A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters

Article abstract of DOI:10.1002/anie.201509302

Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.

Full text of DOI:10.1002/anie.201509302

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201509302
German Edition: DOI: 10.1002/ange.201509302
Organocatalysis
A Catalyst Designed for the Enantioselective Construction of Methyl-
and Alkyl-Substituted Tertiary Stereocenters
AurØlie Claraz, Gokarneswar Sahoo, DØnes Berta, dµm Madarµsz, Imre Pµpai, and
Petri M. Pihko*
Abstract: Tertiary methyl-substituted stereocenters are present
in numerous biologically active natural products. Reported
herein is a catalytic enantioselective method for accessing these
chiral building blocks using the Mukaiyama–Michael reaction
between silyl ketene thioacetals and acrolein. To enable remote
enantioface control on the nucleophile, a new iminium catalyst,
optimized by three-parameter tuning and by identifying
substituent effects on enantioselectivity, was designed. The
catalytic process allows rapid access to chiral thioesters,
amides, aldehydes, and ketones bearing an a-methyl stereo-
center with excellent enantioselectivities, and allowed rapid
access to the C4–C13 segment of (À)-bistramide A. DFT
calculations rationalized the observed sense and level of
enantioselectivity.
T
ertiary stereocenters bearing either methyl, ethyl, or other
simple alkyl groups are present in numerous biologically
active natural products, such as in polyketides and terpenoids.
Over 10000 known natural products bear structural subunits
of this type.[1] Very often, such stereocenters are found
adjacent to a linear chain of methylene (CH2) groups
(Scheme 1a). The conformational flexibility of the methylene
chains usually prevents the induction of stereochemistry from
remote positions.[2]
In the total synthesis of natural products and synthesis of
pharmaceuticals, these methyl-bearing tertiary stereocenters
are usually encoded into the structure with the help of
a stoichiometric amount of a chiral auxiliary (Scheme 1a,
right).[3] Popular solutions include the use of enolate alkyla-
tions reported by the groups of Evans[4] and Myers.[5] In
addition, crotylation reported by the group of Brown[6] and
chiral pool methods are also occasionally used. Scheme 1b
summarizes some recent natural product targets and the
methods used to construct the methyl-bearing tertiary
stereocenters in them.[7,8]
Scheme 1. a) Access to methyl-substituted stereocenters through
stereocontrol on the nucleophile (with a chiral auxiliary) or on the
electrophile (with a chiral catalyst). b) Examples of chiral pool or chiral
auxiliary methods for the construction of methyl-bearing stereocenters
in natural products.
methyl vinyl ketone or to activated acrylates have been
reported by the groups of Gellman[9] and Maruoka.[10] a-
Alkylation of aldehydes[11] can also provide access to alde-
hydes bearing a-substituents, but the simplest methyl sub-
stituents are still challenging and require indirect methods.[12]
While these solutions are attractive, and have already found
use in total synthesis,[13] they are all restricted to easily
epimerizable a-chiral aldehydes.[14]
To enable the catalytic, enantioselective synthesis of
configurationally more stable a-alkyl carboxylic acid deriva-
tives, we report here the successful design of a catalyst which
allows the stereochemistry of a Mukaiyama–Michael reac-
tion[15] between acrolein and enolsilane (Scheme 1a, left).
This approach requires remote control of enantioface selec-
tivity. We have previously reported successful enantioselec-
tive Mukaiyama–Michael reactions of acrolein with silyl-
oxyfuran nucleophiles.[16] Still, it remained far from certain
whether the methodology could extend to enolsilanes (d2
As an alternative to these stoichiometric methods, amine-
catalyzed addition reactions of simple alkyl aldehydes to
[*] Dr. A. Claraz, Dr. G. Sahoo, Prof. Dr. P. M. Pihko
Department of Chemistry, Nanoscience Center
University of Jyväskylä
P. O. B. 35, 40014 JYU (Finland)
E-mail: petri.pihko@jyu.fi
Homepage: http://tinyurl.com/pihkogroup
D. Berta, Dr. . Madarµsz, Dr. I. Pµpai
Institute of Organic Chemistry
Research Centre for Natural Sciences
Hungarian Academy of Sciences, 1525 Budapest (Hungary)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509302.
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nucleophiles), which present a much smaller contact area with
the iminium electrophile compared to the silyloxyfurans (d4
nucleophiles).
Indeed, in initial screens, the enolsilane 1a and acrolein
(2), in combination with our previously successful diaryl-
pyrrolidine catalyst 6a,[16] afforded only moderate enantiose-
lectivities (Scheme 2a).[17] Other iminium catalysts (e.g 4a–c
Scheme 3. Design and optimization of the new catalyst family through
a three-variable (Pg, R, Ar) tuning of the catalyst structure. Pg=pro-
tecting group.
which combined the separately optimized groups (Ar, R, and
Pg) into a single catalyst structure. The catalyst 12n afforded
the product 3a with 95:5 e.r. and excellent conversion.
Insight into the origin of enantioselectivity with 12n was
Scheme 2. a) Preliminary screens for suitable catalysts. Reaction con-
ditions: Acrolein (2; 5 equiv), the catalyst 4–6 (0.2 equiv), 4-nitro-
benzoic acid (0.2 equiv), H2O (2 equiv), CH2Cl2, 08C. The e.r. value
was measured using GC analysis with a chiral stationary phase.
b) Design of new trans-2,5-disubstituted pyrrolidine catalysts from
pyroglutamic acid and evaluation of the first-generation designed
catalysts in the Mukaiyama–Michael reaction. For details, and further
examples, see the Supporting information. n.r.=no reaction.
À
provided by DFT calculations for transition states of the C C
bond formation between the iminium intermediate 14
(derived from 12n and 2) and 1a (Figure 1). The most
favored transition states leading to the major (R) and minor
(S) product are shown in Figure 1. The energy difference
between these diastereomeric structures is related to the
combined effect of repulsive steric and attractive noncovalent
interactions, which varies for the two competing pathways.[17]
For catalysts 12i and 12a, the computations predicted higher,
not lower selectivities compared to 12n (the computed DDG°
was 3.8 kcalmolÀ1 for 12i vs 2.1 kcalmolÀ1 with 12n). This
apparent contradiction with the experimental trend might
result if the more electron-poor catalyst 12i could promote
the reaction via an alternative, racemic mechanism[19] (e.g. via
acid catalysis). However, control experiments[17] appear to
rule out this possibility: neither carboxylic acids nor proton-
ated amines with pKa values close to that of 12i (estimated
pKa 4.2) promoted the reaction. The divergence of the
computed and experimental DDG° values could also indicate
that the counterion (which was not included in the compu-
tations) may alter the energies of the pathways or even alter
the mechanism.[19]
or 5) or aryl-substituted variants of 6 also turned out to be
ineffective.[17] However, pyroglutamic-acid-derived[18] 2,5-di-
substituted pyrrolidines, especially 12a (Scheme 2b),
appeared to be viable candidates for further optimization.
Other designs (9–11) offered inferior selectivities.
Importantly, the design of 12 provided us with three
independently tunable variables (the protecting group Pg, the
R group, and the 5-aryl (Ar) group; Scheme 3). Increasing the
size of the silyl protection (Pg) was not helpful (Scheme 3a).
However, varying the R and Ar groups proved more fruitful
and enhanced enantioselectivity. Most importantly, introduc-
tion of electron-donating groups (12 f versus 12a and 12m
versus 12a) increased the e.r. value, while introduction of
electron-withdrawing substituents on the phenyl ring (12i) led
to decreased e.r. values. When this trend started to emerge
from the data, we quickly arrived at the final catalyst 12n,
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Table 1: Substrate scope for Mukaiyama–Michael reaction of alkylated
silyl ketene thioacetals with acrolein.[a]
Entry
Product
R
1a Z/E
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
3a
Me
Et
nBu
iBu
n-C10H21
PhCH2CH2
BnOCH2CH2
BnO(CH2)3
Allyl
iPr
c-C6H11
c-C5H9
100:0
100:0
96:4
96:4
100:0
95:5
90:10
97:3
95:5
91:9
93:7
93:7
76[d]
62
67
68
69
72
52
67
60
61
64
60
95:5
96.5:3.5
94.5:5.5
94.5:5.5
94.5:5.5
95.5:4.5
94:6
94.5:5.5
94:6
97.5:2.5
98:2
15b
15c
15d
15e
15 f
15g
15h
16i
15j
15k
15l
Figure 1. Diastereomeric transition states computed for reaction cata-
lyzed by 12n. Relative energies, in kcalmolÀ1, are shown within
9
À
parentheses. The developing C C bonds are indicated by red dotted
10
11
12
lines. Hydrogen atoms are omitted for clarity, except those of reacting
carbon atoms. TMS=trimethylsilyl.
97:3
[a] Reaction conditions: a) Acrolein (2; 5 equiv), catalyst 12n (0.2 equiv),
4-nitrobenzoic acid (0.2 equiv), H2O (2 equiv), CH2Cl2, 08C, 12 h
b) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH/H2O, RT. c) LiAlH-
(OtBu)3, THF, 08C. [b] Yield of product after either oxidation or
reduction. [c] Determined by HPLC analysis using a chiral stationary
phase. For 3a, the e.r. value was determined by GC analysis using a chiral
stationary phase. [d] After 22 h with 0.05 equiv of 12n and 0.05 equiv of
4-nitrobenzoic acid.
groups, the yields and enantiomeric ratios of the products
were determined after oxidation of the aldehyde product in
the corresponding carboxylic acid 15, or after reduction to the
alcohol 16 (Table 1). Access to functionalized thioesters with
either long alkyl chains or remote readily tunable substituents
(allyl, benzyloxy, aryl) is possible with good yields and
excellent enantioselectivities ranging from 94:6 e.r. to 98:2
e.r. Importantly, the enantioselectivity of the reaction is not
compromised by the presence of the E isomer impurity in 1.
Only the yield of the isolated product is affected, as the
E isomer appears to be unreactive under the reaction
conditions.
The versatility of the thioester group was first demon-
strated by the straightforward conversion of the product 3a
into the key building block aldehyde 18 (Scheme 4a) with
complete retention of enantiomeric purity. The aldehyde 18
has been frequently used in the total synthesis of natural
products. Typically, its synthesis requires a stoichiometric
amount of either a chiral pseudoephedrine[22] or oxazolidi-
none[23] auxiliary, or resorting to chiral pool sources, such as
ozonolysis of a b-citronellene derivative.[24] Chiral ketone
building blocks can also readily be accessed from 3a via the
corresponding Weinreb amide 19, which was smoothly con-
verted into ethyl ketone 20 in 95:5 e.r. (Scheme 4a).
Figure 2. Correlations between the aryl substituents on the catalyst
and the enantioselectivity. LFER correlating the weighted Hammett
constants (sw) of aryl substituents with enantioselectivity. Herein, sR
and sAr refer to substituent constants associated with R and Ar
groups, respectively. The coefficient 0.36 was obtained from a fitting
procedure (see the Supporting Information).
The observed trend that led us to the structure of 12n can
also be expressed more quantitatively in the form of a linear
free-energy relationship (LFER)[20] relating the observed
enantioselectivities (expressed as the free energy difference
DDG°) with the weighted Hammett constants (sw; Figure 2).
Interestingly, the LUMO energy of the iminium ion corre-
lated reasonably with the enantioselectivity as well. Although
these correlations do not explain the effect of the electron-
donating substituents, they do confirm that the effect is nearly
linear, and also serve as pointers for the design of future
catalysts for similar transformations.[21]
The scope of the Mukaiyama–Michael addition reaction
on acrolein was investigated with various alkylated silyl
ketene thioacetals (Table 1). The adduct 3a, with a methyl
group, was isolated in 70% yield and 95:5 of e.r. Pleasingly, 3a
can also be obtained with the same enantioselectivity (95:5
e.r., 76% yield) at lower catalyst loading (5 mol%). If the
aldehyde is needed in protected form, in situ protection of 3a
gives the corresponding acetal 17a in 76% overall yield from
1a (1 mmol scale, 94:6 e.r., see Scheme 4a). For other R
Finally, the synthetic utility of our methodology was
illustrated by the straightforward access to the C4–C13
segment of bistramide A (Scheme 4b). To date, seven differ-
ent routes for the total syntheses of the bistramides have been
published.[7a,25] Out of them, five synthetic routes, including
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Acknowledgments
This work was supported by the Academy of Finland (project
Nos. 259532 and 139046), by the Hungarian Research
Foundation (OTKA, Grant K-112028), Tekes (2671/31/
2013), COST CM0905, and University of Jyväskylä. We
thank Dr. Elina Kalenius and Ms. Johanna Lind for assistance
with mass spectrometry, and Mr. Esa Haapaniemi for NMR
assistance.
Keywords: asymmetric catalysis ·
density functional calculations · diastereoselectivity ·
natural products · organocatalysis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 669–673
Angew. Chem. 2016, 128, 679–683
[1] Based on a search of the Reaxys database (accessed 13.09.2015).
[2] K. Mikami, M. Shimizu, H.-C. Zhang, B. E. Maryanoff, Tetrahe-
dron 2001, 57, 2917 – 2951.
[3] Y. Gnas, F. Glorius, Synthesis 2006, 1899 – 1930.
[4] D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982,
104, 1737 – 1739.
[5] A. G. Myers, B. H. Yang, H. Chen, J. L. Gleason, J. Am. Chem.
Soc. 1994, 116, 9361 – 9362.
[6] H. Lachance, D. G. Hall, Org. React. 2009, 73, 1 – 574.
[7] a) A. V. Statsuk, D. Liu, S. A. Kozmin, J. Am. Chem. Soc. 2004,
126, 9546 – 9547; b) D. R. Williams, A. A. Shah, J. Am. Chem.
Soc. 2014, 136, 8829 – 8836.
[8] A. Rentsch, M. Kalesse, Angew. Chem. Int. Ed. 2012, 51, 11381 –
11384; Angew. Chem. 2012, 124, 11543 – 11547.
[9] Y. Chi, S. H. Gellman, Org. Lett. 2005, 7, 4253 – 4256.
[10] a) T. Kano, F. Shirozu, K. Tatsumi, Y. Kubota, K. Maruoka,
Chem. Sci. 2011, 2, 2311 – 2313; b) T. Kano, F. Shirozu, M.
Akakura, K. Maruoka, J. Am. Chem. Soc. 2012, 134, 16068 –
16073.
[11] D. M. Hodgson, A. Charlton, Tetrahedron 2014, 70, 2207 – 2236.
[12] A. Gualandi, E. Emer, M. G. Capdevila, P. G. Cozzi, Angew.
Chem. Int. Ed. 2011, 50, 7842 – 7846; Angew. Chem. 2011, 123,
7988 – 7992.
[13] a) K. C. Nicolaou, T. R. Wu, D. Sarlah, D. M. Shaw, E. Rowcliffe,
D. R. Burton, J. Am. Chem. Soc. 2008, 130, 11114 – 11121;
b) M. J. Campbell, J. S. Johnson, J. Am. Chem. Soc. 2009, 131,
10370 – 10371.
[14] For an elegant solution to the epimerization problem, see: K.
Chen, Y. Ishihara, M. M. Galµn, P. S. Baran, Tetrahedron 2010,
66, 4738 – 4744.
[15] a) S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am.
Chem. Soc. 2003, 125, 1192 – 1194; b) C. J. Borths, D. E. Carrera,
D. W. C. MacMillan, Tetrahedron 2009, 65, 6746 – 6753; c) W.
Wang, H. Li, J. Wang, Org. Lett. 2005, 7, 1637 – 1639; d) I. Reile,
A. Paju, T. Kanger, I. Järving, M. Lopp, Tetrahedron Lett. 2012,
53, 1476 – 1478; e) V. Gupta, S. V. Sudhir, T. Mandal, C.
Schneider, Angew. Chem. Int. Ed. 2012, 51, 12609 – 12612;
Angew. Chem. 2012, 124, 12778 – 12781.
[16] a) E. K. Kemppainen, G. Sahoo, A. Piisola, P. M. Pihko, Org.
Lett. 2012, 14, 1086 – 1089; b) E. K. Kemppainen, G. Sahoo, A.
Piisola, A. Hamza, B. Kótai, I. Pµpai, P. M. Pihko, Chem. Eur. J.
2014, 20, 5983 – 5993.
Scheme 4. A) Access to chiral building blocks from 3a. Reagents and
conditions: a) LiAlH(OtBu)3, THF, À208C, 3 h, 90% (63% based on
1a); b) TBDPSCl, imidazole, DMF, RT, overnight, 95%; c) DIBAL-H,
CH2Cl2, À788C, 45 min, 98%; d) p-TsOH (0.1 equiv), neopentyl glycol
(5 equiv), CH2Cl2, 08C, 15 h, 76% over two steps from 1a; e) p-TsOH
(0.2 equiv), ethylene glycol (3 equiv), reflux overnight, 70% over two
steps from 1a; f) MeNHOMe·HCl (4.1 equiv), iPrMgCl (8 equiv), 08C,
THF, overnight, 87%; g) EtMgBr (3 equiv), THF, 16 h, 08C, quant.
B) Synthesis of C4–C13 fragment of (À)-bistramide A. Reagents and
conditions: h) DIBAL-H (1.8 equiv), CH2Cl2, À788C, 1 h, 93%; i) 22
(1.2 equiv), BF3·OEt2 (2 equiv), À788C, 4 h, 65%; j) p-TsOH
(0.2 equiv), MeOH, 508C, 6 h, 84%; k) allyltrimethylsilane (5 equiv),
BiBr3 (0.5 equiv), RT, 12 h, 90%. DIBAL-H=diisobutylaluminum hy-
dride, DMF=N,N-dimethylformamide, TBDPS=tert-butyldiphenylsilyl,
Ts =4-toluenesulfonyl.
the two most recent syntheses,[7a,25b,c,e,f] use either chiral
auxiliary or chiral reagents to access the C9 methyl-bearing
stereocenter. We used the acetal 17a as the starting material
for a four-step synthesis of the C4–C13 fragment of the
bistramides (25; Scheme 4b), with
a diastereoselective
Mukaiyama aldol[26] and a BiBr3-promoted C-allylation[27] of
the tetrahydropyran 24 as the key steps. The fragment 25 was
obtained in 31% overall yield starting from 17a.
In summary, systematic probing of three independent
variables afforded a successful catalyst which allows access to
chiral thioesters, amides, aldehydes, and ketones bearing
either a-methyl or other a-alkyl groups in high enantiomeric
purity. The products are directly useful in natural product
synthesis, as demonstrated by a rapid access to the C4–C13
segment of (À)-bistramide A. We anticipate that the three-
point optimization procedure which led to the successful
catalyst structure should inspire researchers to tackle other
standing challenges in catalytic enantioselective synthesis.
[17] For more details, see the Supporting Information.
[18] B. M. Trost, D. A. Thaisrivongs, E. J. Donckele, Angew. Chem.
Int. Ed. 2013, 52, 1523 – 1526; Angew. Chem. 2013, 125, 1563 –
1566.
[19] H. Gotoh, T. Uchimaru, Y. Hayashi, Chem. Eur. J. 2015, 21,
12337 – 12346.
672
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 669 –673

Angewandte
Communications
Chemie
[20] a) O. Lifchits, M. Mahlau, C. M. Reisinger, A. Lee, C. FarØs, I.
2007, 9, 327 – 330; d) J. S. Yadav, L. Chetia, Org. Lett. 2007, 9,
Polyak, G. Gopakumar, W. Thiel, B. List, J. Am. Chem. Soc.
2013, 135, 6677 – 6693; b) A. Moran, A. Hamilton, C. Bo, P.
Melchiorre, J. Am. Chem. Soc. 2013, 135, 9091 – 9098.
[21] K. C. Harper, M. S. Sigman, J. Org. Chem. 2013, 78, 2813 – 2818.
[22] a) K. M. Graf, M. G. Tabor, M. L. Brown, M. Paige, Org. Lett.
2009, 11, 5382 – 5385; b) Y. Yuan, H. Men, C. Lee, J. Am. Chem.
Soc. 2004, 126, 14720 – 14721; c) L. Raffier, O. Piva, Eur. J. Org.
Chem. 2013, 1124 – 1131.
4587 – 4589; e) L. Tomas, et al., Chem. Eur. J. 2012, 18, 7452 –
7466; f) X. Han, P. E. Floreancig, Angew. Chem. Int. Ed. 2014,
53, 11075 – 11078; Angew. Chem. 2014, 126, 11255 – 11258.
[26] A. P. Davis, S. J. Plunkett, J. E. Muir, Chem. Commun. 1998,
1797 – 1798.
[27] a) N. M. Leonard, L. C. Wieland, R. S. Mohan, Tetrahedron
2002, 58, 8373 – 8397; b) H. H. Jung, J. R. Seiders, P. E. Flor-
eancig, Angew. Chem. Int. Ed. 2007, 46, 8464 – 8467; Angew.
Chem. 2007, 119, 8616 – 8619; c) P. A. Evans, J. Cui, S. J.
Gharpure, R. J. Hinkle, J. Am. Chem. Soc. 2003, 125, 11456 –
11457.
[23] V. P. Kumar, N. Kavitha, S. Chandrasekhar, Eur. J. Org. Chem.
2013, 6325 – 6334.
[24] T. Magauer, H. J. Martin, J. Mulzer, Angew. Chem. Int. Ed. 2009,
48, 6032 – 6036; Angew. Chem. 2009, 121, 6148 – 6152.
[25] a) P. Wipf, T. D. Hopkins, Chem. Commun. 2005, 3421 – 3423;
b) M. T. Crimmins, A. C. DeBaillie, J. Am. Chem. Soc. 2006, 128,
4936 – 4937; c) J. T. Lowe, I. E. Wrona, J. S. Panek, Org. Lett.
Received: October 7, 2015
Published online: November 25, 2015
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