Direct generation of acyclic polypropionate stereopolyads via double diastereo- and enantioselective iridium-catalyzed crotylation of 1,3-diols: Beyond stepwise carbonyl addition in polyketide construction

Article abstract of DOI:10.1021/ja204570w

Under the conditions of transfer hydrogenation employing the cyclometalated iridium catalyst (R)-I derived from [Ir(cod)Cl]₂, allyl acetate, 4-cyano-3-nitrobenzoic acid, and the chiral phosphine ligand (R)-SEGPHOS, α-methylallyl acetate engages 1,3-propanediol (1a) and 2-methyl-1,3-propanediol (1b) in double carbonyl crotylation from the alcohol oxidation level to deliver the C₂-symmetric and pseudo-C ₂-symmetric stereopolyads 2a and 3a, respectively, with exceptional control of anti-diastereoselectivity and enantioselectivity. Notably, the polypropionate stereopentad 3a is formed predominantly as 1 of 16 possible stereoisomers. Desymmetrization of 3a is readily achieved upon iodoetherification to form pyran 4. The direct generation of 3a enables a dramatically simplified approach to previously prepared polypropionate substructures, as demonstrated by the synthesis of C19-C27 of rifamycin S (eight steps, originally prepared in 26 steps) and C19-C25 of scytophycin C (eight steps, originally prepared in 15 steps). The present transfer hydrogenation protocol represents an alternative to chiral auxiliaries, chiral reagents, and premetalated nucleophiles in polyketide construction.

Full text of DOI:10.1021/ja204570w

ARTICLE
pubs.acs.org/JACS
Direct Generation of Acyclic Polypropionate Stereopolyads via Double
Diastereo- and Enantioselective Iridium-Catalyzed Crotylation of 1,3-
Diols: Beyond Stepwise Carbonyl Addition in Polyketide Construction
Xin Gao, Hoon Han, and Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S Supporting Information
b
ABSTRACT: Under the conditions of transfer hydrogenation employing
the cyclometalated iridium catalyst (R)-I derived from [Ir(cod)Cl]2, allyl
acetate, 4-cyano-3-nitrobenzoic acid, and the chiral phosphine ligand (R)-
SEGPHOS, R-methylallyl acetate engages 1,3-propanediol (1a) and
2-methyl-1,3-propanediol (1b) in double carbonyl crotylation from the
alcohol oxidation level to deliver the C2-symmetric and pseudo-C2-sym-
metric stereopolyads 2a and 3a, respectively, with exceptional control of
anti-diastereoselectivity and enantioselectivity. Notably, the polypropionate
stereopentad 3a is formed predominantly as 1 of 16 possible stereoisomers.
Desymmetrization of 3a is readily achieved upon iodoetherification to form
pyran 4. The direct generation of 3a enables a dramatically simplified approach to previously prepared polypropionate substructures,
as demonstrated by the synthesis of C19ÀC27 of rifamycin S (eight steps, originally prepared in 26 steps) and C19ÀC25 of
scytophycin C (eight steps, originally prepared in 15 steps). The present transfer hydrogenation protocol represents an alternative to
chiral auxiliaries, chiral reagents, and premetalated nucleophiles in polyketide construction.
’ INTRODUCTION
The complex issues of stereoselectivity posed by polyketide
natural products are most often addressed through stepwise
carbonyl addition reactions involving the use of chiral auxiliaries,
chiral reagents, and premetalated nucleophiles.1,2 In the course of
exploring hydrogen-mediated CÀC bond formation,3 hydrogen
exchange between primary alcohols and π-unsaturated reactants
was found to trigger generation of electrophileÀnucleophile
pairs that combine to form products of carbonyl addition directly
from the alcohol oxidation level.3À6 A significant outcome of this
approach resides in the ability to rapidly assemble polyacetate
substructures through asymmetric double allylations of 1,3-diols
(eq 1), as illustrated in dramatically simplified syntheses of the
bryostatin A ring7a and the oxo-polyene macrolide roxaticin.7d
Corresponding double crotylations would enable the direct
generation of C2-symmetric polypropionate stereoquintets (eq 2),
which appear as substructures in diverse polyketide natural products,
including rifamycin,8 swinholide,9 scytophycin,10 saliniketal,11
and reidispongiolide12 (Figure 1). However, attempted double
crotylations employing the catalyst generated in situ from
[Ir(cod)Cl]2, 4-cyano-3-nitrobenzoic acid, allyl acetate, and
(R)-SEGPHOS were unsuccessful. We recently observed that
chromatographic isolation of the iridium precatalyst allows
alcohol-mediated carbonyl crotylations to be conducted at a
significantly lower temperature, resulting in enhanced levels of
anti-diastereoselectivity and enantioselectivity.5e More signifi-
cantly, the chromatographically purified precatalyst enables carbonyl
crotylations that are not possible under previously reported
conditions involving in situ generation of the catalyst.
In view of these findings, the generation of polypropionate
stereoquintets using anti-diastereoselective and enantioselective
carbonyl double crotylation of 1,3-diols was revisited. Here we
report that exposure of R-methylallyl acetate to 1,3-propanediol
(1a) and 2-methyl-1,3-propanediol (1b) in the presence of the
chromatographically purified iridium precatalyst (R)-I results in
double carbonyl crotylation from the diol oxidation level to deliver
the C2-symmetric and pseudo-C2-symmetric stereopolyads 2a and
3a, respectively, with exceptional control of the anti diastereoselec-
tivity and enantioselectivity. The present double crotylation process has
Received: May 18, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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Figure 2. Calculated theoretical distribution of stereoisomers 2 ob-
tained in the double crotylation of 1,3-propanediol (1a) based on 98% ee
for both syn- and anti-crotylation events and a 15:1 anti:syn dr. The
observed experimental results are also shown. Yields are of combined
isomeric materials. Regio- and stereoselectivities were determined
by chiral stationary phase GC analysis. Diastereomeric ratios refer
to the proportion of 2a relative to the combination of all of the
stereoisomers.
Figure 1. Representative polyketide natural products possessing
pseudo-C2-symmetric polypropionate stereoquintets.
no counterpart in conventional crotylmetal chemistry and is unique in its
ability to generate acyclic stereoquintets from achiral reactants with
control of the relative and absolute stereochemistry.13À15
To illustrate the utility of this methodology vis-ꢀa-vis polyketide
construction, syntheses of key polypropionate substructures were
executed with dramatic enhancement in step economy. Specifically,
the ansa chain of rifamycin S spanning C19ÀC27 was prepared in
eight steps, as opposed to 26 steps as originally described by Kishi.8cÀf
Additionally, the scytophycin C19ÀC25 stereoquintet was prepared
in eight steps, as opposed to 15 steps as described by Miyashita.10h,i
For the reaction mixture obtained using the BIPHEP-modified
catalyst, chiral-stationary-phase GC analysis revealed 10 distinct
species, presumably the 10 stereoisomers indicated in Figure 2.
Indeed, a good correlation of GC retention times was observed
with the six authentic samples of 2a, ent-2a, anti,syn-2c, anti,anti-
meso-2e, iso-anti,syn-2d, and ent-iso-anti,syn-2d. A dramatic sim-
plification of the product distribution was observed for the
enantioselective reaction employing the chiral catalyst (R)-I.17
Chiral-stationary-phase GC and 1H NMR analysis revealed
predominantly two stereoisomers: the C2-symmetric adduct 2a
and a minor stereoisomer identified as iso-anti,syn-2d. These data
are in excellent agreement with the predicted stereoisomeric
ratios. Isolation by silica gel chromatography delivered 2a in 76%
yield as a single enantiomer and a 5:1 mixture of diastereomers.
Thus, an acyclic array of four stereogenic centers was generated
in a single manipulation from achiral reactants with control of the
relative and absolute stereochemistry (Figure 3).
’ RESULTS AND DISCUSSION
Double Crotylation of 1,3-Propanediols 1a and 1b. En-
antioselective double crotylation of 1a can potentially generate as
many as 10 stereoisomers. Hence, quantitative evaluation of the
product distribution represents a formidable challenge. A calcu-
lation of the theoretical distribution of stereoisomers based on a
99:1 enantiomeric ratio and 15:1 anti:syn diastereomeric ratio
predicts a diastereomeric ratio (dr) of 6.2:1 for 2a versus all of the
other stereoisomers combined (Figure 2).
To quantitatively evaluate the product distributions obtained
in the course of optimization, authentic samples of 2a, ent-2a, and
anti,anti-meso-2e were prepared in a conventional stepwise
manner involving successive monocrotylation.16 Authentic
samples of anti,syn-2c and rac-iso-anti,syn-2d were prepared
conveniently via Mitsunobu inversion of 2a and anti,anti-
meso-2e, respectively. These authentic standards were ana-
lyzed by chiral-stationary-phase GC, and the chromatograms
were compared to those corresponding to the reaction mixtures
arising upon exposure of 1,3-propanediol 1a to R-methyl allyl
acetate in the presence of the iridium catalyst derived from
[Ir(cod)Cl]2, allyl acetate, 4-cyano-3-nitrobenzoic acid, and the
chelating phosphine ligand BIPHEP (2,2’-bis(diphenylphosphino)-
biphenyl), and the reaction mixture obtained using the chro-
matographically purified chiral complex modified by (R)-SEG-
PHOS, termed (R)-I.
Given these favorable results, the double crotylation of 1b was
explored. Here, generation of the pseudo-C2-symmetric18 con-
tiguous polypropionate stereoquintet 3a could potentially be
achieved in a single manipulation. However, 16 stereoisomeric
adducts could potentially arise (Figure 4). The calculated
theoretical distribution of stereoisomers obtained upon use of
the chiral catalyst (R)-I suggested that only three stereoisomers
would be generated in significant proportion: the desired pseudo-
C2-symmetric adduct 3a (86.1%), syn,syn,anti,anti-3b (5.7%),
and syn,anti,syn,anti-3b (5.7%). Accordingly, authentic samples
of these components and ent-3a were prepared in a conventional
stepwise manner involving successive monocrotylation.16
Chiral-stationary-phase GC analysis of the mixture obtained in
the double crotylation of 1b using the BIPHEP-modified catalyst
revealed more than 10 distinct species. However, chiral-station-
1
ary-phase GC and H NMR analysis of the reaction mixture
obtained using chiral catalyst (R)-I revealed that the desired
pseudo-C2-symmetric adduct 3a was formed predominantly,
along with small quantities of syn,syn,anti,anti-3b and syn,anti,
syn,anti-3b (Figure 5). This outcome is in excellent agreement
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Figure 4. Calculated theoretical distribution of stereoisomers 3 ob-
tained in the double crotylation of 2-methyl-1,3-propanediol (1b) based
on 98% ee for both syn- and anti-crotylation events and a 15:1 anti:syn dr.
The observed experimental results are also shown. Yields are of
combined isomeric materials. Regio- and stereoselectivities were deter-
mined by chiral stationary phase GC analysis. Diastereomeric ratios
refer to the proportion of 3a relative to the combination of all of
the stereoisomers. In the compound labels, “s” denotes “syn” and “a”
denotes “anti”.
explore the utility of this methodology in polyketide construc-
tion, the double-crotylation product 3a was applied in a synthetic
approach to the ansa chain (C19ÀC27 stereoheptad) of rifamy-
cin S. A key objective was differentiation of the diastereotopic
hydroxyl moieties and olefinic termini of 3a. Additionally, the
latent stereocenter residing on the pseudo-C2-axis had to be
defined. These goals were achieved in a single operation through
the conversion of 3a to iodoether 4. As corroborated by 1H NMR
analysis of the pyran spin system, the substituents attached to the
two newly formed stereocenters of 4 were equatorially disposed
(eq 3).
Figure 3. Characterization of the product distribution obtained upon
anti-diastereoselective and enantioselective double C-crotylation of 1a.
Reaction products were isolated by silica gel chromatography and
analyzed by chiral-stationary-phase GC analysis using authentic samples
of the indicated stereoisomers (see the Supporting Information for
details).
with the predicted stereoisomeric ratios. Isolation by silica gel
chromatography delivered 3a in 62% yield as a single enantiomer
and a 6:1 mixture of diastereomers. Thus, a contiguous acyclic
array of five stereogenic centers was generated in a single
manipulation from achiral reactants with control of the relative
and absolute stereochemistry (Figure 5). In attempted double
crotylations of the higher congener 2,2-dimethyl-1,3-propane-
diol, only monoadducts were formed. Presumably, steric crowd-
ing prohibits formation of the double-crotylation product.
Formal Synthesis of the Rifamycin S Ansa Chain and the
Synthesis of the Scytophycin C19ÀC25 Stereoquintet. To
Elaboration of iodoether 4 to the ansa chain of rifamycin S was
accomplished in a straightforward manner (Scheme 1). Ozono-
lytic cleavage of iodoether 4 delivered aldehyde 5, which was
subjected to Batey’s crotylation conditions19 to furnish homo-
allylic alcohol 6 as a single stereoisomer (>20:1 dr), as deter-
1
mined by H NMR analysis. Here, synergistic 1,2- and 1,3-
asymmetric induction associated with the R- and β-stereocenters
of the aldehyde, as described by the FelkinÀAnh20 and CramÀ
Reetz21 models, respectively, account for the high level of
stereoselectivity.22 Ozonolytic cleavage of the terminal olefin
followed by NaBH4-mediated reduction of the ozonide delivers
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Scheme 1. Formal Synthesis of Rifamycin S via Construction
of the C19ÀC27 Stereoheptada
a Yields are of material isolated by silica gel chromatography. See the
Supporting Information for experimental details.
Scheme 2. Synthesis of the C19ÀC25 Stereoquintet of
Scytophycin Ca
a Yields are of material isolated by silica gel chromatography. See the
Supporting Information for experimental details.
Figure 5. Characterization of the product distribution obtained upon
anti-diastereoselective and enantioselective double C-crotylation of 1b.
Reaction products were isolated by silica gel chromatography and
analyzed by chiral-stationary-phase GC analysis using authentic samples
of the indicated stereoisomers (see the Supporting Information for
details). In the compound labels, “s” denotes “syn” and “a” denotes “anti”.
ammonium chloride induces β-iodoether cleavage, affording
polypropionate stereoquintet 13. Conversion of the diol to the
acetonide followed by ozonolytic cleavage of the terminal olefin,
again with quenching of the ozonide by NaBH4, delivers primary
alcohol 15 (not shown), which is converted to benzylic ether 16.
Ether 16 is identical in all respects to previously reported
material.9h,i
primary alcohol 7 (not shown). Exposure of 7 to zinc dust in the
presence of ammonium chloride induces β-iodoether cleavage,
affording polypropionate stereohepted 8. Conversion of tetraol 8
to bis-acetonide 9 and, finally, ozonolytic cleavage of the terminal
olefin, again with quenching of the ozonide by NaBH4, delivers
the protected C19ÀC27 stereohepted 10, which is identical in all
respects to previously reported material.7 This eight-step pre-
paration of the ansa chain constitutes a formal total synthesis of
rifamycin S from 1b.8cÀf Paterson reports a 10-step synthesis of
the same C19ÀC27 segment of rifamycin S using asymmetric
aldol reactions mediated by (+)- and (À)-(Ipc)2BOTf.23
’ CONCLUSION
In summary, we report a powerful new process for the direct
generation of polypropionate substructures via iridium cata-
lyzed anti-diastereoselective and enantioselective carbonyl
double crotylation of 1,3-propanediols 1a and 1b. With this
methodology, syntheses of the C19ÀC27 stereoheptad of
rifamycin S and the C19ÀC25 stereoquintet of scytophycin C
were executed with dramatic enhancements in step economy.
To our knowledge, the direct stereoselective generation of
acyclic stereoquintets from achiral/chiral racemic starting
materials, as in the formation of 3a, is without precedent.
Future studies will focus on the development and application
of other alcohol CÀC couplings of relevance to polyketide
construction.
To further illustrate the generality of this approach, a synthesis
of the C19ÀC25 stereoquintet of scytophycin C was undertaken
(Scheme 2). Ozonolytic cleavage of the terminal olefin of iodoether
4 with NaBH4-mediated reduction of the ozonide delivers
primary alcohol 11, which is converted to pivalate 12. Expo-
sure of an ethanolic solution of 12 to zinc dust in the presence of
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’ ASSOCIATED CONTENT
couplings of amines also require preactivated nucleophiles. See: Li, C.-J.
Acc. Chem. Res. 2009, 42, 335.
S
Supporting Information. Experimental procedures and
(7) For selected applications in total synthesis, see: (a) Lu, Y.;
Krische, M. J. Org. Lett. 2009, 11, 3108. (b) Harsh, P.; O’Doherty,
G. A. Tetrahedron 2009, 65, 5051. (c) Sawant, P.; Maier, M. E.
Tetrahedron 2010, 66, 9738. (d) Han, S. B.; Hassan, A.; Kim, I.-S.;
Krische, M. J. J. Am. Chem. Soc. 2010, 132, 15559.
b
spectral data (1H NMR, 13C NMR, IR, HRMS) for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
’ ACKNOWLEDGMENT
The Robert A. Welch Foundation (F-0038) and NIH NIGMS
(R01-GM093905) are acknowledged for partial support of this
research.
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(16) See the Supporting Information for the preparation of the
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