Expedient synthesis of α,α-dimethyl-β-hydroxy carbonyl scaffolds via Evans' aldol reaction with a tertiary enolate

Article abstract of DOI:10.1016/j.tetlet.2011.03.126

An efficient synthetic methodology for 3-hydroxy-2,2-dimethyloctynoic acid (DHOYA) and several variants, which are increasingly common fragments encountered in bioactive marine cyanobacterial metabolites, was developed. These fragments were obtained in three steps via a tertiary aldol reaction utilizing an Evans' chiral auxiliary to afford the desired stereochemistry at the β-hydroxy carbon. Thus far, this methodology has been successfully applied in determination of the absolute stereochemistry of eight cyanobacterial natural products, including the VGSC activator palymramide A.

Full text of DOI:10.1016/j.tetlet.2011.03.126

Tetrahedron Letters 52 (2011) 2929–2932
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Tetrahedron Letters
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Expedient synthesis of a,a-dimethyl-b-hydroxy carbonyl scaffolds via Evans’
aldol reaction with a tertiary enolate
Joshawna K. Nunnery a, Takashi L. Suyama a, Roger G. Linington b, William H. Gerwick a,
⇑
a Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Drive, MC 0212, La Jolla, CA 92093-0212, USA
b Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic methodology for 3-hydroxy-2,2-dimethyloctynoic acid (DHOYA) and several vari-
ants, which are increasingly common fragments encountered in bioactive marine cyanobacterial metab-
olites, was developed. These fragments were obtained in three steps via a tertiary aldol reaction utilizing
an Evans’ chiral auxiliary to afford the desired stereochemistry at the b-hydroxy carbon. Thus far, this
methodology has been successfully applied in determination of the absolute stereochemistry of eight
cyanobacterial natural products, including the VGSC activator palymramide A.
Received 10 February 2011
Revised 21 March 2011
Accepted 23 March 2011
Available online 7 April 2011
Keywords:
DHOYA
Ó 2011 Elsevier Ltd. All rights reserved.
Evans’ chiral auxiliaries
Titanium Lewis acid
Terminal alkyne
Tertiary aldol
The
a
,
a
-dimethyl-b-hydroxy carbonyl functionality is a unique
esterified derivative of 1 (i.e. methyl 3-hydroxy-2,2-dimethyloct-
anoate) to synthetic standards affords a pragmatic approach for
determining the absolute configuration of this stereocenter.9 How-
ever, a critical requirement for this methodology is the availability
of enantiomerically pure synthetic standards.
structural feature of a number of bioactive natural products,
including the epothilones,1 mycalamide A,2 and peloruside A.3 Re-
cently a number of marine cyanobacterial natural products pos-
sessing an
a,a-dimethyl-b-hydroxy carbonyl functionality in the
form of a 3-hydroxy-2,2-dimethyloctynoic acid (DHOYA, 1) frag-
ment, or a derivative thereof, have been described (Fig. 1). Natu-
rally occurring modifications of the structural motif represented
by 1 include varying degrees of saturation, chain shortening,
replacement of the b-hydroxy group by an amine, and mono-meth-
Fragment 1 has previously been synthesized in 9 steps using an
asymmetric Kiyooka–Mukaiyama aldol reaction during total syn-
thesis of yanucamide A13 and pitipeptolide A14 and to provide stan-
dards for chiral GCMS analysis of the wewakpeptins.9 Additional
approaches for construction of the
a,a-dimethyl-b-hydroxy car-
ylation at the
a
-carbon. Other derivatives of 1 feature multiple
bonyl backbone via a tertiary enolate have been applied in partial
and total syntheses of peloruside A,15,16 and in the total synthesis
of pasteurestins A and B;17 in the latter case, a Reformatsky reac-
tion employing a bromoacyl derivative of Evans’ chiral auxiliary
and a TMS-protected terminal alkyne was employed.
However, we conceived a more efficient synthetic route in
which fragment 1 could be achieved enantioselectively via a ter-
tiary aldol reaction with an acylated Evans’ chiral auxiliary and
an aldehyde possessing an unprotected terminal alkyne. As the ter-
minal alkyne of fragment 1 is unstable to acid hydrolysis, which is
usually the first step in the stereochemical determination of depsi-
peptides, saturated 3-hydroxy-2,2-dimethyloctanoic acid (DHOAA,
2) is preferred for chiral GCMS analysis.7,9 Thus, our initial studies
focused on the synthesis of fragment 2.
modifications; examples include antanapeptin B,4 onchidin,5 and
malevamide B.6 Natural products featuring 1 or a variant on this
motif display a variety of biological activities including cytotoxicity
to a number of cancer cell lines,7–9 anti-microbial activity to myco-
bacteria,8 anti-parasitic activity10, and brine shrimp toxicity.11,12
Given the range of biological activities of these molecules and
the diversity of the modifications observed for fragment 1, there
is a compelling need for efficient synthetic methodologies to access
this structural class as well as produce synthetic analogues for drug
development purposes.
Moreover, one of the more difficult aspects of the structure
elucidation of depsipeptides containing 1 is the determination of
absolute configuration of the b-hydroxy ester linkage of fragment
1. Chiral GCMS comparison of the hydrogenated and methyl
Since the key reaction step in this scheme requires an Evans’
chiral auxiliary that is not commercially available, the desired
starting material was obtained via acylation of (R)-4-benzyl-2-oxa-
zolidinone with isobutyryl chloride to give (R)-4-benzyl-3-isobuty-
ryloxazolidin-2-one (3) in good yield (86%). Initially, we attempted
⇑
Corresponding author. Tel.: +1 858 534 0578; fax: +1 858 534 0576.
E-mail address: wgerwick@ucsd.edu (W.H. Gerwick).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.126

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J. K. Nunnery et al. / Tetrahedron Letters 52 (2011) 2929–2932
O
OH
O
N
O
O
HO
N
H
O
N
O
O
O
DHOYA (1)
HN
N
Figure 1. 3-Hydroxy-2,2-dimethyloctynoic acid (DHOYA, 1).
O
O
O
O
the aldol reaction of (40R)-3 and hexanal using LDA alone; however,
the expected aldol product was not formed based on LR-ESI-LCMS
and 1H NMR analyses. We suspected that a stronger Lewis acid was
required for formation and stabilization of the tertiary enolate. We
initially selected a titanium Lewis acid as we thought the titanium
enolate would best facilitate the coordination of the aldehyde via
the Zimmerman–Traxler transition state (see Table 1).18,19 A simi-
lar strategy has been employed previously by the Kobayashi group
in which LDA was used in combination with TiCl(O-i-Pr)3 to form
the titanium enolate in preparation of a 1,2-diol with a quaternary
chiral center.19
Thus, we attempted the aldol addition of hexanal (1.2 equiv)
and (40R)-3 using LDA (1.5 equiv) and TiCl(O-i-Pr)3 (4 equiv). The
reaction was stirred for 1.5 h at ꢀ40 °C and proceeded favorably
to give (3R,40R)-4 in 35% yield (Table 1, entry 1). The configuration
of the b-alcohol in this intermediate was confirmed as R by
Mosher’s analysis, which was consistent with the predicted Zim-
merman–Traxler transition state model.19 The Evans’ chiral auxil-
iary was removed via hydrolysis to furnish (3R)-2 with an overall
yield of 29%. The synthesis was also conducted starting with (S)-
4-benzyl-2-oxazolidinone. The aldol reaction with (40S)-3 gave
(3S,40S)-4 with a 32% yield (Table 1, entry 2), while hydrolysis
afforded the final product (3S)-2 with an overall yield of 24%.
These initial results verified that this three step synthesis was
indeed a viable route for the generation of (3R)-2 and (3S)-2. These
products are invaluable for use as standards in the chiral GCMS
analysis of the b-hydroxy chiral center of marine natural products
featuring 1 or a saturated derivative. One such application was in
the case of mantillamide A (Fig. 2) where 5.2 mg was isolated from
N
N
H
Figure 2. Mantillamide A, a secondary metabolite featuring fragment 1 (high-
lighted in red).
field collections; however, only 0.2 mg of the natural product was
required for chiral GCMS analysis. Comparison of the methyl ester-
ified fragment derived from mantillamide A to methyl esterified
(3R)-2 and (3S)-2 obtained using the described synthetic route re-
vealed that mantillamide A possesses an R-DHOYA unit. The reten-
tion time for the natural product was 53.67, while the retention
time for the R-enantiomer was 53.64 and the retention time for
the S-enantiomer was 52.08. Co-injections of the natural product
with the R- and S-enantiomers confirmed the assignment as R.
While the route was efficient for preparation of standards for ste-
reochemical analyses, the overall yield was quite low. Thus, we
investigated optimization of the aldol reaction to improve the
overall yield making the route more attractive for utilization in to-
tal syntheses.
Suspecting that an additional deprotonation may be occurring
on C-5, resulting in decomposition of the starting material and,
therefore, contributing to the observed low yield, an Evans’ chiral
auxiliary [(40S)-5], featuring gem-dimethyl substitution at C-5,
was employed as the starting material in subsequent reactions.20
Acylation of (40S)-5 gave (40S)-6 (97% yield), which was then uti-
Table 1
Optimization of aldol reaction in the synthesis of 2
O
1) LDA
2)Ti(O-i-Pr)3Cl
3) Hexanal
O
O
O
OH
N
O
O
N
R1
R1
4'
3
R1
R1
4'
THF
R1
R1
Bn
O
O
N
3: R1=H
6: R1=CH3
4: R1=H
(i-PrO)3Ti
O
O
R
7: R1=CH3
Me
Me
Entry
S.M.a
Scaleb
Aldehyde (equiv)
Temperature conditions
Product
Yieldc (%)
1
2
3
4
5
6
7
8
(40R)-3
(40S)-3
(40S)-6
(40S)-6
(40S)-6
(40S)-6
(40S)-6
(40R)-6
3.8
1.7
0.2
0.1
0.2
0.2
0.2
0.2
1.2
1.2
1.2
1.2
3.0
3.0
3.0
3.0
ꢀ40 °C, 1.5 h
(3R,40R)-4
(3S,40S)-4
(3S,40S)-7
(3S,40S)-7
(3S,40S)-7
(3S,40S)-7
(3S,40S)-7
(3R,40R)-7
35
32
41
9
58
98d
91
82
ꢀ40 °C, 1 h
ꢀ40 °C, 3 h
ꢀ78 °C?22 °C, 18 h
ꢀ40 °C, 3 h
ꢀ40 °C, 3 h; 0 °C, 2 h
ꢀ40 °C, 3 h; 0 °C, 2 h
ꢀ40 °C, 3 h; 0 °C, 2 h
a
b
c
S.M.: Starting material.
Scale based on mmol of starting material.
Isolated yield following flash column chromatography.
Enantiomeric ratio P 50:1 according to 1H NMR and chiral GCMS analyses.
d

J. K. Nunnery et al. / Tetrahedron Letters 52 (2011) 2929–2932
2931
Table 2
determined as 50:1 for the desired enantiomer based on peak area.
Repetition of these favorable aldol reaction conditions affirmed the
observed result and high yield (a 91% yield was achieved, entry 7).
Subsequently, the aldol reaction was conducted with (40R)-6 and
an 82% yield was obtained (entry 8).
Tertiary aldol reaction with additional aldehydes
1) LDA
O
O
O
O
OH
2)Ti(O-i-Pr)3Cl
N
N
O
O
3) Aldehyde
3
Additional reactions substituting butanal for hexanal were con-
ducted to provide (S)- and (R)-3-hydroxy-2,2-dimethylhexanoic
acid (DMHHA) for use as standards for chiral analysis of the b-hy-
droxy stereocenter in palmyramide A,21 a natural product which
possesses the DMHHA residue. In both of these reactions, 3 equiv
of aldehyde were used and the final reaction temperature was
ꢀ40 °C. The S-enantiomer was obtained in 54% yield (Table 2, entry
1), while the R-enantiomer was obtained in 35% yield (entry 2).
Comparison of the yield for the S-enantiomer from this aldol reac-
tion to its two carbon extended counterpart reveals that the yields
are not significantly different, 54% for the former compared to 58%
for the latter, suggesting that chain length does not substantially
impact yield.
Having successfully developed a route for generating synthetic
(3R)-and (3S)-2, as well as (3R)- and (3S)-DMHHA, as standards
for stereochemical determination at the b position of fragment 1
and the DMHHA fragment, we wanted to explore the applicability
of this route for generation of chiral fragment 1 itself. Thus, the al-
dol reaction was conducted with (40S)-6 utilizing 1.2 equiv of 5-
hexynl-1-al (prepared from 5-hexyn-1-ol according to Böttcher
and Sieber)22 with the final temperature at ꢀ40 °C for 3 h, resulting
in a 27% yield (Table 2, entry 3) as compared to a 41% yield under
the same conditions using hexanal (Table 1, entry 3). Due to the
considerable lability of the alkynyl aldehyde, in comparison with
the saturated aldehyde, a lower yield was expected for this reac-
tion; however this result revealed that the reaction conditions
were amenable for use with unprotected alkynyl aldehydes. Using
these improved reaction conditions with 3 equivalents of aldehyde
and increasing the final temperature to 0 °C, the aldol reactions
were conducted with 5-hexyn-1-al and both (40S)- and (40R)-6 to
give yields of 58% and 74%, respectively (Table 2, entries 4 and 5).
Next, we verified that the hydrolysis conditions were suitable
for use with these various substrates to provide the desired free
acids. Hydrolysis of (3R,40R)-7 and (3S,40S)-7 with LiOH and H2O2
gave the desired products with a 68% yield for (3R)-2 and an 87%
yield for (3S)-2, resulting in an overall yield of 52% for the R-enan-
tiomer and 83% for the S-enantiomer (Scheme 1). This is a substan-
tial increase in yield in comparison with the initial yields of 29% for
(3R)-2 and 24% for (3S)-2. Hydrolysis of the aldol products featur-
R1
4'
4'
THF
6
8: R1=(CH2)2CH3
9: R1=(CH2)3C CH
Entry S.M.a
Aldehydeb Temperature
conditions
Product
Yieldc
(%)
1
2
3
4
5
(40S)-
Butanal
Butanal
ꢀ40 °C, 3 h
ꢀ40 °C, 3 h
ꢀ40 °C, 3 h
(3S,40S)-
54
35
27
58
74
6
8
(40R)-
6
(3R,40R)-
8
(40S)-
6
5-
Hexynal
5-
Hexynal
5-
Hexynal
(3S,40S)-
9
(40S)-
6
ꢀ40 °C, 3 h; 0 °C, 2 h
ꢀ40°C, 3 h; 0 °C, 2 h
(3S,40S)-
9
(40R)-
6
(3R,40R)-
9
a
S.M.: starting material.
1.2 equiv of aldehyde was used for entry 3, whereas 3 equivalents of aldehyde
b
were used for all other entries.
c
Isolated yield following flash column chromatography.
lized in the aldol reaction, and resulted in an increase in yield from
32% for (3S,40S)-4 to 41% for (3S,40S)-7 (entry 3). In subsequent
reactions, 1 M solutions in THF were prepared from neat TiCl(O-
i-Pr)3 due to concerns that hexanes present in the commercial
1 M preparation may be adversely affecting solvation of the
enolate. Additionally, the amount of aldehyde was increased from
1.2 to 3 equiv and the reaction time was adjusted to 3 h, resulting
in an increase in yield from 41% to 58% (entry 5). Next, the final
temperature was increased to 0 °C after 3 h and the reaction was
run for an additional 2 h, resulting in an excellent yield of 98%
(entry 6). While 1H NMR analysis of the crude aldol product did
not indicate the presence of diastereomers, the aldol product was
hydrolyzed to give (3S)-2, which was methyl esterified and
analyzed by chiral GCMS analysis. The enantiomeric ratio was
O
O
OH
1) LDA,THF, -78°C
O
N
2) Ti(O-i-Pr)3Cl (4 equiv.)
O
OH
3) Hexanal (3equiv.)
1) H2O2
2) LiOH
1) n-BuLi
O
O
HO
O
THF
THF, -78°C
-40°C (3 h), 0°C (2h)
2)
O
THF:H2O, 4:1
O
NH
O
N
(3S)-2: 87% yield, 83%overall yield
Cl
2
(3R)- : 68% yield, 52% overall yield
(3S,4'S)-7: 98% yield
(3R,4'R)-7: 82% yield
97% Yield
O
O
OH
(4'S)-5
(4'R)-5
(3S,4'S)-6: 97% yield
(3R,4'R)-6: 94% yield
O
N
O
OH
1) H2O2
3) Hexynal(3 equiv.)
2) LiOH
HO
THF
-40°C (3 h), 0°C (2h)
THF:H2O, 4:1
(3S)-1: 84% yield,47% overall yield
(3R)- : 81% yield, 56% overall yield
1
(3S,4'S)-9: 58% yield
(3R,4'R)-9: 74% yield
Scheme 1. Optimized reaction conditions for generation of fragments 1 and 2 via tertiary aldol reaction.

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J. K. Nunnery et al. / Tetrahedron Letters 52 (2011) 2929–2932
ing a terminal alkyne afforded (3S)-1 with a yield of 84% (47% over-
all yield) and (3R)-1 with a yield of 81% (56% overall yield). This
represents a significant improvement in the efficiency and yield
for the synthesis of fragment 1 compared to previous published
syntheses.13,14
In summary, we have developed a new synthetic route for the
a,a-dimethyl-b-hydroxy carbonyl motif exemplified by fragment
1. This represents a significant advance in methodology for the to-
tal synthesis of compounds featuring fragment 1 or related resi-
dues. Future directions of this research include exploring the
utility of thiazolidinethiones and oxazolidinethiones to afford the
desired (R) and (S) aldol products from a single chiral auxiliary,
and total synthesis of biologically active cyanobacterial secondary
metabolites featuring fragment 1.
References and notes
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We thank Y. Su (UCSD Chemistry and Biochemistry Mass Spec-
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Supplementary data
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Supplementary data (experimental procedures and spectro-
scopic data for all new compounds) can be found in the online ver-
sion at doi:10.1016/j.tetlet.2011.03.126.
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