Diastereodivergent Aldol reactions of β-alkoxy ethyl ketones: Modular access to (1,4)-syn and -anti polypropionates

Article abstract of DOI:10.1021/ol801292t

(Chemical Equation Presented) Asymmetric substrate-controlled aldol reactions of ethyl ketones of type 4 with aldehyde 3 are reported. Modular access to all possible syn-and anti-aldol products was obtained by careful choice of reaction conditions. To ach

Full text of DOI:10.1021/ol801292t

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3521-3524
Diastereodivergent Aldol Reactions of
ꢀ-Alkoxy Ethyl Ketones: Modular
Access to (1,4)-syn and -anti
Polypropionates
Fatih Arikan,‡ Jun Li,‡ and Dirk Menche*,†,‡
UniVersity of Heidelberg, Department of Organic Chemistry, INF 270,
69120 Heidelberg, Germany, and Helmholtz-Zentrum fu¨r Infektionsforschung,
Medizinische Chemie, Inhoffenstr. 7, 38124 Braunschweig, Germany
dirk.menche@oci.uni-heidelberg.de
Received June 9, 2008
ABSTRACT
Asymmetric substrate-controlled aldol reactions of ethyl ketones of type 4 with aldehyde 3 are reported. Modular access to all possible syn-
and anti-aldol products was obtained by careful choice of reaction conditions. To achieve good selectivities in this diastereodivergent approach,
selection of the protective group on the ꢀ-oxygen of the enolate (R2) was of critical importance.
Polypropionates represent a rich class of natural products of
broad structural diversity and complexity with a wide
spectrum of potent biological activities.1 This renders their
synthesis an objective of high priority from the perspective
of medicinal chemistry and drug discovery. As exemplified
by the immunosuppressive macrolide brasilinolide A (1,
Figure 1)2 or the polyene antibiotic etnangien (2),3 they are
characterized by a sequence of alternating methyl- and
hydroxyl-bearing stereogenic centers that enable large num-
bers of possible stereochemical permuations.
The aldol reaction is widely considered as the most
powerful and convergent method for the stereoselective
synthesis of these stereogenic arrays.4 Particularly attractive
are substrate-controlled variants where the selectivity relies
on the stereoinduction from a pre-existing chiral center in
the sense of a (1,n)-syn or -anti induction.5–10 Surprisingly,
(4) For recent reviews, see: (a) Yeung, K.-S.; Paterson, I. Chem. ReV.
2005, 105, 4237. (b) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed.
2006, 45, 7506.
(5) According to the (1,n)-nomenclature, 1 denotes the newly formed
stereogenic center, while n stands for the pre-existing chiral center.
(6) For a leading reference on substrate-controlled aldol reactions of
enolates bearing different substitution patterns as compared to the one
discussed herein, see ref 4b and Braun, M. In Modern Aldol Reactions;
† University of Heidelberg.
‡ Helmholtz-Zentrum fu¨r Infektionsforschung.
(1) For reviews on polyketide and polypropionate natural products, see:
(a) O’Hagan, D. The Polyketide Metabolites; Ellis Horwood: Chichester,
1991. (b) O’Hagan, D. Nat. Prod. Rep. 1995, 12, 1.
(2) Komatsu, K.; Tsuda, M.; Tanaka, Y.; Mikami, Y.; Kobayashi, J. J.
Org. Chem. 2004, 69, 1535.
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; pp 1-61.
(7) For selected references of aldol additions with substrate control of
ethyl ketones which are structurally related to 4, see: (a) McCarthy, P.;
Kageyama, M. J. Org. Chem. 1987, 52, 4681. (b) Evans, D. A.; Rieger,
D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991, 113, 1047. (c)
Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett. 1995,
36, 3447. (d) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am.
Chem. Soc. 1995, 117, 9073. (e) Evans, D. A.; Cote, B.; Coleman, P. J.;
(3) (a) Ho¨fle, G.; Reichenbach, H.; Irschik, H.; Schummer, D. German
Patent DE 196 30 980 A1: 1-7 (5.2. 1998). (b) Irschik, H.; Schummer,
D.; Ho¨fle, G.; Reichenbach, H.; Steinmetz, H.; Jansen, R. J. Nat. Prod.
2007, 70, 1060.
Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10893
.
10.1021/ol801292t CCC: $40.75
Published on Web 07/17/2008
2008 American Chemical Society

Scheme 1. Working Model for Diastereodivergent 1,4-syn
versus 1,4-anti Aldol Coupling (Exemplarily Shown for
Z-Enolates 5/6)
Figure 1. Contiguous arrays of methyl- and hydroxyl-bearing
stereogenic centers in polypropionate natural products 1 and 2: 1,4-
syn versus 1,4-anti connectivity.
diversity-oriented applications of such methods for the
divergent assembly of polypropionates are much less re-
ported,11,12 despite their importance for library synthesis and
in enabling flexible routes to natural products with unassigned
configurations,13 such as 2.3 Primarily, they rely on chiral
auxiliaries14 or are not fully diverse, i.e., allowing access to
all possible stereoisomeric permutaions.6,7a,c,d,8b Herein, we
report diasterodivergent asymmetric aldol couplings of ethyl-
ketones of type 4 with aldehyde 3 (Scheme 1) to access all
possible aldol products by careful choice of reaction condi-
tions, purely by substate control.
To obtain useful levels of stereoselectivity in substrate-
controlled aldol couplings, it is usually necessary to impart
stereocontrol from the enolate, as the asymmetric induction
from the chiral aldehyde alone is usually insufficient to lead
to highly stereoselective aldol reactions.7–10 Results indicate
that the R-methyl group of ethyl ketones plays a more
important role as compared to the ꢀ-stereocenter.7–10,14c,15
Consequently, our working model, as shown in Scheme 1,
was based on the stereoinduction from the R-methyl group
of ketone 4 to give after coupling with aldehyde 3 either the
1,4-syn or 1,4-antiproduct.16 To access the 1,4-syn diaste-
reomer 7, a chelation-controlled coupling was envisioned.
In analogy to recent calculations of Goodman on boron-
mediated aldol reactions of ꢀ-oxygenated methyl ketones,
albeit without an R-substituent,8f it was envisioned that a
similar hydrogen bond interaction between the formyl
hydrogen of the aldehyde and the ꢀ-oxygen substituent, as
depicted in 5a, may also be present in related reactions of
ethyl ketones with an R-methyl group, such as 4. Alterna-
tively, the ꢀ-oxygen may also internally coordinate to the
metal counterion giving intermediate 5b. In both cases,
diastereoselectivity should then be governed to minimize
steric interaction of the R-methyl group leading to the should
be obtained via a nonchelation transition model.17 In order
to reduce allylic strain, the respective enolate was expected
to reside in a conformation depicted as 6. Diastereofacial
(8) For selected reference of aldol additions with substrate control from
chiral methyl ketones, which are structurally related to 4, see: (a) Evans,
D. A.; Gage, J. R. Tetrahedron Lett. 1990, 31, 6129. (b) Gustin, D. J.;
VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron Lett. 1995, 36, 3443.
(c) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996, 37,
8585. (d) Evans, D. A.; Coleman, P. J.; Cote, B. J. Org. Chem. 1997, 62,
788. (e) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.;
Sereinig, N. Org. Lett. 2003, 5, 35. (f) Paton, R. S.; Goodman, J. M. Org.
Lett. 2006, 8, 4299
(9) For a review on asymmetric boron-mediated aldol reactions, see:
Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1
.
.
(10) For leading references on the stereochemical influence of the R-
and ꢀ-chiral center of the aldehyde in aldol reactions, see: (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
.
(11) For recent examples of diversity-oriented polyketide library syn-
thesis, see: (a) Reggelin, M.; Brenig, V. Tetrahedron Lett. 1996, 6851. (b)
Paterson, I.; Temal-Laib, T. Org. Lett. 2002, 4, 2473. (c) Barun, O.; Sommer,
S.; Waldmann, H. Angew. Chem., Int. Ed. 2004, 43, 3195. (d) Kesavan, S.;
Su, Q.; Shao, J.; Porco, J. A., Jr.; Panek, J. S. Org. Lett. 2005, 7, 4435. (e)
Shang, S.; Iwadare, H.; Macks, D. E.; Ambrosini, L. M.; Tan, D. S. Org.
Lett. 2007, 9, 1895
.
(12) For diversity oriented aldol-couplings of R-chiral silyloxy-ketones,
see: Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock,
(15) In 1,5-anti aldol reactions of certain ꢀ-alkyxyketones, the ꢀ-sub-
stituent appears to be more influential as compared to the R-substituent;
see ref 8f and literature cited therein.
(16) Selection of 3 and 4 was based on preliminary studies on the
configurational assignment of etnangien in our own laboratories.
(17) This noncyclic transition state is in agreement with that proposed
by Evans for a boron-mediated aldol reaction.14c For titanium-mediated aldol
couplings, a different noncyclic model has been discussed.7b
C. T. J. Org. Chem. 1996, 56, 2499
.
(13) For an example, see: Paterson, I.; Britton, R.; Ashton, K.; Knust,
H.; Stafford, J. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 11986.
(14) (a) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem.
1990, 55, 173. (b) Paterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33,
797. (c) Evans, D. A.; Ng, H. P.; Clark, S.; Rieger, D. L. Tetrahedron
1992, 48, 2127.
3522
Org. Lett., Vol. 10, No. 16, 2008

Scheme 2. 1,4-syn versus 1,4-anti Aldol Coupling of Z-Enolates
attack should then be governed by the relative sizes of the
two residues at C-4, the methyl group () small) and the
large ꢀ-chain (RL). Attack of the aldehyde would then
proceed from the si face of this enolate to minimize steric
interactions, leading to the desired 1,4-anti product 8.
Such a noncyclic transition state should be favored by
sterically demanding, electron-withdrawing protecting groups
on the ꢀ-oxygen, while electron-donating groups R2 should
favor transition states 5a/b. Accordingly, both the PMP- and
the TBS-protected ethyl ketones 13 and 14 were prepared.
As shown in Scheme 24, their synthesis was based on a
dicyclohexyl-boron mediated Paterson anti-aldol reaction9
of lactate-derived ethyl-ketone 9 with PMB-protected alde-
hyde 10, which proceeds with excellent diastereoselectivity
and good yields. Intramolecular protection of the newly
generated hydroxyl of 11 as the PMP-acetal and reductive
removal of the benzoate (using SmI2)18 gave ethyl ketone
13. The TBS congener 14 was prepared accordingly (TB-
SOTf, SmI2).
Optimum results in terms of diastereoselectivtiy, yield, and
preparative practicability among those screened20 were
obtained by using a tin-mediated coupling.21 Enolisation was
best performed under modified Mukaiyama conditions using
freshly prepared Sn(OTf)2 (1.3. equiv) and Et3N (1.6 equiv)
in CH2Cl2 at -20 °C for 1 h and performing the aldol
coupling at -78 °C for 1 h giving the desired isomer 15
with very high levels of stereoinduction (dr > 20:1)22 and
yield (74%). The configuration of 15 was rigorously assigned
by NMR analysis on acetonide 19, readily available by 1,3-
syn reduction using a freshly prepared ethereal solution of
Zn(BH4)2 and treatment with dimethoxypropane. When
employing these same conditions to TBS-ketone 14, the
analogous TBS-protected 1,4-syn adduct 17 was likewise
obtained as the major product, albeit with decreased selectiv-
ity (dr 6:1, see Supporting Information), in agreement with
our working model. This result, however, could be improved
by switching to titanium enolates.23 By employing slightly
modified Evans conditions24 using 1.1 equiv of Hu¨nig’s base
To initiate our studies for diastereodivergent aldol cou-
plings,19 we first focused to obtain the all-syn aldol product
15, which should be most readily accessible by reaction of
PMP-ketone 13 with Roche ester derived aldehyde 12.
(20) Analogous boron9 and titanium7b gave lower π-face selectivity and/
or proceeded with lower yields.
(21) Tin enolates were first introduced by Mukaiyama: Mukaiyama, T.;
Iwasawa, N.; Stevens, R. W.; Haga, T. Tetrahedron 1984, 40, 1381.
(22) In all cases, dr refers to the diastereomeric ratio of the 1,4-syn to
the 1,4-anti aldol products.
(23) For a leading reference on titanium-mediated aldol reactions, see:
Ghosh, A. K.; Shevlin, M. In Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004; pp 63-125.
(24) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993,
115, 11446.
(18) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639.
(19) Mukayiama-type aldol reactions were not evaluated within this study
because of practicality, as they require separate silyl-enol-ether
formation.
Org. Lett., Vol. 10, No. 16, 2008
3523

and 1.15 equiv of TiCl4, for enolization at -78 °C (1 h) and
performing the aldol coupling at -78 °C (2 h) and -25 °C
(5 min), the desired aldol adduct 17 was obtained with very
good levels of selectivity (dr 13:1) and yield (70%). This
favorable result is in agreement with excellent selectivities
previously reported for very similar substrates in titanium-
mediated aldol reactions.7b,24
mainly from a favorable 1,5-anti induction in analogy to the
Goodman model8f for methyl ketones, whereas the 1,4-syn
induction should be less attenuated.28 Notably, related
systems with silyl-protecting groups on the ꢀ-oxygen have
previously resulted in high 1,5-syn induction,8d,9 in agreement
with our general working model (Scheme 1). The low
stereochemical induction of the aldehyde in such boron-
mediated aldol reactions has been amply demonstrated.9,10a
This strong 1,5-anti bias toward 21 is no longer present in
the aldol reaction of the corresponding TBS-protected ketone
14, due to the bulk of the protecting group and the electron-
poor oxygen. The respective 1,4-anti product was obtained
as the major product, albeit with only low selectivity (dr
1.8:1). This low degree of asymmetric induction was
surprising, as a very similar aldol coupling had previously
resulted in excellent 1,4-anti selectivity,14c which suggests
that only subtle structural differences may result in highly
variable degrees in aldol couplings of this type. Nevertheless,
the high chemical yield of this reaction allowed access to
diastereomerically pure 22 in 62% isolated yield (see
Supporting Information), which renders this transformation
still preparatively useful. Therefore, the valuable option of
late stage-diversification by substrate control depending on
the choice of the ꢀ-alkoxy substituent may still be considered
even in this case. In general, these results suggest that the
ꢀ-oxygenated stereocenter appears to impart a stronger
influence on the stereoselectivity of dicyclohexyl-boron
mediated aldol reactions of ethyl ketones than originally
suggested.9,14c
The corresponding 1,4-anti-aldol products 16 and 18 were
best accessible by use of lithium enolates. Treatment of 13
and 14 with LiHMDS at -78 °C and subsequent addition
of aldehyde 12 gave the 1,4-anti-aldol products 16 and 18,
respectively, as the major isomers with preparatively useful
levels of selectivity and yield.25 The configuration of the
newly generated stereocenters in the major products was
assigned in an analogous fashion as described above by
conversion to the corresponding acetonides, such as 20.
While the selectivity of the aldol reaction of ketone 14 may
be explicable by model 6, the very similar levels of
π-selectivity of ketone 13 were surprising, as lithium aldol
reactions of structurally related ꢀ-alkoxy-enolates with
donating protective groups, albeit without an R-chiral center,
had resulted in high degrees of 1,5-anti induction.26 These
results may suggest that the R-methyl group has a more
pronounced influence and/or alternative transition models
have to be considered.7a,27
We then turned our attention to the corresponding E-
enolates. As shown in Scheme 3, the dicyclohexyl-boron
In summary, we have devised substrate-controlled aldol
reactions of ꢀ-oxygenated chiral ethyl ketones of type 4 with
chiral aldehyde 12 to give all possible 1,2-/1,4-syn and -anti
aldol products, with excellent to preparatively useful selec-
tivities in all cases. The protective group on the ꢀ-oxygen
was shown to impart a crucial influence on the stereochem-
ical outcome in these reactions. Applications of these findings
to substrate-controlled aldol-type approaches to etnangien
are in progress. It is expected that these findings will be
beneficial in devising future modular synthetic approaches
and will stimulate further research in divergent aldol cou-
plings.
Scheme 3. 1,4-syn versus 1,4-anti Aldol Coupling of E-Enolates
Acknowledgment. This work was supported by the
“Fonds der Chemischen Industrie” (“Liebig-Stipendium” to
D.M., Stipend to F.A.), the DFG, the Wild-Stiftung, and the
HZI. We thank Antje Ritter and Tatjana Arnold (both HZI)
for technical support.
mediated aldol reaction of PMP-protected ethyl ketone 13
with aldehyde 12 enabled a very efficient access to the 1,4-
syn adduct 21, The high selectivity is expected to result
Supporting Information Available: Experimental details,
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.
(25) For good stereoselectivities, short reaction times were beneficial.7c
(26) Schinzer, D.; Limberg, A.; Bauer, A.; Bo¨hm, O. M.; Cordes, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 523.
OL801292T
(27) Schinzer, D. In Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, 2004; pp 311-328.
(28) Dias, L. C.; Bau´, R. Z.; se Sousa, M. A.; Zukerman-Schpector, J.
Org. Lett. 2002, 4, 4325.
3524
Org. Lett., Vol. 10, No. 16, 2008