Enantioselective total synthesis of phomallenic acid C

Article abstract of DOI:10.1021/jo070559i

(Chemical Equation Presented) The newly isolated bacterial FAS II inhibitor phomallenic acid C (3) was synthesized for the first time as a 16:1 mixture of the (R)- and (S)-isomer with the diyne-allene motif constructed using a coupling under Negishi conditions. By comparison with the synthetic sample, the natural phomallenic acid C was estimated to be a 3.8:1 mixture of (R)-/(S)-isomers. This synthesis describes a new synthetic entry to optically active allene diynes.

Full text of DOI:10.1021/jo070559i

Enantioselective Total Synthesis of Phomallenic Acid C
Ya-Jun Jian, Chao-Jun Tang, and Yikang Wu*
State Key Laboratory of Bioorganic And Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
yikangwu@.sioc.ac.cn
ReceiVed March 17, 2007
The newly isolated bacterial FAS II inhibitor phomallenic acid C (3) was synthesized for the first time
as a 16:1 mixture of the (R)- and (S)-isomer with the diyne-allene motif constructed using a coupling
under Negishi conditions. By comparison with the synthetic sample, the natural phomallenic acid C was
estimated to be a 3.8:1 mixture of (R)-/(S)-isomers. This synthesis describes a new synthetic entry to
optically active allene diynes.
Introduction
antibiotics in clinic is a serious problem all over the world,
discovery of novel antibiotics, especially those with a mode of
action different from all known drugs, is an urgent task. It is
already shown that bacterial FAS II (which is essential for
bacteria survival) has individual enzymes responsible for each
reaction in the pathway, whereas human FAS has all reactions
fulfilled by a single multifunctional polypeptide.2 Therefore,
phomallenic acids and related molecules deserve further studies
as potential leads for novel antibacterial agents. Herein we wish
to describe an enantioselective total synthesis of phomallenic
acid C, the most potent component in the family.
Phomallenic acids A-C (1-3) were recently isolated by
Ondeyka and co-workers1a from the fermentation broth of
Phoma sp. (MF7018, CBS118751). These diyne-allene aliphatic
acids have been found1b to be new inhibitors of FabF, an
essential enzyme in bacterial type II fatty acid synthesis pathway
(FAS II).1c-g In particular, phomallenic acid C (3) showed about
20-fold better activity than that of thiolactomycin and cerulenin
against S. aureus. It also exhibited a spectrum of antibacterial
activity against clinically important pathogens including me-
thicillin-resistant Staphylococcus aureus, Bacillus subtilis, and
Haemophilus influenzae. As emergence of resistance to the
(1) (a) Ondeyka, J. G.; Zink, D. L.; Young, K.; Painter, R.; Kodali, S.;
Galgoci, A.; Collado, J.; Tormo, J. R.; Basilio, A.; FVicente, F.; Wang, J.;
Singh, S. B. J. Nat. Prod. 2006, 69, 377-380. (b) Young, K.; Jayasuriya,
H.; Ondeyka, J. G.; Herath, K.; Zhang, C.; Kodali, S.; Galgoci, A.; Painter,
R.; Brown-Driver, V.; Yamamoto, R.; Silver, L. L.; Zheng, Y.; Ventura, J.
I.; Sigmund, J.; Ha, S.; Basilio, A.; Vicente, F.; Tormo, J. R.; Pelaez, F.;
Youngman, P.; Cully, D.; Barrett, J. F.; Schmatz, D.; Singh, S. B.; Wang,
J. Antimicrob. Agent Chemother. 2006, 50, 519-526. For some other known
diyne-allenes, see: (c) Davies, D. G.; Hodge, P. Org. Biomol. Chem. 2005,
3, 1690-1693. (d) Bu’Lock, J. D.; Jones, E. R. H.; Leeming, P. R. J. Chem.
Soc. 1955, 4270-4276. (e) Landor, S. R.; Miller, B. J.; Regan, J. P.;
Tatchell, A. R. Chem. Commun. 1966, 585-586. (f) Odermatt, S.; Alonso-
Gomez, J. L.; Seiler, P.; Cid, M. M.; Diederich, F. Angew. Chem., Int. Ed.
2005, 44, 5074-5078. (g) Bew, R. E.; Chapman, J. R.; Jones, Ewart R.
H.; Lowe, B. E.; Lowe, G. J. Chem. Soc., C: 1966, 129-135. For another
FabF inhibitior, see: (h) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.;
Kodali, S.; Galgoci, A.; Painter, R.; Parthasarathy, G.; Tang, Y. S.;
Cummings, R.; Ha, S.; Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.;
Herath, K.; Zhang, C.; Hernandez, L.; Allocco, J.; Basilio, A.; Tormo, J.
R.; Genilloud, O.; Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.; Michael,
B.; Felcetto, T.; Gill, C.; Silver, L. L.; Hermes, Je. D.; Bartizal, K.; Barrett,
J.; Schmatz, D.; Becker, J. W.; Cully, D.; Singh, S. B. Nature 2006, 441,
358-361.
Results and Discussion
Our synthesis started from acylation (Scheme 1) of the
commercially available bis-trimethylsilylacetylene (4) with
azelaic anhydride3 (5) under the conditions described by
(2) (a) Campbell, J. W.; Cronan, J. E. Annu. ReV. Microbiol. 2001, 55,
305-332. (b) Heath, R. J.; White, S. W.; Rock, C. O. Prog. Lipid Res.
2001, 40, 467-497. (c) Heath, R. J.; Rock, C. O. Curr. Opin. InVestig.
Drugs 2004, 5, 146-153. (d) Smith, S.; Witkowski, A.; Joshi, A. K. Prog.
Lipid Res. 2003, 42, 289-317. (e) White, S. W.; Zheng, J.; Zhang, Y.-M.;
Rock, C. O. Annu. ReV. Biochem. 2005, 74, 791-831.
(3) Sun, M.; Deng, Y.; Batyreva, E.; Sha, W.; Salomon, R. G. J. Org.
Chem. 2002, 67, 3575-3584.
10.1021/jo070559i CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/23/2007
J. Org. Chem. 2007, 72, 4851-4855
4851

Jian et al.
SCHEME 1
reduction was very good. The enantiomeric excess value,
however, was not easy to measure by chiral HPLC at this stage
due to lack of a proper chromophore in the molecule.7d
Therefore, we left this to a later stage of our synthesis.
The TMS protecting group was removed with n-Bu4NF before
activation of the propargylic hydroxyl group to avoid any
potential complication at later stages. The resultant 9 was then
treated with p-TsCl in CH2Cl2 in the presence of catalytic
amounts of DMAP at 0 °C, yielding tosylate 10 in 95% yield.
With a strong UV chromophore in the molecule, the enantio-
meric excess (ee) value of 10 was readily determined (>96%)
on a CHIRAL OD column by HPLC analysis.8i
The chirality of the propargylic position was then transferred
to the allene axis via the corresponding tosylate under the LiBr/
CuBr8a-g conditions. By treatment of 10 with 1.5 equiv of LiBr/
CuBr‚SMe2 in THF at ambient temperature, the key intermediate
11 was obtained in 86% yield with a purity of 88% ee
(determined8j later, Vide infra). It appears that the conversion
from 10 to 11 was not entirely stereospecific because the ee
value dropped from 96% to 88%.8k-l
It is interesting to note that if the reaction was performed at
refluxing temperature in the presence of a larger excess (3.3
equiv) of added LiBr/ CuBr‚SMe2, the transformation proceeded
significantly faster but the optical rotation of the product 11
reduced drastically from +146.5 to only +34.8.
Construction of the allene-diyne partial structure is a key issue
and a major difficulty in the present work. This is because
closely related literature precedents9 are scant, although syn-
thesis10 of allen-yne species from coupling of a bromoallene
with an alkyne is a commonplace. Besides, no chemical
synthesis of optically active allene-diynes or allen-ynes has ever
Martinelli4 and co-workers for synthesizing a similar compound
from glutaric anhydride. Although the yields were rather high
in the original cases, with increase in the ring size of the
anhydride the reaction was no longer that clean if equal amounts
of anhydride and the acetylene were used. Apart from the desired
monoacylated product 6 (ca. 40%), side products containing two
acetylene moieties were also formed in substantial yields. To
circumvent this problem, excess anhydride must be utilized. In
the present case, using 2 equiv of the cyclic anhydride 5, the
yield of 6 was raised to 69%.
The carboxylic group in 6 was then masked as a MOM ester
to prevent otherwise unavoidable concurrent reduction of the
acid functionality. We first tried the conditions reported by
Tanabe5 (MOMCl/Et3N/DMF) but only obtained an unexpected
product without the TMS protecting group at the terminal
alkyne. Another protocol for converting a carboxylic acid into
the corresponding MOM ester in the literature was described
by Nakamura6 (i-Pr2NEt/MOMCl/THF). Although the original
authors reported 100% yield for their product, with 6 as the
substrate, the desired ester 7 was formed in only 53% yield.
Using CH2Cl2 as the reaction solvent proved to be beneficial.
Thus, under the MOMCl/Et3N/CH2Cl2 conditions, the yield of
7 could be raised to 88%.
The next step was to establish a stereogenic center by
asymmetric reduction of the ketone group at the propargylic
position. As the CBS7a-c (Corey-Bakshi-Shibata) reduction
at such positions has been proved to be highly stereoselective
and the absolute configuration of the product is predictable, we
opted to use this method to reduce 7 into 8. The yield of the
(8) (a) Montury, M.; Gore´, J. Synth. Commun. 1980, 10, 873-879. (b)
Elsevier, C. J.; Bos, H. J. T.; Vermeer, P. J. Org. Chem. 1984, 49, 379-
381. (c) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726-3730.
(d) Elsevier, C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.;
Vermeer, P. J. Org. Chem. 1982, 47, 2194-2196. (e) D’Aniello, F.;
Schoenfelder, A.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 9631-
9639. (f) D’Aniello, F.; Mann, A.; Taddei, M.; Wermuth, C.-G. Tetrahedron
Lett. 1994, 35, 7775-7778. (g) Chemla, F.; Bernard, N.; Normant, J. Eur.
J. Org. Chem. 1999, 2067-2078. (h) Feldman, K. S.; Mechem, C. C.; Nader,
L. J. Am. Chem. Soc. 1982, 104, 4011-4012. (i) Because there is only one
chiral element in compounds 8-10 and all the reactions/operations involved
cannot possibly improve the enantiomeric purity, the ee value of 8 is
expected to be at least equal to that of 10. (j) Unlike propargylic alcohol 8,
bromoallene 11 is readily detectable on TLC under UV light and can be
analyzed by chiral HPLC without any difficulty. For the precedents showing
that formation of bromoallenes is not entirely stereospecific, see: (k)
Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533-
1534 (an 8:1 mixture). (l) Grese, T. A.; Hutchinson, K. D.; Overman, L. E.
J. Org. Chem. 1993, 58, 2468-2477 (a 15:1 mixture).
(9) (a) Landor, P. D.; Landor, S. R.; Leighton, P. J. Chem. Soc., Perkin
Trans. 1 1975, 1628-1632. (b) Landor, P. D.; Landor, S. R.; Leighton, P.
Tetrahedron Lett. 1973, 1019-1020. (c) Kleijn, H.; Meijer, J.; Overbeek,
G. C.; Vermeer, P. Recl. TraV. Chim. Pay. B (J. R. Neth. Chem. Soc.) 1982,
101, 97-101. (c) De Graaf, W.; Smits, A.; Boersma, J.; Van Koten, G.
Tetrahedron 1988, 44, 6699-6704. (d) Ruitenberg, K.; Kleijn, H.; Elsevier,
C. J.; Meijer, J.; Vermeer, P. Tetrahedron Lett. 1981, 22, 1451-1452. (e)
Ruitenberg, K.; Meijer, J.; Bullee, R. J.; Vermeer, P. J. Organomet. Chem.
1981, 217, 267-271.
(4) Nayyar, N. K.; Hutchison, D. R.; Martinelli, M. J. J. Org. Chem.
1997, 62, 982-991.
(5) Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917-1924.
(6) Nakamura, H.; Maruyama, K.; Fujimaki, K.; Murai, A. Tetrahedron
Lett. 2000, 41, 1927-1930.
(7) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (c) For a recent
review: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 36, 1986-
2012. (d) In principle, the ee value as well as the absolute configuration of
8 of course could be also determined using its Mosher esters. However,
considering that this would require an extra step of operation and the results
are still empirical, we left the determination of enantiomeric excess to a
later stage of our synthesis.
(10) See e.g.: (a) Condon-Gueugnot, S.; Linstrumelle, G. Tetrahedron
2000, 56, 1851-1857. (b) Yoshida, M.; Ueda, H.; Ihara, M. Tetrahedron
Lett. 2005, 46, 6705-6707. (c) Ma¨rkl, G.; Attenberger, P.; Kellner, J.
Tetrahedron Lett. 1988, 29, 3651-3654. (d) Caporusso, A. M.; Lardicci,
L.; Da Settimo, F. Tetrahedron Lett. 1986, 27, 1067-1068. (e) Caporusso,
A. M.; Da Settimo, F.; Lardicci, L. Tetrahedron Lett. 1985, 26, 5101-
5104. (f) Jeffery-Luong, T.; Linstrumelle, G. Synthesis 1983, 32-34. (g)
Baker, S. L.; Landor, P. D.; Landor, S. R. J. Chem. Soc. 1965, 4659-
4664. (h) Clinet, J.-C.; Linstrumelle, G. Synthesis 1981, 875-878. (i)
Saalfrank, R. W.; Haubner, M.; Deutscher, C.; Bauer, W. Eur. J. Org. Chem.
1999, 2367-2372.
4852 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis of Phomallenic Acid C
SCHEME 2
diyne 12 (which could be prepared from 1,4-dihydroxy-but-2-
yne following the literature16 procedures) led smoothly to the
desired product ester 13. As expected, the configuration of the
allene axis was also inverted, with a specific rotation of -198.5.
The MOM protecting group was then removed by treatment
with F3CCO2H in CH2Cl2 to afford the end product phomallenic
acid C (3).
1
It is noteworthy that while IR,17 UV, MS, and H and 13C
NMR data of our synthetic sample are consistent with those
reported for the natural one, the specific rotation ([R]D23 -241.4
(c 0.40, MeOH) is significantly larger than reported for the
23
natural one (lit.1a [R]D -160 (c 0.40, MeOH), revealing the
latter was substantially racemized. Considering that under the
Negishi conditions the allene axis might partially racemize as
implied by the outcomes of Elsevier and Vermeer11 as well as
our model study, we suspected that even our sample was not
enantiopure. To find out the true situation, after completion of
the synthetic work we also made much effort in examining
enantiomeric purity of our chiral allene species by chiral
HPLC.18
The end product 3 is a free carboxylic acid, which is often
not easy to analyze by chromatography. Therefore, we per-
formed the analysis on the MOM ester 13. Because of the lack
of precedents of successful separation of such chiral diyne-
allenes (without any other stereogenic center in the molecule),
the work along this line was fruitless in the beginning. Many
tries on CHIRAL OD, AD, and OJ columns completely failed.
Finally, the newly marketed CHIRALPAK IC column resolved
the problem. The results clearly showed that the MOM ester
13 was a 16:1 (88% ee) mixture of allenic isomers. As
hydrolysis of the MOM ester is unlikely to affect the allene
axis, the end product 3 is also expected to be a 16:1 mixture
(88% ee). The specific rotation of pure (R)-3 is thus calculated
to be [R]D23 -273.6 (c 0.40, MeOH). Consequently, the natural
3 reported by Ondeyka and co-workers1a should be a 3.8:1
mixture of the (R)- and (S)-isomers.
been published (to the best of our knowledge). Up to now, the
only coupling example involving optically active allenes we can
find in the literature is that reported in 1985 by Elsevier and
Vermeer11 (coupling of halloallenes with PhZnCl or Ph2Zn).
In fact even determination of the optical purity of allenes is
also an unsolved problem if there is no other stereogenic centers
at the positions immediately next to the allene axis. For these
reasons, it is desirable to use a coupling protocol that may offer
highest stereoselectivity so far known.
Before the present project, we already encountered similar
coupling problems in another (still ongoing) project. To gain
knowledge of the stereoselectivity of the existing coupling
protocols in the context of reaction with alkynes, we performed
some model studies. For practical concerns, we chose 14 (cf.
Supporting Information) as the starting bromoallene species and
the commercially available TMSCtCH as the alkyne. It was
hoped that the presence of an additional stereogenic center
immediately next to the allene axis would assist detection, and
perhaps even separation, of the allene isomers.
We first examined the coupling under the Sonogashira12
conditions, which was employed by many previous investigators
in the synthesis of allen-ynes. The yield of the coupling product
1
was rather good (77%, Scheme 2). However, the H NMR
Using the same HPLC conditions, the bromoallene 11 was
shown also to be an allenic mixture with a ratio of 20:1 (90%
ee). As the isomeric ratio dropped from 20:1 (90% ee) to 16:1
(88% ee) when 11 was transferred into 13, partial racemization
must have occurred to the allene axis. This deduction is in line
with the observation of Elsevier and Vermeer11 in their coupling
of bromoallene with phenyl zinc reagents, where the coupling
products were estimated to be of 87% ee (ca. 14.4:1).
The present results suggest that although coupling of a
bromoallene with a diyne appears to be a straightforward
approach to the synthesis of the diyne-allene motif, better
coupling conditions are still to be found if higher enantiose-
lectivity is desired. Perhaps even approaches other than the direct
coupling should also be considered.
spectrum was much more complicated than expected for a single
enantiomer, suggesting presence of an extensively racemized
allene axis. Next, we tried the Negishi’s13 protocol, where the
alkyne was converted to a more reactive zinc salt before the
coupling, and the reaction thus could be carried out under milder
conditions. To our gratification, this time the product gave a
1
much cleaner H NMR spectrum (cf. Supporting Information)
and a specific rotation (+113.7) much higher than that (+57.7)
obtained under the Sonogashira conditions. The sign of specific
rotation is also compatible with what is predicted for (S)-allene
according to the rules14,15 of Lowe and Brewster, confirming
an inversion of the configuration of the allene axis during the
coupling as originally observed by Elsevier and Vermeer11 in
the coupling of bromoallenes with PhZnCl or Ph2Zn.
On the basis of the results of the model study, in the synthesis
of 3 we opted to employ the Negishi protocol to install the diyne
moiety onto the allene. Thus, reaction of bromoallene 11 with
(16) (a) Gupta, P. K.; Jones, J. G. L.; Caspi, E. J. Org. Chem. 1975, 40,
1420-1427. (b) Siegel, K.; Bruckner, R. Chem. Eur. J. 1998, 4, 1116-
1122.
(17) It is noteworthy that there is a very weak peak at 2142 cm-1 in the
IR spectrum of 3, which was not included in the data listing in ref 1a.
Inclusion of this weak signal in the IR spectrum of 3 is rationalized by the
presence of a much more intense/unambiguous peak at the same wave
number in the IR of the MOM ester 13.
(11) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042-3045.
(12) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470. (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46-49.
(c) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834-871.
(13) (a) King, A. O.; Okukado, N.; Negishi, E.-i. J. Chem. Soc., Chem.
Commun. 1977, 683-684. (b) Negishi, E.-i. J. Organomet. Chem. 2002,
653, 34-40.
(14) Lowe, G. J. Chem. Soc., Chem. Commun. 1965, 411-413.
(15) Brewster, J. H. In Topics in Stereochemistry; Allinger, N. L.; Eliel,
E. L., Ed.; John Wiley and Sons, Inc.: New York, 1967; Vol. 2, pp 1-72.
(18) It should be noted that the frequent use of specific rotation data for
quick comparison of enantiomeric purity between different samples in the
present work is warranted as follows: (1) there is only one chiral element
in the molecule, and (2) the specific rotation is rather large. However, in
general specific rotation is not a sensitive/reliable indicator for enantiomeric
purity, especially when the substrate molecule contains more than one chiral
element and/or the absolute value of specific rotation is rather small.
J. Org. Chem, Vol. 72, No. 13, 2007 4853

Jian et al.
Methoxymethyl (9R)-9-Hydroxy-undec-10-ynoate (9). n-Bu4-
NF (1.52 mL, 1 M solution in THF, 1.52 mmol) was added to a
solution of 8 (460 mg,1.47 mmol) in THF (7 mL) stirred in an
ice-water bath. The mixture was stirred for 10 min before being
diluted with Et2O, washed with water, and dried over anhydrous
Na2SO4. The solvent was removed by rotary evaporation, and the
residue was chromatographed on silica gel (6:1 PE/EtOAc) to give
the free alkyne 9 as a colorless oil (352 mg, 1.46 mmol, 99%
yield): [R]D20 +2.80 (c 1.87, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 5.23 (s, 2H), 4.37 (t, J ) 6.1 Hz, 1H), 3.47 (s, 3H), 2.47(d, J )
2.0 Hz, 1H), 2.36 (t, J ) 7.7 Hz, 2H), 1.98 (br s, 1H, OH), 1.76-
1.59 (m, 4H), 1.53-1.28 (m, 8H); 13C NMR (75 MHz, CDCl3) δ
173.4, 90.2, 85.1, 72.8, 62.2, 57.6, 37.6, 34.3, 29.1, 29.0, 28.9, 24.9,
24.7; FT-IR (film) 3466 (br), 3290, 2932, 2857, 2107, 1740, 1464,
1158, 1087, 932 cm-1. ESI-MS m/z 265.2 ([M + Na]+), 260.2 ([M
+ NH4]+); ESI-HRMS Calcd for C13H22O4Na ([M + Na]+)
265.1410; found 265.1408.
Methoxymethyl (9R)-9-(Toluene-4-sulfonyloxy)-undec-10-
ynoate (10). Et3N (0.27 mL, 1.93 mmol) and DMAP (10 mg) were
added in turn to a solution of alcohol 9 (334 mg, 1.38 mmol) in
dry CH2Cl2 (7 mL) stirred at 0 °C. After completion of the addition,
the mixture was stirred at the same temperature for 13 h before
being diluted with Et2O, washed in turn with water and brine, and
dried over anhydrous Na2SO4. The solvent was removed by rotary
evaporation, and the residue was chromatographed (8:1 PE/EtOAc)
to give tosylate 10 as a colorless oil (521 mg, 1.32 mmol, 95%
yield): [R]D23 +40.9 (c 1.42, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 7.82 (d, J ) 8.0 Hz, 2H), 7.34 (d, J ) 7.9 Hz, 2H), 5.23 (s, 2H),
5.05 (t, J ) 5.5 Hz, 1H), 3.46 (s, 3H), 2.45 (s, 3H), 2.41 (s, 1H),
2.35 (t, J ) 7.6 Hz, 2H), 1.89-1.74 (m, 2H), 1.69-1.56 (m, 2H),
1.49-1.22 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 173.2, 144.8,
133.7, 129.6, 128.0, 90.1, 78.9, 76.1, 71.0, 57.5, 35.5, 34.2, 28.9,
28.8, 28.5, 24.6, 24.3, 21.6; FT-IR (film) 3276 (sharp), 2928, 2857,
2124, 1743, 1598, 1466, 1371 cm-1. ESI-MS m/z 419.2 ([M +
Na]+); ESI-HRMS Calcd for C20H28O6NaS ([M + Na]+) 419.1499;
found 419.1497.
In summary, the recently isolated novel FAS II inhibitor
phomallenic acid C (3) has been synthesized for the first time
through an eight-step route with an overall yield of 39% from
acetylene 4. The synthetic sample was a 16:1 mixture of the
(R)- and (S)-isomer (88% ee). The specific rotation for pure
(R)-isomer is calculated to be [R]D -273.6 (c 0.40, MeOH),
which indicates that the isolated natural 3 was a 3.8:1 mixture
(58% ee) rather than a single enantiomer as one might expect.
23
Experimental Section
9-Oxo-11-trimethylsilanyl-undec-10-ynoic Acid (6). Powdered
anhydrous AlCl3 (450 mg, 3.27 mmol) was added in portions to a
solution of bis-trimethylsilylacetylene 4 (170 mg, 1.0 mmol) and
anhydride 5 (340 mg, 2.0 mmol) in dry CH2Cl2 (15 mL) stirred in
an ice-water bath. The stirring was continued at the same
temperature for 2 h, and at ambient temperature for 18 h with
cooling (ice-water bath) 1 N HCl was carefully added to the
viscous dark-brown mixture. The organic layer was separated,
washed in turn with 1 N HCl, water, and brine, and dried over
anhydrous MgSO4. Removal of the solvent left a dark-brown oil,
which was purified by column chromatography (4:1 PE/EtOAc) to
give 6 as a yellowish oil (186 mg, 0.69 mmol, 69% yield): 1H
NMR (300 MHz, CDCl3) δ 2.57 (t, J ) 7.4 Hz, 2H), 2.37 (t, J )
7.4 Hz, 2H), 1.66 (q, J ) 6.9 Hz, 4H), 1.41-1.26 (m, 6H), 0.26 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 188.0, 180.1, 102.0, 97.7, 45.2,
34.0, 28.9, 28.8, 28.7, 24.6, 23.8, -0.75; FT-IR (film) 3500-2400
(a lump), 2932, 2858, 2150, 1710, 1678, 1253, 847, 762 cm-1. EI-
MS m/z (%) 268 (M +, 0.1), 140 (37), 125 (100), 97 (31), 75 (68),
55 (48). Anal. Calcd for C14H24O3Si:C, 62.64, H, 9.01. Found C,
62.61, H, 9.13.
Methoxymethyl 9-Oxo-11-trimethylsilanyl-undec-10-ynoate
(7). Et3N (0.43 mL, 3.12 mmol) was added to a solution of acid 6
(643 mg, 2.40 mmol) in dry CH2Cl2 (12 mL) stirred in an ice-
water bath, followed by MOMCl (0.22 mL, 2.88 mmol). After
completion of the addition, the mixture was stirred at the same
temperature for 7 h before being diluted with Et2O, washed with
water and brine, and dried over anhydrous Na2SO4. Rotary
evaporation and column chromatography (12:1 PE/EtOAc) gave
the MOM ester 7 as a yellowish oil (659 mg, 2.11 mmol, 88%
yield): 1H NMR (500 MHz, CDCl3) δ 5.24 (s, 2H), 3.47 (s, 3H),
2.56 (t, J ) 7.4 Hz, 2H), 2.36 (t, J ) 7.5 Hz, 2H), 1.73-1.59 (m,
4H), 1.40-1.24 (m, 6H), 0.25 (s, 9H); 13C NMR (125 MHz, CDCl3)
δ 187.8, 173.2, 102.0, 97.6, 90.2, 57.5, 45.2, 34.2, 28.9, 28.8, 28.7,
24.7, 23.8, -0.8; FT-IR (film) 2934, 2858, 2149, 1744, 1678, 1464,
1253, 1147, 1086, 933, 847, 763 cm-1. ESI-MS m/z 335.2 ([M +
Na]+). Anal. Calcd for C16H28O4Si:C, 61.50, H, 9.03. Found C,
61.64, H, 9.07.
Methoxymethyl (S)-11-Bromo-undeca-9,10-dienoate (11). A
solution of tosylate 10 (280 mg, 0.71 mmol) in dry THF (1 mL)
was added to a mixture of LiBr (92 mg, 1.07 mmol) and CuBr‚
SMe2 (220 mg, 1.07 mmol) in dry THF (5 mL) stirred at ambient
temperature. The resultant light gray-coffee colored mixture was
stirred at ambient temperature for 6 h before the reaction was
quenched by addition of sat. aq NH4Cl (2.5 mL). The mixture was
diluted with Et2O, washed in turn with water and brine, and dried
over anhydrous Na2SO4. The solvent was removed by rotary
evaporation and the residue was chromatographed (50:1 PE/EtOAc)
to afford bromoallene 11 as a colorless oil (186 mg, 0.61 mmol,
23
1
86% yield): [R]D +146.5 (c 1.30, CHCl3). H NMR (300 MHz,
CDCl3) δ 5.94 (m, 1H), 5.39 (q, J ) 6.8 Hz, 1H), 5.23 (s, 2H),
3.46 (s, 3H), 2.36 (t, J ) 7.5 Hz, 2H), 2.15 (q, J ) 7.4 Hz, 2H),
1.72-1.58 (m, 2H), 1.49-1.22 (m, 8H); 13C NMR (75 MHz,
CDCl3) δ 202.1, 173.3, 100.9, 90.2, 72.2, 57.5, 34.3, 28.98, 28.95,
28.9, 28.7, 28.2, 24.7; FT-IR (film) 3061, 2929, 2856, 1954, 1743,
1464, 1197, 1159, 1086, 932, 653 cm-1. ESI-MS m/z 327.2 ([M +
Na]+), 307.2 ([M + H]+), 305.2 ([M + H]+); ESI-HRMS calcd
for C13H21O3BrNa ([M + Na]+) 327.0566; found 327.0569.
Methoxymethyl (R)-Octadeca-9,10-diene-12,14-diynoate (13).
MeLi‚LiBr (0.80 mL, ca. 1.5 M in Et2O, 1.20 mmol) was added
via a syringe to a solution of diyne 12 (110 mg, 1.20 mmol) in dry
THF (6 mL) stirred at -78 °C under argon. The mixture was stirred
at this temperature for 1.5 h and then at ambient temperature for
another 2 h. A THF solution of dried ZnBr2 (1.2 mL, 1.0 M, 1.20
mmol) was introduced. The mixture was stirred at ambient
temperature for 10 min (to afford a 0.14 M solution of the zincated
diyne), before being transferred to a flask containing Pd(PPh3)4 (22
mg, 0.019 mmol) stirred at -78 °C under argon. A solution of
bromoallene 11 (114 mg, 0.37 mmol) in dry THF (3 mL) was then
introduced via a syringe. After completion of the addition, the
mixture was stirred at 0 °C until TLC showed disappearance of
Methoxymethyl (9R)-9-Hydroxy-11-trimethylsilanyl-undec-
10-ynoate (8). (R)-2-Methyl-CBS-oxazaborolidin (3.12 mL, 1.0 M
in toluene, 3.12 mmol) was added to a solution of the ketone 7
(488 mg, 1.56 mmol) in dry THF (15.6 mL) stirred at -42 °C.
The stirring was continued for 10 min before BH3‚SMe2 (3.9 mL,
2.0 M in THF, 7.8 mmol) was introduced. The mixture was stirred
for another 1 h. The reaction was quenched by addition of EtOH
(5.9 mL), followed by water. The mixture was diluted with Et2O,
washed with water, and dried over anhydrous Na2SO4. Rotary
evaporation and column chromatography (10:1 PE/EtOAc) gave
23
alcohol 8 as a colorless oil (460 mg, 1.47 mmol, 94% yield): [R]D
1
+0.19 (c 1.78, CHCl3). H NMR (300 MHz, CDCl3) δ 5.22 (s,
2H), 4.34 (t, J ) 6.5 Hz, 1H), 3.46 (s, 3H), 2.35 (t, J ) 7.4 Hz,
2H), 2.07 (br s, 1H, OH), 1.73-1.58 (m, 4H), 1.52-1.23 (m, 8H),
0.16 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 173.3, 106.9, 90.1,
89.1, 62.7, 57.5, 37.5, 34.2, 29.0, 28.92, 28.87, 25.0, 24.7, -0.2;
FT-IR (film) 3480 (br), 2927, 2858, 2169, 1743, 1463, 1250, 1088,
843, 761 cm-1. ESI-MS m/z 337.2 ([M + Na]+), 332.3 ([M +
NH4]+); ESI-HRMS Calcd for C16H30O4SiNa ([M + Na]+) 337.1806;
found 337.1804.
4854 J. Org. Chem., Vol. 72, No. 13, 2007

Total Synthesis of Phomallenic Acid C
the starting 11 (ca. 4 h). The mixture was diluted with Et2O, washed
in turn with water and brine, and dried over anhydrous Na2SO4.
Removal of the solvent and column chromatography (50:1 PE/Et2O)
5.46-5.40 (m, 1H), 2.30 (t, J ) 7.5 Hz, 2H), 2.26 (t, J ) 7.6 Hz,
2H), 2.05 (dq, J ) 3.4, 6.9 Hz, 2H), 1.59-1.48 (m, 4H), 1.45-
1.27 (m, 8H), 0.98 (t, J ) 7.4 Hz, 3H); 13C NMR (100 MHz, CD3-
CN) δ 215.1, 175.4, 94.8, 85.2, 75.5, 75.0, 69.6, 65.7, 34.2, 29.74,
29.68, 29.5, 29.3, 28.6, 25.6, 22.5, 21.8, 13.7; FT-IR (film) 3600-
2300 (a lump), 2927, 2855, 2238, 2142, 1946, 1737, 1709, 1463,
1277 cm-1. ESI-MS m/z 295.2 ([M + Na]+), 290.3 ([M + NH4]+),
273.2 [M + H]+); ESI-HRMS Calcd for C18H24O2Na ([M + Na]+)
295.1669; found 295.1668. Compound 3 is not very stable;
additional spot(s) appeared on TLC after storage in neat form for
a couple of months in a -78 °C freezer.
23
gave 13 as a colorless oil (107 mg, 0.34 mmol, 92% yield): [R]D
-198.5 (c 1.15, MeOH). 1H NMR (300 MHz, CD3COCD3) δ 5.58
(q, J ) 6.6 Hz, 1H), 5.56-5.49 (m, 1H), 5.19 (s, 2H), 3.40 (s,
3H), 2.35 (t, J ) 7.4 Hz, 2H), 2.33 (t, J ) 7.7 Hz, 2H), 2.13-2.02
(m, 2H), 1.68-1.30 (m, 12H), 0.98 (t, J ) 7.4 Hz, 3H); 13C NMR
(75 MHz, CD3COCD3) δ 214.8, 173.1, 94.2, 90.3, 84.2, 75.4, 75.0,
69.1, 65.9, 57.2, 34.4, 29.5 (2 C’s), 29.3, 29.1, 28.4, 25.3, 22.3,
21.4, 13.4; FT-IR (film) 2931, 2856, 2238, 2142, 1946, 1743, 1463,
1162, 1086, 933, 864 cm-1. EI-MS m/z (%) 255 (M -OMOM,
10), 144 (66), 129 (100), 115 (48), 45 (89); EI-HRMS Calcd for
C20H28O3 (M+) 316.2038; found 316.2049.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (20372075, 20321202,
20672129, 20621062) and the Chinese Academy of Sciences
(“Knowledge Innovation”, KJCX2.YW.H08).
Phomallenic Acid C (3). With cooling (ice-NaCl-water bath)
and stirring, F3CCO2H (0.3 mL, 4.03 mmol) was added to a solution
of ester 13 (33 mg, 0.105 mmol) in CH2Cl2 (2 mL). The stirring
was continued at the same temperature for 5 h, when TLC showed
completion of the reaction. The mixture was diluted with Et2O,
washed in turn with water and brine, and dried over anhydrous
Na2SO4. Removal of the solvent and column chromatography (2:1
PE/Et2O) gave phomallenic acid C 3 as a yellowish oil (26 mg,
Supporting Information Available: General remarks for
Experimental Section, chiral HPLC analysis of 10, 11, and 13,
1
experimental procedures for the preparation of 14 and 15, H and
13C NMR spectra of 6, 7, 8, 9, 10, 11, 13, and 3, 1H NMR spectra
of 14, 15, 15′, and 17. This material is available free of charge via
the Internet at http://pubs.acs.org.
23
0.096 mmol, 92% yield): [R]D -241.4 (c 0.40, MeOH) (lit.1a
23
[R]D -160 (c 0.40, MeOH)). UV (MeOH)λmax 205 (shoulder),
211, 238, 251, 265, 280 nm. 1H NMR (400 MHz, CD3CN) δ 10.0-
7.50 (very broad/flat lump, 1H, COOH), 5.53 (q, J ) 6.8 Hz, 1H),
JO070559I
J. Org. Chem, Vol. 72, No. 13, 2007 4855