Tandem cross-metathesis/hydrogenation: application to an enantioselective synthesis of pentadecyl 6-hydroxydodecanoate

Article abstract of DOI:10.1016/j.tetlet.2008.09.077

The synthesis of pentadecyl 6-hydroxydodecanoate, a component isolated from the leaves of Artabotrys odoratissimus, has been achieved through a tandem cross-metathesis/hydrogenation sequence. The enantioselective synthesis required first the preparation of a homoallylic alcohol obtained by a free-metal allyl transfer from a camphor derivative to heptanal.

Full text of DOI:10.1016/j.tetlet.2008.09.077

Tetrahedron Letters 49 (2008) 6816–6818
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem cross-metathesis/hydrogenation: application to an
enantioselective synthesis of pentadecyl 6-hydroxydodecanoate
*
Emmanuel Bourcet, Marie-Alice Virolleaud, Fabienne Fache, Olivier Piva
Université de Lyon -Université Lyon 1, CNRS, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (ICBMS), UMR 5246,
Equipe CheOPS, 43, Bd du 11 novembre 1918, 69622 Villeurbanne, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Revised 5 September 2008
Accepted 12 September 2008
Available online 18 September 2008
The synthesis of pentadecyl 6-hydroxydodecanoate, a component isolated from the leaves of Artabotrys
odoratissimus, has been achieved through a tandem cross-metathesis/hydrogenation sequence. The enan-
tioselective synthesis required first the preparation of a homoallylic alcohol obtained by a free-metal allyl
transfer from a camphor derivative to heptanal.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Metathesis
Hydrogenation
Total synthesis
Homoallylic alcohol
Allyl transfer
Long chain hydroxy fatty acids and esters are common frame-
works in nature. Most of them exhibit important biological activi-
ties, or have found application in the cosmetic and perfume
industries.1 Pentadecyl 6-hydroxy-dodecanoate 1 has been iso-
lated and characterized by Mehta et al. from the leaves of Artabot-
rys odoratissimus (Fig. 1).2 Due to its potential biological activities
in the treatment of cholera, the synthesis of this compound has
been performed by Ballini et al. in five steps, including a nitroaldol
condensation as the key-reaction.3
Having developed a straightforward access to substituted pyr-
ones 4 from 3-O-(1,4-pentadienyl) butanoate 2a by a tandem
ring-closing/cross-coupling metathesis reaction4,5 (Scheme 1), we
have now investigated the synthesis of 1 by a similar strategy per-
formed on the homologous ester 2b (n = 2). The RCM could deliver
the unsaturated caprolactone while the vinyl group could be func-
tionalized with hexene (R = C4H9) according to a subsequent cross-
metathesis. Reduction of the two double bonds and ring-opening
N
N
Mes
Cl
Cl
Mes
O
R
Ru
PCy
O
Ph
( )
O
n
3
+
3
( )
O
n
R
CH Cl , 45˚C
2
2
2a (n = 1)
2b (n = 2)
4 (39-75%)
5
Scheme 1.
of the lactone with pentadecanol could be performed to finally
deliver the target molecule 1.
Unsaturated ester 2b, easily prepared by esterification under
DCC activation,6 was first engaged into a ring-closing metathesis
process without addition of an alkene counterpart and in the pres-
ence of catalytic amounts of Grubbs’ type II catalyst 3. Instead of
the expected unsubstituted heptenolide 5, we observed the forma-
tion of two macrodiolides 6a and 6b in similar amounts (Scheme
2). These symmetric compounds result from a cross-coupling/
ring-closing process between two molecules of 2, and differ only
by the relative configuration of one of the two stereocenters.7 1H
NMR spectra show unambiguously that the configuration of the
internal C@C bond is E for the two diastereoisomers (J = 15.1and
15.5 Hz).8 The same reaction performed in the presence of n-hex-
ene delivered an inseparable mixture of compounds.
OH
OC
H
15 31
C H
4
9
O
1
Figure 1.
* Corresponding author. Tel./fax: +33 472 448 136.
E-mail address: piva@univ-lyon1.fr (O. Piva).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.077

E. Bourcet et al. / Tetrahedron Letters 49 (2008) 6816–6818
6817
O
O
OH
C H
6
13
*
O
O
C H
3
HO
6
13
(0.05equiv.)
O
O
(+/-)-7
+
O
CH Cl , Δ
2
2
3
CO C
H
O
2
15 31
(0.025
equiv.)
CO C
H
2
15 31
O
6a (17%)
11 (49%)
8
CH Cl
2
2
50˚C
2b
OH
H2, PtO
AcOEt
2
OC
H
15 31
11
C H
6
13
O
O
1 (94%)
6b (17%)
Scheme 2.
OH
*
12 (0.05equiv.)
C H
6
13
OH
*
O
PtO (0.05 equiv.)
While the tandem RCM/CM appeared unefficient, we turned to
another strategy based on a tandem cross-metathesis/hydrogena-
tion,9,10 which could directly afford the expected structure in a sin-
2
14
7
8
( )
+
C H
( )
O
H , CH Cl
6
13
4
2
2
2
CO C
H
2
15 31
gle step from readily available homoallylic alcohol
7 and
1 (56%)
pentadecanyl but-2-enoate 8. Moreover, in order to develop an
enantioselective synthesis of 1, we synthesized 7 by the allyl-
transfer method reported by Loh and co-workers11 and we previ-
ously used for the synthesis of the hermitamides.12 Thus, heptanal
was treated with the allyl isoborneol 9 in the presence of catalytic
amounts of camphorsulfonic acid at rt to deliver 7 in 72% yield and
in 88% ee (Scheme 3).
N
N
Mes
Cl
Cl
Mes
Ru
: 12
O
The enantiomeric excess was determined by derivatization of
the alcohol 7 with homochiral (S)-2-phenylpropionic acid.13 It
should be noted that 7 in racemic form was also esterified with
the same acid to give a 1:1 mixture of the two diastereoisomers
10, which denotes no kinetic resolution during this process. The
cross-metathesis was first performed between racemic alcohol 7
and 8. Compound 11 was obtained apparently as a single isomer
in 49% yield and according to previous results, the E configuration
has been assigned to the new C@C bond. Hydrogenation over PtO2
gave (+/À)-1 in 94% yield. Starting from enantiomeric enriched 7,
the tandem cross-metathesis/hydrogenation was achieved under
Scheme 4.
In conclusion, the synthesis of (6S)-pentadecyl 6-hydroxydode-
canoate 1 has been performed in only two steps from heptanal.
This strategy can be favorably compared to the previous synthesis,
which required up to five steps, and was performed on racemic
form.
a
hydrogen atmosphere in the presence of Grubbs-Hoveyda
Acknowledgment
reagent 1214 and catalytic amounts of PtO2. By this way, 1 was
directly isolated in 56% yield (Scheme 4).15,16
E.B. and M.-A.V. warmly thank the Ministère de l’Enseignement
Supérieur et de la Recherche for financial support.
References and notes
1. (a) Hasdemir, B.; Yusufoglu, A. Tetrahedron: Asymmetry 2004, 15, 65–68;
(b) Chavan, S. P.; Praveen, C.; Ramakrishna, G.; Kalkote, U. R. Tetrahedron Lett.
2004, 45, 6027–6028; (c) Williams, D. E.; Sturgeon, C. M.; Roberge, M.;
Andersen, R. J. J. Am. Chem. Soc. 2007, 129, 5822–5823; (d) Naka, M.; Takahashi,
K. Jpn Patent WO 20020742296, 2002.
2. Preeti, J.; Singh, N.; Mehta, B. K. Indian J. Chem., Sect. B 1998, 37, 618–620.
3. Ballini, R.; Gil, M. V.; Fiorini, D.; Palmieri, A. Synthesis 2003, 665–667.
4. (a) Virolleaud, M.-A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44, 8081–8084;
(b) Virolleaud, M.-A.; Piva, O. Synlett 2004, 2087–2090; (c) Virolleaud, M.-A.;
Piva, O. Tetrahedron Lett. 2007, 48, 1417–1420.
OH
OH
CSA (0.1 equiv.)
*
+
C6H13
CHO
CH2Cl2, 25°C
7
(72%)
(e.e. = 88%)
9
5. For related tandem RCM/CM reactions performed on terminal alkenes: (a)
Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143–4145; (b) Quinn,
K. J.; Isaacs, A. K.; DeChristopher, B. A.; Szklarz, S. C.; Arvary, R. A. Org. Lett.
2005, 7, 1243–1245; (c) Quinn, K. J.; Smith, A. G.; Cammarano, C. M.
Tetrahedron 2007, 63, 4881–4886; (d) Michaelis, S.; Blechert, S. Org. Lett.
2005, 7, 5513–5516; (e) Schmidt, B.; Nave, S. Chem. Commun. 2006, 2489–2491.
6. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522–524.
7. Data for 6a and 6b: 1H NMR (CDCl3): d 2.37–2.43 (4H, m); 5.19 (1H, d,
J = 10.3 Hz); 5.27 (1H, d, J = 16.9 Hz); 5.46 (1H, dd, J = 7.7, 15.1 Hz); 5.66–5.75
(2H, m); 5.85 (1H, ddd, J = 16.9, 10.3, 5.9 Hz). 1H NMR (CDCl3): d 2.37–2.56 (4 H,
m); 5.19 (1H, d, J = 10.4 Hz); 5.27 (1H, d, J = 17.2 Hz); 5.43 (1H, dd, J = 8.1,
15.5 Hz); 5.65–5.77 (2H, m); 5.88 (1H, ddd, J = 17.2, 10.4, 5.5 Hz).
O
Ph
OH
(S)-Phenyl
O
*
propionic acid
C6H13
C6H13
10
DCC, DMAP,
CH2Cl2, 0°C
7
(99%)
Scheme 3.

6818
E. Bourcet et al. / Tetrahedron Letters 49 (2008) 6816–6818
8. Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826–2830; Prunet, J. Angew. Chem.,
Int. Ed. 2003, 42, 3322.
9. (a) Fogg, D. E.; Amoroso, D.; Drouin, S. D.; Snelgrove, J.; Conrad, J.; Zamanian, F.
J. Mol. Catal. A: Chem. 2002, 190, 177–184; (b) Dragutan, V.; Dragutan, I. J.
Organomet. Chem. 2006, 691, 5129–5147.
10. (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312–
11313; (b) Drouin, S. D.; Zamanian, F.; Fogg, D. E. Organometallics 2001, 20,
5495–5497; (c) Cossy, J.; Bargiggia, F. C.; Bouzbouz, S. Tetrahedron Lett. 2002,
43, 6715–6717; (d) Cossy, J.; Bargiggia, F.; BouzBouz, S. Org. Lett. 2003, 5, 459–
462; (e) Schmidt, B.; Pohler, M. Org. Biomol. Chem. 2003, 1, 2512–2517; (f)
Borsting, P.; Freitag, M.; Nielsen, P. Tetrahedron 2004, 60, 10955–10966; (g)
Whelan, A. N.; Elaridi, J.; Harte, M.; Smith, S. V.; Jackson, W. R.; Robinson, A. J.
Tetrahedron Lett. 2004, 45, 8545–8547.
(367 mg, 3.0 mmol, 0.3 equiv) and DCC (2.27 g, 11.0 mmol, 1.1 equiv) were
added successively at room temperature to a solution of pentadecan-1-ol
(2.28 g, 10.0 mmol, 1 equiv) and vinylacetic acid (947 mg, 11.0 mmol,
1.1 equiv) in DCM (50 mL). The resulting mixture was stirred at room
temperature for 6 h. DCM was then removed under vacuum, and the residue
was dissolved in Et2O. Then urea was filtered off, and rinsed with Et2O. The
filtrate was then concentrated in vacuo, and the residue was purified by flash
chromatography on silica gel (5% ethyl acetate–hexanes) to afford ester 8 as a
colorless oil (2.96 g, 99% yield). 1H NMR (CDCl3): d 0.88 (3H, t, J = 6.8 Hz, H19),
1.25–1.30 (24H, m), 1.60–1.65 (2H, m), 3.08 (2H, d, J = 7.0 Hz), 4.08 (2H, t,
J = 6.8 Hz), 5.13–5.20 (2H, m), 5.93 (1H, ddt, J = 17.3, 9.8, 7.0 Hz). 13C NMR
(CDCl3): d 14.2, 22.8, 26.0, 28.7, 29.3, 29.5, 29.6, 29.7, 29.8, 32.0, 39.3, 64.9,
118.4, 130.5, 171.6. IR (neat):
m .
= 3072, 2925, 2854, 1742, 1467, 1171 cmÀ1
11. (a) Lee, C. L. K.; Lee, C. H. A.; Tan, K. T.; Loh, T. P. Org. Lett. 2004, 6, 1281–1283;
(b) Lee, C. H. A.; Loh, T. P. Tetrahedron Lett. 2004, 45, 5819–5822; (c) Lee, C. H.
A.; Loh, T. P. Tetrahedron Lett. 2006, 47, 809–812; (d) Lee, C. H. A.; Loh, T. P.
Tetrahedron Lett. 2006, 47, 1641–1644.
12. Virolleaud, M.-A.; Menant, C.; Fenet, B.; Piva, O. Tetrahedron Lett. 2006, 47,
5127–5130.
Formation of 11: Nitrogen was bubbled through a solution of homoallylic
alcohol 7 (156 mg, 1.0 mmol) and ester 8 (593 mg, 2.0 mmol) in DCM (0.2 M,
5 mL) for 10 min. Then, Grubbs’ second generation catalyst (21 mg,
0.025 mmol) was added, and the resulting mixture was heated to reflux
and stirred for 15 h. After cooling to room temperature, DCM was evaporated.
The residue was then purified by flash chromatography on silica gel (10%
ethyl acetate–hexanes) to give alkene 11 (210 mg, 49% yield). 1H NMR
(CDCl3): d 0.86–0.90 (6H, m); 1.26–1.30 (34H, m); 1.57–1.62 (4H, m); 3.06
(2H, d, J = 5.7 Hz); 3.58–3.65 (1H, m); 4.07 (2H, t, J = 6.8 Hz); 5.53–5.75 (2H,
m). 13C NMR (CDCl3): d 14.1, 14.1, 22.7, 22.8, 25.7, 25.9, 28.6, 29.3, 29.4, 29.4,
29.6, 29.6, 29.7, 29.7, 31.9, 31.9, 36.9, 38.1, 40.6, 64.9, 70.8, 125.2, 130.8,
13. Tyrrell, E.; Tsang, M. W. H.; Skinner, G. A.; Fawcett, J. Tetrahedron 1996, 52,
9841–9852.
14. (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923; (b)
Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S.
B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8–23; (c) Grubbs,
R. H. Tetrahedron 2004, 60, 7117–7140; (d) Clavier, H.; Grela, K.; Kirschning, A.;
Mauduit, M.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 6786–6801; (e)
Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Schrodi, Y. Org.
Lett. 2007, 9, 1589–1592.
172.1 IR:
m
= 3434, 2956, 2920, 2851, 1734, 1468, 1078 cmÀ1. MS: (ESI) m/z =
447 (M+Na+, 100). HRMS: (ESI) 447.3815 (M+Na+, C27H52O3Na requires
447.3814).
16. Tandem cross-metathesis/hydrogenation procedure: A solution of homoallylic
alcohol 7 (78 mg, 0.50 mmol, 1 equiv) and ester 8 (297 mg, 1.00 mmol, 2 equiv)
in DCM (0.2 M, 2.5 mL) was placed under vacuum, purged with H2. Grubbs-
Hoveyda catalyst (16 mg, 0.025 mmol, 0.05 equiv) and PtO2 (7.1 mg,
0.025 mmol, 0.05 equiv) were introduced at once. The reaction mixture was
degassed again under vacuum and then vigorously stirred under one
atmosphere of hydrogen. After 15 h at room temperature, the solvent was
evaporated, and the residue was purified by flash chromatography (10% ethyl
acetate–hexanes) to give pentadecyl 6-hydroxydodecanoate 1 (120 mg, 56%
yield). 1H NMR (CDCl3): d 0.86–0.90 (6H, m); 1.24–1.68 (42H, m); 2.31 (2H, d,
J = 7.4 Hz); 3.58–3.61 (1H, m); 4.05 (2H, t, J = 6.8 Hz). 13C NMR (CDCl3): d 14.1,
14.2, 22.7, 22.8, 25.1, 25.3, 25.7, 26.0, 28.7, 29.4, 29.5, 29.6, 29.7, 29.8, 29.8,
15. Experimental procedures and data: Homoallylic alcohol 7: CSA (70 mg,
0.30 mmol, 0.1 equiv) was added to
a solution of heptanal (1.14 g,
3.00 mmol, 1 equiv) and allylated camphor (1.75 g, 9.00 mmol, 3 equiv) in
DCM (6 M, 0.5 mL). The resulting mixture was stirred at room temperature
for
5 days. Then NaHCO3 (5 mL) and DCM (5 mL) were added and the
aqueous phase was separated, and extracted with DCM (3 Â 5 mL). The
combined organic extracts were washed with brine (10 mL), and then dried
over magnesium sulfate, and concentrated. Purification of the residue by flash
chromatography (5% ethyl acetate–petroleum ether) afforded alcohol 7 as a
colorless oil (337 mg, 72% yield). 1H NMR (CDCl3): d 0.88 (3H, t, J = 7.0 Hz);
1.29–1.59 (10H, m), 2.08–2.18 (1H, m), 2.26–2.35 (1H, m), 3.60–3.68 (1H, m),
5.11–5.16 (2H, m), 5.83 (1H, ddt, J = 16.2, 9.8, 7.2 Hz). 13C NMR (CDCl3): d
31.9, 32.0, 34.4, 37.1, 37.6, 64.6, 71.7 173.9. IR neat:
1460, 1191 cmÀ1. MS: (ESI) m/z = 449 (M+Na+, 100). HRMS: (ESI) 449.3971
(M+Na+, C27H54O3Na requires 447.3971). [
+0.4 (c 1.6, CHCl3).
m = 3348, 2918, 2850, 1728,
14.1, 22.7, 25.7, 29.4, 31.9, 36.9, 42.0, 70.8, 117.9, 135.1. IR:
m = 3368, 3077,
2930, 2859, 1459, 993, 912 cmÀ1. [
a
]
À8.7 (c 1.06, CHCl3). Ester 8: DMAP
a]
D
D