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meso Compounds Stepchildren or Favored Children of Stereoselective Synthesis.

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Reviews
R. W. Hoffmann
Stereoselective Syntheses
meso Compounds: Stepchildren or Favored Children of
Stereoselective Synthesis?
Reinhard W. Hoffmann*
Keywords:
asymmetric induction · meso
compounds · stereoselective
synthesis · synthetic methods
A symmetrical arrangement of
chiral elements is no problem in
architecture. But certainly in stereoselective synthesis!
Angewandte
Chemie
1096
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433-7851/03/4210-1096 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2003, 42, No. 10
Angewandte
Chemie
meso Compounds
After more than a quarter of a century of development, the methodology of stereoselective synthesis appears to be fully matured. In line
with this, the potential that meso compounds offer in stereoselective
synthesis is clearly recognized. The use of meso compounds in synthesis is, however, in no way commensurate with this potential, because, ironically, the synthesis of meso compounds in the first place is a
problem of stereoselective synthesis. Present-day methodology does
not provide many useful solutions to this problem. This Review
therefore addresses the strategies available for the synthesis of more
elaborate meso compounds whose stereogenic centers have a distance
> 1,4 between them. meso Compounds with more than four stereogenic centers are also considered. The criteria used in choosing from
several strategies in the synthesis of such compounds are discussed.
From the Contents
1. Introduction
1097
2. The Classical Synthesis of meso
Compounds
1098
3. Principal Approaches to meso
Compounds
1099
4. The Bidirectional Approach
1100
5. The Convergent Approach
1103
6. The Linear Approach
1106
1. Introduction
meso Compounds? The name brings back memories of
introductory organic chemistry, when tartaric acid was the
subject of the lecture. meso-Tartaric acid (1) is one of the four
different substances that have the constitution of tartaric acid
(Scheme 1).
COOH
HO C H
H C OH
COOH
D-tartaric
acid
= (S,S)-(–)
COOH
H C OH
HO C H
COOH
COOH
COOH
COOH
HO C H
H C OH
H C OH
H C OH HO C H
H C OH
COOH
COOH
COOH
D,L-tartaric acid
L-tartaric acid
meso-tartaric acid
= (R,R)-(+)
1
m.p. 172–174 °C 172–174 °C
147 °C
210–212 °C
Scheme 1. Overview of the various tartaric acids.
meso Compounds can reach a conformation with a plane
of symmetry in conformation 1 a or a center of inversion in
conformation 1 b among the continuum of freely accessible
conformations (Scheme 2). The symmetrical nature of mesotartaric acid derives from the fact that it has two stereogenic
centers with identical substitution but opposite configuration.
meso-Tartaric acid (1) is therefore optically inactive, as the
contributions of the two stereogenic centers to the Cotton
effect compensate each other.
Is this property more than a superfluous curiosity that one
has to memorize? Some may remember that 100 years ago the
properties of meso compounds were the key feature in the
argumentation that led Emil Fischer to the assignment of the
configuration of the carbohydrates (Scheme 3), one of the
true momentous achievements of chemical science.[1]
(configuration unknown at
time of experiment)
D-xylose
optically active
COOH
CHO
CHOH oxidation H C OH
CHOH
CHOH
H C OH
H C OH
COOH
CH2OH
xylaric acid
optically inactive
= meso
(hence configuration at C2)
(configuration known)
Scheme 3. Configuration assignment at C2 of xylose based on the symmetry of xylaric acid.
Furthermore, meso compounds fell into and rested in
oblivion for a long time until enantioselective synthesis
emerged as a topic of general interest. We therefore take a
brief look at the stereochemical aspects of reactions of meso
compounds. What happens if a meso compound, for example,
anhydride 2 reacts with an achiral reagent at only one of the
two mirror-image-related (i.e. enantiotopic) carbonyl groups
(Scheme 4)? This reaction breaks the symmetry and therefore
generates a chiral product 3. For reasons of symmetry the rate
of reaction is equal at either carbonyl group of 2. The product
3 is therefore obtained as a racemate.
XMgO
O
O
O
COOBn
BnOOC
O
O
+
O
O HO
2
3
O
OH O
1:1
COOBn
ent-3
Scheme 4. Reaction of a meso anhydride with an achiral alkoxide.
COOH
HOOC
HO
HOOC
H OH
H OH
·
H
COOH
H OH
1a
1b
Scheme 2. Symmetric conformations of meso-tartaric acid.
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
[*] Prof. Dr. R. W. Hoffmann
Fachbereich Chemie, Philipps-Universit't Marburg
Hans-Meerwein-Strasse, 35032 Marburg (Germany)
Fax: (+ 49) 6421-282-5677
E-mail: rwho@chemie.uni-marburg.de
2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433-7851/03/4210-1097 $ 20.00+.50/0
1097
Reviews
R. W. Hoffmann
When a meso compound reacts in the same fashion with
an enantiomerically pure chiral reagent, diastereomeric
products are generated. An example is given in Scheme 5
by the reaction of the meso anhydride 2 with the chiral
alkoxide 4.[2] The resulting products 5 and 6 are enantiomerically pure and are formed in a ratio determined by kinetic
4
O
O
O
O
Ph
H
H
Ph
Ph
O OiPr
Ti
O OiPr
Ph
+
O
O
O
O
O
OH
O HO
2
99 : 1
O
O
OH O
Scheme 6. Kinetic resolution applied to the desymmetrization of a
meso compound.
Ph
XMgO
O
Ph
Ph
COOBn
BnOOC
Ph
O
OHO
O
COOBn
O
OH O
5
2
Ph
+
O
6
+,
H Ac2O
and more in our ability to generate meso compounds in the
first place. A short overview (Scheme 7) shows that the meso
compounds typically used in synthesis are small molecules
such as 7–13 with two to four—frequently adjacent—stereogenic centers.
or
Scheme 5. Reaction of a meso anhydride with a chiral alkoxide.
H
OPG
HO
O
O
O
H
OH
O
HO
OH
7
resolution (1:1 for the magnesium alkoxide; 6:1 for the
lithium alkoxide). Being diastereomeric, the products 5 and 6
may be separated by simple means.
This process is in all respects identical to the classical
resolution of racemates. In both cases, one is generally
interested in only one of the diastereomeric products. Thus, at
most 50 % of the starting material can be converted into the
desired product. Fischli et al. pointed out that meso compounds may have an advantage in such situations, the socalled “meso trick”.[3] This advantage is a consequence of the
fact that when starting from a meso compound it is in many
cases possible to convert the undesired diastereomer back
into the precursor meso compound. On account of this
recycling step technically all of a meso compound can be
converted into the desired enantiomer of the product.
Of course, not only classical resolution using an enantiomerically pure “resolving agent” can be applied to meso
compounds. Much more attractive is kinetic resolution,[4]
which allows the effective differentiation between two
enantiotopic functional groups of a meso compound. This
provides directly high yields of a single product with high
enantiomeric enrichment. An example is given in Scheme 6.[5]
These advantageous techniques were developed rapidly
over the last years and have been reviewed frequently.[6] In
turn, the bottleneck of a more general application lies more
Reinhard W Hoffmann studied at the Universitt Bonn (1951–1958) and completed
his PhD under B. Helferich. Two years of
postdoctoral studies at the Pennsylvania
State University were followed by a second
postdoctoral stay with G. Wittig at the Universitt Heidelberg. He completed his habilitation at the Universitt Heidelberg in 1964.
In 1967 he was appointed lecturer at the
TH Darmstadt. Since 1970 he has been professor of organic chemistry at the Universitt
Marburg (emeritus status since 2001). He
has been visiting professor at several universities worldwide.
1098
8
Bn N
10
OH
N Bn
AcO
OAc
H
H
OPG
11
HO
12
O
OH
O
O
OH
9
HO
O
PGO
PGO
O
O
13
Scheme 7. Examples of common meso compounds used in synthesis:
7,[7] 8,[8] 9,[9] 10,[10] 11,[11] 12,[12] and 13.[13]
meso Compounds with more than four stereogenic
centers, or meso compounds with nonadjacent stereocenters
find current interest because of their physical properties, for
example, their conformational behavior.[14] Their main importance, however, relates to subsequent enantiotope-selective desymmetrization, which gives rapid access to enantiomerically pure intermediates with long sequences of stereocenters. The methods to synthesize such meso compounds are,
however, underdeveloped and in clear disproportion to their
importance. We therefore review herein strategies and
problems related to the synthesis of meso compounds with a
> 1,4 distance between stereogenic centers, including those
with more than four stereogenic centers. This review is not
intended to be comprehensive, but illustrates the principles
with examples, among others, from the research of our own
group. We hope to elaborate in this review the criteria by
which a judgement between the alternative strategies and any
combination thereof in the synthesis of complex meso
compounds can be made.
2. The Classical Synthesis of meso Compounds
meso Compounds are symmetrical and therefore their
synthesis may be based on pairwise symmetrical bond
formation, (Scheme 8, [Eq. (1)]), or on the reaction at one
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
Angewandte
Chemie
meso Compounds
COOH
COOH
cis dihydroxylation
HO
HO
COOH
H
H
COOH
O
(1)
ROOC
COOR
cis
O
O
COOH
HOOC
trans
14
H
X
ROOC
exo
COOR
O
COOR
COOR
X
X
X
COOR
ROOC
X
16
X
endo
X
O
15
COOR
COOR
O
O
X
17
COOR
18
Scheme 9. Classical approach to meso compounds through Diels–
Alder addition.
A further discussion of this classical chemistry is not
intended. But if one recognizes that cyclic or open-chain meso
compounds with a distance of > 1,4 between stereocenters or
meso compounds with 4 adjacent stereocenters may not
generally be approached by this classical technique, one
appreciates exceptions from this generalization as spectacular
(Scheme 10).[16]
3. Principal Approaches to meso Compounds
Other routes are required if the synthesis of more
elaborate meso compounds is to be advanced. Principally
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
O
O
O
Scheme 10. Double Diels–Alder addition to give a meso compound
with nine stereogenic centers.
HO
of two symmetry-related homotopic groups, (Scheme 8,
[Eq. (2)]). In the latter approach, the intermediate 14 can
be used as a racemate.
The classical approach of syn addition to a p system can
readily be extended to the Diels–Alder addition and all
related cycloaddition reactions (e.g. photo [2þ2] cycloadditions, oxy–allyl cycloadditions) in which each of the reaction
partners has (or is able to reach a conformation which has) C2v
symmetry. In the generalized cycloaddition shown in
Scheme 9, the formation of two products, the exo-15 and the
endo cycloadduct (17) is possible. exo/endo-Selectivity[15] is an
important issue in synthesis, but this topic is not addressed in
this Review, as both the endo and exo products are meso
compounds (Scheme 9). Although the meso compounds 15
and 17 obtained in this manner are cyclic, opening of a ring
bond that is bisected by the plane of symmetry allows access
to open-chain meso compounds, for example, 16 and 18.
COOR
COOR
H
95 %
Scheme 8. Classical approach to meso compounds by addition to prochiral alkenes.
X
O
COOH (2)
H
trans dihydroxylation via epoxide
X
H
OH
COOH
HOOC
HOOC
ROOC
5 kbar
+
the following three strategies can be used to prepare complex
meso compounds such as 19 (Scheme 11):
1) One could start from a small meso compound, the core
structure, and extend it bidirectionally (from both termini),
thus creating the additional stereogenic centers in a symmetrical fashion. The problem with this approach is that in a
single operation, stereogenic centers of opposite configuration are to be generated. This precludes the use of any chiral
Ar
O
Ar
O
O
O
Ar
O
O
O
Ar
O
O
O
Ar
O
O
O
Ar
O
O
O
O
O
19
divergent from central
building block
convergent from two mirror
image ends
linear from one end
Scheme 11. Principal synthetic approaches to meso compounds.
reagents, catalysts, or auxiliaries and leaves one to deal with
substrate-based asymmetric induction as the only tool to be
used.
2) A second option involves the construction of the
desired meso compound in a convergent fashion. This requires
access to two constitutionally identical, but enantiomeric
building blocks, each with high enantiomeric purity, and to
combine these building blocks. This approach can be successful if the linkage region is devoid of stereogenic centers. If the
linkage region includes several stereogenic centers, as is the
case in 19, this approach becomes problematic: in setting up
these stereocenters there is a potentially opposing asymmetric
induction from each of the two enantiomorphous ends of the
molecule.
3) Clearly, there is always the possibility of a linear
approach starting from one end of the target molecule. In
such an approach, it is normally advantageous to have the
starting building block enantiomerically pure. This then
allows all the additional stereogenic centers to be created
step by step, using the currently available tools of stereoselective synthesis. Evidently, the stereogenic centers have to
be created in such a fashion, that in the end a symmetrical
molecule, the meso compound, is obtained.
In practice, the synthesis of meso compounds may
combine elements of all three strategies. It is the aim of this
Review, to illustrate the three different approaches and to
discuss the advantages and disadvantages associated with
these approaches.
1099
Reviews
R. W. Hoffmann
4. The Bidirectional Approach
OH
MeO
Bidirectional chain extension of a symmetrical molecule
allows rapid evolution of a synthesis, as two skeletal bonds are
formed in a single operation. This has been highlighted in
reviews by Poss and Schreiber[17] and by Magnuson,[18] in
which examples are give for the bidirectional elaboration of
both C2-symmetric and s-symmetric precursor molecules.
Although the former is easy, only the latter gives rise to meso
compounds. The starting compounds may be a small meso
compound, being itself generated by one of the classical
approaches or in a nonstereoselective manner. The latter
holds in an early example of a bidirectional approach to a
meso compound from Schreiber and Goulet (Scheme 12).[19]
O
O
O
tBuOOH
25
CH2=CHMgCl
O
O
O
TIPS
OH O
OH O
O
OMe
O
O
O
95 %
O
TIPS
OH OH O
OH OH O
O
MeO
OMe
27
O
TBS TBS TIPS TBS TBS
O
O
O
O O
O
(–)-(Ipc)2B-allyl
O
28
O
O
O
OH O
TBS TBS TIPS TBS TBS
O
O
O
O
OH
O
HO
74 %
O
MeO
21
82 %
NaBH4
OMe
O
20
epimer.
O
26
TMSOTf
O3
OH
O
MeO
O
O
[VO(OiPr)3]
OMe
29
OH
OH O
22
O
nBuLi
24
23
O
O
O
30
O
OH O
O
O
O
OH
14 %
O
5 steps
O
OMe OMe OMe OMe OMe OMe OMe OMe
tolytoxin
Scheme 13. Bidirectional synthesis of tolytoxin via a meso polyol derivative.
Scheme 12. Bidirectional synthesis of a meso polyol derivative.
The starting material meso dialdehyde 20 was obtained
from a nonstereospecific reaction followed by diastereomer
separation. The addition of vinylmagnesium chloride to 20 in
the next step was also nonstereospecific. However, thermodynamic control was enlisted to give a stereochemically
homogeneous meso product 22 after epimerization of the
dialdehyde derived from 21. Further bidirectional elaboration
was effected via the bisallyl ether 23, Wittig rearrangement of
which proceeded under substrate-based asymmetric induction to give the meso polyol derivative 24.
The starting point for a bidirectional approach does not
necessarily have to be a meso compound such as 20. It is
sufficient when the starting compound has s symmetry, as is
the case with the alcohol 25. Its elaboration into tolytoxin (30;
Scheme 13) was a landmark achievement in synthetic development,[20] and demonstrated a focused access to a complex
meso compound 28 with multiple stereogenic centers and its
ultimate conversion into an enantiomerically pure product.
The sequence started with the bishomoallylic alcohol 25.
The hydroxy group served to direct[21] the epoxidation to give
the meso bisepoxide 26 with 15:1 selectivity. Next, the
aromatic rings were elaborated into b-ketoester functions.
1,3-syn-Selective reductions furnished the tetraol 27 with 12:1
diastereoselectivity. Finally, the product was refunctionalized
1100
to give the meso dialdehyde 28, which marked the end of the
bidirectional elaboration. The symmetry-breaking step was
the reaction with ()-(Ipc)2B-allyl, which produced the diol
29 with > 98 % ee under reagent control of diastereoselectivity. Chemodifferentiation of the end groups was then
achieved by acetonide formation under thermodynamic
control, favoring the all-syn acetonide. The rest of the
synthesis of tolytoxin (30) was unexceptional.
Instructive examples in the synthesis of complex molecules with (latent) s symmetry come from the synthetic
efforts towards rifamycin S. The ansa chain between C19 and
C27 (see 31) has a plane of symmetry (cf. Scheme 14). Hence,
an effective synthesis of rifamycin could be based on a meso
compound of type 31 and ultimate end-group differentiation.
AcO
19
OH OH OH OH OH
OH OH
MeO
27
OH O
27
O
NH
O
O
O
19
31
rifamycin S
O
Scheme 14. Symmetry in the ansa chain of rifamycin S.
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
Angewandte
Chemie
meso Compounds
This was demonstrated in a bidirectional strategy by Still and
Barrish (Scheme 15).[22] Hydroboration of the symmetrical
bisallylic alcohol 32 set up four new stereogenic centers under
TrO
OTr
OH
BH2
1)
OH OH OH
TrO
90 %
d.r. 5:1 33
–
3) HOO
32
OTr
OH OH OH
BH2
1)
OH OH OH OH OH
TrO
76 %, d.r. 4:1
–
3) HOO
34
O
OH O
MeO
OMe
OTr
35
substrate-based asymmetric induction (meso/rac = 5:1). The
triol 33 was then elaborated into the substrate 34 for the next
bidirectional hydroboration, which furnished the pentaol 35
with a 4:1 meso/rac selectivity.
Another landmark paper in the synthetic efforts towards
rifamycin S describes the synthesis by Harada et al.[23] of the
building block 42 (Scheme 16). The starting point was the ssymmetric TBS-protected bisallylic alcohol 36. Diastereose-
HO
O
OH
O
B
39
36
38
37
OH O
TBS
OH
OTBS
Me3SiO
Bn
5 steps
OH OH O
40
OH OH
41
Bn
OH OH O
O
O
O
4 steps
OH O
O
O
O
42
Scheme 16. Bidirectional synthesis of the ansa chain of rifamycin using
a double crotylboration reaction.
lective bidirectional hydroboration provided the meso diol 37
with 13:1 selectivity. Oxidation of 37 gave the latent
dialdehyde 38. The next chain extension is a bidirectional
crotylation with the crotylboronate (E)-39, which proceeded
with high asymmetric induction from the stereocenters a to
the aldehyde function.[24] The resulting meso compound 40
with seven contiguous stereogenic centers was then subjected
to a laborious protecting-group exchange to give 41 in
preparation for the desymmetrization step. The latter was
effected by kinetic resolution of the enantiotopic diol units in
41 with a menthone derivative; a selectivity of 4.5:1 was
attained. Up to this symmetry-breaking step, all new stereocenters had to be created by substrate-based asymmetric
induction while proceeding in a bidirectional manner.
The elegance of this approach becomes apparent when
comparing the route of Harada and co-workers (Scheme 16)
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
O
BnO
5 steps
MeO
TBSPD
O
O
OH
44
45
LiO
O
O
OH O
5 steps
O
O
46
O
OTBS
OH O
TBSPD
HO
OH O
Scheme 15. Double hydroboration for bidirectional synthesis of the rifamycin ansa chain.
TBS
OH O
OH
O
PLE
43
2) BH3,
38 %
OTr 9 steps
TrO
2) BH3,
with an earlier synthesis of a rifamycin building block 50
published by Born and Tamm, (Scheme 17) who also noted
the latent s symmetry of the target structure 31.[25] They
therefore started from the meso diester 43, but broke the
symmetry in the first step by a PLE-catalyzed enantiotopi-
47
O
O
O
OAr
LiO
O
O
OAr
48
49
O
ArO
OH O
O
O
OAr
50
Scheme 17. Sequential bidirectional elaboration of the ansa chain of rifamycin.
cally selective ester hydrolysis. The resulting half-ester 44 was
converted into the ketone 45, reduction of which set the
central pseudostereogenic center in 46 by substrate-based
asymmetric induction. The product 46 was converted into the
aldehyde 47. Chain extension was then effected by an aldol
addition with high asymmetric induction from the stereocenters resident in the aldehyde 47.[26] The resulting bhydroxyester 48 was then subjected to another round of
protecting-group- and functional-group-interconversion steps
to give the aldehyde 49. The same aldol chain extension was
then carried out a second time to give the target molecule 50.
In essence, Born and Tamm used a bidirectional strategy,
but executed the chain extension sequentially, thus requiring
numerous protecting-group manipulations. Harada and coworkers carried out the synthesis via the meso compound 38
and attained a simultaneous chain extension at both ends.
One can speculate that a lithium enolate addition to 38 or an
equivalent dialdehyde may not have succeeded on both
aldehyde functions concomitantly, because the first aldol
formed would have led to an unreactive hemiacetal with the
second aldehyde moiety. In this vein, the crotylboration
reaction used by Harada and co-workers was the right choice,
because hemiacetals also react with crotylboronates, albeit
quite sluggishly.
The lesson from these two syntheses is that a bidirectional
approach to meso compounds works, if the two reacting ends
of the molecule do not interfere with one another. Such
noninterference holds clearly for the two aldehyde functions
in the meso dialdehyde 51 used in our synthesis of 56 by a
bidirectional approach (Scheme 18).[27] Bidirectional Mukaiyama aldol addition to the dialdehyde 51 proceeded with
a 6:1 selectivity favoring the meso dialdol 52. After protection
of the hydroxy groups as pMB ethers, the derived dicyclohex-
1101
Reviews
R. W. Hoffmann
OTMS
O
51
O
O
O
BF3ïOEt2
pMP
OH O
63 %, isolated
O
+ O
OH O
pMP
OH O
6 : 1
52
O
OMe
MeO
O
O
O
4 steps
O
O
OH O
60
59
pMP
HO
O
pMBOC(NH)CCl3, CF3SO3H
pMB
O
O
O O
pMB
O
O
O
pMP
O
O
pMB
O
53
Scheme 20. Synthesis of meso-dimethylsuccindialdehyde.
53
5 : 1
OH O O O O
pMB pMB pMP
Me4N+ (AcO)3BH–
O
O OH O
pMB pMB
54
acetone
+
O
OH O O O O
pMB pMB pMP
OH OH O O O
pMB pMB pMP
55
O
O OH O
pMB pMB
72 %
H2, [Pd(OH)2] / C
48 %
96 %
O
O 62
pMB
cHex2BCl, NEt3
O
OH
61
69 %
O
OH OH OH OH O
OH OH O
pMB pMB
O
OH OH OH
pMP
MeOC(CH3)=CH2
90 %
56
O
O
O
O
O
O
O
O
O
pMP
Scheme 18. Bidirectional synthesis of oligodioxanylmethanes with s-symmetry.
ylboron enolate could be added in a bidirectional manner to
the aldehyde 53 to give the bisaldol with a 5:1 selectivity
favoring the meso compound 54. Subsequent 1,3-anti-selective reduction with triacetoxyborohydride furnished the meso
tetraol 55, again in a twofold manner. The tetraol 55 was than
readily converted into meso-56. The rapid evolution of this
synthesis demonstrates the power of the bidirectional approach to meso compounds with multiple stereocenters.
It is worth repeating that this bidirectional-synthesis
strategy is successful if the reactive end groups do not
interfere with one another. This situation was not the case
when we targeted the meso compound 57 in a bidirectional
approach (Scheme 19).[28] We planned to elaborate the meso
diester 59 into the meso diiodo compound 58 and onward to
the target molecule 57, all in a bidirectional manner. The
meso diester was readily derived by a Claisen rearrangement
of crotyl propionate 60. Bidirectional reduction to the meso
diol 61 was no problem, but after oxidation of 61 to the
dialdehyde 62, a bidirectional Wittig reaction was not possible
(Scheme 20).
Apparently the reactive end groups in 62 interacted
with each another. We were therefore forced to take the
same detour as Born and Tamm and turned to a sequential
chain extension at each end of the molecule (Scheme 21),
certainly not an efficient synthetic sequence. However,
once we had reached the diiodo compound 58, the
reacting ends of the molecule were separated from each
other far enough to allow a bidirectional continuation of
the synthesis up to the end. This allowed the conversion of
OH
the diiodo compound 58 into the bisallylboronate 63. Its
bidirectional reaction with formaldehyde proceeded under unprecedented substrate-based asymmetric induction
(A1,3-strain control)[29] to give the diol 64. The latter was
O
protected and converted into the dialdehyde 65, in which
the carbonyl groups are in the 1,6-positions. These functional groups were apparently remote enough from one
another to allow a bidirectional cuprate addition, which
furnished the diol 66 under Felkin–Anh control. The diol
66 was then readily converted into the target meso compound
57 (Scheme 22). For a related approach to another meso
compound with six adjacent stereocenters, see reference [30].
When dealing with cyclic systems with s symmetry one
usually does not consider them as meso compounds, but there
is really no difference regarding the strategies of synthesis. A
bidirectional synthesis starting from a s-symmetric building
block is the method of choice. Two recent examples may
illustrate this idea. First, Spivey et al.[31] converted the epoxide
67 into the b-cyanoalcohol 68. Epoxidation of the two
symmetry-related double bonds could be effected under the
direction of the tertiary hydroxy group to give the meso
bisepoxide 69. Reaction of the latter with AlMe3 furnished
the meso triol 70 (Scheme 23).
TBSO
HO
Swern
TBSCl
NaH
OH
61
TBSO
I
HO
HF
oxid.
OH
75 %
Ph3P=CHI
I
TPAP
NMO
CH3CN
50 %
90 %
I
Ph3P=CHI
66 %
Scheme 19. Retrosynthetic analysis of open-chain meso compound 57.
1102
I
58
Scheme 21. Sequential bidirectional synthesis of meso bisiodoalkene
58.
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
Angewandte
Chemie
meso Compounds
I
1) nBuLi, –110 oC
I
2) ClCH2 B
58
O
O
63
B
O
O
HO
TBSO
CH2O (gaseous)
TBSCl
THF, –50 oC
imidazole
ca. 50 %
TBSO
OH
64
TBSO
Me2CuLi
O
OTBS
65
99 %
OTBS
90 %
O
1) O3
2) Ph3P
Reaction with 3-trimethylsilylpropyne provided the bisallene
73 with axial entry of the allene moieties. Oxidative degradation furnished the dialdehyde 74, which on reaction with
dimethylsulfoxonium ylide furnished the diepoxide 75 with
20:1 asymmetric induction from the resident stereocenters.
The symmetry of this centrosymmetric diepoxide was then
broken by an enantioselective epoxide hydrolysis,[33] that is, by
kinetic resolution of the two enantiotopic ends of the
molecule to give the desired building block 76. This approach
to 76 is much shorter than a reaction sequence reported
earlier, which did not capitalize on the latent symmetry of the
target structure.[34]
O
B
O
HO
OH
OTBS
66
75 %
5. The Convergent Approach
O
OMe
Bu4N+ F–
O
PyH+ TosO–
As a prelude to a synthesis of a conformationally
preorganized flexible b-turn mimetic,[35] we targeted the meso
diol 77 to study its conformational properties.[36] The stereogenic centers in 77 are not adjacent and span a distance of >
1,4. Especially as the bond that is the locus of the center of
inversion (or that is bisected by a plane of symmetry) is not
attached to stereogenic centers, a convergent approach was
envisaged (Scheme 25), by which two formally enantiomeric
O
66 %
57
O
Scheme 22. Bidirectional synthesis of a meso bisdioxanylethane.
CN
CN
[VO(acac)2]
Et2AlCN
O
O
tBuOOH
67
98 %
OH
68
O
OH 69
87 %
CN
Me3Al
88%
HO
OH
OH
70
Scheme 23. Symmetrical synthesis of a meso triol.
The second example involves the synthesis of 76, a
precursor for polyether antibiotics (Scheme 24). Nelson and
co-workers[32] converted the racemic epoxide 71 in one step
into the centrosymmetric and hence achiral bisacetal 72. This
first step corresponds to the classical route to meso compounds delineated in Scheme 8, as the epoxide is opened with
inversion of configuration. The concomitant acetal formation
proceeded under thermodynamic control to place both
methoxy groups in 72 in axial positions. The bisacetal 72
was then elaborated further in a bidirectional manner:
O
MeO
PPTS
O
O
rac 71
O
·
92 % 73
H
O
MeOH
H
85 % 72
SiMe3
O
OMe
H
1) O3
H
·
O
O
O
H
2) Me2S
98 % 74
H
O
O
75%
75
O
H
H
O
Me3SiOTf
Me3SO+ I–
O
O
ca. 98 % 76
O
O
O
O
LiAlH4
HO
OH
NaH
81
77 %
supported porcine
pancreatic lipase
H
O
O
O
Scheme 24. Synthesis of a centrosymmetric brevetoxin building block.
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
building blocks 78 and 79 were to be linked to one another.
The task of having to prepare two essentially enantiomeric building blocks can be lessened in this case, as 78 and 79
have a latent plane of symmetry themselves. They could
therefore both be derived by enantiotope-selective desymmetrization of a meso compound such as 80. Compound 80 is
readily available by reduction of meso-2,4-dimethylglutaric
anhydride (81; Scheme 26).
Desymmetrization of 80 was effected by lipase-catalyzed
acetylation to give 82 in 62 % yield and 87 % ee. Although
meso
H
O
Scheme 25. Retrosynthetic analysis of extended s-symmetric diol 77.
HO
62 %, 87 % ee
80
MeOAc
OAc
82
AcO
+
OAc
38 %
Scheme 26. Enzymatic desymmetrization of a meso diol.
1103
Reviews
R. W. Hoffmann
longer reaction times could have led to 82 with higher ee
values at the expense of the yield,[37] the use of this option was
not deemed necessary because the ee value would be
increased upon combination of the two building blocks 78
and 79 based on Horeau's principle.[38] The monoacetate 82
with 87 % ee was therefore used as the starting point for the
generation of the building blocks 83 (corresponding to 79)
and 85 (corresponding to 78) as shown in Scheme 27.
Ar
O
Ar
Ar
O
O
O
86
O
O
O
Ar
O
+ ? +
O
O
O
87
O
ent-87
convergent
Scheme 29. Retrosynthesis of a meso terdioxane.
Ph
HO
K2CO3
TIPSCl
OH
OAc
PCC
OH MeSO Cl
2
PhSLi OTIPS
SPh mCPBA OTIPS
84
63 %
DMP
SO2Ph
The monoacetate 82 was directly oxidized to the required
aldehyde 83. Entry into the quasienantiomeric series was
gained by interchange of the end-group protecting groups of
82 to give 84, a possibility opened by the latent symmetry of
the compounds. The elaboration of 84 into the building block
85 was then straightforward. The two quasienantiomeric
building blocks were then joined in an E-selective Julia–
Lythgoe olefination to give the target molecule 77
(Scheme 28).
OAc
OAc
OTIPS
SO2Ph
nBuLi Ac2O
NaHg
NEt3
MeOH
86 %
91 %
OTIPS
62 %
HCl
85
EtOH
OH
90 %
HO
O
O
H
60 %
O
H
ent-87
85
92 %
Scheme 27. Synthesis of two enantio-complementary building blocks
from a single precursor.
83
O
HO
Ph
87 % O
92 %
PhCH(OMe)2
TosOH
83
NEt3
O
COOMe
MeOOC
100 %
82
95 %
95 %
H3B·SMe2
imidazole
MeOH
OTIPS
O
OAc
77
Scheme 28. Convergent synthesis of an extended open-chain meso diol.
Scheme 30. Synthesis of the enantiomerically pure building blocks.
the central ring we envisaged an aldol addition of ketone 88
and the aldehyde 87. This amounts to the creation of two
(ultimately three) stereogenic centers in the linkage region,
and that is where the problem resides.
Both the aldehyde 87 and the ketone 88 have stereogenic
centers from which substrate-based asymmetric induction in
the formation of the new stereogenic centers may originate.
The configuration of the resident stereocenters in 88 and 87 is
opposite, although this fact is not necessarily relevant. It is
thus not known whether the asymmetric induction from the
two components is matched or mismatched.[40] If the latter
situation prevails, low diastereoselectivity is to be expected.
Even, in matched situations the desired stereoisomer is not
necessarily favored. Hence the convergent approach to 86 is a
gamble. All one can hope for is that the odds could somehow
be turned in our favor by recourse to the multitude of variants
of stereoselective aldol additions.[41]
The synthesis began with the conversion of the aldehyde
ent-87 into the ketone 88 (Scheme 31).[39] As the relative
configuration of the stereogenic centers of the central ring in
86 required an anti aldol 89 as precursor, ketone 88 was
Ph
Thus, in the case of 77 the convergent approach proved to
be quite effective as both quasienantiomeric building blocks
83 and 85 could be derived easily in an enantiodivergent
fashion from a simple meso diol 80 and because the linkage
region in the target structure did not contain any stereogenic
centers. If the latter condition does not hold, as in the target
structure 86, the convergent approach becomes unpredictable. Nevertheless, compound 86 suggested a convergent
synthesis from 87 and ent-87 as end groups to be linked by
construction of the central dioxane ring (Scheme 29).[39]
A disadvantage of this approach is the inconvenience of
having to synthesize both 87 and ent-87 in separate, however
identical, reaction sequences from (S)- and (R)-dimethyl
malate through Frater alkylation, borane reduction, regioselective acetalization, and oxidation (Scheme 30). For the
linkage of these two building blocks and the construction of
1104
O
Ph
O
O
O
EtMgBr TPAP
O
NMO
H
ent-87
64 %
Ph
O
O
O
OH O
O
or
O
87
88
Ph
O
H
H
O
H
NEt3
H
O
cHex2BCl
O
Ph
Ph
H
O
Ph
O
OH O
O
H
90
89
Ph
OMe
DIBAL
O
TosOH
77 %
Ph
O
H
78 %
H
H
O
O
O
O
H
86
Scheme 31. Convergent synthesis of a meso terdioxane.
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
meso Compounds
Angewandte
Chemie
converted into an E-enolborinate, which upon addiZ-selective coupling
tion to the aldehyde 87 furnished a single product in
89 % yield. The obtained product was an anti aldol
X
product, but we had no means to establish whether it
O
O +
O
O
O
O
O
O
O
O
is the desired 89 or the undesired 90. Nevertheless, we
meso
D,L
rac-91
converted the aldol into the terdioxane by 1,3-syn
92
reduction followed by acetalization. At this stage, a
(diastereotopic faces of the double bond)
meso/D,L selectivity ?
comparison of experimental and calculated 3JH,H
coupling constants suggested that we had indeed
obtained the desired compound 86.
diastereofacial selectivity ?
cis addition
With hindsight, the convergent approach proved
to be viable in the case of 86; this was rather fortunate
X
X
X
X
as the stereochemical outcome of the aldol addition
was not predictable. In a way, this situation resembles
O
O +
O
O
that in convergent natural product syntheses, in which
O
O
O
O
stereogenic centers have to be formed during the
93
94
linkage of the components, each of which have several
≅ dulcitol
≅ allitol
meso-I
meso-II
stereogenic centers. This is a problematic situation,
Scheme 32. Hypothetical access to meso compounds through Z-selective coupling of a
which one normally tends to avoid.[24, 42]
racemate.
As meso compounds are achiral, it is tempting to
ask why a convergent synthesis of a meso compounds
starting with a racemate of the end groups is not
E-selective coupling
O
O
feasible? The answer lies in the fact that the
O
O
techniques of stereoselective synthesis have not been
X
+
O
O
O
developed to the point at which it is possible to handle
O
O
O
meso/d,l selectivity to an acceptable level. This can be
D,L
meso
illustrated with meso compounds 93 and 94
95
(homotopic faces of the double bond)
rac-91
(Scheme 32).
To reach the meso compounds in such a coupling
cis addition
meso/D,L-selectivity ?
reaction, several selectivities have to be mastered
O
simultaneously. The coupling of the two end groups 91
X
O
could be envisioned, for example, by a McMurry
O
reaction (X = O), olefin metathesis (X = CH2), or
diastereotopic selectivity ?
O
rac !
oxidation (X = PPh3) to form an alkene in the linkage
region. This coupling involves, first, meso/d,l selectiv(diastereotopic positions for nucleophilic attack)
ity. Moreover, the E or Z geometry of the double
bond has to be controlled. If we were in a position to
perform this coupling Z selectively, once compound
O
O
X
X
92 was obtained with sufficient selectivity, its further
O
O
+
conversion into either compound 93 (meso-I) or 94
O
O
X
X
(meso-II) would involve diastereofacially selective
O
O
functionalization of a double bond, a task that appears
93
meso-I ≅ dulcitol
meso-II ≅ allitol 94
to be manageable.[43, 44]
Scheme 33. Hypothetical access to meso compounds through E-selective coupling of
It is quite clear that the key problem in the
a racemate.
conversion of rac-91 into either 93 or 94 is the
mastering of meso/d,l selectivity. Unfortunately, such
selectivity is generally not observed in the doubling up
of a racemate such as 91 by a coupling reaction. Indeed, this
topically selective nucleophilic attack to reach either comfact forms the basis of Horeau's test to determine enantiopound 93 (meso-I) or 94 (meso-II) in a controlled manner.
meric enrichment.[38] Admittedly, there had been no efforts to
The latter selectivity is also an uncharted area of stereoselective synthesis.
optimize meso/d,l selectivity for application in synthesis.
In the approaches just discussed, the hopefully mesoIn a related approach, if we were in a position to perform
selective coupling of the end groups and the establishment of
the coupling of the end groups 91 in an E-selective manner to
the stereogenic centers in the linkage region were assigned to
give 95, meso/d,l selectivity would once again be the main
two different chemical operations. A pinacol coupling of 91
problem (Scheme 33). Once compound 95 were in hand, the
would combine both operations in one step (Scheme 34). The
next step, for example, epoxidation of the homotopic face of
pinacol coupling could, however, give rise to a total of six
the double bond to give a racemate of the epoxide,[45] would
isomeric coupling products. The development of methods in
not present problems of stereochemistry. However, the
stereoselective synthesis has not reached the stage at which
subsequent opening of the epoxide would require a diastereoAngew. Chem. Int. Ed. 2003, 42, 1096 – 1109
1105
Reviews
R. W. Hoffmann
the relative configuration of the product was not
available. We therefore embarked on a linear
synthesis of 96 that would also allow the stereochemical assignment of 86. This overall linear
approach contains some bidirectional and convergent elements (Scheme 35).
The plan was to use enantiomerically pure
building blocks 97 and 98 of defined absolute
configuration, despite the fact that the target
structure 96 is achiral. The synthesis started from
(R,R)-dimethyl tartrate (99), which was converted
into the known bisisopropenyl dioxane 100
(Scheme 36).[49] The two additional stereogenic
centers were created subsequently in a bidirectional
hydroboration to give the diol 101. Since this is a C2symmetric compound, the ends of the molecule are
homotopic. Therefore, monoprotection of one
hydroxy group to give 102 proceeded without a
problem of stereochemistry.
The linear part of the synthesis begins at this
point (Scheme 37): The free hydroxy group in 102
was converted into a sulfone function to set the
Scheme 34. Hypothetical access to meso compounds through reductive pinacol
coupling of a racemic aldehyde.
the three types of selectivities involved in this reaction can be
controlled simultaneously. One such type is simple diastereoselectivity (3,4-syn versus 3,4-anti). The formation of compounds 93 (meso-I) and 94 (meso-II) requires a 3,4-anti
arrangement, which is disfavored in most reported pinacol
coupling reactions.[46, 47]
The current lack of meso-selective coupling reactions of
racemates is reflected in the otherwise spectacular synthesis
of an expanded cubane, which is hampered by separation
problems and substantial losses of material.[58] These deficiencies in stereoselective synthesis demonstrate why convergent synthesis of meso compounds still relies on a pair of
enantiomerically pure starting materials of opposite configuration.
O
O H
H O
2
pMBO
O
H
O
O
H
HO
8
OH
OH O 98
97
96
OH
5
Scheme 35. Retrosynthesis for a linear approach to a meso-terdioxane.
OH
MeOOC
O
COOMe
HO
MeMgI
BF3·OEt2
OH
99
63 %
O
O
O
CH3SO2Cl
OH
O
OH
1) Et2BH
2) H2O2,
NaOH
O
100
98 %
6. The Linear Approach
O
1106
+
2
NEt3, DMAP
The linear approach to stereochemically complex meso
compounds is unattractive, as is the case in any linear
synthesis, because it generally requires more steps than a
convergent approach. On the other hand, a linear synthesis
has the advantage of higher predictability and—in the case of
meso compounds—of not having any restrictions in the
methods to be used. In fact, it is preferable to use enantiomerically pure starting materials, because the total arsenal of
stereoselective synthesis, including chiral reagents, chiral
catalysts, and chiral auxiliaries, may be applied to set up the
stereogenic centers in the target structures. It is therefore not
surprising that the majority of approaches in the synthesis of
the ansa chain 31 of rifamycin S are linear.[42]
Both the advantages and disadvantages of a linear synthesis can be illustrated in a synthesis of 96,[48] which is related
to 86. As pointed out above, the stereochemical outcome of
the synthesis of 86 was unpredictable and concrete proof of
O
O
8
5
HO
O
50 %
101
OpMB
NaH
pMBBr
78 %
HO
O
102
Scheme 36. Linear synthesis via C2-symmetric intermediates.
stage for a Julia–Lythgoe olefination. Combination of the
sulfone 103 with the aldehyde 97 furnished the olefin (E)-104,
which contained minor amounts of the Z counterpart;
however, the latter were unreactive in the next step, the
dihydroxylation reaction, and were therefore not removed.
Simple dihydroxylation of 104, which relies on substratebased asymmetric induction, met with low diastereoselectivity. Here, the advantage of a synthesis in the enantiomerically
pure series becomes clear, as asymmetric dihydroxylation,
that is, reagent control of diastereoselectivity, may be applied.
This allowed the dihydroxylation to proceed with 10:1
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
Angewandte
Chemie
meso Compounds
O
HO
OpMB
O
TosCl
NEt3, DMAP
TosO
99 %
O
102
OH
2) pMBO O
O
103
83 %
O
ROOC
OpMB
Ph
97
SO2 O
COOR 3 steps
HO PhS
NHZ
42 %
O
pMBO
O
ROOC
OpMB
74 %
NHZ
104
PhS
ROOC
DuPHOS
COOR
NHZ
–
TfO
N
Cu
H2/[RhI(cod)],
+
Ph
HOOC
COOR
O
O
Boc2N
Boc2N
O
N
95 %
Ph
NaHg
108
94 %
1) nBuLi
PhSO2
NHBoc
107
NaI, DMF
COOMe
tBuOOC
COOH
tBuOOC
PhSO2Na
O
pMBO
OpMB
O
OpMB
NHZ
H2N
109
COOH
NH2 110
Scheme 39. Synthetic approaches to meso-diaminopimelic acid.
Scheme 37. Elaboration of intermediates for a linear synthesis of a
meso terdioxane.
selectivity in favor of 105. That the major diastereomer is the
correct one, followed from its ultimate conversion into the
symmetrical meso hexaol 106, which in turn was converted
into the terdioxane 96 (Scheme 38).[48]
pMBO
O
OpMB
K2OsO4, K3[Fe(CN)6]
O
104
(DHQD)2PHAL
pMBO
OH
74 %
O
OpMB pMBO
105
OH O
OH
10 : 1
O
OpMB
reagent control of diastereoselectivity, that is, by asymmetric
hydrogenation with a chiral catalyst. In the second synthesis,
the modified amino acid derivative 109 was generated from
the chiral pool. Chiral catalysis of an ene reaction was then
used to set up the second stereocenter. These are typical
examples in which the creation of the second stereocenter
does not depend on the configuration of the (remote) resident
stereocenter.
If, however, long-range (i.e. 1,5) asymmetric induction
can be applied, external asymmetric induction is not necessary (reagent control of the diastereoselectivity) and a linear
synthesis of a meso compound is also possible from a
racemate. This is illustrated in Scheme 40 in the conversion
of the hemiacetal 111 into the diol meso-112.[53]
OH O
OH
TosOH
(CH2SH)2
MeTi(OiPr)3
O
OH
OH
73 %, d.r. 4.2:1
OH OH
OH OH
OMe
O
O
O
O
PyH+OTos–
91 %
OH OH
106
70 %
O
O
96
111
112
Scheme 40. Linear synthesis of a meso 1,5-diol with 1,5-asymmetric induction.
Scheme 38. Final steps in a linear synthesis of a meso terdioxane.
Abbreviations
The synthesis of 96 demonstrated that the linear approach
in the enantiomerically pure series is reliable and lacks any
stereochemical ambiguity, albeit more laborious. The hallmark of the linear approach is that every stereogenic center in
the target molecule is introduced with defined absolute
configuration to afford a symmetrical molecule in the end.
Such an approach is attractive if the number of (remote)
stereogenic centers in the desired meso compound is low. This
is illustrated in Scheme 39 with respect to meso-diaminopimelic acid (110), a compound of continuing interest.[50] Two
syntheses,[51] which feature the independent generation of
stereocenters, are depicted below (for further syntheses, see
reference [52])
In one of the syntheses, the first stereogenic center stems
from natural glutamic acid. This starting compound 107 was
elaborated into the a,b-unsaturated amino ester 108. Subsequently, the second stereogenic center was introduced by
Angew. Chem. Int. Ed. 2003, 42, 1096 – 1109
Bn
Boc
cod
(DHQD)2PHAL
DIBAL
DMAP
DMF
DMP
DPTBS
DuPHOS
Ipc
MCPBA
NMO
PCC
PG
benzyl
tert-butyloxycarbonyl
1,4-cyclooctadiene
dihydroquinidine-(1,4-phthalazinediyl diether) (chiral ligand for asymmetric dihydroxylation)[55]
diisobutylaluminum hydride
4-dimethylaminopyridine
N,N-dimethylformamide
Dess–Martin periodinane[54]
tert-butyldiphenylsilyl
chiral ligand for hydrogenation[56]
isopinocampheyl
m-chloroperbenzoic acid
N-methylmorpholine N-oxide
pyridinium chlorochromate
protecting group
1107
Reviews
PLE
pMB
pMP
PPTS
py
Swern
TBS
TIPS
Tf
TMS
Tos
TPAP
Tr
Z
R. W. Hoffmann
porcine liver esterase
p-methoxybenzyl
p-methoxyphenyl
pyridinium p-toluenesulfonate
pyridine
Swern oxidation[57]
tert-butyldimethylsilyl
triisopropylsilyl
trifluoromethanesulfonyl
trimethylsilyl
p-toluenesulfonyl
tetrapropylammonium perruthenate
triphenylmethyl
benzyloxycarbonyl
The results from the research of our own group described in
this review could not have been obtained without the continued
support from the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft, and the Volkswagen Stiftung.
Received: June 14, 2002 [A542]
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Angewandte
Chemie
meso Compounds
O
O
X
O
O
O
O
+
O
rac-II
O
meso-III
O
rac-I
O
diastereoface-selective dihydroxylation
O
IV
O
OH
O
OH O
Scheme 41. Coupling of a racemate as a potential convergent route to
a meso compound.
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1109
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