Studies on the synthesis of pinnaic acid and halichlorine. Stereoselective preparation of a (Z)-δ-chloro-γ,δ-unsaturated-β-keto phosphonate as a side chain synthon

Full text of DOI:10.1021/jo980904r

J . Org. Chem. 1998, 63, 6739-6741
6739
Ch a r t 1
Stu d ies on th e Syn th esis of P in n a ic Acid
a n d Ha lich lor in e. Ster eoselective
P r ep a r a tion of a
(Z)-δ-Ch lor o-γ,δ-u n sa tu r a ted -â-k eto
P h osp h on a te a s a Sid e Ch a in Syn th on
Stephen P. Keen and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania 16802
Received May 11, 1998
Pinnaic acid (1a ) and tauropinnaic acid (1b) (Chart 1)
are newly discovered marine alkaloids produced by the
Okinawan bivalve Pinna muricata.1a A structurally
related compound, halichlorine (2), was isolated by the
same research group from the marine sponge Halichon-
dria okadai Kadota.1b The relative stereochemistry of
these metabolites was established by NMR methods,
except for the configuration at the hydroxyl-bearing C17
of 1a /b, which is at present indeterminate. Moreover,
pinnaic acid and halichlorine appear to be epimeric at
C14, although these assignments are characterized as
being only tentative at this point.2 The absolute stere-
ochemistry of halichlorine was recently determined by
chemical correlation of a degradation product,1c and one
might reasonably assume that pinnaic acid has the same
configuration. Pinnaic acid and tauropinnaic acid were
found to have activity against phospholipase A2. This
sort of enzyme inhibitor has potential in the treatment
of inflammation. Moreover, halichlorine was found to be
an active inhibitor of VCAM-1 (vascular cell adhesion
molecule-1). Such compounds are potentially useful in
treatment of atherosclerosis, angina, and coronary artery
disease.
We have recently been interested in devising a route
for total synthesis of these unique molecules and consid-
ered the possibility of a convergent appoach for introduc-
tion of the C15-C21 chlorinated divinyl alcohol chain via
a Wadsworth-Emmons-Horner reaction of an aldehyde
with a highly fuctionalized unsaturated keto phosphonate
like 3. This strategy also appeared attractive since it
would potentially allow control of the double bond
geometry at both olefinic sites.3 It might be noted that
we had some initial concerns regarding the possibility
that a keto phosphonate such as 3, or one of its synthetic
precursors, might be prone to undergo facile elimination
of HCl and/or ROH or to 1,4-addition/elimination pro-
cesses.4 In this note we report that this type of Wads-
worth-Emmons-Horner synthon can in fact be easily
prepared and smoothly undergoes the desired stereose-
lective coupling with aldehydes.
ylated to afford 5-hydroxy-2-pentynoic acid (5) (Scheme
1).5 Stereoselective additions of HCl to propiolic acid and
its esters have been previously reported,6 but additions
to higher homologues have received little attention.7,8 We
have found that the procedure of Kurtz et al.,6a which
has been used for CuCl-catalyzed addition of HCl to
simple propiolic acid derivatives, when applied to acid 5
stereoselectively affords the desired Z adduct 6 (anti
addition), thus providing very simple access to the correct
trisubstituted vinyl chloride stereochemistry. The ge-
1
ometry of 6 was established by a H NMR NOE experi-
ment.
To further test the generality of this methodology,
2-heptynoic acid (7) was subjected to similar reaction
conditions, affording Z adduct 8, along with only a trace
of the E isomer (>20:1 from 1H NMR) (eq 1 of Scheme
1). In this case dioxane was needed as a cosolvent to help
dissolve the substrate.
Continuing the sequence, hydroxy acid 6 was bis-
silylated to afford 9, which upon basic hydrolysis gave
acid TBS ether 10 (Scheme 2). This acid could then be
converted to the corresponding N-methoxy-N-methyl
amide 11.9 Addition of dimethyl (lithiomethyl)phospho-
nate10 to amide 11 gave an inseparable ∼2:3 mixture of
the desired product 14 and the corresponding acetylenic
keto phosphonate 13 formed by loss of HCl. However,
use of the corresponding Grignard reagent 12, prepared
by exchange of the lithium compound with MgBr2,11 led
to the requisite â-keto phosphonate 14 in good yield,
(5) Adams, M. A.; Duggan, A. J .; Smolanoff, J .; Meinwald, J . J . Am.
Chem. Soc. 1979, 101, 5364. Hydroxy acid 5 has previously been
prepared by a similar but less convenient route: Haynes, L. J .; J ones,
E. R. H. J . Chem Soc. 1946, 503. Haynes, L. J .; J ones, E. R. H. J .
Chem Soc. 1946, 954.
(6) (a) Kurtz, A. N.; Billups, W. E.; Greenlee, R. B.; Hamil, H. F.;
Pace, W. T. J . Org. Chem. 1965, 30, 3141. (b) Grandjean, D.; Pale, P.;
Chuche, J . Tetrahedron 1993, 49, 5225. (c) Ma, S.; Lu, X.; Li, Z. J .
Org. Chem. 1992, 57, 709.
The synthesis commenced with commercially available
3-butyn-1-ol (4), which could be lithiated and carbox-
(7) Shinada, T.; Yoshihara, K. Chem. Pharm. Bull. 1996, 44, 264.
Application of this procedure to acetylenic acid 5 gave a complex
mixture.
(1) (a) Chou, T.; Kuramoto, M.; Otani, Y.; Shikano, M.; Yazawa, K.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3871. (b) Kuramoto, M.; Tong,
C.; Yamada, K.; Chiba, T.; Hayashi, Y.; Uemura, D. Tetrahedron Lett.
1996, 37, 3867. (c) Arimoto, H.; Hayakawa, I.; Kuramoto, M.; Uemura,
D. Tetrahedron Lett. 1998, 39, 861.
(8) For stereoselective additions of HI to propiolates and higher
homologues see: Meyer, C.; Marek, I.; Normant, J .-F. Synlett 1993,
386. Marek, I.; Alexakis, A.; Normant, J .-F. Tetrahedron Lett. 1991,
32, 5329. Marek, I.; Meyer, C.; Normant, J .-F. Org. Synth. 1996, 74,
194. Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J . Chem. 1994,
72, 1816.
(2) See footnote 6 in ref 1c.
(3) Geometrically pure cross-conjugated dienones have been previ-
ously made by this type of coupling. See for example: Friesen, R. W.;
Blouin, M. J . Org. Chem. 1996, 61, 7202 and references cited.
(4) Cf.: Vedejs, E.; Bershas, J . P. Tetrahedron Lett. 1975, 1359.
(9) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. For
a review see: Sibi, M. Org. Prep. Proc. Int. 1993, 25, 15.
(10) Theisen, P. D.; Heathcock, C. H. J . Org. Chem. 1988, 53, 2374.
(11) Hoffmann, R. W.; Ditrich, K. Liebigs Ann. Chem. 1990, 23.
S0022-3263(98)00904-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/25/1998

6740 J . Org. Chem., Vol. 63, No. 19, 1998
Notes
The stirred solution was cooled to -40 °C, and n-butyllithium
(100 mL, 2.56 M in hexanes, 256 mmol) was then added
dropwise. Once the addition was complete, the reaction mixture
was stirred at -40 °C for 1 h and carbon dioxide gas was then
bubbled through the pale yellow suspension for 1 h, maintaining
the temperature at -40 °C. The resulting reaction mixture was
poured onto crushed dry ice (20 g), acidified with 6 M aqueous
HCl (40 mL), and then extracted with EtOAc (2 × 50 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. The oily solid isolated was washed with CH2Cl2 (2 ×
15 mL) to give acid 5 (9.22 g, 63%) as a beige solid (mp 54-56
°C): IR (Nujol mull) 3650-2400, 2240, 1700 cm-1; 1H NMR (300
MHz, acetone-d6) δ 3.71 (t, J ) 6.5 Hz, 2 H), 2.56 (t, J ) 6.5 Hz,
2 H); 13C NMR (75 MHz, acetone-d6) δ 154.4, 87.4, 74.7, 60.2,
Sch em e 1
23.2; CIMS m/z (relative intensity) 115 (MH+, 22), 97 (MH+
-
H2O, 100).
Sch em e 2
P r ep a r a tion of (Z)-3-Ch lor o-5-h yd r oxyp en t-2-en oic Acid
(6). To a solution of acid 5 (1.98 g, 17.4 mmol) in concentrated
HCl (9 mL) was added CuCl (345 mg, 3.5 mmol). After being
stirred at room temperature for 15 h, the reaction mixture was
diluted with water (20 mL). The aqueous solution was then
washed with CH2Cl2 (5 × 20 mL) and extracted with EtOAc (5
× 20 mL). The combined organic extracts were washed with
brine (40 mL), dried (MgSO4), and concentrated in vacuo to yield
acid 6 (1.57 g, 60%) as a viscous yellow oil: IR (neat) 3650-
2400, 1704, 1641 cm-1 1H NMR (300 MHz, acetone-d6) δ 6.21
;
(t, J ) 0.9 Hz, 1 H), 3.81 (t, J ) 6.1 Hz, 2 H), 2.68 (td, J ) 6.1,
0.9 Hz, 2 H); 13C NMR (75 MHz, acetone-d6) δ 164.9, 147.6, 118.9,
59.4, 44.9; CIMS m/z (relative intensity) 151 (MH+, 100), 133
(MH+ - H2O, 70).
Ad d ition of HCl to Hep t-2-yn oic Acid (7). To a solution
of acid 7 (1.07 g, 8.5 mmol) in 1,4-dioxane (3 mL) was added
CuCl (166 mg, 1.7 mmol) and concentrated HCl (4.5 mL). After
being stirred at room temperature for 30 h, the reaction mixture
was diluted with water (20 mL) and then extracted with EtOAc
(3 × 20 mL). The combined organic extracts were washed with
brine (2 × 20 mL), dried (MgSO4), and concentrated in vacuo to
yield acid 8 (0.90 g, 66%, Z:E > 20:1) as a colorless oil: IR (neat)
3500-2400, 1698, 1633 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.06
(s, 1 H), 2.48 (t, J ) 7.4 Hz, 2 H), 1.69-1.57 (m, 2 H), 1.42-1.31
(m, 2 H), 0.94 (t, J ) 7.3 Hz, 3 H); 13C NMR (91 MHz, CDCl3) δ
169.5, 153.8, 115.5, 41.2, 29.2, 21.6, 13.6.
P r ep a r a tion of ter t-Bu tyld im eth ylsilyl (Z)-5-(ter t-Bu -
tyld im eth ylsiloxy)-3-ch lor op en t-2-en oa te (9). To a solution
of acid 6 (1.31 g, 8.7 mmol) and imidazole (2.42 g, 35.6 mmol) in
DMF (9 mL) was added tert-butyldimethylsilyl chloride (2.75 g,
18.2 mmol). The resulting solution was stirred for 15 h, poured
into water (50 mL), and then extracted with hexanes (3 × 50
mL). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo to yield silyl ester 9 (2.82 g, 86%) as a
contaminated with only a trace (∼6%) of the alkynyl keto
1
phosphonate as determined by H NMR.
We have tested the behavior of this keto phosphonate
in a Wadsworth-Emmons-Horner reaction. Thus, using
the condensation conditions developed by Roush and
Masamune,12 with employment of cyclohexanecarboxal-
dehyde as a model, 14 could be converted to dienone 15,
formed exclusively as the Z,E-stereoisomer. In addition,
dienone 15 can be cleanly reduced13 to yield the divinyl
alcohol 16, which is stable to chromatography and normal
handling procedures.
In summary, the well-behaved (Z)-δ-chloro-γ,δ-unsat-
urated-â-keto phosphonate 14 can be prepared in a short
sequence from acetylenic acid 5. This compound under-
goes stereoselective Wadsworth-Emmons-Horner con-
densation with an aldehyde and is a potentially useful
synthon for construction of the C15-C21 dienol segment
of pinnaic acid and halichlorine.
colorless oil: IR (neat) 1715, 1692, 1637 cm-1 1H NMR (300
;
MHz, CDCl3) δ 6.08 (s, 1 H), 3.85 (t, J ) 6.0 Hz, 2 H), 2.62 (t, J
) 6.0 Hz, 2 H), 0.95 (s, 9 H), 0.88 (s, 9 H), 0.30 (s, 6 H), 0.05 (s,
6 H); 13C NMR (75 MHz, CDCl3) δ 163.7, 146.6, 119.9, 59.7, 44.5,
25.8, 25.5, 18.2, 17.5, -4.8, -5.5; CIMS m/z (relative intensity)
379 (MH+, 100), 321 (MH+ - Me3CH, 44).
P r ep a r a tion of (Z)-5-(ter t-Bu tyld im eth ylsiloxy)-3-ch lo-
r op en t-2-en oic Acid (10). To a solution of silyl ester 9 (2.27
g, 6.0 mmol) in THF (15 mL) and MeOH (45 mL) was added 1
M aqueous K2CO3 (13 mL, 13 mmol). After being stirred for 1
h, the reaction mixture was diluted with brine (50 mL), cooled
to 0 °C, and then acidified by addition of 1 M aqueous KHSO4
(40 mL). The resulting cloudy mixture was extracted with ether
(3 × 50 mL), and the combined organic extracts were dried
(MgSO4) and concentrated in vacuo to yield acid 10 (1.58 g,
100%) as a colorless semisolid: IR (neat) 3400-2300, 1698, 1634
cm-1; 1H NMR (300 MHz, CDCl3) δ 6.13 (s, 1 H), 3.87 (t, J ) 6.0
Hz, 2 H), 2.66 (t, J ) 6.0 Hz, 2 H), 0.89 (s, 9 H), 0.06 (s, 6 H);
13C NMR (75 MHz, CDCl3) δ 169.0, 150.1, 117.5, 59.8, 44.8, 25.8,
18.2, -5.5; CIMS m/z (relative intensity) 265 (MH+, 56), 247
(MH+ - H2O, 20), 207 (MH+ - Me3CH, 42), 145 (88), 89 (100).
P r epar ation of (Z)-5-(ter t-Bu tyldim eth ylsiloxy)-3-ch lor o-
N-m eth oxy-N-m eth ylp en t-2-en a m id e (11). A solution of 1,1′-
carbonyldiimidazole (972 mg, 6.0 mmol) in CH2Cl2 (10 mL) was
added, via a cannula, to a stirred solution of acid 10 (1.57 g, 5.9
mmol) in CH2Cl2 (5 mL). The resulting solution was stirred for
1 h, and N,O-dimethylhydroxylamine hydrochloride (589 mg, 6.0
Exp er im en ta l Section
P r ep a r a tion of 5-Hyd r oxyp en t-2-yn oic Acid (5). 3-Bu-
tyn-1-ol (4, 8.98 g, 128 mmol) and THF (250 mL) were added to
a 500 mL three-necked flask equipped with a mechanical stirrer.
(12) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(13) Luche, J .-L.; Rodriguez-Hahn, L.; Crabbe, P. J . Chem. Soc.,
Chem. Commun. 1978, 601.

Notes
J . Org. Chem., Vol. 63, No. 19, 1998 6741
mmol) was then added. After being stirred for a further 15 h,
the reaction mixture was diluted with ether (75 mL) and washed
sequentially with 0.1 M aqueous HCl (60 mL), saturated aqueous
NaHCO3 (2 × 25 mL), and brine (25 mL). The organic layer
was dried (MgSO4) and concentrated in vacuo to yield a yellow
oil. Purification of this material by flash column chromatogra-
phy (1:1 ether/hexanes) afforded amide 11 (1.09 g, 60%) as a
colorless oil: IR (neat) 1666 cm-1; 1H NMR (300 MHz, CDCl3) δ
6.47 (br s, 1 H), 3.87 (t, J ) 6.1 Hz, 2 H), 3.68 (s, 3 H), 3.24 (s,
3 H), 2.64 (t, J ) 6.1 Hz, 2 H), 0.89 (s, 9 H), 0.06 (s, 6 H); 13C
NMR (75 MHz, CDCl3) δ 164.6, 142.8, 117.4, 61.4, 59.8, 44.1,
31.8, 25.7, 18.0, -5.6; CIMS m/z (relative intensity) 308 (MH+,
100), 250 (MH+ - Me3CH, 26).
P r ep a r a tion of Dim eth yl (Z)-6-(ter t-Bu tyld im eth ylsi-
loxy)-4-ch lor o-2-oxoh ex-3-en ylph osph on ate (14). To a stirred
solution of dimethyl methylphosphonate (190 mg, 1.53 mmol)
in THF (15 mL) was added n-butyllithium (0.61 mL, 2.5 M in
hexanes, 1.53 mmol) at -78 °C. After the mixture was stirred
for 1 h at -78 °C, a solution of magnesium bromide-diethyl
etherate (442 mg, 1.71 mmol) in ether (15 mL) was added. The
cooling bath was removed, and the cloudy reaction mixture was
stirred for 10 min. The resulting clear solution was recooled to
-78 °C, and a solution of amide 11 (235 mg, 0.76 mmol) in THF
(10 mL), cooled to -78 °C, was added via a cannula. Once the
addition was complete, the cooling bath was removed and the
stirred reaction mixture was allowed to warm to room temper-
ature over 30 min. The reaction mixture was then quenched
by addition of saturated aqueous NH4Cl (10 mL), diluted with
water (20 mL), and extracted with CH2Cl2 (2 × 60 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo to yield a pale yellow oil. Purification by flash column
chromatography (EtOAc) afforded keto phosphonate 14 (235 mg,
83%, contaminated with 6% of alkyne 13) as a colorless oil: IR
(neat) 3478, 1697, 1609, 1257 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.54 (s, 1 H), 3.87 (t, J ) 6.1 Hz, 2 H), 3.80 (d, J ) 11.2 Hz, 6
H), 3.23 (d, J ) 22.4 Hz, 2 H), 2.64 (t, J ) 6.1 Hz, 2 H), 0.88 (s,
9 H), 0.05 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 187.9 (d, J ) 6
Hz), 146.3, 124.7 (d, J ) 2 Hz), 59.6, 52.9 (d, J ) 6 Hz), 44.6,
42.2 (d, J ) 129 Hz), 25.6, 18.0, -5.7; CIMS m/z (relative
intensity) 371 (MH+, 100), 313 (MH+ - Me3CH, 29).
being stirred at room temperature for 22 h, the reaction mixture
was concentrated in vacuo. The residue was purified by flash
column chromatography (1:9 ether/hexanes) to yield dienone 15
1
(139 mg, 81%) as a colorless oil: IR (neat) 1666, 1626 cm-1; H
NMR (300 MHz, CDCl3) δ 6.82 (dd, J ) 15.9, 6.8 Hz, 1 H), 6.47
(s, 1 H), 6.18 (dd, J ) 15.9, 1.3 Hz, 1 H), 3.87 (t, J ) 6.0 Hz, 2
H), 2.63 (t, J ) 6.0 Hz, 2 H), 2.24-2.08 (m, 1 H), 1.83-1.59 (m,
5 H), 1.40-1.07 (m, 5 H), 0.89 (s, 9 H), 0.06 (s, 6 H); 13C NMR
(75 MHz, CDCl3) δ 189.1, 153.8, 142.7, 128.4, 124.6, 59.8, 44.4,
40.6, 31.6, 25.8 (2C), 25.6, 18.1, -5.5; CIMS m/z (relative
intensity) 357 (MH+, 100), 323 (35), 299 (MH+ - Me3CH, 35).
P r ep a r a t ion of (1E,4Z)-7-(ter t-Bu t yld im et h ylsiloxy)-5-
ch lor oh ep ta -1,4-d ien -3-ol (16). Sodium borohydride (14 mg,
0.37 mmol) was carefully added over 5 min to a stirred solution
of dienone 15 (127 mg, 0.36 mmol) and CeCl3‚7H2O (133 mg,
0.36 mmol) in MeOH (3 mL). After the reaction mixture was
stirred for a further 5 min, water (5 mL) was added and the
resulting mixture was extracted with ether (3 × 10 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo to yield a pale yellow oil which was purified by flash
column chromatography (1:6 ether/hexanes) to afford dienol 16
1
(121 mg, 95%) as a colorless oil: IR (neat) 3340, 1658 cm-1; H
NMR (300 MHz, CDCl3) δ 5.71 (ddd, J ) 15.5, 6.5, 0.9 Hz, 1 H),
5.62 (d, J ) 7.9 Hz, 1 H), 5.44 (ddd, J ) 15.5, 6.5, 1.3 Hz, 1 H),
5.06-4.98 (m, 1 H), 3.80 (t, J ) 6.4 Hz, 2 H), 2.56-2.49 (m, 2
H), 2.03-1.88 (m, 1 H), 1.79-1.57 (m, 6 H), 1.35-1.00 (m, 5 H),
0.89 (s, 9 H), 0.05 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 138.4,
132.8, 129.1, 127.1, 70.3, 60.2, 42.9, 40.2, 32.6, 26.1, 26.0, 25.9,
18.2, -5.4; FAB+ MS m/z (relative intensity) 359 (MH+, 5), 341
(MH+ - H2O, 66), 209 (MH+ - H2O - TBSOH, 37), 173 (MH+
- H2O - TBSOH - HCl, 46), 145 (85), 115 (75), 105 (100).
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (Grant CA-34303) for financial
support of this research and to Dr. Alan Benesi for help
in obtaining NMR data.
Su p p or tin g In for m a tion Ava ila ble: Copies of the proton
and carbon NMR spectra of new compounds (18 pages). This
material is contained in libraries on microfiche, 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.
P r ep a r a t ion of (1E,4Z)-7-(ter t-Bu t yld im et h ylsiloxy)-5-
ch lor oh ep ta -1,4-d ien -3-on e (15). To a stirred suspension of
LiCl (87 mg, 2.05 mmol) and phosphonate 14 (178 mg, 0.48
mmol) in MeCN (20 mL) was added DBU (0.073 mL, 0.49 mmol)
and cyclohexanecarboxaldehyde (0.079 mL, 0.65 mmol). After
J O980904R