respectively.‡ Reaction of 8a/8b with aldehydes 2–4, catalysed
by the corresponding supersilylating agents under the condi-
tions reported previously,3f gave the expected b-silyloxy
thioesters 10 and 11 [eqn. (3), RL = large, R5 = small] with the
1
2
3
4
sis. Effective methodology is available for substrates with
heteroatom-based substituents,1 while good ‘Cram-type’ se-
lectivity can now be obtained with a-aryl aldehydes, or where
R1 and R2 are alkyl groups of greatly differing steric bulk.2,3
However, in cases where the a-substituents are more subtly
differentiated, it is still difficult to achieve acceptable levels of
selectivity. We now describe a variant of the Mukaiyama aldol
addition which provides useful Cram-type selectivities with
even the most ‘difficult’ of aldehydic substrates.
The new method is related to the conventional Mukaiyama
addition as explored by Heathcock and Flippin [e.g. eqn. (1)],3a
and to our subsequent development exemplified by eqn. (2).3f
RS
O
RL
R3SiB(OTf)4
(5 mol%)
ButMe2SiO
8a/8b
RS
RS
X
SBut
SBut
+
BF3•OEt2
Ph
3
(3)
RL
RL
R3SiO
O
R3SiO
O
Ph
X
X
10
11
(1)
+
OH
'Cram'
1.3–2.5
O
OH
'anti-Cram'
1
O
yields and diastereoselectivities shown in Table 1. Although not
startling, the results were pleasing in that they generalised the
earlier discovery (dependence of selectivity on steric bulk of
SiR3), registered an acceptable selectivity of 5:1 for aldehyde
3, and confirmed that even the exceptionally challenging
substrate 4 could be transformed with significant selectivity
(3.5:1) using reagent 8a.
:
X = Me, But, OMe, OBut
Pri3SiO
Ph
5
Pri3SiB(OTf)4
6
3
Table 1 Additions of silyl ketene thioacetals 8a/8b to a-asymmetric
aldehydes 2–4 catalysed by R3SiB(OTf)a
Ph
Ph
Ph
Ph
(2)
+
:
12:13b
Pri3SiO
7
O
Pri3SiO
1
O
Aldehyde
Nucleophile Yield (%)
2
2
3
3
4
8b
8a
8b
8a
8a
80
79
58
78
88
27:1
77:1
3.6:1
5.5:1
3.5:1
The Heathcock study yielded good selectivities (up to 36:1)
with 2-phenylpropanal 2, but modest results with the more
challenging 3. In our own methodology, use of triisopropylsilyl
enol ether 5, and ‘supersilylating agent’ 64 gave a selectivity of
ca. 100:1 with 2 and [as shown in eqn. (2)] a useful level of 7:1
with 3. The improvement was thought to be due to the bulk of
the Pri3Si group in intermediate 7, requiring the nucleophile to
pass close to the asymmetric centre.5 Control experiments
a
Reaction conditions: R3SiB(OTf)4 (5 mol%), CH2Cl2, 280 °C, 1 h,
b
quenching at low temp. with sat. aq. NaHCO3. Determined by NMR
integration. Cram’s rule was assumed to hold for all substrates, and was
used to assign product stereochemistries.
Chem. Commun., 1998
1797

View Article Online
By contrast, a surprise awaited when, for completeness, we
repeated the reactions employing the conventional promoter
BF3·OEt2 [eqn. (4)]. On the basis of the earlier results with the
attack may occur through the face anti to But(S) and providing
an explanation for the sensitivity of the reactions to the steric
bulk of R3Si. In contrast, 5 adopts conformations in which one
face of the CNC bond is shielded, but the other is essentially free
(Fig. 1). It therefore attacks 3·BF3 with moderate selectivity,
which does not depend greatly on the bulk of R3Si. This analysis
does not explain why catalysis by R3SiB(OTf)4 does not lead to
even greater selectivity with 8, as it does with 5. We can only
assume that the combination of an exceptionally hindered
nucleophile 8 and a similarly hindered electrophile 7 causes a
change in mechanism which degrades selectivity.
RS
O
RL
BF3•OEt2
(1 equiv.)
8a/8b
RS
RS
SBut
SBut
+
(4)
RL
RL
In conclusion, we have discovered an addition to aldehydes
which takes place with unprecedented Cram-type selectivity,
and gives products which can serve as versatile intermediates
for organic synthesis. Our results further highlight the special
utility of the triisopropylsilyl group as a tool for directing
reactivity through long-range steric intervention.9¶
Financial support for this work was provided by Forbairt (the
Irish science and technology agency) and the EU Human
Capital and Mobility Programme.
HO
O
HO
O
12
13
(+ 10 + 11 in some cases; see Table 2)
silyl enol ethers, we expected inferior diastereoselectivity with
little dependence on R3Si. In fact, as shown in Table 2, the
method produced higher selectivities, which did increase with
the bulk of the silyl group. The analysis was complicated by
small amounts of 10 and 11 which appeared in some cases in
addition to the expected products 12 and 13. However, whether
or not these were taken into account, the discrimination
achieved by the triisopropylsilyl reagent 8a was quite out-
standing. For aldehyde 2 the selectivity was raised to the point
where the minor isomer was difficult to detect with certainty,
while for 3 and 4 the ratios were superior to those achieved in
any previously reported additions.7
Although some aspects of this behaviour remain mysterious,
a partial explanation is possible based on computer-based
molecular modelling.8 Systematic conformational searches on
8a and 8b reveal preferred structures in which the bulky But(S)
and R3Si(O) groups are held above and below the plane of the
CNC bond, effectively shielding the nucleophilic carbon from
attack by electrophiles (Fig. 1). As both faces are affected, these
nucleophiles appear highly hindered and might be expected to
react with unusual diastereoselectivity. The R3Si appears to be
the more flexible of the two blocking groups,§ suggesting that
Notes and References
† E-mail: adavis@tcd.ie
‡ Conveniently, the Pri3Si derivative 8a could be purified by flash
chromatography (hexane–Et2O, 40:1). Substantial losses were incurred
when the same technique was applied to 8b.
§ Conformations in which the silicon atom is roughly in the plane of CNC
bond appear at energies !11 kJ mol21 above baseline.
¶ An alternative might be the tert-butyldiphenylsilyl group. However, a
limited series of experiments indicates that, in this system, its effective bulk
lies between that of Pri3Si and TBDMS.
1 Leading ref.; R. S. Atkinson, Stereoselective Synthesis, Wiley,
Chichester, 1995, pp. 300–306.
2 Organometallic reagents: M. T. Reetz, R. Steinbach, J. Westermann,
R. Peter and B. Wenderoth, Chem. Ber., 1985, 118, 1441; M. T. Reetz,
N. Harmat and R. Mahrwald, Angew. Chem., Int. Ed. Engl., 1992, 31,
342; Y. Yamamoto and K. Maruyama, J. Am. Chem. Soc., 1985, 107,
6411; M. T. Reetz, S. Sanchev and H. Haning, Tetrahedron, 1992, 48,
6813; Y. Yamamoto and J. Yamada, J. Am. Chem. Soc., 1987, 109, 4395;
T. Furuta and Y. Yamamoto, J. Chem. Soc., Chem. Commun., 1992, 863;
B. H. Lipshutz, S. H. Dimock and B. James, J. Am. Chem. Soc., 1993,
115, 9283; S. Fukuzawa, K. Mutoh, T. Tsuchimoto and T. Hiyama,
J. Org. Chem., 1996, 61, 5400; G. Cainelli, D. Giacomini, P. Galletti and
A. Marini, Angew. Chem., Int. Ed. Engl., 1996, 35, 2849.
Table 2 Additions of silyl ketene thioacetals 8a/8b to 2–4 catalysed by
a
BF3·OEt2
Aldehyde Nucleophile Yield (%)
12:13b
3 Enolates: (a) C. H. Heathcock and L. A. Flippin, J. Am. Chem. Soc., 1983,
105, 1667; (b) A. I. Meyers and R. D. Walkup, Tetrahedron, 1985, 41,
5089; (c) L. A. Flippin and M. A. Dombroski, Tetrahedron Lett., 1985,
26, 2977; (d) L. A. Flippin and K. D. Onan, Tetrahedron Lett., 1985, 26,
973; (e) C. Gennari, M. G. Beretta, A. Bernardi, G. Moro, C. Scolastico
and R. Todeschini, Tetrahedron, 1986, 42, 893; (f) A. P. Davis and
S. J. Plunkett, J. Chem. Soc., Chem. Commun., 1995, 2173.
4 A. P. Davis and M. Jaspars, Angew. Chem., Int. Ed. Engl., 1992, 31, 470;
A. P. Davis, J. E. Muir and S. J. Plunkett, Tetrahedron Lett., 1996, 37,
9401.
2
2
3
3
4
8b
8a
8b
8a
8a
84
76
43 (51)c
78 (81)c
77 (90)c
54:1
~ 130:1
5.8:1 (5.5:1)c
13:1 (12:1)c
5.4:1 (5.0:1)c
a
Reaction conditions: BF3·OEt2 (1 equiv.), CH2Cl2, 280 °C, 30 min,
b
quenching at low temp. with aqueous phosphate buffer (pH 7). NMR
integration; see Table 1. c Major products 12 and 13 were accompanied by
minor quantities of 10 and 11. Unbracketed figures refer to 12/13 only,
while bracketed figures include contributions from the silylated products.
5 C. H. Heathcock, Aldrichim. Acta, 1990, 23, 99.
6 S. J. Plunkett, Ph.D. thesis, University of Dublin, 1996.
7 For comparison, additions to 4 usually result in ca. 1:1 ratios of
diastereomers (recent example: J. J. Eshelby, P. J. Parsons and
P. J. Crowley, J. Chem. Soc., Perkin Trans. 1, 1996, 191). Even a highly
hindered lithium a,a-bis(alkylthio) enolate gave a ratio of just 3.5 :1 with
this substrate [ref. 3(c)]. Only the arylthionation-allylation of Heathcock,
which is not a simple addition reaction, gives selectivities comparable
with the present method (I. Mori, P. A. Bartlett and C. H. Heathcock,
J. Am. Chem. Soc., 1987, 109, 7199).
8 Macromodel V5.5, MM3* force field. See; F. Mohamadi, N. G. J.
Richards, W. C. Guida, R. Liskamp, C. Caufield, G. Chang, T.
Hendrickson and W. C. Still, J. Comput. Chem., 1990, 11, 440.
9 C. Ru¨cker, Chem. Rev., 1995, 95, 1009.
SiR3
SiR3
S
O
O
H
H
H
H
But
8a/8b
5
Fig. 1 Schematic views of 8a/8b and 5 in their preferred conformations, as
predicted by computer-based molecular modelling
Received in Cambridge, UK, 3rd June 1998; 8/04153I
1798
Chem. Commun., 1998