J. Org. Chem. 1982,47,4013-4018
4013
Carbonate Extension. A Versatile Procedure for Functionalization of Acyclic Homoallylic Alcohols with Moderate Stereocontrol Paul A. Bartlett,* James D. Meadows, Edward G. Brown, Akira Morimoto, and Karen K. Jernstedt Department of Chemistry, University of California, Berkeley, California 94720
Received February 2, 1982 Iodocyclizationof a series of homoallylic tert-butyl carbonates is an efficient and moderately erythro stereoselective method for the functionalization of homoallylic alcohols with 1,3 relative asymmetric induction. Comparison with the anionic carbonate cyclization process of Cardillo et a1.4 reveals a similar stereoselectivity for the two methods. Experiments with a number of carbonate derivatives (tert-butyl, benzyl, and 4-methoxy- and 2,4dimethoxybenzyl)show that loss of the alkyl cation from cyclic intermediate 16 is rate determining. Depending on the cleavage conditions employed, the cyclic iodo carbonates (e.g., 9) can be converted with high selectivity to the iodohydrin methyl carbonate 18, epoxy methyl carbonate 19, or epoxy alcohol 20, offering a significant advantage over our previously reported phosphate cyclization method.
Recently we reported a method for the stereoselective functionalization of homoallylic alcohols by iodocyclization of phosphate esters (Scheme I).l Although treatment of the cyclic phosphates 2 with sodium ethoxide leads to the epoxy phosphates 3 and although erythro diols such as 4 are readily obtained on reduction of the epoxy phosphates with lithium aluminum hydride: the resistance of the phosphate group to hydrolytic removal is a serious limitation. An alternative sequence which allows retention of the epoxide moiety would clearly be advantageous. We explored a number of other "extensions", including the hemiketals formed from hexahaloa~etones,~ diethyl mesoxalate, indantrione, and 1,3-diphenylpropanetrione, among others. Cyclization of tert-butyl carbonates appeared to be the most fruitful, however, as discussed in this paper. Recent communication^^*^ on the halocyclization of homoallylic carbonate monoesters and continued interest in the direct epoxidation of homoallylic alcoholss also provide stimulus for our report. Stereoselectivity of the Iodo Carbonate Cyclization Processes By analogy to the successful iodolactonization of unsaturated carboxylic esters,7T8we expected methyl carbonate 5a to afford the iodo carbonates 6 on treatment with I
0Y"
I
OR
0
0
5a, R = Me b, R = t-Bu c, R = Li
6e
6t
excess iodine in acetonitrile. No cyclization is observed, (1) Bartlett, P. A.; Jemstedt, K. K. J. Am. Chem. SOC.1977,99,4829. ( 2 ) Bartlett, P. A.; Jernstedt, K. K. Tetrahedron Lett. 1980, 1607. (3) For related processes using trihaloacetaldehydes, see: Overman, L. E.; Campbell, C. B. J. Org. Chem. 1974,39,1474. Stork,G.;Kowalski, C.; Garcia, G. J. Am. Chem. SOC.1975,97, 3258. (4) Carddo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Chem. SOC.,Chem. Commun. 1981,465. (5) Haslanger, M. F.; b e d , S . J. Org. Chem. 1981, 46, 4808. (6) Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. J. Am. Chem. SOC. 1981,103,7690. (7) J e e r , V.; Gunther, H. J. Tetrahedron Lett. 1977, 2543. (8) Bartlett, P. A.; Myerson, J. J. Am. Chem. SOC.1978, 100, 3950.
0022-326318211947-4013$01.25/0
Scheme I
CH3CN
b\ P 0 3 E t 2
NaOEt ____)
I
I
o,pOo // \ 6 ' bEt
THF
LiA1H4
3
L
however, even after a prolonged period at room temperature? On the other hand, tert-butyl carbonate 5b cyclizes readily, even at -20 "C,affording iodo carbonates 6 as a 1O:l mixture of isomers. The results obtained on application of this reaction to a variety of homoallylic alcohols are summarized in Table I. Assignment of the erythro stereochemistry to the major isomers was confirmed by their NMR spectra (see Experimental Section) and in the case of the 1,7-octadienol-derived product 9 by conversion to the erythro diol 4b, previously employed in a synthesis of nonactic acid.2 The stereoisomer ratios were determined by 13CNMR analysis of the crude products, before any purification procedure which might lead to isomer separation or selective decomposition. Corroboration of this analytical method was obtained in the case of 9: lithium aluminum hydride reduction of the crude iodocyclization product, acetylation, and VPC analysis gave the same ratio as the 13C NMR method. In the case of iodo carbonates 6, isolation of the erythro isomer 6e and the threo isomer 6t in pure form (in 7.4% and 70% yields, respectively) after flash column chromatography further supported the validity of the 13C method. Cardillo et al. have found that iodocyclization of the carbonate salt 5c in tetrahydrofuran affords cyclic carbonate 6 in 80% chromatographed yield: They investigated the stereoselectivity of this process by deiodination (n(9) See ref 5 for a contrasting result with a bicyclic substrate.
0 1982 American Chemical Society
4014
J. Org. Chem., Vol. 47, No. 21, 1982
Bartlett et al.
Table I. Stereoselectivity of Iodocyclization of Homoallylic Carbonates
entry
substr
1 2 3
5b 5c 7b
4 5 6 7 8
IC
Ra t-Bu Li t-Bu Li t-Bu Li t-Bu Li
8E-b 8E-c 82-b 82-c
R'
R2
R3
product
yield,b 3'%
Me Me CH,=CHCH,CH, CH,=CHCH,CH, Et Et Et Et
H H H H H H Me Me
H H H H Me Me H H
6 6
77d 70 6gdte
9 9 10 10 11 11
erythro/ threo ratioC
(22)f
10 13 6.5 6 4 4
88 82 91 73g
6 6.5
a Cyclization conditions: for R = t-Bu, 3 equiv of I,/CH,CN/-20 "C/5-10 h ; for R = Li4, alcohol + n-BuLilTHF and then Isolated yield of product >95% pure by NMR, unless otherwise indiCO, for 30 min at 21 "C/2 equiv of I, at 0 " C / 1 h. cated. Determined by I3C NMR of the crude product. To minimize possible effects of relaxation differences (expected to be minor for diastereomeric compounds), the ratios of peak areas were averaged for several well-resolved carbons in each Yield of product purified by column chromatography. e No product arising from carbonrite cyclization onto system. the 7,s double bond was detected. f Yield of product purified by preparative TLC (73% m a s recovery); tetrahydrofuran 1 4 isolated in 39% yield. g Product contained some 10% of the starting alcohol.
_1 _4
2 : l
Bu,SnH), hydrolysis, acetylation, and VPC analysis of the diacetate 13. They found less than 5% of the the0 isomer T
RdL LiAIHq
O K 0
OH
0
OH
4a, R = CH, b, R = CH,=CHCH,CH,
9, R = CH,=CHCH,CH2 6,R = CH,
Rn AcO
12, R
=
OAc
CH,=CHCH,CH,
13,R = CH,
to be present. Since this appeared to be a more advantageous process than cyclization of the tert-butyl carbonate, we studied the anionic cyclization with the same series of homoallylic alcohols as for the diester method (Table I). For the substrates we investigated, it appears that the anionic procedure offers no advantage in stereoselectivity or yield over the diester cyclization. In the case of 1,7octadien-4-01 in particular (entry 4, Table I), the major product is iodotetrahydrofuran 14, which apparently arises from preferential cyclization of the alkoxide, as shown in Scheme 11: We feel that the minor discrepancy between our results and those of Cardillo et al.4 with regard to the stereoselectivity of cyclization of 5c can be attributed to the different analytical approaches employed. Influence of the Carbonate Ester Derivative The lower stereoselectivity of the "carbonate extension" process in comparison to the "phosphate extension"' is not surprising in view of the trigonal, rather than tetrahedral, nature of the cyclizing group (Scheme 111). In an attempt to improve this stereoselectivity, we explored a variety of carbonate derivatives of 1,7-octadien-601 (Table 11). The diastereomer ratios of the crude products were determined by the reduction/acetylation/VPC analysis procedure outlined above. As revealed in Table 11, there is no significant influence of the departing cationic group on the stereoselectivity, but there is a marked effect on reaction rate. Although the reaction rates were only crudely determined by monitoring
Scheme I11
+
R'y-, .
e
I2
y
'Id1- Rldl -R+
Y
o
OR
OR
15 --_
-_16_
slow
0
vo II
0
J. Org. Chem., Vol. 47, No. 21, 1982 4015
Carbonate Extension Scheme IV T
MeOH, K2C03 A
MeOH, 3 eq. K2C03 21OC
7 hr
LiA1H4
-
OH
*
\
v OH
OH
-4b; -a
97%b
Yield after column chromatography.
Yield of product,
the disappearance of starting material by TLC, the differences are sufficiently striking to be meaningful. Since it is unlikely that the alkyl group would have such a large effect on the initial cyclization step, these results indicate that loss of the alkyl cation from trialkoxycarbocation intermediate 16 is rate determining (Scheme 111). Furthermore, because this cationic intermediate does not accumulate in the slower reactions, it must be in equilibrium with the starting material, and therefore formed with thermodynamic control over the stereochemistry. The relative invariance of the isomer ratios listed in Table I1 is also consistent with this interpretation. Although judiciously arranged thermodynamic control has been our key to high stereoselectivity in related processes,l,sJoit would not appear that further improvement in the present case can be obtained along these lines, except at significantly lower temperature." The similar stereoselectivities exhibited by the two carbonate cyclization processes (Table I) suggest that the anionic one is thermodynamicdy controlled as well. This interpretation is tentative, although consistent with our experience with iodolactonization reactions of 6,t-unsaturated carboxylic acids8J2 and with the reactivity of six-membered cyclic carbonates (see below).
> 95% purity, by VPC or NMR. A point of practical interest relates to the fate of the tert-butyl cation which is lost during the course of cyclization: it is trapped by acetonitrile solvent to give N tert-butylacetamide on workup. The importance of trapping the tert-butyl cation as the Ritter intermediate is suggested by cyclizations attempted in solvents such as methylene chloride or carbon tetrachloride, which afforded low yields of intractable products. N-tert-Butylacetamide is a bothersome contaminant in the product, but its formation can be avoided almost entirely by introducing dimethylformamide into the reaction mixture 1 h before the workup. This leads to transfer of the tert-butyl group from acetonitrile to DMF and to production of the more volatile tert-butyl formate on workup. Use of DMF as the solvent for the cyclization itself gives iodoformates such as 17 as the major product. I I
17
Hydrolytic Cleavage of the Iodo Carbonates (10) Rychnovsky, S. D.; Bartlett, P. A. J . Am. Chem. SOC.1981,103, 3963. (11)However, attempted iodocyclization of the dimethoxybenzyl carbonate 7f in 4 1 methylene chloride acetonitrile at -78 O c afforded 1,7-octadien-4-01as the only identifiab e product. (12) Equilibration of six-membered iodo lactones can be seen under the classical iodolactonization conditions (KI,/aqueous NaHCOJ ,in certain instances (Myerson, J. Ph.D. Thesis, University of California, Berkeley, 1980).
i
Although formed less stereoselectively than the cyclic phosphates, the carbonates are far more with regard to their hydrolytic reactions. Depending on the vigor of alkaline methanolysis, iodo carbonate 9 can be converted to iodohydrin methyl carbonate Isa, epoxy methyl carbonate 1% Or epoxy alcohol 20a in good to excellent yields (Scheme IV). Further reaction of the
J. Org. Chem., Vol. 47, No. 21, 1982
4016
Bartlett et al. I
Table 11. Influence of Departing Alkyl Group on Iodocyclization I
I
CH3CN, - 2 O O C
O\%J
I
OR
Conclusion The carbonate cyclization sequence at present is the most efficient method for inducing 1,3 relative asymmetric induction in the epoxidation of homoallylic alcohols which lack a cis substituent at the distal end of the double bond (Le., for substrates such as the precursors to 5,7, and 8E). It therefore complements the vanadium-catalyzed procedure, which Mihelich et al. have recently investigated in related systems! The carbonate cyclization also exhibits high regiocontrol, as demonstrated by specific functionalization of the 1,2 double bond of 1,7-octadien-4-01. Finally, a number of selective transformations are facilitated by the hydrolytic reactivity of the cyclic carbonate moiety. The high SN2-typereactivity of this group and how it is exploited in an improved synthesis of nonactic acid via deiodinated compound 22 will be described in a future publication.
I
I
I
I
reac-
tion
en-
try substr 1
2 3 4 5
R
t-BU
7b 7d 7e 7e 7f
PhCH,
4-MeOPhCH2 4-MeOPhCH2
9e/9t
time: h
ratio
8 12 0.5 12b
6.5 6.2 5.7 6.4b 5.5
