4094
C.H. HEATHCOCK et al.
(2SR,3SR) - 2A - Dimethyl - 3 - hydroxypentanoic acid (lid)
was produced in 57% yield from the hydroxy ester, and in 81%
yield from the acetoxy ester.
(54H, br s), 1.27 (12H, d, J = 7), 0.87 (61-I, m). (Found: C, 80.26; H,
12.26. Calc. for C,uHsoO3: C, 80.42; H, 12.27%).
(2SR, 3RS) - 2,4,4 - Trimethyl - 3 - hydroxypentanoic acid (I le)
was produced in 18% yield from the hydroxy ester, and in 79%
yield from the acetoxy ester.
Methyl corynomycolate (30)
(A) From dimethvlohenvl esters. A soln of a 1.5 : I mixture of
DMP esters 26 and 27 (0.103g, 0.172 mmol), prepared as des-
cribed above and NaOMe (98.7 mg, 0.183 retool) in 10mL of 1:1
THF : MeOH was stirred at room temp. for 24 hr. The mixture
was then taken up in ether, washed with water, and dried over
MgSO4. Evaporation of the solvent left 76.0 mg of a white solid,
which was purified by preparative tic, eluting with 10%
ether/hexane, to give 20.0 mg (23%) of epi-methvl corynomy-
colate, m.p. 70-71° (Lit. m.p. 68-70*)18 and 40.2rag (46%) of
methyl corynomycolate, m.p. 56--58~ (Lit. m.p. 57-59*))s
(B) From Bis(l'-Methylethyl)phenyl esters. A soln of a 2:1
mixture of DIPP esters 28 and 29 (19.3 mg, 0.029 mmol), prepared
as described above and NaOMe (15.7 rag, 0.029 retool), in 6 mL of
1:1 THF:MeOH was stirred at room temp. for 2 days. Additional
NaOMe (10.0 rag, 0.019 retool) was added to the mixture, and this
was stirred for ! day. The mixture was taken up in water and
extracted twice with ether. The ether extracts were washed with
brine, dried over MgSO4, and evaporated to yield 18.6 mg of crude
product. Chromatography of the crude material on silica gel, eluting
with 10% ether/hexane, afforded 13.4rag (69%) of recovered
starting material, and 4.8 mg (31%) of a mixture of methyl cory-
nomycolate and methyl epi-corynomycolate, identical with
material obtained from the dimethylphenyl esters.
(2SR, 3RS)-2-Ethyl-3-hydroxy-4-methylpentanoic acid (19)
(a) Using DMP butyrate (15), aldol condensation under stan-
dard conditions provided the aldol in 93% yield after preparative
hplc (20% ether/hexane, R/= 0.33). tH-NMR (CDCI3):
8 1.07
(9H, m), 2.17 (6H, s), 3.50 (2H, m), 7.00 (3H, s). This ester was
hydrolyzed using the standard conditions to give acid 19 in 74%
yield. IR (film): 3400-2500, 1700, 1460, 1200, 990cm-~; ~H-NMR
(CDCh): 8 1.00 (9H, m), 1.65 (2H, m), 2.50 (IH, br q, J = 7), 3.40
(lH, t,J=6), 5.30 (2H, m); ~C-NMR: 8 179.9, 76.9, 49.7, 31.6,
22.0, 19.4, 17.1, 11.6. (Found: C, 59.68; H, 10.35. Calc. for
CsH~6Os: C, 59.98; H, 10.07%).
(b) Using DBHA butyrate (16) the aldol was obtained in 68%
yield after preparative hplc (20% ether/hexane, R! = 0.29). This
material crystallized and was recrystallized from hexane, m.p.
75-76°. If this aldol was trapped as its acetate, the yield was 60%
after preparative hplc (10% ether/hexane, Rt = 0.17). IR (film):
3550, 1730, 1600, 1415, 1360, 1300, 1260, 1200, 1069cm-~; ~H-
NMR (CDCh): ~5 0.97 (3H, d , J = 7 ) , 1.00 (3H, d , J = 7 ) , 1.10
(3H,t,J=7), 1.34 (18H, s), 2.00 (2H, m), 2.80 (IH, m), 3.45
(IH, m), 3.73 (3H, s), 6.80 (2H, s); 13C-NMR: 8 175.8, 111.7, 75.3,
59.4, 55.0, 31.3, 21.1, 20.1, 17.6, 12.3 (Found: C, 72.81; H, 9.87.
Calc. for C~HssO4: C, 72.98; H, 10.11%). Acetate ]H-NMR
(CDCI3):/~ 0.93 (3H, t, J = 7). !.13 (6H, d, J = 7), 1.34 (18H, s), 2.00
(3H, s), 2.75 (IH, m), 3.72 (3H, s), 5.00 (IH, dd,J=4,8), 6.78
(2H, s).
Acknowledgements--This work was supported by a grant from
the United States Public Health Service (AI-15027). M.C.P. ac-
knowledges the Fannie and John Hertz Foundation for financial
assistance in the form of a fellowship.
The hydroxy acid was obtained by CAN oxidation under the
standard conditions in 35% yield from the hydroxy ester and in
85% yield from the acetoxy ester.
R
E F E R E N C E S
2',6'
- Dimethylphenyl (2SR,3SR) - and (2SR,3RS) - 3 -
~For paper 12 in this series see C. H. Heathcock, M. C. Pirrung,
C. T. Buse, S. D. Young and J. Lampe, J. Org. Chem. 46, 2290
(1981).
2A portion of this work has been communicated in preliminary
form: °C. H. Heathcock, William H. Nichols Medal Award
Meeting, 14 March 1980. Marymount College, Tarrytown, New
Y o r k . . C . H . Heathcock and M. C. Pirrung, J. Org. Chem. 45,
1727 (1980).
hydroxy - 2 - tetradecyloctadecanoate (26 and 27): To a soln of
diisopropylamine (0.37 mL, 0.27 g, 2.6 mmol) in 2 mL of THF at
-200 was added 1.47mL (2.21 mmol) of a 1.50M soln of n-BuLi
in hexane. The soln was cooled to - 78°, a soln of 2',6'-dimethyl-
phenyl hexadecanoate (0.721 g, 2.00retool) in 3mL THF was
added, and the mixture was stirred for 10112hr.
A soln of
hexadecanal (0.471 g, 1.96 retool) in 2 mL THF was added, and
the mixture was stirred for I hr. The reaction was quenched with
5mL sat NI'hCI aq and taken up in 2:1 etherlhexane. The
organic phase was washed with water, dried over MgSO,, and the
solvents evaporated to give 0.977 g of the crude aldol product as
a yellow oil. The crude product was purified by hplc, eluting with
aWe use cis and trans, rather than (Z) and (E), to describe
enolates because the latter terminology frequently leads to
confusion in discussing the enolates of esters.
~The stereochemical descriptors erythro and threo are employed
in the following sense: The main chain of the aldol is written in
an extended (zig-zag) fashion. If the bonds to the o-alkyl
substituent and the/]-hydroxy group both project either toward
or away from the viewer, this is the erythro-diastereomer.
5C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung,
I. Lampe and J. E. Sohn, J. Org. Chem. 45, 1066 (1980).
6C. H. Heathcock, M. C. Pirrung and J. E. Sohn, Ibid. 44, 4294
(1979).
5% ether/bexane, to give the aldols (0.509g, 43%) as
a pale
yellow oil. The product was shown by analytical hplc to be a
1.5 : 1 mixture of threo- and erythro-isomers 26 and 27. IR (film):
3500, 1750 cm-~; tH-NMR (CI)Ch): 8 6.90 (3H, s), 3.83 (IH, br s),
2.87-2.03 (2H, m), 2.13 (6H, s), 1.60--1.03 (54H, br s), 0.87 (6H, m).
(Found: C, 79.85; H, 11.96. Calc. for C¢Hr203: C, 79.94; H,
12.08%).
(2',6'- Bis(l" - Methylethyl)phenyl (2SR, 3SR) - and (2SR, 3RS)
- 3 - hydroxy - 2- tetradecyloctadecanoate (28 and 29): To a soln
of diisopropylamine (0.16 mL, 0.11 g, 1.1 mmol) in 2mL THF at
7A. Balsam, G. Ceccarelli, P. Crotti and F. Macclia, Ibid. 40, 473
0975).
Sp. Jacob, P. Caggery, A. Shulgin and N. Castagno]i, Ibid. 41,
-
10° was added a 1.50M soln of n-BuLi (0.74 mL, I.I mmol) in
3627 (197'76).
hexane. The soln was cooled to -78*, 2',6'-Bis(l'-methyl-
ethyl)phenyl bexadecanoate (0.419g, 1.01 retool) was added, and
9Recent work with other aldols has shown that higher overall
yields of acetate are obtained if the aldo] is first isolated, then
treated with LDA in THF, and acetic anhydride. In fact,
evidence is gradually accumulating that the lithium aldolate
produced in the aldol condensation differs from that produced
by reaction of thealdol with LDA in THF. The exactnature of
thesealdolatesis still unknown, and is the subjectof an active
investigation at Berkeley.
the mixture was stirred for 7hr.
A soln of hexadecanal
(0.240g, 1.00mmol) in 2mL THF was added, and the mixture
was stirred for 30 rain. The reaction was quenched with 65 p.L
glacial AcOH (one equiv) and the resulting mixture was taken up
in ether. The mixture was washed with water and brine, dried
over MgSO4, and the solvents evaporated to give 0.630g of the
~o~j. Asselineau, These Dr. Es-Sciences, University of Paris
(1950); Ed. Arnette: Paris (1951); bE. Lederer, A. Adain, R.
Ciorbaru, J. F. Petit and J. Wietzerbin, Mol. and Cell. Biochem.
7, 87 (1975).
HM. Hirama and S. Masamune, Tetrahedron Letters 2225 (1979).
t2D. A. Evans, E. Vogel and J. V. Nelson, J. Am. Chem. Soc.
I01, 6120 (1979).
crude aldols as
indicated that it was 50% condensed products. The crude
material was shown by analytical hplc to be 2.0:1 thr-
eo:erythro mixture. Preparative tic on 0.542g of the crude
material, eluting with 10% etherlhexane, gave 0.106 (19%) of a
pure sample. IR (CCh): 3550, 1740cm- I ; I H-NMR (CDCh):
7.13 (3H, s), 3.93 (IH, brs), 3.07-2.13 (4H,m), 1.70-1.03
a yellow oil, the "H-NMR spectrum of which
a