Beyond the roche ester: A new approach to polypropionate stereotriad synthesis

Article abstract of DOI:10.1021/ol500051e

An efficient, step-economical, and scalable approach to the synthesis of polypropionate stereotriads has been developed. Either 2-butyne or propyne is subjected to rhodium-catalyzed silylformylation and in situ crotylation of the resulting aldehydes. Tamao oxidation under either standard conditions or aprotic conditions then delivers the completed stereotriads in a three-step, two-pot sequence. In contrast to the classical Roche ester approach, the α-stereocenter is obtained for free.

Full text of DOI:10.1021/ol500051e

Letter
pubs.acs.org/OrgLett
Beyond the Roche Ester: A New Approach to Polypropionate
Stereotriad Synthesis
Corinne N. Foley and James L. Leighton*
Department of Chemistry, Columbia University, 3000 Broadway, Mail Code 3117, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: An efficient, step-economical, and scalable
approach to the synthesis of polypropionate stereotriads has
been developed. Either 2-butyne or propyne is subjected to
rhodium-catalyzed silylformylation and in situ crotylation of
the resulting aldehydes. Tamao oxidation under either
“standard” conditions or “aprotic” conditions then delivers
the completed stereotriads in a three-step, two-pot sequence.
In contrast to the classical Roche ester approach, the α-
stereocenter is obtained for “free.”
ince its full development by Roush almost 30 years ago,1
the “Roche ester” approach to the construction of
S
stereotriad building blocks for nonaromatic polyketide natural
products synthesis has emerged as, and remains, one of the
most widely employed.2 In this approach, the Roche ester (and
with it the α stereocenter) is purchased3 and converted in
approximately six to seven steps into stereotriads with, for
example, an aldehyde at one end and an alkene at the other
(Figure 1A). Of those steps, only one is a carbon−carbon bond
forming reaction (typically an asymmetric crotylation or aldol
reaction) while the others all involve protecting group
manipulations or oxidation state adjustments, leading to a
particularly low “ideality” score.4
As recently reported by us as the centerpiece of our highly
step-economical synthesis of dictyostatin,5 commercially
available vinyl acetals may be transformed into fully function-
alized stereotriads in an approximately three-step process
entailing asymmetric hydroformylation (AH) using Landis’
method6 followed by crotylation (Figure 1B). Conceptually,
this approach is attractive in that it entails a one-step synthesis
of an α-methyl-β-ketoaldehyde or β-dialdehyde in configura-
tionally stable form thus obviating most of the protecting group
manipulations and oxidation state adjustments of the Roche
ester approach. Conversely, it does suffer from some practical
liabilities, principally the expense and inaccessibility of the
Landis ligand7 that is used to set the α-stereocenter and the
only moderate to poor regioselectivities of the AH reaction.
An alternative carbonylation-based approach is the tandem
intramolecular alkyne silylformylation−crotylation/Tamao ox-
idation/diastereoselective tautomerization reaction (Figure
1C).8 This sequence rapidly assembles stereotriads from simple
starting materials, and it seemed plausible that we might adapt
it for use in an intermolecular alkyne silylformylation9 reaction
using either propyne or 2-butyne as the starting material
(Figure 1D). Crotylation of the resulting α-methyl-β-silyl-α,β-
unsaturated aldehyde (an α-methyl-β-ketoaldehyde or β-
dialdehyde in masked form) would be followed by Tamao
Figure 1. (A) The “Roche ester” approach to stereotriad synthesis. (B)
The asymmetric hydroformylation (AH)/crotylation approach to
stereotriad synthesis. (C) The tandem intramolecular silyl-
formylation−crotylation/Tamao oxidation−diastereoselective tauto-
merization reaction. (D) The silylformylation, crotylation, Tamao
oxidation approach to stereotriad synthesis.
oxidation10 with concomitant diastereoselective enol tautome-
rization to deliver the target stereotriad building blocks. Such
an approach would be conceptually attractive in that the α-
Received: January 7, 2014
Published: February 6, 2014
© 2014 American Chemical Society
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Letter
stereocenter would be established after the crotylation event
and would rely on the β-stereocenter to induce diastereose-
lectivity; in other words, the α-stereocenter would be
established for “free”. In addition, the starting materials
required for this approach would be 2-butyne or propyne,
CO, and a silane (R3SiH). Herein we describe the results of our
efforts to develop the process described in Figure 1D for a
sustainable, step-economical, and scalable approach to the
synthesis of valuable polypropionate stereotriad building blocks.
At the outset, it was the choice of the silane component that
was most critical, as the silane must facilitate efficient
silylformylation reactions and allow for smooth and highly
enantioselective crotylation reactions while also being activated
enough to participate in efficient Tamao oxidation reactions
under both the “standard”8a and “aprotic”8c conditions that we
have developed for diastereocontrol in the tautomerization
event. This last requirement is the most important and typically
requires the use of an alkoxysilane. Thus, we prepared
ethoxydiphenylsilane and investigated its performance in
Rh(acac)(CO)2-catalyzed silylformylation reactions of 2-
butyne. As we had feared based on Ojima’s observations,11
the alkoxy group slowed the reaction and we had to use a high
catalyst loading and high CO pressures to achieve high levels of
conversion to desired product 1a (R = Et). Thus, even with 5
mol % catalyst and 500 psi CO at 60 °C for 24 h, the reaction
was incomplete as judged by the formation of substantial
amounts of hydrosilylation product 2a (Table 1, entry 1).12
unpurified product mixture from the silylformylation reaction.
Indeed, when the PhCN solution containing 1b was simply
diluted with CH2Cl2 and treated with (S,S)-cis EZ-CrotylMix,13
crotylation proceeded smoothly. It proved most practical and
effective to quench the reaction with n-Bu4NF·3H2O, which
resulted in cyclization to 5, which was conveniently isolated by
chromatography (Scheme 1). After optimization, 5 could be
Scheme 1. Silylformylation−Crotylation of 2-Butyne
obtained in 70% overall yield and 93% ee. The same procedure
using (S,S)-trans EZ-CrotylMix produced anti product 6 in 67%
overall yield and 95% ee. Importantly, this one-pot two-step
protocol scaled well and was used to produce 5 and 6 on an ∼5
g scale in the indicated yields.
a
Table 1. Optimization of the Silylformylation of 2-Butyne
With direct, efficient, and highly enantioselective access to 5
and 6 secured, we turned our attention to the Tamao
oxidation/diastereoselective tautomerization step to install the
carbonyl and establish the α-methyl stereocenter. We have
previously developed two sets of conditions, “standard”8a and
“aprotic,”8c that allow access to the anti (with respect to the β-
hydroxyl stereocenter) and syn products, respectively. Because
they were derived from intramolecular silylformylation
reactions (cf. Figure 1C), however, all previously examined
substrates had β-hydroxyl groups on both sides of the enol, and
the available evidence suggests that both groups contribute to
the diastereoselectivity. It was thus an open question as to
whether the enols derived from structurally simpler substrates 5
and 6 would undergo the tautomerization reactions with high
levels of diastereoselectivity. Gratifyingly, subjection of 5 to the
“standard” conditions (H2O2, KF, THF, i-PrOH, 0 °C) led to
the isolation of 7 as the major product of an 18:1 mixture of
diastereomers in 84% yield (Scheme 2). Conversely, when 5
was subjected to the previously reported8c “aprotic” Tamao
conditions (methylhydroquinone (MeHQ), 1 atm of O2,
quinuclidine·HCl, AgF, PhCN, 60 °C) the reaction was
sluggish, inefficient, and nonselective (≤2:1 dr). Reasoning
that we needed to boost the concentration of the active oxidant
to increase the rate of the reaction in order to carry it out at
lower temperatures to maximize diastereoselectivity, we
switched to the use of trimethylhydroquinone in place of the
MeHQ.14 In fact, this did lead to more efficient reactions that
proceeded smoothly at ambient temperature, and upon
optimization, syn product 8 was obtained as the major product
of a 6:1 mixture of diastereomers in 75% yield. When the same
two sets of Tamao oxidation conditions were applied to anti
crotylation product 6, 9 and 10 were obtained in good yields,
albeit with diminished levels of diastereoselectivity. In the case
of 9, it should be noted that this approach represents an
interesting and effective alternative for the traditionally difficult
entry
R
X
solvent
t
1:2:3:4
1
2
3
4
Et
5.0
2.5
2.5
2.0
PhH
24
14
20
24
1:0.7:0:0
1:0:0.5:0.3
1:0:0:0.7
1:0:0:0.2
Et
CH3CN
CH3CN
PhCN
i-Pr
i-Pr
a
The reactions were performed under the indicated conditions, and
then the Parr apparatus was cooled and vented; analysis of an aliquot
1
by H NMR spectroscopy revealed the product ratio.
Reactions run in acetonitrile were found to be substantially
faster, and complete conversion could be obtained with 2.5 mol
% catalyst in 14 h (entry 2). Unfortunately, however, these
conditions led to the production of substantial amounts of
rearranged silylformylation product 3a (Matsuda observed
similar products when using alkoxysilanes9b) and a different
side product, 4a. Though we have been unable to isolate and
characterize 4a, it is clear that it is derived only from the silane.
In an attempt to suppress the rearrangement product 3a, we
employed the more sterically hindered isopropoxydiphenyl-
silane and were delighted to find that this tactic was successful
in producing 1b (R = i-Pr) unaccompanied by either 2b or 3b
(entry 3). The silane-derived side product 4b was still an issue
that needed to be addressed, however, and extensive
optimization eventually revealed that by switching to PhCN
as the solvent, formation of 4b could be minimized (entry 4).
These conditions were selected for use in the proposed
stereotriad synthesis.
Though it proved possible to isolate aldehyde 1b, we hoped
to develop crotylation conditions that could be used with the
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Scheme 2. “Standard” and “Aprotic” Tamao Oxidation
Scheme 4. “Standard” and “Aprotic” Tamao Oxidation
problem of establishing all-anti stereochemistry in polypropi-
onate building blocks of this type.
yield and with poor diastereoselectivity. The general reliability
of the “standard” conditions was confirmed by the conversion
of 13 to all-anti product 16 in 69% yield and with 17:1
diastereoselectivity, while the “aprotic” conditions applied to 13
resulted in an inefficient and nonselective reaction.
In order to access the perhaps even more generally useful
corresponding aldehyde stereotriads we turned next to an
examination of the use of propyne in the three-step, two-pot
sequence. The desired regioselectivity in the silylformylation
reaction was well-precedented,9,11 and we were optimistic that
the reaction would be significantly more efficient due to
reduced steric hindrance. Indeed, efficient and regio- and
chemoselective silylformylation of propyne to give aldehyde 11
was easily carried out with only 1 mol % of the Rh(acac)(CO)2
catalyst and 300 psi CO at room temperature in just 5 h
(Scheme 3). As above, the silylformylation reaction solution
There are two discernible trends from the oxidation results
described in Schemes 2 and 4 that merit further comment. The
first is the observation that the syn crotylation products 5 and
12 consistently give higher diastereoselectivities than do the
anti substrates 6 and 13, especially under the “standard”
conditions. This observation is consistent with the model we
have advanced8a for the anti-diastereoselectivity under the
“standard” conditions in that substrates 5 and 12 are geared
such that the vinyl group is blocking the approach of the proton
to the front face of the enol, while for substrates 6 and 13 it is
the smaller methyl group that performs this function (Figure
2A). In the case of the “aprotic” Tamao oxidation reactions, the
origins of the syn-selectivity are far murkier, and we have shown
that the structure of the amine in the amine·HF salt has a direct
and dramatic impact on the diastereoselectivity.8c Thus,
although we cannot advance a simple model for this selectivity,
we do note the second discernible trend that the steric size of R
in the enol intermediate 18 is critical. Thus, in the originally
reported substrate,8c R was a quaternary carbon center and the
selectivity was 14:1 (Figure 2B). When R = Me (5 and 6), the
selectivity drops to 6:1 and 3:1 respectively, and when R = H
(12 and 13), there is little to no selectivity at all. The bottom
line is that the “standard” conditions quite reliably lead to
usefully high levels of anti-diastereoselectivity, while the
“aprotic” conditions are less general and reliable and more
substrate-dependent. The development of more general and
reliable syn-selective Tamao oxidation/tautomerization con-
ditions thus remains an important long-term goal of this
program.
Scheme 3. Silylformylation−Crotylation of Propyne
was simply diluted with CH2Cl2 and then treated with the
requisite EZ-CrotylMix, and following quenching with n-
Bu4NF·3H2O cyclized crotylation products 12 and 13 could
be isolated in excellent overall yields and enantioselectivities.
These reactions too scaled well and were carried out on gram
scale in the indicated yields.
After some minor tweaking of the “standard” Tamao
oxidation conditions (KHCO3 instead of KF, no THF), 14
could be obtained as a single diastereomer in 69% yield from 12
(Scheme 4). Unfortunately, the moderate success we had
achieved using the “aprotic” conditions with substrate 5 did not
translate to substrate 12, as 15 was produced in only moderate
We have developed a new synthesis of polypropionate
stereotriad building blocks that we contend represents a
significant conceptual and practical advance relative to the
now classical and still widely used Roche ester strategy. The
synthesis proceeds in just three steps and two pots, employs
exceedingly simple starting materials (2-butyne or propyne,
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ACKNOWLEDGMENTS
The National Institute of General Medical Sciences is gratefully
acknowledged for their support of this work (GM058133).
■
REFERENCES
■
(1) (a) Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J. J. Org. Chem.
1987, 52, 316−318. (b) Roush, W. R.; Palkowitz, A. D.; Ando, K. J.
Am. Chem. Soc. 1990, 112, 6348−6359.
(2) For example, various versions of the Roche ester approach were
employed (often more than once) in most of the total syntheses of
discodermolide, as well as in the Novartis large-scale synthesis. See:
Smith, A. B., III; Freeze, B. S. Tetrahedron 2008, 64, 261−298.
(3) The current Sigma Aldrich prices are ∼$20/g for the S
enantiomer and ∼$25/g for the R enantiomer.
(4) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657−4673.
(5) Ho, S.; Bucher, C.; Leighton, J. L. Angew. Chem., Int. Ed. 2013, 52,
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(6) McDonald, R. I.; Wong, G. W.; Neupane, R. P.; Stahl, S. S.;
Landis, C. R. J. Am. Chem. Soc. 2010, 132, 14027−14029.
(7) Unfortunately, Sigma Aldrich recently discontinued the sale of
the Landis ligand.
(8) (a) Spletstoser, J. T.; Zacuto, M. J.; Leighton, J. L. Org. Lett. 2008,
10, 5593−5596. (b) Harrison, T. J.; Ho, S.; Leighton, J. L. J. Am.
Chem. Soc. 2011, 133, 7308−7311. (c) Harrison, T. J.; Rabbat, P. M.
A.; Leighton, J. L. Org. Lett. 2012, 14, 4890−4893. (d) Reznik, S. K.;
Marcus, B. S.; Leighton, J. L. Chem. Sci. 2012, 3, 3326−3330.
(e) Reznik, S. K.; Leighton, J. L. Chem. Sci. 2013, 4, 1497−1501.
(9) (a) Matsuda, I.; Ogiso, A.; Sato, S.; Izumi, Y. J. Am. Chem. Soc.
1989, 111, 2332−2333. (b) Matsuda, I.; Fukuta, Y.; Tsuchihashi, T.;
Nagashima, H.; Itoh, K. Organometallics 1997, 16, 4327−4345.
(10) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599−7662.
(11) Ojima, I.; Ingallina, P.; Donovan, R. J.; Clos, N. Organometallics
1991, 10, 38−41.
(12) It is our working assumption that most or all of the
hydrosilylation occurs rapidly upon venting of the Parr apparatus
and release of the CO, giving an approximate indication of how much
starting material remained at the time of venting.
(13) Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem. Soc. 2011, 133,
6517−6520.
Figure 2. (A) Our model to explain the anti-diastereoselectivity under
the “standard” Tamao oxidation conditions (curved arrows indicate
minimization of A1,3 strain and syn-pentane like interactions) is
consistent with the observation that substrates 5/12 give higher
selectivity than do 6/13. (B) The size of the R group in the enol
intermediate (18) correlates to the tautomerization diastereoselectivity
under the “aprotic” Tamao oxidation conditions.
Ph2Si(Oi-Pr)H, CO), and is characterized by 100% ideality.4 In
contrast to the Roche ester approach and all other related
approaches in which the α-methyl stereocenter is either
purchased or synthesized by external asymmetric induction
(thereby adding steps and expense), the α-methyl stereocenter
is established after the crotylation event using internal
diastereochemical control and is therefore obtained for “free.”
The method is not yet comprehensive in terms of the
diastereomers that are accessible, but does provide access to
three of the four possible products in the methyl ketone series
(7−9) and two of the four possible products in the aldehyde
series (14 and 16) with moderately good to excellent
diastereoselectivities (6 to >20:1). The sequences have been
demonstrated on gram or multigram scale, and the overall
yields for products 7, 8, 9, 14, and 16 are all in the range of 53−
63%. Attempts to identify a more generally useful set of
conditions for a syn-selective Tamao oxidation/diastereo-
selective tautomerization reaction and the application of this
method to the synthesis of important polyketide natural
products and analogs thereof are ongoing.
(14) In their original report on the use of the O2/hydroquinone
system to generate dry H2O2 for carbon−silicon bond oxidation,
Tamao, Hayashi, and Ito showed that 2,3-dimethylhydroquinone
resulted in a higher rate of oxidation than did methylhydroquinone.
See: Tamao, K.; Hayashi, T.; Ito, Y. Tetrahedron Lett. 1989, 30, 6533−
6536.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectroscopic and analytical data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: leighton@chem.columbia.edu.
Notes
The authors declare no competing financial interest.
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