Stereoarrays with an all-carbon quaternary center: Diastereoselective desymmetrization of prochiral malonaldehydes

Article abstract of DOI:10.1002/anie.201107370

Tamed by chelation: The MgBr₂ chelation of prochiral malonaldehydes allows diastereoselective monoaddition reactions with allyl stannane nucleophiles (see scheme; PG=protecting group, TBDMS=tert- butyldiphenylmethylsilyl, Tr=trityl). In the same pot, addition of a second nucleophile proceeds in high diastereoselectivity to generate nonsymmetric products with up to five contiguous stereogenic centers, including a chiral all-carbon quaternary center. Copyright

Full text of DOI:10.1002/anie.201107370

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DOI: 10.1002/anie.201107370
Synthetic Methods
Stereoarrays with an All-Carbon Quaternary Center: Diastereo-
selective Desymmetrization of Prochiral Malonaldehydes**
Bruno Linclau,* Elena Cini, Catherine S. Oakes, Solen Josse, Mark Light, and
Victoria Ironmonger
The stereocontrolled nucleophilic addition to aldehydes and
to five stereocenters. A model to explain the observed
stereochemical outcomes is presented.
À
ketones is a fundamental C C bond-forming process in
organic synthesis, with a number of models available to
predict or explain facial selectivity.[1] Intermolecular nucleo-
philic addition reactions to 1,3-dicarbonyl groups are rare in
comparison. Nevertheless, additions to a-formyl esters and
amides under chelation control, with stereochemical bias
provided by a central chiral center, have been shown to be
highly diastereoselective.[2] A study by Prantz and Mulzer
involving chiral a-formyl esters showed how the aldehyde
facial selectivity could be reverted depending on whether the
reaction was run under chelation control or not.[2a] Only a few
examples of intermolecular additions to 1,3-dialdehydes are
described, and they proceeded with modest or no diastereo-
selectivity.[3] In fact, Krische and co-workers described an
ingenious transfer hydrogenation approach in which 1,3-
propanediols were used as malonaldehyde synthons in a
highly enantioselective and diastereoselective bidirectional
allylation process.[4]
The malonaldehydes 1–3 (see Table 1) used in this study
were synthesized in quantitative yield[6a,b] by IBX-mediated
(IBX = o-iodoxybenzoic acid) oxidation[6c,d] of the corre-
sponding 1,3-diols, which were easily obtained from exceed-
ingly cheap tris-1,1,1-(hydroxymethyl)ethane.[6a,b]
The reaction of 1–3 with a variety of nucleophiles,
including Grignard reagents, allyl boronates, and allyl boranes
proceeded with low diastereoselectivity and low to moderate
yield (not shown). Allylstannation under BF3·OEt2 activation
led to extensive decomposition, but the use of freshly
prepared MgBr2·OEt2 successfully led to the monoallylation
products 5–7 (Table 1).
Table 1: Chelation-controlled allylstannation reactions of malonalde-
hydes.
Herein we show the tremendous synthetic potential of
prochiral non-enolizable malonaldehydes for the synthesis of
acyclic compounds containing an all-carbon quaternary
center as part of a stereoarray, the synthesis of which is
subject to much contemporary interest.[5] Reactions of
malonaldehydes having a methyl and protected hydroxy-
methyl group at the central position are described, and it is
shown that under MgBr2 chelation, these substituents are able
to exert excellent diastereofacial control for addition reac-
tions onto an aldehyde group, with complementary diaster-
eoselection depending on the nature of the protecting group.
Apart from monoadditions, one-pot bisaddition reactions are
also described, wherein the second addition occurs with
virtually complete stereocontrol. This unprecedented process
allows the synthesis of nonsymmetric products containing up
Entry
T [8C]
Product
Yield [%][a]
a/b[b]
1
2
3
À25
À25
À78
5a,b
6a,b
7a,b
77
53
81
70:30
92:08
05:95
[a] Yield of product isolated after chromatography. [b] Determined by
1H NMR analysis before chromatography. Bn=benzyl, TBDPS=tert-
butyldiphenylsilyl, Tr=trityl.
The reaction of 1 with allyltributyl stannane led to the
products 5a/b in a modest ratio (Table 1, entry 1). The
selectivity was much improved upon switching the protecting
group from TBDPS to trityl (entry 2). In both cases, the 2,3-
syn adduct was the major isomer. However, allylation of the
benzyl-protected 3, which proceeded in slightly higher
diastereoselectivity compared to reaction with 2, resulted in
the 2,3-anti adduct 7b as the major diastereoisomer (entry 3).
Hence, the desymmetrization of the malonaldehyde starting
material leads to the formation of a chiral, all-carbon
quaternary stereocenter, and both diastereomeric products
are accessible in high diastereoselectivity depending upon the
protecting group present. The relative stereochemistry of
these and the following products was determined by X-ray
crystallographic analysis, chemical correlation, and NMR
experiments.[6b]
[*] Dr. B. Linclau, E. Cini, C. S. Oakes, Dr. S. Josse, Dr. M. Light
School of Chemistry, University of Southampton
Highfield, Southampton SO17 1BJ (UK)
E-mail: bruno.linclau@soton.ac.uk
Dr. V. Ironmonger
GlaxoSmithKline
Old Powder Mills, Leigh, Nr Tonbridge, TN11 9AN (UK)
[**] E.C. thanks Prof. M. Taddei and ERASMUS for funding. S.J. thanks
NV Tibotec (Belgium) for funding. C.S.O. thanks the EPSRC,
AstraZeneca, GlaxoSmithKline, and Pfizer (Organic Synthesis
studentship scheme) for funding. We are grateful to Nathan Bartlett
for DFT calculations, and to Dr. Karl Cable (GSK) and Dr. Andrew
Gordon (GSK) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107370.
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Table 2: Chelation-controlled hydroxyallylation reactions of malonalde-
hydes.
the isomers 11b,d were formed by a different facial attack of
the prochiral reagent 8.
The models in Figure 1 are consistent with the observed
stereochemical outcomes. Chelation of MgBr2 with 2 leads to
the flattened boat conformation A,[9] with the trityloxy
Figure 1. Proposed models for 1,3-dialdehyde addition.
substituent in a pseudoequatorial position, which we believe
is due to electronic factors. Taking the pro-R aldehyde group
as a reference, the major product isomer arises from attack on
the least hindered Si face, and the minor isomer is presumed
to arise from reaction of the ring-inverted boat conformation
(not shown). In contrast to the bulky TBDPS and trityl ethers,
benzyl ethers are able to engage in chelation[10] leading to
formation of B. Now Si-face attack to the pro-R aldehyde
group is hindered by the CH2OBn bridge: the large reagent 8
reacts only at the Re face, but the smaller reagent 4 can also
approach from the Si face, thus leading to the minor isomer
7a. DFT calculations support the proposed model, and
further investigations to fully explain the diastereoselection
will be reported in due course.
By employing an excess of the allyl stannane 4, bidirec-
tional addition products were obtained. Starting from malo-
naldehyde 3 [Eq. (1)], only one diastereoisomer 14 could be
identified. Surprisingly, 14 was assigned (NMR) as the
pseudo-C2-symmetric stereoisomer, as opposed to the corre-
sponding possible meso diastereomer(s), which in principle
would have been expected from a substrate-directed bidirec-
tional reaction process.[11] With dialdehyde 1, the bisallylation
product was isolated as a 94:6 mixture of anti and meso
isomers.[6b] Bidirectional hydroxyallylation could not be
achieved, which was attributed to the larger steric bulk of
the less reactive reagent 8.
Entry
T [8C]
Product
Yield [%][a]
a/b/c/d[b]
1[c]
2
3
À20
À25
À30
À25
9a–d
9a–d
10a–d
11a–d
15[d]
64
65
–
86:14:0:0
95:05:0:0
0:91:0:9
4
83
[a] Yield of product isolated after chromatography. [b] Determined by
1H NMR analysis. [c] 1 equiv MgBr2. [d] 63% of 1 recovered. The thermal
ellipsoids of the X-ray crystal are shown at 35% probability.
Encouraged by these results, the hydroxyallylation of 1–3
with (Z)-g-(tert-butyldimethylsilyl-oxyallyl) tributylstannane
(8)[7,8] was investigated next (Table 2). The hydroxyallylation
of 1 and 2 with 8 gave the 2,3-syn- and 2,3-anti-addition
products 9a,b and 10a,b (entries 2 and 3) in higher diaste-
reoselectivity compared to that of the allylation described
above. When one equivalent of MgBr2 was used (entry 1),
63% of the starting malonaldehyde was recovered, thus
indicating no decomposition is taking place under the
reaction conditions. The hydroxyallylation of 3 led to the
formation of 11b,d in excellent yield and diastereoselectivity
(entry 4). The crystal structure of a derivative of 11b (12) is
shown. In all cases, only monoaddition products were
obtained. Interestingly, the stereochemical outcome of the
hydroxyallylation of 1 and 2 differs from that of 3 on three
accounts. First, the relative configuration at C2 and C3 of the
major isomers obtained from reaction of 1 and 2 is different
compared to that of the major isomer arising from 3, which
indicated that the respective major products were formed
from reaction at opposite aldehyde faces (this is consistent
with the allylation results described in Table 1). Secondly, the
major and minor diastereoisomers from the reaction of 1 and
2 have a different relative configuration at C2 and C3, while
the major and minor diastereoisomers 11b,d from reaction of
3 possess the same relative configuration at C2 and C3. This
indicates complete aldehyde facial selectivity for hydroxyal-
lylation of 3 (this is not the case for the allylation of 3, see
Table 1). Thirdly, the major and minor isomers arising from 3
possess a C3/C4 syn and anti relationship, in contrast to the
syn relationship found for both the major and minor isomers
from hydroxyallylation of 1 and 2. This outcome indicates that
This stereochemical outcome is rationalized by formation
of chelate 13 after initial allyl stannane attack, which can
undergo a second reaction by a suitably small nucleophile
such as allylstannane 4, but not by a larger reagent such as 8.
From 13, Si-face attack is prevented by steric hindrance from
the allyl group.[12]
These insights led to exploiting the clean monohydroxy-
allylation process for the synthesis of nonsymmetric double
addition products by subsequent addition of a more reactive
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Table 3: Three-component hydroxyallylation–Grignard/aldol process.
Scheme 1. Confirmation of the relative stereochemistry of the hydroxy-
allylation vinyl magnesium bromide double-addition product. The
hydrogen atoms of the tert-butyl group in the X-ray crystal structure
are omitted for clarity; the thermal ellipsoids are shown at 35%
probability.
Entry
R
d.r. (11)[a] Product Yield [%][b] a/b/c[c]
1
2
3
4
5
6
7
Me[d]
Me[e]
vinyl
Et
Ph
allyl
91:09
93:07
90:10
89:11
90:10
90:10
16a–c
16a–c
17a–c
18a–c
19a–c
20a–c
21a–c
51
56
67
59
60
51
64
79:9:12
87:4:9
>9:0:<1[f]
88:0:12
our delight, the process resulted in the formation of 26 in good
yield and stereoselectivity. Only two major isomers could be
isolated from the crude reaction mixture, along with very
small quantities of two minor diastereomers[6b] (< 1%, not
shown). Both isomers were derived from the major hydroxy-
allylation intermediate. Clearly, compared to the allyl stan-
nane 8, which also reacts through a secondary carbon atom,
the enhanced reactivity of enolate 25 is sufficient to overcome
the hindered nature of intermediate 15 for second addition.
Interestingly, the major isomer was identified as the 2,3-syn
product, thus suggesting that the aldol reaction with the E-
enolate 25 (> 95% E)[13] occurred via an acyclic transition
state enforced by the chelation of the aldehyde group.[14] The
formation of the minor 2,3-anti adduct could be the result of a
competing Zimmerman–Traxler or retro-aldol isomerization
pathway.[13]
90:0:10
>9:0:<1[f]
94:0:6
CH2COOtBu 92:8
[a] Ratio of hydroxyallylation product determined on an aliquot. [b] Yield
of product isolated after chromatography. [c] Determined by 1H NMR
analysis. A fourth possible isomer was never observed. [d] MeLi.
[e] MeMgBr. [f] Precise diastereomeric ratio could not be determined.
The thermal ellipsoids of the X-ray crystal are shown at 35% probability.
nucleophile (Table 3). When using methyl lithium (entry 1),
reaction of the remaining (chelated) aldehyde group led to
stereotetrads 16a–c in a 79:9:12 ratio. X-ray crystallographic
analysis of a derivative of 16a (22a) confirmed the stereo-
selection was as observed for the diallylation reaction to give
14. As a control, an aliquot of the reaction mixture was
subjected to aqueous workup before MeLi addition, and
resulted in a 91:9 ratio of 11b/11d. Hence it was concluded
that the second addition proceeded with good (ca. 9:1)
diastereoselectivity. When 15 was reacted with MeMgBr
(entry 2), the second addition was more selective, and larger
Grignard reagents (entries 3–6), reacted with virtually com-
plete selectivity, thus giving stereotetrads in good yields.
Reaction of intermediate 15 with the lithium enolate derived
from tert-butyl acetate also led to complete selectivity for the
second addition step, with 21 formed in excellent diastereo-
selectivity (entry 7).
A short synthesis of polysubstituted cyclohexenes was
carried out by a facile ring-closing metathesis reaction of the
17a,c mixture (Scheme 1). The resulting separable cyclo-
hexenes 23a,c were each submitted to catalytic hydrogenation
to obtain the corresponding crystalline derivatives 24a and
24c. X-ray crystallographic analysis in both cases clearly
reveals the anti configuration of the 1,3-diol unit flanking the
quaternary center, as well as the different relative config-
urations at the 1,2-OH and 1,2-OTBDMS centers, which
further confirms the complete stereoselectivity of the second
addition reaction.
Hence this malonaldehyde three-component bisaddition
process allows rapid access (3 steps) to acyclic stereoarrays
including an all-carbon quaternary stereocenter from cheap
and simple tris-1,1,1-(hydroxymethyl)ethane. The scope of
this process will be easily extended by employing different
malonaldehydes and nucleophiles. The short de novo syn-
thesis of polysubstituted cyclohexenes 23, which are highly
functionalized building blocks for novel carbasugar and
inositol analogues containing a quaternary center, is an
illustration of the synthetic usefulness of the method. While
the aforementioned enantioselective bidirectional process
developed by Krishe and co-workers[4] is a superior way to
obtain pseudo-C2-symmetric allylation products, our current
Finally, the synthesis of stereopentads was investigated by
a hydroxyallylation propionate aldol sequence [Eq. (2)]. To
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Behnke, A. T. Destree, T. A. McCormack, J. Adams, L. Pla-
focus is on the three-component sequential bisaddition
process to give nonsymmetric adducts. The requirement of a
chelate intermediate for this process suggests a chiral
auxiliary approach is preferable for obtaining enantioen-
riched compounds (addition on the isolated monoaddition
product occurs with significantly lower diastereoselectivi-
ty).[6b] Additional investigations to achieve these goals are
currently ongoing.
In conclusion, chelation of non-enolizable 1,3-dialdehydes
allows diastereoselective monoaddition reactions with the
relative stereochemistry dependent on the choice of protect-
ing group of a pendent hydroxymethyl group. Furthermore, a
second addition reaction is also possible with very high
diastereoselectivity. This work introduces prochiral 2,2-dis-
ubstituted malonaldehydes as versatile substrates for the
synthesis of stereochemically dense acyclic systems including
all-carbon quaternary centers, which is an area of significant
current interest.[5]
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Received: October 19, 2011
Published online: December 23, 2011
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[12] The intermediate chelate leading to the minor isomer (allyl
group equatorial, not shown) can in principle lead to both anti
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[13] C. H. Heathcock, C. T. Buse, W. A. Kleshick, M. C. Pirrung, J. E.
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Keywords: chelates · magnesium · nucleophilic addition ·
stereoselectivity · synthetic methods
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