Efficient method for the deprotection of tert-butyldimethylsilyl ethers with TiCl4-Lewis base complexes: Application to the synthesis of 1β-methylcarbapenems

Article abstract of DOI:10.1021/jo0604484

TiCl₄-Lewis base (AcOEt, CH₃NO₂) complexes smoothly deprotected tert-butyldimethylsilyl (TBDMS) ethers. The reaction velocity with these complexes, which seemed less reactive due to the influence of Lewis bases, was considerably greater than that with TiCl₄ alone. Selective desilylations between aliphatic and aromatic TBDMS ethers (1 and 5), between 1 and benzyl, allyl, tosyl, methoxyphenyl, and chloroacetyl ethers (13, 14, 15, 16, and 17), and between TBDMS and TBDPS ethers (18 and 19) were successfully performed. Desilylation of TBDMS-aldol, acyloin, and β-lactam analogues 9-12 proceeded smoothly due to anchimeric assistance by the neighboring carbonyl groups. The present method was successfully applied to the practical synthesis of 1β-methylcarbapenems 20a′-f′.

Full text of DOI:10.1021/jo0604484

SCHEME 1
Efficient Method for the Deprotection of
tert-Butyldimethylsilyl Ethers with TiCl4-Lewis
Base Complexes: Application to the Synthesis of
1â-Methylcarbapenems
In connection to our studies on the development of practical
reactions5a such as esterifications,5b-d amide formations,5c,d
sulfonylations,6 and silylations,7 we report here an efficient,
practical, and chemoselective method for the deprotection of
TBDMS ethers using economical and available TiCl4-Lewis
base (AcOEt or CH3NO2) complexes (Scheme 1).
The initial trial reaction of 2-(tert-butyldimethylsiloxy)nonane
(1) with TiCl4 resulted in considerable side formation of
2-chlorononane (∼30%), along with the desired 2-nonanol
(Scheme 2, reaction A): SNi chlorination (C-O bond cleavage)
of 1 and/or 2-nonanol proceeded due to the high inherent
reactivity of TiCl4. To circumvent the side chlorination, we
examined less reactive TiCl4-Lewis base complexes. Screening
of nitrogen-type Lewis bases (alkylated amine, amide, aniline,
Akira Iida, Hiroki Okazaki, Tomonori Misaki,
Makoto Sunagawa,† Akira Sasaki,† and Yoo Tanabe*
Department of Chemistry, School of Science and Technology,
Kwansei Gakuin UniVersity, 2-1 Gakuen, Sanda, Hyogo
669-1337, Japan, and Research DiVision, Sumitomo
Pharmaceuticals Co., Ltd. 1-98, Kasugade Naka 3-Chome,
Konohana-ku, Osaka 554-0022, Japan
tanabe@kwansei.ac.jp
ReceiVed March 2, 2006
(3) For recent representative works see: (a) Gopinath, R.; Patel, B. K.
Org. Lett. 2000, 2, 4177. (b) Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron
2000, 41, 5711. (c) Bajwa, J. S.; Vivelo, J.; Slade, J.; Repi, O.; Blacklock,
T. Tetrahedron Lett. 2000, 41, 6021. (d) Hattori, K.; Sajiki, H.; Hirota, K.
Tetrahedron 2001, 57, 2109. (e) Chen, M.-Y.; Lu, K.-C.; Lee, A. S.-Y.;
Lin, C.-C. Tetrahedron Lett. 2002, 43, 2777. (f) Bartoli, G.; Cupone, G.;
Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.; Sambri, L.; Tagarelli,
A. Tetrahedron Lett. 2002, 43, 5945. (g) Rotulo-Sims, D.; Prunet, J. Org.
Lett. 2002, 4, 4701. (h) Sajiki, H.; Ikawa, T.; Hattori, K.; Hirota, K. Chem.
Commun. 2003, 6, 654. (i) Khan, A. T.; Mondal, E. Synlett 2003, 694. (j)
Sharma, G. V. M.; Srinivas, B.; Radha Krishna, P. Tetrahedron Lett. 2003,
44, 4689. (k) Rani, S.; Lokesh Babu, J.; Vankar, Y. D. Synth. Commun.
2003, 33, 4043. (l) Crouch, R. D.; Romany, C. A.; Kreshock, A. C.;
Menconi, K. A.; Zile, J. L. Tetrahedron Lett. 2004, 45, 1279. (m) Kim, S.;
Jacobo, S. M.; Chang, C.-T.; Bellone, S.; Powell, W. S.; Rokach, J.
Tetrahedron Lett. 2004, 45, 1973. (n) Arumugam, P.; Karthikeyan, G.;
Perumal, P. T. Chem. Lett. 2004, 33, 1146. (o) Khan, A. T.; Ghosh, S.;
Choudhury, L. H. Eur. J. Org. Chem. 2004, 10, 2198. (p) Ikawa, T.; Hattori,
K.; Sajiki, H.; Hirota, K. Tetrahedron 2004, 60, 6901. (q) Karimi, B.;
Zamani, A.; Zareyee, D. Tetrahedron Lett. 2004, 45, 9139. (r) Kishore, G.
D.; Baskran, S. J. Org. Chem. 2005, 70, 4520. Other references cited theirin.
(4) (a) Kelly, D. R.; Roberts, S. M.; Newton, R. F. Synth. Commun. 1979,
9, 279. (b) Oriyama, T.; Kobayashi, Y.; Noda, K. Synlett 1998, 1047. (c)
Hunter, T.; Hinz, W.; Richards, P. Tetrahedron Lett. 1999, 40, 3643. (d)
Ranu, B. C.; Jana, U.; Majee, A. Tetrahedron Lett. 1999, 40, 1985. (e)
Yadav, J. S.; Reddy, R. V. S.; Mandan, C. New J. Chem. 2000, 24, 853. (f)
Crouch, R. D.; Polizzi, J. M.; Cleiman, R. C.; Yi, J.; Romany, C. A. Tetra-
hedron Lett. 2002, 43, 7151. (g) Sharma, G. V. M.; Srinivas, B.; Krishna,
P. R. Tetrahedron Lett, 2003, 44, 4689. (h) Gloria, P. M. C.; Prabhakar,
S.; Lobo, A. M.; Gomes, M. J. S. Tetrahedron Lett. 2003, 44, 8819.
(5) Review: (a) Tanabe, Y.; Misaki, T.; Iida, A.; Nishii, Y. J. Synth.
Org. Chem. Jpn. 2004, 62, 1248. Recent works: (b) Wakasugi, K.; Misaki,
T.; Yamada, K.; Tanabe, Y. Tetrahedron Lett. 2000, 41, 5249. (c) Wakasugi,
K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. AdV. Synth. Catal. 2003,
345, 1209. (d) Wakasugi, K.; Nakamura, A.; Iida, A.; Nishii, Y.; Nakatani,
N.; Fukushima, S.; Tanabe, Y. Tetrahedron, 2003, 59, 5337.
TiCl4-Lewis base (AcOEt, CH3NO2) complexes smoothly
deprotected tert-butyldimethylsilyl (TBDMS) ethers. The reac-
tion velocity with these complexes, which seemed less reactive
due to the influence of Lewis bases, was considerably greater
than that with TiCl4 alone. Selective desilylations between
aliphatic and aromatic TBDMS ethers (1 and 5), between 1 and
benzyl, allyl, tosyl, methoxyphenyl, and chloroacetyl ethers (13,
14, 15, 16, and 17), and between TBDMS and TBDPS ethers
(18 and 19) were successfully performed. Desilylation of
TBDMS-aldol, acyloin, and â-lactam analogues 9-12 proceeded
smoothly due to anchimeric assistance by the neighboring
carbonyl groups. The present method was successfully applied
to the practical synthesis of 1â-methylcarbapenems 20a′-f′.
The tert-butyldimethylsilyl (TBDMS) group is utilized in one
of the most reliable protective methods for alcohols in organic
synthesis,1 due to its ready introduction and deprotection.2 A
number of methods for the deprotection have been exploited,
involving representative fluoride anions, acidic and basic condi-
tions, and oxidation, and reduction agents.3 Lewis-acid promoted
reactions are considered to be a complementary deprotection
method; however, this method received relatively little attention.
The use of BF3‚Et2O,4a Sc(OTf)3,4b TMSOTf,4c Zn(BF4)2,4d
(6) (a) Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetre-
hedron 1999, 55, 2183. (b) Tanabe, Y.; Yamamoto, H.; Yoshida, Y.; Miya-
waki, T.; Utsumi, N. Bull. Chem. Soc. Jpn. 1995, 68, 297. (c) Yoshida, Y.;
Shimonishi, K.; Sakakura, Y.; Okada, S.; Aso, N.; Tanabe, Y. Synthesis
1999, 1633. (d) Morita, J.; Nakatsuji, H.; Misaki, T.; Tanabe, Y. Green
Chem. 2005, 7, 711.
(7) (a) Tanabe, Y.; Murakami, M.; Kitaichi, K.; Yoshida, Y. Tetrahedron
Lett. 1994, 35, 8409. (b) Tanabe, Y.; Okumura, H.; Maeda, A.; Murakami,
M. Tetrahedron Lett. 1994, 35, 8413. (c) Misaki, T.; Kurihara, M.; Tanabe,
Y. Chem. Commun. 2001, 2478. (d) Tanabe, Y.; Misaki, T.; Kurihara, M.;
Iida, A.; Nishii, Y. Chem. Commun. 2002, 1628. (e) Iida, A.; Horii, A.;
Misaki, T.; Tanabe, Y. Synthesis 2005, 2677.
InCl3,4e ZnBr2,4f ZrCl4,4g and SbCl5 has been reported.
4h
* Address correspondence to this author at Kwansei Gakuin University. Phone:
+81-(0)795-565-8397. Fax: +81-(0)795-565-9077.
† Sumitomo Pharmaceuticals Co.
(1) Corey, E. J.; Venkateswarlu, A. J. J. Am. Chem. Soc. 1972, 94, 6190.
(2) (a) Corey, E. J.; Snider, B. B. J. Am. Chem. Soc. 1972, 94, 2549. (b)
Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; Wiley: New York, 1999; p 127. (c) Kocienski, P. Protecting Groups;
Thieme: Stuttgart, Germany, 1994; p 28. (d) Corriu, R. J. P.; Young, J. C. In
The Chemistry of Organic Silicon Compounds; Patai, S., Rappoport, Z., Eds.;
John Wiley: New York, 1989. (e) Crouch, R. D. Tetrahedron 2004, 60, 5833.
(8) Brun, L. Acta Crystallogr. 1966, 20, 739.
(9) Misaki, T.; Nagase, R.; Matsumoto, K.; Tanabe, Y. J. Am. Chem.
Soc. 2005, 127, 2854. Other references cited theirin.
10.1021/jo0604484 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/09/2006
5380
J. Org. Chem. 2006, 71, 5380-5383

SCHEME 2
TABLE 1. Desilylation of Various TBDMS Ethers with TiCl4-Lewis Base Complexes
a Isolated. b Reaction temperature was 0-5 °C. c Reaction temperature was -45 to -50 °C.
pyridine) resulted in no reaction (reaction B), while oxygen-
type bases did not decrease the side chlorination (reaction C).
TiCl4 has significant affinity for simple alkyl esters; for example,
the crystal structure of a dimeric complex (TiCl4-AcOEt)2 was
reported8 and the ester carbonyl function exhibited higher reac-
tivity than the ketone carbonyl function during the Ti-Claisen
condensation.9 As expected, use of the TiCl4-AcOEt complex
effected the smooth deprotection of 1 with sufficient suppression
of the side formation of 2-chlorononane (reaction D). Surpris-
ingly, the use of the TiCl4-CH3NO2 complex was also
successful, especially for aromatic and 1â-methylcarbapenem
substrates (vide supra). Presumably, these Lewis bases not only
maintained the reactivity of TiCl4, but also facilitated the release
of Cl-, which selectively attacked the Si atom, but not the C atom.
It should be noted that the reaction velocity with these
complexes, which seemed less reactive due to the influence of
Lewis bases, was considerably greater than that with TiCl4 alone
(Figure 1). This tendency was also observed and amplified in
the deprotection of the TBDMS ether 5 of p-cresol (Figure 2).
Table 1 lists the successful results under optimized conditions
J. Org. Chem, Vol. 71, No. 14, 2006 5381

SCHEME 3
SCHEME 4
(method A with AcOEt and method B with CH3NO2). The pre-
sent method produces smooth desilylation of aliphatic TBDMS
ethers, wherein method A was slightly more advantageous than
method B with regard to the yield (entries 1-4). In contrast,
method B led to the desilylation with less reactive phenolic
TBDMS ethers in a short period under mild conditions (entries
5-7). One desilylation-resistant 4-nitorophenyl analogue3f,4f was
also possible (entry 8). Ketone, ester, and â-lactam functionalities
tolerated the reaction conditions (entries 9-12). Tertiary and allyl-
ic TBDMS ethers, however, generally failed to undergo the desily-
lation due to undesirable formation of the corresponding chlorides.
To further investigate the chemoselectivity, compatibility of
other conventional protecting groups was examined. As shown
in Scheme 3, TBDMS ether 1 was successfully desilylated in
the presence of benzyl, allyl, tosyl, methoxyphenyl, and
chloroacetyl ethers (13, 14, 15, 16, and 17). Methoxybenzyl
ether, unfortunately, did not tolerate identical conditions.
Note that selective desilylation of 1 in the presence of 5 was
performed to give 2-nonanol, because aromatic substrates
required considerably longer time to reach completion with
method A (Scheme 4). In addition, chemoselective desilylation
was successfully performed between TBDMS ether 18 and tert-
butyldiphenylsilyl (TBDPS) ether 19.
Neighboring group participation (anchimeric assistance) by
the carbonyl groups may be expect to effect smooth desilylation
FIGURE 1. Comparable experiments of desilylation of 1 (GC
conversion): b, TiCl4-AcOEt complex; 2, TiCl4-CH3NO2 complex;
and 9, TiCl4 alone.
FIGURE 2. Comparable experiments of desilylation of 5 (GC
conversion): b, TiCl4-AcOEt complex; 2, TiCl4-CH3NO2 complex;
and 9, TiCl4 alone.
FIGURE 3. Comparable experiments of desilylation of TBDMS ethers
1, 9, 10, and 11 (GC conversion): 2, 1; 9, 9; [, 10; and b, 11.
5382 J. Org. Chem., Vol. 71, No. 14, 2006

SCHEME 5
type Ti-Dieckmann condensation was successfully applied to a
short and practical synthesis ofTBDMS-protected 1â- methylcar-
bapenems.13 These backgrounds lead us to apply the present
desilylation method to the final stage of the synthesis (Scheme 6).
Although the reaction with the TiCl4-EtOAc reagent (method
A of Table 1) failed to proceed (decomposition), the use of the
TiCl4-CH3NO2 reagent (method B) was successful for several
1â-methylcarbapenems 20. Table 2 lists these results (entries
1-5), including a precursor 20f ′ of highly useful Meropenem14
(entry 6). Anchimeric assistance by the carbonyl group of the
â-lactam moiety is thought to effect this smooth desilylation.
In conclusion, we developed a novel mild, practical, chemose-
lective method for the desilylation of various TBDMS ethers
using readily available TiCl4-Lewis base (AcOEt, CH3NO2)
complexes. The present method was successfully applied to the
synthesis of 1â-methylcarbapenems and will be a new entry
for desilylation of the TBDMS group.
SCHEME 6
Experimental Section
Desilylation of TBDMS Ethers (Table 1, Method A). General
procedure: A solution of TiCl4 (1.20-2.50 mmol) and AcOEt
(1.20-2.50 mmol) in CH2Cl2 (1.50 mL) was added to a stirred
solution of TBDMS ether (1.0 mmol) in CH2Cl2 (1.0 mL) at 30 °C
under an Ar atmosphere, and the mixture was stirred at the same
temperature for 10 min to 6 h. Water was added to the reaction
mixture, which was extracted with Et2O. The organic phase was
washed with water and brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by silica gel column chro-
matography (hexane:ether ) 6:1 to 1:1) to give the desired alcohol.
Desilylation of TBDMS Ethers (Table 1, Method B). General
procedure: A solution of TiCl4 (228 mg, 1.20 mmol) and CH3-
NO2 (1.20 mmol) in CH2Cl2 (1.50 mL) was added to a stirred
solution of TBDMS ether (1.0 mmol) in CH2Cl2 (1.0 mL) at 30 °C
under an Ar atmosphere, and the mixture was stirred at the same
temperature for 10 min to 2 h. Water was added to the reaction
mixture, which was extracted with diethyl ether. The organic phase
was washed with water and brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by silica gel column chro-
matography (hexane:ether ) 6:1 to 1:1) to give the desired alcohol.
Alcohols 1′, 2′, 3′, 4′, 5′, 6′, 7′, 8′, 11′, and 18′ are commercially
available. Alcohols 9′,15 10′,16 and 12′17 are known compounds.
TABLE 2. Desilylation of 1â-Methylcarbapenems 20
Acknowledgment. This research was partially supported by
Grant-in-Aids for Scientific Research on Priority Areas (A)
(17035087) and Exploratory Research (17655045) from the Ministry
of Education, Culture, Sports, Science and Technology (MEXT).
Supporting Information Available: Experimental details, char-
acterization date, 1H NMR and 13C NMR, and MS spectra for
1â-methylcarbapenems 20a′-f ′. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Isolated. b Use of TiCl4-AcOEt complex. c Reaction time was 11 h.
JO0604484
due to the high chelation ability of the Ti(IV) species. Indeed, with
method B, R- and â-TBDMS groups in 9, 10, and 11 adjacent
to the corresponding carbonyl groups were more rapidly desilyl-
ated than comparable substrate 1 (Figure 3 and Scheme 5).
This notable finding of the anchimeric assistance prompted us
to investigate the desilylation of potent and broad antibacterial
active 1â-methylcarbapenems, because the practical synthesis of
these pharmaceuticals is a major topic of interest.10 One critical
issue lies in the deprotection of the TBDMS of labile 1â-methyl-
carbapenems: (i) conventional TBAF and related mild TBAF-
AcOH methods result in poor yield due to the undesirable â-lac-
tam ring opening11 and (ii) NH4F‚HF is an effective reagent,
but requires 3 days for completion.12 As part of our ongoing
studies of the Ti-crossed Claisen condensation,9 dehydration-
(10) Reviews: (a) Berks, A. H. Tetrahedron 1996, 52, 331. (b) Sunagawa,
M.; Sasaki, A. J. Synth. Org. Chem. Jpn. 1996, 54, 761.
(11) Hanessian, S.; Desilets, D.; Bennani, Y. L. J. Org. Chem. 1990,
55, 3098.
(12) Seki, M.; Kondo, K.; Kuroda, T.; Yamanaka, T.; Iwasaki, T. Synlett
1995, 609.
(13) Tanabe, Y.; Manta, N.; Nagase, R.; Misaki, T.; Nishii, Y.; Sunagawa,
M.; Sasaki, A. AdV. Synth. Catal. 2003, 345, 967.
(14) (a) Snnagawa, M.; Matsumura, H.; Inoue, T.; Funasaka, M.; Kato,
M. J. Antibiot. 1990, 43, 519. (b) Sunagawa, M.; Sasaki, A.; Matsumura,
H.; Goda, K.; Tamoto, K. Chem. Pharm. Bull. 1994, 42, 1381. (c) Sunagawa,
M.; Sasaki, A. Heterocycles, 2001, 54, 497.
(15) Cavicchioli, S.; Savoia, D.; Trombini, C.; Umani-Ronchi, A. J. Org.
Chem. 1984, 49, 1246.
(16) Sharma, A.; Chattopadhyay, S. J. Mol. Catal. 2000, 10, 531.
(17) Melillo, D. G.; Liu, T.; Ryan, K.; Sletzinger, M.; Shinkai, I.
Tetrahedron Lett. 1981, 22, 913.
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