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A synthon for chiral glycolate enolate (roc hcoor'): a camphor-based oxazoline
Tetrahedron Printed in
Letters,Vol.25,No.l,pp Great Britain
39
-
@ 1984
A SYNTHONFOR CHIRAL CLYCOLATE BNOLATB (RO&CO~R’): T. Ross Department
Summary:
Alkylations good yield.
In the
of
a suitably
indicated
in Equation
achieving
practical
Consequently
if
became
, it
Arvanitis
College,
protected
toward that
the
Chestnut
of
synthesis
“boxed”
the
enolate
The achirality
1. levels
even
was small
and Argyrios
Boston
(e.g.,
Hill,
of
portion 2)
of
2 suggested,
the
MA 02167
of
to
incorporate
into
2. features
of
1. might acid
however,
stereochemical control during the n the possibility chirality in RL afforded
oxazoline proceed in acids in high ee.
family
glycolic
of
desirable
-00 Ltd.
A CAMPHOR-BASEDoKA~OLTNB
of the anion (&) derived from a camphor-based Hydrolysis affords the corresponding o-hydroxy
of studies directed 1,2 (11, we envisioned
by alkylation
desired
Chemistry,
course
by tirandamycin
(2’5)
of
Kelly*
$3.00 + Pergamon Press
0040-4039184
42,1984
that
typified
be generated &H~CH~COOH)
the
course
of
of
kinetic
which
molecules
likelihood the
as of
alkylation resolution.
would
ordain
the
outcome.
-2 Of the
technologies
zoline-based
approach
while
oxazolines
chiral their
thesis, Waterloo
available offered
have been 5 to the
application
than
satisfactory
of
the
time
this
only Meyers’ oxawas initiated,3 4 Unfortunately, however, solution. 4 overall contribution to asymmetric syn-
project
applicable
impressive
in their
fabrication of chiral a-alkoxy acids had proved 5a Specifically, employ of 1. as a synthon for 2. failed
a watershed. degrees
at
a potentially
enantiomeric
excess,
with
Xee’s
ranging
from
more of to
a
afford
12 to 42% in the
examples
reported. Nonetheless,
an oxazoline-based
Analysis
suggested
1) anion
generation
anion
should
should
meet
the
S-face
might of
both
in Table
of 1.
the
high
second
the
exist
for
a useful
must be,
exhibit the of
well
that
still
degree
of
at a minimum,
diastereofacial 6 because
criterion
anion; largely
above
method
and consideration with
the
expectations,
appeared ee to obtain
highly
as evidenced
attractive
group
chelation
endo
effects
shown in 1. by the
eels
in principle.
two objectives and 2)
Examination
selectivity.
of
only
stereoselective
the methyl
stereochemistry
highly
to led
of the to
generated,
models
indicated
oxazoline the
We now report
and absolute
need be met:
once
ring
expectation the
the that
that
realization
configuration
5
shields
given
5
Table
Acid prenared
Entry
1 2 3 4 5 6 7 a 9 10 11 12 13 14 15 16
Effect
2:
of
Experimental
Conditionsa
Internal Temnerature
Solventb
Cation
THF THF THF Et20 2:l Et20/THF 1:2 Et20/THF 1:2 Et20/THF 1:4 Et20/THF hexane hexane 1: 1 hexane/THF THF THF THF 1:2 Et20/THF 1:4 Et20/THF
Li Li Li(+l.l Li Li Li Li Li Li Li Li Li,Mgh Li,Mgh Li Li Li
kc 73 79 78 no rxneyf 79 88 88 a8 e no rxn
-7 8OC
-100 eq LiId)
-78
-78 -78 -78
-100 -78 -78
-40
g 56 no rxne decompe 80 85 86
-78
-78 -40 -78 -78 -78
ed on lg 11 in a total volume (excluding hexaneb) of 40mL (assuming b) in the case of mixed solvents the anion was generated in the the anion solution was then diluted with the cosolvent; ~a. 1.6 mL hexane solvent listed first; (from BuLi) was also present. c) determined by conversion to 15 (see text). d) 11 and LiI were stirred 5 min at 20’ before BuLi was added at -78’. e) anion formation proven by quenchf;t;,;i;t E20 and/or CH3CH2CH0. f) anion decomposes at -40’. g) alkylation only 60% complete h) 11 stirred with 1 eq MgBr2 (from Mg + BrCH2CH2Br) ; anion decomposes above -2O’C. before addition of BuLi.
attack.
The lack
of
the
anion.
If
is
configurationally
stereochemical 94:6.
It
isomer,
agents,
further is
is
optimized
ranging
B;
(as
from
in more entry
from
%ee’s
73% (m)
the of
of 2, to
the
which
original
a,
of
for
in Table
2.
14 prepared 1 and 14)
generation
It
of &
a direct
of
88% ee is
of
acids
14 that
the
least amount
from
thus
(addition
of
of
top
1 were
all
alkyl
five
determined that
THF is
anion
necessary
thus
is
the
on chelation
in Table
appears
&
side
in determining
also
consequence
demanding
(ca.5%)
role
were
based
sterically
on only one face 15 that anion &
anions,
ee is
Values
acids
occurs
oxazoline
basis
their
entries 82% (&I.
observed
alkylation
on the
prediction
the
a small
examined
summarized
that other
R chirality
case
were
in Table
selective
the
intrusion
factors
that
anion,
with
in the to
follows
the
suggests shown for
the
the to
dominant
anion
the
alkylating
alkylation
of
anion
stereochemical
halides
using (171
but were
be
considerations.
of
obtained
conditions
using
in ether
alkylation
&.
outcome
THF
uniformly
formation for
of
inferred
lower, results
to occur:
see
4). Efforts
to
would
afford
dered
the
attention
to
its
enhance chelate
unreactive
demonstrated
the more available sufficiently
further
a tighter
anion
Having
is
it
in agreement
are
for
as solvent
as previously
of
follows
attributed
results
in ee therefore
stable,
ee observed
A number of and the
variation
one assumes,
composition
which
The lower
of
employ
toward the
to
of
synthesis
lactate alkylate
by using reaction conditions + Li , hexane as solvent, etc.)
(Table
2) which
generally
ren-
alkylation.
efficacy
in the
(S)-ethyl reactive
the la:& ratio ++ (Mg instead of
b
as an effective
of
1.
as models a.
Other
To our for
their
routes
surrogate
dismay,
neither
enantiomers to 1. are
for j& &
presently
2,
we turned
our
and a [prepared from 16 17 nor (9-20
and b]
under
investigation.
42
5,
R=@CH20CH b,
2
R=MEM CH
H3
In summary, ;la serves its
design
are
vindicated,
as an effective even
though
it
synthon proved
for
chiral
unsuitable
2, for
and the its
concepts
intended
underlying 18
application.
Referencesad Notes 1. 2.
3.
4. 5. 6.
7. 8. 9. 10. 11. 12.
13. 14. 15. 16. 17. 18.
For structural studies see D.J. Duclwp, A.R. Branfsran, A.C. Button and K.L. Rinehart, Jr., J. Am. Ches. Sot., s 4077 (1973) and references therein. For other synthetic efforts directed toward 1. and related cmqxxads see inter alia a) R.E. Ireland, P.G.M. ws and B. Ernst, m., 103. 3205 (1981); b) P. DeSlrmg, S. Ramesh, and J.J. Perez, J. Org. Chas., 3 2118 (1983); c) F.E. Ziegler and J.K. TlxXtathil, Tetrahedron L&t., 4883 (1981); d) S.F. Martin, C.L. Grspbell, R.C. t&perin, D.E. Vogel and R. Gist, 185th National ACSMeeting, Seattle, March 1983, Abstract IXN 5; e) R.W. &gger, m., Abstract oRL;N6; f) R.K. Boeclwn, Jr. and A.J. Ttasas,J. Ore. Chum., & 2823 (1982); g) V.J. Lee, A.R. Branfman, T.R. Herrin and K.L. Rinehsrt, Jr., J. Am. (hem. Sot., 100, 4225 (1978). For a suwey of theavailable metlrxls for the synthesis of chiral whydroxy and balkoxy acids see pp 2830-2832 in J.W. Apsiurm and and R.P. Seguin, Tetrahedron, 21, 2797 (1979). For sore recent methods and other relevant studies see, inter alia a) S. Terashims and S.-s Jew, Tetrahedron l&t., 1005 (19771; b) T. Kaneko, D.L. ‘Dn-ner, M. New& and D.E. Bergbreiter, ibid. 103 (1979); c) D. Alxnhaim, G. Boireau and B. Sabcurault, m., & 3043 (1980); d) G. Frater, U. tiller and W. Gunther, ibid.. 22, 4221 (1981); e) T. tiiym, Tetrahedron, & 4111 (1981); f) D. Enders and H. latter, Ansew. then. Int. Ed. l&xl., & 795 (1981); g) D. Seebach awl R. Naef, Helv. ChhkaActa., 64, 2704 (1981); h) M.M. Midland and P.E. Lee, J. Ore. &XII., s 3933 (1981); E.L. Eliel and J.E. Lynch, Tetrahedron l&t., 22J 2855 (1981); i) D.A. Bvans, M.D. Rmis and D.J. Mathre, J. Am. them. Sot., 104. 1737 (1982); j) G. Boireau, D. Abe&aim, A. Deberly and B. Sabourault, Tetrahedron Lett., a 1259 (1982); k) J.K. Whitesell, A. Bhattacharya, D.A. Aguilar and K. Benke, J. Qlem. Sot. Chem. Caaam., 988, 989 (1982); 1) U. Sctnllkopf and H.-J. Neubawr, Svnthesis, 861 (1982) and adjoining papers. See also refs. 2, 5 and 6. For a slll~~llilly see A.I. Meyers, Act. Chea. Res., 11, 375 (1978). a) A.I. Meyers, G. Knaus and P.M. Ketill, Tetrahedron l&t., 3495 (1974); b) see also A.I. Meyers and J. Slade, J. OIX. Ckn., s 2785 (1980). Amng other uses of -elated chiral auxiliaries see: a) E.L. Eliel and W.J. Frasee, J. Ors. then., 4& 3598 (1979); b) C.R. Noe, them. Ber., 115. 1607 (1982); c) G. Helmchen, A. Selim, D. Dorsch arri I. Taufer, Tetra_ hedron l&t., 2k, 3213 (1983) and earlier wrk cited therein; d) D.F. Taber and K. Ranan, J. Am. Hera. See., 105. 5935 (1983). nived chiral shift reagents have also been widely employed [for a recent application to synthesis see M. Bednarski, C. Msring ard S. Danishefsky, ibid.. 24, 3451 (1983)l. M.O. Forster awl K.A.N. Rae, J. Chern.Sot., 2670 (1926). R.A. Chitterslen and G.H. Cooper, J. Clwa. Sot. CC), 49 (1970) and A.H. Beckett, N.T. Ian and G.R. McDxwgh, Tetra_ hedron. 25, 5689 (1%9). See also A. Daniel and A.A. Pavia, Bull. Sot. Chim. Fr., 1060 (1971). D.J. loader and W.M. Bruner, U.S. Patent 2,398,757 [Chmu Abstr., s 37744 (194611; S.E. Diniso, R.W. Freer ksen, W.E. Pabst and D.S. Watt, J. Orx Chm~, & 2846 (1976). H. Witte anl W. Seeliger, Ann., 996 (li74). Satisfactory analytical and spectral data were obtained for this cuapaxd, General urocedure: To a solution of 1 g 11 in 8 mL dry ether at -78oC was added 1.0 equiv EeuLi (2.5 M in hexAfter stirring 1 h at -78??, the reaction mixture was diluted with 32 ml. dry ‘DfF (precooled to ane) drop&e. -780). Alkyl halide (1.2 equiv) was then added dropwise over 45 ruin; the reaction vas then stirred at -78oC for 2 h arxi quenched at -78oC with sat’d. aq. Cl. Nor& work up then gave the oxazolines in essentially quantitative yield and a high state of plrity (tic, mFBI? . lhe oxazolines were hydrolyzed5 by refluxing for 24 h in 25 mL 4N The aqueous layer was then cooled, extracted twice with ether and the ether twice extracted with 1N Na’Zi. r4* basic phase was acidified with cow. HCl and thrice wtracted with ether. After drying over &SO4 evaporation gave the acids &. J.A. Dale and H.S. Ebsher, J. Am. Ches. Sot., s 512 (19731. K. l4xi, M. Sasaki, S. T;rmada,T. Suguro and S. Ma&a, Tetrahedron, 21, 1601 (1979); @)-&and bare uxnnercially available. M.A. lbobler, D.E. Bergbreiter and M. Newxrb, J. Am. Chm~.Sot., 100. 8182 (1978); A.I. Meyers, B.S. Snyder 100. 8186 (1978). axI J.J.H. A&ermsn, m., The syntheses of 18a and bvill be described elsewhere (unpublished work of R. R. Cwhring, F.R. W&be1 and J.D. Cutting). E.D. Mihelich, K. Daniel6 and D.J. Eidrhoff, J. Am. t&m. See., 103. 7690 (1981). We thank Dr. Mihelich for experimental details. Support of this work by the National Institutes of Health (grant Gtf 28968) is gratefully acknwledged. (Received in USA 6 October 1983)
Letters,Vol.25,No.l,pp Great Britain
39
-
@ 1984
A SYNTHONFOR CHIRAL CLYCOLATE BNOLATB (RO&CO~R’): T. Ross Department
Summary:
Alkylations good yield.
In the
of
a suitably
indicated
in Equation
achieving
practical
Consequently
if
became
, it
Arvanitis
College,
protected
toward that
the
Chestnut
of
synthesis
“boxed”
the
enolate
The achirality
1. levels
even
was small
and Argyrios
Boston
(e.g.,
Hill,
of
portion 2)
of
2 suggested,
the
MA 02167
of
to
incorporate
into
2. features
of
1. might acid
however,
stereochemical control during the n the possibility chirality in RL afforded
oxazoline proceed in acids in high ee.
family
glycolic
of
desirable
-00 Ltd.
A CAMPHOR-BASEDoKA~OLTNB
of the anion (&) derived from a camphor-based Hydrolysis affords the corresponding o-hydroxy
of studies directed 1,2 (11, we envisioned
by alkylation
desired
Chemistry,
course
by tirandamycin
(2’5)
of
Kelly*
$3.00 + Pergamon Press
0040-4039184
42,1984
that
typified
be generated &H~CH~COOH)
the
course
of
of
kinetic
which
molecules
likelihood the
as of
alkylation resolution.
would
ordain
the
outcome.
-2 Of the
technologies
zoline-based
approach
while
oxazolines
chiral their
thesis, Waterloo
available offered
have been 5 to the
application
than
satisfactory
of
the
time
this
only Meyers’ oxawas initiated,3 4 Unfortunately, however, solution. 4 overall contribution to asymmetric syn-
project
applicable
impressive
in their
fabrication of chiral a-alkoxy acids had proved 5a Specifically, employ of 1. as a synthon for 2. failed
a watershed. degrees
at
a potentially
enantiomeric
excess,
with
Xee’s
ranging
from
more of to
a
afford
12 to 42% in the
examples
reported. Nonetheless,
an oxazoline-based
Analysis
suggested
1) anion
generation
anion
should
should
meet
the
S-face
might of
both
in Table
of 1.
the
high
second
the
exist
for
a useful
must be,
exhibit the of
well
that
still
degree
of
at a minimum,
diastereofacial 6 because
criterion
anion; largely
above
method
and consideration with
the
expectations,
appeared ee to obtain
highly
as evidenced
attractive
group
chelation
endo
effects
shown in 1. by the
eels
in principle.
two objectives and 2)
Examination
selectivity.
of
only
stereoselective
the methyl
stereochemistry
highly
to led
of the to
generated,
models
indicated
oxazoline the
We now report
and absolute
need be met:
once
ring
expectation the
the that
that
realization
configuration
5
shields
given
5
Table
Acid prenared
Entry
1 2 3 4 5 6 7 a 9 10 11 12 13 14 15 16
Effect
2:
of
Experimental
Conditionsa
Internal Temnerature
Solventb
Cation
THF THF THF Et20 2:l Et20/THF 1:2 Et20/THF 1:2 Et20/THF 1:4 Et20/THF hexane hexane 1: 1 hexane/THF THF THF THF 1:2 Et20/THF 1:4 Et20/THF
Li Li Li(+l.l Li Li Li Li Li Li Li Li Li,Mgh Li,Mgh Li Li Li
kc 73 79 78 no rxneyf 79 88 88 a8 e no rxn
-7 8OC
-100 eq LiId)
-78
-78 -78 -78
-100 -78 -78
-40
g 56 no rxne decompe 80 85 86
-78
-78 -40 -78 -78 -78
ed on lg 11 in a total volume (excluding hexaneb) of 40mL (assuming b) in the case of mixed solvents the anion was generated in the the anion solution was then diluted with the cosolvent; ~a. 1.6 mL hexane solvent listed first; (from BuLi) was also present. c) determined by conversion to 15 (see text). d) 11 and LiI were stirred 5 min at 20’ before BuLi was added at -78’. e) anion formation proven by quenchf;t;,;i;t E20 and/or CH3CH2CH0. f) anion decomposes at -40’. g) alkylation only 60% complete h) 11 stirred with 1 eq MgBr2 (from Mg + BrCH2CH2Br) ; anion decomposes above -2O’C. before addition of BuLi.
attack.
The lack
of
the
anion.
If
is
configurationally
stereochemical 94:6.
It
isomer,
agents,
further is
is
optimized
ranging
B;
(as
from
in more entry
from
%ee’s
73% (m)
the of
of 2, to
the
which
original
a,
of
for
in Table
2.
14 prepared 1 and 14)
generation
It
of &
a direct
of
88% ee is
of
acids
14 that
the
least amount
from
thus
(addition
of
of
top
1 were
all
alkyl
five
determined that
THF is
anion
necessary
thus
is
the
on chelation
in Table
appears
&
side
in determining
also
consequence
demanding
(ca.5%)
role
were
based
sterically
on only one face 15 that anion &
anions,
ee is
Values
acids
occurs
oxazoline
basis
their
entries 82% (&I.
observed
alkylation
on the
prediction
the
a small
examined
summarized
that other
R chirality
case
were
in Table
selective
the
intrusion
factors
that
anion,
with
in the to
follows
the
suggests shown for
the
the to
dominant
anion
the
alkylating
alkylation
of
anion
stereochemical
halides
using (171
but were
be
considerations.
of
obtained
conditions
using
in ether
alkylation
&.
outcome
THF
uniformly
formation for
of
inferred
lower, results
to occur:
see
4). Efforts
to
would
afford
dered
the
attention
to
its
enhance chelate
unreactive
demonstrated
the more available sufficiently
further
a tighter
anion
Having
is
it
in agreement
are
for
as solvent
as previously
of
follows
attributed
results
in ee therefore
stable,
ee observed
A number of and the
variation
one assumes,
composition
which
The lower
of
employ
toward the
to
of
synthesis
lactate alkylate
by using reaction conditions + Li , hexane as solvent, etc.)
(Table
2) which
generally
ren-
alkylation.
efficacy
in the
(S)-ethyl reactive
the la:& ratio ++ (Mg instead of
b
as an effective
of
1.
as models a.
Other
To our for
their
routes
surrogate
dismay,
neither
enantiomers to 1. are
for j& &
presently
2,
we turned
our
and a [prepared from 16 17 nor (9-20
and b]
under
investigation.
42
5,
R=@CH20CH b,
2
R=MEM CH
H3
In summary, ;la serves its
design
are
vindicated,
as an effective even
though
it
synthon proved
for
chiral
unsuitable
2, for
and the its
concepts
intended
underlying 18
application.
Referencesad Notes 1. 2.
3.
4. 5. 6.
7. 8. 9. 10. 11. 12.
13. 14. 15. 16. 17. 18.
For structural studies see D.J. Duclwp, A.R. Branfsran, A.C. Button and K.L. Rinehart, Jr., J. Am. Ches. Sot., s 4077 (1973) and references therein. For other synthetic efforts directed toward 1. and related cmqxxads see inter alia a) R.E. Ireland, P.G.M. ws and B. Ernst, m., 103. 3205 (1981); b) P. DeSlrmg, S. Ramesh, and J.J. Perez, J. Org. Chas., 3 2118 (1983); c) F.E. Ziegler and J.K. TlxXtathil, Tetrahedron L&t., 4883 (1981); d) S.F. Martin, C.L. Grspbell, R.C. t&perin, D.E. Vogel and R. Gist, 185th National ACSMeeting, Seattle, March 1983, Abstract IXN 5; e) R.W. &gger, m., Abstract oRL;N6; f) R.K. Boeclwn, Jr. and A.J. Ttasas,J. Ore. Chum., & 2823 (1982); g) V.J. Lee, A.R. Branfman, T.R. Herrin and K.L. Rinehsrt, Jr., J. Am. (hem. Sot., 100, 4225 (1978). For a suwey of theavailable metlrxls for the synthesis of chiral whydroxy and balkoxy acids see pp 2830-2832 in J.W. Apsiurm and and R.P. Seguin, Tetrahedron, 21, 2797 (1979). For sore recent methods and other relevant studies see, inter alia a) S. Terashims and S.-s Jew, Tetrahedron l&t., 1005 (19771; b) T. Kaneko, D.L. ‘Dn-ner, M. New& and D.E. Bergbreiter, ibid. 103 (1979); c) D. Alxnhaim, G. Boireau and B. Sabcurault, m., & 3043 (1980); d) G. Frater, U. tiller and W. Gunther, ibid.. 22, 4221 (1981); e) T. tiiym, Tetrahedron, & 4111 (1981); f) D. Enders and H. latter, Ansew. then. Int. Ed. l&xl., & 795 (1981); g) D. Seebach awl R. Naef, Helv. ChhkaActa., 64, 2704 (1981); h) M.M. Midland and P.E. Lee, J. Ore. &XII., s 3933 (1981); E.L. Eliel and J.E. Lynch, Tetrahedron l&t., 22J 2855 (1981); i) D.A. Bvans, M.D. Rmis and D.J. Mathre, J. Am. them. Sot., 104. 1737 (1982); j) G. Boireau, D. Abe&aim, A. Deberly and B. Sabourault, Tetrahedron Lett., a 1259 (1982); k) J.K. Whitesell, A. Bhattacharya, D.A. Aguilar and K. Benke, J. Qlem. Sot. Chem. Caaam., 988, 989 (1982); 1) U. Sctnllkopf and H.-J. Neubawr, Svnthesis, 861 (1982) and adjoining papers. See also refs. 2, 5 and 6. For a slll~~llilly see A.I. Meyers, Act. Chea. Res., 11, 375 (1978). a) A.I. Meyers, G. Knaus and P.M. Ketill, Tetrahedron l&t., 3495 (1974); b) see also A.I. Meyers and J. Slade, J. OIX. Ckn., s 2785 (1980). Amng other uses of -elated chiral auxiliaries see: a) E.L. Eliel and W.J. Frasee, J. Ors. then., 4& 3598 (1979); b) C.R. Noe, them. Ber., 115. 1607 (1982); c) G. Helmchen, A. Selim, D. Dorsch arri I. Taufer, Tetra_ hedron l&t., 2k, 3213 (1983) and earlier wrk cited therein; d) D.F. Taber and K. Ranan, J. Am. Hera. See., 105. 5935 (1983). nived chiral shift reagents have also been widely employed [for a recent application to synthesis see M. Bednarski, C. Msring ard S. Danishefsky, ibid.. 24, 3451 (1983)l. M.O. Forster awl K.A.N. Rae, J. Chern.Sot., 2670 (1926). R.A. Chitterslen and G.H. Cooper, J. Clwa. Sot. CC), 49 (1970) and A.H. Beckett, N.T. Ian and G.R. McDxwgh, Tetra_ hedron. 25, 5689 (1%9). See also A. Daniel and A.A. Pavia, Bull. Sot. Chim. Fr., 1060 (1971). D.J. loader and W.M. Bruner, U.S. Patent 2,398,757 [Chmu Abstr., s 37744 (194611; S.E. Diniso, R.W. Freer ksen, W.E. Pabst and D.S. Watt, J. Orx Chm~, & 2846 (1976). H. Witte anl W. Seeliger, Ann., 996 (li74). Satisfactory analytical and spectral data were obtained for this cuapaxd, General urocedure: To a solution of 1 g 11 in 8 mL dry ether at -78oC was added 1.0 equiv EeuLi (2.5 M in hexAfter stirring 1 h at -78??, the reaction mixture was diluted with 32 ml. dry ‘DfF (precooled to ane) drop&e. -780). Alkyl halide (1.2 equiv) was then added dropwise over 45 ruin; the reaction vas then stirred at -78oC for 2 h arxi quenched at -78oC with sat’d. aq. Cl. Nor& work up then gave the oxazolines in essentially quantitative yield and a high state of plrity (tic, mFBI? . lhe oxazolines were hydrolyzed5 by refluxing for 24 h in 25 mL 4N The aqueous layer was then cooled, extracted twice with ether and the ether twice extracted with 1N Na’Zi. r4* basic phase was acidified with cow. HCl and thrice wtracted with ether. After drying over &SO4 evaporation gave the acids &. J.A. Dale and H.S. Ebsher, J. Am. Ches. Sot., s 512 (19731. K. l4xi, M. Sasaki, S. T;rmada,T. Suguro and S. Ma&a, Tetrahedron, 21, 1601 (1979); @)-&and bare uxnnercially available. M.A. lbobler, D.E. Bergbreiter and M. Newxrb, J. Am. Chm~.Sot., 100. 8182 (1978); A.I. Meyers, B.S. Snyder 100. 8186 (1978). axI J.J.H. A&ermsn, m., The syntheses of 18a and bvill be described elsewhere (unpublished work of R. R. Cwhring, F.R. W&be1 and J.D. Cutting). E.D. Mihelich, K. Daniel6 and D.J. Eidrhoff, J. Am. t&m. See., 103. 7690 (1981). We thank Dr. Mihelich for experimental details. Support of this work by the National Institutes of Health (grant Gtf 28968) is gratefully acknwledged. (Received in USA 6 October 1983)