J . Org. Chem. 1985,50, 5687-5696
5687
Selective Transformation of 2,3-Epoxy Alcohols and Related Derivatives. Strategies for Nucleophilic Attack at Carbon-1 Carl H. Behrens, So0 Y. KO, K. Barry Sharpless,* and Frederick J. Walker Department of Chemistry, Massachusetts Institute
of
Technology, Cambridge, Massachusetts 02139
Received July 31, 1984 In connection with the continuing recent interest in the stereoselective synthesis of epoxy alcohols, a systematic investigation of the bimolecular nucleophilic ring-opening reactions of acyclic 2,3-epoxy alcohols was undertaken. Strategies for nucleophilic attack a t C-1 of a 2,3-epoxy alcohol, each of which depends upon the regioselective ring-opening of a 1,2-epoxy 3-01, were explored. Under Payne rearrangement conditions, t-BuSNa was found to react with 2,3-epoxy alcohols to afford 1-tert-butylthio 2,3-diols. These diols can be readily converted to 1,2-epoxy 3-0k via S-alkylation followed by treatment with base. Alternatively, 1,2-epoxy3-01s can be prepared from 2,3-epoxy alcohols by sulfonylation and acidic hydrolysis followed by ring-closure of the diol sulfonate intermediate. Dialkylamines were also found to react selectively with 2,3-epoxy alcohols under Payne rearrangement conditions to afford 1-amino 2,3-diols.
“If carbonyl compounds have been said to be ‘virtually the backbone of organic synthesis’, the epoxides correspond to a t least ‘one of the main muscles’.’’ This sentiment, recently expressed by Seebach,‘ effectively conveys to the reader the importance of epoxides in synthesis. Indeed, the literature confirms that much effort has been expended on the investigation of epoxide chemistry in the past.’S2 More importantly, it indicates that syntheses of natural products via epoxide-containing intermediates are of great interest. Epoxides are easily prepared from a variety of compounds. In addition, epoxides are easily opened under a wide range of conditions. One very favorable aspect of epoxide-opening reactions is that they are usually stereospecific, proceeding with inversion of configuration at the site of ring opening via an SN2mechanism. For this reason, methods for the highly enantioselective synthesis of epoxides would be quite valuable. Unfortunately, the known enantioselective epoxidations of isolated olefins usually provide only a modest level of asymmetric induction. In contrast, general methods for the syntheses of enantiomerically pure (homochiral) 2,3-epoxy alcohols ars k n ~ w n . ~The - ~ regioselective ring-opening reactions of (1) Seebach, D.; Weidmann, B.; Wilder, L. In “Modern Synthetic Methods 1983”; Scheffold, R., Ed.; Otto Salk Verlag: Frankfurt, 1983; p 323. (2) The following are reviews concerned with the synthesis and selective transformations of epoxides: (a) Gorzynski-Smith, J. Synthesis 1984,629. (b) Behrens, C. H.; Sharpless, K. B. Aldrichimica Acta 1983, 16,67. (c) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323. (d) Arata, K.; Tanabe, K. Catal. Rev.-Sci. Eng. 1983,25,365. (e) Sharpless, K. B.; Behrens, C. H.; Kabuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Pure Appl. Chem. 1983,55,589. (0 Sharpless, K. B.; Verhceven, T. R.; Aldrichimica Acta 1979,12,63. (g) Berti, G. In “Topics in Stereochemistry”;Allinger, N. L., Eliel, E. L., Eds.; Interscience Publishers: New York, 1973; Vol. 7, p 93. (h) Buchanan, J. G.; Sable, H. Z. In “Selective Organic Transformations”;Thyagarajan, B. S., Ed.; Wiley: New York, 1972; Vol. 2, p 1. (i) Yandovskii, V. N.; Ershov, B. A. Russ. Chem. Rev. (Engl. Transl.) 1972,41,403. (j) Swern, D. In “Organic Peroxides”; Swern, D., Ed.; Wiley-Interscience: New York, 1971; Vol. 2, Chapter 5. (k)Williamms, N. R. In ’Advances in Carbohydrate Chemistry and Biochemistry”; Tipson, R. S., Horton, D., Eds.; Academic Press: New York, 1970; Vol. 25, p 109. (1) Rosowsky, A. In “The Chemistry of Heterocyclic Compounds”;Weissberger, A., Ed.;Interscience: New York; Vol. 19, Part 1, Chapter 1. (m) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59,737. (n) Winstein, S.; Henderson, R. B. In “HeterocyclicCompounds”; Elderfield, R. C., Ed.; Wiley: New York, 1950, Vol. 1, Chapter 1. (3) (a) Kabuki, T.; Sharpless, K. B. J.Am. Chem. Soc. 1980,102,5974. (b) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. SOC. 1981, 103, 6237. (e) Lu, L. D.-L.; Johnson, R. A.; Finn, M. G.; Sharpless, K. B. J. Org. Chem. 1984,49, 728. (4) (a) Hungerbuhler, E.; Seebach, D. Helu. Chim.Acta 1981, 64, 687. (b) Hungerbuhler,E.; Seebach, D.; Wasmuth, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 958.
0022-3263/85/1950-5687$01.50/0
Scheme I. Payne Rearrangement-Opening Reaction
-
R+OH
-I
0 5 M NaOH , i-BuOH rearrangement
-
OH
6R*
I
NU
,OH -R
2 -
ring opening
W
I
N
U
OH
3 -
2,3-epoxy alcohols provide convenient access to useful, highly functionalized homochiral molecules. However, this subject has not been systematically explored in the literature. In principle, there are three reactive sites for nucleophilic substitution in a 2,3-epoxy alcohol corresponding to the carbon backbone of the epoxy alcohol. In this paper, strategies for nucleophilic substitution at C-1 of a 2,3-epoxy alcohol are explored. In the following paper, strategies for nucleophilic substitution at C-3 or C-2 of a 2,3-epoxy alcohol are discussed.
Results and Discussion Payne Rearrangement-Opening Reactions of 2,3Epoxy Alcohols with t-BuSNa. A subtle latent reactivity at the C-1 position of 2,3-epoxy alcohol 1 can be revealed in one step by means of the Payne rearrangement.6 The Payne rearrangement of a 2,3-epoxy alcohol is carried out in an aqueous sodium hydroxide solution, usually in the presence of a cosolvent, and involves the equilibration of the epoxy alcohol 1 with the isomeric 1,2-epoxy 3-01 2 as shown in Scheme I. This epoxide migration reaction was well-known to sugar chemists.2h,k However, Payne was the first to publish detailed observations of the epoxide migration reaction in simple acyclic epoxides. He found that the relative proportions of the 2,3- and 1,Zepoxy alcohols at equlibrium are highly substrate dependent. Since the Payne rearrangement usually produces a mixture of epoxy alcohols, it is of limited preparative value per se. For this reason, it was regarded as more of a curiosity than a useful reaction. However, due to the renewed interest in the chemistry of epoxy alcohols, the Payne rearrangement has been reinvestigated.7,8 A major advance in the synthetic utility of the Payne rearrangement came with the realization that a nucleophile which is introduced into an equlibrating mixture of epoxy (5) Ladner, W. E.; Whitesides, G. M. J. Am. Chem. SOC.1984, 106, 7250. (6) Payne, G. B. J. Org. Chem. 1962,27, 3819. (7) Koizumi, N.; Ishiguro, M.; Yasuda, M.; Ikekawa, N. J. Chem. SOC., Perkin Trans. 1 1983, 1401. (8) Rokach, J.; Lau, C.-K.; Zamboni, R.; Guindon, Y. Tetrahedron Lett. 1981, 22, 2763.
0 1985 American Chemical Society
Behrens et al.
5688 J . Org. Chem., Vol. 50, No. 26, 1985
Table I. Payne Rearrangement-Opening Reaction of 2,3-Epoxy Alcohols with t -BuSNa NaOH
l:I!-BuOH-0.5M
R
4 --E
slow addition of R'SH
7o-ao*c
OH II
-
17
yield: entry
2,3-epoxy alcohol
product
regioselectivity
OH
I
3
% 47
(20l)b
81
(20:l)b
85
(20:l)b
88
(20:l)b
84
(15:l)b
75
6 -
4
0nOY
O
H
7
5 o x G O H OH 15 -
6
X O
0
G
O
"6
H
9 -
7
OH
16 -
"Indicates the ratio of the C-1 to C-3 to C-2 regioisomers. bIndicates the ratio of the C-1 product to the combined C-3 and C-2 regioisomers. cThe major contaminant was the C-3regioisomer. dIndicates the isolated yield of C-1 product.
alcohols may react selectively with one of the epoxy alcohols (see Scheme I). The rate of reaction of 2 with any given nucleophile is expected to be much faster than that of 1 with the same nucleophile because the C-1 position of 2 is much less hindered than either the C-2 or C-3 position of 1. Therefore, it appeared plausible that 2, continuously regenerated in situ via the Payne rearrangement of 1, could be selectively and irreversibly captured by a nucleophile to afford high'yields of 3 in a process that is designated as a Payne rearrangement-opening reaction. This reaction was independently conceived and developed by Masamune and Sharpless at MITg and the Ganem group at Cornell.lO The Payne rearrangement-opening reaction of a 2,3epoxy alcohol to afford a 1-thio 2,3-diol is a fairly complex reaction in that the product distribution is affected by several factors including the reaction temperature, sodium hydroxide concentration, and the rate of addition of the (9) This new concept was conceived, discovered, and developed in full collaboration with Professor S. Masamune and his group as part of a joint program directed toward the synthesis of polyhydroxylated natural products. (a) Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982,47,1373. (b) Masamune, S.; Choy, W. Aldrichimica Acta 1982,15, 47. (c) KO,S. Y.; Lee, A. W. M.; Masamune, S.;Reed, 111,L. A.; Sharpless, K. B.; Walker, F. J. Science (Washington, D.C.)1983,220, 949. (IO) Wrobel, J. E.; Ganem, B. J. Org. Chem. 1983, 48, 3761.
thiol. The rate of addition of the thiol is probably the most important concern in these reactions. If the thiol is introduced rapidly the undesired products of the ring opening of 1 at C-3 and C-2 (i.e., 1,2- and 1,3-diols) may be present in the product mixture in greater amounts than when slow addition of the thiol is practiced. An experimental procedure that was successfully employed by Masamune and Sharpless required that a solution of the epoxy alcohol 1 in a 1:l t-BuOH4.5 M NaOH mixture be immersed in an oil bath (70-80 "C) and treated with a solution of PhSH in t-BuOH (slow addition) over a period of 1-2 h.9a Normally, 1.2 equiv of PhSH and 2.5 equiv of NaOH (based on 1) were employed. In the present work, this rearrangement-opening procedure was applied to a series of 2,3-epoxy alcohols, and the results are given in Table I. The reaction conditions employed are the same as those previously described with the exception that t-BUSHwas used in place of PhSH as the nucleophile. It was thought that the greater reactivity of dialkyl sulfides compared to alkyl aryl sulfides with alkylating agents would be useful in the subsequent reactions of the thio diol (vide infra). In addition, it was felt that the greater steric bulk of the tert-butyl group relative to the phenyl group might improve (or at least should not diminish) the regioselectivity exhibited for ring opening at C-1.
Selective Transformation of 2,3-Epoxy Alcohols
J . Org. Chem., Vol. 50, No. 26, 1985 5689
Scheme 11. Diol Sulfonate Method cat HC104
OH
-OMS
0
ref.
13
ref.
13
eq. 1
-OMS
3 ' 1 DMSO/H20
OH
77 % yield cat. HCIO4
OMe
-OMS
0
-OMS
eq. 2
MeOH
6H 9 5 % yield
I ) TsCl , P Y OH 2) cat. HCIQ * G I
aq. THF,
-? No2C03
O
T
A
s
o':"\
MeOH
K2C03
QH
6H
14a
87% yield OH
Me02C -0Ts
ref.
eq. 3
MeOH
,
Me02C-
,.
ref. 14b
eq.4
V
r.t
98 8/o yield ref. 14c
eq. 5 J
-
&
THF, cat. DMSO
7 2 % yield
From the results in Table I it is apparent that the regioselectivity in the Payne rearrangement-openingreaction depends on the structure of the epoxy alcohol. The regioselectivity is very good with epoxy alcohols 8-10 in which ring-opening at the C-3 position is sterically hindered by branching at (2-4. Much poorer regioselectivity is found with epoxy alcohols such as 4 and 5 in which there is no branching at C-4. I t is interesting to note that the regioselectivity found with 6 and 7 is very good even though there is no branching at C-4 in these cases. Evidently, the benzyloxy group in 6 and 7 serves to suppress the unwanted ring-opening at C-3.l' Another factor that may affect the regioselectivity is the geometry (Le., cis or trans) of the epoxy alcohol. It is known from the original work of Payne6 and a study by Seebach4"that the thermodynamic equilibration of a cis-disubstituted 2,3-epoxy alcohol with a threo-1,2-epoxy 3-01 via the Payne rearrangement affords approximately a 1:l mixture of each, whereas a similar equilibration of a trans-disubstituted 2,3-epoxy alcohol with an erythro-1,2-epoxy 3-01 leads to about a 9:l mixture of the respective epoxy alcohols. However, a comparison of entries 1-4 reveals that this effect on the Payne rearrangement equilibrium does not greatly affect the regioselectivity of the Payne rearrangement-opening reaction. A nucleophile must naturally be stable to the typical reaction conditions (Le., 0.5 N NaOH at 80 "C) in order to participate effectively in the Payne rearrangementopening reaction. These criteria are stringent enough to preclude the use of many potentially useful nucleophiles. Furthermore, some reagents that do survive the reaction conditions (e.g., N&H4) have been found effective only with certain favorable 2,3-epoxy alcohol substrates.% One way to circumvent this problem has been described in the literature. (11) Observations such as these are central to the h u e of regioselective ring opening reactions of 2,3-epoxy alcohols at C-2 or C-3 and are dealt with in greater detail in the following paper in this issue.
In this method (Scheme 11) the C-1 hydroxyl group of 1 is converted into a good leaving group, usually a maylate or a tosylate. Under basic conditions, the reaction of a nucleophile with a 2,3-epoxy 1-sulfonate ester normally results in selective displacement of the sulfonate group rather than epoxide opening.2eJ2 However, a 2,3-epoxy 1-sulfonate ester reacts in acidic aqueous media to give a 2,3-diol-l-sulfonateester, as shown in eq 1-3.13J4 A careful examination of the products revealed that in each case (eq 1-3) the hydrolysis of the 2,3-epoxy 1-sulfonate ester was regioselective for ring-opening at C-3 and was stereospecific with inversion of configuration at C-3. The 2,3-diol-l-sulfonate ester can be converted to a 1,2-epoxy 3-01 by treatment with a suitable base such as K&03 or NaH as illustrated in eq 3-5.14 With the isolated 1,2-epoxy3-01 in hand, ring opening at C-1 with almost any nucleophile that is known to open epoxides should present little difficulty. This three-step route to a 1,Zepoxyalcohol from a 2,3-epoxy alcohol, the "diol sulfonate method", affords a convenient and useful alternative to the Payne rearrangement for unveiling the latent reactivity at the C-1 position of a 2,3-epoxy alcohol. The Payne rearrangement-opening reaction with tBuSNa also offers a solution to the problem of nucleophilic substitution at C-1 of a 2,3-epoxy alcohol with nonsulfur nucleophiles that is similar to the "diol sulfonate method". Since the Payne rearrangement is stereospecific with inversion at (2-2, and the ring-opening with t-BuSNa is regioselective for C-1, the enantiomeric excess in the 2,3epoxy alcohol will be completely retained in the product (12) ja) Mori, K.; Ebata, T. Tetrahedron Lett. 1981, 22, 4281. (b) Kigoshi, H.; Ojika, M.; Shizuri, Y.; Niwa, H.; Yamada, K. Tetrahedron Lett. 1982,23,5413. (c) Chen, R.; Rowand, D. A. J. Am. Chem. SOC.1980, 102.6609. ..I
(13)We thank Steven M. Viti for performing this experiment. (14) (a) Morgans, D. J., Jr.; Sharpless, K. B.; Traynor, S. G. J. Am. Chem. SOC.1981, 103, 462. (b) Carey, E. J.; Marfat, A.; Goto, G.; Brian, F. J . Am. Chem. SOC.1980, 102,7984. (c) White, J. D.; Kang, M.; Sheldon, B. G. Tetrahedron Lett. 1983,24,4539. (d) See also: Salomon, I.; Reichstein, T. Helu. Chim. Acta 1947, 30, 1929.
5690
Behrens et al.
J. Org. Chem., Vol. 50, No. 26, 1985 Scheme 111. Comparison of the “Diol Sulfonate” and “Diol Sulfide” Methods
2) cat. HCIO4 , 3 : I D M S O / H 2 0 , A
OH 32 -
7 7 % yield CO
86 %
8 0
4 2 ,CH2C12)
(-1-5
9 5 % e.e
\ c+,-n 4 7 % yield +
2,3-diol. The transformation of a 2,3-diol-l-sulfide to a 1,a-epoxy 3-01may then be accomplished by the conversion of the C-1 sulfide to a good leaving group (e.g., via S-alkylation) followed by treatment with a suitable base to effect ring-closure.15 Freshly prepared Me30BF4 was found to be a very effective reagent for S-alkylation.16 In a typical procedure, a solution of 13 in CH2C12was treated with Me30BF4(added portion-wise as a solid) until complete consumption of 13 was observed by TLC. The reaction mixture (in CH,C12) was then treated with an excess of a 10% aqueous NaOH solution and stirred vigorously. After 1-2 h, a new product was visible by TLC of an Rf slightly greater than that of 13. A standard extractive workup afforded the threo-1,2-epoxy3-01 18 in 88% yield (entry 1, Table 11). The S-alkylation of 14 with Me30BF4 proceeds efficiently as above, but a similar treatment of the sulfonium salt (in CH2C12)with 10% aqueous NaOH unexpectedly did not provide pure 19 but rather a mixture of 19 and 7. Evidently the erythro-1,2-epoxy 3-01 19 is so easily rearranged to the trans-2,3-epoxy alcohol 7 that it is not stable to contact with aqueous base, even in a heterogeneous medium. Rokach and co-workers have made similar observations? However, treatment of the sulfonium salt with NaH in CH2C12afforded pure 19 (entry 2).17 (15) (a) Fujisawa, T.; Sato, T.; Kawara, T.; Ohashi, K. Tetrahedron Lett. 1981,22,4823. (b) Pirkle, W. H.; Rmaldi, P. L. J. Org. Chem. 1978, 43,3803. (c) Shanklin, J. R.; Johnson, C. R.; Ollinger, J.; Coates, R. M. J. Am. Chem. SOC.1973,95,3429. (d) Kano, S.; Yokomatsu, T.; Shibuya, S.J. Chem. SOC.Chem. Commun. 1978, 785. (e) Ikeda, Y.; Furuta, K.; Meguriya, N.; Ikeda, N.; Yamamoto, H. J. Am. Chem. SOC.1982, 104, 7663. (0 Townsend,J. M.; Sharpless, K. B. TetrahedronLett. 1972,3313. (9) Johnson, C. R.; Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. SOC. 1973,95,7424. (h) Schauder, J. R.; Krief, A. TetrahedronLett. 1982,23, 4389. (i) Van Ende, D.; Krief, A. Tetrahedron Lett. 1976, 457. (16) Curphey, T. J. Org. Synth. 1971,51, 142. (17) The epoxy alcohols 18 and 19 can be purified by flash chromatography, but a significant loss of product is inevitable. These 1,a-epoxy 3-01s are rather easily opened and even undergo partial decomposition during chromatography. It is more convenient to use these compounds directly and then purify the product at a later stage.
12.4’ ( c 2.19,EIOH )
entry
Table 11. Synthesis of 1,f-Epoxy 3-01s 1-tert-butylthio reactn 2,3-diol conditns product
1
13
2
14
yield, %
I8 -
a, d
9H
89
OnoO 19 -
4
17
21
*
a Me30BF4,CH2C12,room temperature. Me30BF4,2,6-tert-butylpyridine, CH2C12,room temperature. 10% aqueous NaOH, CHzClz,room temperature. NaH, CH2ClZ,room temperature.
When the tert-butylthio diol to be alkylated contains an acid-labile functional group it is advisable to introduce to the reaction a buffer such as 2,6-di-tert-butylpyridine mixture. For example, the reaction of 15 or 17 with Me30BF4alone produces a complex mixture. Presumably acid-catalyzed migration and/or removal of the acetonide protecting groups of 15 or 17 is at least partially responsible for the problem. However, the use of 2-3 equiv of 2,6di-tert-butylpyridine circumventsthe problem. Treatment of the sulfonium salts with NaH in CH2C12as before affords the 1,2-epoxy3-oh 20 and 21 (entries 3 and 4) in good yield.
J. Org. Chem., Vol. 50, No. 26, 1985 5691
Selective Transformation of 2,3-Epoxy Alcohols Table 111. 1,2-Epoxy 3-01 Ring-OpeningReactions
P 18 -9 1,2-epoxy . . entry
3-01
1
18
2
19
3 4 6
18 19 18
6
19
7
18
8
19
9
18
10
19
Nu
OH
2 2 - 2 reactn conditns product a 22. R = OH: R' = H: Nu N3 a 23, R = H; R' = OH; Nu N3 b 24, R = OH; R' = H; Nu b 25, R = H; R' = OH; Nu c 26, R = OH; R' = H; Nu CH, c 27, R = H; R' = OH; Nu CH3 d 28, R = OH; R' = H; Nu C=CCH,OTHP d 29, R = H; R = OH; Nu C=CCH,OTHP e 30, R = OH; R' = H; Nu CN e 31, R = H; R' = OH; Nu CN
yield, % =
83
=
93
=H =H =
83
=
73
=
76
=
64
=
89
=
