A two-directional approach to a (-)-dictyostatin C11-C23 segment: Development of a highly diastereoselective, kinetically-controlled Meerwein-Ponndorf-Verley reduction

Article abstract of DOI:10.1021/ja077336u

A three-step synthesis of a precursor to the C11-C23 segment of (-)-dictyostatin is described. The sequence features a sonication-assisted, enantioselective double hetero Diels-Alder (HDA) reaction catalyzed by Jacobsen's Cr(III) Schiff base catalyst, followed by a novel, highly diastereoselective Meerwein-Ponndorf-Verley (MPV) reduction of the hydropyranone subunits under kinetic control to yield the bis-(axial alcohol) 4. Generalized studies of both the HDA and MPV methodologies are also described.

Full text of DOI:10.1021/ja077336u

Published on Web 11/30/2007
A Two-Directional Approach to a (-)-Dictyostatin C11-C23
Segment: Development of a Highly Diastereoselective,
Kinetically-Controlled Meerwein-Ponndorf-Verley Reduction
Andrew K. Dilger, Vijay Gopalsamuthiram, and Steven D. Burke*
Contribution from the Department of Chemistry, UniVersity of Wisconsin-Madison, 1101
UniVersity AVenue, Madison, Wisconsin 53706-1322
Received September 25, 2007; E-mail: burke@chem.wisc.edu
Abstract: A three-step synthesis of a precursor to the C11-C23 segment of (-)-dictyostatin is described.
The sequence features a sonication-assisted, enantioselective double hetero Diels-Alder (HDA) reaction
catalyzed by Jacobsen’s Cr(III) Schiff base catalyst, followed by a novel, highly diastereoselective Meerwein-
Ponndorf-Verley (MPV) reduction of the hydropyranone subunits under kinetic control to yield the bis-
(axial alcohol) 4. Generalized studies of both the HDA and MPV methodologies are also described.
Introduction
In the course of initiating a synthetic approach to the potent
anticancer agent (-)-dictyostatin,1 we found existing methodol-
ogy to be inadequate for two of the first three steps. Develop-
ment of an operational improvement in Jacobsen’s powerful
catalytic asymmetric hetero Diels-Alder method2 and discovery
of
a kinetic Meerwein-Ponndorf-Verley protocol for
selective reduction of hydropyran-4-ones to axial alcohols were
required. Illustration of the strategic incentive provided by the
dictyostatin C11-C23 segment and generalization of the
methodological developments beyond that context are detailed
herein.
(-)-Dictyostatin (1, Figure 1) was first isolated in 1994 by
Pettit and co-workers1 from a marine sponge Spongia sp. off
the coast of Maldives and later by Wright and co-workers3 from
Corralistidae sponges. It was subsequently found to act as an
efficient inhibitor of human cancer cell growth with GI50 values
ranging from 50 pM to 1 nM. In addition, it retains activity
against some taxol-resistant cell lines by stabilizing microtu-
bules. This mode of action is analogous to that of the potential
chemotherapeutic agent discodermolide, which is structurally
similar.4
Dictyostatin comprises a 22-membered macrolactone with 11
stereogenic centers, 10 of which are in common with disco-
dermolide. In addition, dictyostatin displays an endocyclic
2Z,4E-dienoate (C1-C5) and a Z-1,3-diene at C23. These
interesting structural features coupled with its attractive biologi-
cal profile have led to five total syntheses of dictyostatin5 as
well as significant synthetic efforts toward that end.6
Figure 1. Structure of (-)-dictyostatin.
Curran recently reported that a synthetic analogue, 16-
normethyldictyostatin, is a subnanomolar antiproliferative against
human ovarian carcinoma 1A9 cells, making it equipotent to
dictyostatin.7 This observation, in combination with recent
success in using a catalytic, enantioselective hetero Diels-Alder
reaction in the context of synthesizing the C20-C32 subunit
of the phorboxazoles,8 stimulated us to evaluate a synthetic
approach to both 16-normethyldictyostatin and the parent natural
product. We noted the possiblity of employing a two-directional
(5) (a) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K. G.
Angew. Chem., Int. Ed. 2004, 43, 4629-4633. (b) Shin, Y.; Fournier, J.
-H.; Fukui, Y.; Bru¨ckner, A. M.; Curran, D. P. Angew. Chem., Int. Ed.
2004, 43, 4634-4637. (c) Fukui, Y.; Bru¨ckner, A. M.; Shin, Y.; Balachan-
dran, R.; Day, B. W.; Curran, D. P. Org. Lett. 2006, 8, 301-304. (d) O’Neil,
G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340-5341. (e)
Ramachandran, P. V.; Srivastava, A.; Hazra, D. Org. Lett. 2007, 9, 157-
160.
(6) (a) O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253-4256.
(b) Kangani, C. O.; Bru¨ckner, A. M.; Curran, D. P. Org. Lett. 2005, 7,
379-382. (c) Prusov, E.; Ro¨hm, H.; Maier, M. E. Org. Lett. 2006, 8, 1025-
1028. (d) Ja¨gel, J.; Maier, M. E. Synlett 2006, 5, 693-696. (e) Sharon, O.;
Monti, C.; Gennari, C. Tetrahedron 2007, 63, 5873-5878. (f) Monti, C.;
Sharon, O.; Gennari, C. J. Chem. Soc., Chem. Commun. 2007, 4271-4273.
(g) Saibaba, V.; Sampath, A.; Mukkanti, K.; Iqbal, J.; Das, P. Synthesis
2007, 2797-2802.
(7) (a) Shin, Y.; Fournier, J.-H.; Balachandran, R.; Madiraju, C.; Raccor, B.
S.; Zhu, G.; Edler, M. C.; Hamel, E.; Day, B. W., Curran, D. P. Org. Lett.
2005, 7, 2873-2876. (b) Jung, W.-H.; Harrison, C.; Shin, Y.; Fournier,
J.-H.; Balachandran, R.; Raccor, B. S.; Sikorski, R. P.; Vogt, A.; Curran,
D. P.; Day, B. W. J. Med. Chem. 2007, 50, 2951-2966.
(8) (a) Lucas, B. S.; Luther, L. M.; Burke, S. D. J. Org. Chem. 2005, 70,
3757-3760. (b) Lucas, B. S.; Gopalsamuthiram, V.; Burke, S. D. Angew.
Chem., Int. Ed. 2007, 46, 769-772.
(1) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M. J. Chem.
Soc., Chem. Commun. 1994, 1111-1112.
(2) (a) Chavez, D. E.; Jacobsen, E. N. Org. Synth. 2005, 82, 34-39. (b)
Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 2398-2400.
(3) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.; Wright,
A. E. Biochem. Pharmacol. 2003, 66, 75.
(4) (a) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley, R. E.;
Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996, 35,
243-250. (b) For a review, see: Paterson, I.; Florence, G. J. Eur. J. Org.
Chem. 2003, 12, 2193-2208.
9
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J. AM. CHEM. SOC. 2007, 129, 16273-16277
16273

A R T I C L E S
Dilger et al.
Scheme 1. Retrosynthesis of the C11-C23 Segment Precursor
Figure 3. Elimination byproducts.
presence of 4 mol % of Cr(III)-catalyst 6a afforded a complex
mixture of products in variable yields. The standard conditions
for this type of transformation involve a combination of aldehyde
and diene neat, in the presence of powdered 4 Å molecular
sieves, and the heterogeneous catalyst 6a.2 In this case, the
dialdehyde 3 and diene 2 are only partially miscible, and the
viscosity and heterogeneity of the reaction made efficient mixing
and product formation monitoring difficult. The reaction was
sluggish (>12 h, 45 °C), and attempts to achieve high
conversion via elevated temperatures or longer reaction times
led to decomposition of desired bis(cycloadduct) 5, leading to
significant amounts of elimination byproducts 7 and 8 (Figure
3). We thus sought to modify the reaction conditions described
by Jacobsen.2
The physical effects of sonication12 on heterogeneous reac-
tions have been of recent interest.13 Ultrasonic agitation provides
thermal and pressure effects due to cavitation. Performing the
asymmetric double HDA reaction between 2 and 3 in an
ultrasonic cleaning bath for 1 h at room temperature resulted
in a significant improvement in rate, yield, and product purity
(Scheme 2). It was not necessary to isolate and purify the Diels-
Alder adduct 5; immediate treatment with aqueous HF buffered
in pyridine effected axial protonation of the silyl enol ether
moieties and established the C12 and C22 equatorial methyl
groups in the diketone 9, which was obtained in 66% overall
yield from 2 and 3.14,15
strategy9 for the C11-C23 subunit of dictyostatin and 16-
normethyldictyostatin via C2-symmetric intermediates upon
imposing local symmetry by modifying C15 and C16 (Scheme
1). If a hydroxyl group is temporarily installed at C15 with (R)-
configuration and the C16 methyl group is removed, the resultant
region from C11-C23 exhibits C2-symmetry about C17. In
addition to its role in conferring symmetry to the C11-C23
subunit, the imposed oxygen functionality could also be used
to install the C16 methyl group. Furthermore, we envisioned
the stereotetrads10 at C12-C15 and C22-C19 in 4 to be readily
obtainable via an asymmetric double hetero Diels-Alder (HDA)
reaction between 2 equiv of Danishefsky’s diene (2)11 and
glutaraldehyde (3) under the influence of Jacobsen’s Cr(III)
Schiff base complex2 (6a, Figure 2). Axial protonations of bis-
(silyl enol ether) 5 at C12 and C22 followed by unprecedented
carbonyl reduction (Vide infra) at C13 and C21 would afford
diaxial diol 4. Masked aldehydes at C11 and C23 in 4 are suited
for eventual olefinations.
For the desired stereochemistry at C13 and C21, both
hydroxyls must be oriented axially. Original results by Dan-
ishefsky14 suggested that bulky reducing reagents such as
L-selectride16 cease to favor equatorial hydride delivery in
tetrahydro-4-pyranone systems such as 9 when the anomeric
methoxy substituent is oriented equatorially. This result was
rationalized by the Cieplak model,17,18 although the reason for
this result remains under debate.
In addition, synthetic efforts toward the axial alcohol 4-pyra-
nol-containing natural products ratjadone A,19 sorangicin A,20
and lasonolide A21 have faced difficulty in efficiently reducing
the corresponding tetrahydropyran-4-one to the axial diastere-
(12) Lee, J.; Snyder, J. K. J. Am. Chem. Soc. 1989, 111, 1522-1524.
(13) (a) Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S. Synthesis
2003, 1286-1291. (b) Avalos, M.; Babiano, R.; Cabello, N.; Cintas, P.;
Hursthouse, M. B.; Jime´nez, J. L.; Light, M. E.; Palacios, J. C. J. Org.
Chem. 2003, 68, 7193-7203. (c) Kegelaers, Y.; Eulaerts, O.; Reisse, J.;
Segebarth, N. Eur. J. Org. Chem. 2001, 3683-3688.
(14) Danishefsky, S. J.; Langer, M. E. J. Org. Chem. 1985, 50, 3672-3674.
(15) Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-268.
(16) (a) Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159-
7161. (b) Brown, H. C.; Krishnamurthy, S. Aldrichimica Acta 1979, 12, 3.
(17) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540-4552.
(18) For reviews, see: (a) Gung, B. W. Tetrahedron 1996, 52, 5263-5301. (b)
Cieplak, A. S. Chem. ReV. 1999, 99, 1265-1336.
(19) Cossey, K. N.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 12216-12217.
(20) Smith, A. B., III; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099-
3102.
(21) Ghosh, A. K.; Gong, G. Org. Lett. 2007, 9, 1437-1440.
Figure 2. Jacobsen hetero Diels-Alder catalysts.
Results and Discussion
Initiation of the synthetic sequence by enantioselective double
HDA immediately revealed a problem. Reaction of 2 equiv of
Danishefsky’s siloxy diene9 2 with glutaraldehyde (3) in the
(9) (a) Keller, V. A.; Kim, I.; Burke, S. D. Org. Lett. 2005, 7, 737-740. (b)
Magnuson, S. R.; Tetrahedron 1995, 51, 2167-2213. (c) Poss, C. S.;
Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17.
(10) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677-690.
(11) (a) Danishefsky, S. J.; Harvey, D. F. J. Am. Chem. Soc. 1985, 107, 6647-
6652. (b) Myles, D. C.; Bigham, M. H. Org. Synth. 1992, 70, 231-236.
9
16274 J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007

Precursor to (−)-Dictyostatin C11−C23 Segment
A R T I C L E S
Scheme 2. Synthesis of the C11-C23 Subunit
Several conditions were screened to optimize for the produc-
tion of bis(axial alcohol) 4 (Table 1). The MPV reagents were
preformed by adding the alcohol hydride donor to a solution of
the aluminum source at 0 °C and stirring for 1 h at room
temperature, followed by addition of diketone 9. Using condi-
tions analogous to those of Snaith,24a the MPV reagent derived
from DIBAL-H and isopropanol proved disappointing, affording
desired diaxial alcohol 4 (25%) and the undesired diastereomers
10 (45%) and 11 (23%) as shown in Table 1 (entry 1). This
low level of selectivity was changed only modestly with
i-PrOAl(i-Bu)2 in toluene, but use of diphenylmethanol (ben-
zhydrol) as the hydride source gave an enhanced yield ratio of
40:14:3 for 4/10/11, substantially favoring the diaxial diol 4.
Optimal conditions utilized tris(diphenylmethoxy)aluminum,
preformed from 12 equiv of benzhydrol and 4 equiv of AlMe3
in dichloromethane at 0 °C. Crystalline diaxial diol 4 was
produced in 73% yield, with 12% of the axial, equatorial
diastereomer and no observable formation of bis(equatorial) diol
11. Prolonged reaction times did not increase the yields or
change the ratio of 10 and 11, suggesting that this reaction is
kinetically controlled. This conclusion is further supported by
two additional experiments. Resubjection of bis(equatorial) diol
11 to the reaction conditions (AlMe3, benzophenone, CH2Cl2)
slowly yields diketone 9 and diols 4 and 10, whereas resub-
jection of bis(axial) diol 4 only yields diketone 9, 4, and minor
amounts of half-oxidized (monoketone) material.
An X-ray crystal structure of 4 (Figure 4) was obtained to
confirm the relative stereochemistry generated in the double
hetero Diels-Alder reaction, the enol ether protonations, and
the MPV reductions. In addition, the enantiomeric purity of 4
was very high26 as a consequence of two enantioselective hetero
Diels-Alder reactions on a single substrate, illustrating the
Horeau principle or the Eliel effect.9c,27,28
With optimized conditions in-hand for the production of 4,
the generality of these methods was evaluated by preparing and
reducing a variety of monocyclic tetrahydropyran-4-ones. Reac-
tions of the highly activated siloxy diene 2a (Table 2) proceeded
smoothly at room temperature under the influence of Jacobsen
catalyst 6a. Notably, the electron-rich p-anisaldehyde (entry c)
reacted to completion in 19 h using sonication, whereas after 5
days of stirring at room temperature the reaction had still not
reached completion. All other aldehydes reacted to completion
with diene 2a in 5 h or less. The less activated diene 2b required
a longer reaction time even in the presence of the more active
Jacobsen catalyst 6b. These reactions were complete in 19-27
h, a slight improvement over previously reported results.2b
Entries e and h-j were aimed at systematically determining
the effect of various steric requirements about the carbonyl as
well as the nature of the R2 substituent on the diastereoselectivity
of the MPV reduction.29
omer. In all cases, extensive screening of reduction conditions
led to equimolar quantities of axial and equatorial diastereomers,
or worse.
This precedent presented us with the challenge to find a
general method for accessing axial alcohols upon reduction of
variously substituted hydropyran-4-ones. Thus, we explored
methods of directly accessing the bis(axial alcohol) 4. As
expected, use of L-selectride failed, yielding a complex mixture
of products, none of which was the desired diaxial diol. With
no reason to expect equatorial hydride delivery using other
aluminum hydrides or borohydrides, a mechanistically distinc-
tive solution was sought. Our attention was drawn to the
Meerwein-Ponndorf-Verley reduction22,23 after recent reports
of its use in highly diastereoselective transformations.24 In
particular, recent observations24a on the effect of solvent on
axial/equatorial alcohol ratios in MPV reductions of substituted
cyclohexanones with i-PrOAl(i-Bu)2 were intriguing, with
CH2Cl2 notably favoring axial alcohol formation.
Traditionally, the MPV reduction is an equilibrium process,
yielding the thermodynamically more stable equatorial alcohol
product from six-membered cyclic ketones. However, we felt
that design of a kinetically controlled reaction in which
equatorial hydride delivery was favored by a very bulky hydride
donor and reversibility was disfavored by slow aluminum
alkoxide exchange might allow efficient access to 4. Excess
bulky MPV reagent and a hydride donor that afforded a ketone
with a low reduction potential25 were also incorporated as
reaction design elements to disfavor equilibration.
The Meerwein-Ponndorf-Verley reductions proceeded with
good to excellent stereoselectivities (Table 3). Diastereoselec-
tivities as high as 14:1 can be obtained regardless of the nature
(22) (a) Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 444, 221.
(b) Ponndorf, W. Angew. Chem. 1926, 39, 138. (c) Verley, M. Bull. Soc.
Chim. Fr. 1925, 37, 871.
(26) The enantiomeric ratio was determined by chiral HPLC to be >200:1 by
synthesizing the bis(PMB ethers) 12 and ent-12 from 4 and ent-4 and
injecting against a mixture of both enantiomers on a Chiralcel OD-H
column.
(27) (a) Kogure, T.; Eliel, E. L. J. Org. Chem. 1984, 49, 576-578.
(28) Rautenstrauch, V. Bull. Soc. Chim. Fr. 1994, 131, 515-524.
(29) A lack of stereocontrol over the silyl enol ether geometry in diene 2c (entry
i, Table 1) and lack of regiocontrol for the formation of diene 2d resulted
in low yields of 13i and 13j, although sufficient quantities were generated
for use in evaluating the subsequent kinetic MPV reductions.
(23) For a review, see: (a) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.;
Huskens, J. Synthesis 1994, 1007-1017. (b) Nishide, K.; Node, M. Chirality
2002, 14, 759-767.
(24) (a) Bahia, P. S.; Jones, M. A.; Snaith, J. S. J. Org. Chem. 2004, 69, 9289-
9291. (b) Yin, J.; Huffman, M. A.; Conrad, K. M.; Armstrong, J. D., III.
J. Org. Chem. 2006, 71, 840-843.
(25) Adkins, H.; Cox, F. W. J. Am. Chem. Soc. 1938, 60, 1151-1159.
9
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A R T I C L E S
Dilger et al.
Table 1. Examination of MPV Reductions on Diketone 9
entry
Al source
R1
R2
solvent
% yield 4
% yield 10
% yield 11
1a
DIBAL-H
DIBAL-H
DIBAL-H
AlMe3
i-Pr
i-Pr
CH(Ph)2
CH(Ph)2
i-Bu
i-Bu
i-Bu
OCH(Ph)2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
25
33
40
73
45
25
14
12
23
24
3
2a
3a,b
4b,c
0
b
a Reactions were carried out using 4 equiv of DIBAL-H and 4 equiv of the alcohol. Minor amounts of half-reacted (mono-axial alcohol, mono-ketone)
c
material were also observed. 4 equiv of AlMe3 and 12 equiv of benzhydrol were used.
Table 2. Study of Sonicated Hetero Diels-Alder Reactions
entry
diene
R1
R2
R3
catalyst
time (h)
% 13
a
b
c
d
e
f
g
h
i
2a
2a
2a
2a
2a
2b
2b
2b
2c
2d
Ph
OMe Me
6a
6a
6a
6a
6a
6b
6b
6b
6a
6b
3
5
19
3.5
4
19
27
22
3
69
79
64
63
73
66
60
82
nd
nd
(CH2)2OPMB OMe Me
PMPa
OMe Me
OMe Me
OMe Me
CH2PH
2-furyl
Ph
(CH2)2Ph
2-furyl
2-furyl
2-furyl
Me
H
Figure 4. X-ray crystal structure and line drawing of diol 4.
Me
H
Me
H
OMe
Me
H
Me
of the R2 substituent, suggesting steric effects are controlling,
rather than stereoelectronic effects.14,17,18 These results illustrate
the generality of this method and suggest that it will be useful
in other natural product syntheses.
j
12
a PMP ) p-methoxyphenyl.
than the axial diastereomers. Furthermore, these calculations
also suggest that the energy differences parallel the observed
stereoselectivities. The equatorial alkoxide of 15e is ∼8.7 kcal/
mol less stable than that of 14e, the alcohols being obtained in
a 12:1 ratio in favor of the 14e. Alcohols 14g and 15g are,
however, closer in energy. These alcohols are isolated in a 1.7:1
ratio of axial to equatorial alcohols.
Qualitatively evaluating the structures of the transition states
(Figure 6) leading to equatorial and axial aluminum alkoxides
also provides evidence for this proposal. TS1 depicts axial
The observed stereoselectivity can be explained on the basis
of several contributing factors. The requirement in an MPV
reduction that complexation and hydride transfer occur simul-
taneously in a six-membered transition state suggests that this
transition state would be late and productlike.30 This should
allow for a correlation of the structure and energy of the
intermediate aluminum alkoxides resulting from axial versus
equatorial hydride delivery and the corresponding transition
states. We have thus concluded that this MPV reduction
proceeds with product development control and that its stere-
ochemical course is driven by the stability of the aluminum
alkoxide species rather than the product alcohols. Molecular
mechanics calculations using Gaussian at the PM3 level of
theory on energy-minimized structures of the corresponding
aluminum alkoxides of 14/15e and g (14/15e* and g*, Figure
5) reveals that the equatorial aluminum alkoxides are less stable
(30) Gerlt, J. A.; Gassman, P. G. J. Am. Chem. Soc. 1993, 115, 11552-11568.
Figure 5. Aluminum alkoxides for molecular modeling calculations.
9
16276 J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007

Precursor to (−)-Dictyostatin C11−C23 Segment
A R T I C L E S
13 to axial alcohols with a variety of substituents equatorially
oriented at the C2 and C6 positions. This represents a general
solution to a problem which has hampered the otherwise
attractiveuseoftheHDAreactioninpolypropionatesynthesis.10,11a,14
Experimental Methods
General Procedure for Hetero Diels-Alder Reactions: Ketone
13b: To a 250 mL round-bottom flask were added diene 2a (2.94 g,
14.70 mmol, 1.2 equiv), aldehyde (2.38 g, 12.25 mmol, 1 equiv),
Jacobsen catalyst 6a (0.119 g, 0.245 mmol, 0.02 equiv), and powdered
4 Å molecular sieves (1.23 g, 100 mg/mmol aldehyde). The mixture
was sonicated for 5 h (see Supporting Information), keeping the
sonicator bath water at room temperature. To 150 mL of a 1:1 mixture
of methanol-pyridine was added 50% aqueous HF (2 equiv). This
mixture was cooled in a methanol/ice bath (-15 °C). The hetero Diels-
Alder adduct was dissolved in methanol (10 mL) and slowly added to
the HF/pyridine. Upon completion as determined by TLC, saturated
aqueous NaHCO3 (100 mL) was added and then solid Na2CO3 (2 g).
The mixture was diluted with ether (500 mL), and the layers were
separated. The aqueous layer was saturated with NaCl and extracted
with ether (3 × 150 mL). The combined organic layers were washed
with saturated CuSO4, dried (MgSO4), and concentrated. Flash column
chromatography (hexanes-ether) yielded 3.11 g (79%) of pure 4-pyra-
none (13b).
General Procedure for Meerwein-Ponndorf-Verley Reductions
of Tetrahydropyran-4-ones 13a-j: To a clean and dry round-bottom
flask was added benzhydrol (9 equiv) under an atmosphere of nitrogen
and dissolved in dichloromethane (0.25 M). The resulting solution was
cooled to 0 °C, and trimethylaluminum [2 M in toluene, 3 equiv] was
added dropwise via a syringe. The reaction was continued at room
temperature for 1 h at which time visible evolution of methane had
subsided, leading to the formation of tris(benzhydryloxyalane). The
ketone 13 (1 equiv) was then added either neat or as a solution in
dichloromethane into the above flask so that the overall concentration
was 0.07 M, and the progress of the reaction was monitored by TLC
for completion. The reaction was quenched with 2 N hydrochloric acid
(until aqueous solution was acidic) and extracted with anhydrous ether
(100 mL × 2). Drying the organic layer over anhydrous sodium sulfate
was followed by evaporation of the solvent under reduced pressure to
afford the crude product which was purified by silica-gel chromatog-
raphy to give the axial alcohol 14 and the equatorial alcohol 15.
Figure 6. Transition state drawings leading to equatorial and axial alcohols.
Table 3. Results of MPV Reductions
entry
R1
R2
R3
% 14
% 15
ax/eq
a
b
c
d
e
f
g
h
i
Ph
OMe
OMe
OMe
OMe
OMe
Me
Me
Me
OMe
Me
Me
Me
Me
Me
Me
H
H
H
H
Me
76
71
78
65
69
55
61
73
79
79
16
18
18
6.5
5.7
19
36
14
6
4.2:1
3.9:1
4.3:1
10:1
12:1
2.7:1
1.7:1
5.2:1
13:1
14:1
(CH2)2OPMB
PMP
CH2PH
2-furyl
Ph
(CH2)2Ph
2-furyl
2-furyl
2-furyl
j
6
hydride delivery, leading to equatorial aluminum alkoxides, and
TS2 shows the transition state leading to axial aluminum
alkoxides. Significant flattening of substituted pyrans relative
to cyclohexanes causes a near-eclipsing interaction between the
equatorial aluminum alkoxide and the flanking equatorial
substituents (H or Me). In addition, TS1 encounters severe steric
interactions between the two axial hydrogens flanking the ring
oxygen and the phenyl rings of the benzhydryloxy group
delivering the hydride. No such interaction exists in TS2,
suggesting a reason for the significant preferences for axial
alcohol production. The reaction is then rendered slow to reverse
by virtue of the formation of benzophenone, which is known
to undergo slow MPV reduction,25 thereby preventing deteriora-
tion of the axial/equatorial product ratio.
Acknowledgment. We gratefully acknowledge Dr. Ilia Guzei
for elucidation of the X-ray crystal structure of 4 and NIH Grants
CA74394 and CA108488 for generous support. The NSF (CHE-
0342998, CHE-9629688, and CHE-8813550) and the NIH (1
S10 RR04981-01) are acknowleged for support of the NMR
facilities at the University of Wisconsin-Madison Department
of Chemistry. We thank Mr. Xin Wei (UW-Madison) for initial
experiments in this study, Mr. Grant Geske (UW-Madison)
for performing calculations on the aluminum alkoxides of 14/
15e* and g*, and Dr. Brian S. Lucas for advice.
Conclusion
In summary, a high-yielding, three-step synthesis of a C11-
C23 segment 4, applicable to (-)-dictyostatin and (-)-16-
normethyldictyostatin, has been developed. The sequence of a
double enantioselective hetero Diels-Alder reaction, axial-
selective silyl enol ether protonations, and kinetically controlled
axial-selective Meerwein-Ponndorf-Verley reductions ef-
ficiently installs 10 stereogenic centers, including those at C12,
C13, C14, C19, C20, C21, and C22 present in (-)-dictyostatin.
Studies directed at desymmetrization and elaboration of this C2-
symmetric intermediate are currently in progress. The newly
developed MPV reagent tris(diphenylmethoxy)aluminum allows
for a general method of efficiently reducing hydropyran-4-ones
Supporting Information Available: Experimental procedures
and spectroscopic data for compounds 4 and 9-15, chiral HPLC
traces of 12 and ent-12, and .cif file for 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA077336U
9
J. AM. CHEM. SOC. VOL. 129, NO. 51, 2007 16277