Tandem intramolecular silylformylation-crotylsilylation: Highly efficient synthesis of polyketide fragments

Article abstract of DOI:10.1021/ja026511y

Polyketide fragments may be rapidly and efficiently assembled in the tandem intramolecular silylformylation-crotylsilylation of alkenes and alkynes. The reactions establish up to three new stereocenters with good-to-excellent diastereoselectivity, and the

Full text of DOI:10.1021/ja026511y

Published on Web 06/12/2002
Tandem Intramolecular Silylformylation-Crotylsilylation: Highly Efficient
Synthesis of Polyketide Fragments
Michael J. Zacuto, Steven J. O’Malley, and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received April 11, 2002
Scheme 1. NaH-Catalyzed Dihydrosilane Alcoholysis
Tandem intramolecular silylformylation-allylsilylation of al-
kenes1 (eq 1) and alkynes2 allows the rapid synthesis of polyol
fragments for polyketide/macrolide synthesis.3 In an effort to expand
the scope and utility of these reactions we have investigated the
substitution of (Z)- and (E)-crotyl groups for the allyl groups on
silicon. We report herein that such substitution leads to the
stereospecific incorporation of both anti and syn propionate units
into the growing polyol chain, and demonstrate the power of the
Scheme 2. Tandem Intramolecular
Silylformylation-Crotylsilylation
methodology for the rapid assemblage of polyketide-like structures.
It is a unique feature of this allylsilylation chemistry that the
silicon must carry two diastereotopic allyl (crotyl) groups in order
to avoid the presence of an additional element of chirality at silicon.
Syntheses of di-cis-crotylsilane and di-trans-crotylsilane were
therefore required. Although the latter has proven surprisingly
Scheme 3. Tandem Intramolecular
Silylformylation-Crotylsilylation
elusive (discussed in greater detail below), the former may be
prepared efficiently. Double Pd(PPh3)4-catalyzed 1,4-hydrosilylation
of 1,3-butadiene with dichlorosilane,4 and reduction of the resulting
dichloro-di-cis-crotylsilane with LiAlH4 (0.56 equiv) produced di-
cis-crotylsilane in 75% yield (eq 2).
Requiring an efficient method for the silylation of the substrate
established in a single tandem reaction. In every case the yield
alcohols, we focused on catalytic hydrosilane alcoholysis.5 Only a
shown is the isolated yield of purified major diastereomer. The
few reports have described the selective monoalcoholysis of
diastereoselectivities (major diastereomer: all other diastereomers)
dihydrosilanes,5m,6 and we were further constrained to catalysts that
parallel closely those observed in the corresponding diallylsilane
would not also catalyze hydrosilylation of the silyl ether products.7
reactions,1 and we therefore conclude that the crotylation event is
We therefore focused on metal alkoxides.5a,n Treatment of a mixture
of an alcohol and di-cis-crotylsilane with 20 mol % NaH provided
a mixture of the desired silyl ether and the dialkoxysilane that was
highly dependent on the solvent, temperature, and time of reaction.
essentially stereospecific.
Both the silylation chemistry and the tandem intramolecular
silylformylation-crotylsilylation chemistry work equally well with
alkyne substrates to produce ketodiol 4 and diacetate 59 in 65 and
Eventually, it was discovered that refluxing hexane allowed the
52% overall yields, respectively (Scheme 3). As above, the
selective monoalcoholysis reaction, and under these conditions
diastereoselectivities parallel closely those observed in the corre-
alcohols 1a, 1b, and 1c8 could be converted to silyl ethers 2a, 2b,
sponding diallylsilane reactions,2 leading to the conclusion that the
crotylation event is stereospecific.
As mentioned above, our attempts to prepare di-trans-crotylsilane
have been fruitless. The most obvious proposal was to adapt the
procedure for the synthesis of trans-crotyl-trichlorosilane.4b,c,10 Even
under harsh conditions with many different catalysts, however, we
could not induce a successful reaction between dichlorosilane and
and 2c in excellent yields (Scheme 1).
With access to the desired silyl ethers secured, we investigated
their performance in the tandem intramolecular silylformylation-
crotylsilylation reaction (Scheme 2). Subjection of silanes 2a, 2b,
and 2c to the standard reaction conditions1 led to the isolation of
triols 3a, 3b, and 3c, in which three new stereocenters have been
trans-crotyl chloride. Desiring nevertheless to establish that trans-
crotyl groups would result in syn propionate units in the tandem
* To whom correspondence should be addressed. E-mail: leighton@
chem.columbia.edu.
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J. AM. CHEM. SOC. 2002, 124, 7890-7891
10.1021/ja026511y CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Scheme 4. Rapid Synthesis of a Polyketide-like Fragmenta
intramolecular silylformylation-allylsilylation chemistry, we syn-
thesized trans-crotyl-phenylsilane as shown in eq 3.
To avoid the creation of a mixture of diasteromers in the silane
alcoholysis reaction, we employed an achiral alcohol (eq 4). As
shown, the silylation chemistry and the tandem intramolecular
silylformylation-allylsilylation chemistry work equally well with
a trans-crotylsilane to give diol 6 in 64% overall yield. As expected,
a syn-propionate unit was obtained stereospecifically.
a (a) 2,2-Dimethoxypropane, (+)-camphorsulfonic acid, CH2Cl2. (b) 20
mol % NaH, di-cis-crotylsilane, hexane, reflux. (c) i. 3.0 mol % Rh(acac)-
(CO)2, 900 psi CO, PhH, 60 °C; ii. H2O2, NaHCO3, THF, MeOH, reflux.
applications to the efficient synthesis of stereochemically complex
targets may be readily envisioned.
Acknowledgment. The National Institutes of Health (National
Institute of General Medical Sciences: R01 GM58133) is acknowl-
edged for financial support of this work. We thank Pharmacia for
graduate fellowships to M.J.Z. and SOM. J.L.L. is a recipient of
the Pfizer Award for Creativity in Organic Chemistry.
We have proposed that following the silylformylation an un-
catalyzed intramolecular aldehyde allylation/crotylation proceeds
through a closed cyclic transition state.1,2 The unusual observation
of anti-propionate units from cis-crotyl groups and of syn-propionate
units from trans-crotyl groups was predicted by, and is fully
consistent with, this model. Thus, a chairlike arrangement of the
six reacting atoms necessitates that the alkyl chain of the aldehyde
occupy a pseudoaxial position, leading to the observed sense of
induction (eq 5).
Supporting Information Available: Experimental procedures,
characterization data, and stereochemical proofs (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587-8588.
(2) O’Malley, S. J.; Leighton, J. L. Angew. Chem., Int. Ed. 2001, 40, 2915-
2917.
(3) Dreher, S. D.; Leighton, J. L. J. Am. Chem. Soc. 2001, 123, 341-342.
(4) This procedure was adapted from the reported method for the synthesis
of (Z)-crotyltrichlorosilane: (a) Tsuji, J.; Hara, M.; Ohno, K. Tetrahedron
1974, 30, 2143-2146. (b) Kira, M.; Hino, T.; Sakurai, H. Tetrahedron
Lett. 1989, 30, 1099-1102. (c) Iseki, K.; Kuroki, Y.; Takahashi, M.;
Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53, 3513-3526.
(5) The literature prior to 1985 has been reviewed. See: (a) Lukevics, E.;
Dzintara, M. J. Organomet. Chem. 1985, 295, 265-315. See also: (b)
Caseri, W.; Pregosin, P. S. Organometallics 1988, 7, 1373-1380. (c)
Yamamoto, K.; Takemae, M. Bull. Chem. Soc. Jpn. 1989, 62, 2111-
2113. (d) Luo, X.-L.; Crabtree, R. H. J. Am. Chem. Soc. 1989, 111, 2527-
2535. (e) Doyle, M. P.; High, K. G.; Bagheri, V.; Pieters, R. J.; Lewis, P.
J.; Pearson, M. M. J. Org. Chem. 1990, 55, 6082-6086. (f) Bedard, T.
C.; Corey, J. Y. J. Organomet. Chem. 1992, 428, 315-333. (g) Barton,
D. H. R.; Kelly, M. J. Tetrahedron Lett. 1992, 33, 5041-5044. (h) Burn,
M. J.; Bergman, R. G. J. Organomet. Chem. 1994, 472, 43-54. (i) Gregg,
B. T.; Cutler, A. R. Organometallics 1994, 13, 1039-1043. (j) Lorenz,
C.; Schubert, U. Chem. Ber. 1995, 128, 1267-1269. (k) Chang, S.;
Scharrer, E.; Brookhart, M. J. Mol. Catal. A 1998, 130, 107-119. (l) Ito,
H.; Ishizuka, T.; Okumura, T.; Yamanaka, H.; Tateiwa, J.-I.; Sonada, M.;
Hosomi, A. J. Organomet. Chem. 1999, 574, 102-106. (m) Blackwell,
J. M.; Foster, K. L.; Beck, V. H.; Piers, W. E. J. Org. Chem. 1999, 64,
4887-4892. (n) Le Bideau, F.; Coradin, T.; He´nique, J.; Samuel, E. Chem.
Commun. 2001, 1408-1409. (o) Chung, M. K.; Ferguson, G.; Robertson,
V. Can. J. Chem. 2001, 79, 949-957.
To demonstrate the power of this methodology for the iterative
and rapid synthesis of polyketide-like fragments, triol 3b (two steps
and 66% yield from alcohol 1b) was selectively (g7:1 at equilib-
rium) protected to give acetonide 7 in 81% yield (Scheme 4). A
second application of the tandem intramolecular silylformylation-
crotylsilylation produced triol 8 (>10:1 ds) in 58% overall yield.
The synthesis of 8, which contains eight stereogenic centers, was
thus achieved in five steps from alcohol 1b in 31% overall yield,
and the complete list of required stoichiometric reagents for the
synthesis is: di-cis-crotylsilane, CO, H2O2, NaHCO3, and 2,2-
dimethoxypropane. This both indicates the power and efficiency
of the tandem intramolecular silylformylation-crotylsilylation
methodology and suggests the possibility not only of applying this
methodology to the synthesis of natural products but also of rapidly
generating several such fragments and employing them as platforms/
building blocks for diversity-oriented synthesis of polyketide/
macrolide-like structures.
(6) Corriu, R. J. P.; Moreau, J. J. E. J. Organomet. Chem. 1976, 120, 337-
346.
(7) Indeed, tandem alcoholysis-hydrosilylation using dihydrosilanes and
allylic and homoallylic alcohols has been described. See: (a) Corriu, R.
J. P.; Moreau, J. J. E. J. Organomet. Chem. 1976, 114, 135-144. (b)
Xin, S.; Harrod, J. F. J. Organomet. Chem. 1995, 499, 181-191. (c) Wang,
X.; Ellis, W. W.; Bosnich, B. Chem. Commun. 1996, 2561-2562.
(8) All chiral alcohol starting materials used in this study were racemic.
(9) The diacetate was prepared to facilitate analysis of the diastereoselectivity
by gas chromatography. The diol may be isolated.
The reactions described here significantly expand the scope of
the tandem intramolecular silylformylation-allylsilylation reaction.
The crotylsilanes are easily prepared, and a new, convenient,
catalytic dihydrosilane alcoholysis has been developed. Further
(10) Furuya, N.; Sukawa, T. J. Organomet. Chem. 1975, 96, C1-C3.
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