Stereocontrolled synthesis of C1-C17 fragment of narasin via a free radical-based approach

Article abstract of DOI:10.1021/ol902414u

Chemical Equation Presented An efficient synthesis of the C1-C17 western unit of narasin was achieved from (S)-Roche ester. Highlights in our synthesis include the successful exploitation of three stereoselective sequences of Lewis acid mediated reaction followed by free-radical-based hydrogen transfer.

Full text of DOI:10.1021/ol902414u

ORGANIC
LETTERS
2010
Vol. 12, No. 1
36-39
Stereocontrolled Synthesis of C1-C17
Fragment of Narasin via a Free
Radical-Based Approach
Jean-Franc¸ois Brazeau, Audrey-Anne Guilbault, Jummey Kochuparampil,
Philippe Mochirian, and Yvan Guindon*
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry,
Laboratory, 110 aVenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7,
Department of Chemistry, UniVersite´ de Montre´al, C.P. 6128, succursale Centre-Ville,
Montre´al, Que´bec, Canada H3C 3J7, and Department of Chemistry, McGill
UniVersity, 801 Sherbrooke Street West, Montre´al, Que´bec, Canada H3A 2K6
yVan.guindon@ircm.qc.ca
Received October 20, 2009
ABSTRACT
An efficient synthesis of the C1-C17 western unit of narasin was achieved from (S)-Roche ester. Highlights in our synthesis include the
successful exploitation of three stereoselective sequences of Lewis acid mediated reaction followed by free-radical-based hydrogen transfer.
Narasin is produced by Streptomyces aerofaciens and was
first isolated in 1973 (Figure 1).1 This complex polyether
ionophore is known for its antibacterial and anticoccidal
activity.2 A remarkable total synthesis of this molecule was
reported in 1982 by Kishi.3,4
a sequence of Mukaiyama aldol and free radical reduction
on R-alkyl-ꢀ-alkoxy aldehydes, both reactions being con-
trolled by Lewis acid.5 We have shown that the aldol step
could lead to either a 3,4-syn or -anti relation depending on
the presence of a monodentate or a bidentate Lewis acid in
the reaction mixture. As seen in Scheme 1A, no efforts were
invested to control the stereochemistry of the resulting C2
tertiary bromides, the creation of a free radical being planned
in the next step. A mixture tetrasubstituted enoxysilane (E/
Z) was indeed used in these reactions, an interesting
characteristic of our strategy. The aldol products could then
be reduced to give either the corresponding 2,3-anti or 2,3-
(3) (a) Kishi, Y.; Hatakeyama, S. Lewis, M. D. Total Synthesis of
Narasin and Salinomycin. In Frontiers of Chemistry; Laidler, K. J., Ed.;
Pergamon: Oxford, 1982. (b) Tino, J. A.; Lewis, M. D.; Kishi, Y.
Heterocycles 1987, 25, 97.
Figure 1. Representative polyethers.
(4) There has been considerable effort toward the synthesis of salino-
mycin: (a) Horita, K.; Nagato, S.; Oikawa, O.; Yonemitsu, O. Chem. Pharm.
Bull. 1989, 37, 1726. (b) Kocienski, P. J.; Brown, R. C. D.; Pommier, A.;
Procter, M.; Schmidt, B. J. Chem. Soc., Perkin Trans. 1 1998, 9. (c) Larossa,
I.; Romea, P.; Urp`ı, F. Org. Lett. 2006, 8, 527.
Recently, we reported a versatile methodology for the
synthesis of propionate or polypropionate subunits by using
(1) Seto, H.; Yahagi, T.; Miyazaki, Y.; Otake, N. J. Antibiot. 1977, 30,
530.
(5) (a) Mochirian, P.; Cardinal-David, B.; Gue´rin, B.; Pre´vost, M.;
Guindon, Y. Tetrahedron Lett. 2002, 43, 7067. (b) Guindon, Y.; Brazeau,
J.-F. Org. Lett. 2004, 6, 2599. (c) Brazeau, J.-F; Mochirian, P.; Pre´vost,
M.; Guindon, Y. J. Org. Chem. 2009, 74, 64.
(2) Ruff, M. D. Veterinary Applications. In Polyether Antibiotics;
Westley, J. W. , Ed.; M. Dekker: New York, Basel, 1982.
10.1021/ol902414u  2010 American Chemical Society
Published on Web 12/02/2009

syn isomers (Scheme 1-B). The 2,3-anti isomer could be
obtained by taking advantage of the acyclic stereoselection
(T.S. I).6 A boron-based Lewis acid (Bu2BOTf) and DIEA
were used in this case to create a borinate that serves as a
temporary protecting group. Minimization of both the 1,3-
allylic strain and the intramolecular dipole-dipole interac-
tions are at the origin of the preferred transition state I.
However, when R1 bears a methylene group at C4, the ratio
may be lowered. We found that the diastereoselectivity could
be enhanced by creating a ring R to the carbon-centered free
radical (T.S. II, exocyclic effect).7 Finally, a 2,3-syn relative
stereochemistry could also be induced by adding a bidentate
Lewis acid (AlMe3) to the reaction mixture. The radical
center is now embedded in a temporary ring, and the
diastereoselectivity is resulting from T.S. III (endocyclic
effect).8
The first disconnection planned is between C12 and C13.10
An anti-Felkin aldol reaction between the aldehyde 511 and
the corresponding ketone 4 would be required.12 This ketone
would in turn originate from the aldehyde 6 reacting with
enoxysilane 7. The 8,9-syn relative stereochemistry indicates
that a monodentate Lewis acid be used in the aldol step and
that the radical reduction under the acyclic stereoselection
be performed to access the 9,10-anti relation. The 2,3-anti
stereochemistry in tetrahydropyran 6 would come from the
reduction of the carbon-centered radical at C2 under the
exocyclic effect. The tertiary bromide, precursors of the
radical intermediate, would be the products of the addition
of enoxysilane 8 on the cyclic oxonium derived from acetal
10, a 3,7-anti relative stereochemistry being sought after.
The acetal, in turn, would originate from the coupling of
the iodide 11 via Myers’ alkylation.13 Finally, this primary
halide would come from the transformation of the 2,3-syn-
3,4-anti stereotriad derived from a sequence of Cram-chelated
Mukaiyama aldolisation and a free radical hydrogen transfer
using starting material 12.
Scheme 1. Substrate-Controlled Strategies with Mukaiyama
Aldol Reactions and Radical Reductions
Our synthesis began with a titanium-mediated Mukaiyama
aldol reaction under chelation control using the tetrasubsti-
tuted enoxysilane 7 and aldehyde 12 derived from (S)-Roche
ester (Scheme 3). The ꢀ-hydroxy esters having a tertiary
bromide at C2 were isolated in good yield and excellent 3,4-
anti selectivity. These products were treated with AlMe3 (3
equiv) in CH2Cl2 at -78 °C before tributyltin hydride
(Bu3SnH) was added and the free radical cascade was
initiated with Et3B in presence of air. The desired 2,3-syn-
3,4-anti propionate 13 was isolated in good yield with high
diastereoselectivity.14 The hydroxyl at C3 was protected
using TESOTf and 2,6-lutidine followed by reduction to the
primary alcohol 14 in almost quantitative yield. The alcohol
14 was then transformed into the sensitive iodide 11 using
Corey’s procedure.15 The subsequent Myers’ alkylation was
performed by adding the primary iodide to the enolate
derived from the corresponding amide containing (S,S)-
pseudoephedrine. Excellent stereoselectivity was obtained,
and the diastereoisomer 15 was isolated (dr >20:1, 91%).16
The amide was refluxed under acidic conditions (PPTS) in
benzene to give lactone 16 in good yield without any
noticeable epimerization. Reduction of the lactone with
DIBAL-H at -78 °C led to the lactol that was transformed
to the corresponding acetals (10a or 10b).
(10) Precedents from Evans suggest the stereodifferentiation between
those to be fully matched. See: (a) Evans, D. A.; Rieger, D. L.; Bilodeau,
M. T.; Urp`ı, F. J. Am. Chem. Soc. 1991, 113, 1047. (b) Evans, D. A.; Dart,
M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem. Soc. 1995, 117, 9073.
(11) Compound 5 was obtained by oxidation of the corresponding known
alcohol (96%). See: Vong, B. G.; Abraham, S.; Xiang, A. X.; Theodorakis,
E. A. Org. Lett. 2003, 5, 1617.
Our objective in the present study was to investigate the
robustness of these reactions in the synthesis of various
polyether ionophores containing polypropionate subunits,
including a fragment of narasin (1), on which we are
reporting herein.9 Our retrosynthetic analysis of the western
fragment of narasin is illustrated in Scheme 2.
(12) In previous works towards the synthesis of narasin and salinomycin,
the C9-C10 bond was generated by an anti aldol reaction with moderate
stereoselectivities. See ref 4.
(13) Myers, A. M.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(6) (a) Guindon, Y.; Jung, G.; Gue´rin, B.; Ogilivie, W. W. Synlett 1998,
3, 213. (b) Cardinal-David, B.; Brazeau, J.-F.; Katsoulis, I. A.; Guindon,
Y. Curr. Org. Chem. 2006, 10, 1939.
(14) Guindon, Y.; Houde, K.; Pre´vost, M.; Cardinal-David, B.; Landry,
S. R.; Daoust, B.; Bencheqroun, M.; Gue´rin, B. J. Am. Chem. Soc. 2001,
123, 8496.
(7) Guindon, Y.; Faucher, A.-M.; Bourque, E.; Caron, V.; Jung, G.;
Landry, S. R. J. Org. Chem. 1997, 62, 9276.
(15) Corey, E. J.; Pyne, S. G.; Su, W. Tetrahedron Lett. 1983, 24, 4883.
(16) At this stage, the presence of amide rotamers complicated the
determination of the diastereoselectivity of the newly formed stereocenter.
The dr was determined after cleavage of the pseudoephedrine moiety.
(8) Guindon, Y.; Rancourt, J. J. Org. Chem. 1998, 63, 6566.
(9) For a review on polyether ionophores, see: Faul, M. M.; Huff, B. E.
Chem. ReV. 2000, 100, 2407.
Org. Lett., Vol. 12, No. 1, 2010
37

treatment at -78 °C with BF3·OEt2 gave also disappointing
results (entry 3). Our first positive results came from the
pretreatment of 10b with TiCl4 followed by addition of
enoxysilane 8. A significant yield of aldol products was
obtained albeit with no diastereoselectivity (entry 4). For-
tunately, changing to tin-based Lewis acids led to exciting
results. The 3,7-anti products 17a,b were obtained selec-
tively, and not surprisingly, epimers at C2 were noted (entry
5). Similar results were noted with SnBr4 (entry 6). Interest-
ingly, switching 8 for enoxysilane 9 (6:1 ratio), in which
the bromide is replaced by a hydrogen, gave also a
diastereoselective reaction at C3 (3,7-anti) and a mixture of
isomers at C2 (entry 7).
Scheme 2. Retrosynthetic Analysis
Table 1. Optimization of Reaction Conditions for the Lewis
Acid Catalyzed Mukaiyama Aldol Reaction
3,7-anti: 3,7-syn
enoxy- Lewis
entrya substrate silane
acid
yieldc
products ratiob (%)
1
2
3
4
5
6
7
10a, R ) Me
10a, R ) Me
10b, R ) Ac
10b, R ) Ac
10b, R ) Ac
10b, R ) Ac
10b, R ) Ac
8
8
8
8
8
8
9
BF3OEt2 17a,b:18a,b nd
TiCl4 17a,b:18a,b nd
BF3OEt2 17a,b:18a,b nd
0d
0d
nd
57
TiCl4
SnCl4
SnBr4
SnCl4
17a,b:18a,b 1:1
17a,b:18a,b >20:1e 83
17a,b:18a,b >20:1e 72
19a,b:20a,b >20:1f 84
Scheme 3. Synthesis of Acetals 10a and 10b
a Reaction conditions: Acetal 10a or 10b (0.1 M) in CH2Cl2 was
precomplexed at -78 °C with the appropriate Lewis acid followed by
addition of enoxysilane (1.3 equiv). b Ratios were determined by 1H NMR
spectroscopy. c Yields of isolated products. d Elimination product was
observed as the major product. e 1:1 ratio of bromides 17a:17b was observed
f 1:1 ratio of esters 19a:19b was observed.
Our mechanistic rationale is based on the formation of
the cyclic oxonium ion from 10b as depicted in Scheme 4.19
An axial attack of the nucleophile on the oxocarbenium was
postulated for stereoelectronic reason.20 The presence of a
sterically encumbered substituent at C3 should be of
significant importance for the diastereoselectivity of this
reaction. Therefore, minimization of the steric interactions
between the incoming nucleophile (8) and the R chain should
favor transition state A leading to the 3,7-anti products 17a,b.
More has to be done both experimentally and theoretically
to fully determine the reaction mechanism of this transfor-
mation.21
To address the challenge of constructing the less thermo-
dynamically favorable trans pyran, an approach based on a
Lewis acid catalyzed condensation of an acetal derivative
with enoxysilane 8 that bear a carbon-bromide bond was
explored (Table 1).17,18 Treatment of the ꢀ-methoxy acetal
10a with BF3·OEt2 (entry 1) and TiCl4 (entry 2) led to a
complex mixture of products, the elimination product (glycal)
being the major one. The ꢀ-acetal 10b was then studied, and
With tertiary bromides 17a,b in hand, we then turned our
attention to the free radical hydrogen transfer (Scheme 5).
(19) Only the conformers of the chair-like T.S. are considered as the
kinetically controlled reaction should not favor the attack that proceeds
through the boat-like T.S.
(20) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Baldwin, J. E. , Ed.; Pergamon Press: Oxford, 1983.
(17) Holmes, C. P.; Bartlett, P. A. J. Org. Chem. 1989, 54, 98
(18) Lewis, M. D.; Cha, J. D.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976
.
(21) For recent studies related to nucleophilic substitutions of tetrahy-
dropyran acetals, see: Krumper, J. R.; Salamant, W. A.; Woerpel, K. A. J.
Org. Chem. 2009, 74, 8039, and references therein.
.
38
Org. Lett., Vol. 12, No. 1, 2010

selectively form the 8,9-syn radical precursors (dr >20:1).
The 9,10-anti stereochemistry was finally established by
treatment of 23a,b with Bu2BOTf, DIEA, and Bu3SnH. This
procedure led exclusively to 24 with all the desired stereo-
centers in place (dr > 20:1).22 The resulting ester was
protected (TBSOTf) and reduced (DIBAL-H) to the alde-
hyde. Propynylmagnesium bromide was directly added to
the nonpurified aldehyde to avoid racemisation. Oxidation
using Dess-Martin periodinane23 afforded the desired ketone
4 with good yield (88%).
Scheme 4. Proposed Transition States
As illustrated in Scheme 6, the final coupling involved a
syn-aldol reaction with aldehyde 5 to give the C1-C17
western fragment of narasin (dr >20:1).22 The enantiomeri-
cally pure unit 3 was isolated in 67% yield along with
unreacted ketone starting material 4 (15%).
This reaction was achieved with high yield (91%) and
excellent diastereoselectivity (dr 17:1) to give the 2,3-anti
desired product (19a).22 Then, reduction of ester 19a led to
21 with good yield (94%).
Scheme 6. Final Step
Scheme 5. Synthesis of 4
In conclusion, we have described here a stereoselective
synthesis of the western subunit of narasin in 21 steps from
aldehyde 12 (7.5% overall yield). The synthetic sequence
features three key stereoselective Lewis acid activated
addition reactions followed by efficient hydrogen transfer
reductions. Efforts are now underway to construct narasin
and other natural products of this family.
Acknowledgment. The authors wish to express their
gratitude to the Natural Sciences and Engineering Research
Council of Canada (NSERC) and the Institut de recherches
cliniques de Montre´al (IRCM) for their financial support.
Fellowship support from NSERC PGS D and FQRNT B2
(J.-F.B) is also gratefully acknowledged.
A sequence of protection with TBDPS and debenzylation
furnished the desired alcohol 22. The latter was oxidized to
aldehyde 6, which was treated immediately with BF3·OEt2
and enoxysilane 7 to give exclusively the aldol products
23a,b with a 8,9-syn relative stereochemistry. The mono-
dentate activation suggests a Felkin-Anh pathway to
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902414U
(22) See Supporting Information for details that provide proof of
stereochemical assignments.
(23) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Org. Lett., Vol. 12, No. 1, 2010
39