1-Alkoxyallene as an effective precursor for regio- and stereocontrolled allylation reactions with aliphatic aldehydes via bis-stannylation

Article abstract of DOI:10.1021/ja054201k

Bis-stannylation of 1-(methoxy)methoxyallene yields (E)-(3-(methoxymethoxy)prop-2-ene-1,2-diyl) bis-tributylstannane (2) as a highly reactive allylation reagent. Stereoselective reactions of functionalized stannane 2 with a variety of aldehydes provide good yields of 1,2-diol derivatives. Reactions with α-alkoxyaldehydes proceed with chelation-controlled addition to afford efficient constructions of 3,4-anti-4,5-syn-relationships in stereotriads bearing three differentiated oxygen (alkoxy and hydroxy) substituents. Mechanistic considerations are presented, and derivatives for NMR experiments support the stereochemical assignments. An X-ray diffraction study is included. Copyright

Full text of DOI:10.1021/ja054201k

Published on Web 10/04/2005
1-Alkoxyallene as an Effective Precursor for Regio- and Stereocontrolled
Allylation Reactions with Aliphatic Aldehydes via Bis-Stannylation
David R. Williams* and Micheal W. Fultz
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue, Bloomington, Indiana 47405-7102, USA
Received June 24, 2005; E-mail: williamd@indiana.edu
Previous studies in these laboratories have developed a strategy
to utilize stereocontrolled allylation reactions in tandem with Pd-
catalyzed couplings to efficiently prepare complex dienes as
exemplified in amphidinolide K.1 These studies were facilitated by
the quantitative and facile bis-stannylation of allene2 and the
convenient use of 1 in asymmetric allylations.3 Similarly, recent
reports have featured advances for the analogous Pd-catalyzed
diboration of allenes.4,5 In addition, the hydroboration of allenyl-
boronates has provided for regiocontrolled 1,3-bifunctionalization
of the allyl unit and for sequential condensations with aldehydes.6
To address key issues of convergency in an ongoing natural product
synthesis, we required the assembly of three contiguous stereogenic
carbons, as illustrated in 3 (eq 1), each with differentiated oxygen
substitution, and the feasibility for subsequent Stille coupling. In
this report, we describe the bis-stannylation of 1-alkoxyallenes and
the use of fully functionalized (E)-(3-(methoxymethoxy)prop-2-
ene-1,2-diyl) bis-tributylstannane (2) for a study of stereocontrolled
allylation reactions with aldehydes.
yields with high stereoselectivity using magnesium bromide ether-
ate. In many cases, only a single diastereomer could be observed
by NMR analyses of crude reaction product. A mechanistic rationale
featuring a chelation-controlled addition as described for 5 illustrates
a synclinal SE2′ reaction via the open transition state arrangement
of 6 to yield 7 (83%; dr >95:5).9
The bidentate MgBr2 provides a mild Lewis acid which is
compatible with a number of acid-sensitive protecting groups.
Additionally, we have found no evidence for R-epimerization of
sensitive starting aldehydes of entries 2-5 and 6 under these
conditions. Reactions that were run to 50% completion led to the
reisolation of starting aldehyde without loss of optical purity.10
Similarly, nonracemic cis-epoxide of entry 7 is not affected despite
reduced stereocontrol observed in this reaction.
To broaden the scope of our study, several simple aldehydes
(entries 8-12) have also been examined. Reactions are accelerated
by the use of boron trifluoride etherate, and Felkin-Anh addition
is favored in chiral, racemic examples which contain R-alkyl/aryl
substitution delivering the 3,4-anti-4,5-syn-stereochemistry (entries
10 and 11). Diastereomeric ratios were determined from NMR
spectra of the initial product mixtures, and subsequently, major
products were purified using flash chromatography.
Early developments concerning the bis-stannylation of 1-meth-
oxyallene described product mixtures which are derived from kinetic
and thermodynamic processes.7 Tius and co-workers have reported
the preparation and utility of 1-(methoxy)methoxyallene for sig-
nificant advances of the Nazarov cyclopentannelation.8 This allene
proved to be a worthy point of departure for our studies as reactions
with neat hexabutylditin at 95 °C in the presence of tetrakis-
(triphenylphosphine)palladium catalyst yielded 2 (88%) as a single
olefin isomer.
Functionalized 2-propenylstannane 2 is highly reactive with a
variety of aliphatic aldehydes, as highlighted by stereoselective
formation of alcohol 3 (57%) as a single diastereomer bearing the
3,4-anti-4,5-syn-relationship. Reactions with nonracemic 4 have
been conducted in CH2Cl2 at -78 °C using a slight excess of
stannane 2 (1.5 equiv) followed by the addition of MgBr2 etherate
(2 equiv). To avoid side product arising from destannylation of
product 3, 2,6-di-tert-butyl-4-methylpyridine is introduced prior to
the Lewis acid, and reactions are quenched with aqueous NaHCO3.
A survey of reactions with aliphatic aldehydes is summarized
in Table 1. The added presence of the pyridine base permits reaction
temperatures of -40 to 0 °C without destannylation. However, this
acid-catalyzed decomposition was generally avoided by maintaining
reactions at -78 °C. As exemplified by the formation of 3 (eq 1),
chiral R-alkoxyaldehydes (entries 1-6, Table 1) provided excellent
The unambiguous assignment of stereochemistry in 7 is based
on an X-ray diffraction study,11 confirming the determinations of
a series of NMR experiments. Distinctive similarities of the proton
NMR spectra of products 3 and 7 and entries 1-7 display
characteristic 3,4-anti-stereochemistry (J ) 6-7 Hz). In the case
of 7, as well as the adducts of entries 1, 3, 4, and 8-12, this
relationship was established by conversion to the cyclic cis-
acetonides. Treatment with 2,2-dimethoxypropane and catalytic
protic acid led to protodestannylation and exchange of MOM ethers,
1
yielding the five-membered acetonides for H NMR characteriza-
1
tions. Observed H chemical shifts for methyl signals of trans-
substituted acetonides document similar electronic environments
due to facile ring inversion, whereas cis-substituted ketals, which
are produced from our major products, display widely distinguished
methyl singlets.12 In addition, the chirality of the pure, nonracemic
homoallylic alcohols obtained in entries 2-7 was assigned by
modified Mosher ester analysis.13 Finally, the racemic adducts of
9
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J. AM. CHEM. SOC. 2005, 127, 14550-14551
10.1021/ja054201k CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Examples of SE′ Allylation
controlled allylations. In the case of R-alkoxyaldehydes, this
methodology is highly effective for bond construction of a
stereotriad bearing the 3,4-anti-4,5-syn-relationship of alkoxy and
hydroxy substituents. Applications to natural product synthesis are
underway.
Acknowledgment. We thank the National Institutes of Health
(GM42897) for support of this research.
Supporting Information Available: Procedures for allylation
reactions and preparation of 2; characterization data of 2, 3, 7, major
1
products of Table 1 and vinylic iodide i; H and 13C NMR spectra of
2, 3, 7 and products of Table 1 (58 pages, print/PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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the benzoate i as shown. Crystal data for i (Ar ) 3,5-dinitrophenyl):
colorless needle, (mp 131-132 °C) 0.12 × 0.12 × 0.10 mm, C17H19
-
IN2O9, M ) 522.24, monoclinic, space group P21/c, a ) 13.1326(16) Å,
b ) 5.8396(8) Å, c ) 26.555(3) Å, â ) 91.813(4)°, V ) 2035.5(4) Å3,
T ) 123(2) K, Z ) 4, Fcalcd ) 1.704 Mg m-3, µ ) 1.625 mm-1, 2θmax
)
55.08, Mo KR (λ ) 0.71073). A total of 43925 reflections were measured,
of which 4692 were independent (Rint ) 0.1479). Final residuals were R1
) 0.0852 and wR2 ) 0.1715 (for 4065 observed reflections with I >
2σ(I), 263 parameters, 0 restraints) with GOF ) 1.368, and largest residual
peak 1.265 e Å-3 and hole -2.192 e Å-3. The C4H7O ring is disordered
over two positions. Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-277461.
(12) For cis-disubstituted acetonides, the chemical shift difference of the
observed methyl singlets (1H NMR) is greater than 0.12 ppm. For recent
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Chem. 2003, 68, 997. (b) Chen, G.; Schmieg, J.; Tsuji, M.; Franck, R.
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Org. Chem. 2005, 70, 2843.
a Reactions carried out under Ar atmosphere in CH2Cl2 at -78 °C with
MgBr2‚OEt2 (2 equiv) for 6 h. b Reactions carried out under Ar atmosphere
in CH2Cl2 at -78 °C with BF3‚OEt2 (1.1 equiv) for 2 h.
entries 10 and 11 were identified by the consistency of comparisons
for proton NMR coupling constants with the careful analysis of
related stereotriads pertaining to the elucidation of AAL toxin TA
by Kishi and co-workers.14
In conclusion, the bis-stannylation of 1-(methoxy)methoxyallene
provides a reactive and fully functionalized derivative for stereo-
(13) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(14) The 3,4-anti-4,5-syn-stereochemistry of the major products of entries 10
and 11 displays the expected 1H NMR coupling constants (JC4-H ) 3.6
and 7.2 Hz) as recorded by: Boyle, C. D.; Harmange, J.-C.; Kishi, Y. J.
Am. Chem. Soc. 1994, 116, 4995.
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