Stereoselective synthesis of 1,3-anti diols by an Ipc-mediated domino aldol-coupling/reduction sequence

Article abstract of DOI:10.1021/ol3033303

A novel domino process for 1,3-anti diol synthesis by the union of a methyl ketone with an aldehyde is described. The operationally simple procedure is based on an Ipc-boron-aldol coupling and subsequent Ipc-mediated reduction of the intermediate β-hydrox

Full text of DOI:10.1021/ol3033303

ORGANIC
LETTERS
2013
Vol. 15, No. 1
228–231
Stereoselective Synthesis of
1,3-anti Diols by an Ipc-Mediated Domino
Aldol-Coupling/Reduction Sequence
Michael Dieckmann† and Dirk Menche*,‡
ꢀ
Kekule-Institut fur Organische Chemie und Biochemie der Universitat Bonn,
Gerhard-Domagk-Str. 1, D-53121 Bonn, Germany, and Universitat Heidelberg,
€
€
€
Institut fu€r Organische Chemie, INF 270, D-69120 Heidelberg, Germany
dirk.menche@uni-bonn.de
Received December 5, 2012
ABSTRACT
A novel domino process for 1,3-anti diol synthesis by the union of a methyl ketone with an aldehyde is described. The operationally simple
procedure is based on an Ipc-boron-aldol coupling and subsequent Ipc-mediated reduction of the intermediate β-hydroxy-ketone. The sequence
proceeds with excellent anti-selectivities and enables the rapid construction of complex polyketide fragments.
The 1,3-diol motif represents a ubiquitous structural
feature in numerous natural products, particularly among
polyketides, as well as bioactive agents and pharmaceuticals,1
rendering the development of efficient methods for their
synthesis an important research goal. Undoubtedly, the aldol
reaction and subsequent reduction of the derived β-hydroxy-
ketones constitutes one of the most powerful and versatile
synthetic procedures for the preparation of this prevalent
synthon.2 However, as shown in Scheme 1 (top part), this
approach usually requires two separate synthetic steps, i.e.,
a CꢀC bond formation (viz coupling product A) and a
reduction (i.e., transformation of A to B).3,4 From the
perspective of step economy, a more direct combination of
these two transformations in a domino type fashion by
suitable reagent design would be highly desirable. As
part of our efforts to develop new sequential processes
for polyketide synthesis,5 we report a domino aldol/
reduction sequence that enables a highly stereoselective
access to 1,3-anti diols by an operationally simple pro-
cedure that may be readily applied in complex polyke-
tide synthesis.
†
€
Universitat Heidelberg.
‡
€
Universitat Bonn.
(1) (a) Cragg, G. M.; Newman, D. J. Cancer Invest. 1999, 17, 153. (b)
Demain, A. L. Biotechnol. Adv. 2000, 18, 499. (c) Weissman, K. J.;
€
Muller, R. Nat. Prod. Rep. 2010, 27, 1276.
(2) (a) Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Heathcook, C. H., Eds.;
Pergamon: Oxford, 1991; Vol. 2, p 229. (b) Yeung, K.-S.; Paterson, I.
Chem. Rev. 2005, 105, 4237. (c) Schetter, B.; Mahrwald, R. Angew.
(4) The Paterson group described a one-pot method for boron-aldol
reactions and subsequent reduction of the intermediate β-oxo-boron-
aldolate by addition of a suitable reducing agent to afford the corre-
sponding 1,3-syn diols: (a) Paterson, I.; Perkins, M. V. Tetrahedron
1996, 52, 1811. (b) Paterson, I.; Wren, S. P. J. Chem. Soc., Chem.
Commun. 1993, 1790.
(5) (a) Wang, L.; Li, P.; Menche, D. Angew. Chem., Int. Ed. 2010, 49,
9270. (b) Morgen, M.; Bretzke, S.; Li, P.; Menche, D. Org. Lett. 2010, 12,
4494. (c) Wang, L.; Menche, D. Angew. Chem., Int. Ed. 2012, 51, 9425.
(d) Debnar, T.; Dreisigacker, S.; Menche, D. Chem. Commun. 2013,
49, 725.
€
Chem., Int. Ed. 2006, 45, 7506. (d) Brodmann, R.; Lorenz, M.; Schackel,
R.; Simsek, S.; Kalesse, M. Synlett 2009, 174. (e) Li, J.; Menche, D.
Synlett 2009, 2293.
(3) For 1,3-syn reduction of β-hydroxy ketones, see: (a) Chen, K.-M.;
Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. J. Tetrahedron
Lett. 1987, 28, 155. (b) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990,
55, 5190. For 1,3-anti reduction of β-hydroxy ketones, see: (c) Anwar,
S.; Davis, A. P. Tetrahedron 1984, 40, 2233. (d) Evans, D. A.; Chapman,
K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560. (e) Evans,
D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
r
10.1021/ol3033303
Published on Web 12/21/2012
2012 American Chemical Society

obtained in high yields (95%).9,10 Importantly, detailed
structural analysis revealed that out of the four possible
stereoisomeric products, only the two anti-isomers could
be detected by NMR, viz. 3 and the other anti-isomer [i.e.,
(18-epi, 20-epi)-3, not shown]. The stereochemistry of both
isomers was assigned by NMR methods11 and confirmed
by transformation into acetonide 4. Finally, the structure
was proven by oxidative removal of the boronate12 and
comparison of the obtained diol 5 with material indepen-
dently synthesized in our group.8a
Scheme 1. Domino Concept for Direct 1,3-Diol Synthesis
Scheme 2. One-Pot Coupling of Ketone 1 with Aldehyde 2
Auxiliary-controlled aldol reactions play an important
role in introducing stereoselectivity, and among these, the
use of chiral isopinocampheyl (Ipc) boron enolates has
emerged as a powerful tool in the construction of both
complex polyacetates and polypropionates.6 Importantly,
this chiral auxiliary may be installed in an intermediate
fashion to various ketones, which adds to the unique
efficiency of this reagent. Motivated by the intrinsic ability
of the Ipc-residue to act likewise as a reducing agent,7 we
envisioned that a suitable reaction design might enable
a combination of these processes in a one-pot fashion.
Consequently, as shown in Scheme 1, our synthetic con-
cept capitalizes ona three-step sequentialprocessinvolving
an Ipc-aldol reaction between a methyl ketone and an
aldehyde (1) resulting in the corresponding boron-aldolate
C, which might then undergo an intramolecular Ipc-
mediated reduction to cyclic boronate D (2) and then
generate the desired 1,3-diol motif during workup in a
highly concise fashion (3). Notably, two new stereogenic
centers are assembled along this process, demonstrating a
high increase in structural complexity from very simple
starting materials.
For realization of this concept we studied the challeng-
ing aldol coupling of aldehyde 1 and methyl ketone 2
(Scheme 2) within our synthetic campaign directed toward
the polyketide rhizopodin.8 To enhance the reactivity of
the hindered aldehyde 1 as well as to simultaneously enable
an Ipc-induced reduction, this coupling was evaluated at
more elevated temperatures as compared to those con-
ventionally used for this type of boron mediated aldol
coupling.6 This approach proved to be indeed successful.
By raising the temperature to 25 °C, a clean conversion to
cyclic boronate 3 was observed. This reduced product was
As shown in Table 1, various aldehydes (6ꢀ10)13 and
methyl ketones (2, 11, and 12) were then submitted to this
domino sequence and both Ipc-isomers were used to study
the influence of this chiral auxiliary on the stereochemical
outcome of the reduction process. As expected, the cou-
pling of aldehyde 6 as a structurally closely related homo-
logue to 1 (Scheme 2) with methyl ketone 2 resulted in
very similar degrees of selectivity and yield (entry 1). An
analogous coupling with (ꢀ)-DIPCl afforded the same
anti-product 13, again with excellent anti/syn selectivities,
albeit lower asymmetric induction in the initial aldol
coupling, suggesting pronounced substrate control in this
(9) Boronate 3 was shelf-stable under air at ambient temperature for
months and showed similar TLC properties as the starting aldehyde 1.
(10) In analogous reactions with Ipc2BOTf only decomposition of
the starting material was observed, possibly due to the higher Lewis
acidity of this reagent under these conditions.
(11) The stereochemistry was assigned by NOE correlations and
characteristic 13C NMR signals of the acetonide moiety together with
comparison of the NMR data of the product obtained by an analogous
aldol coupling and an 1,3-anti reduction using the EvansꢀCarreira
procedure: See ref 3d.
(12) In accordance with the high steric hindrance of this specific
substrate, treatment with H2O2/NaOH (25 °C, 90 min) was required
for oxidative cleavage, while no reaction was observed at neutral pH
(H2O2/MeOH/buffer pH = 7, 25 °C, 2 h).
(13) The aldehyde substrates 6ꢀ9 were synthesized using Krische’s
allylation strategy: Hassan, A.; Lu, Y.; Krische, M. J. Org. Lett. 2009,
11, 3112. For details, see the SI.
(6) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(7) (a) Midland, M. M.; Greer, S.; Tramantano, A.; Zderic, S. A.
J. Am. Chem. Soc. 1979, 101, 2352. (b) Brown, H. C.; Chandrasekharan,
J.; Ramachandran, P. V. J. Am. Chem. Soc. 1988, 110, 1539. (c)
Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16.
(d) Ramachandran, P. V.; Lu, Z.-H.; Brown, H. C. Tetrahedron Lett.
1997, 38, 761.
(8) (a) Dieckmann, M.; Kretschmer, M.; Li, P.; Rudolph, S.; Herkommer,
D.; Menche, D. Angew. Chem., Int. Ed. 2012, 51, 5667. (b) Dieckmann, M.;
Rudolph, S.; Dreisigacker, S.; Menche, D. J. Org. Chem. 2012, 77,
10782. (c) Kretschmer, M.; Menche, D. Org. Lett. 2012, 14, 382.
Org. Lett., Vol. 15, No. 1, 2013
229

Table 1. Scope of the Ipc-Mediated Domino Aldol Coupling/Reduction
a Isolated yields after oxidative workup (H2O2/NaOH, 25 °C); yields in parentheses correspond to yields of cyclic boronates of type D (see Scheme 1);
see also ref 14 and the Supporting Information (SI). b Stereochemistry and selectivity were assigned by the following methods: entries 1, 3, 5, 7: (H6/H8)
NOESY-NMR correlations between H6 and H8 of cyclic boronate D; entries 1, 5: (H8/H9) NOESY-NMR correlations of the respective PMP-acetal;
entries 2, 4, 6, 8, 10: comparison of NMR data with the cyclic boronate D and 1,3-diol from the experiment using (þ)-Ipc2BCl under otherwise identical
conditions; entry 9: (H6/H8) NOESY-NMR correlations of the respective acetonide; entry 11: HPLC (AD-H) analysis, measurement of the optical
rotation value and comparison with literature data.17 The anti/anti-products were obtained as mixtures of diastereomers, which were not separable by
column chromatography on silica gel; see SI.
specific aldol coupling, which cannot be overturned by the
chirality of the Ipc-ligand used. To evaluate the potentially
critical influence of the gem-dimethyl center of aldehydes 1
and 6, a range of sterically less hindered aldehydes were
evaluated (7ꢀ9). In all cases, the 1,3-anti diol products
(14ꢀ17) were efficiently obtained, without the necessity of
adopting additional reaction parameters, which clearly
demonstrates that a sterically congested aldehyde is not
required for this domino process.14 The observed selec-
tivities for the initial Ipc-mediated aldol coupling are in
agreement with previously described examples.6,15 In de-
tail, very high selectivities in the initial CꢀC bond forming
reaction were obtained in cases with a matched stereo-
induction, e.g., entries 5 and 7, which additionally benefit
from a 1,3-anti-induction from aldehydes 8/9 and a 1,4-
syn-induction of methyl ketone 2.16 Along these lines, the
remarkable influence of the type of protective group on the
(14) The oxidative cleavage of cyclic boronates D (Scheme 1) has not
been optimized within this study. Steric demand as in the case of
substrates 6ꢀ8 (Table 1) required treatment with H2O2/NaOH (25 °C,
2 h) to liberate the respective 1,3-anti diol, which decreased the yield due
to partial TBS-cleavage (entries 1ꢀ6, 9, and 10). Sterically less burdened
cyclic boronates such as those derived from benzyl protected aldehyde 9
could be cleaved much faster and without decomposition (entries 7, 8,
and 11). To guarantee reproducibly high yields, an aqueous workup
prior to the oxidative cleavage proved beneficial.
(15) Similar selectivities were observed in the corresponding direct
aldol coupling.
(16) (a) Roush, W. R. J. Org. Chem. 1991, 56, 4151. (b) Reetz, M. T.
Acc. Chem. Res. 1993, 26, 462. (c) Evans, D. A.; Dart, M. J.; Duffy, J. L.;
Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
230
Org. Lett., Vol. 15, No. 1, 2013

β-substituent of the aldehyde was observed (viz. entries 5
and 7 as well as 6 and 8), with a Bn-group exerting a much
stronger influence as compared to a TBS group. Only
moderate selectivities were observed in nonmatched cases
(entries 2, 6, 10) or in examples where the selectivity is
exclusively derived from the Ipc-ligand (entry 11), again in
full agreement with previous examples.6c
Importantly, in all cases 1,3-anti diol products were ob-
tained with very high selectivities [dr (anti/syn) > 19:1],
independently of the Ipc-isomer used. To unambiguously
exclude any substrate control or coordinating effects in the
reduction step, we investigated the coupling of benzalde-
hyde and acetone, which resulted again in the exclusive
formation of 1,3-anti diol 18 (entry 11).17 This allows the
confident conclusion that the selectivity of the reduction
step is independent of the nature of Ipc as well as substrate
control.
stereochemical influence of the Ipc-ligand observed in this
domino reaction, as both isomers would proceed through
closely related transition states (i.e., E and E0), leading to
the same cyclic boronate D.
Scheme 3. Mechanistic Proposal for the 1,3-anti Reduction
Process
Presumably, the high stereoselectivity observed in the
reduction step may only be explained by a closed transition
state with an intramolecular hydride transfer, in agreement
with lower asymmetric inductions previously observed in
intermolecular Ipc-mediated reductions.7 Based on the
accepted mechanism,7c an Ipc-induced transfer hydroge-
nation to the carbonyl group under extrusion of R-pinene
would also be expected for the domino sequence developed
herein, which was confirmed by identification of R-pinene
in the NMR of the crude product. In agreement with
the proposed transition state for Ipc-mediated aldol cou-
plings,18 a six-membered twist-boat-like transition state
may also be proposed for the reduction step. As shown in
Scheme 3, the reduction may be directed by the twist
geometry of the six-membered borate E, which explains
the observed 1,3-anti selectivity of this process.19 This type
of transition state is also in agreement with the lack of
In conclusion, we have developed a novel domino pro-
cess for the highly diastereoselective synthesis of 1,3-anti
diols from simple starting materials. Mechanistically, the
procedure is based on a sequential Ipc-mediated aldol
coupling/reduction sequence. It generates two new stereo-
genic centers in a highly concise fashion with excellent
anti-selectivity and may be readily used for polyketide
synthesis. It is expected that this cascade reaction will be
efficiently applied in diverse syntheses of polyketides and
polyfunctional substrates with 1,3-diol motifs.
Acknowledgment. This work was generously supported
by the ’Deutsche Forschungsgemeinschaft’ (Me 2756/4-1).
We thank S. Schmid for technical support (Master student,
Univ. of Heidelberg). Dr. M. Kretschmer (Columbia Univ.
New York) and T. Debnar (Univ. of Heidelberg) are
gratefully acknowledged for fruitful discussions.
(17) Acetti, D.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. Eur.
J. Org. Chem. 2010, 142.
(18) (a) Hoffmann, R. W.; Ditrich, K.; Froech, S.; Cremer, D.
Tetrahedron 1985, 41, 5517. (b) Li, Y.; Paddon-Row, M. N.; Houk,
K. N. J. Am. Chem. Soc. 1988, 110, 3684. (c) Paterson, I.; Goodman,
J. M. Tetrahedron Lett. 1989, 30, 997.
(19) Notably, an intermolecular reduction of chelated β-hydroxy
ketones results in 1,3-syn product formation via a chairlike or half
chairlike transition state. The proposed transition state for a 1,3-anti
reduction requires using the EvansꢀCarreira protocol, which requires
acidic conditions and proceeds via a hydride transfer within the six-
membered chairlike transition state, which would not be possible for our
system. See ref 3.
Supporting Information Available. Experimental de-
tails, spectral data, and copies of NMR spectra for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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