Polyoxygenated Tertiary Alcohols: A Kiyooka Approach

Article abstract of DOI:10.1002/chem.201902589

A Kiyooka aldol approach for the stereoselective synthesis of tertiary alcohols is presented. This approach allows for the incorporation of different substituents at all three remaining positions at the chiral center bearing the tertiary alcohol. To demon

Full text of DOI:10.1002/chem.201902589

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Title: Polyoxygenated Tertiary Alcohols - A Kiyooka Approach
Authors: Markus Kalesse and Daniel Lücke
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Polyoxygenated Tertiary Alcohols - A Kiyooka Approach
Daniel Lücke, Markus Kalesse*
Dedicated to Prof. Hans-Ulrich Reißig on the occasion of his 70th birthday
Abstract: A Kiyooka aldol approach for the stereoselective synthesis
of tertiary alcohols is presented. This approach allows for the
incorporation of different substituents at all three remaining positions
at the chiral center bearing the tertiary alcohol. To demonstrate the
validity of this approach different chiral alcohols were depicted and
the relationship of double bond geometry of the ketene acetal and the
diastereoselectivity was established.
As several natural products feature tertiary alcohols flanked by
three oxygenated carbon atoms or functional groups derived from
them and further stereogenic centers in close proximity (Figure 1),
we planned on expanding the scope of our methodology to such
motifs. Here, we describe the general applicability of this
transformation using different and/or chiral aldehydes as
such motifs are often found in a variety of other natural products[7]
and not only in tedanolide C (1).
In the course of our program to provide synthetic access to
biologically active natural products[1] we chose the tedanolides[2]
as promising targets. Within this family of secondary metabolites
tedanolide C (1)[3] (Figure 1) attracted our attention due to its
unusual polyoxygenated structure exhibiting a tertiary alcohol.
Additionally, the ongoing discussion about its configuration
prompted us to focus on the Kiyooka aldol reaction with ketene
acetal 7. In general, tertiary alcohols are important structural motifs
in the synthesis of natural products as well as challenging
synthetic targets.[4] In 2011 our group reported a Kiyooka aldol[5]
protocol for the stereoselective synthesis of tertiary alcohols
flanked by three additional oxygenated carbon atoms (Figure
2).[3c] This was recently applied by Trauner and co-workers to their
total synthesis of kweichowenol A (3).[6] In our initial studies only
achiral aldehydes or such with distal stereocenters were used.
Figure 2. Structural motifs accessible via Kiyooka aldol reaction.
Scheme 1. Kiyooka aldol reaction for the synthesis of tertiary alcohols flanked
by three oxygenated carbon atoms. TBS = tert-butyldimethylsilyl, Ts = tosyl, Val
= valine.
We started our investigations with the Kiyooka aldol reaction of
the (R)-Roche ester derived aldehyde 8[3c], [8] (Table 1). Utilization
of our previously established conditions[3c] provided TBS
protected hemiacetal 9 in low yield due to major amounts of non-
reacted aldehyde (entry 1). Conversion and yield were improved
by increasing the amounts of ketene acetal 7 and the Lewis acid
added to the reaction (entries 2 to 4). We rationalized the latter by
coordination of the oxazaborolidinone to the PMB-ether. However,
we were unable to push the reaction to full conversion as at some
point massive formation of unknown by-products were observed
(entry 5).
Figure 1. Natural products featuring polyoxygenated tertiary alcohols.
[*]
D. Lücke and Prof. Dr. M. Kalesse
Institute for Organic Chemistry
Gottfried Wilhelm Leibniz Universität Hannover
and
Centre of Biomolecular Drug Research (BMWZ)
Schneiderberg 1B, D-30167 Hannover, Germany
E-mail: markus.kalesse@oci.uni-hannover.de
Prof. Dr. M. Kalesse
Helmholtz Centre for Infection Research (HZI)
Inhoffenstrasse 7, D-38124 Braunschweig, Germany
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Selected optimization results for the Kiyooka aldol reaction of aldehyde
8.[a]
entry
1[c]
2[c]
3[c]
4[c]
5
8 (eq.)
1.30
1.30
2.00
2.50
3.00
N-Ts-D-Val (eq.)
BH3∙THF (eq.)
1.00
Yield[b]
18%
50%
61%
67%
nd[d]
1.20
2.20
2.20
2.70
3.20
2.00
2.00
2.50
3.00
[a] Reaction conditions 8 (1.00 eq., 0.31 – 0.37 mmol), c = 0.1 M. [b] Isolated
yield after column chromatography. [c] Reaction did not go to full conversion. [d]
Product
could
not
be
separated
from
unknown
byproducts.
PMB = p-methoxybenzyl.
When using different batches of ketene acetal 7 we were faced
with problems of strongly varying diastereoselectivities for the
newly formed tertiary and secondary alcohol. This we rationalized
by different ratios of double bond isomers of ketene acetal 7. To
confirm this hypothesis we enriched both double bond isomers by
fractionated distillation and applied the so-separated isomers to
the Kiyooka aldol reaction. The obtained products were analyzed
Figure 3. Dependency between stereoselcetivity and double bond geometry
determined by 1H-NMR of TBS protected hemiacetal 9.
With the optimized conditions in hand, we examined the scope of
the reaction. We started with α- or β-chiral aldehydes respectively,
investigating both enantiomers of N-tosyl-valine for potential
matched and mismatched cases (Scheme 2).[11], [12] For
simplification, the diastereomeric ratio was determined after base
initiated silyl migration and liberation of the masked aldehyde of
the obtained TBS protected hemiacetals. For the products derived
from aldehyde 8 (aldehydes 10 and 14) comparable yields were
achieved with both enantiomers of valine, whereas the selectivity
dropped in the mismatched case. Better yields and comparable
selectivities were obtained, when the stereocenter of the starting
material was in the β-position (aldehydes 11 and 15). For
aldehydes bearing the PMB-ether in α-position in the matched
case similar results as for aldehyde 8 were obtained (aldehyde
12). In contrast, the mismatched case provided an unexpected
result, as ester 16 was the main product isolated from the Kiyooka
aldol reaction, meaning that no reduction occurred. A protecting
group swap from PMB to TBDPS led to a slight increase in
selectivity (aldehyde 13), showing that the reaction conditions are
applicable to silyl-ethers as well.
1
by H-NMR focusing on the proton at the hemiacetal (Figure 3,
highlighted in red). By doing so we observed a strong dependency
between the formation of the desired diastereomer and the double
bond geometry of the applied ketene acetal. (Figure 3, a to d).
The required double bond geometry could be identified as Z using
NOE correlations between the methoxy and methylene group
(see Supporting Information). To further optimize this
transformation we investigated different conditions to increase the
amount of Z-configured ketene acetal. In accordance with the
literature,[9] the use of potassium hexamethyldisilazide instead of
its lithium analogue provided a massive increase of the Z-isomer
(E:Z = 1:6 after distillation). Usage thereof not only provided the
best diastereoselectivities (Figure 3, e), but also gave full
conversion of aldehyde 8. Even though it is known that ketene
acetal double bond geometry can affect the diastereoselectivity of
Mukaiyama aldol reactions,[10] we consider this observation
noteworthy as there are no systematic investigations on this
dependency. In this context it should also be mentioned that we
obtained good selectivities in our previous Kiyooka study on
achiral substrates using an excess of E-configured ketene
acetal.[3c]
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Scheme 3. Scope of Kiyooka aldol reaction with α- and β-chiral aldehydes.
[a] all reactions were run on a 0.40 mmol scale, employing the conditions of
table 1, entry 4. [b] Yield refers to isolated yield over two steps after column
chromatography. Isolated yield of Kiyooka aldol reaction is given in parentheses.
[c] dr was determined via 1H-NMR after column chromatography. [d] Esters
were obtained after Kiyooka aldol reaction. [e] Stereochemistry was determined
via NMR experiments (Karplus relation,[14] NOE correlations).
Scheme 2. Scope of Kiyooka aldol reaction with α- or β-chiral aldehydes. [a] all
reactions were run on a 0.40 mmol scale, employing the conditions of table 1,
entry 4. [b] Yield refers to isolated yield over two steps after column
chromatography. Isolated yield of Kiyooka aldol reaction is given in parentheses.
[c] dr was determined via 1H-NMR after column chromatography. [d] Ester was
obtained after Kiyooka aldol reaction. [e] Stereochemistry was determined via
NMR experiments (acetonide method,[13] Karplus relation,[14] NOE correlations)
Having evaluated the scope of the reaction we were also
interested in its scalability, running a Kiyooka aldol reaction of
aldehyde 8 on a 2.55 mmol scale (Scheme 4). For simplification
we did only isolate the major diastereomer of this reaction, as it is
formed in large excess compared to all other diastereomers
(Figure 3). The yield of 62% is comparable to the previously run
reactions (Scheme 2), showing stability on up-scale.
or
X-ray
analysis.
HMDS = hexamethyldisilazide.
TBDPS = tert-
butyldiphenylsilyl.
Having shown the general applicability for α- or β-chiral aldehydes
we put our focus on α-, β-chiral aldehydes bearing a methyl group
in α- and a PMB-ether in β-position. Thereby a 1,2-anti as well as
a 1,2-syn substitution pattern for the aldehydes was investigated
(Scheme 3). For the 1,2-anti substituted aldehyde the best yield
of all substrates was achieved for the matched case, along with a
very good selectivity (aldehyde 17). For the mismatched case
again no reduction took place, leading to ester 19 as the main
product. Interestingly, aldehyde 17 and ester 19 showed the
same stereochemistry, implying that the oxazaborolidinone only
acted as a Lewis acid without any asymmetric induction. Similar
results were observed when using the 1,2-syn substituted
aldehyde, were it is noteworthy that the stereocenter in α-position
did overrule the one in β-position entirely in terms of
stereochemical induction favoring formation of the Felkin-
product[11a] (products 18 and 20).
Scheme 4. Up-scaling of Kiyooka aldol reaction of aldehyde 7.
Furthermore, potential synthetic applications of the Kiyooka aldol
products were investigated by the modification of aldehyde 10.
Horner-Wadsworth-Emmons
olefination[15]
with
triethyl
phosphonoacetate led to ester 21 in very good yield, allowing for
different further functionalization. Addition of a synthetically useful
vinyl handle gave allylic alcohol 22 with the expected
stereochemistry.[6] Hydrogenation followed by Ley-Griffith
oxidation[16] delivered highly substituted tetrahydropyrone 23 in
very good yield.
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Scheme 5. Downstream functionalization of aldehyde 10. TPAP = tetrapropyl-
ammonium perruthenate, NMO = N-Methylmorpholine N-oxide, MS = molec-
ular sieves.
In summary, we have expanded our Kiyooka protocol for the
stereoselective synthesis of tertiary alcohols to α- and/or β-chiral
aldehydes. For this, the reaction conditions had to be re-
developed and a strong dependency between the double bond
geometry of the ketene acetal and the diastereoselectivity of the
reaction was observed. However, in all cases good to excellent
selectivities and synthetically useful yields were observed.
Furthermore, a detailed substrate scope investigation showed
possible synthetic applications and constrains. Finally, we were
able to show that this transformation is also applicable to larger
scales.
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We thank Dagmar Körtje and Monika Rettstadt for NOE
measurements as well as Dr. Jörg Fohrer for helpful discussion
regarding the NOE correlations. We thank Dr. Gerald Dräger for
X-ray analysis. Pascal Lienig is acknowledged for predominant
studies about the Kiyooka aldol reaction with lactic acid derived
aldehydes.
[8]
[9]
Keywords: aldol reaction • chiral aldehydes • double bond
geometry • ketene acetal • structure elucidation
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Layout 2:
COMMUNICATION
Daniel Lücke, Markus Kalesse*
Page No. – Page No.
Polyoxygenated Tertiary Alcohols – A
Kiyooka Approach
A Kiyooka protocol for the stereoselective synthesis of tertiary alcohols is presented.
The obtained highly complex building blocks feature up to four contiguous
stereogenic centers and feature motifs of several natural products. Furthermore, a
strong dependency between diastereoselectivity and double bond geometry of the
ketene acetal was observed.
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