Efficient protiodesilylation of unactivated C(sp3)-SiMe 2Ph bonds using tetrabutylammonium fluoride

Article abstract of DOI:10.1021/ol0506821

(Chemical Equation Presented) The protiodesilylation of unactivated C(sp³)-SiMe₂Ph bonds proceeds efficiently by treatment with tetrabutylammonium fluoride in wet DMF or THF via isolable dimethylsilanol intermediates.

Full text of DOI:10.1021/ol0506821

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2405-2408
Efficient Protiodesilylation of
Unactivated C(sp3)
SiMe2Ph Bonds
−
Using Tetrabutylammonium Fluoride
Cheryl L. Heitzman, William T. Lambert, Eric Mertz, J. Brad Shotwell,
Jennifer M. Tinsley, Porino Va, and William R. Roush*,#
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
roush@umich.edu
Received March 30, 2005
ABSTRACT
The protiodesilylation of unactivated C(sp3)
−SiMe2Ph bonds proceeds efficiently by treatment with tetrabutylammonium fluoride in wet DMF
or THF via isolable dimethylsilanol intermediates.
An important strategy for the stereoselective synthesis of
highly substituted tetrahydrofurans involves the [3+2]-
annulation of chiral crotyl- and allylsilanes with aldehydes.1
Our laboratory has contributed to this area by demonstrating
the predictable stereochemical outcome of [3+2]-annulation
reactions of chiral allylsilanes via a formal three-component
coupling of two aldehydes and the chiral γ-silyl-substituted
allylborane 1 (Figure 1).2,3 Initial coupling of chiral allylbo-
rane 1 with an aldehyde (R1CHO) followed by exposure of
the protected R-hydroxy allylsilane 2 to a Lewis acid and a
second aldehyde (R2CHO), selectively affords either cis- or
trans-substituted tetrahydrofurans 3 or 4 in good yields.
Importantly, the stereochemistry of the [3+2]-annulation
reaction is determined by the nature of the Lewis acid
employed (Figure 1).2a The 2,5-cis tetrahydrofuran 3 is
obtained typically with g20:1 selectivity when BF3‚OEt2 is
employed, while the diastereomeric 2,5-trans disubstituted
Figure 1. Three-component coupling strategy for the stereocon-
trolled synthesis of tetrahydrofurans.
# Address correspondence to this author at Scripps Florida, 5353 Parkside
Drive, RF-2, Jupiter, FL 33458. E-mail: roush@scripps.edu.
(1) (a) Panek, J.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. (b) Panek,
J.; Beresis, R. J. Org. Chem. 1993, 58, 809. (c) Masse, C. E.; Panek, J. S.
Chem. ReV. 1995, 95, 1293. (d) Peng, Z. H.; Woerpel, K. A. Org. Lett.
2002, 4, 2945. (e) Peng, Z. H.; Woerpel, K. A. J. Am. Chem. Soc. 2003,
125, 6018.
(2) (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461. (b)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949. (c) Shotwell, J.
B.; Roush, W. R. Org. Lett. 2004, 6, 3865.
tetrahydrofuran 4 is obtained, also typically with g20:1 d.s.,
by using SnCl4 (via a chelate-controlled transition state,
requiring that R2CHO be capable of chelate formation). In
principle, manipulation of the -SiMe2Ph substituent in 3 or
4 via Tamao-Fleming oxidation4 or protiodesilylation5
(3) Roush, W.; Pinchuk, A.; Micalizio, G. Tetrahedron Lett. 2000, 41,
9413.
10.1021/ol0506821 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/14/2005

should allow for general access to tetrahydrofurans 5 and 6,
respectively.
Scheme 2. Protiodesilylations of Tetrahydrofurans 11 and
14R/â by Using TBAF-Modified Literature Conditions
The established literature procedure for protiodesilylation
of unactivated C(sp3)-SiMe2R bonds (i.e., RCH2SiMe3 or
RCH2SiMe2Ph f RCH3) involves extended basic hydrolysis
(DMSO/H2O, 5-10% KOtBu, 18-crown-6, 95 °C, 2-7
days).2,5 Although tetrahydrofurans 6 can be obtained from
3 or 4 using this procedure,2 the extended reaction times and
extremely harsh conditions severely limit the potential
applications of this method, with protiodesilylation generally
failing for substrates with any reasonably complex R1 or R2
(vida infra). 2c
During the course of several ongoing studies in natural
product synthesis, it became paramount that a mild method
for accomplishing this protiodesilylation (e.g., 3 or 4 f 6)
reaction be developed. In particular, in connection with
studies on the synthesis of amphidinolide F,6 we demon-
strated that protiodesilylation of highly functionalized tet-
rahydrofurans of general structure 4 could be effected by
treatment with tetrabutylammonium fluoride (TBAF) in DMF
(Scheme 1).2c We report herein a much wider range of
ylsilyl analogues explored by Landais,5d and the isolated
siloxanes investigated by Hoveyda and Stork.5e,8 Accordingly,
TBAF was added to the standard Hudrlik reaction conditions
(DMSO/H2O, 5-10% KOtBu, 18-crown-6, 95 °C) to effect
in situ desilylation of the TBS ethers present in both
substrates. Unfortunately, these reactions were highly irre-
producible, requiring reaction times from 1 day to 1 week
for complete conversion. The long reaction times necessitated
that these experiments be performed in sealed pressure tubes
(to prevent evaporation of solvent), which proved highly
inconvenient for reaction monitoring. In addition, significant
decomposition of even the relatively simple tetrahydrofuran
11 was observed.
Scheme 1. Key TBAF-Mediated Protiodesilylation of an
Amphidinolide F Precursor (7)3c
Interestingly, brief treatment of both 11 and 14R or 14â
under the TBAF-modified Hudrlik conditions led to the
generation of the sensitive but isolable silanols 15, 17R, and
17â after aqueous workup (Scheme 2).9 Both 15 and 17R/â
were competent in the further conversion to 16 and 18R/â
upon exposure to the reaction conditions. These silanol
intermediates are likely not accessible from the corresponding
trimethylsilyl derivatives explored by Hudrlik.5 This sug-
gested to us that the protiodesilylation of -SiMe2Ph groups
might occur via a different mechanistic pathway compared
to the -SiMe3 derivatives and that a cyclic silicate or
siloxane may not be a required intermediate.
Significant differences in substrate scope for the present
process compared to the -SiMe3 substrates studied by
Hudrlik quickly became evident. Tetrahydrofurans 19-2110
undergo smooth carbon-silicon bond cleavage to afford
protiodesilylated adducts 22-24 in good yields (entries 1-3,
conditions A, Table 1). Interestingly, the protiodesilylation
of 20 and 21 proceeds smoothly even though they lack a
examples of this process, which serve to define the scope of
this mild and efficient protiodesilylation reaction.
We began with a careful exploration of the original
Hudrlik-type conditions5a-c by using tetrahydrofurans 11 and
14R/â (Scheme 2).7 Initially, we anticipated that a neighbor-
ing hydroxyl group was required to activate the -SiMe2Ph
group toward protiodesilylation by analogy to the trimeth-
ylsilane substrates investigated by Hudrlik,5a-c the diphen-
(4) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(5) (a) Hudrlik, P.; Hudrlik, A.; Kulkarni, A. J. Am. Chem. Soc. 1982,
104, 6809. (b) Hudrlik, P.; Holmes, P.; Hudrlik, A. Tetrahedron Lett. 1988,
29, 6395. (c) Hudrlik, P.; Gebreselassie, P.; Tafesse, L.; Hudrlik, A.
Tetrahedron Lett. 2003, 44, 3409. (d) Landais, Y.; Mahieux, C. Tetrahedron
Lett. 2005, 46, 675. (e) Stork, G.; Sofia, M. J. J. Am. Chem. Soc. 1986,
108, 6826.
(6) Kobayashi, J.; Ishibashi, M.; Wa¨lchli, M.; Nakamura, H.; Hirata, Y.;
Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490.
(7) Tetrahydrofurans 11 and 14â were prepared as summarized below.
(8) Hale, M.; Hoveyda, A. J. Org. Chem. 1992, 57, 1643.
(9) See: Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.;
Andersson, P.; Ito, Y. J. Am. Chem. Soc. 1995, 115, 6487. In our hands,
silanols 17R/â show a marked propensity toward oligomerization upon
attempted isolation (see Supporting Information). These oligomeric mixtures
are competent intermediates toward further protiodesilylation.
(10) Available from the [3+2]-annulation of 12 with R-benzyloxy-
acetaldehyde under nonchelate conditions and subsequent standard trans-
formations (see Supporting Information).
2406
Org. Lett., Vol. 7, No. 12, 2005

Scheme 3. Protonation of Intermediate Silanols Proceeds with
Table 1. Probing the Role of Neighboring Hydroxyl
Assistance in the Protiodesilylation of 19-21
Retention of Stereochemistry
initial step.12a-c The deuterium-labeling study illustrated in
Scheme 3 indicates that the Si-substrate bond in a subse-
Table 2. Key Protiodesilylation Reactions Directed toward
Natural Product Syntheses
proximal hydroxyl groupsclearly indicating that a neighbor-
ing hydroxyl group is not required for the protiodesilylation
of -SiMe2Ph groups.11
A systematic study of the reagents employed for the
conversion of 21 to 24 indicated that TBAF played a role
beyond simple in situ desilylation of the silicon protecting
groups. In fact, commercial (wet) TBAF alone12 (added as a
solution in tetrahydrofuran) to 19-21 in either wet DMF or
THF led to rapid and clean conversion to the corresponding
protiodesilylated products 22-24, again via the intermediacy
of the corresponding silanols (entries 1-3, conditions B,
Table 1).13 Importantly, a substantial improvement in the
isolated yield of 16 from the protiodesilylation of 11 was
realized under these new conditions (entry 4, Table 1).
The reproducible isolation of silanol intermediates in all
the systems studied, as well as the competence of these
silanols toward further protiodesilylation, suggests that the
Ph-SiMe2R bond undergoes rapid protiodesilylation as an
(11) Silanols corresponding to 20 and 21 (R ) SiMe2OH) have been
isolated and fully characterized. These silanols are easily handled, suggesting
that the oligomerization of 17R/â proceeds via condensation of the C(7)
hydroxyl and silanol (see Supporting Information).
(12) For protiodesilylations of stabilized or C(sp2) systems via silanol
intermediates, see: (a) Anderson, J.; Flaherty, A. J. Chem. Soc., Perkin
Trans. 1 2000, 3025. (b) Anderson, J. C.; Munday, R. H. J. Org. Chem.
2004, 69, 8971. (c) Anderson, J. C.; Anguille, S.; Bailey, R. Chem. Commun.
2002, 2018. Where silanols have not been implicated: (d) Hulme, A. N.;
Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60, 1265. (e) Ni, Y.;
Montgomery, J. J. Am. Chem. Soc. 2004, 126, 11162.
(13) TBAF is apparently unique in promoting this reaction, as screening
of several other fluoride sources for protiodesilylation of 21 (CsF, KF, TAS-
F) in various solvent/temperature combinations (MeCN, DMF, DMSO, 23
°C f 90 °C, pressure tube) led only to recovered starting materials.
Additionally, tetrabutylammonium hydroxide does not promote this trans-
formation (see ref 2c).
Org. Lett., Vol. 7, No. 12, 2005
2407

quently formed silicate intermediate (e.g., 25)14 is sufficiently
nucleophilic to undergo efficient and stereoselective proto-
nolysis with complete retention of stereochemistry in the one
case studied (i.e., 25 f 26, Scheme 3). The significant
enhancement of reaction rate (5 d f 4 h) of the TBAF-
mediated protiodesilylation reaction (new conditions) com-
pared to the original hydroxide-mediated reaction conditions5
indicates that a fluorosilicate intermediate analogous to 25
with -F replacing one or more -OD groups in 25 may be
a key intermediate in the TBAF-mediated process.
This TBAF-mediated procedure for protiodesilylation of
unactivated C(sp3)-SiMe2Ph bonds has proven to be crucial
in our efforts to apply the [3+2]-annulation reaction strategy
in a variety of ongoing total synthetic endeavors. Specifically,
amphidinolide E precursors 27 and 28, which could only be
coaxed into slow decomposition using the original Hudrlik-
type protocol,5 now undergo efficient protiodesilylation in
>90% yield (entries 1-2, Table 2). Furthermore, global
desilylation of 7 and 29 afford versatile C(15)-C(26)2c and
C(1)-C(9) fragments of amphidinolide F (entries 3-4, Table
2). Bis-tetrahydrofurans 30-32, assembled using sequential
[3+2] annulations,15 can be efficiently protiodesilylated using
this modified protocol (entries 5-7, Table 2) and represent
important steps in our ongoing efforts toward asimicin and
a variety of other Annonaceous acetogenins. The protiode-
silylation of the benzhydryldimethylsilane 33 (entry 8, Table
2) is noteworthy in that the reaction proceeded with
comparable efficiency using either method A or B. Interest-
ingly, the conversion of 33 to 40 was found to proceed
through a stable cyclic siloxane intermediate, the only such
example uncovered during the course of these studies.16
In conclusion, a systematic investigation of the protiode-
silylation reactions of Me2PhSi-substituted tetrahydrofurans
has revealed that (i) free hydroxyl groups adjacent to the
silicon substituent are not required for activation of the
C(sp3)-SiMe2Ph bond (20 f 23, 21 f 24, 28 f 35, and
29 f 36), (ii) silanols (i.e., RSiMe2OH) are isolable
intermediates and are competent for conversion to protiode-
silylated products when resubjected to the reaction condi-
tions, and (iii) use of TBAF (wet) rather than KOtBu and
18-crown-6 leads to a substantial increase in reaction rate,
functional group tolerance, and overall efficiency in the
protiodesilylation of -SiMe2Ph groups. Applications of this
method in the total synthesis of natural products will be
reported in due course.
Acknowledgment. This work was supported by the
National Institutes of Health (GM 38907). J.B.S., E.M., and
W.T.L. gratefully acknowledge the National Cancer Institute
for postdoctoral fellowships (CA 103339, CA 103507, and
CA 108191, respectively). C.L.H. thanks the University of
Michigan REU program for a summer fellowship (NSF Grant
No. 0353553).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0506821
(16) Siloxane 41 was formed cleanly upon brief exposure of 33 to excess
TBAF at room temperature:
(14) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. ReV. 1993,
93, 1371.
(15) Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc., submitted for
Siloxane 41 was efficiently protiodesilylated to give 40 upon exposure to
publication.
the reagent combination of method B (89% yield).
2408
Org. Lett., Vol. 7, No. 12, 2005