Asymmetric conjugate addition of crotylstannane: Synthesis of (-)-lasiol

Article abstract of DOI:10.1055/s-0029-1219381

Lasiol, the major component of the mandibular gland secretion, serves as the primary sex attractant of the male ant, Lasius meridionalis. Our interest in lasiol stems from the stereochemistry of the chiral methyl substituents and the synthetic challenges

Full text of DOI:10.1055/s-0029-1219381

LETTER
793
Asymmetric Conjugate Addition of Crotylstannane: Synthesis of (–)-Lasiol
S
ynthesisof (–)
m
-Lasiol ily E. Wilding, John J. Gregg, Richard J. Mullins*
Department of Chemistry, Xavier University, 3800 Victory Parkway, Cincinnati, OH 45207-4221, USA
Fax +1(513)7453695; E-mail: mullinsr@xavier.edu
Received 29 September 2009
Dedicated to Professor David R. Williams, on the occasion of his 60th birthday
species.12 Pioneered in the Hruby laboratory,13 nonracem-
ic 4-phenyl-1,3-oxazolidinone has been especially pro-
ductive as a chiral auxiliary in these reactions.
Abstract: Lasiol, the major component of the mandibular gland se-
cretion, serves as the primary sex attractant of the male ant, Lasius
meridionalis. Our interest in lasiol stems from the stereochemistry
of the chiral methyl substituents and the synthetic challenges posed
by this common structural motif. As such, an asymmetric 1,4-con-
jugate addition of an allylic stannane to produce the 1,2-anti-dime-
thyl arrangement with high stereocontrol has resulted in the
synthesis of (–)-lasiol.
In 1992, Wu and co-workers14 developed the TiCl4-medi-
ated conjugate addition reaction of allyltrimethylsilane to
2, resulting in a reported 8.1:1 ratio of diastereomers 3a
and 3b (Equation 1). These data were consistent with the
mode of selectivity achieved in the extensive organocop-
per studies by Hruby and Williams. More recently, Koert
and Gesson have exploited the TiCl4-promoted conjugate
addition of an allylsilane toward the synthesis of lauli-
malide analogues.15 The stereochemistry obtained in their
reaction was reported to converge with the results initially
reported by Wu.
Key words: asymmetric synthesis, 1,4-addition, (–)-lasiol, chiral
auxiliaries, Lewis acids
In 1990, lasiol (1, Figure 1) was isolated and identified by
Jones and co-workers1 as a mandibular gland secretion of
the male ant Lasius meridionalis. Its structure, specifical-
ly, the anti relationship of the vicinal methyl stereocenters
was determined by a combination of synthesis and spec-
troscopic techniques. The groups of Mori2 and Kuwahara3
later elucidated the absolute stereochemistry via synthesis
of both enantiomers.
O
O
O
O
X
Y
SiMe3
N
N
O
2
O
TiCl4
CH2Cl2, –78 °C
2
3a/3b = 8.1:1
Ph
Ph
3a: X = Me, Y = H
3b: X = H, Y = Me
Me
Equation 1 Conjugate addition reported by Wu and co-workers
OH
Me
In 2003, seeking to exploit the heightened reactivity of al-
lylic stannanes as compared to allylic silanes, Williams
and Mullins16 described the asymmetric conjugate addi-
tion of allyl- and crotylstannanes to Lewis acid precom-
plexed nonracemic a,b-unsaturated N-enoyl-1,3-
oxazolidinones. These studies revealed a curious reversal
in stereochemical outcome when compared to the well-
known conjugate addition of organocopper reagents to
these same systems.17 Perhaps more interestingly, these
results ran contrary to those reported by Wu and co-work-
ers in the conjugate addition of allyltrimethylsilane. Via a
thorough reevaluation of Wu’s reaction and comparison
(–)-lasiol (1)
Figure 1
Owing to the difficulty posed by synthesis of the adjacent
methyl stereogenic centers, several groups have undertak-
en and reported the synthesis of lasiol utilizing a variety
of creative strategies.4–6 Notable amongst these approach-
es are the application of a silyloxy-Cope rearrangement by
Schneider,7 the asymmetric allylic alkylation–cross meta-
thesis–conjugate addition protocol by Feringa8 and the
stereoselective conjugate addition of a chiral enolate by
Tadano.9
1
of the characteristic H NMR absorption pattern of the
diastereotopic C-2 methylene obtained in all three conju-
gate addition reactions (allyltrimethylsilane, allyltributyl-
tin and allylcopper), Williams and Mullins corrected the
stereochemical assignment of Wu, while conclusively es-
tablishing the convergence of the silane and stannane re-
sults. It was clearly demonstrated that, under both sets of
conditions, the silane and stannane additions proceed with
selectivity opposite to that of the analogous organocopper
reagents (instead favoring 3b).18 In order to further clarify
and bring attention to the stereochemical course of these
conjugate addition reactions, as well as to demonstrate the
The use of 1,3-oxazolidinones as chiral auxiliaries is well
known and has been widely exploited for imparting high
levels of stereocontrol in a variety of C–C bond-forming
reactions.10 Nonracemic N-enoyl-1,3-oxazolidinones
have found substantial utility in natural product synthe-
sis,11 particularly in providing for the highly diastereose-
lective conjugate addition reactions of organocopper
SYNLETT 2010, No. 5, pp 0793–0795
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6.
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Advanced online publication: 08.02.2010
DOI: 10.1055/s-0029-1219381; Art ID: S11409ST
© Georg Thieme Verlag Stuttgart · New York

794
E. E. Wilding et al.
LETTER
utility of this reaction for the stereoselective introduction ing diisobutylaluminum hydride to yield lactol 10 as an
of adjacent methyl stereogenic centers, we report herein inconsequential mixture of diastereomers. Finally, treat-
our synthesis of (–)-lasiol.
ment of the lactol mixture with an excess of
Ph3P=C(CH3)220 resulted in the formation of (–)-lasiol (1),
the spectral data of which was identical to that reported
previously.9
As illustrated in Scheme 1, our synthesis begins with the
conjugate addition to enoyloxazolidinone 2. Precomplex-
ation between 2 and zirconium tetrachloride is followed
by addition of (E)-crotyl-tri-n-butylstannane to provide 4 In conclusion, a concise, stereoselective synthesis of (–)-
with good facial selectivity (10:1).19 Notably, this addi- lasiol has been completed. Utilizing the asymmetric con-
tion occurs with complete allylic transposition of the allyl- jugate addition of crotylstannane, the challenging 1,2-
ic stannane, resulting in the selective formation of the two anti-dimethyl stereoarray has been assembled in a single
vicinal stereogenic centers of lasiol in a single reaction. At transformation. Efforts toward the development of a ratio-
this point, ozonolysis of the alkene was to be followed by nale for the interesting reversal in facial selectivity ob-
reduction of the resulting aldehyde 5, with the hope that served in these conjugate addition reactions are ongoing.
spontaneous cyclization and extrusion of the chiral auxil-
iary would occur to give the lactone product. Unfortunate-
ly, our attempts to selectively reduce the aldehyde
resulted in overreduction to give diol 6. Although unex-
pected, these results can be rationalized by internal deliv-
ery of hydride to the imide carbonyl via the alkoxide
which results from aldehyde reduction.
Synthesis of 4
Zirconium tetrachloride (3.5 g, 15 mmol) was added in one portion
to a solution of enoyloxazolidinone 2 (2.3 g, 10 mmol) in dry
CH2Cl2 (100 mL) at –78 °C. The mixture was left to stir at –78 °C
for 30 min, at which point (E)-crotyl-tri-n-butylstannane (6.9 g, 20
mmol) was introduced dropwise over 10 min. The reaction mixture
was slowly warmed from –78 to –20 °C and left to stir at this tem-
perature for 16 h. The reaction was quenched by the addition of sat.
aq NaHCO3 and allowed to warm to r.t. The phases were separated
and the aqueous layer extracted with CH2Cl2 (3 × 100 mL). The or-
ganic layers were combined, dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by flash silica gel
chromatography (hexanes → hexanes–EtOAc = 6:1) to afford 2.4 g
(85%) of 4 as a white solid; Rf = 0.41 (hexanes–EtOAc = 4:1); mp
74–76 °C. FTIR (thin film): 3069, 2965, 1782, 1706 cm–1. 1H NMR
(300 MHz, CDCl3): d = 7.34–7.19 (m, 5 H), 5.74–5.64 (m, 1 H),
5.36 (dd, J = 8.9, 3.6 Hz, 1 H), 4.94–4.85 (m, 2 H), 4.61 (t, J = 8.9
Hz, 1 H), 4.12 (dd, J = 8.9, 3.6 Hz, 1 H), 3.00 (A of ABX,
JAB = 16.0 Hz, JAX = 5.3 Hz, 1 H), 2.84 (B of ABX, JAB = 16.0 Hz,
JBX = 8.6 Hz, 1 H), 2.10–1.93 (m, 2 H), 0.91 (d, J = 6.6 Hz, 3 H),
0.75 (d, J = 6.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d = 172.5,
153.7, 141.1, 139.2, 129.1, 128.7, 125.9, 114.7, 69.9, 57.6, 41.7,
O
Me
O
O
O
a
N
N
O
O
85%
Me
2
4
Ph
Ph
O
Me
O
Me
CHO
b
c
N
HO
OH
O
80%
Me
Me
5
Ph
6
Scheme 1 Reagents and conditions: (a) (E)-crotyl-tri-n-butylstan-
nane, ZrCl4, CH2Cl2, –78 to –20 °C; (b) O3, CH2Cl2, –78 °C, then
Ph3P; (c) NaBH4, EtOH, 0 °C.
Given this result, our scheme was modified as shown in 39.9, 34.1, 17.0, 15.9. HRMS: m/z calcd for C17H21O3N [M]+:
Scheme 2. Hydrolysis of 4 resulted in acid 7, which was
287.1521; found: 287.1521.
subjected to ozonolysis conditions to provide aldehyde 8.
Synthesis of 7
Aldehyde 8 was immediately reduced and, upon quench-
A 30% aq solution of H2O2 was added slowly to a solution of ox-
ing and stirring in the presence of H2SO4, spontaneous cy-
clization of the resulting alcohol occurred to provide
lactone 9. Reduction of the lactone was accomplished us-
azolidinone 4 (0.36 g, 1.3 mmol) in THF–H2O (4:1, 6 mL) at 0 °C.
A solution containing LiOH·H2O (73 mg, 1.7 mmol) in H2O (4 mL)
was added slowly to the reaction mixture. The reaction was left to
stir at 0 °C for 1 h, at which point it was quenched by the addition
of a solution containing Na2SO3 (0.64 g, 5.1 mmol) in H2O (4 mL).
The THF was removed in vacuo and the basic solution extracted
with CH2Cl2 (3 × 10 mL) to remove the chiral auxiliary. The re-
maining aqueous layer was cooled to 0 °C, acidified with 6 N HCl
to pH ca. 1 and extracted with EtOAc (5 × 10 mL). The organic lay-
ers were combined, dried over MgSO4, filtered, and concentrated in
vacuo to yield 0.17 g (94%) of 7 as a clear oil; Rf = 0.5 (hexanes–
O
Me
O
O
Me
a
N
HO
O
b
94%
Me
Me
Me
4
7
Ph
O
O
c
Me
O
CHO
HO
1
EtOAc = 4:1). FTIR (thin film): 3500–2500, 2966, 1716 cm–1. H
75%
Me
8
Me
Me
NMR (300 MHz, CDCl3): d = 5.76–5.62 (m, 1 H), 5.04–4.96 (m, 2
H), 2.44–2.34 (m, 1 H), 2.24–1.96 (m, 3 H), 1.00 (d, J = 6.8 Hz, 3
H), 0.928 (d, J = 6.8 Hz, 3 H). 13C NMR (75 MHz, CDCl3): d =
180.0, 141.0, 115.0, 42.2, 39.1, 35.0, 17.6, 16.2. HRMS: m/z calcd
for C8H15O2 [M + H]+: 143.1072; found: 143.1073.
9
O
d
Me
OH
e
OH
87%
47%
10
Me
Me
1
Synthesis of 9
Scheme 2 Reagents and conditions: (a) LiOH, H2O2, THF–H2O
(1:1); (b) O3, CH2Cl2, –78 °C, then Ph3P; (c) NaBH4, aq THF, then
H2SO4; (d) DIBAL-H, CH2Cl2, –78 °C; (e) Ph3P=C(CH3)2, THF, –78
to 0 °C.
Ozone gas was bubbled through a solution of alkene 7 (194 mg, 1.36
mmol) in dry CH2Cl2 (14 mL) at –78 °C until a light blue color per-
sisted (ca. 5 min). Oxygen gas was then bubbled through the solu-
Synlett 2010, No. 5, 793–795 © Thieme Stuttgart · New York

LETTER
Synthesis of (–)-Lasiol
795
tion until the blue color dissipated, at which point Ph3P (393 mg,
1.50 mmol) was added in one portion. The reaction was warmed to
r.t. and left to stir overnight at which point it was concentrated and
filtered through a plug of silica gel (hexanes–EtOAc = 2:1) to yield
8. 1H NMR (300 MHz, CDCl3): d = 9.86 (d, J = 1.7 Hz, 1 H), 2.52–
2.38 (m, 3 H), 2.30–2.20 (m, 1 H), 1.10 (d, J = 6.9 Hz, 3 H), 1.08
(d, J = 5.8 Hz, 3 H). NaBH4 (102 mg, 2.72 mmol) was added to a
solution of the resulting aldehyde 8 (1.36 mmol) in aq THF at r.t.
After stirring for 12 h, the reaction was acidified to pH 1 by the ad-
dition of concd H2SO4. The mixture was diluted with H2O (30 mL),
and extracted with Et2O (3 × 30 mL). The combined organic layers
were washed with sat. aq NaHCO3, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica gel
chromatography (hexanes–EtOAc = 4:1) to afford 130 mg (75%) of
9 as a clear oil; Rf = 0.3 (hexanes–EtOAc = 4:1). FTIR (thin film):
2964, 1732 cm–1. 1H NMR (300 MHz, CDCl3): d = 4.29 (dd,
J = 11.3, 4.4 Hz, 1 H), 4.12 (dd, J = 9.9, 6.9 Hz, 1 H), 2.61 (dd,
J = 18.1, 6.0 Hz, 1 H), 2.30 (dd, J = 18.1, 7.7 Hz, 1 H), 2.20–2.05
(m, 2 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.96 (d, J = 7.1 Hz, 3 H). 13C
NMR (75 MHz, CDCl3): d = 170.8, 73.4, 36.4, 31.2, 29.9, 15.8,
11.5. HRMS: m/z calcd for C7H13O2 [M + H]+: 129.0916; found:
129.0910.
Acknowledgment
The author gratefully acknowledges Research Corporation for a
Cottrell College Science Award (CC6432). Professor David R.
Williams is also acknowledged for assistance with mass spectra ac-
quisition.
References and Notes
(1) Lloyd, H. A.; Jones, T. H.; Hefetz, A.; Tengö, J. Tetrahedron
Lett. 1990, 31, 5559.
(2) Kasai, T.; Watanabe, H.; Mori, K. Bioorg. Med. Chem. 1993,
1, 67.
(3) Kuwahara, S.; Shibata, Y.; Hiramatsu, A. Liebigs Ann.
Chem. 1992, 993.
(4) Donaldson, W. A.; Jin, M.-J. Tetrahedron 1993, 49, 8787.
(5) Vasil’ev, A. A.; Vielhauer, O.; Engman, L.; Pietzsch, M.;
Serebryakov, E. P. Russ. Chem. Bull., Int. Ed. 2002, 51, 481.
(6) Södergren, M. J.; Bertilsson, S. K.; Andersson, P. G. J. Am.
Chem. Soc. 2000, 122, 6610.
(7) Schneider, C. Eur. J. Org. Chem. 1998, 1661.
(8) van Zijl, A. W.; Szymanski, W.; López, F.; Minnaard, A. J.;
Feringa, B. L. J. Org. Chem. 2008, 73, 6994.
(9) Asano, S.; Tamai, T.; Totani, K.; Takao, K.; Tadano, K.
Synlett 2003, 2252.
(10) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (b) Ager,
D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30,
3.
(11) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem.
Soc. 1984, 106, 4261. (b) Evans, D. A.; Chapman, K. T.;
Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238.
(12) For representative examples, see: (a) Williams, D. R.; Nold,
A.; Mullins, R. J. J. Org. Chem. 2004, 69, 5374.
(b) Williams, D. R.; Li, J. J. Tetrahedron Lett. 1994, 35,
5113. (c) Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2,
3217. (d) White, J. D.; Lee, C.-S.; Xu, Q. Chem. Commun.
2003, 2012.
(13) For representative examples, see: (a) Nicolás, E.; Russell,
K.; Hruby, V. J. J. Org. Chem. 1993, 58, 766. (b) Li, G.;
Jarosinski, M. A.; Hruby, V. J. Tetrahedron Lett. 1993,
2561. (c) Liao, S.; Han, Y.; Qui, W.; Bruck, M.; Hruby,
V. J. Tetrahedron Lett. 1996, 37, 7917.
(14) (a) Wu, M.-J.; Wu, C.-C.; Lee, P. C. Tetrahedron Lett. 1992,
33, 2547. (b) Wu, M.-J.; Yeh, J.-Y. Tetrahedron 1994, 50,
1073.
(15) Faveau, C.; Mondon, M.; Gesson, J.-P.; Mahnke, T.;
Gebhardt, S.; Koert, U. Tetrahedron Lett. 2006, 47, 8305.
(16) Williams, D. R.; Mullins, R. J.; Miller, N. A. Chem.
Commun. 2003, 2220.
Synthesis of (–)-Lasiol (1)
DIBAL-H (1.0 M in toluene, 1.8 mL, 1.8 mmol) was added to a so-
lution of lactone 9 (0.16 g, 1.3 mmol) in dry CH2Cl2 (13 mL) at
–78 °C. After stirring at –78 °C, the reaction was quenched with
EtOAc and allowed to warm to r.t. Sat. aq Rochelle salt (15 mL) was
added and the reaction mixture allowed to stir vigorously for 14 h.
The layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The organic layers were combined, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash silica gel chromatography (hexanes–EtOAc = 4:1) to
afford 0.14 g (87%) of 10 as a mixture of diastereomers.
n-BuLi (2.0 M in hexanes, 1.1 mL, 2.2 mmol) was added dropwise
to isopropyltriphenylphosphonium iodide (0.94 g, 2.2 mmol) dis-
solved in dry THF (5 mL) at 0 °C. Following addition of n-BuLi, the
deep red reaction mixture was stirred at 0 °C for 5 min before being
cooled to –78 °C. To this mixture was added a solution of lactol 10
(120 mg, 0.91 mmol) in dry THF (5 mL) over the course of 5 min.
After stirring at –78 °C for 30 min, the reaction mixture was trans-
ferred to an ice–water bath and allowed to warm to 0 °C over the
course of 1 h. The reaction was quenched by the addition of sat. aq
NH4Cl (5 mL) and diluted with EtOAc (15 mL). The layers were
separated and the aqueous layer extracted with CH2Cl2 (3 × 30 mL).
The organic layers were combined, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica gel
chromatography (hexanes → hexanes–EtOAc = 6:1) to afford 66
mg (47%) of (–)-lasiol (1) as a clear oil; Rf = 0.5 (hexanes–EtOAc
= 4:1); [a]D24 –8.0 (c 1.9, n-hexane). FTIR (thin film): 3333, 2964
cm–1. 1H NMR (300 MHz, CDCl3): d = 5.07–5.14 (m, 1 H), 3.64 (A
of ABX, JAB = 10.4 Hz, JAX = 5.5 Hz, 1 H), 3.46 (B of ABX,
JAB = 10.4 Hz, JBX = 7.03 Hz, 1 H), 2.09–1.99 (m, 1 H), 1.85–1.74
(m, 1 H), 1.69 (s, 3 H), 1.68–1.47 (m, 2 H), 1.59 (s, 3 H), 0.92 (d,
J = 6.6 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 132.1, 123.5, 66.2, 40.2, 35.5, 31.4, 25.8, 17.8, 17.0,
13.8. HRMS: m/z calcd for C10H20O [M]+: 156.1509; found:
156.1502.
(17) The facial selectivity observed in the organocopper reactions
has been rationalized by addition to the face opposite the
bulky phenyl group in a bidentate Lewis acid complex first
proposed by D. A. Evans11 and subsequently characterized:
Castellino, S.; Dwight, W. J. J. Am. Chem. Soc. 1993, 115,
2986.
(18) A similar reversal in facial selectivity for conjugate addition
of O-benzylhydroxylamine has been reported: Amoroso, R.;
Cardillo, G.; Sabatino, P.; Tomasini, C.; Trerè, A. J. Org.
Chem. 1993, 58, 5615.
(19) The relative and absolute stereochemistry of the major
product 4 was proven via X-ray crystallography, see ref. 16.
(20) Similar endgame has been utilized in previous lasiol
syntheses, see ref. 1 and 2.
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