Synthetic Routes to Allenic Acids and Esters and Their Stereospecific Conversion to Butenolides

Article abstract of DOI:10.1021/jo9618740

The synthesis of allenic acids and esters and their conversion to butenolides has been examined in some detail. Racemic butenolides 10 are efficiently prepared from the esters 8 through treatment with BCl₃ and exposure of the derived acid 9 to catalytic AgNO₃ in acetone. Conversion of the enantioenriched allenylstannane (S)-17 to the acid 18 through lithiation and subsequent carboxylation with CO₂ afforded racemic product. The enantioenriched propargylic mesylates 16 and 22 afforded the allenic esters 19 and 23 with inversion of configuration through treatment with Pd(Ph₃P)₄, CO, and the appropriate alcohol in THF. These reactions proceeded with ca. 10% or less of racemization. The allenic esters 23 yielded the iodobutenolides 24 by reaction with IBr. Hydrogenolysis to the butenolide 25 was achieved with Pd(PPh₃)₄ and Bu3SnH. Alternatively, the allenic acids 27 could be prepared directly from mesylates 22 with Pd(PPh₃)₄ and CO in aqueous THF. Cyclization to the butenolides 25 was achieved, as before, with catalytic AgNO₃.

Full text of DOI:10.1021/jo9618740

J . Org. Chem. 1997, 62, 367-371
367
Syn th etic Rou tes to Allen ic Acid s a n d Ester s a n d Th eir
Ster eosp ecific Con ver sion to Bu ten olid es
J ames A. Marshall,* Mark A. Wolf, and Eli M. Wallace
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received October 3, 1996X
The synthesis of allenic acids and esters and their conversion to butenolides has been examined in
some detail. Racemic butenolides 10 are efficiently prepared from the esters 8 through treatment
with BCl3 and exposure of the derived acid 9 to catalytic AgNO3 in acetone. Conversion of the
enantioenriched allenylstannane (S)-17 to the acid 18 through lithiation and subsequent carboxyl-
ation with CO2 afforded racemic product. The enantioenriched propargylic mesylates 16 and 22
afforded the allenic esters 19 and 23 with inversion of configuration through treatment with
Pd(Ph3P)4, CO, and the appropriate alcohol in THF. These reactions proceeded with ca. 10% or
less of racemization. The allenic esters 23 yielded the iodobutenolides 24 by reaction with IBr.
Hydrogenolysis to the butenolide 25 was achieved with Pd(PPh3)4 and Bu3SnH. Alternatively, the
allenic acids 27 could be prepared directly from mesylates 22 with Pd(PPh3)4 and CO in aqueous
THF. Cyclization to the butenolides 25 was achieved, as before, with catalytic AgNO3.
In connection with ongoing projects relating to the
synthesis of furanocembrane, pseudopterolide, and An-
nonaceous acetogenin natural products1 we became in-
terested in developing versatile and efficient routes to
butenolides.2 The approach that we chose to explore was
based on our previous findings that allenylcarbinols 1/3
are smoothly and stereospecifically converted to 2,5-
dihydrofurans 2/4 upon treatment with catalytic AgNO3
in acetone, or supported on silica gel (eq 1).3
with BCl3.5 The resulting acids were smoothly converted
to the butenolides 10a , 10b, and 10c with 10% AgNO3
in acetone (eq 3).6
As an aside, saponification of the foregoing allenic
esters with LiOH led to mixtures of allenic acids and
alkynylacetic acids. In fact, when the sequence was
carried out with the monosubstituted allenic esters 11a
and 11b, obtained by treatment of acid chlorides 7a and
7b with methyl 2-(triphenylphosphoranylidene)acetate,
the alkynylacetic acids 12a and 12b were the sole isolable
saponification products. Interestingly, these acids were
efficiently converted to the labile enol lactones 13a and
13b by catalytic AgNO3 in acetone (eq 4).
Accordingly, we reasoned that allenic acids 5 might be
expected to follow a similar course to afford butenolides
6 (eq 2).
In the next stage of these investigations, we explored
possible routes to nonracemic allenic acids, as precursors
to enantioenriched butenolides. We had previously found
that chiral allenic stannanes of high ee could be prepared
through SN2′ displacement of enantioenriched propargylic
mesylates with a Bu3Sn cuprate reagent.3b It therefore
seemed worth attempting to convert such stannanes to
the related acids through lithiation and carboxylation.
To test this possibility we first prepared the racemic
stannane 17 and subjected it to MeLi followed by CO2.
This sequence led to the racemic allenic acid 18 in 64%
yield. Subsequently, enantioenriched alcohol 15 of 70%
ee was prepared by reduction of the ketone 14 with
To test the feasibility of this cyclization approach we
prepared the racemic allenic acids 9a , 9b, and 9c by
treatment of the acid chlorides 7a , 7b, and 7c with
methyl 2-(triphenylphosphoranylidene)propionate4 and
subsequent cleavage of the allenic esters 8a , 8b, and 8c
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) Cf. (a) Marshall, J . A.; Bartley, G. S.; Wallace, E. M. J . Org.
Chem. 1996, 61, 5729. (b) Marshall, J . A.; Hinkle, K. W. J . Org. Chem.
1996, 61, 4247.
(2) For a recent review, see: Knight, D. W. Contemp. Org. Synth.
1994, 1, 287.
(3) (a) Marshall, J . A.; Sehon, C. A. J . Org. Chem. 1995, 60, 5966.
(b) Marshall, J . A.; Yu, R. H.; Perkins, J . F. J . Org. Chem. 1995, 60,
5550.
(5) Manchand, P. S. J . Chem. Soc., Chem. Commun. 1971, 667.
(6) For other Ag(I)-catalyzed cyclizations leading to exocyclic enol
lactones, see: Pale, P.; Chuche, J . Tetrahedron Lett. 1987, 28, 6447.
Dalla, V.; Pale, P. Tetrahedron Lett. 1994, 35, 3525.
(4) Lang, R. W.; Hansen, H. J . Helv. Chim. Acta 1980, 63, 438.
S0022-3263(96)01874-9 CCC: $14.00 © 1997 American Chemical Society

368 J . Org. Chem., Vol. 62, No. 2, 1997
Marshall et al.
in satisfactory yield by exposure of the mesylates 22 to
CO and Pd(PPh3)4 in the presence of the alcohol (eq 8).
Evaluation of ee was possible through analysis of the
allenic ester product 23 or the derived iodobutenolide 24
(eq 9) by HPLC.
Chirald-LAH. The mesylate derivative 16 was converted
to the nonracemic allenylstannane 17, with inversion of
configuration. The assignment is based on our previous
findings.3b Treatment of stannane 17 with MeLi followed
by CO2 led to the allenic acid 18. The derived methyl
ester 19 was found to be racemic (eq 5).
Conversion of the propargylic mesylate 22b to allenic
esters 23d or 23e was highly enantioselective. The more
substituted analogue 22a , however, afforded allenic
esters 23a -c with partial racemization. This difference
may be related to the configurational stability of the
intermediate Pd species in the carbonylation reaction.11
It could also reflect a slightly lower rate of CO insertion
for this Pd species relative to the one derived from
mesylate 22a . The allenic esters 23a and 23b were
unaffected by prolonged exposure to the carbonylation
reaction conditions as determined by analysis of aliquots
removed during the course of the reaction and beyond.
The conversion of allenic esters 23 to the butenolides
25 via the allenic acids proved troublesome. Treatment
of ester 23c of ca. 90% ee with BCl3 and subsequent
exposure to AgNO3, as in eq 3, afforded butenolide 25a
of ca. 40% ee.9 An alternative protocol involving cleavage
of the TMSE ester 23b of 65% ee with TBAF followed by
esterification of the resulting acid with CH2N2 led to
allenic ester 23c of ca. 20% ee.
We next attempted to prepare ester 19 in nonracemic
form through methoxycarbonylation of the carbonate
derivative 20 of alcohol 15 following the procedure of
Tsuji et al.7 Treatment of this ester with CO in methanol-
benzene in the presence of catalytic Pd(PPh3)4 at 50-60
°C gave ester 19, but as a virtual racemate (eq 6).
In view of these unpromising results, we examined an
alternative two-step conversion of allenic esters 23 to the
butenolides 25. This could be efficiently accomplished
by iodolactonization with IBr and subsequent hydro-
genolysis (eq 9).10 The ee values of the intermediate
iodobutenolides 24, as determined by HPLC analysis,
were essentially identical to those of the starting allenic
esters 23. The iodobutenolides 24a -c were converted
to butenolides 25a -c through Pd(0)-catalyzed hydro-
genolysis with Bu3SnH.12
In view of the potential for Ph3P-catalyzed racemiza-
tion of allenic esters at elevated temperatures in the
foregoing carbonylation sequence,1a we explored the use
of the more reactive mesylate derivative 16 of alcohol 15.
We also increased the effective CO concentration by
conducting the reaction at higher pressure (200 psi). With
these modifications, we obtained ester 19 in high yield
and significant ee (eq 7).
The absolute stereochemistry of butenolide 25a was
determined through an unambiguous synthesis of the
enantiomer ent-25a from the (S) propargylic alcohol 21a
of established configuration and ee (eq 10).13,3b The
(9) In our preliminary work we determined the ee of ester 24c
through use of the Eu(hfc)3 shift reagent and integration of the vinylic
CH3 signals in the 1H NMR spectrum. The derived butenolide 25a could
likewise be analyzed through integration of the CH3 signals. Subse-
quent analysis by HPLC was in close agreement.
(10) Cf. Smith, A. B., III; Duan, J . J .-W.; Hull, K. G.; Salvatore, B.
A. Tetrahedron Lett. 1991, 32, 4855.
(11) Racemization of allenyl/propargyl Pd intermediates has previ-
ously been studied. Granberg, K. L.; Ba¨ckvall, J .-E. J . Am. Chem. Soc.
1992, 114, 6858.
Encouraged by these results, we examined a number
of representative propargylic mesylates with several
different participating alcohols. These experiments were
conducted with mesylates 22a -c derived from alcohols
21a -c of ∼95% ee. The alcohols were obtained through
reduction of the acetylenic ketones with (S)-BINAL-H.8
In all cases, enantioenriched allenic esters were formed
(12) Baillargeon, V. P.; Stille, J . K. J . Am. Chem. Soc. 1986, 108,
452.
(7) Tsuji, J . Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27, 731.
(8) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J . Am. Chem.
Soc. 1984, 106, 6709.
(13) Noyori has shown that (S) propargylic alcohols are formed
through reduction of acetylenic ketones with (S)-BINAL-H.8

Synthetic Routes to Allenic Acids and Esters
J . Org. Chem., Vol. 62, No. 2, 1997 369
optical rotation of the two enantiomeric lactones 25a and
ent-25a were nearly equal but of opposite signs. Accord-
ingly, the carbonylation reaction of mesylates 22 must
proceed by a net anti SE2′ process. The stereoselectivity
of this conversion was highest when minimal catalyst and
Ph3P ligand were employed.11 With 10 mol % Pd(PPh3)4,
significant erosion of ee was observed. Best results were
obtained with 1 mol % of catalyst.
Exp er im en ta l Section 16
(()-Meth yl 2-Meth yl-2,3-n on a d ien oa te (8a ). A modifi-
cation of the method of Lang and Hansen was employed.4
Triethylamine (1.16 g, 1.60 mL, 11.52 mmol) was added to a
stirred solution of methyl 2-(triphenylphosphoranylidene)-
propionate (3.68 g, 10.57 mmol) in CH2Cl2 (50 mL) in the
presence of 4 Å activated molecular sieves. Heptanoyl chloride
(1.41 g, 1.46 mL, 9.49 mmol) was added, and the reaction
mixture was stirred for 16 h. The reaction mixture was
concentrated under reduced pressure and triturated twice with
pentane. The residue was chromatographed on silica gel.
Elution with 5% ethyl acetate in hexanes gave 1.40 g (95%) of
allenic ester 8a as an oil: IR (film) 1959, 1718 cm-1; 1H NMR
δ 5.44 (tq, 1H, J ) 5.4, 2.9 Hz), 3.71 (s, 3H), 2.08 (q, 2H, J )
7.1 Hz), 1.84 (d, 3H, J ) 2.9 Hz), 1.42 (m, 2H), 1.31 (m, 4H),
0.87 (t, 3H, J ) 7.1 Hz); 13C NMR δ 210.0, 168.4, 95.2, 93.8,
51.9, 31.1, 28.4, 27.8, 22.4, 15.2, 14.0. Anal. Calcd for
C11H18O2: C, 72.49; H, 9.96. Found: C, 72.61; H, 10.00.
(()-2-Meth yl-2,3-n on a d ien oic Acid (9a ). A modification
of the method of Manchand was employed.5 To a solution of
allenic ester 8a (0.396 g, 2.176 mmol) in 20 mL of CH2Cl2 with
stirring at -78 °C was added 8.70 mL (8.70 mmol) of a 1.0 M
BCl3 solution in hexanes. After 5 min, the reaction mixture
was quenched by the addition of a 10% NaOH solution and
warmed to rt. The reaction mixture was extracted with Et2O,
and the aqueous layer was then acidified with 10% HCl. The
acidified aqueous layer was extracted with Et2O. The com-
bined Et2O extracts of the acidified aqueous layer were dried
over MgSO4 and concentrated under reduced pressure to give
0.314 g (86%) of acid 9a as an oil: IR (film) 3077, 1959, 1682
The correlation of butenolides 25a and ent-25a also
confirms that the hydrogenolysis of iodobutenolide 24a
proceeds without loss of ee. This conclusion is based on
the reasonable assumption that the sequence leading to
ent-25a does not affect the carbinyl stereocenter.
In a preliminary report of these results, we noted that
allenic acids could be prepared from mesylates 22 by
Pd(PPh3)4-catalyzed carbonylation in aqueous THF, but
only in low yield.14 However, by using minimal amounts
of Pd catalyst and elevated CO pressures, we have
considerably improved this process. Thus butenolide 25a
can be prepared in 62% overall yield with >90% enan-
tioselectivity from mesylate 22a by the two-step sequence
(eq 11). Unfortunately significant racemization is seen
with mesylates 22b (eq 11) and 16 (eq 12). In these two
cases, the three-step process via allenic esters 23d /e and
19 proceeds in comparable yield and with higher ee than
the direct hydroxycarbonylation-lactonization sequence.
In view of the ease with which nonracemic propargylic
alcohols can be prepared from alkynones through reduc-
tion with chiral hydrides8 or from chiral pool polyols,15
the propargyl mesylate methodology offers an attractive
route to nonracemic butenolides. Racemization is mini-
mized when the carbonylation step is performed in the
presence of alcohols to produce allenic esters. These can
be converted to iodobutenolides through iodolactoniza-
tion. Presumably, reactions other than hydrogenolysis
could be carried out on the vinylic iodide function, if
desired. Although the hydroxycarbonylation route to
butenolides such as 25 is more direct, it suffers from
partial racemization. Efforts to improve this process are
currently in progress.
1
cm-1; H NMR δ 5.51 (m, 1H), 2.08 (q, 2H, J ) 7.1 Hz), 1.83
(d, 3H, J ) 2.8 Hz), 1.43 (m, 2H), 1.30 (m, 4H), 0.87 (t, 3H, J
) 7.1 Hz); 13C NMR δ 211.2, 173.8, 95.2, 94.3, 31.1, 28.4, 27.7,
22.4, 14.8, 14.0. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59.
Found: C, 71.19; H, 9.62.
(()-4-Hydr oxy-2-m eth yl-2-n on en oic Acid Lacton e (10a).
To a solution of acid 9a (0.381 g, 2.27 mmol) in 10 mL of
acetone was added AgNO3 (0.077 g, 0.45 mmol) with stirring.
The reaction mixture was sealed under N2, the flask was
covered with foil, and stirring was continued for 16 h. The
mixture was then diluted with Et2O and dried over MgSO4.
Filtration of the solution through a pad of silica gel and
concentration of the filtrate under reduced pressure gave 0.343
(16) For a description of experimental protocols, see Marshall J . A.;
Wang, X-j. J . Org. Chem. 1991, 56, 960. Unless otherwise stated, 1H
and 13C NMR spectra were determined on dilute solutions of sample
in CDCl3 at 300 and 75 MHz, respectively.
(14) Marshall, J . A.; Wolf, M. A. J . Org. Chem. 1996, 61, 3238.
(15) Yadav, J . S.; Chandler, M. C.; Rao, C. S. Tetrahedron Lett. 1989,
30, 5455. Takano, S.; Yoshimitsu, T.; Ogasawara, K. Synlett 1994, 119.

370 J . Org. Chem., Vol. 62, No. 2, 1997
Marshall et al.
g (90%) of butenolide 10a as an oil that was pure according to
the 1H NMR spectrum. An analytical sample was obtained
by bulb to bulb distillation: bath 85 °C (1 mmHg); IR (film)
(5 mL) at -78 °C was added 0.38 mL of a 1.4 M solution of
MeLi in hexanes. After 20 min, CO2 was bubbled into the
reaction mixture. After 2 h, CO2 addition was stopped and
the reaction mixture warmed to rt, diluted with H2O, and
extracted with Et2O. The aqueous layer was acidified with
10% HCl and extracted with Et2O. The combined Et2O
extracts of the acidified aqueous layer were dried over MgSO4
and concentrated under reduced pressure to yield 0.033 g
(64%) of allenic acid 18 as an oil: IR (film) 3204, 2650, 1952,
1
2930, 1756, 1660, 1098 cm-1; H NMR δ 7.00 (q, 1H, J ) 1.6
Hz), 4.82 (m, 1H), 1.86 (t, 3H, J ) 1.8 Hz), 1.60 (m, 2H), 1.39
(m, 2H), 1.27 (m, 4H), 0.83 (t, 3H, J ) 7.0 Hz); 13C NMR (101
MHz, CDCl3) δ 174.4, 148.9, 129.7, 81.2, 33.4, 31.5, 24.7, 22.4,
13.9, 10.6. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59.
Found: C, 71.20; H, 9.44.
1
1679 cm-1; H NMR δ 5.57 (m, 1H), 4.59 (s, 2H), 3.53 (t, 2H,
(()-Meth yl 2,3-Non a d ien oa te (11a ). The procedure de-
scribed for allenic ester 8a was employed with 2.50 mL (2.40
g, 16.16 mmol) of heptanoyl chloride and 5.94 g (17.78 mmol)
of methyl (triphenylphosphoranylidene)acetate to afford 1.93
J ) 6.5 Hz), 3.33 (s, 3H), 2.27 (dt, 2H, J ) 7.8, 2.7 Hz), 2.09
(q, 2H, J ) 7.1 Hz), 1.72 (app p, 2H, J ) 7.1 Hz), 1.44-1.25
(m, 8H), 0.85 (t, 3H, J ) 6.8 Hz); 13C NMR (101 MHz, CDCl3)
δ 210.8, 172.8, 99.7, 96.3, 95.8, 67.0, 55.1, 31.5, 28.8, 28.7, 28.2,
27.9, 24.9, 22.6, 14.0. Anal. Calcd for C15H26O4: C, 66.63; H,
9.69. Found: C, 66.54; H, 9.65.
g (71%) allenic ester 11a as an oil: IR (film) 1959, 1723 cm-1
;
1H NMR (400 MHz, CDCl3) δ 5.56 (m, 2H), 3.71 (s, 3H), 2.11
(m, 2H), 1.44 (m, 2H), 1.30 (m, 4H), 0.87 (t, 3H, J ) 7.0 Hz);
13C NMR (101 MHz, CDCl3) δ 212.4, 166.7, 95.4, 87.8, 51.9,
31.0, 28.3, 27.4, 22.3, 14.0.
B. F r om En a n tioen r ich ed Allen yl Sta n n a n e 17. The
procedure described for allenic acid 18 was used with enantio-
enriched allenyl stannane 17 (70% ee). The ee of the derived
acid was determined by analysis of the methyl ester 19,
prepared as follows: To a solution of the foregoing sample of
allenic acid 18 (0.028 g, 0.104 mmol) in Et2O (2 mL) at 0 °C
was added CH2N2 (1.04 mmol) in Et2O (2 mL). After 1 h, the
cooling bath was removed, and N2 was bubbled through the
reaction mixture. The reaction mixture was dried over MgSO4
and concentrated under reduced pressure to give 0.029 g (98%)
of allenic ester 19 as an oil: 1H NMR δ 5.51 (m, 1H), 4.59 (s,
2H), 3.70 (s, 3H), 3.52 (t, 2H, J ) 6.5 Hz), 3.33 (s, 3H), 2.29
(dt, 2H, J ) 7.1, 2.8 Hz), 2.08 (q, 2H, J ) 7.1 Hz), 1.71 (app p,
2H, J ) 6.8 Hz), 1.44-1.23 (m, 8H), 0.86 (t, 3H, J ) 6.8 Hz);
[R]D 0.0 (CHCl3, c 1.0).
3-Non yn oic Acid (12a ). To a solution of allenic ester 11a
(0.227 g, 1.351 mmol) in a 1:1 mixture of THF-H2O (10 mL)
was added LiOH (0.162 g, 6.756 mmol). After 15 min, the
reaction mixture was diluted with H2O and extracted with
Et2O. The aqueous layer was acidified with 10% HCl and
extracted with Et2O. The combined Et2O extracts of the
acidified aqueous layer were dried over MgSO4 and concen-
trated under reduced pressure to give 0.167 g (80%) of acid
12a as an oil: IR (film) 3165, 1959, 1719 cm-1; 1H NMR δ 3.31
(t, 2H, J ) 2.5 Hz), 2.18 (m, 2H), 1.49 (m, 2H), 1.31 (m, 4H),
0.88 (t, 3H, J ) 7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 175.3,
87.7, 70.5, 31.0, 28.3, 25.9, 22.1, 18.7, 13.9.
4-Hyd r oxy-3-n on en oic Acid La cton e (13a ). The proce-
dure described for butenolide 10a was employed with acid 12a
(0.150 g, 0.974 mmol) to afford 0.142 g (95%) of enol lactone
13a as an oil: IR (film) 1799, 1755, 1668 cm-1; 1H NMR δ 5.08
(app p, 1H, J ) 1.2 Hz), 3.16 (q, 2H, J ) 2.3 Hz), 2.26 (dt, 2H,
J ) 7.6, 1.4 Hz), 1.54 (m, 2H), 1.30 (m, 4H), 0.88 (t, 3H, J )
7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 177.0, 157.2, 98.1, 33.9,
31.1, 28.1, 25.3, 22.3, 13.8.
Meth yl 2-[3-(Meth oxym eth oxy)pr opyl]-2,3-decadien oate
(19). A. F r om Ca r bon a te 20. A modification of the method
of Tsuji and co-workers was employed.7 To a purple mixture
of Pd2dba3 (0.028 g, 0.031 mmol) in C6H6 (1 mL) under argon
was added Ph3P (0.032 g, 0.123 mmol). The reaction mixture
was stirred for 5 min, after which time it had turned yellow.
A solution of carbonate 20 (0.184 g, 0.613 mmol, 70% ee) in 2
mL of 1:1 C6H6-MeOH was added. The reaction mixture was
placed under 1 atm of CO (balloon) and stirred for 4.5 h at 50
to 60 °C. The reaction mixture was cooled to rt, diluted with
Et2O, and filtered through a pad of Celite 545. The residue
was chromatographed on silica gel. Elution with 10% ethyl
acetate in hexanes gave 0.122 g (70%) of allenic ester 19 as
(R)-(+)-12-(Meth oxym eth oxy)d od ec-8-yn -7-ol (15). The
procedure of Marshall and Wang3b was employed to prepare
1.84 g (57%) of enantioenriched alcohol 15 from ketone 14 (3.16
g, 13.07 mmol): [R]25 +4.2 (CHCl3, c 1.20); IR (film) 3419,
D
2227, cm-1; H NMR δ 4.60 (s, 2H), 4.32 (tt, 1H, J ) 6.6, 2.0
1
Hz), 3.60 (t, 2H, J ) 6.2 Hz), 3.35 (s, 3H), 2.32 (tt, 2H, J )
7.1, 2.0 Hz), 1.77 (app p, 2H, J ) 6.5 Hz), 1.71-1.17 (m, 11H),
0.87 (t, 3H, J ) 6.9 Hz); 13C NMR (101 MHz, CDCl3) δ 96.2,
83.9, 82.0, 66.0, 62.4, 55.0, 38.1, 31.7, 28.9, 28.7, 25.1, 22.5,
an oil: [R]25 +1.1 (CHCl3, c 1.80). Anal. Calcd for C16H28O4:
D
C, 67.57; H, 9.92. Found: C, 67.53; H, 9.98
B. F r om Mesyla te 16. In a flame-dried, argon-flushed
flask, a solution of 0.0023 g (0.0025 mmol) of Pd2dba3 and
0.0026 g (0.01 mmol) of Ph3P in 2.5 mL of THF was stirred
under a stream of CO gas for ∼2 min. This Pd(0) solution
was transferred by syring to a Parr pressure reactor containing
0.160 g (0.50 mmol) of mesylate 16 (from alcohol 15 of 80%
ee) in 2.5 mL of THF, and then 0.41 mL (10.0 mmol) of MeOH
was added. The Parr reactor was charged with 200 psi of CO
gas. After stirring for 1 h at rt, the reaction was quenched
with brine and extracted with Et2O. The extracts were washed
with brine and dried over MgSO4. Following filtration and
concentration under reduced pressure, the crude residue was
purified by flash chromatography on silica gel to afford 0.121
g (85%) of allenic ester 19 as a yellow oil: [R]D +17.7 (CHCl3,
c 0.97). HPLC analysis on a Regis (R,R) Whelk-O column
showed 70% ee for this sample.
1
15.4, 14.0. The ee of this alcohol was found to be 70% by H
NMR analysis of the (R)-O-methylmandelate derivative through
integration of signals at 4.59, 4.56 ppm, 3.56, 3.49 ppm, and
2.30, 2.22 ppm.
(S)-(+)-1-(Met h oxym et h oxy)-4-(t r ib u t ylst a n n yl)-4,5-
d od eca d ien e (17). The procedure of Marshall and Wang3b
was employed to prepare enantioenriched stannane 17 from
alcohol 15 of 70% ee. To a flame-dried, argon-flushed, three-
necked flask equipped with a side arm charged with 3.30 g
(16.0 mmol) of CuBr‚SMe2 were added 2.49 mL (17.7 mmol)
of diisopropylamine and 40 mL of THF. To this stirring
solution at 0 °C was added 4.32 mL of Bu3SnH. After stirring
0.5 h, the reaction was cooled to -78 °C and the CuBr‚SMe2
was added. After 1 h at -78 °C, a solution of 2.70 g (8.45
mmol) of mesylate 16 in 5 mL of THF was added with stirring.
After 45 min at -78 °C, the reaction was quenched by pouring
into a stirring solution of NH4Cl-NH4OH (9:1). This mixture
was extracted with Et2O, and the extracts were dried over
MgSO4. Following filtration and concentration under reduced
pressure, the crude oil was purified by flash chromatography
on silica gel to afford 3.37 g (78%) of allenyl stannane 17 as a
(R)-(+)-Meth yl 1-Hexyl-6-(m eth oxym eth oxy)-2-h exyn -
yl Ca r bon a te (20). Alcohol 15 (0.20 g, 0.82 mmol) of 70% ee
was added to a stirred slurry of hexane-washed KH (0.400 g
of 35% KH by wt in oil) in THF (5 mL) and DMPU (1 mL) at
0 °C. After 1 h, methyl chloroformate (0.32 mL, 0.39 g, 4.10
mmol) was added and the reaction mixture was warmed to rt.
After 16 h, the reaction mixture was quenched with H2O and
diluted with Et2O. The layers were separated, and the Et2O
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was chromato-
graphed on silica gel. Elution with ethyl acetate in hexanes
colorless oil: [R]25D +59.1 (CHCl3, c 0.83); IR (film) 1930 cm-1
;
1H NMR δ 4.62 (m, 1H), 4.60 (s, 2H), 3.53 (t, 2H, J ) 6.6 Hz),
3.34 (s, 3H), 2.09 (dt, 2H, J ) 4.9, 3.0 Hz), 1.90 (q, 2H, J ) 7.1
Hz), 1.72 (p, 2H, J ) 7.3 Hz), 1.51-0.85 (m, 38H); 13C NMR
(101 MHz, CDCl3) δ 202.2, 96.4, 92.5, 82.8, 67.3, 55.0, 31.8,
30.0, 29.7, 29.4, 29.2, 29.03, 29.03, 27.3, 22.7, 14.1, 13.7, 10.0.
2-[3-(Met h oxym et h oxy)p r op yl]-2,3-d eca d ien oic Acid
(18). A. F r om Ra cem ic Allen yl Sta n n a n e 17. To a stirred
solution of allenyl stannane 17 (0.099 g, 0.192 mmol) in THF
gave 0.19 g (76%) of carbonate 20 as an oil: [R]25 +54.7
D
(CHCl3, c 1.80); IR (film) 2242, 1748 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.13 (t, 1H, J ) 6.3 Hz), 4.55 (s, 2H), 3.73 (s, 3H),
3.53 (t, 2H, J ) 6.4 Hz), 3.29 (s, 3H), 2.28 (t, 2H, J ) 6.6 Hz),

Synthetic Routes to Allenic Acids and Esters
J . Org. Chem., Vol. 62, No. 2, 1997 371
1.72 (m, 4H), 1.39-1.23 (m, 8H), 0.82 (t, 3H, J ) 6.6 Hz); 13
C
of THF was added, followed by 0.088 mL (0.32 mmol) of
Bu3SnH. After 40 min at rt the mixture was extracted with
Et2O, washed with brine, and dried over MgSO4. After
filtration and concentration under reduced pressure, the crude
product was purified by flash chromatography on silica gel to
afford 0.058 g (96%) of butenolide 25a as a yellow oil: [R]D
-37.9 (CHCl3, c 0.33); IR (film) 3082, 1754, 1658 cm-1; 1H NMR
δ 6.89 (m, 10H, 4.90 (m, 1H), 2.18 (m, 2H), 1.31 (d, 3H, J )
7.0 Hz), 1.21 (m, 10H), 0.79 (t, 3H, J ) 7.0 Hz); 13C NMR 173.7,
148.7, 134.1, 77.3, 31.7, 29.2, 29.0, 27.4, 25.2, 22.7, 19.3, 14.1.
Anal. Calcd for C12H20O2: C, 73.43; H, 10.27. Found: C,
73.30; H, 10.22. HPLC analysis on a Chiracel OB-H column
showed 84% ee for this sample.
NMR (101 MHz, CDCl3) δ 155.0, 96.3, 86.1, 77.5, 68.6, 65.9,
55.0, 54.7, 35.0, 31.6, 28.7, 28.5, 24.8, 22.5, 15.5, 14.0.
(S)-1-Meth yl-2-d ecyn yl Meth a n esu lfon a te (22a ). To a
solution of 0.84 g (0.50 mmol) of (S)-3-undecyn-2-ol of 95% ee3b
in 3.3 mL of CH2Cl2 at -78 °C were added 0.14 mL (1.0 mmol)
of Et3N and 0.06 mL (0.75 mmol) of methanesulfonyl choride.
After stirring for 1 h, the reaction was quenched with
saturated NaHCO3 and extracted with Et2O. The extracts
were washed with saturated NaHCO3 and brine and dried over
MgSO4. After filtration, the extract was concentrated under
reduced pressure and used directly: 1H NMR δ 5.20 (tq, 1H,
J ) 6.9, 1.8 Hz), 3.01 (s, 3H), 2.14 (dt, 2H, J ) 6.9, 1.4 Hz),
1.52 (d, 3H, J ) 6.9 Hz), 1.45-1.17 (m, 13H).
B. F r om Mesyla te 22a . In a flame-dried, argon-flushed
flask, a solution of 6.4 mg (0.0070 mmol) of Pd2dba3 and 0.014
g (0.056 mmol) of Ph3P in 7.0 mL of THF was stirred under a
stream of CO gas for ∼2 min. This Pd(0) solution was
transferred by syringe to a Parr pressure reactor containing
0.342 g (1.39 mmol) of mesylate 22a in 7.0 mL of THF, and
then 1.0 mL of water was added. The Parr reactor was
charged with 200 psi of CO gas. After 1 h at rt, the gas was
vented and the mixture was extracted with EtOAc, washed
with brine (2×), and dried over MgSO4. After filtration, the
extract was concentrated under reduced pressure at rt afford-
ing acid 27a which was used directly.
(R)-2-(Tr im eth ylsilyl)eth yl 2-n -Heptyl-2,3-pen tadien oate
(23b). In a flame-dried, argon-flushed flask, a solution of 0.031
g (0.12 mmol) of Ph3P, 0.014 g (0.015 mmol) of Pd2dba3, and
0.090 g (0.65 mmol) of K2CO3 in 4.0 mL of THF was stirred
for 5 min at rt with an attendant color change from violet to
yellow. The mixture was placed under a CO atmosphere
(balloon), and a solution of 0.15 g (0.59 mmol) of mesylate 22b
in 1.9 mL of THF and 0.42 mL (2.95 mmol) of 2-(trimethyl-
silyl)ethanol was added; a progressive color change from yellow
to red to green was observed. After stirring for 1 h at rt under
CO, the reaction was quenched with water and extracted with
hexanes. The extracts were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure to
a volume of ∼6 mL. This solution was purified by flash
chromatography to afford 0.14 g (80%) of ester 23b as a yellow
oil: IR (film) 2923, 1954, 1708 cm-1; 1H NMR δ 5.45 (m, 1H),
4.24 (ddd, 2H, J ) 8.98, 5.68, 2.01 Hz), 2.20 (m, 2H), 1.75 (d,
3H, J ) 7.15 Hz), 1.44-1.22 (m, 10H), 1.03-0.84 (m, 5H), 0.04
(s, 9H); 13C NMR δ 210.3, 167.9, 100.2, 89.5, 62.9, 31.8, 29.1,
29.0, 28.5, 28.0, 22.6, 17.2, 14.1, 13.4, -1.5; [R]D -19.2 (CHCl3,
c 0.64).
The above acid was dissolved in 14 mL of hexanes, and the
flask was covered in aluminum foil to exclude light. To this
was added 0.47 g (0.28 mmol) of 10% AgNO3 on silica gel. After
stirring for 0.5 h, the reaction mixture was filtered through
Celite. The filtrate was washed with saturated NaHCO3 and
brine and dried over MgSO4. Following filtration and concen-
tration under reduced pressure, the crude product was purified
by flash chromatography to afford 0.168 g (62%) of butenolide
25a as a yellow oil: [R]D -41.1 (CHCl3, c 0.76). HPLC analysis
on a Chiracel OB-H column showed 90% ee for this sample.
(R)-Meth yl 2-n -Hep tyl-2,3-p en ta d ien oa te (23c). In a
flame-dried, argon-flushed flask, a solution of 2.0 mg (0.0022
mmol) of Pd2dba3 and 2.3 mg (0.0088 mmol) of Ph3P in 2.2
mL of THF was stirred under a stream of CO gas for ∼2 min.
This Pd(0) solution was transferred by syringe to a Parr
pressure reactor containing 0.108 g (0.44 mmol) of mesylate
22a in 2.2 mL of THF, and then 0.36 mL of MeOH was added.
The Parr reactor was charged to 200 psi with CO gas. The
mixture was stirred for 1 h at rt, the gas was vented, and the
residue was extracted with Et2O, washed with brine, and dried
over MgSO4. Following filtration and concentration under
reduced pressure, the crude product was purified by flash
chromatography on silica gel to afford 0.079 g (86%) of ester
23c as a colorless oil: IR (film) 2927, 1958, 1718, 1436, 1270,
(S)-5-Meth yl-3-n -h ep tyl-2(5H)-fu r a n on e (en t-25a ). In a
flame-dried and argon-flushed flask, a solution of 0.077 g (0.29
mmol) of Ph3P and 0.034 g (0.037 mmol) of Pd2dba3 in 0.74
mL of THF was stirred for 10 min at rt. To the resulting
yellow-violet solution was added a solution of vinyl iodide 26
in 1.0 mL of THF. A color change from yellow-violet to red
was observed. The reaction mixture was place under a CO
atmosphere (balloon) and stirred for 25 h. The mixture was
diluted with hexanes, washed with water and brine, and dried
over MgSO4. After filtration and concentration under reduced
pressure, the crude product was purified by flash chromatog-
raphy to afford 0.048 g (33%) of butenolide ent-25a ; [R]D +43.8
(CHCl3, c 0.63).
1
1130, 1085, 799 cm-1; H NMR δ 5.47 (m, 1H), 3.71 (s, 3H),
(S,Z)-4-Iod o-3-u n d ecen -2-ol (26). To a solution of 0.37 g
(2.0 mmol) of alcohol 21a in 5.7 mL of THF at rt under a
nitrogen atmosphere was added 0.97 mL (3.3 mmol) of 3.4 M
Red-Al in toluene. After stirring overnight, the reaction
mixture was cooled to -78 °C and 0.84 g (3.3 mmol) of iodine
was added. After stirring for 20 min at -78 °C, the reaction
mixture was diluted with Et2O, washed with saturated Na2S2O3
and brine, and dried over MgSO4. After filtration and con-
centration under reduced pressure, the crude product was
purified by flash chromatography to afford 0.24 g (41%) of iodo
alcohol 26 as a colorless oil: [R]D 0.0 (CHCl3, c 0.35).
2.19 (m, 2H), 1.74 (d, 3H, J ) 7.2 Hz), 1.40-1.26 (m, 10H),
0.86 (t, 3H, J ) 6.9 Hz); 13C NMR δ 210.4, 168.1, 99.8, 89.6,
51.9, 31.8, 29.08, 28.97, 28.4, 28.0, 22.6, 14.0, 13.3; [R]D -16.6
(CHCl3, c 0.32). This ester showed a single peak on both of
the aforementioned HPLC columns.
(R)-5-Meth yl-3-n -h ep tyl-4-iod o-2(5H)-fu r a n on e (24a ).
To a solution of 0.070 g (0.33 mmol) of allenic ester 23c in 3.3
mL of CH2Cl2 at -78 °C was added 0.50 mL of 1.0 M iodine
monobromide in CH2Cl2. After being stirred for 1 h at -78
°C, the reaction was quenched with water and extracted with
CH2Cl2. The extracts were washed with saturated Na2S2O3
and dried over MgSO4. After filtration and concentration
under reduced pressure, the crude product was purified by
flash chromatography on silica gel to afford 0.103 g (97%) of
iodobutenolide 23a as a yellow oil: [R]D 0.0 (CHCl3, c 1.04);
Ack n ow led gm en t. This work was supported by
research grants R01-GM39998 and R01-GM29475 from
the National Institutes of General Medical Sciences.
1
IR (film) 2917, 1763, 1641 cm-1; H NMR δ 4.92 (q, 1H, J )
6.8 Hz), 2.32 (t, 2H, J ) 7.3 Hz), 1.49 (d, 3H, J ) 6.8 Hz),
1.36-1.23 (m, 10H), 0.88 (t, 3H, J ) 6.6 Hz); 13C NMR 169.7,
139.0, 122.2, 82.2, 31.7, 29.3, 29.0, 27.4, 27.1, 22.7, 19.5, 14.1.
Anal. Calcd for C12H19O2I: C, 44.74; H, 5.94. Found: C, 44.81;
H, 5.93. HPLC analysis on a Regis (R,R) Whelk-O column
showed 85% ee for this sample.
(R)-5-Meth yl-3-n -h eptyl-2(5H)-fu r an on e (25a). A. Fr om
Iod obu ten olid e 24a . In a flame-dried, argon-flushed flask,
a solution of 5.7 mg (0.0062 mmol) of Pd2dba3 and 3 mg (0.050
mmol) of Ph3P in 2.1 mL of THF was stirred for ∼5 min. A
solution of 0.10 g (0.31 mmol) of iodobutenolide 24a in 1.0 mL
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
9b, 9c, 11a , 12a , 13a , 13b, 15, 15 (mandelate), 17, 20, 22a ,
22b, 22c, 23b, 23f, 24c, 25b, 25c, 26, 28, 29. Experimental
procedures for 8b, 8c, 9b, 9c, 10b, 10c, 11b, 12b, 13b, 15,
17, 22b, 22c, 23a , 23d , 23e, 23f, 24b, 24c, 25b, 25c, 28, 29
(31 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O9618740