On the structure of passifloricin A: Asymmetric synthesis of the δ-lactones of (2Z,5S,7R,9S,11S)- and (2Z,5R,7R,9S,11S)-tetrahydroxyhexacos-2-enoic acid

Article abstract of DOI:10.1021/ol034182o

(Matrix presented) Stereoselective syntheses of the δ-lactone of (2Z,5S,7R,9S,11S)-tetrahydroxyhexacos-2-enoic acid, the structure reported for passifloricin A, and of its (5R)-epimer are described. The creation of all stereogenic centers relied upon Brown's asymmetric allylation methodology. The lactone ring was created via ring-closing metathesis. The NMR data of both synthetic products, however, were different from those of the natural product. The published structure of passifloricin A is thus erroneous and will require further synthetic work to be unambiguously assigned.

Full text of DOI:10.1021/ol034182o

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1447-1449
On the Structure of Passifloricin A:
Asymmetric Synthesis of the δ-Lactones
of (2Z,5S,7R,9S,11S)- and
(2Z,5R,7R,9S,11S)-Tetrahydroxyhexacos-2-enoic
Acid
,†
,‡
Jorge Garc´ıa-Fortanet,† Juan Murga,† Miguel Carda,* and J. Alberto Marco*
Departamento de Qu´ımica Inorga´nica y Orga´nica, UniVersidad Jaume I, Castello´n,
E-12080 Castello´n, Spain, and Departamento de Qu´ımica Orga´nica, UniVersidad de
Valencia, E-46100 Burjassot, Valencia, Spain
alberto.marco@uV.es
Received February 3, 2003
ABSTRACT
Stereoselective syntheses of the δ-lactone of (2Z,5S,7R,9S,11S)-tetrahydroxyhexacos-2-enoic acid, the structure reported for passifloricin A,
and of its (5R)-epimer are described. The creation of all stereogenic centers relied upon Brown’s asymmetric allylation methodology. The
lactone ring was created via ring-closing metathesis. The NMR data of both synthetic products, however, were different from those of the
natural product. The published structure of passifloricin A is thus erroneous and will require further synthetic work to be unambiguously
assigned.
Lactone rings constitute a structural feature of many natural
products.1,2 Many naturally occurring lactones, particularly
those that are Michael acceptors (R,â-unsaturated),3 display
pharmacological properties of interest, e.g., some exhibit
antitumoral activity, while others are tumor promoting. One
such lactone is the polyketide-type R-pyrone passifloricin
A 1, isolated two years ago, together with the closely related
passifloricins B 2 and C 3, from the resin of Passiflora
foetida var. hispida, a species from the family Passifloraceae
that grows in tropical zones of America. Their structures were
elucidated on the basis of purely spectroscopic findings, but
only the relative configuration of the stereogenic centers was
given. Conjugated lactone 1 was found to be active in the
Artemia salina test, whereas the unconjugated lactones 2 and
3 showed no activity.4
Within our recently initiated program on synthesis of
bioactive lactones where ring-closing metathesis (RCM)
reactions are used as one of the key steps,5 we decided to
undertake a stereoselective synthesis of 1 with the additional
aim of establishing the absolute configuration of the natural
† Universidad Jaume I, Castello´n.
‡ Universidad de Valencia.
(1) Negishi, E.; Kotora, M. Tetrahedron 1997, 53, 6707-6738.
(2) Collins, I. J. Chem. Soc., Perkin Trans. 1 1999, 1377-1395.
(3) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. 1985, 24, 94-
110.
(4) Echeverri, F.; Arango, V.; Quin˜ones, W.; Torres, F.; Escobar, G.;
Rosero, Y.; Archbold, R. Phytochemistry 2001, 56, 881-885.
10.1021/ol034182o CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/29/2003

molecule. To start with, we selected the (5S,7R,9S,11S)-
diastereoisomer, arbitrarily depicted for 1 in the original
paper, as the target molecule. The 1,3-polyol segment of
lactone 1 suggested several synthetic approaches.6,7 Our
retrosynthetic concept, depicted in Scheme 1, relied exclu-
Scheme 2a
Scheme 1
sively upon asymmetric allylations to create new C-C bonds.
Starting with n-hexadecanal, an iterative three-step sequence
(asymmetric allylation/hydroxyl protection/CdC oxidative
cleavage) was conceived to create a new stereogenic carbon
atom in each cycle. Acylation of the hydroxyl group
generated in the last cycle, followed by ring-closing me-
tathesis,8 should finally afford the desired unsaturated lactone.
In view of our favorable experiences with asymmetric
allylations using Brown’s chiral allylboranes,5d,f we selected
this methodology for the present purposes.9-11 Thus, n-
hexadecanal12 was allowed to react with B-allyl diisopi-
nocampheylborane (allylBIpc2), prepared from allylmagne-
sium bromide and (+)-DIP-Cl (diisopinocampheylboron
chloride).13 This gave homoallyl alcohol 4 as a 96:4
enantiomeric mixture (Scheme 2), as judged from NMR
a Reagents and conditions: (a) allylBIpc2 [from (+)-DIP-Cl and
allylmagnesium bromide], Et2O, 1 h, -100 °C (82%, 96:4 enan-
tiomeric mixture). (b) TBSCl, DMF, imidazole, rt, 18 h, 93%. (c)
O3, CH2Cl2, -78 °C, then PPh3, 3 h, rt. (d) AllylBIpc2 [from (+)-
DIP-Cl], Et2O, -100 °C, (64% overall for the two steps, 93:7
diastereomeric mixture). (e) TBAF, THF, rt, 1.5 h, then chromato-
graphic separation of the two diastereomers, 75% yield of pure 7.
(f) TBSOTf, 2,6-lutidine, rt, 1 h, CH2Cl2., 86%. (g) O3, CH2Cl2,
-78 °C, then PPh3, 3 h, rt. (h) AllylBIpc2 [from (-)-DIP-Cl],
Et2O, 1 h, -100 °C (82:18 diastereomeric mixture), then stereo-
isomer separation, 60% overall. (i) TBSOTf, 2,6-lutidine, rt, 1 h,
CH2Cl2., 94%. (j) O3, CH2Cl2, -78 °C, then PPh3, 3 h, rt. (k)
allylBIpc2 [from (-)-DIP-Cl], Et2O, 1 h, -100 °C (91:9 diaster-
eomeric mixture), then stereoisomer separation, 64% overall. (l)
(E)-Cinnamoyl chloride, NEt3, cat. DMAP, CH2Cl2, rt, 3 h, 76%.
(m) 10% catalyst B, CH2Cl2, ∆, 3 h, 77%. (n) PPTS, aqueous
MeOH, 70 °C, 18 h, 75% (TBS ) tert-butyldimethylsilyl).
(5) (a) Carda, M.; Rodr´ıguez, S.; Segovia, B.; Marco, J. A. J. Org. Chem.
2002, 67, 6560-6563. (b) Carda, M.; Gonza´lez, F.; Castillo, E.; Rodr´ıguez,
S.; Marco, J. A. Eur. J. Org. Chem. 2002, 2649-2655. (c) Murga, J.;
Falomir, E.; Garc´ıa-Fortanet, J.; Carda, M.; Marco, J. A. Org. Lett. 2002,
4, 3447-3449. (d) Falomir, E.; Murga, J.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2003, 44, 539-541. (e) Carda, M.; Rodr´ıguez, S.; Castillo,
E.; Bellido, A.; D´ıaz-Oltra, S.; Marco, J. A. Tetrahedron 2003, 59, 857-
864. (f) Murga, J.; Garc´ıa-Fortanet, J.; Carda, M.; Marco, J. A. Tetrahedron
Lett. 2003, 44, 1737-1739.
analysis of the Mosher ester. Protection of the hydroxyl group
as the tert-butyldimethylsilyl derivative14 was followed by
ozonolysis of the olefinic bond to yield the intermediate
â-silyloxy aldehyde, which without chromatographic puri-
fication was subjected to asymmetric allylation with the same
reagent as above. This gave homoallyl alcohol 615 with the
desired syn relative configuration of the two oxygen func-
tions.16 Silylation to 815 and oxidative cleavage of the olefinic
bond was followed by asymmetric allylation of the inter-
mediate â-silyloxy aldehyde. The allylating reagent was now
(6) Oishi, T.; Nakata, T. Synthesis 1990, 635-645.
(7) For further, more recent methodologies toward 1,3-polyol segments,
see, for example: (a) Palomo, C.; Aizpurua, J. M.; Urchegi, R.; Garc´ıa, J.
M. J. Org. Chem. 1993, 58, 1646-1648. (b) Schneider, C.; Rehfeuter, M.
Chem. Eur. J. 1999, 5, 2850-2858. (c) Trieselmann, T.; Hoffmann, R. W.
Org. Lett. 2000, 2, 1209-1212. (d) Sarraf, S. T.; Leighton, J. L. Org. Lett.
2000, 2, 3205-3208. (e) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001,
3, 2777-2780. See also ref 11b.
(8) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012-3043. (b)
Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(9) Allylation under Keck and related conditions (ref 10) was unsuccessful
here (extremely slow reaction). The use of the Duthaler-Hafner allylation
reagent (ref 11) was discarded because of its very high price.
(10) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467-8468. (b) Doucert, H.; Santelli, M. Tetrahedron:
Asymmetry 2000, 11, 4163-4169.
(14) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; pp 127-141.
(15) Chomatographic separation of diastereomers (6 + epimer) proved
to be unfeasible. After desilylation, separation was possible and the pure
diol 7 was then resilylated to 8.
(11) (a) Duthaler, R. O.; Hafner, A. Chem. ReV. 1992, 92, 807-832. (b)
Cossy, J.; BouzBouz, S.; Pradaux, F.; Willis, C.; Bellosta, V. Synlett 2002,
1595-1606.
(12) Freshly prepared by PCC oxidation of n-hexadecanol.
(13) (a) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C. Tetrahedron
Lett. 1997, 2417-2420. (b) For a recent review on asymmetric allylbora-
tions, see: Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23-35.
(16) This was shown by means of 13C NMR and NOE measurements
on the acetonide of diol 7. See: Rychnovsky, S. D.; Rogers, B. N.;
Richardson, T. I. Acc. Chem. Res. 1998, 31, 9-17.
1448
Org. Lett., Vol. 5, No. 9, 2003

prepared from (-)-DIP-Cl and allylmagnesium bromide in
order to have the desired (S)-configuration at the new
stereogenic carbon. This afforded the protected triol 9, which
was silylated to 10 and subjected once more to the same
protocol to yield alcohol 11, where the hydroxyl function
was suitably placed to build up the unsaturated lactone ring.
To this end, 11 was treated with acryloyl chloride to furnish
the corresponding acrylate. However, the yield was very low.
In view of this, we made use of another recently proposed
alternative. Alcohol 11 was treated with cinnamoyl chloride17
to provide cinnamate 12 with good yield. Ester 12 proved
to be unresponsive to RCM using the standard ruthenium
complex A but gave the desired lactone 13 in the presence
of the second-generation ruthenium catalyst B.8 Finally, acid-
catalyzed cleavage18 of all silyl protecting groups in 13 gave
lactone 1 in a very satisfactory 75% yield. Disappointingly,
however, the NMR data of synthetic 1 proved to be distinctly
different from those published for the natural product.4,19 The
optical rotation was also markedly different in value and
opposite in sign.
Scheme 3a
a Reagents and conditions: (a) O3, CH2Cl2, -78 °C, then PPh3,
3 h, rt. (b) allylBIpc2 [from (+)-DIP-Cl], Et2O, 1 h, -100 °C (88:
12 diastereomeric mixture), followed by chromatographic separa-
tion, 60% overall. (c) (E)-Cinnamoyl chloride, NEt3, cat. DMAP,
CH2Cl2, rt, 3 h, 77%. (d) 10% catalyst B, CH2Cl2, ∆, 3 h, 71%. (e)
PPTS, aqueous MeOH, 70 °C, 18 h, 83%.
According to the data published by Echeverri and co-
workers,4 only the diastereoisomeric structures 1 and 17
should be possible for passifloricin A. We must therefore
conclude that the data they presented are partly erroneous
and that the structure they proposed for the natural lactone
is incorrect as regards the configuration of some of the
stereogenic centers. As a consequence, other stereoisomers
of the δ-lactone of 5,7,9,11-tetrahydroxyhexacos-2-enoic acid
(up to five)20 will have to be prepared in order to establish
the actual structure of passifloricin A. Work toward this goal
is currently being performed in our laboratory and will be
reported in due course.
In view of this unexpected result, we reexamined the
available spectral data,4 which served to elucidate the
structure of passifloricin A. The authors based their stereo-
chemical assignments on the formation of two monoaceto-
nides through treatment of the natural product with acetone
and an acid catalyst. In one of them, the dioxolane ring was
located (HMBC experiments) between the C-9 and C-11
hydroxyl groups and found to be syn on the basis of 13C
NMR and NOE measurements. In the other acetonide, the
dioxolane ring was located between the C-7 and C-9
hydroxyl groups and reported to be anti. However, the
reasonings used to assign the (S)-configuration at C-5 were
not well grounded, in our opinion. For this reason, we
decided to synthesize the epimer of 1 having the (R)-
configuration at this carbon atom. To this purpose, the
â-oxygenated aldehyde resulting from the oxidative cleavage
of compound 10 (Scheme 2) was reacted with an allylating
reagent prepared from (+)-DIP-Cl and allylmagnesium
bromide (Scheme 3). The resulting alcohol 14 was treated
with cinnamoyl chloride to yield cinnamate 15, which was
then subjected to RCM using catalyst B to afford 16.
Cleavage of all protecting groups in 16 provided compound
17, the epimer of 1 at C-5. Once again, however, the spectral
data and the optical rotation of synthetic lactone 17 proved
to be different from those of the natural product.19
Acknowledgment. Financial support has been granted by
the Spanish Ministry of Education (DGICYT Project
BQU2002-00468) and by the BANCAJA-UJI foundation
(Project PI-1B2002-06). J.G.-F. thanks the Spanish Ministry
of Education for a predoctoral grant (FPU program). J.M.
thanks the Spanish Ministry of Science and Technology for
a Ramo´n y Cajal fellowship. The authors further thank Prof.
F. Echeverri, from the University of Antioqu´ıa, Colombia,
for sending copies of NMR spectra of passifloricin A.
Supporting Information Available: 1H and 13C NMR
spectra of compounds 1 and 17 and tabulated IR and NMR
data and optical rotation values for these compounds and
for their peracetylated derivatives. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem.
2002, 67, 7547-7550.
OL034182O
(18) Basic desilylation reagent TBAF gives rise to lactone-opening
reactions in this type of compound: Nakata, T.; Hata, N.; Oishi, T.
Heterocycles 1990, 30, 333-334.
(20) (5S,7R,9R,11R)-Stereoisomer, found in another plant source, is also
different from passifloricin A. Its structure has been confirmed by
stereoselective synthesis: Nakata, T.; Suenaga, T.; Nakashima, K.; Oishi,
T. Tetrahedron Lett. 1989, 30, 6529-6532.
(19) Comparison with NMR spectra of the authentic sample showed clear
differences, most particularly in the 13C signals around 70 and 40 ppm.
Org. Lett., Vol. 5, No. 9, 2003
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