Iterative approach to polyketide-type structures: Stereoselective synthesis of 1,3-polyols utilizing the catalytic asymmetric Overman esterification

Article abstract of DOI:10.1039/b708248g

An iterative systematic approach to the 1,3-polyol motif has been developed to provide access to all possible stereoisomers by utilizing the catalytic asymmetric Overman esterification for the construction of all stereogenic centres. The Royal Society of

Full text of DOI:10.1039/b708248g

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Iterative approach to polyketide-type structures: stereoselective
synthesis of 1,3-polyols utilizing the catalytic asymmetric Overman
esterification{
Jo¨rg T. Binder and Stefan F. Kirsch*
Received (in Cambridge, UK) 31st May 2007, Accepted 19th July 2007
First published as an Advance Article on the web 6th August 2007
DOI: 10.1039/b708248g
motif through substrate controlled asymmetric induction,6,7 the
An iterative systematic approach to the 1,3-polyol motif has
most widely used methods to prepare 1,3-polyols in an iterative
fashion are by allyl addition sequences utilizing stoichiometric
amounts of chiral boron8 or titanium9 reagents. An alternative and
catalytic approach involves sequential construction of carbon–
oxygen bonds through asymmetric epoxidation,10 although these
approaches are somewhat limited due to stereochemical restric-
tions.5
been developed to provide access to all possible stereoisomers
by utilizing the catalytic asymmetric Overman esterification for
the construction of all stereogenic centres.
Polyketide-derived natural products often combine a specific
biological activity with both complexity and broad skeletal
diversity. As a synthetic challenge, they have stimulated the
development of numerous methods for their stereoselective
synthesis, many of which resulted in de-novo syntheses.1,2
However, nature has evolved an iterative and flexible approach
for the synthesis of polyketides utilizing only a few building
blocks.3 By mimicking this processive mechanism, a conceptually
related strategy towards polyketide-type structures was envisioned
in which repetition of a simple sequence provides the desired
structural units through chain extension, with each iteration
attaching a C2-building block. We initiated the research described
in this communication with the premise that a general and
synthetic approach to polyketides will be well suited for efforts
aimed at the construction of natural products and polyketide
libraries. As a start, herein we report an iterative approach to the
synthesis of 1,3-polyols4 that makes all possible stereoisomers
freely accessible.
In 2005, Overman and Kirsch reported that prochiral (Z)-allylic
trichloroacetimidates react with carboxylic acids to give branched
allylic esters using chiral palladium(II) catalysts. When the
palladium(II) catalyst is COP-OAc, achiral substrates were
efficiently transformed into chiral products of high enantiopurity.11
Our preliminary experiments indicated that the asymmetric
Overman esterification is also a powerful method for the reaction
of chiral substrates. In these cases, asymmetric induction is
completely controlled by the chiral catalyst affording a predictable
creation of new stereogenic centres. In this communication, we
utilize the Overman esterification for the construction of both the
first and all further stereogenic centres in a 1,3-polyol chain.
The first stereogenic center was introduced by reaction of
trichloroacetimidate 112 with benzoic acid in the presence of
palladacyclic (+)-COP-OAc (1 mol%).13 The conversion in CH2Cl2
at 23 uC provided (R)-allylic ester 2 in 93% yield and 92% ee after
16 h (Scheme 2).
Within this context, allylic alcohols were identified as a
potentially useful class of substrates. It was envisaged that the
existing allylic alcohol group is extended by a C2-unit through each
chain extension cycle (Scheme 1). Since the chirality of the already
established 1,3-polyol chain makes the stereoselective chain
elongation a challenging process,5 a versatile synthetic method
that addresses the flexible construction of all possible stereoisomers
is required. Despite numerous strategies for accessing the 1,3-diol
Starting from allylic ester 2, the projected C2 extension was
conveniently achieved using a multistep sequence (1OH-3ROH),
which resulted in the formation of (R,R)-diol 5 in 53% overall yield
(Scheme 3). A series of transformations consisting of transester-
ification,14 ring-closing metathesis,15 and base-catalyzed double-
bond isomerization8a,16 led to the formation of a,b-unsaturated
d-lactone 3.17 The lactone ring was opened with NaBH4/
Scheme 1 Iterative strategy for the synthesis of 1,3-polyols.
Department Chemie, Technische Universita¨t Mu¨nchen, Lichtenbergstr.
4, 85747, Garching, Germany. E-mail: stefan.kirsch@ch.tum.de;
Fax: (+49) 89-2891-3315
{ Electronic supplementary information (ESI) available: Representative
experimental procedures, and copies of 1H and 13C NMR of 2, 3, 5–11, 14
and 15. Copies of HPLC traces used to determine enantiopurity for 2 and
14. See DOI: 10.1039/b708248g
Scheme 2 Synthesis of allylic ester 2. Reagents and conditions: (i) 1.
(PhO)2P(O)CH2CO2Et, NaH, 0 uC, THF; 2. 3-phenylpropionaldehyde,
278 uC, 85%, dr . 95 : 5; (ii) DIBAL-H, 278 uC, CH2Cl2, 80%; (iii)
Cl3CCN, DBU (10 mol%), 23 uC, CH2Cl2, 94%; (iv) PhCOOH (3 equiv.),
(+)-COP-OAc (1 mol%), 23 uC, CH2Cl2, 93%, 92% ee.
4164 | Chem. Commun., 2007, 4164–4166
This journal is ß The Royal Society of Chemistry 2007

View Online
Scheme 3 Synthesis of (R,R)-diol 5 (via 1OH-3ROH) and (R,S)-diol 6 (via
1OH-3SOH). Reagents and conditions: (i) 1. DIBAL-H, 278 uC, CH2Cl2; 2.
CH2LCHCH2CO2H, DCC, DMAP (15 mol%), 23 uC, CH2Cl2, 88%; (ii) 1.
Grubbs II (1 mol%), 38 uC, CH2Cl2; 2. DBU (10 mol%), 23 uC, CH2Cl2,
82%; (iii) NaBH4, CeCl3?7H2O, 0 uC, MeOH, 91%; (iv) 1. TESOTf,
lutidine, 0 uC, CH2Cl2; 2. K2CO3, 0 uC, MeOH, 90%; (v) Cl3CCN, DBU
(10 mol%), 23 uC, CH2Cl2, 94%; (vi) PhCOOH (3 equiv), (+)-COP-OAc
(1 mol%), 23 uC, CH2Cl2, 95%, dr = 94 : 6; (vii) PhCOOH (3 equiv.), (2)-
COP-OAc (1 mol%), 23 uC, CH2Cl2, 94%, dr = 97 : 3.
Scheme 4 Stereoselective synthesis of triol derivatives 7, 8, 9 and 10. R1 =
Et3Si, R2 = Bz.
aromatic compactin analogue presumably with a related bio-
synthetical origin.19 To this end, Heck reaction20 of 1-bromo-2-
methylnaphthalene (12) with ethyl acrylate and subsequent
reductions provided aldehyde 13 (Scheme 5). Olefination of this
product under Ando conditions21 followed by reduction with
DIBAL-H and reaction with trichloroacetonitrile yielded the
Z-configured trichloroacetimidate, which upon esterification11
with benzoic acid catalyzed by (+)-COP-OAc gave allylic ester
14 (94% ee). The extended allylic ester 15 was then formed in 40%
overall yield and excellent diastereoselectivity (dr = 94 : 6) by
employing the 1OH-3ROH sequence. Hydroboration gave the
primary alcohol, which was subjected to oxidation and acid
mediated deprotection to provide (+)-solistatin (11) ([a]20D = +32.5
CeCl3?7H2O followed by the formation of the corresponding bis-
silyl ether. The protecting group on the primary alcohol was
removed selectively, and then the Z-configured allylic alcohol was
converted into trichloroacetimidate 4. The imidate was subse-
quently reacted with benzoic acid in the presence of (+)-COP-OAc
(1 mol%) to create the next stereogenic center. Under catalyst
control, syn-1,3-diol 5 was produced in high diastereoselectivity
(dr = 94 : 6). It was also possible to conduct the sequence with (2)-
COP-OAc (1OH-3SOH), a modification that resulted in the
formation of anti-1,3-diol 6 in excellent yield and diastereo-
selectivity (dr = 97 : 3).
[c = 0.8, EtOH]; natural product:19 [a]20 = +32.0 [c = 0.251,
D
EtOH]).
In conclusion, an iterative sequence for the stereoselective
construction of 1,3-polyols is described. Within each iteration, the
creation of the stereogenic center proceeds with catalyst-controlled
stereoinduction. Further modifications of this sequence to
introduce structural elements such as CLC-double bonds and
carbonyls are in progress. Applications to the synthesis of more
complex polyketides will be reported in due course.
This sequence for the stereoselective synthesis of 1,3-diols is
particularly attractive since a catalytic amount of the chiral reagent
is sufficient to install all possible stereogenic centres with a
predictable stereoinduction. Without diminishing yield and
diastereoselectivity, the reaction can be run at lower catalyst
loadings (up to 0.1 mol% of COP-OAc), although a significantly
longer period of time is required for the reaction to reach
completion. In addition, COP-OAc is commercially available in
both enantiomeric forms. The overall chain extension cycle
proceeds under mild reaction conditions in reproducibly high
yields, thus reducing the fundamental drawback of this protocol
that is due to the high number of synthetic steps per iteration.18 Of
primary importance, this concept might be a step towards a
general approach to polyketide-type structures, primarily since
straightforward modifications of the synthetic intermediates enable
the construction of other structural elements of polyketides. For
example, lactone 3 and allylic alcohol derivatives 5 and 6 are
suitable substrates for further functionalizations.
Scheme 5 Synthesis of (+)-Solistatin (11). Reagents and conditions: (i)
CH2LCHCO2Et, Pd(OAc)2 (10 mol%), PPh3 (15 mol%), 100 uC, NEt3,
86%; (ii) H2, Pd–C (5 mol%), 23 uC, EtOH, 91%; (iii) DIBAL-H, 278 uC,
CH2Cl2, 67%; (iv) 1. (PhO)2P(O)CH2CO2Me, NaH, 0 uC, THF; 2. 13,
278 uC, 80%, dr . 95 : 5; (v) DIBAL-H, 278 uC, THF, 96%; (vi)
Cl3CCN, DBU (10 mol%), 23 uC, CH2Cl2, 87%; (vii) PhCOOH (3 equiv.),
(+)-COP-OAc (1 mol%), 23 uC, CH2Cl2, 92%, 94% ee; (viii) 1OH-3ROH
(see Scheme 3), 40%, dr = 94 : 6; (ix) 1. DIBAL-H, 278 uC, CH2Cl2; 2.
TESCl, im, 23 uC, DMF, 72%; (x) 1. 9-BBN-H, 0 uC, THF; 2. NaOH,
H2O2, 0 uC, 79%; (xi) IBX, 23 uC, DMSO, 66%; (xii) 1. NaClO2, 2-methyl-
2-butene, NaH2PO4, 23 uC, tBuOH–H2O; 2. pTsOH, 23 uC, EtOH, 85%.
To illustrate the feasibility of synthesizing 1,3-polyols in this
way, the sequences 1OH-3ROH and 1OH-3SOH were employed to
selectively prepare the four stereoisomers 7, 8, 9 and 10 (Scheme 4).
While the average yields for the second cycle were somewhat
lowered, the stereoselective syntheses of the target compounds
were realized as expected.
The utility of this sequence for the formation of polyketide-type
structures was realized in an expedient total synthesis of (+)-
solistatin (11). Isolated from Penicillium solitum, solistatin is an
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 4164–4166 | 4165

View Online
Synlett, 1990, 759; S. L. Schreiber and M. T. Goulet, J. Am. Chem. Soc.,
1987, 109, 8120.
9 S. BouzBouz and J. Cossy, Org. Lett., 2000, 2, 501; P. Knochel,
W. Brieden, M. J. Rozema and C. Eisenberg, Tetrahedron Lett., 1993,
34, 5881.
We thank the Fonds der Chemischen Industrie (FCI) for
support and Professor Thorsten Bach for helpful discussions.
Notes and references
10 S.-y. Tosaki, Y. Horiuchi, T. Nemoto, T. Ohshima and M. Shibasaki,
Chem.–Eur. J., 2004, 10, 1527; S. Gerber-Lemaire and P. Vogel, Eur.
J. Org. Chem., 2003, 2959; S. A. Burova and F. E. McDonald, J. Am.
Chem. Soc., 2002, 124, 8188; P. Ma, S. Martin, S. Masamune,
K. B. Sharpless and S. M. Viti, J. Org. Chem., 1982, 47, 1378.
11 S. F. Kirsch and L. E. Overman, J. Am. Chem. Soc., 2005, 127, 2866.
12 L. E. Overman, C. E. Owen and M. M. Pavan, Org. Lett., 2003, 5, 1809.
13 C. E. Anderson, S. F. Kirsch, L. E. Overman, C. J. Richards and
M. P. Watson, Org. Synth., 2007, 84, 148; A. M. Stevens and
C. J. Richards, Organometallics, 1999, 18, 1346.
14 The transesterification step consisting of reductive cleavage and
subsequent esterification was required, since vinylacetic acid does not
react in the allylic esterification reactions catalyzed by COP-OAc.
15 For a review, see: A. Deiters and S. F. Martin, Chem. Rev., 2004, 104,
2199; for a related example, see: P. R. Andreana, J. S. McLellan,
Y. Chen and P. G. Wang, Org. Lett., 2002, 4, 3875.
1 For reviews, see: A. K. Miller and D. Trauner, Synlett, 2006, 2295;
B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed., 2006, 45, 7506;
D. O’Hagan, Nat. Prod. Rep., 1995, 12, 1.
2 For selected examples, see: K. C. Nicolaou, A. L. Nold, R. R. Milburn
and C. S. Chindler, Angew. Chem., Int. Ed., 2006, 45, 6527; M. J. Mitton-
Fry, A. J. Cullen and T. Sammakia, Angew. Chem., Int. Ed., 2007, 46,
1066.
3 For leading references, see: C. T. Walsh, Science, 2004, 303, 1805;
M. A. Fischbach and C. T. Walsh, Chem. Rev., 2006, 106, 3468;
J. Staunton, Angew. Chem., Int. Ed. Engl., 1991, 30, 1302.
4 S. D. Rychnovsky, Chem. Rev., 1995, 95, 2021.
5 S. Masamune, W. Choy, J. S. Peterson and L. S. Sita, Angew. Chem.,
Int. Ed. Engl., 1985, 24, 1.
6 For reviews, see: S. E. Bode, M. Wolberg and M. Mu¨ller, Synthesis,
2006, 557; C. Schneider, Angew. Chem., Int. Ed., 1998, 37, 1375.
7 For selected examples, see: S. Shang, H. Iwadare, D. E. Macks,
L. M. Ambrosini and D. S. Tan, Org. Lett., 2007, 9, 1895; K. Ko¨rber,
P. Risch and R. Bru¨ckner, Synlett, 2005, 2905; J. W. Bode, N. Fraefel,
D. Muri and E. M. Carreira, Angew. Chem., Int. Ed., 2001, 40, 2082;
I. Paterson, M. Donghi and K. Gerlach, Angew. Chem., Int. Ed., 2000,
39, 3315; A. M. Misske and H. M. R. Hoffmann, Chem.–Eur. J., 2000,
6, 3313; D. Enders and T. Hundertmark, Tetrahedron Lett., 1999, 40,
4169; M. Reggelin, V. Brenig and R. Welcker, Tetrahedron Lett., 1998,
39, 4801; D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am.
Chem. Soc., 1988, 110, 3560.
8 A. B. Garcia, T. Leßmann, J. D. Umarye, V. Mamane, S. Sommer and
H. Waldmann, Chem. Commun., 2006, 3868; S. D. Dreher and
J. L. Leighton, J. Am. Chem. Soc., 2001, 123, 341; A. G. M. Barrett,
D. C. Braddock, P. D. de Koning, A. J. P. White and D. J. Williams,
J. Org. Chem., 2000, 65, 375; C. Schneider and M. Rehfeuter, Chem.–
Eur. J., 1999, 5, 2850; I. Paterson, D. J. Wallace and K. R. Gibson,
Tetrahedron Lett., 1997, 38, 8911; R. W. Hoffmann and R. Stu¨rmer,
16 M.-A. Virolleaud and O. Piva, Synlett, 2004, 2087.
17 For a review, see: V. Boucard, G. Broustal and J. M. Campagne, Eur. J.
Org. Chem., 2007, 225; for selected examples, see: B. M. Trost and
V. S. C. Yeh, Org. Lett., 2002, 4, 3513; S. BouzBouz and J. Cossy, Org.
Lett., 2003, 5, 1995.
18 To reduce the number of steps per cycle, the C2 extension of 2 was
briefly investigated utilizing a sequence of hydroboration, oxidation, and
Ando olefination21 to generate the Z-configured allylic alcohol precursor
that is required for the next allylic esterification reaction. Although
feasible, this attempt was found significantly less efficient than the one
depicted in Scheme 3.
19 D. Sorensen, T. O. Larsen, C. Christophersen, P. H. Nielsen and
U. Anthoni, Phytochemistry, 1999, 51, 1027.
20 B. A. Patel, C. B. Ziegler, N. A. Cortese, J. E. Plevyak, T. C. Zebovitz,
M. Terpko and R. F. Heck, J. Org. Chem., 1977, 42, 3903.
21 K. Ando, J. Org. Chem., 1998, 63, 8411.
4166 | Chem. Commun., 2007, 4164–4166
This journal is ß The Royal Society of Chemistry 2007