A triple-aldol cascade reaction for the rapid assembly of polyketides

Article abstract of DOI:10.1002/anie.200907076

(Figure Presented) Triple play: The title reaction of 1 with simple aldehydes gives 3,5,7-trisilyloxy aldehydes in high yields and diastereoselectivities with extremely low catalyst loading (see scheme). lodobenzene facil-itates the third aldol reaction by apparently acting as a Lewis base towards the silyl catalyst. Tf=trifluoromethanesulfonyl.

Full text of DOI:10.1002/anie.200907076

Angewandte
Chemie
DOI: 10.1002/anie.200907076
Cascade Reactions
A Triple-Aldol Cascade Reaction for the Rapid Assembly of
Polyketides**
Brian J. Albert and Hisashi Yamamoto*
Polyketides have long provided synthetic organic chemists
with a variety of complex architectures to construct and
develop new chemical tools for, and provided medicine with,
many useful drugs. About 1% of polyketides display drug
activity, which is five times the average for natural products.[1]
A common strategy in the synthesis of polyketides is the
cross-aldol reaction, although it can be complicated by
uncontrolled oligomerization and dehydration reactions.[2]
There has been significant advances in the development of
the asymmetric aldol and allylation reactions of aldehydes.[3,4]
However, further manipulations, such as alcohol protection or
redox reactions, are often required before the next iteration
can proceed. Therefore, there has been increasing interest in
one-pot cascade aldol reactions;[5,6] however, only one
example successfully proceeded to the third aldol iteration,
and in low yields.[5a] Inspired by the seminal work of
Mukaiyama et al.,[2a] our research group reported an aldol
cascade reaction using tris(trimethylsilyl)silyl enol ethers,
such as the easily prepared 1,[7] to give versatile aldehyde
products 2 (Scheme 1). Moreover, these aldehydes can be
number of steps. Despite several attempts, treatment of
dimethylpropanal with 1 (4.0 equivalents) and Tf2NH in
dichloromethane gave only the double-aldol product 2a
(R = tBu), without the formation of any triple-aldol product
3a (Table 1, entry 1). Heating the reaction mixture also failed
Table 1: Optimization of the triple aldol reaction.
Entry Solvent
T
Additive
[mol%]
Yield
Yield
[8C]
of 2a [%][a] of 3a [%][a,b]
1
2
3
4
5
6
7
8
9
10
11[c]
12[c]
13[c]
14[c]
15[c]
16[c]
17[c]
CH2Cl2
hexanes 23 to 65
0 to 40
none
none
none
none
none
75
<5
<5
60
20
37
0
0
0
<5
<5
31
13
52
27
0
toluene ꢀ78 to 80
PhCl
C8F18
0 to 50
0 to 60
0 to 23
CH2Cl2
ICH2CH2I (10)
MeI (10)
PhI (10)
CH2Cl2 ꢀ78 to 23
71
30
CH2Cl2 ꢀ40 to 0
CH2Cl2 ꢀ40 to 23 1,2-C6H4I2 (10) 49
CH2Cl2 ꢀ40 to 23
CH2Cl2 ꢀ40 to 23
CH2Cl2 ꢀ40 to 23
CH2Cl2 ꢀ40 to 0
2-I-py (10)
I2 (5.0)
<5
65
<5
64
29
15
7
PhI (10)
PhI (10)
PhI (10)
PhI (10)
PhI (2.0)
PhI (0.5)
85
32
51
47
77
26
CH2Cl2
CH2Cl2
0
23
Scheme 1. Synthesis of 3,5-disilyloxyaldehydes utilizing silyl enol ether
1. TMS=trimethylsilyl; Tf=trifluoromethanesulfonyl.
CH2Cl2 ꢀ40 to 0
12
46
CH2Cl2 ꢀ40 to 0
treated with Grignard or polyhalomethyllithium reagents in
the same reaction pot to generate mono-protected diols.[8]
The formation of these compounds is highly diastereoselec-
tive because of the extreme steric bulk of the tris(trimethyl-
silyl)silyl group.[7a,8a,9] Significantly, further addition of 1 to 2 is
strictly prevented, because of the steric bulk of the
(TMS)3SiNTf2·2 complex.
We set out with the challenging aim of extending this aldol
cascade reaction to three or more additions of 1 to an
aldehyde for the construction of polyketides in a minimal
[a] Yield of combined isolated diastereomers. [b] d.r.=87:10:2:<1 as
determined by crude 1H NMR spectroscopic and HPLC analyses.
[c] 5.0 equivalents of 1.
to produce the desired triple aldol adduct. Evidently, a new
approach was required. Simple solvent screening had inter-
esting effects on the reaction: performing the reaction in
hexane or toluene gave only the mono-aldol adduct (Table 1,
entries 2 and 3), whilst when chlorobenzene or perfluoro-
octane were used, 2a was obtained in 60 and 20% yields,
respectively, with little or no formation of 3a (Table 1,
entries 4 and 5).
[*] Dr. B. J. Albert, Prof. Dr. H. Yamamoto
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60635 (USA)
Fax: (+1)773-702-5059
Because the solvent seemed to be playing a critical role in
affecting the active catalytic species, different additives were
then screened. The use of a substoichiometric amount of 1,2-
diiodoethane, which was chosen because 3a was formed in
low yield when 1,2-dichloroethane was used as the reaction
solvent, gave 2a and 3a in 37 and 31% yields, respectively
(Table 1, entry 6). Surprised by the large effect that the
iodine-containing additive had on the reaction, other iodides
were screened. Iodomethane gave 2a and 3a in 71 and 13%
yields, respectively, and iodobenzene afforded the products in
E-mail: yamamoto@uchicago.edu
[**] This work was made possible by the generous support of NIH (P50
GM086 145-01) and the University of Chicago. We would addition-
ally like to thank Antoni Jurkiewicz for his NMR expertise and Prof.
V. V. Fokin for insightful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907076.
Angew. Chem. Int. Ed. 2010, 49, 2747 –2749
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2747

Communications
30 and 52% yields, respectively (Table 1, entries 7 and 8). The
The relative configurations for aldehydes 3 were eluci-
dated from their reduction and subsequent deprotection with
TBAF or UV light,[10] utilizing the powerful NMR spectros-
copy method described by Kishi and Kobayashi (for full
details, see the Supporting Information).[11] Furthermore, 3a
could be treated with tBuMgCl in the same reaction vessel to
generate a meso tetraol (4) after deprotection (Scheme 2).
use of two other aryl iodides, 1,2-diiodobenzene and 2-
iodopyridine, were less successful (Table 1, entries 9 and 10).
Finally, the use of I2 as an additive proved ineffective in
forming 3a (Table 1, entry 11). Therefore, iodobenzene was
chosen to be the optimal additive for our investigation.
This reaction was optimized using iodobenzene as an
additive and dichloromethane as the solvent. Gratifyingly, 3a
was obtained in a remarkable 85% yield when the reaction
was performed at ꢀ40 to 08C, using 5.0 equivalents of 1
(Table 1, entry 12). The temperature played a critical role in
the generation of 3a. Too low a reaction temperature did not
allow the third aldol reaction to occur, whereas too high a
temperature caused decomposition of 1, 2a, and 3a (Table 1,
entries 13–15). Although, the amount of iodobenzene could
be lowered (Table 1, entries 16 and 17), it caused a decrease in
the yield of 3a.
ꢀ
This method is able to create four C C bonds and four
stereocenters in high efficiency in a one-pot operation.
Scheme 2. One-pot preparation of tetraol 4. TBAF=tetrabutylammo-
nium fluoride.
With our optimized triple-aldol reaction conditions in
hand, the aldehyde substrate scope was then investigated
(Table 2). Octanal and cyclohexanecarboxaldehyde were
Intrigued by the critical role of iodobenzene in the
promotion of the third aldol reaction in this cascade, the
following experiments were designed. With the hypothesis in
mind that iodobenzene is acting as a Lewis base towards
(TMS)3SiNTf2, the steric and electronic environments of
iodobenzene were varied. Somewhat sterically more-hin-
dered aryl iodides had little effect on the synthesis of 3a
(Table 3, entries 2 and 3), whereas a very bulky aryl iodide
gave diminished reactivity (Table 3, entry 5). The electroni-
Table 2: Scope of the aldehyde substrate in the triple-aldol reaction
with 1.
Entry
1
Product
Yield [%][a]
84
d.r.[b]
3b
79:10:9:<2
Table 3: Perturbation of the aryl iodide.
2
3
4
3c
3d
3e
87
75
87
81:9:8:<2
81:9:8:<2
71:14:12:2
Yield [%][a]
Entry
ArI
2a
3a
5[c]
3 f
89
87:8:3:2
1[b]
2
3
4
5
iodobenzene
29 (<5)
51 (85)
1,3-dimethyl-2-iodobenzene
3,5-dimethyl-1-iodobenzene
1-iodo-3,5-bis(trifluoromethyl)benzene
1-iodo-2,4,6-triisopropylbenzene
73
52
78
87
24
40
12
7
[d]
6
3g
3h
54
57
–
7[e]
–
[d]
[a] Yield of combined isolated diastereomers. [b] Yields in parentheses
refer to when 5.0 equivalents of 1 are employed.
[a] Yield of combined isolated diastereomers, unless otherwise noted.
[b] The diastereomeric ratios were determined by crude 1H NMR
spectroscopic and HPLC analyses. [c] 0.2 mol% Tf2NH was used.
[d] this yield is for the diastereomer shown only; [e] 10 mol% 1-iodo-
3,3-dimethyl-1-butyne was employed in this reaction. Cy=cyclohexyl,
Bn=benzyl, TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl.
cally less-Lewis-basic 1-iodo-3,5-bis(trifluoromethyl)benzene
was also less effective as an additive (Table 3, entry 4).
Indeed, the mass spectra of (TMS)3SiNTf2 in the presence of
iodobenzene showed signals at m/z 536 and 656, which
correspond to [(TMS)3Si + IPh + CH2Cl2]+ and [(TMS)3Si +
(IPh)2]+, respectively. These results are supported by the
previously reported crystal structure of 1,2-dichlorobenzene
and iPr3Si+ [CHB11Cl11]ꢀ.[12] Although 29Si NMR spectroscopy
experiments with (TMS)3SiNTf2 did not show a significant
difference on addition of iodobenzene (Dd = 0.4 ppm of the
central silicon atom), this could be due to the rapid
equilibration or a screening effect of the multiple TMS
groups.
good substrates for the triple-aldol reaction, giving 3b and
3c along with their minor diastereomers in 84 and 87% yields,
respectively (Table 2, entries 1 and 2). This reaction was
tolerant of different functionalities on the aldehyde. Benzyl-
oxyacetaldehyde and 3-tert-butyldimethylsilyloxypropanal
gave 3d and 3e in 75 and 87% yields, respectively (Table 2,
entries 3 and 4). Furthermore, 3-nitropropanal produced 3 f
and its minor diastereomers in 89% yield (Table 2, entry 5).
Chiral aldehydes 2-phenylpropanal and 3-triisopropyl-
silyloxybutanal afforded 3g and 3h in 54% and 57% yields,
respectively, as a mixture of easily separated diastereomers
(Table 2, entries 6 and 7).
In the search for a better co-catalyst for the triple-aldol
cascade reaction, we required a smaller yet electronically
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Angewandte
Chemie
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (50 mL) eluting with dichloromethane/
hexanes (1:19!1:4) to give 3a (409 mg, 85%) as a white foam.
stabilized organoiodide. Towards this end, a 1-iodo-2-phenyl-
acetylene was prepared, and it proved to be a more effective
additive than iodobenzene for the production of 3a, effective
as low as 0.1 mol% (Table 4, entries 1–4). 1-Iodo-3,3-
Received: December 15, 2009
Published online: March 12, 2010
Table 4: Improved organoiodide co-catalysts.
Keywords: aldol reaction · diastereoselectivity · Lewis acids ·
.
organocatalysis · polyketides
Entry
R [mol%]
Yield [%][a]
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1
2
3
4
5
6
Ph (10)
80
71
65
56
85
77
Ph (2.0)
Ph (0.5)
Ph (0.1)
tBu (0.5)
tBu (0.1)
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[a] Yield of combined isolated diastereomers.
dimethyl-1-butyne further improved the production of 3a to
85 and 77% yields, when employed in 0.5 and 0.1 mol%,
respectively. These results showed little drop-off in the yield
of 3a, as compared to the yields in Table 2, and clearly
demonstrate the power of using organoiodides in this
reaction.
We propose that organoiodides (RI) can react with
(TMS)3SiNTf2, to afford the cationic and sterically less-
demanding complex 5 [Eq. (1)], in analogy with the crystal
structure reported by Reed and co-workers.[12] This more-
reactive complex is able to promote the reaction of 1 and 2.
[4] For the allylation of aldehydes, see: a) I. Fleming in Compre-
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therein.
In summary, we have developed an efficient triple-aldol
cascade reaction for the preparation of 3,5,7-trisilyloxy
aldehydes in high diastereoselectivities from a diverse set of
simple aldehydes. This method can produce these complex
structures with unprecedented ease. The key to allowing the
triple-aldol reaction to proceed efficiently was the addition of
iodobenzene or 1-iodoalkynes, which generated a more
reactive catalytic system. However, as an asymmetric version
of this reaction is not yet available, simple chiral aldehydes
can be employed in this reaction to generate enantiopure
complex aldehydes 3 with unmatched speed.
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Experimental Section
Representative procedure for the triple aldol condensation of
aldehydes and silyl enol ether 1: A stirred solution of 1 (729 mg,
2.50 mmol), PhI (5.6 mL, 0.050 mmol), and dimethylpropanal (55 mL,
0.50 mmol) in CH2Cl2 (2.5 mL) was cooled to ꢀ408C before Tf2NH
(0.010m in CH2Cl2, 50 mL, 0.50 mmol) was added to the mixture. The
reaction mixture was stirred for 30 minutes at the same temperature,
then warmed to 08C. After an additional 30 minutes at the same
temperature, the reaction was quenched by the addition of a pH 7
buffer (5 mL). The layers were separated, and the aqueous phase was
extracted with dichloromethane (3 mL). The combined organic layers
were dried over Na2SO4, filtered through cotton, and concentrated
[12] S. P. Hoffmann, T. Kato, F. S. Tham, C. A. Reed, Chem.
Commun. 2006, 767 – 769.
Angew. Chem. Int. Ed. 2010, 49, 2747 –2749
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