A new construction of 2-alkoxypyrans by an acylation-reductive cyclization sequence

Article abstract of DOI:10.1021/ol070573h

A new convergent synthetic approach to a pyran motif common to many naturally occurring structures is described. In this approach, two fragments are joined by esterification, and a subsequent intramolecular reductive cyclization affords the 2-hydroxypyran.

Full text of DOI:10.1021/ol070573h

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1951-1954
A New Construction of 2-Alkoxypyrans
by an Acylation
Sequence
−Reductive Cyclization
Lars V. Heumann and Gary E. Keck*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received March 7, 2007
ABSTRACT
A new convergent synthetic approach to a pyran motif common to many naturally occurring structures is described. In this approach, two
fragments are joined by esterification, and a subsequent intramolecular reductive cyclization affords the 2-hydroxypyran.
Certain structural elements are often found as recurring
themes in a variety of natural products. One such motif is
represented by substituted 2-hydroxypyrans, which are found
in a large number of biologically relevant molecules. Two
examples of recent interest would include bryostatin 1 (1)1-3
and acutiphycin (2) (Figure 1).4
Of the methods available to access such pyrans, two are
most commonly employed (Scheme 1). The first of these
begins with the synthesis of a lactone, which is then subjected
to a nucleophilic addition reaction with a carbanion.5 The
second, and most common, method exploits the ease of
cyclization of 1,5-hydroxyketones.3e,g,h Both techniques have
successfully been utilized in natural product synthesis; their
execution, nonetheless, must be carefully synchronized with
the overall synthetic strategy. In most cases, hydroxypyran
structures are “stored” as mixed ketals (2-methoxypyrans)
during other synthetic steps.
Because of our interest in such structures, we have been
led to investigate a new procedure that addresses the
asymmetric synthesis of these pyrans by an inherently
convergent strategy (Scheme 2). In this approach, we chose
an initial disconnection of the desired 2-hydroxypyran 3
between C2 and C3. This somewhat unusual disconnection
(1) For a recent review see: Hale, K. J.; Hummersone, M. G.;
Manaviazar, S.; Frigerio, M. Nat. Prod. Rep. 2002, 19, 413 and references
cited therein.
(2) (a) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.; Nishiyama, S.;
Yamamura, S. Angew. Chem., Int. Ed. 2000, 39, 2290. (b) Evans, D. A.;
Carter, P. H.; Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc.
1999, 121, 7540. (c) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J.
C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990,
112, 7407.
Figure 1. Structures of bryostatin and acutiphycin.
10.1021/ol070573h CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/12/2007

hydrocinnamaldehyde, was acylated with propionyl chloride
to provide ester 10 (Table 1). Initial attempts to effect the
desired reductive cyclization reaction by using magnesium
as the reductant resulted in low yields of the cyclization
product along with considerable amounts of recovered
starting material. Attempts to improve the yield by replacing
magnesium with SmI2 (either alone or in the presence of
catalytic amounts of NiI2 and HMPA as additives) were not
successful.6,7
Scheme 1. Typical Lactol Syntheses
gives rise to an ester intermediate 5, which can be obtained
by acylation of alcohol 7 with an acid 6. This approach offers
the advantage of making the subsequent C-C coupling
reaction intramolecular. The alcohol 7 can in principle be
prepared in a number of ways, but the preparation of this
intermediate by the reaction of aldehyde 8 with allylstannane
9 is particularly direct.
Table 1. Conditions for Reductive Cyclizations
compda
reductant
solvent
Et2O
temp, °C
rt
yield,b %
10
10
10
10
10
11
11
11
11
Mg
Mg
11
rt to reflux NR
THF
THF
SmI2
rt
rt
NR
NR
NR
54
Scheme 2. Retrosynthetic Approach
SmI2/cat.NiI2 THF
SmI2/cat.NiI2 THF/HMPA rt
Mg
In
t-BuLi
SmI2
Et2O
THF
THF
THF
rt
rt
-78
0
complex mixture
33
quant
a In some cases the racemic ester was used. b In some cases a mixture
of the two anomers was obtained.
The detection of some pyran product together with the
isolation of unreacted starting material, however, led us to
examine the use of the corresponding iodide 11 in this
reaction. By using magnesium as the reducing agent, the
pyran was obtained in higher yield, but as before the reaction
was incomplete.8 Use of indium resulted in the formation of
a complex reaction mixture. Metal halogen exchange with
tert-butyllithium also afforded some of the pyran. However,
SmI2 was found to be the reagent of choice, as this provided
pyran 12 from iodide 11 in near quantitative yield.
The initial work on substrates 10 and 11 also allowed us
to obtain some information about the properties of these
pyrans. After the cyclization of iodide 11, the 2-hydroxypyran
was isolated after chromatography on silica gel but with a
considerable loss of material. However, workup and subse-
quent methanolysis of the initial cyclization product prior
to purification by chromatography afforded the corresponding
2-methoxypyran 12 in excellent yield. Hence, the 2-meth-
oxypyrans became our derivative of choice for product
isolation and purification. Interestingly, simple addition of
an excess of methanol or trimethyl orthoformate to the
reaction mixture after the SmI2-mediated cyclization was
Thus the initial reaction in this sequence takes advantage
of an earlier development from our laboratory. Addition of
tributyl(2-chloromethyl)allylstannane 9 to aldehydes 8 with
the BINOL/Ti(OiPr)4 (BITIP) catalytic asymmetric allylation
(CAA) protocol has previously been shown to produce
homoallylic alcohols 7 in high yield and with excellent
enantioselectivity.3e It was our intent to now utilize the allylic
chloride as a precursor to a carbanion intermediate 4, after
acylation of the homoallylic alcohol moiety in 7.
As a starting point of our investigation, the homoallylic
alcohol, prepared via CAA reaction between stannane 9 and
(3) For additional recent synthetic work in this area, see: (a) Trost, B.
M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S. J. Am. Chem.
Soc. 2007, 129, 2206. (b) Keck, G. E.; Welch, D. S.; Poudel, Y. B.
Tetrahedron Lett. 2006, 47, 8267. (c) Keck, G. E.; Welch, D. S.; Vivian,
P. K. Org. Lett. 2006, 8, 3667. (d) Ball, M.; Bradshaw, B. J.; Dumeunier,
R.; Gregson, T. J.; MacCormick, S.; Omori, H.; Thomas, E. J. Tetrahedron
Lett. 2006, 47, 2223. (e) Keck, G. E.; Yu, T.; McLaws, M. D. J. Org. Chem.
2005, 70, 2543. (f) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D.
Org. Lett. 2004, 6, 4045. (g) Voight, E. A.; Roethle, P. A.; Burke, S. D. J.
Org. Chem. 2004, 69, 4534. (h) Ball, M.; Baron, A.; Bradshaw, B.; Omori,
H.; MacCormick, S.; Thomas, E. J. Tetrahedron Lett. 2004, 45, 8737. (i)
Hale, K. J.; Frigerio, M.; Hummersone, M. G.; Manaviazar, S. Org. Lett.
2003, 5, 503. (j) Hale, K. J.; Frigerio, M.; Manaviazar, S.; Hummersone,
M. G.; Fillingham, I. J.; Barsukov, I. G.; Damblon, C. F.; Gescher, A.;
Roberts, G. C. K. Org. Lett. 2003, 5, 499 and references cited therein.
(4) (a) Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106.
(b) Kiyooka, S.-i.; Hena, M. A. J. Org. Chem. 1999, 64, 5511. (c) Smith,
A. B., III; Chen, S. S. Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A.
J. Am. Chem. Soc. 1997, 119, 10935. (d) Barchi, J. J.; Moore, R. E.;
Patterson, G. M. L. J. Am. Chem. Soc. 1984, 106, 8193.
(6) (a) Machrouhi, F.; Hamann, B.; Namy, J.-L.; Kagan, H. B. Synlett
1996, 633. (b) Inanaga, J; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485.
(7) For an isolated example of a related cyclization using an unfunc-
tionalized saturated alkyl iodide, see: Kawamura, K.; Hinou, H.; Matsuo,
G.; Nakata, T. Tetrahedron Lett. 2003, 44, 5259.
(8) Since the reaction could be driven by steady addition of portions of
dibromoethane, we attribute the low yields to a combination of a lack of
adequate reactivity of the allyl chloride and surface activation of the
magnesium; the reaction scale was 0.36 mmol of starting chloride.
(5) Smith, A. B., III; Razler, T. M.; Meis, R. M.; Pettit, G. R. Org. Lett.
2006, 8, 797.
1952
Org. Lett., Vol. 9, No. 10, 2007

Table 2. Isolated Yields for CAA Reactions, Esterifications, and SmI2-Promoted Cyclizations
a The corresponding acid chloride was used. b A mixture of the R- and â-anomer was isolated. c A mixture of the R- and â-anomer was obtained and the
anomers were isolated separately as pure compounds.
complete did not afford any of the desired 2-methoxypyran;
addition of CSA to this mixture also did not have any
observable effect.
for an R,â-unsaturated ester substrate, it is not clear whether
the cyclization or methanolysis step was compromised (Table
2, entry 6). Nonetheless, the yield in this case was still
preparatively useful.
Table 2 summarizes the assembly of several representative
2-methoxypyrans using this sequence. The initial CAA
proceeded in high yield and with excellent er in all cases
examined. The cyclization precursors were then obtained
from the chiral alcohols through a simple esterification. The
iodides proved accessible in essentially quantitative yield
through a Finkelstein reaction. The details of these reactions
for each case are provided in the Supporting Information. It
is worthy of note that the allylic iodides proved to be
surprisingly stable. Generally, the pyran products were also
stable and could be stored at -20 °C neat or in solution
without noticeable decomposition for several months. How-
ever, we also found that some batches of CDCl3 used as an
NMR solvent led to decomposition of the 2-methoxypyrans.
Therefore, CDCl3 was filtered through a small plug of
alumina prior to use.
As can be seen from Table 2 the cyclization yields are
uniformly high, near quantitative in most cases. Aliphatic
as well as aromatic substituents are tolerated for the alcohol
segment (R1). This is also the case for the carbonyl portion
(R2). In addition, the cyclization proceeded without elimina-
tion for substrates with benzyl ethers â to the carbonyl (Table
2, entries 3 and 8) and without epimerization for a substrate
with an R-stereocenter (Table 2, entry 2). The sterically
demanding tert-butyl substituent did not interfere with the
addition into the ester carbonyl during the cyclization (Table
2, entry 4). Although a significant drop in yield was observed
The formation of the R-isomer (axial methyl ether) is
generally preferred during the methanolysis. In some cases
both isomers were obtained and the product was isolated as
a mixture. The 2-methoxypyrans in entries 5 and 9 represent
exceptions (Table 2): while both anomers were formed, the
Rf values were sufficiently different to allow for the isolation
and identification of the individual diastereomers.
To put our approach to these functionalized pyrans into
perspective with respect to possible applications, we decided
to investigate these conditions in the context of our ongoing
bryostatin analogue studies9 and also to investigate the
application of this methodology in the construction of a
macrocycle with an embedded pyran.
A simplified version of the bryostatin AB ring system was
accessed by using a combination of the pyran annulation
protocol developed earlier in our laboratory9c in tandem with
the procedure described in this paper (Scheme 3). Thus, pyran
16 was synthesized in two steps starting with a CAA between
aldehyde 13 and reagent 14, which was followed by an
annulation with aldehyde 15.9c Deprotection of the silyl ether
and a two-step oxidation sequence provided acid 17.9b,c
Alcohol 18 was obtained as described above through a CAA
(9) (a) Keck, G. E.; Truong, A. P. Org. Lett. 2005, 7, 2149. (b) Keck,
G. E.; Truong, A. P. Org. Lett. 2005, 7, 2153. (c) Keck, G. E.; Covel, J.
A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189.
Org. Lett., Vol. 9, No. 10, 2007
1953

Scheme 3. Synthesis of the Simplified Bryostatin AB Ring
Scheme 4. Synthesis of a Macrocyclic 2-Methoxypyran
System
of the intermediate iodide with SmI2 followed by metha-
nolysis provided the bicyclic compound 24, again as a single
isomer. It should be noted that, contrary to what might have
been anticipated in this reaction sequence, the allylic chloride
survives a number of conditions and procedures without
incident.
In summary we have developed a versatile new method
for the convergent assembly of chiral 2-methoxypyrans. This
methodology offers an attractive alternative strategy to those
presently available. In this context, it should be noted that,
of the two bond-forming reactions required, fragment as-
sembly is achieved by bimolecular esterification (C-O bond
formation), while the reductive C-C bond-forming event is
intramolecular. This is an important strategic advantage, as
methodologies for bimolecular esterification reactions are
well developed and highly reliable. The subsequent intra-
molecular reductive cyclization reaction has been shown (this
work) to also be quite reliable and high yielding. Use of the
allylic iodide incorporates a malleable and flexible functional
group in the product where required for structures of
polyacetate or propionate origin, such as those in 1 and 2.
Thus the overall approach provides an expeditious assembly
of such pyrans.
reaction between aldehyde 15 and the chloromethylallyl-
stannane reagent 9. An esterification between acid 17 and
alcohol 18 with EDCI provided the substrate for reductive
cyclization, ester 19. Following the new protocol, the chloride
was exchanged for an iodide, using NaI in acetone. Reductive
cyclization of the iodide by reaction with SmI2 in THF at 0
°C followed by methanolysis provided the bryostatin AB ring
segment analogue 20 as a single diastereomer, in 91%
isolated yield from chloroester 19.
An example of this SmI2-mediated cyclization in the
context of a macrocycle is provided (Scheme 4). Aldehyde
21 was accessed from ω-hydroxy hexadecanoic acid in two
steps.10 Addition of reagent 9 under BITIP catalysis and
subsequent silylation of the alcohol afforded compound 22.
Hydrolysis of the thiol ester11 and desilylation12 gave the
seco-acid which was transformed into macrocycle 23 in
excellent yield following a carefully modified Yamaguchi
procedure.13,14 Following the standard protocol, the chloride
was exchanged for an iodide, using NaI in acetone. Treatment
Supporting Information Available: Full experimental
details as well as spectral and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(10) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(11) Evans, D. A.; Wu, L. D.; Wiener, J. J. M.; Johnson, J. S.; Ripin, D.
H. B.; Tedrow, J. S. J. Org. Chem. 1999, 64, 6411.
OL070573H
(12) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(13) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 72, 1989. (b) Hikota, M.; Tone, H.; Horita,
K.; Yonemitsu, O. Tetrahedron 1990, 46, 4613.
(14) This macrolactonization procedure has been thoroughly optimized
and care has also been taken to document the reproducibility of the yield
for this reaction.
1954
Org. Lett., Vol. 9, No. 10, 2007