Rapid and stereochemically flexible synthesis of polypropionates: Super-silyl-governed aldol cascades

Article abstract of DOI:10.1002/anie.201108325

Polypropionates made EZ: The E/Z geometry of tris(trimethylsilyl)silyl super silyl enol ethers derived from propionaldehyde controls diastereoselectivity in the aldehyde crossed-aldol reaction. These silyl enol ethers can participate in polyaldol cascade reactions, thus allowing the one-pot synthesis of four different dipropionate stereotetrads (see scheme), and polyketides bearing up to five contiguous stereocenters.

Full text of DOI:10.1002/anie.201108325

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Angewandte
Communications
DOI: 10.1002/anie.201108325
Synthetic Methods
Rapid and Stereochemically Flexible Synthesis of Polypropionates:
Super-Silyl-Governed Aldol Cascades**
Patrick B. Brady and Hisashi Yamamoto*
The polypropionate motif is an important structural unit
present in polyketide natural products, many of which are of
great interest because of their wide range of biological
activities.[1] For instance, members of the erythromycin and
rifamycin families have long been used as commercial anti-
biotics.[2] The importance of these pharmaceutical agents, as
Scheme 1. Conventional aldol approach to polypropionates.
well as the potential to discover new biologically active
polypropionates, makes their efficient, stereoselective chem-
ical synthesis an important ongoing challenge. The polypro-
pionate structure is recognized by its characteristic carbon
chain decorated with alternating methyl and hydroxy groups.
The numerous stereogenic centers allow for many possible
stereochemical permutations. Even in the case of a simple
dipropionate bearing four stereogenic centers, up to 16
diastereomers are possible. This structural complexity has
inspired numerous methods for stereoselective synthesis.[3] Of
these methods, the aldol reaction is perhaps the most well
studied and widely used in the synthesis of polypropionate
natural products.[4] Other methods include crotylation,[5,6]
epoxide opening,[7] [2+2] cycloaddition,[8] borylative alde-
hyde–diene coupling,[9] and reductive aldol addition.[10]
While many of these methods have been developed to
synthesize polypropionates with high enantio- and diastereo-
control, the synthesis of complex polypropionates using these
methods usually requires a great number of steps. For
instance, a conventional aldol synthesis of polypropionates
begins with an aldol reaction of an ester enolate and an
aldehyde (Scheme 1). To install a second propionate unit, the
resulting b-hydroxy group must first be protected, and the
ester reduced to the corresponding aldehyde oxidation state.
As a result, in this route each carbon–carbon bond-forming
event requires numerous additional step-consuming protec-
tive group manipulations, redox adjustments, and purifica-
tions. Additionally, control of the stereochemistry in subse-
quent aldol reactions is often complicated.
Recently, the efficiency of complex molecule synthesis has
been evaluated by the concepts of redox economy,[11] which
strives to build molecules with a minimal number of oxidation
and reduction steps, and step economy,[12] which emphasizes
reactions that build complexity and avoid extraneous chem-
ical steps. Given these considerations, a more efficient aldol
route to polypropionates would be the aldehyde crossed-aldol
reaction, in which the nucleophilic species is derived from an
aldehyde rather than an ester. The product of the reaction is
therefore also an aldehyde, thus circumventing the need for a
redox adjustment. However, aldehyde crossed-aldol reac-
tions,[13] especially those employing metalloenolates[14] and
silyl enol ethers[15] are uncommon because of the instability of
the product and side reactions. Toward this end, we have
developed the aldol addition of the tris(trimethylsilyl)silyl
super silyl enol ether of acetaldehyde with simple aldehydes
(Scheme 2, X = H).[16] The product of the reaction is a
protected b-hydroxy aldehyde, and it is stable yet suitable
for nucleophilic addition. Careful choice of reaction con-
ditions allow for the controlled, stereoselective single, double,
and triple aldol reactions in a one-pot manner. By using this
methodology, polyketides including the natural product EBC-
23, were synthesized in a short sequence of steps, with
minimal protecting group manipulation and functional group
interconversion. The super silyl group plays a critical role in
these polyaldol cascades, acting as both a reactive group and a
[*] P. B. Brady, Prof. Dr. H. Yamamoto[+]
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
E-mail: yamamoto@uchicago.edu
[+] Adjunct affiliation:
Chemistry Department, King Abdulaziz University
Jeddah, 21589 (Saudi Arabia)
[**] This work was supported by the NIH (P50 GM086 145-01). P.B.B. is
grateful for support as a trainee of the NIH NIGMS Predoctoral
Chemistry & Biology Interface Training Program (T32 GM087 20).
We would like to thank Dr. Antoni Jurkiewicz, Dr. Ian Steele, and Dr.
Jin Qin for their expertise in NMR spectroscopy, X-ray crystallog-
raphy, and mass spectrometry, respectively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108325. CCDC 855406–
855408 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Scheme 2. Synthesis of polypropionates by one-pot aldol cascades
using aldehyde-derived super-silyl enol ethers. Si=Si(TMS)3.
TMS=trimethylsilyl.
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Table 1: Addition of propionaldehyde enol ethers to aldehydes.
stereodirecting group, thus allowing for high yields
and diastereoselectivities. Herein, we describe our
approach to the challenging polypropionate struc-
ture by stereoselective aldol cascades utilizing the
silyl enol ethers derived from propionaldehyde
(Scheme 2, X = CH3).
Entry Enol
ether
Substrate
Product
Yield
[%]
d.r.[a,b]
The first challenge was to develop a diastereose-
lective single aldol reaction between propionalde-
hyde-derived silyl enol ethers and simple aldehydes.
In preliminary experiments, we reported the stereo-
selective synthesis of the Z-silyl enol ether (Z)-1 (for
structure see Table 1) and found that it reacted
smoothly with simple aldehydes to generate 2,3-syn
products in high diastereoselectivity.[16a] We hypothe-
sized that the unique steric and electronic properties
of the super silyl group would allow control of the
2,3-stereochemistry based on the enol ether geom-
etry. The E-silyl enol ether (E)-1 was generated as a
single diastereomer by iridium-catalyzed isomeriza-
tion of the corresponding allyl silyl ether following
the protocol from Miyaura and co-workers.[17] When
1
2
3
4
5
6
7
8
(E)-1 R1 =CH3
anti-3a
anti-3b
anti-3c
74
87
82
58
67
76
54
95
91
95
84
66
63
79:21
87:13
86:14
97:3
79:21
96:4
93:7
>97:3
>97:3
>97:3
90:10
96:4
(E)-1 R1 =nPent
(E)-1 R1 =cHex
1
=
(E)-1 R =(E)-PhCH CH anti-3d
1
ꢀ
(E)-1 R =TMSC C
anti-3e
anti-3 f
(E)-1 R1 =Ph
(E)-1 R1 =4-(OCH3)C6H4 anti-3g
(E)-1 R1 =2-furyl
(E)-1 R1 =2-ClC6H4
(E)-1 R1 =4-NO2C6H4
(E)-2 R1 =CH3
anti-3h
anti-3i
anti-3j
anti-4a
anti-4c
anti-4e
9
10
11
12
(E)-2 R1 =nPent
1
ꢀ
treated with 0.1 mol% triflimide (HNTf2) in CH2Cl2 13
at À788C, (E)-1 underwent smooth aldol addition
with simple aldehydes (Table 1). Gratifyingly, the
2,3-anti adducts were obtained, thus complementing
the syn-selective addition using (Z)-1. This remark-
(E)-2 R =TMSC C
94:6
14
(Z)-1
syn,syn-3k
76
88:12
able stereospecific Z to syn and E to anti correlation
is not usually observed in Mukaiyama-type aldol
reactions. Rather, the diastereoselection is usually
substrate controlled as a result of an open transition
state.[18]
15
(E)-2
(Z)-1
(E)-2
(Z)-1
anti,syn-4k
syn,syn-3l
79
85
74
84
>97:3
The anti-selective propionaldehyde aldol reac-
tion displays a wide substrate scope with simple
achiral aldehydes (Table 1, entries 1–13). Good
yields and high anti selectivity are obtained for
16
87:10:3
linear and branched aliphatic aldehydes (entries 1–
3), as well as unsaturated aldehydes (entries 4 and 5).
Aromatic aldehydes of varying electronic and steric
properties give excellent selectivity and good yields.
The anti selectivity of the reaction could be addi-
tionally improved by using the E-enol ether of
propionaldehyde bearing the larger tris(triethylsi-
lyl)silyl super silyl group [(E)-2; entries 11–13,
compared to entries 1–3].[19]
17[c]
anti,syn-4l
syn,syn-3m
90:10
18
83:13:3:2
(e.r.=96:4)
To further expand the scope of the reaction, and
to examine its potential use in the synthesis of
molecules of greater stereochemical complexity, we
investigated the propionaldehyde aldol addition to
chiral aldehydes (Table 1, entries 14–20).[20] Reaction
of (Z)-1 with b-triisopropylsiloxy hexanal resulted in
good yield and high selectivity (entry 14). After
derivatization, the major diastereomer was found to
have 2,3,5-syn,syn stereochemistry, thus demonstrat-
ing 1,3-syn asymmetric induction. The use of (E)-2
resulted in 2,3,5-anti, syn as a single diastereomer
(entry 15). Aldehydes bearing a stereocenter in the
a position were also investigated (entries 16–20).
Remarkably, in all cases the major product was the
3,4-syn adduct, thus in accord with the Felkin model
19
20
(E)-1
anti,syn-3m
syn,syn-3n
77
78
76:21:3
(Z)-1 (e.r.>99:1)
>97:3
(e.r.=99:1)
[a] Ratio of detectable diastereomers by integration of the 1H NMR signals for the
crude reaction mixture. [b] Enantiomeric ratio of major diastereomer was deter-
mined by HPLC analysis using a chiral stationary phase. [c] Me2AlNTf2 (0.5 mol%)
was used in place of HNTf2. Bn=benzyl, TES=triethylsilyl, Tf=trifluoromethane-
sulfonyl, TIPS=triisopropylsilyl, Ts=p-toluenesulfonyl.
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of stereocontrol.[21] Both the challenging 2,3-syn[22] and the
2,3-anti[23] products can be obtained, even when aldehydes
bearing similarly sized alkyl groups were used (entries 18 and
19). Importantly, the use of enantiopure a-substituted chiral
aldehydes led to products with high enantiopurity, thus
indicating no substantial racemization under the reaction
conditions (entries 18 and 20).
With highly selective syn and anti propionaldehyde aldol
additions in hand, we turned our attention to multicomponent
aldol reactions for the one-pot synthesis of highly complex
molecules.[24] Our first goal was to see if a one-pot propion-
aldehyde/acetaldehyde cascade addition could be accom-
plished. Benzaldehyde was treated with (E)-1 under standard
conditions and monitored by TLC. After the first aldol
reaction was judged complete, the acetaldehyde-derived enol
ether 5 was added (Table 2, entry 1) to generate the double
addition product in 67% yield with an excellent d.r. (95:5).
The high diastereoselectivity indicates that the second
addition step is nearly completely selective. The product
was determined to have 2,3-syn stereochemistry, which is
consistent with the Felkin model of 1,2-stereocontrol. Alter-
natively, the super silyl enol ether of acetone 6 could be
employed as the second nucleophile, thereby producing the
Table 2: One-pot consecutive aldehyde crossed-aldol additions.
Entry[a]
R1
First enol ether
Second enol ether
Product
Yield
[%][b]
d.r.[c]
95:5
1
Ph
(E)-1
5
7
8
9
67
2[d]
3[e]
4
Ph
(E)-1
(Z)-1
5
6
86
96:4
[g]
cHex
tBu
5
57[f]
–
(2.5 equiv)
[g]
(Z)-1
10
43[f]
–
(2.0 equiv)
(2.0 equiv)
[g]
5
6
7
8
tBu
5
(E)-1
11
12
13
14
45[f]
63
–
cHex
(Z)-1
(Z)-1
(Z)-1
–
–
–
81:13:2:4
94:4:1:1
95:5
72
CH3
47
(1.5 equiv)
(1.5 equiv)
9
BnOCH2
BnOCH2
(Z)-1
(E)-1
(E)-1
–
–
–
15
16
17
48
63
74
89:7:2:2
86:14
97:3
10
11
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Table 2: (Continued)
Entry[a]
R1
First enol ether
Second enol ether
Product
Yield
[%][b]
d.r.[c]
95:5
12
Ph
(E)-1
–
18
19
20
57
92
80
13
14
Ph
(E)-1
(Z)-1
(Z)-1
89:7:4
(E)-1
84:7:6:3
[a] Reactions conducted on 0.30 mmol scale. [b] Combined yield of all isolated diastereomers. [c] Ratio of detectable diastereomers by integration of
1
ꢀ
the H NMR signals of the crude reaction mixture. [d] Reaction conducted at 7.0 mmol scale. [e] tBuC CI (5 mol%) added with 5. [f] Yield of the
1
isolated single diastereomer after chromatography. [g] d.r. could not be determined by H NMR analysis of the crude reaction mixture.
Ts =4-touenesulfonyl.
methyl ketone double aldol adduct in high yield and
selectivity on preparative scale (7.0 mmol; Table 2, entry 2).
Consecutive aldol additions to aliphatic aldehydes proved
to be more challenging. Monoaldol adducts varied greatly in
reactivity, with small R groups displaying the highest reac-
tivity. Use of HNTf2 alone did not result in double aldol
addition to more sterically demanding aldehydes. However,
after optimization of the reaction conditions, it was found that
HNTf2 or our previously developed carbon acid
of (E)-1 to alanine-derived (S)-N-benzyl-N-tosyl 2-amino-
propanal[26] (entry 11) showed excellent selectivity, thereby
producing predominantly one out of 16 possible diastereo-
mers (d.r. = 97:3). After derivatization, the stereochemistry of
17 was determined by X-ray crystallographic analysis. Curi-
ously, the anti,anti,anti,anti stereochemistry was obtained,
thus indicating that the first aldol addition takes place with
anti-Felkin selectivity.[27] The anti,anti,anti stereochemistry
was also obtained by double addition of (E)-1 to benzalde-
hyde and benzyloxy acetaldehyde (entries 10 and 12).
Having generated double aldol products with 2,3,4,5-
syn,syn,syn stereochemistry and 2,3,4,5-anti,anti,anti stereo-
chemistry, we wondered if it would be possible to generate
other stereotetrads with high diastereoselection by sequential
addition of (Z)-1 and (E)-1 or vice versa. Gratifyingly,
benzaldehyde underwent addition of (E)-1 followed by (Z)-
1 in one pot in excellent yield (92%) and diastereoselectivity
(d.r. = 89:7:4; Table 2, entry 13). After derivatization, the
product 19 was found to have 2,3,4,5-syn,syn,anti stereochem-
istry. By using 2-methyl butanal as a substrate, we reversed
the order of addition (first (Z)-1 then (E)-1), and obtained the
2,3,4,5,6-anti,syn,syn,syn product 20 in good yield (80%) and
high selectivity (84:7:3:2).
[25]
C6F5C(H)Tf2 promoted the acetaldehyde addition to pro-
pionaldehyde adducts when paired with 5 mol% tert-butyl
iodoacetylene.[16d] Still higher reactivity was observed with
less than 0.5 mol% of the Lewis acid AlMe2NTf2. Thus, under
optimized reaction conditions, cyclohexane carboxaldehyde
underwent propionaldehyde addition followed by double
acetaldehyde addition to give the syn,syn,syn triple aldol
product in one pot (Table 2, entry 3). Alternatively, the order
of silyl enol ether addition could be changed to give double
acetaldehyde addition to pivalaldehyde followed by propio-
naldehyde addition (entries 4 and 5). Both (Z)-1 and (E)-1
gave triple aldol products 10 and 11, which were isolated after
facile separation from their minor diastereomers in 43% and
45% yields, respectively.
We then turned our attention to consecutive propional-
dehyde additions. Double aldol addition of (Z)-1 with a range
of aldehydes gave the 2,3,4,5-syn,syn,syn stereochemistry
(Table 2, entries 6–9). Interestingly, when acetaldehyde was
used as a substrate, limiting the amount of (Z)-1 to just 1.5
equivalents resulted in 48% yield of the syn,syn,syn double
aldol adduct with an excellent d.r. (95:5) along with 22% of
the predominantly anti monoaldol adduct (d.r. = 85:15;
entry 8). When more than 1.5 equivalents was used, the
yield of the double aldol product increased but the diaste-
reomeric ratio of the product decreased. This observation can
be explained by a kinetic resolution of diastereomers: the first
aldol reaction is nonselective, thus resulting in an approx-
imately 1:1 mixture of anti-3a and syn-3a. However, syn-3a
undergoes a selective second aldol addition more rapidly than
anti-3a.
In summary, we have developed a general propionalde-
hyde crossed-aldol reaction affording syn or anti aldol
products with high diastereoselectivity and wide substrate
scope. These aldol products can themselves undergo acetal-
dehyde, acetone, and double acetaldehyde aldol additions to
rapidly assemble polyketide fragments in excellent step
economy and without redox manipulations. Double propion-
aldehyde aldol reactions were also developed, thereby
producing molecules with up to five contiguous stereogenic
centers with high control of diastereoselectivity. The Z/E
geometry of the silyl enol ether and the order of addition are
convenient handles for controlling the stereochemistry of the
product, thus making this method highly flexible. Overall, this
report represents a highly efficient alternative to lengthy
classical aldol syntheses of polypropionates.
Double propionaldehyde aldol addition of (E)-1 to
aldehydes was also possible (Table 2, entries 10–12). Addition
Received: November 26, 2011
Published online: January 17, 2012
Angew. Chem. Int. Ed. 2012, 51, 1942 –1946
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1945

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Keywords: aldol reaction · cascade reactions ·
diastereoselectivity · polyketides · synthetic methods
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[27] See the Supporting Information for further discussion.
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