J. Org. Chem. 1990, 55, 5132-5139
5132
, H2'), 4.6 (m, 1 , H3'), 4.15 (m, 1 , H4'), 3.45 (m, 2 , H5'), 3.0 (m, 4 , H7 and H8), 4.45 (m, 1 , H9), 3.3 (m, 2 , H10), 1.6 (s, 9 , H16), 1.4 (s, 9 , H18), 3.8 (s, 6 , H20).
of 20% CFgCOOH in CH2C12 (5 mL) was added to the stirred reaction mixture. After 30 min, the mixture was concentrated to dryness and the resulting solid was dissolved in water (10 mL). The aqueous solution was washed with CH2C12 (2X5 mL) and ether
(m, 2
FABMS m/z 988+, (M + Li). Exact culated for C51H63N7013Li 949.3933.
(2x5 mL) and then concentrated to give the desired product
15 (0.16 g, 0.33 mmol, 87%). 13C NMR (D20, ppm): 88.5 (V C), 42.3 (2' C), 73.8 (3' C), 89.9 (4' C), 64.5 (5' C), 168.7 (4 CO), 154.8 (2 CO), 116.6 (5 C), 141.5 (6 C), 26.2 (7 C), 37.7 (8 C), 41.7 and 42.1 (9 C and 10 C), 34.4 (11 C), 130.0 (12 C), 120.8 (13 C), 136.9 NMR (D20): 6 6.25 (t, 1 (14 C), 178.7 (15 C), 173.9 (16 C). H, HI', J = 7.0 Hz), 2.35 (m, 2 , H2'), 4.45 (m, 1 , H3'), 4.05 (m, 1 , H4')> 3.8 (m, 2 , H5'), 7.7 (s, 1 , H6), 2.5 (m, 4 , H7 and H8), 3.3 (hr s, 4 , H9 and H10), 3.8 (s, 2 , Hll), 7.4 (s, 1 , H13), 8.7 (s, 1 , H14). FABMS m/z 463+ (M + 2 Li H), 457+ (M + Li), 341+ (M + Li sugar). Exact mass found 457.2094, calculated for C19H26N607Li 547.2022.
mass
found 949.3960, cal-
5-[[2-[[2-Amino-3-(lfl'-imidazol-4-yl)-l-oxopropyl]-
amino]ethyl]thio]-2'-deoxyuridine (18). The nucleoside 17 (0.2 g, 0.212 mmol) was dissolved in CH2C12 (5 mL), and a solution of 25% CF3COOH in CH2C12 (5 mL) was added to the stirred reaction mixture. After 10 min, the mixture was concentrated to dryness. The solid was dissolved in water (10 mL), washed with CH2C12 (2x5 mL) and ether (2X5 mL), and concentrated
to give the desired product 18 (0.086 g, 0.184 mmol, 87%). 13C NMR (D20, ppm): 89.3 (V C), 42.4 (2' C), 73.5 (3' C), 90.2 (4' C), 64.3 (5' C), 167.9 (4 CO), 154.5 (2 CO), 109.5 (5 C), 149.2 (6
-
-
C), 36.2 (7 C), 41.6 (8 C), 55.6 (9 C), 29.4 (10 C), 129.3 (11 C), 121.7 NMR (D20): 6.25 (t, 1 (12 C), 137.7 (13 C), 171.1 (14 C). H, HI', J = 7.0 Hz), 2.45 (m, 2 , H2'), 4.5 (m, 1 , H3'), 4.05 (m, 1 , H4'), 3.85 (m, 2 , H5'), 8.2 (s, 1 , H6), 2.75 (m, 2 H, H7), 3.35 (m, 2 , H8), 4.3 (t, 1 , H9), 3.4 (m, 2 , H10), 7.45 (s, 1 , H12), 8.75 (s, 1 , H13). FABMS m/z 447+ ( + Li). Exact mass found 447.4694, calculated for C20H29N7O7Li 447.4644.
5'-0-[Bis(4-methoxyphenyl)phenylmethyl]-5-[[2-[[2[[(2,2-dimethylethoxy)carbonyl]amino]-3-[l-[(2,2-dimethylethoxy)carbonyl]-lFf-imidazol-4-yl]-l-oxopropyl]amino]ethyl]thio]-2'-deoxyuridine (17). 5'-0-[Bis(4-methoxyphenyl)phenylmethyl]-5-[(2-aminoethyl)thio]-2'-deoxyuridine (16) (1.25 g, 2.07 mmol), Et3N (0.3 mL, 2 mmol, and Boc-L-his(Boc)-O-pfp 4 (1.19 g, 2.5) mmol) were dissolved in CH2C12 (10 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and chromatographed on a silica gel column eluting with a gradient of 0 to 10% EtOH in CH2C12. The desired product 17 (1.5 g, 1.59 mmol, 77%) eluted with 8% EtOH in CH2C12 (Rf -0.52). Mp: 142 °C. 13C NMR (CDC13, ppm): 85.8, (V C), 41.3 (2' C), 72.3 (3' C), 86.6 (4' C), 63.8 (5' C), 163.4 (4 CO), 150.3 (2 CO), 107.3 (5 C), 145.0 (6
Acknowledgment. We wish to thank Dr. W. B. Wise for his valuable discussions and assistance with the indirect detection, HETCOR, and COSY NMR spectroscopy on compounds 5, 6, and 8; Drs. E. W. Kolodziej and P. C. Toren for mass spectral data; and Ms. A. M. Huber for literature searches and nomenclature. Supplementary Material Available: NMR spectra of representative compounds and the experimental conditions are given
C), 34.9 (7 C), 38.6 (8 C), 54.3 (9 C), 31.3 (10 C), 139.2 (11 C), 114.8 (12 C), 136.9 (13 C), 171.6 (14 C), 87.0 (15 C), 27.9 (16 C), 79.8 (17 C), 28.4 (18 C), 85.7 (19 C), 55.3 (20 C), 155.6, (21 C), 147.0 NMR (CDClg): 6.35 (t, 1 H, HI', J = 7.0 Hz), 2.4 (22 C).
in supplementary material (29 pages). Ordering information is on any current masthead page.
given
Organotin-Mediated Monoacylation of Diols with Reversed Chemoselectivity: A Convenient Synthetic Method1 Gianna Reginato, Alfredo Ricci, Stefano Roelens,* and Serena Scapecchi CNR, Centro di Studio sulla Chimica e la Struttura dei Composti Eterociclici e loro Applicazioni, c/o Department of Organic Chemistry, University of Florence, 50121 Florence, Italy
Received December
7,
1989
The organotin-mediated monoesterification of unsymmetrical diols with reversed chemoselectivity has been explored to ascertain scope and limits of the method and to provide an easy and convenient synthetic procedure. The reaction has been performed on a set of substituted diols with some acylating agents usually employed as protecting groups. Two different procedures have been devised to obtain either the desired diol monoesters directly or the corresponding trialkylsilyl ethers as protected derivatives. The latter provides a convenient approach to the preparation of easily interconvertible diol monoesters. Also, the reaction has been optimized as a one-pot procedure, avoiding the isolation and purification of the stannylated intermediates. The reversed monoesterification method has been successfully applied to 1,2-, 1,3-, and 1,4-diols of primary-secondary, primary-tertiary, and secondary-tertiary types and to ether functions containing 1,2-diols. Within its limits, the described method represents the first direct one-pot monoesterification of diols at the most substituted site, allowing some remarkable achievements as (a) an almost regiospecific reversed monobenzoylation of some 1,2-diols, (b) the selective acylation of the tertiary hydroxyl of a primary-tertiary diol, and (c) a highly selective preparation of the secondary pivalate of primary-secondary diols.
edented in the chemical literature: while chemoselective esterification reactions of diols and polyols,3 including regioselective manipulation of hydroxyl groups via organotin derivatives,4 were reported to enhance the natural
In a previous paper,2 we reported experimental evidence that the reactivity order of hydroxyl groups toward acylating agents can be reversed by activation through their stannyl derivatives. In particular, unsymmetrically substituted ethylene glycols could be efficiently esterified at the most substituted site. Such observation was unprec-
(3) (a) Greene, T. W. Protective Groups in Organic Synthesis·, Wiley-Interscience: New York, 1981; p 50. (b) Rana, S. S.; Barlow, J. J.; Malta, K. L. Tetrahedron Lett. 1981, 22, 5007. (c) Mukaiyama, T.; Pai, F. C.; Onaka, M.; Narasaka, K. Chem. Lett. 1980,563. (d) Posner, G. H.; Oda, M. Tetrahedron Lett. 1981, 22, 5003. (e) Therisod, M.; Klibanov, A. M. J. Am. Chem. Soc. 1986, 108, 5638. (4) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663.
(1) Group 14 Organometallic Reagents. 9. Part 8: Mordini, A.; Roelens, S. J. Org. Chem. 1989, 54, 2643. (2) Ricci, A.; Roelens, S.; Vannucchi, A. J. Chem. Soc., Chem. Commun.
1985, 1457.
0022-3263/90/1955-5132$02.50/0
©
1990 American Chemical Society
J. Org. Chem., Vol. 55, No. 17, 1990 5133
Organotin-Mediated Monoacylation of Diols Table I. Quenching of the Monobenzoylation Reaction of RCHOHCH2OH (Equation 1)° mono-
entry 1
2 3 4
5 6 7
8 9 10 11
ester
quenching reagent Me3SiCl PhMe2SiCl6 PhMejSiCl6 Et3SiCl Bu3SiCl t-BuMe2SiCl H20 H20/HC1 (10:1)
H20/HC1 (2:1) (COOH)2/CHCl3c (COOH)2/CH3CN
R
yield, %
mME:lME
Me Me Ph Me Me Me Ph Ph Ph Ph Ph
79 84 90 54 50 30 89 89
80:20 85:15 95:5 83:17 80:20 60:40 75:25 81:19 82:18 49:51 79:21
91
85 84
0 Crystallized dioxastannolanes were used as starting material. 6Data from ref 2. 'Incomplete destannylation.
hydroxyl group reactivity, i.e., primary > secondary » tertiary, no reports had been published on reversed selectivity.
Since the above paper, no general method has yet appeared, to our knowledge, to perform the reversed esterification of diols.5 Because a method of potentially wide application, complementary to known reactions, would be an extremely useful tool for the synthetic chemist, we have explored in this paper the possibility of providing a convenient synthetic procedure, trying to optimize yields and selectivities, and to establish scope and limitations of the organotin-mediated method for the selective monoesterification of diols at the most substituted hydroxyl.
Results and Discussion As described for the monobenzoylation of 1,2propanediol and l-phenyl-l,2-ethanediol,2 azeotropic dehydration with toluene of the diol in the presence of dibutyltin oxide affords the corresponding dibutylstannylene derivative, which is isolated and purified by crystallization. The dioxastannane is then reacted with 1 equiv of benzoyl chloride in concentrated chloroform solution and subsequently quenched with 1 equiv of phenyldimethylsilyl chloride (eq 1). Besides diesters (DE) R
(1) PhCOCI
BUiSnO
toluene
N^°x I
(2) PhMejSiCI
SnBu2
CHGb
reflux
A-^OCOPh
R>-OSiMe2Ph (1)
X>SiMe2Ph
R
=
mME major Me, Ph
OCOPh IME
minor
and disilylated starting material (DS), the silyl-protected diol monoester, functionalized at the most substituted hydroxy group (most substituted monoester, mME), is selectively obtained, together with minor amounts of the regioisomeric primary ester (least substituted monoester, IME). The pure mME can then be obtained in most cases by flash column chromatography on silica gel. Quenching. A preliminary screening of commercial trialkylsilyl chlorides as quenching reagents, analyzing the reaction by 1H NMR spectroscopy, showed best results when the stannylation mixture was quenched with phenyldimethylsilyl chloride (PhMe^iCl). However, the more convenient trimethylsilyl chloride (Me3SiCl) gave very good yields and selectivities as well (Table I, entries 1-6).6 (5) See, however: Pautará, A. M.; Evans, S. A. J. Org. Chem. 1988, 53, 2300.
Destannylation of the acylation mixture can also be achieved by either aqueous or anhydrous direct protonolysis. The latter is conveniently performed in chloroform or acetonitrile solution with oxalic acid, which induces complete precipitation of organotin oxalates. In Table I, the results relative to the neutral or acidic (HC1) aqueous quenching of the benzoylation mixture of l-phenyl-1,2ethanediol (entries 7-9) are compared with anhydrous quenching with oxalic acid (entries 10 and 11) and with PhMe2SiCl (entry 3). As shown, all procedures are efficient, except for protonolysis in chloroform. Quenching in acetonitrile is particularly convenient, in that it allows clean elimination of tin byproducts by simple filtration. It is also a preferable procedure with reactive esters, when hydrolysis might occur during aqueous quenching. Care should be paid to the fact that the stoichiometric amount of added oxalic acid is crucial: It has been verified that a drastic decrease in yields and selectivity is observed for an excess of the latter. Quenching with trialkylsilyl chlorides is suitable when isomerically stable hydroxy esters are required, for example when products should undergo subsequent transformations. As a control experiment on their stability, two different regioisomeric mixtures of silyl-protected 1- and 2-benzoyl esters of 1,2-propanediol; i.e., 92:8 (from a blank experiment) and 23:77 (from the stannylation method, in the presence of the dibutyltin dichloride formed in the reaction), respectively, showed no detectable isomerization after a 16-h reflux in chloroform.7 An additional 4-h reflux, after the addition of 50 mol % of the corresponding dioxastannolane, still gave unaltered isomeric ratios. In this context, it is important to stress that hydroxy esters, in particular monoesters of 1,2-diols, are known to isomerize8 (eq 2) and that such isomerization is very fast in acidic9 or alkaline media.10 While for moderately rer
ocor
T
