Total synthesis of the gypsy moth pheromones (+)- and (-)-disparlure from a single nonracemic α-silyloxy allylic stannane

Full text of DOI:10.1021/jo982353a

2152
J . Org. Chem. 1999, 64, 2152-2154
For these studies, we targeted the sex attractant of the
Tota l Syn th esis of th e Gyp sy Moth
female gypsy moth, (+)-disparlure (13). This relatively
simple substance has been the object of numerous
synthetic investigations.6 The earliest approaches em-
ployed chiral pool starting materials with extant diol
functionality of appropriate chirality. More recently, the
Sharpless asymmetric epoxidation6b and dihydroxylation6c
have been employed to introduce the requisite epoxide
chirality.
Our approach differs from the others by combining
chain elongation and introduction of the chiral diol
centers in a single step. The stannane reagent provides
the desired stereogenicity. Initially, we planned to pursue
the route outlined in eq 2 in which the (S)-stannane 8
would undergo BF3-promoted addition to 2-undecenal (9)
to afford the syn adduct 10. Our choice of a conjugated
P h er om on es (+)- a n d (-)-Disp a r lu r e fr om a
Sin gle Non r a cem ic r-Silyloxy Allylic
Sta n n a n e
J ames A. Marshall,* J ill A. J ablonowski, and
Hongjian J iang
Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22901
Received December 1, 1998
In 1991, we described studies on the stereospecific 1,3-
isomerization of enantioenriched R-alkoxy allylic stan-
nanes 1 to their γ-isomers 2 and the subsequent Lewis
acid-promoted addition of these γ-isomers to various
aldehydes to afford monoprotected syn 1,2-diols 3 (eq 1).1
Since that time, we have employed this reaction as a
key step in the synthesis of various prototypes of carbo-
hydrates, amino sugars, and acetogenins.2 Initially, these
applications utilized crotyl OMOM or OTBS stannanes
(2, R1 ) MOM or TBS; R2 ) CH3) as the chiral reagents.3
More recently, we have directed our attention to longer
chain and more highly functionalized stannane reagents
for the synthesis of natural products bearing chiral
vicinal diol units or derivatives thereof.4 Although ap-
plications of this nature may appear to be routine
extensions of our crotyl stannane work, we observed a
significant loss of diastereoselectivity with a longer chain
stannane (2, R1 ) TBS; R2 ) n-C10H21) vs crotyl (2, R1 )
TBS; R2 ) CH3) in our synthesis of (+)- and (-)-
muricatacin.3b Moreover, recent findings by Quintard and
co-workers on BF3-promoted additions of γ-ethoxy allylic
stannanes (2 R1 ) Et) with branched R-substituents (R2)
to benzaldehyde showed significant erosion of syn dia-
stereoselectivity.5 In fact, the i-Pr and t-Bu reagents (2,
R1 ) Et; R2 ) i-Pr, t-Bu) yielded mainly the anti adducts.
Additional investigations of additions involving long-
chain γ-oxygenated allylic stannanes therefore seemed
desirable.
aldehyde for this step was based on the higher syn/anti
ratios of adducts observed with such aldehydes as op-
posed to their saturated counterparts.2,3b Hydrogenation
of the dienic adduct 10 followed by tosylation would lead
to the precursor 12, which upon silyl ether cleavage with
TBAF, would expectedly cyclize to (+)-disparlure (13).
However, this plan was stymied by our inability to
separate stannane 8 from tin byproducts. Accordingly,
we reversed the aldehyde and stannane partners hoping
for an easier purification of the long-chain OTBS stan-
nane 16 (eq 3). This, in fact, turned out to be the case.
Thus, addition of Bu3SnLi to (E)-2-undecenal (9)7 followed
by in situ oxidation afforded the acylstannane 14. Reduc-
tion with (S)-BINAL-H8 and in situ treatment with
TBSOTf yielded the (R)-γ-silyloxy stannane 16 via the
R-isomer 15 in 42% overall yield (eq 3).2
(1) Marshall, J . A.; Welmaker, G. S.; Gung, B. W. J . Am. Chem.
Soc. 1991, 113, 647.
(2) For a recent review, see: Marshall, J . A. Chem. Rev. 1996, 96,
31.
(3) (a) Marshall, J . A.; Luke, G. P. J . Org. Chem. 1993, 58, 6229.
(b) Marshall, J . A.; Welmaker, G. S. J . Org. Chem. 1994, 59, 4122. (c)
Marshall, J . A.; J ablonowksi, J . A.; Elliott, L. M. J . Org. Chem. 1995,
60, 2662.
(4) Marshall, J . A.; J iang, H. Tetrahedron Lett. 1998 39, 1493.
Marshall, J . A.; Hinkle, K. W. Tetrahedron Lett. 1998 39, 1303.
Marshall, J . A.; Chen, M.-Z. J . Org. Chem. 1997, 62, 5996. Marshall,
J . A.; Hinkle, K. W. J . Org. Chem. 1997, 62, 5989
(5) Sandrine, W.-B.; Parrain, J .-L.; Quintard, J .-P. J . Org. Chem.
1997, 62, 8261.
(6) (a) For a review of synthetic work on insect phermones, see:
Mori, K. Tetrahedron 1989, 45, 3233. For more recent work on
disparlure, see: (b) Kleinman, E.; Sinka, S. C.; Sinka-Bagchi, A.; Wang,
Z.-M.; Zhang, X.-L.; Sharpless, B. K. Tetrahedron Lett. 1992, 33, 6411.
(c) Kang, S.-K.; Kim, Y.-S.; Lim, J .-S.; Kim, K.-S.; Kim, S.-G. Tetra-
hedron Lett. 1991, 32, 363.
(7) Huang, Y.-Z.; Shi, L.; Yang, J . J . Org. Chem. 1987, 52, 3558.
(8) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J . Am. Chem.
Soc. 1984, 106, 6709.
10.1021/jo982353a CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/19/1999

Notes
J . Org. Chem., Vol. 64, No. 6, 1999 2153
conjugated aldehydes to yield syn adducts with γ-oxygen-
ated allylic stannanes.11 Nonetheless, quite useful levels
of syn selectivity can be realized with this combination
as illustrated in the present synthesis of disparlure.
Exp er im en ta l Section
(+)-(7R,8S)-cis-7,8-Ep oxy-2-m eth ylocta d eca n e [(+)-Dis-
p a r lu r e] (13). Tosylate 19 (59 mg, 0.10 mmol) and TBAF (1.0
M in THF, 400 µL, 0.40 mmol) in 1 mL of THF was stirred
overnight, at which point TLC analysis indicted that all the
starting material had been consumed. The reaction was quenched
with saturated NH4Cl solution, and the aqueous layer was
extracted three times with CH2Cl2. The combined organic
extracts were dried over sodium sulfate, and the solvent was
removed under reduced pressure. The crude product was purified
by column chromatography on silica gel with 2.5% ethyl acetate
Stannane 16 was readily purified by column chroma-
tography on silica gel. Addition of 16 to enal 49 in the
presence of BF3‚OEt2 afforded the syn adduct 17 in 73%
yield. Analysis of the (S)-Mosher ester derivative10 indi-
cated an ee of >95% for this adduct. Less than 5% of the
anti diastereomer was formed in the addition.
in hexane as eluent affording 24 mg (89%) of epoxide 13: [R]26
Hydrogenation of 17 over Rh/Al2O3 afforded the tet-
rahydro adduct 18 quantitatively. The tosylate derivative
19, upon treatment with TBAF in THF, smoothly cyclized
to (+)-disparlure (13) in high yield. The spectral data and
optical rotation of this material compared favorably with
the reported values (eq 4).6
D
0.9 (c 1.1, CCl4) [lit.6 [R]23D 0.8 (c 10, CCl4)]; 1H NMR (300 MHz)
δ 2.91 (dm, J ) 3.8 Hz, 1H), 2.89 (dm, J ) 4.6 Hz, 1H), 1.69-
1.10 (m, 29H), 1.04-0.72 (m, 9H) ppm; 13C NMR (75 MHz,
CDCl3) δ 57.2, 38.9, 31.9, 29.5, 29.3, 27.9, 27.3, 26.6, 22.7, 22.6,
14.1 ppm. Anal. Calcd for C19H38O C, 80.78; H, 13.56. Found:
C, 80.85; H, 13.63.
(Z)-(R)-1-(ter t-Bu tyld im eth ylsilyloxy)-3-(tr i-n -bu tylsta n -
n yl)-1-u n d ecen e (16). Diisopropylamine (1.67 mL, 11.9 mmol)
in 75 mL of anhydrous THF was cooled to 0 °C, n-BuLi was
added (2.5 M solution in hexane, 4.72 mL, 11.8 mmol) followed
after 15 min by tributyltin hydride (3.17 mL, 11.8 mmol), and
the resulting yellow solution was stirred for 20 min. The solution
was cooled to -78 °C, and aldehyde 97 (1.81 g, 10.8 mmol) was
added, followed after 30 min by 1,1′-(azodicarbonyl)dipiperidine
(4.15 g, 16.5 mmol), and the resulting dark red reaction mixture
was warmed to 0 °C and stirred for 1 h. The reaction was then
quenched with dilute aqueous ammonium chloride solution and
extracted with ether. The organic extracts were combined and
dried over magnesium sulfate, and the solvent was removed
under reduced pressure. Hexane was added to the orange
residue, and the solution was concentrated under reduced
pressure to remove any traces of THF. The acyl stannane was
purified by adding hexane to precipitate residual ADD. The solid
was removed by vacuum filtration and the filtrate concentrated
to provide the acyl stannane. Because of the lability of the acyl
stannane it is important to have a freshly prepared solution of
BINAL-H at -78 °C ready for the subsequent reduction. This
is best achieved by starting the following procedure for BINAL-H
just prior to the acyl stannane sequence.
LiAlH4 powder (1.02 g, 27.0 mmol) was suspended in 50 mL
of THF. Over a period of 15 min, a solution of EtOH (1.24 g,
27.0 mmol) in 5 mL of THF was added with vigorous evolution
of hydrogen gas, after which (S)-1,1′-bi-2-naphthol (7.73 g, 27.0
mmol) in 50 mL of THF was added by cannula over 1 h. The
resulting cloudy, milky solution was refluxed for 1 h and allowed
to cool to room temperature. The solution was cooled to -78 °C,
and a solution of the acyl stannane in 45 mL of THF was added
by cannula over 1.0 h. After being stirred for 16 h at -78 °C,
the solution was quenched at -78 °C with dilute aqueous
ammonium chloride (100 mL) over 0.5 h. The solution was
allowed to warm to room temperature and then diluted with
water and ether. The layers were separated, and the aqueous
phase was diluted with 1 M HCl and extracted with ether. The
organic extracts were combined, dried over magnesium sulfate,
and filtered, and the solvent was removed under reduced
pressure. The residual hydroxy stannane (yellow oil) and bi-
naphthol (white powder) were triturated twice with hexane. The
binaphthol was recovered by filtration, and the hexane extracts
were concentrated under reduced pressure to afford crude
hydroxy stannane.
The enantiomer (-)-disparlure (23) was also prepared
from alcohol 18. This was achieved through acetylation
followed by silyl ether cleavage with BF3‚OEt2 in CH2-
Cl2 and tosylation. The more conventional desilylation
with TBAF led to a mixture of acetate regioisomers.
Treatment of the tosylate 22 with Triton-B in methanol
effected saponification and cyclization to 23. As expected,
this material was identical to the (+)-enatiomer 13 except
for the sign of its optical rotation.
Returning to the issue of diastereoselectivity, our
present findings indicate that high levels of syn stereo-
control are possible with long-chain γ-oxygenated allylic
stannanes. Our previous observations to the contrary
were based on additions to aliphatic aldehydes with polar
â-substituents,3b and Quintard’s studies did not involve
aliphatic aldehydes.5 Thus, it would appear that aldehyde
structure and stannane substituents both play a role in
controlling the diastereoselectivity of such additions.
Current mechanistic thinking on these reactions fails to
account for subtleties such as the strong preference of
The hydroxy stannane was dissolved in CH2Cl2 and cooled to
0 °C. Diisopropylethylamine (2.5 mL, 27.0 mmol) was added
followed by TBSOTf (4.96 mL, 21.6 mmol). The reaction mixture
was stirred overnight to ensure complete isomerization. The
(9) Reich, H. J .; Clark, M. C.; Willis, W. W., J r. J . Org. Chem. 1982,
47, 1618.
(10) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(11) Cf. Fleming, I. ChemtractssOrg. Chem. 1991, 4, 21. Keck, G.
E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J . Org. Chem. 1994,
59, 7889.

2154 J . Org. Chem., Vol. 64, No. 6, 1999
Notes
reaction was then quenched with saturated NaHCO3, and the
aqueous layer was extracted three times with CH2Cl2. The
combined organic extracts were dried over sodium sulfate, and
the solvent was removed under reduced pressure. The material
was purified by column chromatography on silica gel with
127.8, 84.8, 72.1, 38.7, 32.0, 30.4, 29.7, 29.6, 29.4, 27.8, 27.5,
27.0, 26.0, 25.8, 25.7, 22.8, 22.6, 21.7, 18.0, 14.2, -4.3, -4.7 ppm;
IR (film) ν 2950, 2900, 1550, 1450, 1350 cm-1. Anal. Calcd for
C
32H60O4SiS C, 67.55; H, 10.63. Found: C, 67.65; H, 10.68.
(7S,8S)-7-Acetoxy-8-(ter t-bu tyld im eth ylsilyloxy)-2-m eth -
hexane as eluent, affording 2.6 g (42%) of stannane 16: [R]26
ylocta d eca n e (20). To a solution of 0.10 g (0.24 mmol) of alcohol
18 in 0.50 mL of pyridine was added 0.15 mL (1.6 mmol) of acetic
anhydride. The reaction mixture was stirred for 12 h, quenched
with water, and extracted with ether. The ether extracts were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (elution with 5% EtOAc in hexane)
to afford 0.11 g (96%) of acetate 20: [R]D -13.4 (c 1.0, CHCl3);
D
1
117 (c 1.6, CHCl3); H NMR (300 MHz, CDCl3) δ 5.99 (dd, J )
4.8, 1.0 Hz, 1H), 4.24 (ddd, J ) 11.1, 5.7, 1.0 Hz, 1H), 2.55 (dq,
J ) 11.0, 6.4 Hz, 1H), 1.64-1.39 (m, 6H), 1.40-1.12 (m, 18H),
1.02-0.69 (m, 20H), 0.92 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3) 134.0, 115.1, 33.4, 32.0, 30.6, 29.7,
29.5, 29.4, 27.7, 25.8, 23.0, 22.8, 18.4, 14.2, 13.8, -2.8, -5.0, -5.3
ppm; IR (film) ν 3563, 3450 cm-1
.
1
(E,E)-(7S,8S)-8-(ter t-Bu t yld im et h ylsilyloxy)-2-m et h yl-
octa d eca -5,9-d ien -7-ol (17). A solution of stannane 16 (552 mg,
0.97 mmol) and aldehyde 49 (67 mg, 0.54 mmol) in CH2Cl2 was
cooled to -78 °C, BF3‚OEt2 (96 µL, 0.94 mmol) was added, and
the mixture was stirred for 1.5 h. TLC analysis indicated that
the aldehyde had not been consumed, so additional BF3‚OEt2
(100 µL, 0.98 mmol) was added. After 1 h, the reaction was
quenched with saturated NaHCO3 solution, and the aqueous
layer was extracted three times with CH2Cl2. The combined
organic extracts were dried over sodium sulfate, and the solvent
was removed under reduced pressure. The crude product was
purified by column chromatography on silica gel with 2.5% ethyl
acetate in hexane as eluent to afford 213 mg (73%) of adduct
17: 1H NMR (300 MHz, CDCl3) δ 5.64 (m, 2H), 5.35 (m, 2H),
3.84 (m, 2H), 2.04 (m, 4H), 1.56 (m, 1H), 1.46-1.08 (m, 16H),
1.03-0.73 (m, 9H), 0.90 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H) ppm;
13C NMR (75 MHz, CDCl3) 133.8, 133.7, 129.6, 128.4, 77.9, 76.0,
38.3, 32.2, 31.9, 30.3, 29.5, 29.3, 29.2, 29.1, 27.4, 25.9, 22.7, 22.6,
IR (film) 1737 cm-1; H NMR (300 MHz, CDCl3) δ 4.80 (ddd, J
) 7.9, 2.7, 1.6 Hz, 1 H), 3.66 (m, 1 H), 2.05 (s, 3 H), 1.70-1.01
(m, 27 H), 0.92-0.80 (m, 18 H), 0,09 (s, 3 H), 0.06 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 170.5, 76.3, 72.3, 38.9, 32.2, 31.9, 29.9,
29.7, 29.6, 29.4, 28.6, 28.0, 27.3, 26.2, 25.9, 25.5, 22.8, 22.7, 22.6,
21.3, 14.1, -4.3, -4.4.
(7S,8S)-7-Acetoxy-2-m eth yloctadecan -8-ol (21). To a stirred
solution of 0.022 g (0.05 mmol) of silyl ether 20 in 1.5 mL of
CH2Cl2 was added 0.014 mL (0.11 mmol) of BF3‚OEt2. The
reaction mixture was stirred for 1 h, quenched with saturated
NaHCO3, and extracted with ether. The ether extracts were
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel (elution with 15% EtOAc in hexane)
to afford 0.016 g (95%) of alcohol 21: [R]D -11.2 (c 0.22, CHCl3);
IR (film) 3458, 1728 cm-1 1H NMR (300 MHz, CDCl3) δ 4.83
;
(m, 1 H), 3.58 (m, 1 H), 2.09 (s, 3 H), 1.67-1.13 (m, 27 H), 0.96-
0.74 (m, 9 H).
22.5, 18.2, 14.1, -3.8, -4.7 ppm; IR (film) ν 3563, 3450 cm-1
.
(7S,8S)-7-Acetoxy-8-(p-tolu en esu lfon yloxy)-2-m eth yloc-
ta d eca n e (22). To a solution of 0.044 g (0.13 mmol) of alcohol
21 in 0.50 mL of pyridine was added 0.12 g (0.63 mmol) of
p-TsCl. The reaction mixture was stirred for 12 h, quenched with
water and extracted with ether. The ether extracts were washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography on silica gel (elution with 8% EtOAc in hexane) to
afford 0.060 g (92%) of tosylate 22: [R]D -7.4 (c 0.39, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.80 (d, J ) 7.7 Hz, 2 H), 7.33 (d,
J ) 7.7 Hz, 2 H), 4.95 (m, 1 H), 4.62 (m, 1 H), 2.44 (s, 3 H), 2.01
(s, 3 H), 1.62-1.01 (m, 27 H), 0.92-0.80 (m, 9 H).
(-)-Disp a r lu r e (23). To 0.017 g (0.03 mmol) of tosylate 22
was added 0.50 mL (1.1 mmol) of benzyltrimethylammonium
hydroxide (Triton B). The reaction mixture was stirred for 1 h,
quenched with water, and extracted with ether. The ether
extracts were washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The crude product was
purified by column chromatography on silica gel (elution with
5% EtOAc in hexane) to afford 0.009 g (95%) of (-)-disparlure
(23): [R]D -0.9 (c 0.21, CCl4). Anal. Calcd for C19H38O: C, 80.78;
H, 13.56. Found: C, 80.93; H, 13.58.
Anal. Calcd for C25H50O2Si C, 73.10; H, 12.27. Found: C, 73.00;
H, 12.24.
1H NMR analysis of the (S)-Mosher ester10 indicated an ee of
>95%.
(7S,8S)-8-(ter t-Bu tyld im eth ylsilyloxy)-2-m eth ylocta d ec-
a n -7-ol (18). A mixture of 0.10 g (0.24 mmol) of dienol 17 and
a catalytic amount of Rh/Al2O3 (5%) in 2.0 mL of EtOAc was
placed under a H2 atmosphere. The reaction mixture was stirred
for 8 h and filtered through Celite. Solvent was removed under
reduced pressure to afford 0.10 g (100%) of alcohol 18: [R]D +4.9
(c 0.60, CHCl3); IR (film) 3465 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.49 (m, 1 H), 3.42 (m, 1 H), 1.65-1.07 (m, 27 H), 0.90 (m, 12
H), 0.86 (d, J ) 6.5 Hz, 6 H), 0.08 (s, 3 H), 0.07 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 76.2, 75.2, 39.0, 34.2, 34.0, 32.0, 30.0,
29.6, 29.4, 28.0, 27.5, 26.2, 26.0, 25.1, 22.7, 18.2, 14.2, -4.0, -4.5.
Anal. Calcd for C25H54O2Si: C, 72.39; H, 13.12. Found: C, 72.40;
H, 13.18.
(7S,8S)-8-(ter t-Bu tyld im eth ylsilyloxy)-2-m eth yl-7-(p-tol-
u en esu lfon yloxy)octa d eca n -7-ol (19). Alcohol 18 (45 mg, 0.11
mmol) and p-toluenesulfonyl chloride (25 mg, 0.13 mmol) in 1.5
mL of pyridine was stirred for 48 h, quenched with saturated
aqueous CuSO4, and diluted with CH2Cl2. The organic extract
was washed first with saturated aqueous CuSO4 three times and
then with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography on silica gel with 2.5% ethyl acetate in hexane as
eluent, affording 59 mg (95%) of tosylate 19: [R]26D -28.3 (c 0.7,
Ack n ow led gm en t. This work was supported by
research grant CHE 9529574 from the National Science
Foundation.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR spectra
for 16, the (S)-Mosher ester of 17, 20, 21, and 22. This ma-
terial is available free of charge from the Internet at
http://pubs.acs.org.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.79 (d, J ) 8.1 Hz, 2H),
7.32 (d, J ) 8.5 Hz, 2H), 4.32 (ddd, J ) 9.6, 6.6, 3.5 Hz, 1H),
3.74 (ddd, J ) 8.9, 6.9, 3.8 Hz, 1H), 2.44 (s, 3H), 1.75-1.03 (m,
18H), 0.98-0.60 (m, 12H), 0.86 (s, 9H), 0.81 (d, J ) 6.9 Hz, 6H),
0.06 (s, 3H), 0.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 129.6,
J O982353A