An alkyne hydrosilylation-oxidation strategy for the selective installation of oxygen functionality

Article abstract of DOI:10.1021/ja051578h

Alkynes bearing propargylic, homopropargylic, and bishomopropargylic hydroxyl groups are shown to serve as precursors for ketone or α-hydroxy ketone functionality. The approach hinges on the intermediacy of vinylsilanes created through regioselective hydrosilylation catalyzed by the complex [Cp*Ru(MeCN)₃]-PF₆. Several oxidative pathways of linear and cyclic vinylsilanes are studied, and the possibility of diastereoselective epoxidation of cyclic vinylsilanes is demonstrated. The sequences constitute the equivalent of stereoselective aldol, homo-aldol, and bishomo-aldol type processes. The method is applied to a short synthesis of the piperidine alkaloid, spectaline.

Full text of DOI:10.1021/ja051578h

Published on Web 06/18/2005
An Alkyne Hydrosilylation-Oxidation Strategy for the Selective
Installation of Oxygen Functionality
Barry M. Trost,* Zachary T. Ball, and Kai M. Laemmerhold
Contribution from the Department of Chemistry, Stanford UniVersity,
Stanford, California 94305-5080
Received March 11, 2005; E-mail: bmtrost@stanford.edu
Abstract: Alkynes bearing propargylic, homopropargylic, and bishomopropargylic hydroxyl groups are shown
to serve as precursors for ketone or R-hydroxy ketone functionality. The approach hinges on the intermediacy
of vinylsilanes created through regioselective hydrosilylation catalyzed by the complex [Cp*Ru(MeCN)3]-
PF6. Several oxidative pathways of linear and cyclic vinylsilanes are studied, and the possibility of
diastereoselective epoxidation of cyclic vinylsilanes is demonstrated. The sequences constitute the equivalent
of stereoselective aldol, homo-aldol, and bishomo-aldol type processes. The method is applied to a short
synthesis of the piperidine alkaloid, spectaline.
Scheme 1. Alkyne Building Blocks for Highly Oxygenated Targets
Introduction
The controlled introduction of heteroatom functional groups
is part and parcel of complex molecule synthesis. Introduction
of oxygenation at the ketone or hydroxyl oxidation state from
hydrocarbon “feedstock” alkanes, alkenes, and alkynes is a
useful way to introduce complex functionality. The use of C-C
unsaturation for the installation of oxygenation can reduce the
reliance on protecting-group manipulation, thereby improving
synthetic efficiency. The selective oxygenation of alkenes,
processes such as dihydroxylation, hydration (typically as
hydroboration-oxidation), and Wacker-type oxidation, is a
successful and pervasive method; the development of alkyne
oxygenation strategies, on the other hand, lags far behind, despite
the potential for increased flexibility and the potential to access
different oxidation states at either alkyne carbon.
In principle, alkynes could serve as the basis for the selective
syntheses of 1,2-diols, 1,2-dicarbonyl compounds, or R-hydroxy
carbonyl compounds, in addition to the simple ketone or
aldehyde hydration products (Scheme 1). This flexibility makes
alkynes attractive building blocks, and terminal alkynes have
been used to afford carbonyl products available by direct
hydration1 or through the intermediacy of vinylmetal species.
In contrast, the selective introduction of oxygenation to internal
alkynes is not well developed.2b Hydroboration can be used to
provide ketones after oxidation with good control of regio-
chemistry based on steric differentiation,2 and recently the direct
hydration of propargylic alcohols has been demonstrated with
a gold catalyst.3 In addition, intramolecular diol-alkyne bis-
cyclization catalyzed by palladium can be used in the selective
synthesis of spiroketals.4 Despite these achievements, the use
of alkynes as substrates for oxygenation in the context of
functionalized molecules remains underutilized. Of additional
synthetic benefit, alkyne oxygenation methods may well be
orthogonal to known olefin oxidation pathways, allowing
multiple oxygen-containing functional groups to be incorporated
at a late stage in a controlled manner for facile synthetic design.
Recently, we disclosed preliminary reports of regio- and
stereoselective hydrosilylation of internal alkynes, catalyzed by
the ruthenium complex [Cp*Ru(MeCN)3]PF6 (1), providing
unique vinylsilanes previously available only by circuitous
means (Scheme 2).5-8 Of special interest to this work, propar-
(1) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079-3159.
For a rare direct hydration to form aldehyde products: Tokunaga, M.;
Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867-2869. Tokunaga,
M.; Suzuki, T.; Koga, N.; Fukushima, T.; Horiuchi, A.; Wakatsuki, Y. J.
Am. Chem. Soc. 2001, 123, 11917-11924. Tokunaga, M.; Wakatsuki, Y.
J. Synth. Org. Chem., Jpn. 2000, 58, 587-596. Grotjahan, D. B.; Incarvito,
C. D.; Rheingold, A. L. Angew. Chem., Int. Ed. 2001, 40, 3884.
(3) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed.
2002, 41, 4563-4565.
(4) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845-1852. Trost, B. M.; Horne,
D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42, 5987-5990.
(5) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2003, 125, 30-31.
(6) Trost, B. M.; Machacek, M. R.; Ball, Z. T. Org. Lett. 2003, 5, 1895-
1898.
(2) (a) Tucker, C. E.; Davidson, J.; Knochel, P. J. Org. Chem. 1992, 57, 3482-
(7) Trost, B. M.; Ball, Z. T.; Jo¨ge, T. Angew. Chem., Int. Ed. 2003, 42, 3415-
3485. (b) Stork, G.; Bouch, R. J. Am. Chem. Soc. 1964, 86, 935-936.
3418.
9
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J. AM. CHEM. SOC. 2005, 127, 10028-10038
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An Alkyne Hydrosilylation-Oxidation Strategy
A R T I C L E S
Scheme 2. Hydrosilylation Directed by Hydroxy Groupsa
Scheme 3. Hydrosilylation of Propargylic Alcohols
At the onset of our work, the regioselective functionalization
of propargylic alcohols by hydrosilylation in a general sense
was a challenging problem.15 We demonstrated efficient inter-
molecular hydrosilylation with reasonable regio- and stereose-
lectivity of a variety of propargylic alcohols catalyzed by
complex 1, providing the (Z)-â-vinylsilane as the major product.7
Recently, a regiocomplementary process has been demonstrated
using an extended linker for intramolecular hydrosilylation of
3-octyn-1-ol.16
a BDMS ) benzyldimethylsilyl; TDMS ) 1,1,3,3-tetramethyldisilazane
[(HMe2Si)2NH)].
gylic,7 homopropargylic,5 and bishomopropargylic5 alcohols all
allow selective access to the (E)-vinylsilane with distal regi-
oselectivity relative to the hydroxyl group by either intramo-
lecular or intermolecular processes, as appropriate (Scheme 2).
The wealth of oxidation chemistry available from vinylsilane
intermediates led us to consider the use of alkyne hydrosilylation
together with vinylsilane oxidation9-12 to introduce functionality
distal to a hydroxyl group, which could control regio- and
stereochemistry.7 In this paper, we provide a full account of
these regioselective hydrosilylations and the use of these adducts
as an equivalent of an aldol, homo-aldol, and bishomo-aldol
process.
We chose to pursue selective incorporation of a vinyl C-Si
bond to serve as a versatile ketone precursor. Implicit in the
approach is a need for a silane oxidation under conditions mild
enough to prevent â-hydroxy elimination and destruction of
sensitive functionality. The most obvious silane targets, then,
are alkoxy silanes. Although these do function in the hydrosi-
lylation reaction, the selectivity and product stability are
compromised with propargylic alcohol substrates (Scheme 3,
9-â and 9-r). These problems were both solved upon moving
to a trialkylsilane reagent (i.e., formation of 10). However,
trialkylsilanes are not readily oxidized. Dimethylphenylsilyl is
the most studied silyl group for use where robust stability is
required,17 but oxidation of the dimethylphenylsilyl group can
be incompatible with sensitive functionality, especially acid-
sensitive groups. Our search for a balance between stability and
ease of oxidation led us to employ benzyldimethylsilane
(BDMS-H), an especially attractive silane useful in a number
of contexts.6,7,18 We have retained a BDMS group through
multiple synthetic operations, including those involving orga-
nolithium reagents, aqueous acid and base, buffered fluoride
necessary for silyl ether deprotection, and strong hydride
reductants (i.e., Red-Al). Activation of the BDMS group occurs
through loss of toluene and formation of a silyl fluoride or
silanol species upon treatment with unbuffered TBAF. Typically
addition of 1 equiv of TBAF produces complete conversion in
Propargylic Alcohols
Propargylic alcohols are surrogates for â-hydroxy ketones
provided that a chemo- and regioselective introduction of a
carbonyl group at the alkyne carbon â to the alcohol can be
performed. Homopropargylic alcohols have been previously
utilized for such a purpose via a platinum-catalyzed intramo-
lecular hydrosilylation of homopropargylic alkynes for the
selective introduction of a carbonyl group.9,11 The asymmetric
access to propargylic alcohols, most notably by enantioselective
hydrogenation of a ketone13 or addition of a zinc acetylide to
an aldehyde,14 makes this approach attractive. Although the
direct hydration of a propargylic alcohol is a potentially
attractive solution, obtaining regioselectivity has proven dif-
ficult,3 and elimination of the hydroxy ketone product under
generally acidic hydration conditions is a concern.
(8) Chung, L. W.; Wu, Y.-D.; Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc.
2003, 125, 11578-11582. Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc.
2001, 123, 12726-12727.
(9) Marshall, J. A.; Yanik, M. M. Org. Lett. 2000, 2, 2173-2175.
(10) Tamao, K.; Maeda, K. Tetrahedron Lett. 1986, 27, 65-68.
(11) Tamao, K.; Maeda, K.; Tanaka, T.; Ito, Y. Tetrahedron Lett. 1988, 29,
6955-6956.
(12) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
(13) Noyori, R.; Ohkuma, T. Pure Appl. Chem. 1999, 71, 1493-1501. Noyori,
R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40-73.
(14) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687-9688.
Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605-2606.
Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806-1807.
(15) Fensterbank, L.; Malacria, M.; Sieburth, S. N. Synthesis 1997, 813-854.
Isobe, M.; Nishizawa, R.; Nishikawa, T.; Yoza, K. Tetrahedron Lett. 1999,
40, 6927-6932. Kahle, K.; Murphy, P. J.; Scott, J.; Tamagni, R. J. Chem.
Soc., Perkin Trans. 1 1997, 997-999. Murphy, P. J.; Spencer, J. L.; Procter,
G. Tetrahedron Lett. 1990, 31, 1051-1054.
(16) Denmark, S. E.; Pan, W. Org. Lett. 2003, 5, 1119-1122.
(17) Fleming, I.; Henning, R.; Parker, D. C.; Plaut, H. E.; Sanderson, P. E. J. J.
Chem. Soc., Perkin Trans. 1 1995, 317-337.
(18) Miura, K.; Hondo, T.; Takahashi, T.; Hosomi, A. Tetrahedron Lett. 2000,
41, 2129-2132.
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A R T I C L E S
Trost et al.
Scheme 4. An Aldol Surrogate
5 min at 0 °C in THF or DMF. Subsequent addition of oxidant
(aqueous H2O2, urea-hydrogen peroxide adduct, or m-CPBA)
furnishes the oxidized product. Generally, use of KHCO3 and
H2O2 in methanol was preferred.18,19 As shown in Scheme 4,
the compatibility of the conditions for debenzylation and
Tamao-Fleming oxidation with hydrosilylation allows the
process to be performed as a one-pot operation. While the
proposed intermediates 12 and 13 have not been isolated, their
involvement seems probable. It is interesting to note that no
dehydration products are observed in this sequence. The
involvement of a cyclic silylene 13 wherein such an elimination
is geometrically disfavored may account for this behavior. In
earlier work using other catalysts to effect intramolecular
hydrosilylation of homopropargylic alcohols followed by oxida-
tion to form â-hydroxy ketones, elimination from the initial enol
is not possible.9
An additional advantage of this methodology is the ability
to further elaborate the vinylsilane 11 prior to unmasking the
ketone. As aldol adducts are prone to further reactions such as
eliminations, further substitution at the R-carbon becomes
difficult.20 Therefore, an important feature of this approach is
the ability to introduce additional complexity at the R-carbon.
For example, epoxidation occurs with complete diastereoselec-
tivity with m-CPBA to provide hydroxy epoxide 15. Others
demonstrated the importance of the silyl substituent for good
diastereoselectivity.21 Thus, as shown in eq 1, path a, this
sequence serves as an efficient route to the epoxy alcohols 16
diastereoselectively. On the other hand, treatment of 15 with 1
equiv of TBAF in THF followed by the standard Tamao-
Fleming oxidation10 provides the syn diol 17 (eq 1, path b).
The amount of TBAF in the initial stage of the oxidative
cleavage is crucial because significant protodesilylation occurs
if excess is employed. Purification of the epoxide prior to the
Tamao-Fleming oxidation minimized this issue. In this way,
the added alkyne unit functions as a hydroxymethyl ketone
equivalent with the hydroxy and ketone groups being unmasked
simultaneously.
aldol adducts. Diastereoselective addition of acetylide anions
to aldehydes has been a challenging problem due to their small
size and high reactivity.22 The Felkin-Ahn process has been
achieved using a tris-alkoxytitanium acetylide, which presum-
ably acts as a very sterically demanding nucleophile which is
coordinatively saturated and thus leaves open no possibility for
chelation.23 Indeed, addition of a titanium acetylide complex
converts aldehyde 18 into the anti adduct 19 with a diastereo-
meric ratio of 9:1 (eq 2). Chelation control, on the other hand,
has been achieved with an alkynylzinc species.24 Employing
the published conditions, we were able to demonstrate that
chelation-controlled addition to the R-alkoxy aldehyde 21 using
zinc bromide provides the syn adduct 22 (10:1 dr) (eq 3). In
both cases, one-pot hydrosilylation followed by oxidation
unmasks the aldol adducts. The final â-hydroxy ketones 20 and
23 are isolated as single diastereomers.
For this aldol surrogate process, the stereochemistry of the
â-hydroxy group derives from the acetylide addition. To the
extent that can be controlled in terms of both relative and
absolute stereochemistry, the utility of this process is much
enhanced. We were interested in finding methods to allow both
Felkin-Ahn and chelate-controlled alkyne addition and hence
As previously, the intermediate vinyl silane 24 undergoes
clean diastereoselective epoxidation (eq 4), and the resultant
silylated epoxide 25 provides the epoxy alcohol 26 as a single
diastereomer (path a). Alternatively, oxidative cleavage of the
silyl group provides diol 27 (path b). Because the ketone 27
(19) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi, A. Org. Lett.
2000, 2, 385-388.
(20) Frater, G.; Guenther, W.; Mueller, U. HelV. Chim. Acta 1989, 72, 1846-
1851.
(22) Evans, D. A.; Halstead, D. P.; Allison, B. D. Tetrahedron Lett. 1999, 40,
4461-4462.
(23) Shimizu, M.; Kawamoto, M.; Niwa, Y. Chem. Commun. 1999, 1151-1152.
(24) Mead, K. T. Tetrahedron Lett. 1987, 28, 1019-1022.
(21) Hasan, I.; Kishi, Y. Tetrahedron Lett. 1980, 21, 4229. Also see: Tomioka,
H.; Suzuki, T.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982, 23, 3387-
3390.
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An Alkyne Hydrosilylation-Oxidation Strategy
A R T I C L E S
Scheme 5. Asymmetric Aldol and Oxidative Aldol Surrogate
Scheme 6. Vinylsilane Analysis of γ- and δ-Hydroxy Systems
5-phenyl-2-pentanone would not be trivial considering regio-
and enantioselectivity issues. Scheme 5 illustrates a similar
sequence from isobutyraldehyde 30 with a more functionalized
acetylene. An improved enantioselectivity in forming adduct
31 is obtained in this case under identical conditions. Thus, an
excellent overall yield of the aldol type product 33 of 94% ee
is available in a two-pot operation from isobutyraldehyde. On
the other hand, the intermediate vinylsilane 32 may be diaste-
reoselectively oxidized to epoxide 34. Derivatizing the free
alcohol to the MOM ether 35 prior to unmasking the R-hy-
droxyketone provides the diol product 36 with the two alcohols
chemodifferentiated.
can undergo diastereoselective reduction, the initial stereogenic
center then propagates into three more.
Homo- and Bishomopropargylic Alcohol Substrates
We were also interested in developing alkyne nucleophiles
as methyl ketone enolate or hydroxymethyl ketone enolate
equivalents in homoaldol processes, where traditional aldol
processes are not successful. Homoaldol products could be
targeted through formation of either the â,γ C-C bond (e.g., a
homoenolate-aldehyde coupling) or the R,â bond (e.g., an
enolate-epoxide coupling). Several examples of the first, â,γ
approach using homoenolate equivalents have been demon-
strated, and some recent methods indicate that homoenolates
may be important synthetic methods for some target classes.25
Formation of the R,â bond, however, has few effective solutions,
because enolate nucleophiles are typically very poor partners
with the requisite epoxide electrophiles. Extending the method
of the previous section to view terminal alkynes as functional
An asymmetric aldol surrogate requires an enantioselective
addition of a terminal alkyne to aldehydes or ketones. Following
the Carreira protocol14 with (+)-N-methylephedrine, cyclohex-
anecarboxyaldehyde was converted to the propargyl alcohol 28
in good ee (85% ee) (eq 5). The one-pot hydrosilylation
oxidative cleavage then gives the “aldol” product 29 of the same
ee. Providing this system via an asymmetric aldol addition of
(25) Kalkofen, R.; Brandau, S.; Wibbeling, B.; Hoppe, D. Angew. Chem., Int.
Ed. 2004, 43, 6667-6669. Oezluegedik, M.; Kristensen, J.; Reuber, J.;
Froehlich, R.; Hoppe, D. Synthesis 2004, 2303-2316. Seppi, M.; Kalkofen,
R.; Reupohl, J.; Froehlich, R.; Hoppe, D. Angew. Chem., Int. Ed. 2004,
43, 1423-1427.
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A R T I C L E S
Trost et al.
Scheme 7. A Methyl Ketone Enolate Equivalent for Homoaldol
Processes
Scheme 8. Synthesis of R,γ-Dihydroxy Ketone by a Cyclic Silyl
Epoxide Method
Encouraged by the apparent opportunity for diastereoselective
epoxidation of vinyl silacycles, where no hydroxyl directing
group is present, we examined alcohol 43, readily available by
addition of an alkynylaluminum reagent to benzyl glycidyl ether
(Scheme 8). Hydrosilylation produced the vinylsilane, which
could be oxidized to the epoxide 45. The use of m-CPBA gave
the desired epoxide in reasonable diastereoselectivity (4:1). The
stereoselectivity of the nondirected epoxidation of cyclic olefins
has not been good; silacycles, which possess significantly more
conformational freedom than their carbocycle counterparts,
might have been expected to be even worse. Interestingly, the
use of dimethyldioxirane27 (DMDO) at low temperatures
resulted in a significant increase in selectivity (10:1).28 At this
stage, we set about finding a method for vinylsilane oxidation
to reveal the dihydroxy ketone. The epoxide substrate 45 was
significantly more unstable than the vinylsilane 41 (see Scheme
7), and we initially were plagued by low mass recovery. Sensing
that control of the amount of TBAF might be the source of the
problem, a solution was found employing a protocol of slow
addition (ca. 4 h) of TBAF to a premixed suspension of
anhydrous hydrogen peroxide-urea adduct (UHP) in a THF
solution of the epoxy-silane. We originally developed this
protocol for oxidation of the benzyldimethylsilyl group where
protodesilylation competes with oxidation at high fluoride
concentration.29 It may well be that creating the pentavalent
silicon fluoride is crucial to maintaining an open coordination
site for peroxide. Decomposition pathways such as protodesi-
lylation may result from the coordinatively saturated hexavalent
silicon difluoride in the presence of significant quantities of
TBAF. The protocol has proven useful for diverse reactions
including those for which the original rationale does not
necessarily apply. Employing those conditions to the problem
at hand allowed complete conversion without the extensive
decomposition observed when the TBAF is introduced dropwise
over just several minutes. The R,γ-dihydroxy ketone was
isolated in diastereomerically pure form after protection of the
hydroxyl groups as the bis-triethylsilyl ether (46).
equivalents of methyl ketone enolates allows access to a method
for the synthesis of the R,â bond because alkynyl anions are
good nucleophiles for epoxide-opening reactions.
The homoaldol process requires a γ-silyl homoallylic alcohol.
The cyclic siloxane derivative of such compounds is readily
constructed through an intramolecular hydrosilylation reaction
with the same catalyst 1 as we previously disclosed (Scheme
6, i).5
An example of such a process using an alkyne as a methyl
ketone enolate equivalent is shown in Scheme 7. Opening the
epoxide 37 with an alkynyllithium occurs cleanly to generate
highly diastereoselectively the homopropargylic alcohol 38. A
regioselective endo-dig hydrosilylation affords cyclic siloxane
39. At this stage, we encountered some difficulty in performing
a silane oxidation. Traditional conditions (aqueous H2O2, KF,
KHCO3, THF/MeOH) provided no turnover even at elevated
temperatures (50 °C). Switching the solvent to DMF and heating
to 80 °C resulted in decomposition, as did the basic conditions
developed by Woerpel.26b However, we found that a little-used
protocol utilizing acidic conditions by introduction of acetic
anhydride served to furnish the desired hydroxyl ketone, isolated
after conversion to the acetate.26 The reasons for the difficulty
in obtaining clean oxidation are not obvious for this substrate,
although the increased stability of the six-membered ring
silacycle relative to acyclic or five-membered substrates,
together with the steric interactions from the significant substitu-
tion about the silacycle, may play an important role.
In an effort to introduce further molecular complexity to
cyclic vinylsilane intermediates such as 39, we examined epoxi-
dation, which would allow either protodesilylation to synthesize
remote trans-epoxides with control of stereochemistry or silane
oxidation to furnish the hydroxyl ketone functionality. The
treatment of silane 39 with m-CPBA resulted in clean conversion
to a single epoxide product, as judged by 1H NMR analysis of
the crude reaction mixture. However, the epoxide was not stable
to silica gel and was isolated in only 31% yield after chroma-
tography. Analysis of 1H NMR coupling constants or nOe
spectra was not instructive, and the relative stereochemistry of
epoxide 41 is based solely on conformational speculation and
analogy to later examples.
The relative stereochemistry of ketone 46 was established
through conversion to the acetonide 48 by the sequence
summarized in Scheme 9. The acetonide 13C NMR shifts
establish a 1,3-syn arrangement (13C NMR acetal ca. 98.9 ppm,
methyl groups ∆ >9 ppm) rather than a 1,3-anti arrangement
(13C NMR acetal ca. 100.6 ppm, methyl groups ∆ <5 ppm).30
(27) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853.
(28) Stachel, S. J.; Danishefsky, S. J. Tetrahedron Lett. 2001, 42, 6785-6787.
(29) Trost, B. M., Ball, Z. T., unpublished results.
(26) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics 1983,
2, 1694-1696. (b) Smitrovich, H. H.; Woerpel, K. A. J. Org. Chem. 1996,
61, 6044-6046.
(30) Rychnovsky, S. D.; Rogers, B.; Yang, G. J. Org. Chem. 1993, 58, 3511-
3515.
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An Alkyne Hydrosilylation-Oxidation Strategy
A R T I C L E S
Scheme 9. Determination of Relative Stereochemistry
Scheme 10. Synthesis of R,γ-Dihydroxy Ketone with Selective
Methyl Ketal Formation for Diol Differentiation
Figure 1. Conformational analysis of a bishomopropargylic alcohol system.
Scheme 11. Oxidation Problems for a Homopropargylic Alcohol
with Additional Steric Hindrance
Because we anticipated that R-face attack would lead to
significant torsional strain in the transition state (44 model A,
projection down C-Si bond, below), obtention of the product
derived from an R-face attack of the oxidant on the vinylsilane
44 was somewhat surprising. The difference between our
expectation and experimental observation may be that the longer
Si-C bonds remove torsional strain as a significant factor, and
the observed product derives from steric screening of the top
face (44 model b).
1
stereochemistry on the basis of H NMR coupling constants
(Scheme 11). The epoxide, however, proved much more stable
and resistant to oxidation. Screening of a variety of oxidation
conditions did not result in the formation of the desired ketone
products. In general, no reaction is observed, and decomposition
is seen only at elevated temperatures (80 °C). The vastly
different reactivity of 45, 52, and 58 toward silane oxidation is
curious.
The use of hydroxyl groups to direct selective formation of
R-hydroxy ketones from alkyne precursors could prove a
valuable means of installing oxygenation functionality with
control of diastereoselectivity even at more remote centers. With
this in mind, we targeted the bishomopropargylic alcohol 61a
(Scheme 12). We performed reduction of ketone 60 as previ-
ously reported to allow diastereoselective access to homopro-
pargylic alcohol 61 after alkyne methylation. The original
authors reported 15:1 diastereoselectivity in the ketone reduction,
directed by coordination to the pendent alkyne, but we observed
variable selectivity (ca. 15:1 to 5:1) favoring the syn alcohol
61a and were unable to determine the source of the variation.
Pleasantly, a similar hydrosilylation-epoxidation-silane oxidation
pathway performed on the mixture of diastereomeric alcohols
afforded the analogous 1,4-diol deriviatives 63. This time, the
product was best isolated as the bis-silyl ether. We do not
observe any evidence of the diastereomeric epoxides by crude
1H NMR analysis of the reaction mixture, a gratifying result
given the conformational flexibility of seven-membered rings.
To determine the relative stereochemistry of the newly formed
stereocenter, acetonide formation of the mixture of 63a and 63b
produced a mixture of two inseparable compounds (ca. 5:1)
(Scheme 13). The major product 64 exhibited a strong nOe
Homopropargylic alcohol 50 behaved similarly, producing
ketal 54 by a similar route (Scheme 10). In this instance,
treatment of the crude keto-diol 53 with acidic methanol served
to form a single ketal product for characterization purposes.
Ketalization also has the effect of differentiating the two
hydroxyl functionalities for further synthetic operations. The
relative stereochemistry of the 1,3-diol 54 is assumed by analogy
to the previous example (see Schemes 8 and 9). The stereo-
chemistry at the ketal carbon is assumed to follow from the
anomeric effect.
Oxidation problems arose in the context of a more highly
substituted system (Scheme 11). A homopropargylic alcohol 56
with a 1,2-syn stereochemical relationship was synthesized by
coupling of a propargylic mesylate with isobutyraldehyde using
in situ formation of an organozinc compound catalyzed by Pd-
(O). Although we employed racemic starting mesylate, it has
been shown that enantiomerically pure mesylates do faithfully
transmit chirality to the product, allowing access to single
enantiomerically pure product alcohols.9,31
Hydrosilylation and epoxidation proceed without incident to
afford an epoxide 58, tentatively assigned the â-epoxide
(31) Marshall, J. A.; Bourbeau, M. P. Org. Lett. 2002, 4, 3931-3934.
9
J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005 10033

A R T I C L E S
Trost et al.
Scheme 12. Utilization of Bishomopropargylic Alcohol Substrates
Scheme 13. Determination of Stereochemistry
Scheme 14. Retrosynthetic Analysis of (+)-Spectaline
azimic acid, cassine, and prosafrinine. Hydroxylated piperidine
alkaloids can possess important biological activity, stemming
from their abilities as carbohydrate mimics in the context of
enzyme inhibition.33 These compounds have been the targets
of numerous synthetic efforts.34 However, extant syntheses are
plagued by protecting group manipulations and functional group
interconversions leading to synthetic inefficiency. Reductive
amination of an amino-ketone has been shown to be a
diastereoselective and efficient strategy for the synthesis of
3-hydroxy piperidine alkaloids, and such a retrosynthetic
disconnection in this case furnishes the δ-amino, γ-hydroxyke-
tone 68. The ease of forming such γ-hydroxyketone “homoal-
dol” products by the method described here interested us in the
use of intramolecular hydrosilylation for the selective installation
of ketone functionality. This approach to the spectaline alkaloids
allows simultaneous late-stage elaboration of ketone and hy-
droxyl functionality. By installing the amine functionality as
an azide group, this overall strategy avoids use of any protecting
groups for the synthesis of the piperidine core (Scheme 14).
The atom-economical approach employs only dimethylsiloxane
and dinitrogen as wasted atoms in the synthesis of the central
core and allows a short step count as well.
correlation between the methyl doublet and the proton R to the
ketone, establishing the all-syn stereochemistry of 63a. Alter-
natively, treatment of the crude product from the oxidation of
62a with acidic methanol produced two compounds in similar
amounts: a ketal 65, and another unstable ketal, which
decomposed readily on standing. The hydroxylated C3-H of
ketal 65 exhibits coupling constants of 6.7, 3.4, and 3.5 Hz in
1
its H NMR spectrum. These peaks are indicative of an axial
orientation of the hydroxyl group. The relative stereochemistry
of the other groups can be inferred from a 1,3 nOe correlation
between the ketal methoxy group and the benzylic C-H,
requiring an equatorial arrangement of the aryl group. Finally,
the small (3.2 Hz) coupling present for the benzylic peak
requires axial arrangement of the neighboring methyl group;
this must be the case because syn-1,2 stereochemistry was
established in the starting material 81.32
The observed product derives from â-face attack of the
oxidant on the convex face, as depicted in Figure 1. Molecular
dynamics calculations indicate that the preferred conformation
is the pseudo-boat form as shown (Figure 1).
In the synthetic direction, straightforward processes furnish
alkyne 73 (Scheme 15). Starting from the known epoxide 75,
(33) Fodor, G.; Fumeaux, J. P.; Sankaran, V. Synthesis 1972, 464. Cook, G. R.;
Beholz, L. G.; Stille, J. R. J. Org. Chem. 1994, 59, 3575-3584.
(34) Momose, T.; Toyooka, N.; Jin, M. J. Chem. Soc., Perkin Trans. 1 1997,
2005-2013. Makabe, H.; Kong, L. K.; Hirota, M. Org. Lett. 2003, 5, 27-
29. Cook, G. R.; Beholz, L. G.; Stille, J. R. Tetrahedron Lett. 1994, 35,
1669-1672. Lee, Y. S.; Shin, Y. H.; Kim, Y. H.; Lee, K. Y.; Oh, C. Y.;
Pyun, S. J.; Park, H. J.; Jeong, J. H.; Ham, W. H. Tetrahedron: Asymmetry
2003, 14, 87-93. Singh, R.; Ghosh, S. K. Tetrahedron Lett. 2002, 43,
7711-7715. Wang, Q.; Sasaki, N. A. J. Org. Chem. 2004, 69, 4767-
4773. Pahl, A.; Wartchow, R.; Meyer, H. H. Tetrahedron Lett. 1998, 39,
2095-2096.
A Synthesis of (+)-Spectaline Using a
Vinylsilane-Based Homoaldol Equivalent
Spectaline is a member of a class of all-cis 2,6-disubstituted,
3-hydroxy piperidine alkaloids that includes carpamic acid,
(32) We believe the second, unstable product to be the anomer of 65, existing
as the alternative chair conformation relieving 1,3-diaxial interactions. We
have not been able to sufficiently characterize this compound.
9
10034 J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005

An Alkyne Hydrosilylation-Oxidation Strategy
A R T I C L E S
Scheme 17. Strategic Approach to Hydroxyketones
Scheme 15. Synthesis of the Requisite Homopropargylic Alcohol
Scheme 18. Complementary Behavior Based upon Hydrosilylation
Catalyst
Scheme 16. Completion of the Synthesis of Spectaline
oxidation. Again we found that dropwise addition of TBAF over
4 h to a mixture of vinylsilane and oxidant provided the solution.
In this case, dropwise addition in THF resulted in a clean
reaction, but did not significantly improve the reaction rate.
However, switching the solvent to DMF improved the reaction
rate and allowed complete conversion without the extensive
decomposition observed when all of the TBAF is introduced
within 5 min.
It thus remained only to perform the reductive amination and
remove the distal ketal protecting group to complete the
synthesis. Fortunately, treatment of the azido-ketone with Pd/C
under a pressure of H2 (60 psi) served in one step to reduce the
azide, revealing the amine functionality, and to bring about imine
formation and reduction to the desired piperidine target (Scheme
16).38 Treatment of the crude mixture with aqueous HCl
removed the ketal functionality to allow isolation of the (+)-
spectaline target. Of note, our endo-dig hydrosilylation-oxidation
strategy allows for a convergent strategy and avoids the need
for any traditional protecting groups in the piperidine core and
only one protecting group for the side chain. The net result is
a synthesis having a longest linear sequence of 9 steps (11 total
steps) and proceeding in >18% yield.
available by resolution of (()-1-buten-3-ol (74) through catalytic
asymmetric epoxidation,35 followed by Mitsunobu displacement
with Zn(N3)2‚2pyr36 gave a volatile azido-expoxide. Although
we could isolate the azido-epoxide in low yield, it was far more
convenient and efficient to treat the crude azido-epoxide with
the alkynyllithium generated from terminal alkyne 73 to furnish
the epoxide-opening product 76.
The azido-alcohol 76 sets the stage for a key regioselective
ketone introduction at the distal position of the alkyne. Intramo-
lecular hydrosilylation proceeds well to furnish the product
cyclic siloxane in nearly quantitative yield (Scheme 16). The
tolerance of the azide functionality in the ruthenium-catalyzed
hydrosilylation is demonstrated for the first time with this
substrate. The stage is now set for unmasking the ketone. The
oxidation of silanes containing azide functionality has been
demonstrated for a single substrate,37 so we were encouraged
to pursue direct oxidation to the ketone 78. The oxidation was
quite slow under typical conditions (H2O2, KF, KHCO3, MeOH/
THF at room temperature provided 38% conversion over 6 d).
Unfortunately, raising the temperature or switching to more
active oxidation conditions (TBAF, H2O2, DMF) resulted in
significant decomposition. We also pursued initial azide reduc-
tion prior to silane oxidation. Treatment of the azide 78 with
triphenylphosphine or trimethylphosphine allowed clean conver-
sion to an intermediate iminophosphorane. Unfortunately, we
had difficulty hydrolyzing the intermediate iminophosphorane
in the presence of the rather sensitive cyclic siloxane, and
product characterization became troublesome. As a result of
these difficulties and the step economy of performing the
oxidation in the presence of the azide, we reexamined the
Conclusions
Strategically, the availability of the ruthenium-catalyzed
regioselective hydrosilylation provides the very useful â-, γ-,
and δ-hydroxyketones as illustrated in Scheme 17. The comple-
mentary behavior of rhodium, platinum, or palladium-catalyzed
hydrosilylation as compared to ruthenium translates into regio-
complementary products as summarized in Scheme 18. The
masking of the ketone or R-hydroxyketone in the form of the
vinylsilane has the additional advantage of serving as a
chemically unreactive form. Furthermore, the prospect of
introducing substituents other than hydroxyl by electrophilic
(35) Kang, M. C. Thesis, Department of Chemistry, Oregon State University:
Corvallis, 1983. Chandrasekhar, S.; Reddy, C. R. Tetrahedron: Asymmetry
2002, 13, 261-268.
(38) Kajimoto, T.; Liu, K. K. C.; Pederson, R. L.; Zhong, Z.; Ichikawa, Y.;
Porco, J. A., Jr.; Wong, C. H. J. Am. Chem. Soc. 1991, 113, 6187-6196.
Takaoka, Y.; Kajimoto, T.; Wong, C. H. J. Org. Chem. 1993, 58, 4809-
4812.
(36) Bessodes, M.; Saiah, M.; Antonakis, K. J. Org. Chem. 1992, 57, 4441-
4444.
(37) Panek, J. S.; Zhang, J. J. Org. Chem. 1993, 58, 294-296.
9
J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005 10035

A R T I C L E S
Trost et al.
(R)-[(2S,3R)-3-(Benzyldimethylsilyl)-3-hexyl-oxiranyl]-((R)-2,2-
dimethyl-[1,3]dioxolan-4-yl)-methanol, 25. Following the general
procedure for the synthesis of (()-(R)-[(2S,3R)-3-(benzyldimethylsilyl)-
3-methyloxiranyl]-phenylmethanol (15), vinylsilane 24 (205 mg, 0.52
mmol) was treated with m-CPBA (260 mg, 1.04 mmol) in CH2Cl2 (5.0
mL) to give 180 mg (84%) of the desired epoxide as a 9:1 mixture of
relative epimers at C2 from the initial alkyne addition. Purification was
done on silica gel (eluent: 20:1 to 10:1 pet. ether:acetone).
Data for Major Isomer. 1H NMR (500 MHz, C6D6): δ 7.09-7.13
(m, 2H), 6.94-7.00 (m, 3H), 4.03 (ddd, J ) 5.3, 5.3, 1.6 Hz, 1H),
3.92-3.99 (m, 2H), 3.62 (m, 1H), 2.96 (d, J ) 6.7 Hz, 1H), 2.31 (d,
J ) 13.7 Hz, 1H), 2.22 (d, J ) 13.7 Hz, 1H), 1.99 (d, J ) 4.1 Hz,
1H), 1.90 (m, 1H), 1.35 (3, 3H), 1.22 (s, 3H), 1.08-1.26 (m, 9H),
0.84 (t, J ) 7.1 Hz, 3H), 0.09 (s, 3H), 0.08 (s, 3H). 13C NMR (100
MHz, C6D6): δ 139.5, 128.8, 128.6, 124.8, 109.6, 77.3, 71.6, 67.6,
65.8, 58.7, 37.8, 32.1, 29.7, 26.8, 25.7, 25.3, 24.8, 23.0, 14.3, -3.0,
-3.1. IR (thin film): 3452 (br, OH), 2931, 1600 (w), 1251, 1207, 1067,
828, 700 cm-1. [R]26D +14.3° (c 1.0, CH2Cl2). This compound is further
characterized after conversion to ketone 33.
(1S,2S)-1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-1,2-dihydroxy-
nonan-3-one, 27. Following the general procedure for the oxidative
desilylation given for 17, employing epoxy silane (90.0 mg, 0.216
mmol), TBAF (0.216 mL, 0.216 mmol, 1.0 M in THF), KHCO3 (65
mg, 0.64 mmol), and aqueous H2O2 (0.3 mL, 30% soln) in THF (0.7
mL) and MeOH (0.7 mL) provided 51.8 mg (85%), of the desired diol,
isolated as an inseparable 9:1 mixture of relative epimers at C-2 carried
through from the initial alkyne addition. Chromatography eluent: 80:
20:1 to 66:33:1 pet. ether:EtOAc:MeOH.
additions to the vinylsilane offer the promise of further
broadening of the scope of this strategy.
Here, we present a strategy for the introduction of regio- and
stereodefined oxygen functionality from internal alkyne building
blocks though vinylsilane intermediates. In addition to discrimi-
nating between the two termini of the alkyne, the silyl
intermediate serves as a diastereocontrol element, allowing even
quite remote stereocontrol of olefin functionalization by enforc-
ing A1,3 strain with allylic alcohols or through cyclic intermedi-
ates with homo- and bishomopropargylic alcohols. The use of
such cyclic vinylsilane intermediates may well provide a means
of achieving remote stereocontrol in olefin addition reactions
in general.
Experimental Section
(2R,3S)-4-Undecyn-1,2,3-triol 1,2-Isopropylidene Ketal, 19. This
procedure was adapted from the method of Shimizu.7 A solution of
1-octyne (1.59 mL, 10.8 mmol) in THF (10 mL) under Ar at -78 °C
was treated with butyllithium (1.59 mL, 10.8 mmol, 1.48 M in hexanes)
dropwise. After 30 min, ClTi(Oi-Pr)3 (2.57 mL, 10.8 mmol) was added,
and the flask was warmed to -60 °C. To maintain solubility, additional
THF (20 mL) was added, and the solution was stirred for 90 min prior
to recooling to -78 °C. (R)-Glyceraldehyde isopropylidene ketal1 (0.70
g, 5.38 mmol) was then added via syringe in one portion, and the
mixture was stirred for 2 h prior to quenching with saturated aqueous
NH4Cl (20 mL) at -78 °C. Water (30 mL) was then added, and the
reaction was extracted with ether (3 × 30 mL). The ether extracts were
washed with brine (20 mL) and dried over MgSO4, and the solvents
were removed in vacuo. Silica gel chromatography gave 1.19 g (92%)
of the desired alcohol as a 9:1 mixture of epimeric diols favoring the
trans. 1H NMR spectra of trans and cis components are very similar to
a previously reported addition.8
Rf: 0.37 (67:33:1 pet.ether:EtOAc:methanol). 1H NMR (500 MHz,
CDCl3): δ 4.41 (d, J ) 2.4 Hz, 1H), 4.12-4.15 (m, 2H), 4.07 (m,
1H), 3.89 (m, 1H), 3.78 (d, J ) 3.6 Hz, 1H), 2.48-2.63 (m, 2H), 2.10
(d, J ) 10.4 Hz, 1H), 1.66 (m, 2H), 1.48 (s, 3H), 1.38 (s, 3H), 1.26-
1.35 (m, 6H), 0.89 (t, J ) 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 210.4, 109.4, 76.1, 75.6, 72.4, 66.8, 37.7, 31.5, 28.8, 27.0, 25.0, 23.4,
22.4, 14.0. IR (thin film): 3445 (br, OH), 2933, 1715, 1372, 1216,
Data for Major Isomer. 1H NMR (500 MHz, CDCl3): δ 4.48 (m,
1H), 4.21 (ddd, J ) 6.5, 6.5, 4.0 Hz, 1H), 4.03-4.08 (m, 2H), 2.26 (d,
J ) 4.4 Hz, 1H), 2.20 (td, J ) 7.2, 2.1 Hz, 2H), 1.45-1.51 (m, 2H),
1.46 (s, 3H), 1.37 (s, 3H), 1.24-1.36 (m, 6H), 0.88 (t, J ) 7.0 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 110.0, 87.3, 78.1, 77.0, 65.2,
62.4, 31.3, 28.5, 28.4, 26.3, 25.2, 22.5, 18.7, 14.0. IR (thin film): 3452
1069, 847 cm-1. [R]26 +51.4° (c 1.0, CHCl3). Anal. Calcd for
D
C14H26O3: C, 61.29; H, 9.55. Found: C, 61.42; H, 9.52.
General Procedure for the One-Pot Hydrosilylation and Oxida-
tive Desilylation: (S)-1-Cyclohexyl-1-hydroxy-6-phenyl-hexan-3-
one, 28. To a solution of (R)-1-cyclohexyl-6-phenyl-2-hexyn-1-ol (21)
(50 mg, 0.20 mmol) and BDMS-H (87.9 mg, 0.59 mmol) in CH2Cl2
(0.4 mL) was added complex 1 (4.9 mg, 0.01 mmol) at 0 °C. The
solution was allowed to warm to room temperature and stirred for 30
min. The solution was cooled to 0 °C, and THF (0.7 mL) and TBAF
(0.58 mL, 0.58 mmol, 1.0 M in THF) were added and the solution was
stirred for 15 min. Aqueous H2O2 (1.9 mL, 10.7 mmol), MeOH (0.7
mL), and KHCO3 (176 mg, 1.76 mmol) were added to the solution.
The solution was then warmed to room temperature and stirred for 18
h. Brine (10 mL) was added, and the mixture was extracted with ether
(2 × 30 mL). The organic layer was washed with saturated aqueous
Na2S2O3 (10 mL) and brine (10 mL) and dried over MgSO4. Purification
on silica gel column (eluent: 8:1 pet. ether:EtOAc) afforded (S)-1-
cyclohexyl-1-hydroxy-6-phenyl-3-hexanone (46.3 mg, 87%).
(br, OH), 2933, 2234 (w), 1372, 1254, 1216, 1153, 1070, 851 cm-1
.
[R]26D +17.8° (c 1.0, CHCl3). Anal. Calcd for C14H24O3: C, 69.96; H,
10.07. Found: C, 69.79; H, 10.15.
(2R,3S)-1,2,3-Trihydroxy-5-undecanone 1,2-Isopropylidene Ketal,
20. The alkyne 19 (120 mg, 0.50 mmol) and BDMS-H (104 µL, 0.60
mmol) in acetone (1.0 mL) was treated at 0 °C with complex 1 (7.8
mg, 0.015 mmol). The mixture was allowed to warm to room
temperature over 30 min. It was then recooled to 0 °C, diluted with
THF (1.5 mL), and TBAF (0.60 mL, 0.60 mmol, 1.0 M soln in THF)
was added dropwise. After 20 min, MeOH (1.0 mL) was introduced,
followed by solid potassium bicarbonate (150 mg, 1.5 mmol) and
aqueous H2O2 (0.80 mL, 30% soln). The mixture was then stirred for
36 h at room temperature, at which time it was diluted with water (10
mL) and extracted with EtOAc (3 × 10 mL). The organic extracts were
washed with brine (10 mL), dried over Na2SO4, and concentrated in
vacuo. The residue was purified on a silica gel column (eluent: 85:
15:1 pet. ether:EtOAc:MeOH) to give 99 mg (77%) of the desired
ketone as a single isomeric compound.
1
Rf: 0.57 (4:1 P.E.:EtOAc). H NMR (300 MHz, CDCl3): δ 7.15-
7.30 (m, 5H), 3.78 (s, 1H), 2.95 (s, 1H), 2.42-2.64 (m, 5H), 1.61-
1.96 (m, 7H), 0.95-1.43 (m, 7H). 13C NMR (75 MHz, CDCl3): δ
212.4, 141.4, 128.41, 128.36, 126.0, 71.6, 46.1, 42.9, 42.8, 34.9, 28.8,
28.2, 26.4, 26.1, 26.0, 27.9. IR (thin film): 3363 (br), 2915, 2850,
1702 (s), 1446 (w), 1403 (w), 1087 (w), 699 cm-1. Anal. Calcd for
C18H26O2: C, 78.79; H, 9.55. Found: C, 79.00; H, 9.45. [R]25D +33.9°
(c 1.0 in CHCl3). mp 65-67 °C.
(R)-Methyl 12-Hydroxy-13-methyl-10-tetradecynoate, 31. This
was adapted from the method of Carreira.14 A flask charged with zinc
triflate (360 mg, 1.0 mmol) was placed under vacuum (1 mmHg) and
heated to 125 °C for 2 h. (+)-N-Methylephedrine (197 mg, 1.10 mmol)
was added to the flask, which was placed under an Ar atmosphere.
1H NMR (500 MHz, CDCl3): δ 4.08 (m, 1H), 3.92-3.95 (m, 3H),
3.27 (br OH, 1H), 2.82 (dd, J ) 7.5, 1.8 Hz, 1H), 2.57 (m, 1H), 2.45
(t, J ) 7.5 Hz, 2H), 1.57 (m, 2H), 1.39 (s, 3H), 1.34 (s, 3H), 1.26-
1.30 (m, 6H), 0.87 (t, J ) 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3):
δ 212.4, 109.4, 77.5, 69.1, 66.9, 45.1, 43.7, 31.5, 28.8, 26.7, 25.1, 23.5,
23.5, 22.4, 14.0. IR (thin film): 3472 (br, OH), 2932 (s), 1713, 1372,
1215, 1066 (s), 851 (w) cm-1. [R]26 -21.3° (c 1.3, CHCl3). Anal.
D
Calcd for C14H26O4: C, 65.09; H, 10.14. Found: C, 64.84; H, 9.92.
9
10036 J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005

An Alkyne Hydrosilylation-Oxidation Strategy
A R T I C L E S
Toluene (5.0 mL) was added to the flask, and the mixture was stirred
for 2 h. Methyl 10-undecynoate (1.18 g, 6.0 mmol) was added to the
flask, and, after 15 min, isobutyraldehyde (454 µL, 5.0 mmol) was
added to the flask, which was then heated to 60 °C and stirred for 12
h. The mixture was then quenched by addition of saturated aqueous
NH4Cl (20 mL) and extracted with ether (3 × 15 mL). The extracts
were washed with brine (15 mL), dried over MgSO4, and concentrated
under reduced pressure. Purification on silica gel (eluent 80:20:1, then
70:30:1 pet. ether:EtOAc:MeOH) gave the desired alcohol (1.09 g, 81%)
as a colorless oil. The enantiomeric excess was determined to be 94%,
presumed to be the (R) stereochemistry by analogy to Careira’s
published results. For purposes of ee determination, racemic material
was generated in acetonitrile using Zn(OTf)2.14
(()-(3S,5R)-6-Benzyloxy-3,5-bis-triethylsilanyloxy-hexan-2-
one, 46. To a solution of the cyclic siloxane 44 (100 mg, 0.381 mmol)
in acetone (1 mL) was added DMDO (19.1 mL, 0.1 M soln in acetone,
1.91 mmol) under Ar at -78 °C via cannula. After being stirred
overnight at -78 °C, the reaction was allowed to warm to -20 °C
over 2 h. At that temperature, the reaction was quenched with dimethyl
sulfide (355 mg, 5.716 mmol). After warming to room temperature
and drying over MgSO4, the mixture was concentrated under reduced
pressure, which afforded the crude epoxide 45 (157 mg, 148%) as a
colorless oil.
Rf: 0.49 (4:1 pet. ether:EtOAc). 1H NMR (400 MHz, C6D6): δ 7.07-
7.28 (m, 5H), 4.33 (s, 2H), 4.21 (m, 1H), 3.38 (dd, J ) 9.6, 4.8 Hz,
1H), 3.28 (dd, J ) 9.6, 5.2 Hz, 1H), 2.82 (d, J ) 3.6 Hz, 1H), 1.96
(ddd, J ) 15.2, 5.6, 3.6 Hz, 1H), 1.76 (dd, J ) 15.2, 11.2 Hz 1H),
1.04 (s, 3H), 0.25 (s, 3H), 0.12 (s, 3H).
UHP (179 mg, 1.90 mmol) was added to a solution of the crude
epoxide (157 mg, assume 0.381 mmol) in THF (3.8 mL) under Ar at
0 °C. The reaction was allowed to warm to room temperature and
treated with TBAF (1.41 mL, 0.81 M soln in THF, 1.143 mmol)
dropwise via syringe pump over 4 h. After being stirred for 20 h at
room temperature, the reaction was stopped by diluting with EtOAc
(15 mL) and aqueous Na2S2O3 (10 mL, 0.1 M soln). Extraction with
EtOAc (3 × 10 mL) and drying over MgSO4 afforded a crude oil (189
mg, 208%), which was used directly in the next reaction.
1
Rf: 0.43 (80:20:1 pet. ether:EtOAc:MeOH). H NMR (300 MHz,
CDCl3): δ 3.66 (s, 1H), 2.30 (t, J ) 7.4 Hz, 2H), 2.20 (td, J ) 6.8, 1.6
Hz, 2H), 1.77-1.87 (m, 2H), 1.61 (m, 2H), 1.48 (m, 2H), 1.24-1.40
(m, 8H), 0.98 (d, J ) 6.1 Hz, 3H), 0.96 (d, J ) 6.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 174.3, 86.1, 79.8, 68.1, 51.4, 34.6, 34.0, 29.04,
28.99, 28.8, 28.6, 24.9, 18.6, 18.1, 17.4. [R]26D +0.94° (c 1.3, CHCl3).
Anal. Calcd for C16H28O3: C, 71.60; H, 10.52. Found: C, 71.60; H,
10.34. Enantiomeric excess determined by HPLC [Chiralcel AS column,
eluting with 94:6 heptane/iPrOH, 1 mL/min, 225 nm: (R)-enantiomer
tR 9.32 min, (S)-enantiomer tR 10.84 min].
Methyl (S)-12-Hydroxy-13-methyl-10-oxo-tetradecanoate, 33.
Following the general procedure for one-pot hydrosilylation and
oxidative desilylation given for 28, employing alkyne 31 (134 mg, 0.50
mmol), BDMS-H (103 mg, 0.60 mmol), complex 1 (5.0 mg, 0.012
mmol) in CH2Cl2 (0.5 mL) at -30 °C, and TBAF (0.60 mL, 0.60 mmol,
1.0 M in THF) and KHCO3 (150 mg, 1.5 mmol) and aqueous H2O2
(0.6 mL, 30% soln) in THF (1.0 mL) and MeOH (1.0 mL) provided
the product hydroxyl ketone (114 mg, 80%). Chromatography eluent:
80:20:1 pet. ether:EtOAc:MeOH.
The crude diol (189 mg, assume 0.381 mmol) and imidazole (431
mg, 6.34 mmol) were solved in CH2Cl2 (7.9 mL) under N2 at 0 °C.
Et3SiCl (660 µL, 3.966 mmol) was then added via syringe at 0 °C.
After warming to room temperature, the mixture was stirred for 2 h.
The reaction was quenched with H2O (10 mL) and diluted with diethyl
ether (30 mL). The aqueous layer was extracted with Et2O (3 × 5 mL),
and the organic extracts were washed with brine (5 mL) and dried over
MgSO4. The resulting oil was purified on a silica gel column (30:1,
then 20:1 pet ether:diethyl ether), which afforded the protected product
(138 mg) in 77% yield over three steps.
Rf: 0.31 (80:20:1 pet.ether:EtOAc:methanol). 1H NMR (500 MHz,
CDCl3): δ 3.83 (m, 1H), 3.69 (s, 3H), 3.02 (br OH, 1H), 2.60 (dd, J
) 17.3, 2.3 Hz, 1H), 2.51 (dd, J ) 17.3, 9.8 Hz, 1H), 2.46 (t, J ) 7.5
Hz, 2H), 2.32 (t, J ) 7.5 Hz, 2H), 1.57-1.73 (m, 5H), 1.27-1.33 (m,
8H), 0.96 (d, J ) 6.7 Hz, 3H), 0.93 (d, J ) 6.8 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 212.9, 174.3, 72.3, 51.5, 45.9, 43.7, 34.0, 33.0,
29.1, 29.03, 29.02, 24.9, 23.5, 18.3, 17.8. IR (thin film): 3526 (br,
1
Rf: 0.28 (10:1 pet. ether:Et2O). H NMR (500 MHz, CDCl3): δ
7.26-7.35 (m, 5H), 4.53 (d, J ) 12.1, 1H), 4.49 (d, J ) 12.1 Hz, 1H),
4.15 (t, J ) 6.5 Hz, 1H), 3.96-4.00 (m, 1H), 3.38-3.43 (m, 2H), 2.14
(s, 3H), 1.76-1.95 (m, 2H), 0.94 (t, J ) 7.8, 18H), 0.55-0.62 (m,
12H). 13C NMR (125 MHz, CDCl3): δ 210.9, 138.3, 128.3, 127.6,
127.5, 75.7, 74.3, 73.2, 67.8, 39.9, 24.9, 6.83, 6.81, 6.74, 5.03, 4.87,
4.69. IR (thin film): 2955, 2877, 1717, 1456, 1415, 1352, 1239, 1100,
1006, 740 cm-1. Anal. Calcd for C25H46O4Si2: C, 64.32; H, 9.93.
Found: C, 64.16; H, 10.08.
OH), 2931 (s), 2857, 1740 (s), 1711, 1438, 1368, 1173 cm-1. [R]26
D
-24.7° (c 1.0, CHCl3). Anal. Calcd for C16H30O4: C, 67.10; H, 10.56.
Found: C, 66.94; H, 10.35. HRMS-EI (m/ z): [M - OH]+ calcd for
C16H29O3, 269.2117; found, 269.2127.
General Procedure for Intramolecular Hydrosilylation. (()-6-
Benzyloxymethyl-2,2,3-trimethyl-5,6-dihydro-2H-[1,2]oxasiline, 44.
A round-bottomed flask was charged with 1-benzyloxy-hex-4-yn-2-ol
(43) (300 mg, 1.469 mmol) under Ar at room temperature. To the neat
alcohol was added 1,1,3,3-tetramethyldisilazane (1.3 mL, 7.344 mmol),
and the flask was heated to 50 °C for 2 h. Next, the flask was cooled
to ambient temperature and placed under vacuum (ca. 1 mmHg) for
45 min to remove the volatile species. An Ar atmosphere was then
reintroduced and the residue taken up in CH2Cl2 (3.6 mL). The flask
was cooled to 0 °C, and solid [Cp*Ru(MeCN)3]PF6 (14.8 mg, 0.029
mmol) was added to the solution. The flask was allowed to warm to
room temperature, and, after 2 h, the solution was diluted with ether
(15 mL) and filtered through a short plug of florisil, washing with
additional ether (20 mL). After concentration under reduced pressure,
the cyclic siloxane was obtained as a colorless oil (347 mg, 90%).
(+)-Spectaline, 67. The azido-siloxane 77 (7.1 mg, 0.016 mmol)
and solid urea-hydrogen peroxide adduct (6 mg, 0.064 mmol) were
taken up in DMF (0.16 mL) and treated at 0 °C with TBAF (63 µL,
0.063 mmol, 1.0 M in THF) dropwise via a syringe pump over 4 h.
The mixture was then allowed to warm to room temperature and was
stirred for 10 h. At this time, TLC analysis indicated incomplete
consumption of the starting vinylsilane, and so additional urea-hydrogen
peroxide adduct (6 mg, 0.064 mmol) was added, followed by additional
TBAF (63 µL, 0.063 mmol, 1.0 M in THF) via syringe over 4 h as
before. The mixture was then allowed to warm to room temperature
and was stirred for 20 h. The mixture was diluted with water (5 mL)
and extracted with EtOAc (3 × 4 mL). The organic layers were dried
over Na2SO4 and concentrated in vacuo. The residue was purified on
a silica gel column (eluent 7:1, then 4:1 pet. ether:EtOAc) to afford
5.2 mg (84%) of the desired ketone 6.129. IR (thin film): 3456 (br,
OH), 2923 (s), 2109 (s), 1713, 1463, 1377, 1256, 1060 cm-1. MS-CI
(m/z): [M + Na]+ calcd for C22H41N3O4Na, 434.3; found, 434.3.
The keto-azide (2.4 mg, 0.0058 mmol) was taken up in EtOH (0.5
mL) and treated with 10% Pd/C (1 mg). The mixture was placed under
60 psi of H2 and stirred for 24 h. The mixture was filtered through
Celite, washing with additional EtOH (2 mL). The filtrated was
concentrated in vacuo and taken up in THF (0.5 mL). The solution
was treated with aqueous HCl (0.05 mL, 2.0 M soln) and stirred for
1
Rf: 0.48 (10:1 pet. ether:EtOAc). H NMR (400 MHz, C6D6): δ
7.06-7.29 (m, 5H), 6.25 (m, 1H), 4.38 (d, J ) 12.4, 1H), 4.34 (d, J )
12.4 Hz, 1H), 4.14-4.20 (m, 1H), 3.58 (dd, J ) 9.6, 4.8 Hz, 1H), 3.39
(dd, J ) 9.6, 6.4 Hz, 1H), 2.19 (m, 2H), 1.62-1.66 (m, 3H), 0.17 (s,
3H), 0.19 (s, 3 H). 13C NMR (100 MHz, C6D6):
δ 139.7, 139.3, 135.1, 128.5, 127.9, 127.6, 75.2, 73.4, 71.0, 33.6,
20.5, -1.5, -1.6. IR (thin film): 2855, 1614, 1454, 1251, 1097, 967,
827, 781 cm-1
.
9
J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005 10037

A R T I C L E S
Trost et al.
24 h at room temperature. The mixture was then quenched by addition
of aqueous NaOH (0.5 mL, 1.0 M soln). The mixture was extracted
with EtOAc (2 × 3 mL), dried over Na2SO4, and concentrated in vacuo.
The residue was purified on a column of basic alumina (eluent 100:1
CHCl3: EtOH), affording 1.0 mg (53%) of (+)-spectaline.
(S)-6-((S)-1-Azido-ethyl)-2,2-dimethyl-3-[3-(2-methyl-[1,3]diox-
olan-2-yl)-dodecanyl]-5,6-dihydro-2H-[1,2]oxasiline, 77. A mixture
of alkyne 76 (50 mg, 0.127 mmol) and 1,1,3,3-tetramethyldisilazane
(85 mg, 0.635 mmol) was heated to 70 °C for 20 h. The neat mixture
was cooled to room temperature and concentrated in vacuo (ca. 1 Torr)
to remove volatile organic species. After 30 min under vacuum, the
residue was taken up in CH2Cl2 (0.3 mL) and treated with solid 1 (3.2
mg, 0.0064 mmol) at 0 °C. The solution was allowed to warm to room
temperature over 2 h and was then filtered through florisil (ca. 3 cm),
eluting with ether (5 mL), to afford 56 mg (98%) of spectroscopically
homogeneous cyclic vinylsilane without additional purification.
1H NMR (400 MHz, C6D6): δ 6.21 (m, 1H), 3.59 (ddd, J ) 11.0,
4.6, 2.6 Hz, 1H), 3.55 (s, 4H), 2.88 (dq, J ) 6.7, 4.6 Hz, 1H), 2.22 (m,
1H), 2.08 (t, J ) 7.5 Hz, 2H), 1.52-1.78 (m, 6H), 1.34 (s, 3H), 1.30-
1.40 (m, 19H), 0.95 (d, J ) 6.7 Hz, 3H), 0.26 (s, 3H), 0.22 (s, 3H).
13C NMR (125 MHz, C6D6): δ 139.9, 138.8, 110.2, 75.3, 64.6, 61.0,
39.8, 35.8, 32.5, 30.4, 30.11, 30.07, 30.0, 29.9, 24.6, 24.1, 15.3, -0.7,
1H NMR (500 MHz, CDCl3): δ 3.54 (m, 1H), 2.75 (qd, J ) 6.5,
1.4 Hz, 1H), 2.52 (m, 1H), 2.42 (t, J ) 7.5 Hz, 2H), 2.14 (s, 3H), 1.90
(m, 1H), 1.24-1.52 (m, 27H), 1.09 (d, J ) 6.6 Hz, 3H). IR (thin
film): 2926, 2112, 1251, 1049, 833, 784 cm-1. [R]27 +5.8 (c 0.1,
D
CHCl3). Lit.16 [R]D +8.0 (c 0.16, CHCl3).
(2S,3S)-2-Azido-9-(2-methyl-[1,3]dioxolan-2-yl)-5-octadecyn-3-
ol, 76. The terminal alkyne 73 (150 mg, 0.54 mmol) was taken up in
THF (2.0 mL) and treated with butyllithium (0.34 mL, 0.54 mmol, 1.6
M in hexanes) at -78 °C and stirred for 30 min. The azido-epoxide 84
(137 mg of 34 wt % solution assuming 100% yield in previous step)
was added to THF (2.0 mL) over 4 Å molecular sieves (ca. 0.1 g) and
allowed to stand for 10 min before it was added to the reaction flask
via cannula. BF3‚OEt2 (0.067 mL, 0.54 mmol) was then added, and,
after 15 min, no epoxide was present by TLC analysis. Saturated
aqueous NH4Cl (3 mL) and water (10 mL) were added, and the mixture
was extracted with ether (3 × 15 mL). The organic layers were washed
with brine (5 mL) and dried over MgSO4. Solvent removal in vacuo
and purification on a silica gel column (eluent 100:10:1, then 85:15:1
pet. ether:EtOAc:methanol) gave 89 mg (55% from epoxy alcohol) of
the alcohol as a colorless oil.
-0.8. IR (thin film): 2926, 2112, 1251, 1049, 833, 784 cm-1. [R]27
D
-313.4 (c 1.0, CH2Cl2). HRMS-EI (m/z): [M - CH3]+ calcd for
C23H42N3O3Si, 436.3004; found, 436.3006.
Acknowledgment. We thank Thomas Jo¨ge for important
initial experiments. We acknowledge the National Science
Foundation and the National Institutes of Health (GM13598)
for their generous support of our programs. Z.T.B. received
support from an Althouse Family Stanford Graduate Fellowship.
Mass spectra were provided by the Mass Spectrometry Facility,
University of San Francisco, supported by the NIH Division of
Research Resources.
1H NMR (500 MHz, CDCl3): δ 3.90-3.97 (m, 4H), 3.64 (m, 1H),
3.58 (dq, J ) 5.5 Hz, 1H), 2.43-2.45 (m, 2H), 2.14-2.18 (m, 3H),
1.61-1.64 (m, 2H), 1.48 (m, 2H), 1.24-1.40 (m, 20H), 1.33 (d, J )
6.6 Hz, 3H), 1.31 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 110.2,
83.7, 74.8, 73.2, 64.5, 60.3, 39.2, 29.8, 29.57, 29.56, 29.54, 29.52, 29.48,
29.1, 28.85, 28.84, 24.6, 24.1, 23.7, 18.7, 15.7. IR (thin film): 3458
Supporting Information Available: Experimental procedures
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(br, OH), 2927 (s), 2100 (s), 1377, 1256, 1062 cm-1. [R]27 +40.4 (c
D
1.0, CH2Cl2). HRMS-EI (m/z): [M - CH3]+ calcd for C21H36N3O3,
378.2757; found, 378.2772. Anal. Calcd for C22H39N3O3: C, 67.14;
H, 9.99; N, 10.68. Found: C, 67.32; H, 10.06; N, 10.58.
JA051578H
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10038 J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005