Formation of highly substituted tetrahydropyranones: Application to the total synthesis of cyanolide A

Article abstract of DOI:10.1021/ol402095g

A new tetrahydropyranone synthesis has been developed that leads to cis-2,6-disubstituted 3,3-dimethyltetrahydropyran-4-one rings by condensation of an aldehyde and a hydroxy silyl enol ether. The reaction works with a variety of aldehydes to produce the tetrahydropyranone products in moderate to high yields. This new method was applied to the enantioselective synthesis of cyanolide A and its aglycone.

Full text of DOI:10.1021/ol402095g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Formation of Highly Substituted
Tetrahydropyranones: Application to the
Total Synthesis of Cyanolide A
Gidget C. Tay, Michael R. Gesinski, and Scott D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, University of California;Irvine,
Irvine, California 92697, United States
srychnov@uci.edu
Received July 24, 2013
ABSTRACT
A new tetrahydropyranone synthesis has been developed that leads to cis-2,6-disubstituted 3,3-dimethyltetrahydropyran-4-one rings by conden-
sation of an aldehyde and a hydroxy silyl enol ether. The reaction works with a variety of aldehydes to produce the tetrahydropyranone products
in moderate to high yields. This new method was applied to the enantioselective synthesis of cyanolide A and its aglycone.
Highly substituted tetrahydroyrans (THPs) are preva-
lent in the structure of many natural products, where they
act as rigidifying scaffolds.1 The natural products cyano-
lide A (1)2 and psymberin (irciniastatin A, 2)3 have been
the focus of considerable interest from synthetic chemists
in part because both have THP rings containing quater-
nary centers (Figure 1).4 Cyanolide A has been prepared a
numberof times,5 including a particularly elegant synthesis
from the Krische group.6 Our interest in the synthesis of
cyanolide A stimulated the development of a robust and
convergent method for the synthesis of 3,3-disubstituted
THPs. Herein we present this new method and its applica-
tion to the synthesis of cyanolide A.
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Figure 1. Tetrahydropyran rings containing quaternary centers
are found in natural products such as cyanolide A and
psymberin.
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9729. (f) Sharpe, R. J.; Jennings, M. P. J. Org. Chem. 2011, 76, 8027–
8032.
r
10.1021/ol402095g
XXXX American Chemical Society

Tetrahydropyrans are commonly prepared by hetero-
DielsÀAlder reactions and by Prins cyclizations, among
other methods.7 Synthesis of tetrahydropyran-4-ones fol-
lowed by reduction also has been used to prepare complex
4-hydroxytetrahydropyran rings. Examples include the
synthesis of phorboxazole and other natural products by
the Smith lab8 using the PetasisÀFerrier and related
reactions.9 Michael additionÀcyclizations have also been
used to prepare these rings.10 Other synthetic methods that
focus on the preparation of tetrahydropyran-4-ones in-
clude oxacarbenium ion cyclizations of enol ethers11,12 or
enamines.13 Our method is designed around a new oxa-
carbenium ion cyclization.
The tetrahydropyranone synthesis is shown in Scheme 1.
Silyl ketene acetal14 3 reacted with dimethylketene,15 pre-
pared by zinc reduction of the 2-bromo-2-methylpropionyl
bromide,16 to produce deconjugated silyl enol ether 4 in
moderate yield. The ester was converted to Weinreb amide 5,17
and addition of an organometallic reagent produced the
expected ketone. Reduction of the ketone led to the desired
enol ether alcohol 6. Cyclization to tetrahydropyranone 7
takes place upon treatment with an aldehyde and a Lewis
acid. The many points of variation in this sequence ensure
a wide scope for the method.
Scheme 1. Tetrahydroyran-4-one Synthesis from Weinreb
Amide 5, an Organomatallic Reagent and an Aldehyde
Syntheses of a variety of enol ether alcohols 6aÀe are
presented in Table 1. Grignard and alkyllithium reagents
were added to amide 5 to deliver the expected ketones 8 in
good yields. Reduction to the alcohol generally yields
racemic products, although enantioselective reductions are
plausible for several substrates.18 The β-oxy-alkyllithium
reagent in entry 4 was optically pure,19 and syn-selective
reduction of the ketone produced 6d as a single diastereomer
in good yield. Tertiary alcohol 6e was available by methyl-
magnesium bromide addition to ester 4. The intermediates
6aÀe are poised to form tetrahydropyran-4-one rings.
Table 1. Preparation of the Silyl Enol Ether Alcohols 6aÀe
(6) Waldeck, A. R.; Krische, M. J. Angew. Chem., Int. Ed. 2013, 52,
4470–4473.
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Springer-Verlag: Berlin, 2014.
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D. B.; Shirakami, S.; Bauer, D.; Zhu, W.; Doughty, V. A. Org. Lett.
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Commun. 2012, 49, 193–195.
a Crude ketone was directly reduced with DIBAL-H. b Double
addition to ester 4 gave the observed product.
(11) (a) Dalgard, J. E.; Rychnovsky, S. D. J. Am. Chem. Soc. 2004,
126, 15662–15663. (b) Dalgard, J. E.; Rychnovsky, S. D. Org. Lett. 2005,
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Optimization of the tetrahydropyranone synthesis was
conducted using diol 6d, and the results are displayed in
Table 2. Initial studies were carried out with benzaldehyde.
Formation of tetrahydropyranone 7 was best achieved
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12217.
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1300.
with BF3 OEt2 at low temperature (entry 1), although
3
TESOTF was also effective. Saturated aldehydes proved
to be more difficult substrates; dihydrocinnamaldehyde
failed to form the desired product in significant quantities
(16) (a) Smith, W. C.; Norton, D. G.; Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, pp 348À350. (b) Baigrei, L. M.; Lenoir, D.;
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4223.
B
Org. Lett., Vol. XX, No. XX, XXXX

with a variety of Lewis acids, including BF3 OEt2 and
3
TESOTf (entries 4 and 5). After testing a range of Lewis
acids, the highly reactive TMSOTf was identified as a
reasonable promoter. The yield in this case is moderate,
but the reaction does produce the desired tetrahydropyr-
anone as a single diastereomer. The preferred Lewis acids
Table 3. Scope of the Tetrahydropyran-4-one Synthesis with
Different Enol Ethers and Aldehydesa
for the cyclization step are BF3 OEt2 for unsaturated
aldehydes and TMSOTf for saturated aldehydes.
3
Table 2. Optimization of Tetrahydropyridin-4-one Formation
Using Diol Enol Ether 6d
entrya
Lewis acid
R
yield of 7 (%)
64
1
2
BF3 OEt2
Ph
Ph
Ph
3
TESOTf
TiCl4
54
3
<5
4
BF3 OEt2
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
CH2CH2Ph
0
3
5
TESOTf
TiCl4
10
6
<5
7
Sc(OTf)3
Et2AlBr
TiBr4
0
8
NR
9
decomposition
55
10
TMSOTf
a The reactions were conducted with 1.0 equiv of 6d, 3.0 equiv of
aldehyde and Lewis acid, and run at 0.4 M in DCM at À78 °C for 4 h.
The scope of the tetrahydropyran-4-one synthesis was
then explored (Table 3). The C2 substituent comes from
the aldehyde, and the C6 substituent comes from the
organometallic reagent (Table 1). Aside from the examples
in Table 2, the reaction works well with a variety of
aromatic aldehydes (entries 2À6). In general, electron-rich
aromatic substrates (entries 2À3) appear to be more
effective than electron-poor substrates (entry 6), probably
due to the stability of the intermediate oxacarbenium ions.
Unsaturated aldehydes appear to be particularly good
substrates and lead to the highest yields (entries 7 and 8).
The reaction is compatible with halides, Boc-protected
amines, esters, and alcohols. It is worth noting that two
quaternary centers were introduced in high yield using this
cyclization reaction (entry 8). Tetrahydropyran 7i was
produced with high optical purity (entry 7).20 The aliphatic
example leads to a modest yield of product using the
preferred TMSOTf catalyst (entry 1). In all of these
examples, the cyclizations were highly stereoselective and
only the 2,6-cis diastereomer was isolated.
a The reactions were run with 1.0 equiv 6, 1.5 equiv of aldehyde and
Lewis acid, and run at 1.0 M in DCM at À78 °C for 4 h. b TMSOTf was
used as a Lewis acid instead of BF3 OEt2.
3
The key intermediate, THP 20, would be assembled from
the optically pure diol 6d and the aliphatic aldehyde 21.21
There is precedent for the key dimerization and macro-
cyclization of acid 20 to generate the cyanolide core
19 based on work by Hong and other groups.5,6
The versatility of the tetrahydropyranone synthesis as
demonstrated in Table 3 suggests that this route would be
amenable to the preparation of analogues of cyanolide A.
The synthesis of cyanolide A aglycone is presented in
Scheme2. The synthesisof 6dwas outlined in Table 1 and is
shown in more detail below. Generation of the dianion
from optically pure 22,19 followed by addition to Weinreb
amide 5, gave the β-hydroxy ketone 23 in good yield.
Reduction under Narasaka’s conditions22 delivered the
syn-1,3-diol 6d as a single diastereomer. The THP ring was
formed by reaction of the aldehyde 21 with diol 6d and
TMSOTf at low temperature. The reaction presumably
occurs through formation and cyclization of an oxacarbe-
nium ion intermediate and produces 24 as the 2,6-cis
The tetrahydropyranone method was designed to facil-
itate the synthesis of cyanolide A and its aglycone (Figure 2).
(20) The enantiomeric ratio of alcohol 22, the precursor to 6d
(Scheme 2), was 98.0:2.0, and the enantiomeric ratio of 7i (entry 7)
was 97.9:2.1, demonstrating that essentially no optical purity is lost in
the cyclization reaction. Enantiomeric ratios for compounds 22 and 7i
were measured by HPLC on a Chiralpak AD column using 10% i-
PrOH/n-hexane. Details are provided in the Supporting Information.
(21) Wang, J.; Chen, J.; Kee, C. W.; Tan, C.-H. Angew. Chem., Int.
Ed. 2012, 51, 2382–2386.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Synthesis of Cyanolide A Aglycone
Figure 2. Retrosynthetic analysis of cyanolide A aglycone (19)
with the tetrahydropyran-4-one synthesis and an esterificationÀ
macrolactonization.
diastereomer. The TBS group was lost in the transformation.
Selective oxidation of the primary alcohol to the acid with
TEMPO and PhI(OAc)2, followed by direct macrocycliza-
tion using Shiina’s conditions,23 gave the C2 symmetric
diolide 25 in a very modest yield. This sequence resisted
optimization despite numerous attempts. The problem is
attributed to the reactivity of the ketone; the cyclization
reaction was messy, but no identifiable side products were
isolated from the reaction. Reduction of the ketones with
NaBH4 delivered the desired cyanolide A aglycone in good
yield, and in only six steps from alcohol 22.The configuration
of aglycone 19 arose from the enantiopure alcohol 22.
The modest yield in the prior sequence led to the
exploration of an alternative route to cyanolide A, which
is presented in Scheme 3. The presence of a ketone
imparted unexpected fragility to the cyclization precursor,
and thus the revised sequence would remove the ketone
and introduce the xylose derivative prior to cyclization.
The diol 24 was protected as the bis-PMB ether.24 Reduc-
tion of the ketone, followed by glycosidation with phenyl
sulfide 2725 using MeOTf activation, generated the desired
β-anomer 28 as the major component of a 3.5:1 mixture.
The anomers were separated, and the major isomer was
taken on in the synthesis. Deprotection of the PMB ethers
led to the diol 29, a cyclization precursor analogous to the
diol 24 used in Scheme 2. In this case, selective oxidation
with TEMPO and cyclization with Shiina’s conditions23
produced cyanolide A directly in 88% yield. The use of
protecting groups adds two steps to the synthesis, but the
overall process is more effective because it avoids the
problematic cyclization of ketone 24.
Scheme 3. Synthesis of Cyanolide A
The new method provides ready access to a variety
of substituted tetrahydropyran-4-ones in moderate to
good yields. Syntheses of cyanolide A and its aglycone
were accomplished easily by building upon the tetrahy-
dropyran-4-one 24 prepared using the method. The flex-
ibility of the THP formation makes it suitable for
preparing analogues of cyanolide A for biological evalua-
tion and for the synthesis of other natural products.
Acknowledgment. Support was provided by the Na-
tional Institute of General Medicine (GM-43854). M.R.
G. was supported by a Lilly Graduate Research Fellow-
ship. We acknowledge Yu Yi (Chloe) Huang at UC Irvine
for her assistance in substrate preparation.
(22) (a) Chen, K.-M.; Hardtman, G. E.; Prasad, K.; Repic, O.;
Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155–158. (b) Narasaka, K.;
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(24) In addition to the bis-PMB ether, the mono-PMB ether was
isolated in 31% yield and resubjected to the protection conditions to
deliver more bis-PMB material.
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737–745. (b) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth,
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Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX