Anti -diols from α-oxyaldehydes: Synthesis and stereochemical assignment of oxylipins from dracontium loretense

Article abstract of DOI:10.1021/ol501263y

Differentially protected 1,2-diols were synthesized by enantioselective aldehyde α-oxygenation followed by organomagnesium or -lithium addition. Contrary to a previous report, the resultant diols possess an anti configuration. Good selectivity was achieved regardless of the hybridization state of the nucleophile or the presence or absence of branching. This method was applied to short syntheses of all possible stereoisomers of two oxylipins from Dracontium loretense with incomplete stereochemical assignments. Spectroscopic comparisons between the synthetic and natural oxylipins led to unambiguous assignments.

Full text of DOI:10.1021/ol501263y

Letter
pubs.acs.org/OrgLett
anti-Diols from α‑Oxyaldehydes: Synthesis and Stereochemical
Assignment of Oxylipins from Dracontium loretense
Gayan A. Abeykoon,† Shreyosree Chatterjee,† and Jason S. Chen*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: Differentially protected 1,2-diols were synthesized
by enantioselective aldehyde α-oxygenation followed by organo-
magnesium or -lithium addition. Contrary to a previous report, the
resultant diols possess an anti configuration. Good selectivity was
achieved regardless of the hybridization state of the nucleophile or
the presence or absence of branching. This method was applied to
short syntheses of all possible stereoisomers of two oxylipins from
Dracontium loretense with incomplete stereochemical assignments.
Spectroscopic comparisons between the synthetic and natural oxylipins led to unambiguous assignments.
a
Scheme 1. Some Published α-Oxyaldehyde Reactions
hiral 1,2-diols are commonly found in natural products.
1
CSharpless asymmetric dihydroxylation offers a general
means to prepare chiral syn-1,2-diols from trans alkenes but
often gives only modest enantioselectivity when preparing anti-
1,2-diols. Many alternative approaches to chiral anti-1,2-diols
involve carbon−carbon bond formation. Addition of α-
oxycarbonyl compounds2−4 or functionalized allyl reagents5,6
to aldehydes forges the central carbon−carbon bond. Addition
to α-oxyaldehydes with substrate-,7,8 reagent-,9 or catalyst-
based10 stereocontrol constructs the carbon−carbon bond next
to the diol. Ring-opening of a hydroxy epoxide11 (optionally
prepared by kinetic resolution of a racemic allylic alcohol12)
affords carbon−carbon bond formation one position further
removed. Other approaches to anti-1,2-diols include functional
group transformations (e.g., epoxide opening13 or allylic
substitution14) and desymmetrization reactions.15 Addition to
α-oxyaldehydes is appealing because of its broad substrate
scope, but chiral α-oxyaldehydes often require multiple
synthetic steps to prepare. Enantioselective aldehyde α-
oxygenation16,17 offers direct access to α-oxyaldehydes,
potentially streamlining the synthesis of anti-1,2-diols. Herein
we report that aldehyde α-oxygenation followed by organo-
magnesium or -lithium addition yields differentially masked
anti-1,2-diols, not the previously reported syn diols.17c We
demonstrate the substrate scope of this process and apply it to
the synthesis and stereochemical assignment of oxylipins from
the Peruvian plant Dracontium loretense.18
a
See ref 17c. TMP = 2,2,6,6-tetramethylpiperidinyl.
Intrigued by this stereochemical oddity, we decided to
investigate a related Grignard reaction. Toward that end,
organocatalytic α-oxygenation of hexanal (3) (Scheme 2) gave
oxyaldehyde 5 in 77% yield and 89:11 er. Superior
enantioselectivity often can be attained using a tryptophan-
derived catalyst,17c but the more lengthy synthesis of that
catalyst encouraged us to use imidazolidinone 4. Table 1
summarizes our investigations into the conversion of aldehyde
5 into alcohol 6a. Conducting the addition of n-butylmagne-
sium chloride in ether (Table 1, entry 1) afforded only modest
selectivity and yield; significant aldehyde reduction to the
corresponding primary alcohol was observed. Changing the
solvent to tetrahydrofuran (Table 1, entry 2) gave better
selectivity and suppressed primary alcohol formation. Both
yield and selectivity improved at lower temperature (Table 1,
entry 3). Using n-butyllithium in place of n-butylmagnesium
We selected the imidazolidinone-catalyzed incorporation of
TEMPO17 as our starting point because, unlike nitrosobenzene-
based methods,16 this reaction delivers stable α-oxyaldehydes.
MacMillan reported that Grignard reagents (see 1, Scheme 1)
and enolates (see 2) may be added with no degradation of
enantiomeric ratio.17c However, we were puzzled that Grignard
product 1 appeared to be formed through a chelation-
controlled addition, yet aldol product 2 appeared to be the
result of a polar Felkin−Anh addition.19
Received: May 2, 2014
Published: June 11, 2014
© 2014 American Chemical Society
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Letter
a
Scheme 2. Assigning Relative Stereochemistry
Table 2. Varying the Carbon Nucleophile
b
c
entry
6, R
6a, n-Bu
dr
yield (%)
d
1
10:1
10:1
6:1
86
e
2
6b, i-Pr
35
f
3
6b, i-Pr
85
g
4
5
6
7
6c, CHCH2
6d, C(Me)CH2
6e, Ph
>20:1
>20:1
14:1
8:1
89 (78)
g
84 (79)
g
77 (73)
g
6f, CCH
83 (67)
a
b
1.0 mmol scale. Determined by 1H NMR analysis of the crude
c
d
a
mixture. Isolated yield of a mixture of diastereomers. Used n-
Table 1. Tuning Diastereoselectivity
e
butylmagnesium chloride. Estimated by 1H NMR analysis. Major
f
product was primary alcohol derived from aldehyde reduction. 1.5
equiv of CeCl3 added. Isolated yield of a single diastereomer.
g
Surprisingly, the hydroxyl proton of compounds 6a−f
1
consistently appeared in the H NMR spectrum in CDCl3 at
b
c
ca. 2 ppm for the major diastereomer (6a, 2.03 ppm) and at ca.
7 ppm for the minor diastereomer (epi-6a, 7.28 ppm). We
therefore assigned the anti configuration to all six major
products. We also used this built-in stereochemical probe to
correct the stereochemistry of Grignard product 1 (Scheme 1)
(hydroxyl proton at 2.14 ppm) and confirm the stereo-
chemistry of aldol product 2 (hydroxyl proton at ca. 2.9 ppm).
The above chemistry was applied to the synthesis of all
stereoisomers of oxylipin 16 (Scheme 3) in order to assign the
stereochemistry of two isomeric natural products from D.
loretense with incomplete stereochemical assignments. One
oxylipin has an anti diol at C9 and C10 (as in Scheme 3) and is
an immunostimulant; the other has a syn diol (as in Scheme 4)
and is inactive.18 Despite four prior syntheses,24 the
configurations of these oxylipins remained in doubt. The
unfortunate choice by three groups24a−c to obtain NMR spectra
of their synthetic material in a solvent (CDCl3) different from
that used by the isolation team (CD3OD) made comparisons
with the natural oxylipins impossible. Recently, one group24d
obtained NMR spectra in CD3OD but compared their
spectroscopic data only against data for another synthetic
oxylipin.
entry
M
solvent
temp (°C)
dr
yield (%)
d
1
2
3
4
5
MgCl
MgCl
MgCl
Li
Et2O
0
0
4:1
60
THF
6:1
10:1
6:1
70
86
81
84
THF
−78
−78
−78
1
THF
Li
hexanes
b
12:1
a
0.8−1.0 mmol scale. Determined by H NMR analysis of the crude
c
d
mixture. Isolated yield of a mixture of diastereomers. Estimated by
1H NMR analysis of the crude mixture. The major byproduct was the
primary alcohol derived from aldehyde reduction.
chloride (Table 1, entry 4) led to degraded diastereoselectivity,
but the selectivity could be rescued by employing hexanes as
the solvent (Table 1, entry 5). To determine the relative
configuration of differentially masked 1,2-diol 6a, the 2,2,6,6-
tetramethylpiperidinyl (TMP) group was reductively cleaved
(Zn, AcOH)20 to give diol 7 (Scheme 2) in 76% yield. NMR
spectroscopic comparisons against the known syn21 and anti22
stereoisomers established the anti configuration for diol 7 and
its precursor (6a).
Since the functional group tolerance of both reactions in this
two-step diol synthesis is well established, we focused on
evaluating stereoselectivity using different classes of Grignard
reagents. Addition of isopropylmagnesium bromide (Table 2,
entry 2) gave good diastereoselectivity, but significant reduction
of aldehyde 5 to the corresponding primary alcohol was
observed. Premixing with cerium(III) chloride23 (Table 2, entry
3) suppressed formation of the undesired primary alcohol, but
also resulted in some degradation of diastereoselectivity.
Excellent selectivities were observed in the additions of sp2
nucleophiles (Table 2, entries 4−6). Selectivity of ethynylmag-
nesium bromide addition was somewhat lower (Table 2, entry
7), possibly due to reduced steric interactions. The reaction is
not only general, but also scalable; in the total synthesis below,
a related organolithium addition was performed on 15 mmol
scale. Many of the stereoisomer mixtures (6c−f) can be
separated by routine silica gel flash chromatography; in all of
these cases the major product eluted first, facilitating its
isolation.
Our synthesis commenced with organocatalytic α-oxygen-
ation of decanal (8). The low cost of decanal and the
expectation of a second enantioenriching step encouraged us to
again select imidazolidinone 4 over more expensive alternatives.
Along with cupric chloride, imidazolidinone 4 catalyzed
oxidative incorporation of TEMPO to give α-oxyaldehyde 9
in 79% yield and 86:14 er (20 mmol scale).25 Addition of lithio
species 1126 afforded alcohol 12 as an 8:1 mixture of
chromatographically separable isomers; the major product
was isolated in 79% yield (15 mmol scale) with no degradation
of enantiomeric ratio. Scrupulous removal of oxygen was critical
to the lithiation of distannane 10. Use of distannane 10 that
had previously been exposed to air and not deoxygenated
afforded a reactant that evolved a gas (not yet identified) upon
exposure to electrophiles (e.g., aldehyde 9 or water).
Silylation of alcohol 12 and Stille cross-coupling27 with acid
chloride 13 afforded enone 14 in 77% yield over two steps.
Asymmetric enone reduction was effected by borane−dimethyl
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Letter
(6R,9R,10S)-16 as previously claimed.24c,30,31 Only seven steps
long, our synthesis is tied for the shortest32 to oxylipins
containing the 3-en-1,2,5-triol moiety. Furthermore, it is
significantly shorter than other syntheses of related oxylipins
containing an anti-1,2-diol (11−19 linear steps).24a,c,d,33
Scheme 3. Synthesis of Oxylipin (6S,9R,10S)-16
The above diol synthesis currently cannot provide syn diols
directly. However, syn diols can be prepared through an
oxidation−reduction sequence. As shown in Scheme 4, IBX
oxidation of alcohol 12 followed by Luche reduction (11:1 dr)
provided chromatographically separable epimer 17 in 79% yield
over two steps with no degradation of enantiomeric ratio.
Alcohol 17 was converted into oxylipins (6R,9S,10S)-16
(shown in Scheme 4) and C6 epimer (6S,9S,10S)-16 in the
same manner as described in Scheme 3 (see the Supporting
Information); spectral comparisons revealed one of the natural
oxylipins from D. loretense to be (6S,9S,10S)-16. Thus, the two
oxylipins from D. loretense are C10 epimers of each other.
In conclusion, aldehyde α-oxygenation followed by addition
of an organomagnesium or -lithium reagent is a promising
means to access differentially masked anti-1,2-diols from simple
aldehydes. The utility of this approach and the suitability of the
2,2,6,6-tetramethylpiperidinyl moiety as an alcohol masking
group were demonstrated in the concise synthesis of all
possible diastereomers of the oxylipins isolated from D.
loretense. This synthetic work led to unambiguous stereo-
chemical assignment of the natural oxylipins. Efforts are under
way to extend this method to the use of other carbon
nucleophiles and to improve the stereochemical flexibility so
that both syn- and anti-1,2-diols may be prepared directly.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and graphical NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Synthesis of Oxylipin (6R,9S,10S)-16
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jschen@iastate.edu.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Iowa State University (J.S.C.
startup). Some NMR spectrometers were supported by
National Science Foundation funding (CHE 0946687 and
MRI 1040098).
sulfide complex in the presence of the (R)-Me-CBS
oxazaborolidine28 to give a 6:1 mixture of diastereomers.29
These isomers became chromatographically separable after
zinc- and acetic acid-mediated cleavage of the TES and TMP
moieties; triol 15 was isolated as a single diastereomer in 59%
yield over two steps. The additional enantioenrichment during
the CBS reduction delivered material with 98:2 er. Ester
hydrolysis (69% yield) completed the synthesis of oxylipin
(6S,9R,10S)-16. The C6 epimer (6R,9R,10S)-16 (see the
Supporting Information) was prepared similarly. Spectroscopic
comparisons of these two C6-epimeric synthetic compounds
with the published data for the natural substances revealed one
of the natural oxylipins from D. loretense to be (6R,9S,10R)-16
(enantiomer of the compound shown in Scheme 3), not
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