Stereoselective Alkylation of the Vinylketene Silyl N,O-Acetal and Its Application to the Synthesis of Mycocerosic Acid

Article abstract of DOI:10.1021/acs.orglett.5b03422

Stereoselective alkylation of the vinylketene silyl N,O-acetal possessing a chiral auxiliary has been achieved by using activated alkyl halides including allyl iodides, benzyl iodides, and propargyl iodide with Ag(I) ion in the presence of BF₃·

Full text of DOI:10.1021/acs.orglett.5b03422

Letter
pubs.acs.org/OrgLett
Stereoselective Alkylation of the Vinylketene Silyl N,O‑Acetal and Its
Application to the Synthesis of Mycocerosic Acid
Tatsuya Nakamura, Kei Kubota, Takanori Ieki, and Seijiro Hosokawa*
Department of Applied Chemistry, Faculty of Science and Engineering, Waseda University 3-4-1 Ohkubo, Shinjuku-ku, Tokyo
169-8555, Japan
S
* Supporting Information
ABSTRACT: Stereoselective alkylation of the vinylketene silyl N,O-acetal
possessing a chiral auxiliary has been achieved by using activated alkyl halides
including allyl iodides, benzyl iodides, and propargyl iodide with Ag(I) ion in the
presence of BF3·OEt2. The reaction proceeded to give reduced polyketides in
high stereoselectivity. The synthesis of mycocerosic acid, a component of the cell
envelope of Mycobacterium tuberculosis, has been accomplished by this
methodology. During the synthetic studies, 2-methylbenzimidazole was found
to be a bulky proton source which worked in the presence of liquid ammonia.
Scheme 1. Remote Asymmetric Induction Reactions Using
the E,E-Vinylketene Silyl N,O-Acetal 1
educed polyketides are ubiquitous in natural products
1
Rincluding secondary metabolites
and pheromones of
insects.2 Methodologies toward reduced polypropionates have
been developed by several groups. Some of them are iterative
routes3 while others include organometallic reactions.4 Recently,
we reported the stereoselective and short-step synthesis of all
isomers of the branched methyl groups of 2,4,6-trimethylocta-
noic acid derivatives having a hydroxy group at the C5 position
by using our remote asymmetric induction reaction5 and the
regio- and stereoselective reductions.6 We applied the method-
ology to accomplish the first total synthesis of septoriamycin A.6
This methodology is a powerful tool to synthesize partially
reduced polyketides having a hydroxy group or a δ-lactone.
However, further steps for deoxygenation are required to prepare
the reduced polypropionate having no oxygen in their chains. A
stereoselective alkylation of a dienolate would be a straightfor-
ward and concise method to prepare reduced polypropionates.
To the best of our knowledge, there is no precedent of the
asymmetric alkylation of the γ-position of a dienolate derived
from α,β-unsaturated carboxylic acid.7 Herein, we report the
stereoselective alkylation of the vinylketene silyl N,O-acetal
possessing a chiral auxiliary and its application to the synthesis of
mycocerosic acid [(2R,4R,6R,8R)-2,4,6,8-tetramethyloctacosa-
noic acid], a component of the cell envelope of Mycobacterium
tuberculosis.
During the course of our synthetic studies on acyclic
polyketides, we have developed remote asymmetric induction
reactions including the vinylogous Mukaiyama aldol reactions
and the acylation reaction (Scheme 1).5,8 These reactions
showed high stereoselectivity, although the reaction position
(the terminal carbon of the dienol ether) was directed far from
the chiral center of the auxiliary. These reactions construct
stereogenic centers and introduce the enone attaching the chiral
auxiliary simultaneously, so that they realize short-step syntheses
of polypropionates.6,8c,9 Based on these results, we examined a
stereoselective alkylation of silyl dienol ether 1, which would be a
straightforward method to synthesize reduced polyketides.10
At first, we investigated various Lewis acids in the presence of
allyl iodide (Table 1). Frequently used Lewis acid including
Received: November 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03422
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Table 1. Reaction of the E,E-Vinylketene Silyl N,O-Acetal 1
and Allyl Iodide in the Presence of Lewis Acid
Table 2. Reaction with the E,E-Vinylketene Silyl N,O-Acetal 1
and Alkyl Halide in the Presence of AgTFA and BF3·OEt2
a
entry
Lewis acid
additive
temp (°C)
yield (%)
dr
1
TiCl4
0
0
0
0
2
SnCl4
3
AlCl3
0
0
4
BF3·OEt2
ZnBr2
rt
0
5
rt
0
6
AgNO3
Ag2SO4
AgClO4
AgBF4
AgOTf
AgTFA
AgTFA
AgTFA
AgTFA
rt
10
18
24
45
46
58
65
80
10:1
6:1
7
rt
8
0
18:1
9
−20
−20
−20
−20
−20
10:1
10
11
12
>20:1
>20:1
>20:1
>20:1
>20:1
BF3·OEt2
BF3·OEt2
b
13
b
14
−40
1
83
b
a
The ratio was determined by 400 MHz H NMR. Allyl iodide (3
equiv), AgTFA (3 equiv), and BF3·OEt2 (0.2 equiv) were used.
TiCl4, SnCl4, AlCl3, BF3·OEt2, and ZnBr2 did not provide the
allylated product 6 (Table 1, entries 1 to 5), while silver(I) salts11
facilitated the reaction to give γ-adduct 6 with good to excellent
stereoselectivity (entries 6−11).12 Among silver(I) salts, silver
trifluoromethanesulfonate (AgOTf) and silver trifluoroacetate
(AgTFA) gave the adduct 6 in moderate yield with excellent
selectivity (entries 10 and 11). No α-alkylated compound was
a
b
1
11a
The ratio was determined by 400 MHz H NMR. BnI (1.5 equiv)
observed. Addition of a catalytic amount of BF3·OEt2 in the
and AgTFA (1.2 equiv) were employed.
presence of AgTFA gave better yield without affecting the
stereoselectivity (entry 12). Increasing the amount of AgTFA
and allyl iodide gave a higher yield of 6 (entry 13). After all, the
reaction in the presence of BF3·OEt2 proceeded at −40 °C to
afford γ-adduct 6 in high yield with excellent regio- and
stereoselectivity (entry 14). Therefore, the conditions of entry
14 were employed for the following reactions.
Scheme 2. Alkylation with Z-Allyl Iodide 8
Next, we examined the alkylation reaction with a variety of
alkyl iodides. Although n-Pr-I gave no adducts, activated iodides
reacted with dienol ether 1 to provide γ-alkylated compounds
(Table 2). Disubstituted allyl iodides gave the corresponding
adducts in good yield with excellent stereoselectivity (Table 2,
entries 2−4). Trisubstituted allyl iodide gave the adduct in
moderate yield but stereoselectivity was high (entry 5). Benzyl
iodides including benzyl iodide, p-bromobenzyl iodide, and p-
nitrobenzyl iodide gave adducts in good yield with excellent
selectivity (entries 6−8); however, p-methoxybenzyl iodide gave
moderate yield with good selectivity (entry 9). In this reaction,
we observed production of p-methoxybenzyl trifluoroacetate as a
byproduct. Propargyl iodide also facilitated the reaction to give
the corresponding propargyl adduct in good yield with good
stereoselectivity (entry 10).
To investigate the reaction mechanism Z-olefin 8 was used as
an electrophile in the alkylation reaction (Scheme 2). The
reaction proceeded at −90 °C and provided a mixture of allylated
compounds 9 and 10. The E-isomer 10 was produced about the
same amount as Z-isomer 9. Additionally, ethyl iodoacetate did
not afford the corresponding adduct (not shown in Scheme 2).
These results suggest that the reaction involves cation
intermediates.
Based on these results, we applied this alkylation reaction to
natural product synthesis. Mycocerosic acid is a component of
phthiocerol dimycocerosate (PDIM), a virulent factor of
Mycobacterium tuberculosis (Figure 1).13 Tuberculosis is a
worldwide problem as a leather infection disease caused by
Mycobacterium tuberculosis. PDIM is required for further
investigation of the infection system of M. tuberculosis. The
Minnaard group has achieved the total syntheses of mycocerosic
acid and PDIM by the iterative catalytic asymmetric conjugate
addition of methyl group to α,β-unsaturated thioester.14 During
the course of synthesis of polyketide compounds in our
B
DOI: 10.1021/acs.orglett.5b03422
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unsaturated imide and removal of the benzyl group. In this
reaction, we examined the proton source to prepare C2 position
of the desired 15 (Table 3). When we added ammonium chloride
Table 3. Birch Reduction of Imide 11
Figure 1. Structure of PDIM.
laboratory, we started the synthesis of PDIM. Herein, we report
the concise synthesis of mycocerosic acid by using our
stereoselective alkylation reaction. As shown in Scheme 3, we
Scheme 3. Synthetic Plan toward Mycocerosic Acid
planned to synthesize mycocerosic acid by regio- and stereo-
selective reductions of two olefins of imide 11, which would be
synthesized by the stereoselective alkylation reaction with allyl
iodide 12 and dienol ether 1.
a
1
The ratio was determined by 400 MHz H NMR.
The synthesis started from the remote asymmetric induction
reaction using vinylketene silyl N,O-acetal 1 and dibenzyl acetal
13 (Scheme 4). The reaction proceeded to give 14 in a
as a proton source, diastereoisomer at the C2 position (16) was
produced as a minor product in a ratio of 2:1 (Table 3, entry 1).
Although we employed 2,6-di-tert-butylphenol,15 a frequently
used phenol as a bulky proton source, the diastereoselectivity was
not improved (entry 2). 2-Pyridone, reported by the Davies
group16 as a good proton source to react with the enolate
attaching an oxazolidinone, improved the diastereoselectivity to
4:1 (entry 3). Considering the acidity of the proton source, we
examined benzimidazole (pKa 12.7517), which gave 15 in good
yield with high stereoselectivity (entry 4). Finally, we added 2-
methylbenzimidazole as a more bulky and commercially available
proton source, and the desired 15 was obtained in good yield
with excellent selectivity (entry 5).
Scheme 4. Synthesis of C1−C9 Moiety of Mycocerosic Acid
After achieving the stereoselective reduction of α,β-unsatu-
rated imide accompanied by deprotection to give primary alcohol
15, the stereoselective reduction of the internal olefin was
performed by the hydroxy group directed hydrogenation
(Scheme 5). Shrock−Osborn catalyst worked very well to
produce all-syn compound 17 in high yield with excellent
stereoselectivity.18 Oxidation of the primary alcohol was
followed by Kocienski olefination to give olefin 18, which was
hydrogenated to give saturated imide 19. Hydrolysis of the imide
afforded mycocerosic acid, spectral data of which were identical
to those reported previously14a in all respects. Therefore,
mycocerosic acid has been synthesized in 10 steps from 1.
In conclusion, we have established the remote asymmetric
induction-type alkylation of vinylketene silyl N,O-acetal 1 with
activated alkyl halides in the presence of silver(I) salt and boron
trifluoride diethyl etherate and applied the reaction to synthesize
stereoselective manner. Reduction of the imide to the primary
alcohol, followed by Appel reaction, afforded unstable allyl iodide
12 which was immediately used in the next reaction. The reaction
of 12 with vinylketene silyl N,O-acetal 1 in the presence of silver
triflate gave 11 in good yield with good stereoselectivity.
Subsequent Birch reduction promoted both reduction of α,β-
C
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(4) (a) Sugimura, T.; Sato, Y.; Im, C. Y.; Okuyama, T. Org. Lett. 2004,
6, 4439−4442. (b) Diez, P. S.; Micalizio, G. C. Angew. Chem., Int. Ed.
2012, 51, 5152−5156 and references therein.
(5) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki,
A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604−
13605.
Scheme 5. Synthesis of Mycocerosic Acid
(6) Nakamura, T.; Harachi, M.; Kano, T.; Mukaeda, Y.; Hosokawa, S.
Org. Lett. 2013, 15, 3170−3173.
(7) To the best of our knowledge, only one example of the catalytic
asymmetric allylic substitution of silyl dienolates from dioxinones has
been reported, which yielded allylated dioxinones. See: Chen, M.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2014, 53, 12172−12176.
(8) (a) Mukaeda, Y.; Kato, T.; Hosokawa, S. Org. Lett. 2012, 14, 5298−
5301. (b) Tsukada, H.; Mukaeda, Y.; Hosokawa, S. Org. Lett. 2013, 15,
678−681. (c) Takahashi, Y.; Otsuka, M.; Harachi, M.; Mukaeda, Y.;
Hosokawa, S. Org. Lett. 2014, 16, 4106−4109.
(9) (a) Hosokawa, S. Yuki Gosei Kagaku Kyokaishi 2009, 67, 24−37.
and references therein (b) Kato, T.; Sato, T.; Kashiwagi, Y.; Hosokawa,
S. Org. Lett. 2015, 17, 2274−2277.
(10) For the alkylation of silyl enol ethers, see: (a) Paterson, I.
Tetrahedron Lett. 1979, 20, 1519−1520. (b) Fleming, I.; Goldhill, J.;
Paterson, I. Tetrahedron Lett. 1979, 20, 3209−3212. (c) Reetz, M. T.
Angew. Chem., Int. Ed. Engl. 1982, 21, 96−108. and references therein
(d) Reetz, M. T.; Walz, P.; Hubner, F.; Huttenhain, S. H.; Heimbach, H.;
Schwellnus, K. Chem. Ber. 1984, 117, 322−335. (e) Maruoka, K.; Sato,
J.; Yamamoto, H. J. Am. Chem. Soc. 1992, 114, 4422−4423.
(11) (a) Takagaki, H.; Yasuda, N.; Asaoka, M.; Takei, H. Bull. Chem.
Soc. Jpn. 1979, 52, 1241−1242. (b) Jefford, C. W.; Sledeski, A. W.;
Boukouvalas, J. Tetrahedron Lett. 1987, 28, 949−950. (c) Jefford, C. W.;
Sledeski, A. W.; Boukouvalas, J. J. Chem. Soc., Chem. Commun. 1988,
364−365. (d) Padwa, A.; Ishida, M. Tetrahedron Lett. 1991, 32, 5673−
5675. (e) Angers, P.; Canonne, P. Tetrahedron Lett. 1994, 35, 367−370.
(12) The absolute configuration of compound 6 was determined by
conversion into the known compound. See the Supporting Information.
(13) (a) Noll, H. J. Biol. Chem. 1957, 224, 149−164. (b) Polgar, N.;
Smith, W. J. Chem. Soc. 1963, 3081−3085. (c) Jacobs, W. R., Jr.; Cox, J.
S.; Chen, B.; McNeil, M. Nature 1999, 402, 79−83. (d) Camacho, L. R.;
Ensergueix, D.; Perez, E.; Gicquel, B.; Guilhot, C. Mol. Microbiol. 1999,
34, 257−267.
mycocerosic acid. In the Birch reduction of an unsaturated imide,
2-methylbenzimidazole was found to be an effective bulky proton
source. These methods are useful to the synthesis of reduced
polypropionates. Further application of these method to total
synthesis of natural products is in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03422.
Experimental procedure and physical property of new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
(14) (a) ter Horst, B.; Feringa, B. L.; Minnaard, A. J. Chem. Commun.
2007, 489−491. (b) Casas-Arce, E.; ter Horst, B.; Feringa, B. L.;
Minnaard, A. J. Chem. - Eur. J. 2008, 14, 4157−4159.
(15) (a) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J.
Chem. Soc., Chem. Commun. 1993, 1153−1155. (b) Hanessian, S.;
Reinhold, U.; Gentile, G. Angew. Chem., Int. Ed. Engl. 1997, 36, 1881−
1884.
■
*E-mail: seijiro@waseda.jp.
Notes
The authors declare no competing financial interest.
(16) Beddow, J. E.; Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A.
J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 2812−2825.
(17) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles; John Wiley & Sons, 2003; Chapter 5, Section 35.
(18) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc. 1984, 106,
3866−3868.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the NOVARTIS
Foundation (Japan) for the Promotion of Science, The Kurata
Memorial Hitachi Science and Technology Foundation, and The
Naito Foundation.
REFERENCES
■
(1) (a) Carmen Paul, M.; Ortega, M. J.; Salva, J. Tetrahedron 1997, 53,
2303−2308. (b) Kohno, J.; Nishio, M.; Sakurai, M.; Kawano, K.;
Hiramatsu, H.; Kameda, N.; Kishi, N.; Yamashita, T.; Okuda, T.;
Komatsubara, S. Tetrahedron 1999, 55, 7771−7786. (c) Schulze, C. J.;
Bray, W. M.; Loganzo, F.; Lam, M. H.; Szal, T.; Villalobos, A.; Koehn, F.
E.; Linington, R. G. J. Nat. Prod. 2014, 77, 2570−2574. (d) Tripathi, A.;
Schofield, M. M.; Chlipala, G. E.; Schultz, P. J.; Yim, I.; Newmister, S. A.;
Nusca, T. D.; Scaglione, J. B.; Hanna, P. C.; Tamayo-Castillo, G.;
Sherman, D. H. J. Am. Chem. Soc. 2014, 136, 1579−1586.
(2) Ando, T.; Yamakawa, R. Nat. Prod. Rep. 2015, 32, 1007−1041 and
references therein.
(3) (a) ter Horst, B.; Minnaard, A. J.; Feringa, B. L. Chem. Commun.
2010, 46, 2535−2547. and references therein (b) Balieu, S.; Hallett, G.
E.; Burns, M.; Bootwicha, T.; Studley, J.; Aggarwal, V. K. J. Am. Chem.
Soc. 2015, 137, 4398−4403.
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DOI: 10.1021/acs.orglett.5b03422
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