Highly substituted tetrahydropyrones from hetero-Diels-Alder reactions of 2-alkenals with stereochemical induction from chiral dienes

Article abstract of DOI:10.1021/jo0488311

(Chemical Equation Presented) A new method for the stereoselective synthesis of libraries of 2,3,5-trisubstituted tetrahydro-γ-pyrones and the corresponding tetrahydropyran-4-ols is reported. Dienes with a chiral moiety at position 5 were synthesized star

Full text of DOI:10.1021/jo0488311

Recently, the Prins cyclization and related reactions
have received significant attention as a means for the
(asymmetric) synthesis of tetrahydropyran derivatives.10-14
An important advantage of this methodology is the
possibility to construct tetrahydropyrans in one step from
readily available starting materials (e.g., homoallylic
alcohols and simple aldehydes), and in some cases yield
and diastereoselectivity are excellent.13 The major draw-
back is the formation of side products, probably arising
from an oxonia-Cope-type rearrangement, especially
when substituents at the 2- or 6-position stabilize the
cationic intermediate.15,16
Another possibility of constructing a new carbon-
carbon bond and the ring ether in a single step is
provided by the hetero-Diels-Alder (HDA) reaction.17,18
In the 1980s, Danishefsky et al. demonstrated the
synthetic potential of this reaction.19 Up to three new
stereocenters can be formed, and several chiral HDA
catalysts (including chiral aluminum20 and boron21 com-
plexes) have been developed to control the stereochemical
outcome. Most of these, however, require doubly activated
dienes such as Danishefsky’s diene [1-methoxy-3-(tri-
methylsilyloxy)butadiene] as substrate, which limits their
applicability substantially. Only Jacobsen’s recently de-
veloped Cr(III) catalyst accepts monoactivated dienes as
substrates.22 Paterson and Lockhurst recently demon-
strated that this catalyst may also be applied in more
complex systems, using a catalytic asymmetric HDA
reaction for the construction of a phorboxazole A frag-
ment.23 However, applicability still seems to be limited,
depending on the nature of the aldehyde and steric bulk
of either of the substrates.
Highly Substituted Tetrahydropyrones
from Hetero-Diels-Alder Reactions of
2-Alkenals with Stereochemical Induction
from Chiral Dienes
Eelco Ruijter, Heike Schu¨ltingkemper, and
Ludger A. Wessjohann*
Department of Bioorganic Chemistry, Leibniz Institute of
Plant Biochemistry, Weinberg 3,
06120 Halle (Saale), Germany
wessjohann@ipb-halle.de
Received July 10, 2004
A new method for the stereoselective synthesis of libraries
of 2,3,5-trisubstituted tetrahydro-γ-pyrones and the corre-
sponding tetrahydropyran-4-ols is reported. Dienes with a
chiral moiety at position 5 were synthesized starting from
(triphenylphosphoranylidene)acetone. In hetero-Diels-Alder
(HDA) reactions, especially with R,â-unsaturated aldehydes,
they induce diastereomeric ratios from 4:1 to 14:1. Through
selective epimerization and reduction, further building
blocks are available. These constitute ideal starting points
for their use in the total synthesis of complex polyketide
macrocycles, especially with the vinyl group available for
metathetic coupling.
In these catalytic asymmetric methods, especially R,â-
unsaturated aldehydes lack reactivity, and typically
doubly activated dienes are required as reaction partners.
Their incorporation is highly desirable, since the result-
ing exocyclic vinyl group provides the THP-building block
with a handle for metathetic connection or macrocycliza-
tion procedures. Unfortunately, to the best of our know-
ledge, no diastereo- or enantioselective HDA reaction of
Substituted di- and tetrahydropyran rings are fre-
quently occurring structural motifs in biologically active
natural products, including laulimalide (1),1-5 the bry-
ostatins (2a,b),6,7 the phorboxazoles (3), and ratjadone
(4) (Scheme 1).8,9 Commonly, in the 4-position an oxygen
substituent is encountered, as would be expected from
polyketide metabolism, which is the origin of almost all
pyran-containing natural products. The remarkable bio-
logical activity of these compounds makes them attractive
targets for synthetic chemists. There are, however, few
generally applicable synthetic routes to such highly
substituted tetrahydropyran systems.
(10) Crosby, R. C.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 3407-3410.
(11) Dobbs, A. P.; Martinovic, S. Tetrahedron Lett. 2002, 43, 7055-
7057.
(12) Hu, Y.; Skalitzky, D. J.; Rychnovsky, S. D. Tetrahedron Lett.
1996, 37, 8679-8682.
(13) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4,
1189-1192.
(14) Sasmal, P. K.; Maier, M. E. Org. Lett. 2002, 4, 1271-1274.
(15) Crosby, R. C.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 577-580.
(1) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J.
J. Org. Chem. 1988, 53, 3644.
(2) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642.
(3) Ghosh, A. K.; Wang, Y. J. Am. Chem. Soc. 2000, 122, 11027-
11028.
(4) Dorling, E. K.; O¨ hler, E.; Mantoulidis, A.; Mulzer, J. Synlett 2001,
1105-1108.
(5) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149-
3152.
(6) Pettit, G. R.; Gao, F.; Blumberg, P. M.; Herald, C. L.; Coll, J. C.;
Kamano, Y.; Lewin, N. E.; Schmidt, J. M.; Chapuis, J.-C. J. Nat. Prod.
1996, 59, 286-289.
(7) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Charette, A. B.;
Prunet, J. A.; Lautens, M. Angew. Chem. 1998, 110, 2526-2530.
(8) Schummer, D.; Gerth, K.; Reichenbach, H.; Ho¨fle, G. Liebigs Ann.
1995, 685-688.
(9) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse,
M. J. Org. Chem. 2001, 66, 1885-1893.
(16) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001,
3, 3815-3818.
(17) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987.
(18) Boger, D. L. In Comprehensive Organic Synthesis; Pergamon:
New York, 1991; Vol. 5, pp 451-512.
(19) Danishefsky, S.; Kerwin, J. F. J. J. Org. Chem. 1982, 47, 3183-
3184.
(20) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 310-312.
(21) Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H. J. Org. Chem.
1992, 57, 1951-1952.
(22) Dosseter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.
1999, 111, 2549-2552.
(23) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749-
3754.
10.1021/jo0488311 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/04/2005
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J. Org. Chem. 2005, 70, 2820-2823

SCHEME 1
TABLE 1. Preparation of Dienes
SCHEME 2. Versatile Synthesis of
2,3,5-Trisubstituted Tetrahydro-4-pyronesa
ylide
enone
diene
entry ylide R1 ) yield (%) enone yield (%) diene yield (%)
1
2
3
4
5
5
6
7
8
9
H
10
11
12
13
80
42
43
54
14
15
16
17
95
88
93
93
a Key: (a) n-BuLi, R1I, THF, -78 °C to rt; (b) R2CHO, CH2Cl2;
(c) TBSOTf, Et3N, Et2O, 0 °C; (d) R3CHO, BF3‚Et2O, Et2O,
-30 °C; AcOH, TBAF, THF.
Me
Et
94
88
100
95
iPr
iBu
R,â-unsaturated aldehydes with monoactivated dienes
has been described so far.
TABLE 2. Hetero-Diels-Alder (HDA) Reaction of
2-Alkenals
Another means of controlling the stereochemical out-
come of the HDA reaction is the use of enantiomerically
pure starting materials. Several examples of asymmetric
HDA reactions with enantiomerically pure chiral alde-
hydes have been described.24,25 Martin et al. have de-
monstrated a synergistic effect between a chiral aldehyde
and a chiral diene.26 Also, Hu et al. described an asym-
metric HDA reaction using a chiral diene and a chiral
Co(II) salen catalyst.27 However, to the best of our
knowledge, the use of a chiral diene as sole means of
controlling the stereochemical outcome of the HDA
reaction has not been described to date.
We now report a stereoselective route to all-cis 2,3,6-tri-
substituted tetrahydro-γ-pyrones and related enol ethers
and alcohols using an HDA reaction between enantio-
merically pure chiral dienes and R,â-unsaturated alde-
hydes. The general strategy is outlined in Scheme 2.
â-Keto ylides 6-9 were obtained by alkylation of
commercially available ylide 5 with the appropriate alkyl
iodides after deprotonation with n-BuLi (Table 1).28
Enones 10-13 were obtained by Wittig reaction of ylides
5-8 with aldehydes, especially with (R)-2,2-dimethyl-1,3-
dioxolane-4-carboxaldehyde (available in two steps from
inexpensive mannitol29,30) as summarized in Table 2. In
yield
HDA
(% over
entry diene R1 )
R2 )
product THP-4-one two steps)
6
7
14
14
15
15
16
16
17
17
H
H
CH3CHdCH
PhCHdCH
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
78
85
84
85
84
72
77
69
8
Me CH3CHdCH
Me PhCHdCH
9
10
11
12
13
Et
Et
CH3CHdCH
PhCHdCH
iPr CH3CHdCH
iPr PhCHdCH
all cases, only the E-enone was isolated; the Z-product
was either absent or present as a very minor impurity
that was easily removed by flash chromatography. This
is in contrast to a literature report where 10 was formed
(24) Cink, R. D.; Forsyth, G. J. J. Org. Chem. 1997, 62, 5672-5673.
(25) Mujica, M. T.; Alfonso, M. M.; Galindo, A.; Palenzuela, J. A. J.
Org. Chem. 1998, 63, 9728-9738.
(26) Martin, M.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett
2001, 117-119.
(29) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.;
Prather, D. E.; Schantz, R. D.; Sear, N. D.; Vianco, C. S. J. Org. Chem.
1991, 56, 4056-4058.
(30) Earle, M. J.; Abdur-Rashid, A.; Priestley, N. D. J. Org. Chem.
1996, 61, 5697-5700.
(27) Hu, Y.-J.; Huang, X.-D.; Yao, Z.-J.; Wu, Y.-L. J. Org. Chem.
1998, 63, 2456-2461.
(28) Schuda, P. F.; Ebner, C. B.; Potlock, S. J. Synthesis 1987, 1055-
1057.
J. Org. Chem, Vol. 70, No. 7, 2005 2821

TABLE 3. Diastereoselectivity of 2-Alkenal-HDA
that the products arise from a tandem Mukaiyama-
Michael-type addition, rather than a (pseudo-)concerted
[4 + 2] cycloaddition. HDA reactions with R,â-unsatur-
ated aldehydes (typically less reactive than ethyl glyoxy-
late) reported here generally afford only the all-cis iso-
mers, and thus most likely proceed through a more selec-
tive (pseudo-)concerted [4 + 2] cycloaddition mechanism.
Reactions
The absolute stereochemistry of the tetrahydropyran-
ones was assigned on the basis of the conversion of 28a
(major isomer) to 35a (Scheme 3). K-Selectride reduction
of 28a afforded a 1:4 mixture of axial alcohol 34a and
equatorial alcohol 34b. Axial/equatorial assignments
HDA product
entry
R1 )
R2 )
no.
ratio a/b
14
15
16
17
18
19
20
21
H
H
CH3CHdCH
PhCHdCH
CH3CHdCH
PhCHdCH
CH3CHdCH
PhCHdCH
CH3CHdCH
PhCHdCH
26
27
28
29
30
31
32
33
2:1
1.6:1
4:1
1
were made on the basis of H NMR coupling constants.
Me
Me
Et
Et
iPr
iPr
Also, the presence of an axial C4 alcohol causes a
characteristic downfield shift of H2 and H6. Subsequent
acetonide cleavage of 34a gave triol 35a, which was
10:1
7:1
8:1
1
shown by H NMR to be nonidentical to known 35b.9
7:1
4:1
Further evidence for the exclusive formation of the all-
cis products was supplied by HDA reaction of achiral
dienes 38 and 39 (i.e., with an isopropyl group instead
of the dimethyldioxolane substituent) with crotonalde-
hyde or cinnamaldehyde (Scheme 4). Here, only one pair
of (enantiomeric) diastereomers of the desilylated HDA
products 40-42 was formed. The all-cis configuration
was confirmed by NOE spectroscopy for 41 and based on
analogy of 1H NMR coupling constants for the other
tetrahydropyran-4-ones 40 and 42.
Interestingly, reaction of diene 44, which has an aro-
matic ring conjugated to the diene system, with crotonal-
dehyde and cinnamaldehyde gave the classical Diels-
Alder adducts 45 and 46 as the sole isolated products,
rather than the expected HDA products (Scheme 5).
in a 3:1 E/Z ratio.27 The sometimes mediocre yields are
caused by difficulties in the purification of the â-keto
ylides, a problem that should not prevail if large scales
are required, or isolation and purification are omitted.
Enones 10-13 were then smoothly converted to the corre-
sponding TBS enol ethers 14-17. Racemization was not
observed, but partial racemization cannot be excluded if,
e.g., triethylamine is applied in excess for extended
periods.
Hu et al. reported that treatment of 14 with BF3‚Et2O
resulted in decomposition.27 Although we found this to
be the case at room temperature, BF3‚Et2O-mediated
decomposition of silyloxydienes 14-17 was not observed
at temperatures below -20 °C. Thus, dienes 14-17 were
subjected to BF3‚Et2O-mediated HDA reaction with cro-
tonaldehyde or cinnamaldehyde at temperatures between
-20 and -35 °C. The resulting dihydropyrans 18-25
were desilylated with TBAF, which was acidified with
2.5 equiv of AcOH to prevent partial epimerization at C3
to give tetrahyropyran-4-ones 26-33 (Table 2).
A possible rationalization for this observation is a
decrease in the HOMO energy of the diene through
conjugation to the aromatic ring.
An expansion of the applicability of the current meth-
odology would be the selective base-catalyzed epimeriza-
tion at C3. Especially in the case of a bulky substituent,
the equatorial position should be favored over the axial
one. Indeed, when 33a was treated with base, it was
slowly converted to 33c (Scheme 6). The product was
shown to be different from 33a and 33b (and the above-
mentioned third unidentified isomer) by 1H and 13C NMR,
showing coupling constants typical for a trans relation-
ship of the C2 and C3 substituents.
Even though the recovery rate needs to be improved,
the isomerization provides easy access to related tet-
rahydropyran-4-ones with different relative configura-
tion.
Another method to increase diversity of this strategy
is nucleophilic addition to the ketone function. As an
example, 27a was reacted with MeMgBr to afford a single
diastereomer of tertiary alcohol 47 (Scheme 7). The
excellent diastereoselectivity is presumably caused by the
adjacent axial methyl group, which makes equatorial
attack unfavorable.
Also in this case, the yields are not optimized. How-
ever, this reaction demonstrates that the described
tetrahydro-γ-pyrones can be easily and selectively modi-
fied by nucleophilic addition.
Yields (Table 2) and diasteromeric ratios (Table 3) of
the HDA products range from good to excellent. The
isolated tetrahydropyran-4-ones were typically mixtures
of the two isomers that have all-cis configuration of the
ring substituents. This was confirmed by NOE spectros-
copy for 33a (Figure 1, Supporting Information) and
1
based on analogy of H NMR coupling constants for the
other tetrahydropyran-4-ones 26-32 and 33b. Diaster-
eomeric ratios for compounds 26-33 were determined
from the amounts of the pure, isolated diastereomers and
are summarized in Table 3. Traces of a third diastere-
omer could be observed for 26, 27, and 33. Only the latter
could be separated from the â-isomers and probably is
the 2,6-trans-isomer with a downfield-shifted H-6.
It should be noted that compounds such as 26-33 (i.e.,
with a 2- or 6-alkenyl substituent) are not available
through the alternative HDA reaction, disconnecting at
the other side of the oxygen. In this case, the required
diene would be a conjugated triene, which does not react
properly in HDA reactions. Thus, the current method
provides access to a class of compounds that was previ-
ously inaccessible by related methods.
HDA reaction of diene 14 with ethyl glyoxylate under
various conditions, including Co(II) salen catalysis, has
been reported to afford not only both cis diastereomers,
but both trans isomers as well.27 These results suggest
Finally, quenching the HDA-products with other elec-
trophiles than protons provides a further possible expan-
sion. The Mukaiyama-type aldol reaction of the inter-
mediate TBS enol ether may be used to modify position
2822 J. Org. Chem., Vol. 70, No. 7, 2005

SCHEME 3. Assignment of the Induced Stereochemistrya
a Key: (a) K-Selectride, THF, -78 °C (100%, eq/ax ) 80:20); (b) PPTS, acetone/H2O 1:1, 58%.
SCHEME 4a
SCHEME 7. Functionalization at C-4a
a Key: (a) MeMgBr, THF (52%).
a Key: (a) TBSOTf, Et3N, Et2O; (b) R2CHO, BF3‚Et2O, Et2O;
as building blocks for polyketide type compounds because
they allow a differential coupling to the substituents of
the crucial 2-position and 6-position. Thus, the 2-alkenyl
group is suitable for further coupling via metathesis
reaction, whereas the 6-position principally can be pro-
vided with any type of connection handle, e.g., an alcohol
(f aldehyde or halide).
(c) AcOH, TBAF, THF.
SCHEME 5a
Experimental Section
General Procedure for HDA Reactions with Alkenals.
To a solution of a diene in Et2O the alkenal (1.5 equiv) was added
at -30 °C followed by BF3‚Et2O (1.5 equiv). The mixture was
stirred at -20 to -30 °C for 1.5-4 h, quenched by addition of
Et3N (3 equiv), diluted with water (50 mL), and extracted with
tBuOMe (3 × 35 mL). The combined organic fractions were
washed with brine (50 mL), dried (Na2SO4), filtered, and
concentrated in vacuo to give the crude HDA products which
were analyzed by 1H NMR for identity and diastereomeric ratio
of the products, and used in the next step without further
purification.
a Key: (a) TBSOTf, Et3N, Et2O; (b) RCHdCHCHO, BF3‚Et2O,
Et2O, -30 °C.
SCHEME 6. Epimerization at C-3a
For desilylation, to the TBS enol ethers in THF were added
acetic acid (2.5 equiv) and TBAF‚3H2O (1.5 equiv) at 0 °C. The
mixture was stirred at room temperature until the starting
material had been consumed (TLC). The mixture was diluted
with satd aq NaHCO3 solution (50 mL) and extracted with
tBuOMe (3 × 35 mL). The combined organic fractions were dried
(Na2SO4), filtered, concentrated in vacuo, and purified by flash
chromatography on silica.
a Key: (a) KOtBu, MeOH, 2 d (53%).
5. More details will be reported in a forthcoming publica-
tion.
Acknowledgment. We thank Dr. A. Porzel for
NOESY measurements and assistance in confirming
relative configurations. E.R. is thankful for financial
support from an EU grant (Combiocat) and HWP
support from the state of Saxony-Anhalt.
In conclusion, we described the synthesis of a diene
controlled asymmetric hetero-Diels-Alder reaction of R,â-
unsaturated aldehydes with full chemo- and regioselec-
tivity and good to excellent diastereoselectivity. The
presented method allows the stepwise introduction of
three substituents and a fourth one based on the enol
ether (position 5) or the 4-oxo group. It is therefore of
use for the construction of combinatorial libraries of 2,3,6-
substituted tetrahydro-γ-pyrones, 2,3,5,6-substituted tet-
rahydro-γ-pyrones, and the corresponding tetrahydropy-
ran-4-ol derivatives. The presented compounds can serve
Supporting Information Available: General experimen-
tal procedures and detailed experimental and characterization
data (1H and 13C NMR and HRMS) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0488311
J. Org. Chem, Vol. 70, No. 7, 2005 2823