A synthesis of (-)-mintlactone

Article abstract of DOI:10.1021/jo801433f

(Chemical Equation Presented) Mintlactone is synthesized in a concise and efficient way by using a highly diastereoselective intramolecular propargylic Barbier reaction, followed by an allenol cyclocarbonylation. Tin(II) chloride is found to be the most effective reagent for the Barbier reaction.

Full text of DOI:10.1021/jo801433f

A Synthesis of (-)-Mintlactone
Roderick W. Bates* and S. Sridhar
DiVision of Chemistry and Biological Chemistry, School of
Physical and Mathematical Sciences, 21 Nanyang Link,
Nanyang Technological UniVersity, Singapore 637371
FIGURE 1. The mintlactones.
roderick@ntu.edu.sg
SCHEME 1. Butenolide Synthesis
ReceiVed July 11, 2008
SCHEME 2. Mintlactone Synthesis
Mintlactone is synthesized in a concise and efficient way
by using a highly diastereoselective intramolecular propar-
gylic Barbier reaction, followed by an allenol cyclocarbo-
nylation. Tin(II) chloride is found to be the most effective
reagent for the Barbier reaction.
The butenolide moiety is widespread among natural products.1
One way to synthesize butenolides is by the cyclocarbonylation
of allenic alcohols.2 Allenic alcohols may, in turn, be obtained
by the Barbier reaction between propargylic halides and
aldehydes.3 This reaction, however, may give either allenic
alcohols or propargylic alcohols according to the substitution
pattern and the reagents employed. If such a propargylic Barbier
reaction were carried out in an intramolecular fashion, it could
be constrained to give only the allenic alcohol. To our
knowledge, there are only two reports of such an intramolecular
transformation, neither addressing stereochemical issues.4 The
intramolecular propargylic Barbier reaction would lead to a
bicyclic butenolide after cyclocarbonylation (Scheme 1).
The simplest such bicyclic butenolide natural products are
mintlactone 1 and isomintlactone 2 (Figure 1).5,6 They make
appropriate targets for exploring this route, but also raise
the issue of diastereoselectivity during cyclization. In this
paper we wish to report the application of this chemistry to
the synthesis of (-)-mintlactone 1 (Scheme 2).
For the synthesis of the natural product, we planned to
introduce the methyl group using Feringa’s asymmetric conju-
gate addition methodology.7 The required thioester substrate was
prepared by reacting the lithium derivative of the THP ether of
propargyl alcohol with oxetane in the presence of BF3 ·OEt2
according to the procedure of Ganem.8 Oxidation of primary
alcohol 3 and Wittig reaction of the aldehyde without isolation
of the intermediate aldehyde yielded the required unsaturated
thioester 4 in 71% yield. Addition of methyl magnesium
bromide in the presence of the copper(I)-(R)-Tol-BINAP
complex (from copper(I) iodide 1 mol % and (R)-Tol-BINAP
1.4 mol %), as described by Feringa,7 gave the desired
(1) Knight, D. W. Contemp. Org. Synth. 1994, 1, 287. Collins, I. J. Chem.
Soc., Perkin Trans. 1 1999, 1377.
(2) Yoneda, E.; Zhang, S.-W.; Onitsuka, K.; Takahashi, S. Tetrahedron Lett.
2001, 42, 5459. Yoneda, E.; Kaneko, T.; Zhang, S.-W.; Onitsuka, K.; Takahashi,
S. Org. Lett. 2000, 2, 441.
(3) Isaac, M. B.; Chan, T. H. J. Chem. Soc., Chem. Commun. 1995, 1003.
(4) Ivkovic, A.; Matovic, R.; Saicic, R. N. J. Serb. Chem. Soc. 2002, 67,
141. Kang, H.-Y.; Kim, Y.-T.; Yu, Y.-K.; Cha, J. H.; Cho, Y. S.; Koh, H. Y.
Synlett 2004, 45. For a related reaction employing low-valent titanium that works
only for ketones, see: Yoshida, Y.; Nakagawa, T.; Sato, F. Synlett 1996, 437.
For an interesting transformation using NaCpW(CO)3 that involves an allenol
intremediate, see: Shieh, S.-J.; Tang, T.-C.; Lee, J.-S.; Lee, G.-H.; Peng, S.-M.;
Liu, R.-S. J. Org. Chem. 1996, 61, 3245.
(5) Takahashi, K.; Someya, T.; Muraki, S.; Yoshida, T. Agric. Biol. Chem.
1980, 44, 1535.
(6) Pandey, R. K.; Upadhyay, R. K.; Shinde, S. S.; Kumar, P. Synth. Commun.
2004, 34, 2323.
(7) Ruiz, B. M.; Geurts, K.; Fernandez-Ibanez, M. A.; ter Horst, B.; Minnaard,
A. J.; Feringa, B. L. Org. Lett. 2007, 9, 5123.
(8) Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106, 3693.
8104 J. Org. Chem. 2008, 73, 8104–8105
10.1021/jo801433f CCC: $40.75 2008 American Chemical Society
Published on Web 09/24/2008

TABLE 1. Barbier Reaction Conditions
entry
conditions
time/h
T/°C
yield/%
1
2
3
4
5
6
7
Zn, NH4Cl, THF
In, H2O, DMF
SnCl2, NaI, DMF
SnCl2, NaI, H2O, DMF
Sn(BF4)2, NaI, H2O, DMF
Sn(O2C8H15)2, NaI, H2O, DMF
SnI2, NaI, H2O, DMF
12
24
48
56
48
48
12
0 to rt
rt
0
-10
-10
-10
-10
36a
47b
13
75b
10
24
0
FIGURE 2. Chair transition state.
Ru3(CO)12. This completed a concise and highly stereoselective
synthesis of (-)-mintlactone 1. The spectroscopic data (1H and
13C NMR) were in good agreement with that reported. An
optical rotation of -59.2 (c 2.4, CHCl3) was measured for the
synthetic material (lit.5,16 -51.8 (c 10, EtOH), -57 (c 2.4,
CHCl3)).
a 3:1 ratio of diastereoisomers; b e5% of the minor diastereoisomer.
The completion of the synthesis demonstrates a concise route
to butenolides and shows that the intramolecular propargylic
Barbier reaction is a valuable transformation and can proceed
with remarkably high diastereoselectivity. The role of water in
these reactions requires further study.
ꢀ-methylated ester 5 in 84% yield. Removal of the THP group
allowed determination of the ee as 94% by chiral HPLC of the
corresponding 3,5-dinitrobenzoate 6a. To continue the synthesis,
the propargylic alcohol 6 was converted to bromide 8, via the
mesylate in an overall yield of 84% (three steps). The thioester
was then reduced to aldehyde 9 by DIBAL reduction in 92%
yield.9 Bromoaldehyde 9 was subjected to propargylic Barbier
cyclization by using a variety of reagents (Table 1). Cyclization
with zinc/ammonium chloride10 gave quite modest diastereo-
selectivity (entry 1). On the other hand, cyclization with
indium11 in water (entry 2) or tin(II) chloride in DMF in the
presence of sodium iodide12 proceeded with high diastereose-
lectivity to give the cis-cyclohexyl product 10. As tin(II) chloride
gave the cleanest conversion to the desired allenol and the
highest yield, our efforts were focused on optimizing this
reaction. Due to an initial concern about the possible deleterious
effect of residual moisture in commercial “anhydrous” DMF,
we examined the use of carefully dried DMF (distilled from
CaH2 under reduced pressure). To our surprise, the yield was
reduced to a meagre 13% (entry 3). On the other hand,
employing a DMF-water mixture at -10 °C resulted in an
increase in yield to 75% (entry 4).13 Only a trace (e5%) of the
other diastereoisomer was discernible by high-field 1H NMR.14
The choice of tin(II) reagent was also found to be critical: the
use of tin(II) tetrafluoroborate (aq), tin(II) iodide, or tin(II)
2-ethylhexanoate resulted in low yields (0-24%, entries 5-7).
Thus both water and chloride appear to be essential for this
tin(II)-mediated reaction. The stereochemistry of the allenol
product was assigned based upon the observation of coupling
constants of 11 and 4.3 Hz for the proton R to the hydroxyl
group, after decoupling of the allenic protons. These coupling
constants are consistent with the alcohol group and, presumably,
the methyl group being equatorial. This assignment was
subsequently confirmed by X-ray crystallography. The stereo-
chemistry is consistent with a chair transition state15 with an
equatorial methyl group during cyclization (Figure 2).
Experimental Section
(1R,5R)-5-Methyl-2-vinylidenecyclohexanol (10). To a solution
of compound 9 (780 mg, 3.5 mmol) in DMF (16 mL) and water (2
mL) under nitrogen at -10 °C was added SnCl2 (1 g, 5.4 mmol)
followed by NaI (808 mg, 5.4 mmol). After stirring at -10 °C for
56 h, 20 mL of water and 50 mL of Et2O were added. The mixture
was stirred at room temperature for 30 min, then filtered through
celite, washing with Et2O. The organic layer was separated and
washed with water and brine and dried (MgSO4). The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography on silica gel (30 g, 10% EtOAc/hexane)
to give allenic alcohol 10 (372 mg, 75%) as a colorless solid. Mp
54-56 °C. [R]24D +15.1 (c 1, CHCl3). 1H NMR (300 MHz, CDCl3)
δ 4.99-4.85 (2H, m), 4.05-3.91 (1H, m), 2.39 (1H, ddd, J ) 13.7,
3.9, 2.6 Hz), 2.16-1.92 (3H, m), 1.79-1.63 (1H, m), 1.61-1.45
(1H, m), 1.08-0.97 (2H, m), 0.94 (3H, J ) 6.6 Hz). 13C NMR
(75.4 MHz, CDCl3) δ 199.7, 107.1, 79.7, 67.9, 44.5, 34.7, 31.3,
29.5, 22.2. IR (KBr, cm-1) νmax 3382 (br), 2951, 2924, 1956, 1458,
1166. HRMS m/z calcd for C9H15O 139.1123 (M+ + H), found
139.1117.
(-)-Mintlactone (1). Triruthenium dodecacarbonyl (4.6 mg,
0.0072 mmol) was added to a mixture of compound 10 (50 mg,
0.36 mmol) and Et3N (0.2 mL, 1.45 mmol) in dioxane (2 mL) at
room temperature in a Fisher-Porter tube. The tube was flushed
with carbon monoxide and pressurized to 100 psi, then stirred at
100 °C for 14 h. The reaction mixture was cooled to 0 °C for 10
min, then the carbon monoxide was released, the solvent was
removed under reduced pressure, and the residue was purified by
column chromatography on silica gel (10 g, 15% EtOAc/hexane)
to give (-)-mintlactone 1 (50 mg, 83%) as a pale yellow oil. [R]24
D
1
-59.2 (c 2.4, CHCl3). H NMR (300 MHz, CDCl3) δ 4.60 (1H,
dd, J ) 11.0, 6.0 Hz), 2.77 (1H, ddd, J ) 14.2, 4.3, 1.8 Hz),
2.43-2.35 (1H, m), 2.17 (1H, td, J ) 13.7, 5.4 Hz), 1.95-1.85
(1H, m), 1.78 (3H, t, J ) 1.4 Hz), 1.76-1.62 (1H, m), 1.09-0.86
(2H, m), 0.98 (3H, d, J ) 6.6 Hz). 13C NMR (75.4 MHz, CDCl3)
δ 174.9, 162.4, 119.6, 80.0, 42.0, 34.6, 29.8, 25.5, 21.2, 8.2. IR
(neat, cm-1) νmax 2953, 2927, 1747, 1730, 1687.
The synthesis was completed by treatment of the allenic
alcohol 10 with triruthenium dodecacarbonyl and triethylamine
under a pressure of 100 psi of CO.2 A yield of 83% of
mintlactone 1 was obtained by using only 2 mol % of
Acknowledgment. We thank the Singapore Minstry of
Education Academic Research Fund Tier 2 (grant T206B1220RS)
and Nanyang Technological University for generous support
of this work.
(9) Use of Et3SiH-Pd/C (Fukuyama T.; Tokuyama H. Aldrich. Acta; 2004,
37, 87) resulted in competing alkyne reduction.
(10) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910.
(11) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149.
(12) Mukaiyama, T.; Harada, T. Chem. Lett. 1981, 621.
(13) In contrast, Liu et al. have reported that excess water reduces the yield
of SnCl2-mediated allylation: Tan, X.-H.; Hou, Y.-Q.; Huang, C.; Liu, L.; Guo,
Q.-X. Tetrahedron 2004, 60, 6129.
Supporting Information Available: Experimental details for
compounds 3-9, spectroscopic data for compounds 1 and 3-10,
and the ORTEP structure and crystallographic information for
compound 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) The isomeric ꢀ-hydroxyalkyne was not observed.
(15) Chairtransitionstateshavebeenproposedinrelatedallylreactions:Schlosser,
M.; Franzini, L.; Bauer, C.; Leroux, F. Chem. Eur. J. 2001, 7, 1909. Keck, G. E.;
Dougherty, S. M.; Savin, K. A. J. Am. Chem. Soc. 1995, 117, 6210. Gevorgyan,
V.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett. 1993, 34, 1313.
(16) Chavan, S. P.; Zubaidha, P. K.; Dhonge, V. D. Tetrahedron 1993, 49,
6429.
JO801433F
J. Org. Chem. Vol. 73, No. 20, 2008 8105