Facile synthesis of (-)-6-acetoxy-5-hexadecanolide by size-selective ring-closing/cross metathesis

Article abstract of DOI:10.1016/j.tetlet.2009.09.179

A total synthesis of (-)-6-acetoxy-5-hexadecanolide, in six steps and 37% overall yield from (2R,3S)-1,2-epoxy-4-penten-3-ol is reported. The key synthetic step is a size-selective ring-closing/cross metathesis reaction in which lactone formation and alky

Full text of DOI:10.1016/j.tetlet.2009.09.179

Tetrahedron Letters 50 (2009) 7121–7123
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of (ꢀ)-6-acetoxy-5-hexadecanolide by size-selective
ring-closing/cross metathesis
*
Kevin J. Quinn , John M. Curto, Kevin P. McGrath, Neal A. Biddick
Department of Chemistry, College of the Holy Cross, Worcester, MA 01610-2395, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of (ꢀ)-6-acetoxy-5-hexadecanolide, in six steps and 37% overall yield from (2R,3S)-1,2-
epoxy-4-penten-3-ol is reported. The key synthetic step is a size-selective ring-closing/cross metathesis
reaction in which lactone formation and alkyl chain extension are accomplished in an efficient one-pot
process.
Received 14 September 2009
Revised 25 September 2009
Accepted 30 September 2009
Available online 4 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycle synthesis
Olefin metathesis
Ring-size selectivity
OAc
(ꢀ)-6-Acetoxy-5-hexadecanolide (1) is the major component of
the apical droplets that form on the eggs of the mosquito Culex
pipiens fatigans and has been shown to attract and induce oviposi-
tion in gravid female mosquitoes of this species.1 Culex pipiens fat-
igans is found throughout the world and is a known vector for
filarial infections, malaria, and West Nile virus.2 Due to the poten-
tial of 1 in controlling mosquito populations, it has received con-
siderable attention from the synthetic community, and numerous
enantioselective syntheses have been reported.3 Herein, we report
a short and flexible synthesis of 1 employing a one-pot, size-selec-
tive ring-closing metathesis (RCM)/cross metathesis (CM) reaction
as the key step.
O
(-)-6-acetoxy-
5-hexadecanolide, 1
O
OBn
O
OBn
CM
( )7
O
2
3
O
O
OBn
Our retrosynthetic analysis is outlined in Scheme 1. Central to
our plan was the assembly of protected 6-(1-hydroxy-2-undece-
nyl)-3,6-dihydropyranone 2 from acyclic triene 4 by RCM/CM. It
was anticipated that initial RCM of vinylacetate 4 would provide
six-membered lactone 3, and subsequent CM between 1-decene
and the exocyclic olefin of 3 would complete the process to provide
2. Although two modes of closure are possible in the RCM (six- vs
seven-membered ring formation), our previous studies on size-
selective RCM of acrylate esters related to 4 gave us reason to be-
lieve that formation of the smaller ring would be preferred.4
Metathesis substrate 4 was expected to be available by elaboration
of known (2R,3S)-1,2-epoxy-4-penten-3-ol (5),5 which possesses
the requisite erythro stereochemistry of 1.
OH
RCM
O
O
5
4
O
Scheme 1. Retrosynthetic analysis.
homologation upon treatment with dimethylsulfonium methylide7
to give allylic alcohol 6, a desymmetrized analogue of meso-hexa-
1,5-diene-3,4-diol. Subsequent acylation with vinylacetic acid
completed an efficient synthesis of 4 (57% over three steps).
With 4 in hand, we set out to establish the size selectivity of its
RCM. As noted earlier, two ring closure products are possible—
dihydropyranone 3 or oxepanone 7—by metathesis between the
vinylacetate group and the proximal olefin or the distal olefin,
respectively. We found that treatment of 4 with 10 mol % of the
second-generation Grubbs’ catalyst8 [PhCH@RuCl2(PCy3)(IMes)]
Metathesis substrate 4 was prepared from 5 in three steps as
outlined in Scheme 2. Benzylation was followed by one carbon
* Corresponding author. Tel.: +1 508 793 3576; fax: +1 508 793 3530.
E-mail address: kquinn@holycross.edu (K.J. Quinn).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.179

7122
K. J. Quinn et al. / Tetrahedron Letters 50 (2009) 7121–7123
ple of an isomerization of this type has been reported.13 As we did
1. NaH, BnBr,
Bu4NI, THF,
94%
not observe isomerization in the RCM of 4 (reaction time of 1 h),
we speculate that the extended reaction time required for the
CM results in decomposition of the propagating metathesis-active
catalyst and corresponding build-up of an isomerization-active Ru
species, which promotes the isomerization of 2 subsequent to CM
or intermediate 3 prior to CM.
OBn
OH
2. Me3S+I-, nBuLi,
THF, 82%
O
OH
5
6
OBn
CO2H
DIC, DMAP,
CH2Cl2, 79%
O
OBn
4
( )7
O
OBn
O
OBn
O
Grubbs' II, CH2Cl2,
2 (41%)
40 oC, 1h;
Grubbs' II
CH2Cl2, 40 oC
O
or
4
ð2Þ
O
O
OBn
1-decene,
40 oC, 36 h
3 (90%)
7
O
( )7
O
Scheme 2. Preparation and RCM of 4.6
9 (27%)
O
Although both dihydropyranones 2 and 9 are useful in our syn-
thetic plan, we felt the yield of the RCM/CM process may be improved
if isomerization could be prevented. Previously, we found that isom-
erization could be suppressed by use of the second-generation Hov-
eyda–Grubbs’ catalyst14 [o-isopropoxyPhCH@RuCl2(IMes)] rather
than the second-generation Grubbs’ catalyst,15 so we chose to exam-
ine its use in the sequential RCM/CM procedure. We were pleased to
find that use of 10 mol % of the second-generation Hoveyda–Grubbs’
catalyst provided 77% yield of 2 in just 22 h (Scheme 3).16 Isomeriza-
tion product 9 was not observed even if the reaction was allowed to
run for up to 36 h. Although not important in our synthesis of 1, it
should be noted that CM generated 2 with complete (E)-selectivity
for the exocyclic olefin as determined by 1H NMR (J = 15.5 Hz).
Completion of the synthesis was accomplished by catalytic
hydrogenation/hydrogenolysis of 2 followed by acetylation of the
resulting secondary alcohol to give 1 as a colorless oil in 80% yield.
(ꢀ)-6-Acetoxy-5-hexadecanolide produced in this manner dis-
played spectral data and optical rotation consistent with those re-
ported in the literature.17
In summary, an efficient strategy for the synthesis of 6-(1-hy-
droxy-2-alkenyl)-3,6-dihydropyranones via sequential RCM/CM
has been demonstrated by its application in a short synthesis of
the mosquito oviposition pheromone (ꢀ)-6-acetoxy-5-hexadecan-
olide. The flexibility inherent in this approach and the high degree
of functionality present in RCM/CM products like 2 make it broadly
applicable. Extension to the synthesis of more complex natural
products and studies on the size-selective RCM of unsaturated es-
ters of diene diols are underway and results will be reported in due
course.
in refluxing CH2Cl2 resulted in the exclusive formation of 3 in 90%
isolated yield within an hour. The assignment of 3 as dihydropyr-
anone was based on the upfield shift of the C@O resonance in its
13C NMR spectra (d 170.0) relative to the expected position of the
corresponding resonance for the isomeric oxepanone (d ꢁ175)
and later confirmed by comparison (vide infra).
Encouraged by the yield and selectivity observed for RCM of 4, we
turned our attention to its incorporation into the proposed RCM/CM
process for the preparation of the chain-extended dihydropyranone
2. In an attempt to conduct a tandem RCM/CM, second-generation
Grubbs’ catalyst (10 mol %) was added to a refluxing 0.01 M CH2Cl2
solution of triene 4 and five equivalents of 1-decene. Unfortunately,
the major product isolated from the reaction was chain-extended
triene 8, which arose from CM between the vinylacetate alkene
and 1-decene (Eq. 1). This outcome was not wholly unexpected
considering (1) the stoichiometry employed which likely favors ini-
tiation with 1-decene, and (2) the relative reactivity of the vinylace-
tate alkene and 1-decene (both type I) compared to that of the C1–C2
and C5–C6 alkenes (both type II).9 However, it was somewhat
surprising that no trace of the desired RCM/CM product 2 could be
isolated under our reaction conditions given reports by Piva and
coworkers of successful tandem RCM/CM of vinylacetates of divinyl
carbinol with terminal alkenes10 and tandem RCM/intramolecular
alkenyl transfer of substituted vinylacetates of divinyl carbinol.11
OBn
Grubbs' II,
1-decene
4
ð1Þ
O
CH2Cl2,
( )7
8
40 oC, 54%
O
In order to prevent the formation of undesired CM product 8,
we turned to a sequential procedure in which a 0.01 M solution
of 4 in CH2Cl2 and second-generation Grubbs’ catalyst (10 mol %)
was heated to reflux until RCM was judged to be complete by
TLC analysis (1 h) followed by addition of 5 equiv of 1-decene.
Heating was then continued until complete consumption of RCM
product 3 was observed (36 h). We were surprised to find that this
procedure gave a separable mixture of expected dihydropyranone
2 and its isomer 9, in a roughly 1.5:1 ratio and 68% combined yield
(Eq. 2). It is well known that Ru metathesis initiators are capable of
catalyzing olefin isomerization, through their presumed conver-
sion to Ru hydride species;12 however, conjugative isomerization
OBn
O
Hoveyda-Grubbs' II,
CH2Cl2, 40 oC, 1 h ;
( )7
4
1-decene, 40 oC,
21 h, 77%
2
O
OAc
O
1. H2, Pd/C, THF
2. Ac2O, pyr, CH2Cl2
( )7
80% (two steps)
1
O
to an
a,b-unsaturated system, as in the formation of 9, is exceed-
Scheme 3. Completion of the synthesis of 1.6
ingly rare. To the best of our knowledge, only one previous exam-

K. J. Quinn et al. / Tetrahedron Letters 50 (2009) 7121–7123
8. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
7123
Acknowledgments
9. Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360.
Financial support of this research by the National Science Foun-
dation (CHE-0848128) and the Pfizer Undergraduate Research Fel-
lowship Program is gratefully acknowledged. Mass spectral data
were obtained at the University of Massachusetts Mass Spectrom-
etry Facility, which is supported, in part, by the National Science
Foundation.
10. Virolleaud, M. A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003, 44, 8081.
11. Virolleaud, M. A.; Piva, O. Synlett 2004, 2087.
12. For
a review of the non-metathetic reactivity of Ru carbene complexes
including olefin isomerization, see: Alcaide, B.; Almendros, P.; Luna, A. Chem.
Rev. 2009, 109, 3817.
13. Formentin, P.; Gimeno, N.; Steinke, J. H. G.; Vilar, R. J. Org. Chem. 2005, 70, 8235.
14. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168.
15. Quinn, K. J.; Curto, J. M.; Faherty, E. E.; Cammarano, C. M. Tetrahedron Lett.
2008, 49, 5238.
References and notes
16. RCM//CM of 4 and 1-decene. To a solution of triene 4 (202.0 mg, 0.74 mmol) in
CH2Cl2 (74 mL) was added second-generation Hoveyda–Grubbs’ catalyst
(46.3 mg, 0.074 mmol). The reaction mixture was heated to reflux for 1 h, at
which time TLC analysis indicated that RCM was complete. 1-Decene (0.70 mL,
3.70 mmol) was added by syringe, and heating was continued for an additional
21 h. After cooling to room temperature, the brown solution was filtered
through a short pad of silica gel, and the filtrate was concentrated in vacuo.
Purification by silica gel chromatography (4:1 hexanes/Et2O) gave RCM/CM
1. (a) Laurence, B. R.; Pickett, J. A. J. Chem. Soc., Chem. Commun. 1982, 59; (b)
Laurence, B. R.; Mori, K.; Otsuka, T.; Pickett, J. A.; Wadhams, L. J. J. Chem. Ecol.
1985, 11, 643.
2. Anderson, J. F.; Andeadis, T. G.; Vossbrinck, C. R.; Tirrell, S.; Waken, E. M.;
French, R. A.; Garmendia, A. E.; Van Kruiningen, H. J. Science 1999, 286, 2331.
3. For recent syntheses and leading references, see: (a) Singh, S.; Guiry, P. J. Eur. J.
Org. Chem. 2009, 1896; (b) Prasad, K. R.; Anbarsan, P. Tetrahedron: Asymmetry
2007, 18, 2479; (c) Sabitha, G.; Swapna, R.; Reddy, E. V.; Yadav, J. S. Synthesis
2006, 4242; (d) Ikishima, H.; Sekiguchi, Y.; Ichikawa, Y.; Kotsuki, H. Tetrahedron
2006, 62, 311; (e) Dhotare, B.; Goswami, D.; Chattopadhyay, A. Tetrahedron Lett.
2005, 46, 6219; (f) Sun, B.; Peng, L.; Chen, X.; Li, Y.; Yamasaki, K. Tetrahedron:
Asymmetry 2005, 16, 1305.
4. (a) Quinn, K. J.; Smith, A. G.; Cammarano, C. M. Tetrahedron 2007, 63, 4881; (b)
Quinn, K. J.; Isaacs, A. K.; DeChristopher, B. A.; Szklarz, S. C.; Arvary, R. A. Org. Lett.
2005, 7, 1243; (c) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143.
5. Prepared in gram quantities and high enantiopurity (>98% ee) from
commercially available divinyl carbinol via modified Sharpless asymmetric
epoxidation using cumene hydroperoxide instead of t-butylhydroperoxide, see:
Romero, A.; Wong, C. H. J. Org. Chem. 2000, 65, 8264.
product 2 (203.1 mg, 77%) as a yellow oil. Data for 2: ½a D22
ꢂ
+70.1 (c 1.55, CHCl3);
1H NMR (CDCl3, 400 MHz) d 7.37–7.24 (m, 5H), 5.95–5.87 (m, 2H); 5.81 (dt,
J = 15.5, 6.8 Hz, 1H), 5.33 (ddt, J = 15.5, 8.1, 1.5 Hz, 1H), 4.90 (m, 1H), 4.57 (d,
J = 11.6 Hz, 1H), 4.37 (d, J = 11.6 Hz, 1H), 4.09 (dd, J = 8.1, 3.4 Hz, 1H), 3.12–2.96
(m, 2H), 2.09 (q, J = 6.8 Hz, 2H), 1.45–1.22 (m, 12H), 0.88 (t, J = 6.9, 3H);13C
NMR (CDCl3, 100 MHz) d 169.8, 137.9, 137.8, 128.4, 127.8, 127.7, 124.6, 124.0,
121.9, 82.0, 81.6, 70.7, 32.3, 31.9, 30.8, 29.4, 29.3, 29.1, 29.0, 22.6, 14.1; HRMS
calcd for C23H33O3 (MH+) 357.2430, found 357.2434.
17. Data for (ꢀ)-6-acetoxy-5-hexadecanolide (1): ½a D22
ꢂ
ꢀ36.1 (c 0.85, CHCl3); lit.3a
½
a 2D0
ꢂ
ꢀ35.4 (c 0.85, CHCl3); 1H NMR (CDCl3, 400 MHz) d 4.98 (dt, J = 7.8, 5.0 Hz,
1H), 4.35 (ddd, J = 11.0, 4.8, 3.4 Hz, 1H), 2.60 (m, 1H), 2.46 (m, 1H), 2.08 (s, 3H),
2.02–1.76 (m, 2H), 1.73–1.52 (m, 4H), 1.48–1.20 (m, 16H), 0.88 (t, J = 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 170.8, 170.5, 80.5, 74.3, 31.9, 29.5, 29.4, 29.3,
25.2, 23.5, 22.7, 21.0, 18.3, 14.1; HRMS calcd for C18H33O4 (MH+) 313.2379,
found 313.2375.
6. Yields cited in the schemes are for chromatographically and spectroscopically
homogeneous substances. All structural assignments are supported by 1H and
13C NMR and high-resolution mass spectrometric analyses.
7. Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall, T.; Shin, D. S.;
Falck, J. R. Tetrahedron Lett. 1994, 35, 5449.