1,4-Induction in aldol reactions of (tertiary α′-alkoxy)methyl ketones: Synthesis of the C8-C11 stereotriad of ent-fostriecin

Article abstract of DOI:10.1016/j.tetlet.2012.01.130

A diastereoselective, boron-mediated aldol process inspired by the natural product fostriecin is described. Using a tertiary α′-stereocenter as the induction element, aldol adducts are provided with high yields, good to excellent levels of diastereoselect

Full text of DOI:10.1016/j.tetlet.2012.01.130

Tetrahedron Letters 53 (2012) 1837–1839
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1,4-Induction in aldol reactions of (tertiary a0-alkoxy)methyl ketones:
synthesis of the C8–C11 stereotriad of ent-fostriecin
Nicholas Cowper a, Soula Azzi b, Kristina Dupont-Gaudet b, Jason D. Burch a,b,
⇑
a Genentech Research and Early Development – Small Molecule Drug Discovery, 1 DNA Way, South San Francisco, CA 94080, USA
b Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy., Kirkland, QC, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective, boron-mediated aldol process inspired by the natural product fostriecin is described.
Using a tertiary a0-stereocenter as the induction element, aldol adducts are provided with high yields,
good to excellent levels of diastereoselection, and broad substrate scope. An Evans–Tischencko reduction
of the aldol adduct from cinnamaldehyde resulted in the C8–C11 stereotriad of ent-fostriecin.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 20 January 2012
Revised 25 January 2012
Accepted 30 January 2012
Available online 7 February 2012
Keywords:
Aldol reaction
Fostriecin
Acyclic stereocontrol
Introduction
Discussion
Isolated in 1983 from Streptomyces pulveraceus by scientists at
Warner–Lambert/Parke–Davis,1 fostriecin (1, Fig. 1) has attracted
considerable attention from the medical community due to its
broad in vitro and in vivo antitumor activities.2 The accepted
mechanism of action of this interesting natural product is linked
to potent and selective inhibition of protein serine/threonine phos-
phatases PP2A and PP4, with the C9 phosphate acting as an impor-
tant recognition element.3
Although the planar structure was determined in the context of
the original isolation, it was not until 1997 that Boger and co-
workers determined the relative and absolute stereochemistry of
the natural product via degradation studies,4 and then completed
the first total synthesis five years later.5 Over the course of the last
decade, numerous total syntheses6,7 and synthetic studies8,9 have
appeared in the chemical literature.
The aldol reaction, while a powerful synthetic tool for the
construction of polyketide stereoarrays, is under-represented in
the fostriecin prior art. The only examples, in the Trost7h and
Shibasaki7g syntheses, involve chiral catalyst or stoichiometric
modifier control to construct the C9–C10 bond and set the C9
stereochemistry. We were interested in investigating a fundamen-
tally different approach (Fig. 1): the C10–C11 is targeted and the C11
stereochemistry is controlled by induction from the a0-tertiary
alkoxy stereocenter of the methyl ketone reaction partner.
Prior to this work, the only (a0-tertiary alkoxy) methyl ketone
substrate which had demonstrated the ability to control the
stereochemical course of an aldol process involved a sterically-
encumbered and conformationally rigid camphor-based auxil-
iary.10 Nonetheless, we found inspiration for our planned discon-
nection through the combination of two loosely related aldol
processes (Fig. 2). Urpi has previously shown that secondary
a0-alkoxy groups provide good to excellent levels of 1,4-induction
in titanium aldol reactions (Eq. 1).11 Carda and Marco have shown
that the a0-alkoxy protecting group can lead to reversal of stereo-
induction in a poly-oxygenated enolate (Eq. 2).12 Combining
elements of these two studies, we hoped that a ketone possessing
an a0-tertiary alkoxy group and b0-oxygenation would be success-
ful in controlling the stereochemical course of our desired process
O
NaO
HO 8
P
OH
O
OH
11
O
O
5
1
10
OH
Me
1
Fostriecin (CI-920)
1-4 anti induction?
O
O
+
8
R
Me
Me OPG
H
R'
11
⇑
Corresponding author.
E-mail address: burch.jason@gene.com (J.D. Burch).
Figure 1. The structure of fostriecin and the planned bond disconnection.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.130

1838
N. Cowper et al. / Tetrahedron Letters 53 (2012) 1837–1839
O
O
OH
Urpi:
i
O
O
OH
PrOTiCl3
RCHO
a
BnO
BnO Me
Me
BnO
Ph
(eq. 1)
R'
R'
BnO Me
Me
Me
R
2
3a
Me
Me
O
OBn
dr 2.2-13:1
OBn
b
OH
O
BnO
BnO Me
Ph
LnMX
RCHO
O
O
OH
8
BnO
BnO
R
BnO Me
BnO Me
Scheme 2. Reagents and conditions: (a) 1.8 equiv Cy2BCl, 2.0 equiv Et3N, Et2O, 0 °C
then cinnamaldehyde, 7.8:1 dr, 99%; (b) 5 equiv iPrCHO, 0.15 equiv SmI2, THF,
ꢀ10 °C, >20:1 dr, 87%.
2
3
Carda and Marco:
results in a 1,3-anti-hydroxy relationship, provides the added ben-
efit of leaving the directing hydroxyl protected as an ester while
leaving the newly formed center unprotected. Mosher ester forma-
tion on this hydroxyl allowed establishment of the overall stereo-
chemistry, which proved to be the desired 1,2-syn/1,4-anti
relationship present in fostriecin.17
With a synthesis of the fostriecin stereotriad completed, we
were interested to investigate the substrate scope of the aldol pro-
cess. As Table 1 shows, synthetically useful yields and levels of dia-
stereoselection can also be achieved with aryl (entries b–d) and
alkyl aldehydes (entries e–h). In general, diastereoselectivity is
marginally improved for electron poor aromatics, and selectivity
improves slightly as steric hindrance increases in the alkyl series.
To explain the sense of induction observed, we examined the
Zimmerman–Traxler transition states18 possible for the two poten-
tial aldol adducts. Houk has determined computationally that
twist-boat cyclic transition states are preferred for unsubstituted
boron enolates, contrary to the chair transition state commonly ac-
cepted for ethyl ketone enolates.19 Four possible transition struc-
tures, two for each diastereomeric product, are provided in
O
O
OH
Cy2BCl
RCHO
(eq. 2)
1
PO
PO
4 R
dr > 9:1
OP OTBS
OP OTBS
P = Bn: 1,4-anti
P = Bz: 1,4-syn
Figure 2. Merger of Urpi and Carda/Marco strategies.
through judicious selection of protecting groups and enolization
conditions. To this end, we targeted ketone 2 for the first iteration
of aldol studies.
Due to the commercial availability of only one enantiomer of
Weinreb amide 4 (Scheme 1), we chose to target the antipode of
the fostriecin stereotriad.13 Despite the availability of this advanced
intermediate, however, synthesis of ketone 2 was not straightfor-
ward. Treatment of 4 with sodium hydride and benzyl bromide pro-
vided low and variable levels of the desired dibenzyl ether 5.14
Careful analysis of the reaction mixture from these conditions
revealed the formation of a significant quantity of demethylation
product 6. This observation allowed us to find an acceptable solu-
tion: subjection of 4 to forcing benzylation conditions provided trib-
enzyl derivative 7. Treatment of 7 with methyl lithium provided
desired ketone 2, demonstrating that the O-benzyl Weinreb analog
is an acceptable surrogate for the traditional N,O-dimethyl variant.
With a scalable synthesis of ketone 2 in place, we were
prepared to test the key aldol process (Scheme 2). Trans-cinnamal-
dehyde was selected as the initial reaction partner in order to pro-
vide a potential synthetic handle for future modifications. To our
delight, enolization of ketone 2 with dicyclohexylboron chloride,
followed by addition of the aldehyde coupling partner, provided
a quantitative yield of the aldol adduct 3a as a 7.4:1 mixture of dia-
stereomers. By contrast, lithium enolate conditions resulted in an
unselective aldol process.15
Table 1
Substrate scope for the diastereoselective aldol process
OH
O
O
Cy2BCl, Et3N;
RCHO
BnO
Me
BnO
BnO Me
3a-i
R
BnO Me
Entry
Aldehyde
Diastereoselectiona
Isolated yieldb
>95%
Ph
a
7.4:1
5.8:1
CHO
b
c
>95%
>95%
CHO
Br
Stereochemical determination through Mosher ester formation
was not possible at this stage due to concomitant elimination of
the activated b-acyloxy group. As an alternative, formation of the
final stereocenter of the triad was first accomplished via an
Evans–Tischencko reduction16 to alcohol 8. This operation, which
8.2:1
8.4:1
CHO
O N
2
d
73%
CHO
CHO
Ph
O
O
O
e
f
5.7:1
6.2:1
84%
86%
OMe
OMe
OH
a
Me
HO
N
BnO
N
BnO
N
+
HO Me
BnO Me
HO Me
Me
Me
Me
Me
CHO
4
5
6
O
O
g
6.6:1
6.4:1
92%
b
CHO
Me
OBn
c
BnO
Me
BnO
N
Me
Me
BnO Me
BnO Me
Me
h
>95%
7
2
CHO
a
Determined by integration of the methyl singlet from a 500 MHz 1H NMR
Scheme 1. Reagents and conditions: (a) 2.2 equiv NaH, 2.2 equiv BnBr, 0.2 equiv
TBAI, DMF, 0–15% 5; (b) 5 equiv NaH, 4 equiv BnBr, 2 equiv 15-crown-5, 0.2 equiv
KI, THF, 75%; (c) MeLi, Et2O, 58% (84% br s m).
spectrum (see Supplementary data for further details).
b
Yield of the purified mixture of diastereomers.

N. Cowper et al. / Tetrahedron Letters 53 (2012) 1837–1839
1839
stereochemical analysis of 8 and images of 1H NMR for the methyl
singlet used in determination of diastereoselectivity for examples
in Table 1) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2012.01.130.
Bn
OBn
Me
Bn
BnO
O
O
H
Me
Cy
Cy
O
O
B
H
B
Cy
Cy
References and notes
O
O
R
R
1. (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983, 36, 1595; (b)
Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Wilmer, N. E.; Brankiewicz, A. J.;
Steinman, C. E.; French, J. C. J. Antibiot. 1983, 36, 1601.
TS1
TS2
2. (a) De Jong, R. S.; De Vries, E. G. E.; Mulder, N. H. Anti-Cancer Drugs 1997, 8, 413;
(b) Scheithauer, W.; Hoff, D. D. V.; Clark, G. M.; Shilis, J. L.; Elslager, E. F. Eur. J.
Clin. Oncol. 1986, 22, 921.
3. For reviews see: (a) Lewy, D. S.; Gauss, C. M.; Soenen, D. R.; Boger, D. L. Curr.
Med. Chem. 2002, 9, 2005; (b) McCluskey, A.; Sim, A. T. R.; Sakoff, J. A. J. Med.
Chem. 2002, 45, 1151.
O
OH
1,4-syn
BnO
R
BnO Me
4. Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62, 1748.
5. Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001, 123, 4161.
6. For reviews see: (a) Shibasaki, M.; Kanai, M. Heterocycles 2005, 66, 727; (b)
Miyashita, K.; Ikejiri, M.; Tsunemi, T.; Matsumoto, A.; Imanishi, T. J. Synth. Org.
Chem. Jpn. 2007, 65, 874.
O
OH
1,4-anti
favored
BnO
BnO Me
R
7. (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2001, 40, 3667; (b) Reddy,
Y. K.; Falck, J. R. Org. Lett. 2002, 4, 969; (c) Miyashita, K.; Ikejiri, M.; Kawasaki,
H.; Maemura, S.; Iminishi, T. Chem. Commun. 2002, 742; (d) Miyashita, K.;
Ikejiri, M.; Kawasaki, H.; Maemura, S.; Iminishi, T. J. Am. Chem. Soc. 2003, 125,
8238; (e) Wang, Y. G.; Kobayashi, Y. Org. Lett. 2002, 4, 4615; (f) Esumi, T.;
Okamoto, N.; Hatakeyama, S. Chem. Commun. 2002, 3042; (g) Fujii, K.; Maki, K.;
Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733; (h) Trost, B. M.; Frederiksen, M.
U.; Papillon, J. P. N.; Harrington, P. E. J. Am. Chem. Soc. 2005, 127, 3666; (i) Maki,
K.; Motoki, R.; Fujii, K.; Kanai, M.; Kobayashi, T.; Tamura, S.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 17111; (j) Yadav, Y. S.; Prathap, I.; Tadi, B. P. Tetrahedron
Lett. 2006, 47, 3773; (k) Robles, O.; McDonald, F. E. Org. Lett. 2009, 11, 5498; (l)
Sarkar, S. M.; Wanzala, E. N.; Shibahara, S.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Chem. Commun. 2009, 5907; (m) Shibhara, S.; Fujino, M.;
Tashiro, Y.; Okamoto, N.; Esumi, T.; Takahashi, K.; Ishihara, J.; Hatakeyama, S.
Synthesis 2009, 2935; (n) Gao, D.; O’Doherty, G. A. Org. Lett. 2010, 12, 3752; (o)
Hayashi, Y.; Yamaguchi, H.; Toyoshima, M.; Okado, K.; Toyo, T.; Shoji, M. Chem.
Eur. J. 2010, 16, 10150; (p) Li, D.; Zhao, Y.; Ye, L.; Chen, C.; Zhang, J. Synthesis
2010, 19, 3325.
Bn
Me
O
BnO
Me
Bn
O
O
BnO
Cy
O
Cy
H
B
Cy
H
B
Cy
O
R
O
TS3
R
TS4
Figure 3. Transition structures explaining the observed sense of induction.
8. (a) Just, G.; O’Connor, B. Tetrahedron Lett. 1988, 29, 753; (b) Liu, S. Y.; Huang, D.
F.; Huang, H. H.; Huang, L. Chin. Chem. Lett. 2000, 11, 957; (c) Cossy, J.; Pradaux,
F.; BouzBouz, S. Org. Lett. 2001, 3, 2233; (d) Kiyotsuka, Y.; Igarishi, J.; Kobayashi,
Y. Tetrahedron Lett. 2002, 43, 2725; (e) Marshall, J. A.; Bourbeau, M. P. Org. Lett.
2003, 5, 3197; (f) Ramachandran, P. V.; Liu, H. P.; Reddy, M. V. R.; Brown, H. C.
Org. Lett. 2003, 5, 3755.
Figure 3. Only one of these structures (TS4) has the possibility to
combine three stabilizing features: orientation of the methyl ste-
reocenter away from the reacting center, minimization of the di-
pole moment of the a0-alkoxy and enolate oxygens (red bonds in
TS4), and formation of a stabilizing formyl hydrogen bond with
the b0-alkoxy group as the acceptor.20
In conclusion, a general diastereoselective aldol process has
been developed, using a tertiary a0-alkoxy group as the stereo-
chemical control element. This process has been applied to the
synthesis of the C8–C11 stereotriad of ent-fostriecin. Future work
will involve modification of the protecting group scheme to vali-
date the proposed transition state model, and to explore if the
sense of induction can be reversed.
9. For
a review of the use of modern aldol methods for the synthesis of
polyketides see: Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45,
7506.
10. Palomo, C.; Oiarbide, M.; Aizpurua, J. M.; Gonzalez, A.; Garcia, J. M.; Landa, C.;
Odriozola, I.; Lindon, A. J. Org. Chem. 1999, 64, 8193.
11. Pellicena, M.; Solsona, J. G.; Romea, P.; Urpi, F. Tetrahedron Lett. 2008, 49, 5265.
12. (a) Carda, M.; Falomir, E.; Murga, J.; Castillo, E.; Gonzalez, F.; Marco, J. A.
Tetrahedron Lett. 1999, 40, 6845; (b) Murga, J.; Falomir, E.; Gonzalez, F.; Carda,
M.; Marco, J. A. Tetrahedron 2002, 58, 9697.
13. The current synthesis is amenable to the synthesis of the natural antipode of
fostriecin since ent-4 is known in the chemical literature: Avenoza, A.;
Cativiela, C.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Tetrahedron:
Asymmetry 2001, 12, 1383.
Acknowledgments
14. Alternative conditions such as benzyl trichloroacetimidate and triflic acid
provided none of the desired dibenzyl ether.
15. Formation of the unselective mixture of aldol adducts allowed for
Grateful acknowledgment is extended to Devan Wang for per-
forming HRMS analysis of all new compounds, and to Drs. Steve
Staben, James Crawford and Mathew Volgraf for careful editing
of the manuscript.
establishment of
a 500 MHz NMR assay to determine selectivity by
integration of the methyl singlet for the two isomers (included as
Supplementary data). This process was possible for all aldol adducts 3 in
Table 1. Attempts to establish HPLC assays were unsuccessful.
16. Evans, D. A.; Hoyveda, A. H. J. Am. Chem. Soc. 1990, 112, 6447.
17. For details of the stereochemical assignment see the Supplementary data.
18. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
19. Li, Y.; Padden-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481.
20. Such a stabilizing formyl hydrogen bond has been implicated in a model for the
Evans/Patterson 1,5-induction of methyl ketone boron enolates: Paton, R. S.;
Goodman, J. M. J. Org. Chem. 2008, 73, 1253.
Supplementary data
Supplementary data (general reaction conditions for the diaste-
reoselective aldol process are provided, as well as details of the