Asymmetric tandem additions to chiral 2,3-dihydronaphthyloxazolines: Synthesis of the triptoquinone/triptinin a ring system

Article abstract of DOI:10.1055/s-2002-34373

A study to reach the diterpenoid (+)-triptoquinone A (3) or its analog (+)-triptinin A (4) via an asymmetric tandem addition to naphthyloxazolines is described. The tandem addition to the chiral dihydronophthalene 6 resulted in a 70% yield of a single diastereomer 10. Further manipulation gave the natural products' tricyclic ring system, compounds 20 and 29 via ring-closing metathesis in 90% yield, using the Schrock catalyst. Final assault to the target compounds 3 or 4 fell short due to the failure to either reduce a neopentyl hydroxymethyl group to a methyl or to install the conjugated carboxylic acid present in 3 or 4.

Full text of DOI:10.1055/s-2002-34373

2064
PAPER
Asymmetric Tandem Additions to Chiral 2,3-Dihydronaphthyloxazolines:
Synthesis of the Triptoquinone/Triptinin A Ring System
C
hira
l
D
ihydron
a
aphthylox
u
azolines ra F. Basil, Hiroto Nakano, Rogelio Frutos, Michael Kopach, A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
E-mail: aimeyers@lamar.colostate.edu
Received 25 April 2002
This is dedicated to Professor Dieter Seebach, an old and dear friend and an excellent scientist, for his outstanding contributions
to organic chemistry.
of tandem intermolecular additions on chiral naphthyl ox-
Abstract: A study to reach the diterpenoid (+)-triptoquinone A (3)
azolines and electrophiles.1,5–6 Therefore, in one reaction,
two adjacent stereocenters are set very selectively, and
furthermore, one center appears as a stereogenic quaterna-
or its analog (+)-triptinin A (4) via an asymmetric tandem addition
to naphthyloxazolines is described. The tandem addition to the
chiral dihydronophthalene 6 resulted in a 70% yield of a single di-
astereomer 10. Further manipulation gave the natural products’ tri- ry carbon which historically has been more difficult to ac-
cyclic ring system, compounds 20 and 29 via ring-closing
cess selectively than a tertiary carbon center. We now
metathesis in 90% yield, using the Schrock catalyst. Final assault to
report an effort to further expand the utility of this asym-
the target compounds 3 or 4 fell short due to the failure to either re-
metric tandem addition. The target chosen was the tricy-
duce a neopentyl hydroxymethyl group to a methyl or to install the
clic system present in (+)-triptoquinone A (3) or its
conjugated carboxylic acid present in 3 or 4.
closely reduced analog, triptinin A (4) (Figure 2).
Key words: ring closing metathesis, alkyllithiums, chiral oxazo-
lines, conjugate additions, deoxygenation, triflates, tetralones
O
N
Ox*
1. RLi
2. E+
Chiral 2-oxazolines, first introduced from this laboratory,
have found significant use in asymmetric synthesis for the
past three decades.1a The oxazoline functionality has
served not only as a carboxylic masking group, but also as
a chiral ligand and auxiliary in many carbon–carbon
bond-forming reactions.1b,c For the latter, the chiral ox-
azoline has been used in this laboratory in the total synthe-
sis of several important natural products such as (–)-
steganone (an antileukemic),2 (–)-podophyllotoxin (an
antitumor agent),3 and (S)-gossypol (an antispermatoge-
nic)4 (Figure 1).
E
H
E= Me, Et, Bn, Allyl, etc.
RLi = Butyl, Vinyl, Phenyl, etc.
R
2, 90%; >99:1 dr
1
Scheme 1
CO2H
CO2H
O
H
H
O
OMe
4 (+)-triptinin A
Tandem nucleophilic/electrophilic alkylations on various
chiral naphthyloxazolines have, in the past on many occa-
sions, furnished adducts in good to excellent chemical
yields and very high stereoselectivity (Scheme 1).5 After
the nucleophilic addition by RLi, the subsequently added
electrophile was invariably found to enter trans to RLi.
This pattern has been observed with numerous examples
3 (+)-triptoquinone A
Figure 2 The structures of (+)-triptoquinone A (3) and (+)-triptinin
(4)
O
OH
O
O
O
H3C
CHO OH
OH
OH
O
O
O
HO
HO
O
MeO
MeO
OH CHO
O
CH3
MeO
OMe
OMe
OMe
(-)-steganone
(S)-gossypol
(-)-podophyllotoxin
Figure 1 The structures of (–)-steganone, (–)-gossypol and (–)-podophyllotoxin
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,2064,2074,ftx,en;C01402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Chiral Dihydronaphthyloxazolines
2065
(+)-Triptoquinone A (3) and (+)-triptinin A (4) are mem- Scheme 4, see preparation of 6a). It was readily apparent,
bers of a family of structurally related diterpenoid natural after early attempts at tandem additions, that there was
products isolated from the plant Tripterygium wilfordii something unusual about additions to the dihydronaph-
var regelii.7,8 This plant has been used in traditional Chi- thyloxazoline compared to the corresponding naphthylox-
nese medicine to treat rheumatoid arthritis and spondyli- azolines reported earlier from our laboratory.5,6 Where
tis. Triptoquinone A (3) has been shown to inhibit IL-1
previous examples of alkyllithium additions followed by
and IL-1 release from lipopolisaccharide-stimulated hu- electrophiles gave essentially one trans-disposed diastere-
man peripheral mononuclear cells.7 Also, it has been omer (>30:1), the stereoselective addition affording 9 pro-
shown to inhibit the expression of inducible nitric oxide ceeded in relatively poor diastereomeric ratio (4:1,
synthase (iNOS) gene with an IC50 = 25.5 M in rat glial Scheme 3). Furthermore, conversion of the oxazoline
cells.9 Triptinin A (4) has been indicated as a competitive moiety to a carbinol by many earlier utilized acidic and
leukotriene-d4 (LTD4) antagonist with guinea pig smooth basic routes2–4 was unsuccessful, yielding mainly the
tracheal muscle.8 Shishido et al.10 have recently complet- starting material or decomposition products. At this stage
ed a total synthesis of racemic-3 and (+)-3.
it seemed that the steric crowding between the oxazoline
ring and the peri-positioned methoxyl group in 6b may be
contributing to both lack of stereoselectivity in the tandem
addition and hindering smooth removal of the oxazoline
ring. This notion was verified when the less encumbered
des-methoxyoxazoline derivative 6a was examined, and
the high trans-diastereoselectivity was once again ob-
served (>95%). Thus, adduct 10 was now obtained as a
single diastereomer in 76% yield. After several attempts,
a modification of earlier procedures, requiring heating in
a sealed tube followed by acidic hydrolysis and reduction,
led to the carbinol 11a.6c Protection of the hydroxyl group
as the tert-butydimethylsilyl (TBDMS) ether, or methyl
ether, followed by ozonolysis of both double bonds pro-
vided the requisite dicarbonyl groups as an aldol precur-
sor, 11b. However, after numerous attempts, no
satisfactory aldol condensation products were observed
from 11b, and this route to the construction of the C-ring
was eventually abandoned.
With two adjacent stereocenters, one quaternary, it can be
imagined to initiate this study from a naphthalene system.
(+)-Triptoquinone A (3) appeared to be an ideal target for
demonstrating the utility of the tandem addition chemistry
mentioned above. It was the goal of this project to first
evaluate the behavior to 2,3-dihydronaphthyl rather than
the fully aromatic naphthyloxazolines and then secondly
to complete the total synthesis of 3 in a more convergent
and efficient manner than previously reported.10
The retrosynthetic route is shown in Scheme 2. The oxi-
dation of the aromatic ring to the quinone 3 was planned
to be delayed until the final step. The C-ring was expected
to be introduced by ozonolysis of the olefin 5b to the ke-
tone 5a, followed by an intramolecular aldol condensa-
tion. The stereogenic quaternary methyl group in 3 would
ultimately arise from transformation of the oxazoline moi-
ety in 5a by reductive methods previously performed in
our laboratory. The latter oxazoline ring would be affixed
to the tetralone 1, via an earlier procedure also reported
from our laboratory,11 to give 6. It should also be noted
that due to the more accessible (S)-tert-leucinol [versus
(R)-tert-leucinol] necessary for constructing the chiral ox-
azoline, the actual synthetic target would be the (–)-enan-
tiomer of natural triptoquinone A (3) or triptinin A (4).
The synthesis of the requisite chiral oxazoline 6a began
with 2-bromo-6-isopropylanisole (12) (Scheme 4).12 Met-
al-halogen exchange with butyllithium gave the oxygen-
sensitive aryllithium which was then treated with
BF3 Et2O followed by ethylene oxide, yielding phenethyl
alcohol 13, which was transformed into the iodide 14, by
triphenylphosphine and iodine. To this was added the lith-
ium enolate of tert-butyl acetate in the presence of HMPA
affording the homologated ester 15. Cyclization of the es-
ter using polyphosphoric acid furnished tetralone 7. Hav-
The starting material, 5,8-dimethoxy substituted oxazo-
line 6b was derived from the known 5,8-dimethoxy-6-iso-
propyl- -tetralone10 via its triflate (cf. vide supra,
O
CO2H
O
A
R
OH
C
N
O
R
B
H
H
X
X
C-ring formation
Oxidation to quinone
O
OMe
OMe
5a X=O
5b X= CH2
R= H, OMe
(-)-3
O
O
R
N
Oxazoline formation
Conjugate addition
OMe
OMe
7
6a R= H
6b R= OMe
( chiral)
Scheme 2
Synthesis 2002, No. 14, 2064–2074 ISSN 0039-7881 © Thieme Stuttgart · New York

2066
L. F. Basil et al.
PAPER
Scheme 3
ing the acid labile tert-butyl ester in 15 allowed for direct diolefin would simplify the synthesis and eliminate the
conversion to the tetralone, without the necessity of a sep- ozonolysis steps of 11a to 11b. In the event, adduct 19 was
arate saponification step. The tetralone 7 was transformed acquired as a single diastereomer in 87% yield, after addi-
to vinyl triflate 16 (KHMDS, PhNTf2) which underwent a tion of propenyllithium to 6a followed by but-3-enyl bro-
palladium-catalyzed amidation11 to yield the chiral amide mide. Treatment of 19 with 20% catalyst A13 and heat
alcohol (+)-17. Cyclization, using thionyl chloride, gave resulted in a good yield (90%) of cyclized material 20
the chiral 2,3-dihydronaphthyloxazoline (–)-6a.
(Scheme 5). This represented the first example of a ring-
closing metathesis being performed in the presence of a
chiral basic oxazoline, and not surprisingly, a good yield
was obtained. Also, the desired tricyclic ring system 20 of
the natural products 3 and 4 had now been constructed
from a chiral oxazoline intermediate.
After the unsuccessful attempts to cyclize the diketone
11b, via aldol methodology, a ring-closing metathesis of
the diolefin 11a was considered. Furthermore, use of the
O
OTf
In order to increase the efficiency to 3 and 4 and render the
synthesis more convergent, the construction of the appro-
priate tetrasubstituted olefin, such as 21 (R = protecting
group), was considered (Figure 3). Because a carboxylic
acid or its ester would not be compatible with the organo-
lithium reagent during the tandem addition or with the re-
moval of the oxazoline moiety, a functional group was
required that could withstand these conditions, and also be
readily converted to the carboxylic acid found in the tar-
geted products 4. Therefore, it was felt that the protected
MEM alcohol 21 might serve the purpose at hand.14
d
e
R
OMe
OMe
OMe
16
7
12 R= Br
a
13 R= CH2CH2OH
14 R= CH2CH2I
15 R= (CH2)3CO2But
b
c
OH
O
N
O
NH
The synthesis of 21 required an appropriately protected
vinyl halide 22 to be utilized as the electrophile in the di-
astereoselective tandem addition step. Due to the synthet-
ic constraints mentioned above, the protecting group
chosen for this task was a 2-methoxyethoxy methyl
(MEM) ether. The synthetic sequence to reach the desired
electrophile is summarized in Scheme 6. The vinyl bro-
mide 22 (from 3-bromobut-3-en-1-ol) was converted to
the methyl ester 23 by metal-halogen exchange to form
the organolithium species, and this was followed by the
g
f
OMe
OMe
(-)-6a
(+)-17
Scheme 4 Reagents and conditions: (a) BuLi, BF3 Et2O, ethylene
oxide, 80%; (b) I2, Ph3P, imidazole; (c) LDA, MeCO2Bu-t, HMPA,
72% (two steps); (d) PPA, 75–85%; (e) KHMDS, PhNTf2, quantita-
tive; (f) Pd(OAc)2, dppp, CO, Et3N, DMSO, (S)-tert-leucinol, 78%;
(g) SOCl2, sat. aq K2CO3, MeCN, 83%
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PAPER
Chiral Dihydronaphthyloxazolines
2067
N
N
Li
1.
2.
20% catalyst A
DCE, ∆
O
O
(-)-6a
90%
Br
87%
OMe
19
OMe
20
single diastereomer
PCy3
Cl
Cl
N
Ph
Me
Me
Ru Ph
PCy3
(F3C)2MeCO
(F3C)2MeCO
Mo
A
B
Scheme 5
were the keys to achieve consistently high yields of the
chiral adduct (–)-28, which was invariably obtained as a
single diastereomer. In the subsequent ring-closing met-
athesis, the more reactive catalyst B15 (Scheme 5) was
found to be necessary to form the cyclic tetrasubstituted
olefin of 29.16 The structure of 28 and 29 were supported
N
CO2H
O
OP
OMe
(-)-4
OMe
21, P = OCH2OMe
1
by H NMR, 13C NMR and HRMS (see Experimental).
The synthesis of the tricycle (–)-29 efficiently puts in
place not only the ring system of 3 and 4 but all the requi-
site carbon atoms. Only the transformation of the oxazo-
line to a methyl group and conversion of the protected
Figure 3 The structures of compounds 21 and 4
addition of methyl chloroformate. Ester reduction of 23 primary alcohol remained to complete the synthesis.
with DIBAL-H gave the allylic alcohol 24, which was
then treated with MEMCl to give the MEM-ether 25. The
TBS group was removed and the resulting alcohol 26 was
converted to the requisite protected alkyl iodide 27.
In order to achieve these goals, the oxazoline of 29 was
converted to a carbinol following the earlier procedures,
with slight modifications (Scheme 8). These conditions
led to the neopentyl carbinol (+)-30 with the MEM group
The tandem addition was undertaken with oxazoline 6a intact. No isomerization of the olefin linkage was ob-
(Scheme 7) and the olefin halide 27 as the electrophile. served during the course of removing the oxazoline ring.
The addition of HMPA and a cold temperature (–78 °C) Using a variety of analogous model compounds, many
a
b
OR'
R
TBSO
CO2Me
TBSO
Br
23
22
24 R= OTBS, R'= H
c
d
e
25 R= OTBS, R'= CH2O(CH2)2OCH3
26 R= OH, R'= CH2O(CH2)2OCH3
27 R= I, R'= CH2O(CH2)2OCH3
Scheme 6 Reagents and conditions: (a) t-BuLi, Et2O, ClCO2CH3, 50%; (b) DIBAL-H, THF, 90%; (c) MEMCl, Hunig’s base, CH2Cl2, 85%;
(d) TBAF, THF, 94%; (e) I2, Ph3P, imidazole, 91%
Scheme 7
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2068
L. F. Basil et al.
PAPER
O
P
N
OMEM
N
OMEM
O
HO
a-d
e
(-)-29
OMe
OMe
(+)-30
(-)-31
Scheme 8 Reagents and conditions: (a) MeOTf, CaH2, CH2Cl2; (b) NaBH4, THF, H2O; (c) oxalic acid, THF, H2O, 70 °C (d) NaBH4, THF,
H2O, 75% over four steps; (e) P(=O)Cl2N(CH3)2, Me2NH, 85%
deoxygenation conditions were attempted to obtain the
quaternary methyl group (Table 1). Conversion of the hin-
dered neopentyl hydroxyl to leaving groups such as ha-
lides, mesylates, and xanthate esters did not lead to the
desired methyl group. When the phosphorodiamidate
(Table 1, entry 4) was formed from the primary alcohol
and reductively cleaved by lithium naphthalenide,17 54%
of the desired material was obtained. The phosphorodia-
midate (–)-31 was subsequently prepared using condi-
tions reported for sterically encumbered alcohols.18
Reductive cleavage of the phosphorodiamidate 31, con-
taining all the rings and carbons in place, was initially at-
tempted in the presence of the allylic MEM-ether 31. The
Scheme 9
reaction was performed with both lithium naphthalenide
and lithium 4,4 -di-tert-butylbiphenyl under various reac-
tion concentrations, molar equivalents of reductant, and
tert-butylbiphenyl and lithium (or Li-naphthalenide), the
temperatures. Unfortunately, only a very small amount of
resulting allylic alcohol 32a was too unstable to purify
angular methyl derivative 32 was obtained19 (Scheme 9).
and proceed further.
The deoxygenated derivatives 33 and 34 were also isolat-
ed; this allylic deoxygenation has been previously ob- By changing the order of functional group manipulation,
served with ethers using these reducing agents.20
the phosphorodiamidate 31 was left intact, while removal
of the MEM-ether moiety was performed (Scheme 10).
Conversion of 31 to the unstable allylic alcohol 36 (used
crude and never subjected to any acidic conditions), was
followed by oxidation to the aldehyde 37. Subsequent ox-
idation to the carboxylic acid, 38 was also successful in
the presence of the phosphorodiamidate group. Reductive
cleavage of the phosphoramide group of the alcohol, alde-
In the anticipation that the MEM ether was responsible for
the poor reductive cleavage of the phosphorodiamidate
31, the MEM group was removed using BBr3, CaH2 in
CH2Cl2 at –78 °C affording the desired allylic alcohol
(compound 36 in Scheme 10). In this fashion, only the
MEM group was cleaved, leaving the aromatic methoxy
group intact. Unfortunately, after treatment with 4,4 -di-
Table 1 Summary of Deoxygenation Attempts
Leaving Group
Formation
Reductive
Cleavage
HO
LG
MeO
MeO
MeO
Entry
1
LG
Conditions
Results
OTs, OMs
LiBHEt2, NaBH4/DMSO, LiAlH4
either starting material
or complex mixtures
2
3
4
5
I, Br
as above
LiNp
unable to convert
hydroxyl to halide
C(=S)SMe, C(=S)Imid.
P(=O)(NMe-2)2
either starting material
or complex mixtures
LiNp, LiDBB
NA
54% desired
deoxygenated product
SCH2CH2S, =NHNH2
unable to form thioketal
or hydrazone
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Chiral Dihydronaphthyloxazolines
2069
13C NMR (CDCl3, 75 MHz): = 20.5, 23, 23.7, 26, 26.5, 33.9, 61.1,
67.5, 77.6, 122.6, 124, 127.5, 128.9, 130.6, 135.1, 141, 153.9,
162.3.
HRMS (FAB+): m/z Calcd for C21H30NO2 (M + H)+ 328.2276.
Found 328.2281.
hyde, or acid, 36–38, respectively, did not produce any of
the desired corresponding products 40a–c. While we have
demonstrated the synthetic versatility of the phosphoro-
diamidate moiety as a hydroxyl-masking and potential
methyl group, it seemed apparent that efficient reductive
cleavage to a methyl group could not be achieved in the
presence of an allylic ether or conjugated carbonyl
groups, 40 in this particular ring system.
(4S)-4-tert-Butyl-2-(6-isopropyl-5,8-dimethoxy-3,4-dihydro-
naphthalen-1-yl)oxazoline (6b)
Oxazoline 6b was obtained in a similar manner as 6a starting from
5,8-dimethoxytetralone;10 [ ]D25 –67.5 (c = 0.79, MeOH).
O
R
IR (film): 1657, 1478 cm–1.
R
N
P
O
1H NMR (CDCl3, 300 MHz): = 0.97 (s, 9 H), 1.20 (d, J = 6.9 Hz,
6 H), 2.17–2.14 (m, 2 H), 2.73 (t, J = 7.8 Hz, 2 H), 3.30 (sept,
J = 6.9 Hz, 1 H), 3.62 (s, 3 H), 3.73 (s, 3 H), 3.91 (t, J = 9.2 Hz, 1
H), 4.09 (t, J = 8.5 Hz, 1 H), 4.25 (t, J = 9.1 Hz, 1 H), 6.62 (s, 1 H),
6.68 (t, J = 5.0 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 21.6, 22.4, 23.7, 26.1, 26.8, 33.6,
56.4, 61.3, 68.9, 75.6, 107.9, 119.9, 126.6, 131.0, 134.5, 142.0,
148.1, 152.2, 166.5.
N
d
OMe
OMe
40a-d (R - CH2OH, CHO, CO2H, H)
31 R= CH2OMEM
36 R= CH2OH
37 R= CHO
38 R= CO2H
39 R= H
a
b
c
HRMS (FAB+): m/z Calcd for C22H32NO3 (M + H)+ 358.2382.
Found 358.2386.
Scheme 10 Reagents and conditions: (a) BBr3, CaH2, CH2Cl2, –78
°C; (b) MnO2, CH2Cl2, r.t., 60% over 2 steps; (c) NaClO2, NH2SO3H,
aq dioxane, r.t., 80%; (d) Li-naphthalenide (or LDBB): unsatisfactory
with 31,36–38, 54% with 39
6-Isopropyl-5-methoxy-3,4-dihydro-2H-naphthalen-1-one (7)
Using a mechanical stirrer and an oil bath that had been equilibrated
to 95 °C, ester 15 (2 g, 6.85 mmol) was heated in polyphosphoric
acid (20 mL) for 2 h. The red reaction mixture was cooled, diluted
with H2O (100 mL), and extracted with EtOAc (3 50 mL). The
EtOAc solution was washed with sat. aq NaHCO3 (2 75 mL) and
brine (100 mL). The solution was dried (MgSO4), filtered, and con-
centrated. Flash chromatography (5% EtOAc–hexane) of the crude,
yellow residue gave 1.19 (80%) g of 7 as an off-white solid (80%);
mp 102–104 °C.
Nonaqueous reactions were performed under argon with flame-
dried glassware. Et2O, THF, and benzene were dried by distillation
over sodium-benzophenone. CH2Cl2, diisopropylamine, Et3N, tolu-
ene, DMSO, and HMPA were distilled over CaH2. Thin layer and
flash chromatography were performed with E. Merck Kieselgel sil-
ica gel 60 (230–400 mesh A.S.T.M.) unless otherwise stated.
Schrock catalyst was purchased from Strem Chemical, Inc. and was
washed with hexane under argon prior to use. N,N-Dimethylphos-
phoroamidic dichloride was purchased from Lancaster Synthesis,
Inc. and used without further purification. All other commercial
compounds were purchased from Aldrich Chemical Co. and unless
otherwise indicated, used without further purification. Melting
points are uncorrected. Microanalyses were performed by Atlantic
Microlab, Inc., Norcross, Georgia.
IR (film): 1681, 1416 cm–1.
1H NMR (CDCl3, 300 MHz): = 1.24 (d, J = 6.6 Hz, 6 H), 2.11
(dddd, J = 6.3, 6.3, 6.3, 6.3 Hz, 2 H), 2.62 (dd, J = 7.0, 6.0 Hz, 2 H),
2.98 (dd, J = 6.0, 6.0 Hz, 2 H), 3.37 (sept, J = 6.6 Hz, 1 H), 3.75 (s,
3 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 22.9, 23.5, 26.9, 38.8, 61.1, 123. 2,
124.6, 131.9, 137.7, 147.7, 154.5, 198.1.
HRMS (FAB+): m/z Calcd for C14H19O2 (M + H)+ 219.1385. Found
219.1382.
(4S)-4-tert-Butyl-2-(6-isopropyl-5-methoxy-3,4-dihydronaph-
thalen-1-yl)oxazoline (6a)
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 76.96; H,
8.33.
To a solution of the amide alcohol 17 (500 mg, 1.45 mmol) in
CH2Cl2 (15 mL) at 0 °C was slowly added SOCl2 (0.23 mL, 3.19
mmol). After stirring for 2 h, the solvent was removed. The residue
was dissolved in MeCN (8 mL) and sat. aq K2CO3 (5 mL) and the
solution was refluxed for 6 h. Upon cooling, the solvent was re-
moved and the residue was dissolved in EtOAc (100 mL) and
washed with brine (2 50 mL). The EtOAc solution was dried
(Na2SO4), filtered, and concentrated. The crude material was puri-
fied by flash chromatography (5% EtOAc–hexanes and 10%
EtOAc–hexanes) to yield (–)-6a as a slow-forming, cream colored
solid. The product could be stored under argon at –18 °C for several
weeks; however, at r.t., decomposition began to occur within 24 h;
mp 78–80 °C; [ ]D25 –149 (c = 0.55, CHCl3).
1-Bromo-3-isopropyl-2-methoxybenzene (12)
To a solution of 2-isopropylphenol (18.3 g, 0.13 mmol) in CS2 (500
mL) was added solid N-bromosuccinimide (24 g, 0.13 mmol) over
1 h. The reaction mixture was stirred at r.t. for 12 h and an off-white
precipitate was formed. The solvent was removed, and the residue
was dissolved in Et2O (350 mL). The Et2O solution was washed
with 10% aq Na2S2O3 (2 150 mL), and brine (100 mL). After dry-
ing (MgSO4), the solution was filtered and concentrated. Flash
chromatography (0.5% EtOAc–hexanes) of the crude material pro-
duced 24.9 g of the desired 1-bromo-3-isopropyl-2-hydroxyben-
zene (86%). Following the procedure of McKillop et al.,21
a
IR (film): 1650, 1482 cm–1.
biphasic mixture of the preceding phenol (15.8 g, 17.6 mmol), di-
methyl sulfate (14 g, 111 mmol), LiOH H2O (4.9 g, 118 mmol), and
benzyltributylammonium chloride (2.3 g, 7.3 mmol) in CH2Cl2–
H2O (1:1, 600 mL) was stirred at r.t. for 12 h. The phases were sep-
arated, and the aqueous phase was extracted with CH2Cl2 (2 100
mL). The CH2Cl2 extracts were combined and stirred with 10%
NH4OH solution (300 mL) for 5 h. The phases were separated and
the organic phase was dried (Na2SO4) and concentrated. Flash chro-
1H NMR (CDCl3, 300 MHz): = 1.21 (d, J = 2.25 Hz, 3 H), 1.24 (d,
J = 2.25 Hz, 3 H), 2.66 (ddd, J = 15.3, 11.7, 6.4 Hz, 1 H), 2.94 (ddd,
J = 15.2, 6.6, 6.6 Hz, 1 H), 3.32 (ddd, J = 13.8, 6.8, 6.8 Hz, 1 H),
3.67 (s, 3 H), 4.04 (dd, J = 10.1, 7.7 Hz, 1 H), 4.13 (dd, J = 8.1, 8.1
Hz, 1 H), 4.24 (dd, J = 10.1, 8.4 Hz, 1 H), 6.88 (dd, J = 5.4, 4.35 Hz,
1 H), 7.14 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H).
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L. F. Basil et al.
PAPER
matography (1% EtOAc–hexanes) gave 15.5 g (92%) of 12 as a
clear liquid; bp 120–125 °C/20 mmHg.
mmol) and anhyd HMPA (982 mg, 5.48 mmol) were mixed in THF
(5 mL) and cooled to –78 °C. The acetate anion was then added
dropwise via cannula into the iodide 14/HMPA solution. After stir-
ring for 5 h at –78 °C, the solution was quenched with sat. aq NH4Cl
(20 mL) and allowed to warm to r.t. The mixture was extracted with
EtOAc (3 25 mL), the combined organic phases were washed
with brine (50 mL), dried (Na2SO4), filtered and concentrated. Flash
chromatography (step gradient: hexanes to 2% EtOAc–hexanes)
gave 685 mg (85%) of 15 as a colorless oil.
1H NMR (CDCl3, 300 MHz): = 1.23 (d, J = 6.9 Hz, 6 H), 3.36
(sept, J = 6.9 Hz, 1 H), 3.83 (s, 3 H), 6.97 (t, J = 7.8 Hz, 1 H), 7.2
(dd, J = 7.8, 1.5 Hz, 1 H), 7.37 (dd, J = 7.8, 1.5 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 23.7, 27.2, 61.3, 117.4, 125.6,
125.9, 130.8, 144, 154.2.
MS: m/z = 228/230 (M+).
IR (neat): 1729, 1462 cm–1.
Anal. Calcd for C10H13BrO: C, 52.42; H, 5.72. Found: C, 52.13; H,
5.90.
1H NMR (CDCl3, 300 MHz): = 1.23 (d, J = 6.6 Hz, 6 H), 1.45 (s,
9 H), 1.9 (q, J = 7.5 Hz, 2 H), 2.28 (t, J = 7 Hz, 2 H), 2.66 (t, J = 7.8
Hz, 2 H), 3.32 (sept, J = 6.6 Hz, 1 H), 3.73 (s, 3 H), 7.04–7.02 (m,
2 H), 7.12 (dd, J = 6.3, 3.3 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 24.1, 26.2, 26.4, 28.2, 29.3, 35.4,
61.7, 80, 124.2, 124.4, 127.4, 134.4, 141.8, 155.4, 172.8.
2-(3-Isopropyl-2-methoxyphenyl)ethanol (13)
A solution of 12 (3 g, 13.1 mmol) in anhyd THF (10 mL) (com-
pound dried over NaH in THF and decanted) at –78 °C was de-
gassed by evacuating the system under vacuum until the solvent
bubbled by purging the system with argon. This process was repeat-
ed 5 times. The solution was then slowly added via cannula to a so-
lution of BuLi (2.4 M in hexane, 5.7 mL, 13.7 mmol) at –78 °C,
which had also been degassed as described above. After stirring 15
min, BF3 Et2O (2.04 g, 14.4 mmol) was added and the reaction mix-
ture was stirred for 30 min, which became brightly yellow over
time. Ethylene oxide ( 1 mL) was condensed into the reaction mix-
ture. After stirring for 2 h at –78 °C, sat. aq NH4Cl (30 mL) was add-
ed and the mixture was allowed to warm to r.t. and extracted with
EtOAc (3 50 mL). The combined extracts were dried (Na2SO4),
filtered, and concentrated. Flash chromatography (gradient from 10
to 25% EtOAc–hexanes) gave 2.03 g (80%) of 13 as a light yellow
oil.
HRMS (FAB+): m/z Calcd for C18H28O3 (M)+ 292.2038. Found
292.2040.
Anal. Calcd for C18H28O3: C, 73.93; H, 9.65. Found: C, 73.98; H,
9.72.
Trifluoromethanesulfonic Acid 6-Isopropyl-5-methoxy-3,4-di-
hydronaphthalen-1-yl Ester (16)
To a solution of 7 (500 mg, 2.29 mmol) in THF (8 mL) at –78 °C
was slowly added potassium bis(trimethylsilyl)amide (0.5 M in tol-
uene, 5.5 mL, 2.75 mmol). The reaction mixture was stirred for 1 h,
till it became homogeneous. To this was added N-phenyltriflamide
(1.07 g, 3 mmol) in THF (3 mL). After stirring for 1 h at –78 °C, the
mixture was allowed to warm to r.t. Sat. aq NH4Cl (20 mL) was add-
ed, and the mixture was extracted with EtOAc (3 20 mL). The
EtOAc solution was dried (Na2SO4), filtered and concentrated. The
crude residue was purified by flash chromatography (2.5% EtOAc–
hexanes) to yield 16 as a light brown oil (800 mg, 99%). The mate-
rial could be stored at –18 °C under argon for several days. After
that, significant decomposition was noted.
1H NMR (CDCl3, 300 MHz): = 1.23 (d, J = 6.9 Hz, 6 H), 2.48
(ddd, J = 8.4, 4.2, 4.2 Hz, 2 H), 2.9 (dd, J = 8.1, 8.1 Hz, 2 H), 3.32
(sept, J = 6.8 Hz, 1 H), 3.71 (s, 3 H), 5.96 (dd, J = 4.6, 4.6 Hz, 1 H),
7.12 (d, J = 8.4 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1H).
13C NMR (CDCl3, 75 MHz): = 20.4, 22.1, 23.7, 26.7, 61.2, 116.8,
117.5, 124.6, 127.6, 128.9, 130 [q, J (13C,19F) = 75 Hz], 143.4,
146.2, 154.3.
IR (neat): 3358 (br), 1462 cm–1.
1H NMR (CDCl3, 300 MHz): = 1.24 (d, J = 6.9 Hz, 6 H), 1.98 (t,
J = 5.4 Hz, 1 H), 2.93 (t, J = 6.6 Hz, 2 H), 3.33 (sept, J = 6.9 Hz, 1
H), 3.77 (s, 3 H), 3.87 (q, J = 6 Hz, 2 H), 7.02–7.10 (m, 2 H), 7.17
(dd, J = 6.6, 2.8 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 24, 26.3, 33.9, 61.7, 63.5, 124.6,
128.1, 131.7, 142.1, 155.8.
HRMS (FAB+): m/z Calcd for C12H18O2 (M)+ 194.1307. Found
194.1289.
1-(2-Iodoethyl)-3-isopropyl-2-methoxybenzene (14)
To CH2Cl2 (40 mL) at 0 °C was added Ph3P (2.76 g, 10.5 mmol) and
I2 (2.89 g, 11.38 mmol). After stirring for 20 min, imidazole (835
mg, 12.3 mmol) was added, followed by a solution of 13 in CH2Cl2
(10 mL). The reaction mixture was allowed to warm to r.t. slowly.
After 12 h, the mixture was diluted with EtOAc (100 mL), washed
with 10% aq Na2S2O3 (2 75 mL) and brine (50 mL). The EtOAc
solution was dried (Na2SO4), filtered, and concentrated. The crude
residue was flushed through a plug of silica gel with 10% EtOAc–
hexanes gave 2.49 g (94%) of 14 as a light yellow oil.
HRMS (FAB+): m/z Calcd for C15H17F3O4S (M)+ 350.0800. Found
350.0801.
6-Isopropyl-5-methoxy-3,4-dihydronaphthalene-1-carboxylic
Acid (1S)-2Hydroxy-1-tert-butylethyl)amide (17)
The following were combined in order: vinyl triflate 16 (810 mg,
2.34 mmol), (S)-tert-leucinol (548 mg. 4.68 mmol), Et3N (0.82 mL,
5.88 mmol), 1,3-bis(diphenylphosphino)propane (48 mg, 0.12
mmol), and Pd(OAc)2 (16 mg, 0.07 mmol). After diluting with an-
hyd DMSO (2 mL), the reaction was aerated with CO from a bal-
loon for 15 min, and then heated at 65 °C for 12 h under a CO
atmosphere. After cooling to r.t., the mixture was diluted with
EtOAc (75 mL) and washed with brine (50 mL). The EtOAc solu-
tion was dried (Na2SO4), filtered, and concentrated. The crude resi-
due was purified by flash chromatography (15% EtOAc–hexanes
and 45% EtOAc–hexanes) to give 624 mg (77%) of 17 as a colorless
foam; [ ]D25 +13.7 (c = 0.54, CHCl3).
IR (neat): 1463 cm–1.
1H NMR (CDCl3, 300 MHz): = 1.23 (d, J = 7.5 Hz, 6 H), 3.21 (t,
J = 7.5 Hz, 2 H), 3.32 (sept, J = 6.6 Hz, 1 H), 3.37 (t, J = 7.5 Hz, 2
H), 3.76 (s, 3 H), 7.01 (dd, J = 10.5, 2.1 Hz, 1 H), 7.07 (t, J = 7.5
Hz, 1 H), 7.2 (dd, J = 10.5, 2.1 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 4.6, 24, 26.4, 35.5, 61.9, 124.5,
125.7, 127.3, 133.6, 142.2, 155.4.
4-(3-Isopropyl-2-methoxyphenyl)butyric Acid tert-Butyl Ester
(15)
IR (film): 1644, 1610 cm–1.
To a solution of anhyd diisopropylamine (0.31 g, 3.01 mmol) in an-
hyd THF (6 mL) at –78 °C was added BuLi (1.95M in hexane, 2.74
mmol, 1.4 mL). After stirring for 15 min, tert-butyl acetate (315 mg,
2.74 mmol) was added dropwise, and the reaction mixture was
stirred for 30 min at –78 °C. In a separate flask, iodide 14 (1g, 3.29
1H NMR (CDCl3, 300 MHz): = 1.02 (s, 9 H), 1.23 (d, J = 7.2 Hz,
6 H), 2.31–2.42 (m, 2 H), 2.85 (ddd, J = 7.5, 7.5, 3.3 Hz, 2 H), 3.33
(sept, J = 6.9 Hz, 1 H), 3.57–3.74 (m, 2 H), 3.7 (s, 3 H), 3.94–4.06
Synthesis 2002, No. 14, 2064–2074 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Chiral Dihydronaphthyloxazolines
2071
(m, 2 H), 5.97 (br d, J = 9.3 Hz, 1 H), 6.51 (app t, J = 4.6 Hz, 1 H),
7.12 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = –5.5, 18.3, 25.9, 37.1, 63.4, 66.4,
112.5, 147.2.
13C NMR (CDCl3, 75 MHz): = 20.6, 22.6, 23.7, 26.5, 27, 33.6,
59.7, 61.1, 63.3, 121.4, 124.4, 128.8, 130.2, 130.4, 136.5, 141.8,
154.3, 170.2.
Anal. Calcd for C11H24O2Si: C, 61.06; H, 11.18 Found: C, 61.33; H,
11.28.
tert-Butyl-[3-(2-methoxyethoxymethoxymethyl)but-3-eny-
loxy]dimethylsilane (25)
HRMS (FAB+): m/z Calcd for C21H32NO3 (M + H)+ 346.2382.
Found 346.2388.
To a solution 24 (2 g, 9.26 mmol) and diisopropylethylamine (5.32
mL, 30.7 mmol) in CH2Cl2 (6 mL) at r.t. was added 2-methoxy-
ethoxymethyl chloride (MEM-Cl) (1.6 mL, 14 mmol). After stirring
for 24 h, the mixture was diluted with EtOAc (40 mL), and washed
with 10% aq CuSO4 (2 40 mL) and brine (40 mL). The organic
layer was dried (Na2SO4), filtered, and concentrated. Flash chroma-
tography (10% EtOAc–hexanes) gave 2.4 g (85%) of 25 as an oil.
Anal. Calcd for C21H31NO3: C, 73.01; H, 9.04 Found: C, 72.87; H,
9.20.
(3-Bromobut-3-enyloxy)-tert-butyldimethylsilane (22)
To a solution of 3-bromobut-3-en-1-ol (Aldrich) (860 mg, 5.7
mmol) in DMF (4 mL) was added tert-butyldimethylsilyl chloride
(1.12 g, 7.4 mmol), imidazole (582 mg, 8.55 mmol) and a catalytic
amount of 4,4-dimethylaminopyridine. The reaction mixture was
allowed to stir at r.t. for 12 h, and then was diluted with Et2O (50
mL). The solution was washed with brine (3 150 mL), dried
(Na2SO4), and concentrated. The material was purified by flash
chromatography (2% EtOAc–hexanes) to give 22 as a clear liquid.
IR (neat): 1652, 1464 cm–1.
1H NMR (CDCl3, 300 MHz): = 0.04 (s, 6 H), 0.88 (s, 9 H), 2.28
(dd, J = 6, 6 Hz, 2 H), 3.39 (s, 3 H), 3.55–3.56 (m, 2 H), 3.69–3.74
(m, 4 H), 4.02 (br s, 2 H), 4.73 (s, 3 H), 4.93 (br s, 1 H), 5.08 (br s,
1 H).
1H NMR (CDCl3, 300 MHz): = 0.07 (s, 6 H), 0.89 (s, 9 H), 2.62
(t, J = 6.3 Hz, 2 H), 3.79 (t, J = 6.3 Hz, 2 H), 5.45 (s, 1 H), 5.63 (s,
1 H).
13C NMR (CDCl3, 75 MHz): = –5.3, 18.3, 25.9, 44.8, 60.8, 118.4,
130.8.
13C NMR (CDCl3, 75 MHz): = –5.3, 18.3, 25.9, 36.7, 59, 62.1,
66.8, 70.4, 71.8, 94.7, 113, 142.8.
HRMS (FAB+): m/z Calcd for C15H33O4Si (M + H)+ 305.2148.
Found: 305.2143.
3-(2-Methoxyethoxymethoxymethyl)but-3-en-1-ol (26)
To a solution of allylic MEM-ether 25 (2 g, 6.58 mmol) in THF (20
mL) at r.t. was added tetrabutylammonium fluoride (1 M in THF,
8.6 mL) and the reaction mixture was stirred for 3 h. The solvent
was removed and the residue was dissolved in EtOAc (75 mL). The
EtOAc solution was washed with brine (2 50 mL), dried
(Na2SO4), filtered, and concentrated. Flash chromatography (25%
EtOAc–hexanes and 50% EtOAc–hexanes) gave 1.18 g (94%) of 26
as a clear oil.
Anal. Calcd for C10H21BrOSi: C, 45.28; H, 7.98 Found: C, 45.30; H,
8.04.
4-(tert-Butyldimethylsilyloxy)-2-methylenebutyric Acid Methyl
Ester (23)
t-BuLi (2 M in pentane, 4 mL, 8 mmol) was added slowly to a solu-
tion 22 (1 g, 3.77 mmol) in anhyd Et2O (30 mL). After 15 min, me-
thyl chloroformate (465 mg, 4.92 mmol) was added and the solution
was stirred for 30 min. Sat. aq NH4Cl (15 mL) was added and the
mixture was allowed to warm to r.t. The layers were separated and
the aqueous layer was extracted with Et2O (2 15 mL). The organic
layers were combined, dried (Na2SO4), filtered, and concentrated at
r.t. (30 mmHg). The crude residue was purified by flash chromatog-
raphy (2.5% Et2O–petroleum ether) to give 460 mg (50%) of 23 as
a tan oil.
IR (neat): 3444 (br), 1652 cm–1.
1H NMR (CDCl3, 300 MHz): = 2.36 (t, J = 6 Hz, 2 H), 3.39 (s, 3
H), 3.55–3.58 (m, 2 H), 3.70–3.77 (m, 4 H), 4.05 (s, 2 H), 4.75 (s, 2
H), 5.03 (br s, 1 H), 5.16 (br s, 1 H).
13C NMR (CDCl3, 75 MHz): = 37.1, 59, 61.1, 67, 70.4, 71.7, 94.7,
115, 142.5.
HRMS (FAB+): m/z Calcd for C9H18O4 (M + H)+ 191.1283. Found:
191.1282.
IR (neat): 1723, 1632 cm–1.
1H NMR (CDCl3, 300 MHz): = 2.53 (t, J = 6.6 Hz, 2 H), 3.72 (t,
J = 6.6 Hz, 2 H), 3.74 (s, 3 H), 5.62 (d, J = 1.5 Hz, 1 H), 6.2 (d,
J = 1.5 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = –5.4, 18.3, 25.9, 35.5, 51.8, 61.8,
127, 137.2, 167.5.
4-Iodo-2-(2-methoxyethoxymethoxymethyl)but-1-ene (27)
To a solution of Ph3P (497 mg, 1.89 mmol) in CH2Cl2 (8 mL) at 0 °C
was added I2 (522 mg, 2.06 mmol), and the mixture was stirred for
30 min. Imidazole (150 mg, 2.2 mmol) was added followed by the
alcohol 26 (300 mg, 1.58 mmol) in CH2Cl2 (3 mL). The mixture was
stirred for 10 h while allowing to warm to r.t., and the insolubles
were removed by filtration and washed with Et2O (50 mL). After
concentration of the filtrate, the crude residue was flushed through
a plug of basic alumina (30% EtOAc–hexanes) to give 430 mg
(91%) of 27 as a yellow oil.
4-(tert-Butyldimethylsilyloxy)-2-methylenebutan-1-ol (24)
To a solution of 23 (520 mg, 2.13 mmol) in THF (15 mL) at 0 °C
was slowly added DIBAL-H (2 M in toluene, 3.2 mL, 6.4 mmol).
The reaction mixture was stirred for 3 h, and aq 1 N NaOH (25 mL)
was slowly added. The phases were separated and the aqueous
phase was extracted with EtOAc (2 25 mL). The organic phase
was dried (Na2SO4), filtered and concentrated. Flash chromatogra-
phy (5% EtOAc–hexanes and 10% EtOAc–hexanes) gave 414 mg
(90%) of 24 as a light yellow oil.
IR (neat): 1652, 1455 cm–1.
1H NMR (CDCl3, 300 MHz): = 2.66 (t, J = 7.8 Hz, 2 H), 3.28 (t,
J = 7.8 Hz, 2 H), 3.4 (s, 3 H), 3.55–3.58 (m, 2 H), 3.70–3.73 (m, 2
H), 4.04 (s, 2 H), 4.72 (s, 2 H), 4.99 (s, 1 H), 5.16 (s, 1 H).
13C NMR (CDCl3, 75 MHz): = 3.2, 37.7, 59.1, 67, 69.5, 71.8, 94.6,
114.3, 143.9.
IR (neat): 3357 (br), 1649 cm–1.
1H NMR (CDCl3, 300 MHz): = 0.07 (s, 6 H), 0.9 (s, 9 H), 2.34 (t,
J = 6 Hz, 2 H), 2.77 (t, J = 6 Hz, 1 H), 3.75 (t, J = 6 Hz, 2 H), 4.07
(d, J = 5.7 Hz, 2 H), 4.9 (br s, 1 H), 5.04 (br s, 1 H).
HRMS (FAB+): m/z Calcd for C9H18O3I (M + H)+ 301.0301. Found:
301.0303.
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2072
L. F. Basil et al.
PAPER
(4S)-4-tert-Butyl-2-{(1S,2R)-2-isopropenyl-6-isopropyl-5-meth-
oxy-1-[3-(2-methoxyethoxymethoxymethyl)but-3-enyl]-1,2,3,4-
tetrahydronaphthalen-1-yl}oxazoline (28); Representative
Tandem Addition
Mo(CHCMe2Ph)[N(2,6-i-Pr)2C6H3][OCMe(CF3)2]2 (Schrock cata-
lyst, B, 50 mg). The reaction was stirred for 45 min at r.t., then 1.5
h in a 60 °C oil bath. After cooling, the crude reaction mixture was
flushed through a plug of silica gel (1:1 EtOAc–hexanes). The ma-
terial was concentrated and purified by flash chromatography (5%
EtOAc–hexanes, 10% EtOAc–hexanes) to give 210 mg (90%) of 29
as a yellow oil; [ ]D25 –146 (c = 0.5, CHCl3).
1H NMR (CDCl3, 300 MHz): = 0.75 (s, 9 H), 1.20 (d, J = 6.9 Hz,
3 H), 1.22 (d, J = 6.9 Hz, 3 H), 1.72 (ddd, J = 12.8, 11.1, 7.6 Hz, 1
H), 1.83 (s, 3 H), 2.12–2.49 (m, 4 H), 2.62–2.77 (m, 2 H), 2.86 (dd,
J = 12.8, 5.6 Hz, 1 H), 2.98–3.10 (m, 1 H), 3.29 (sept, J = 6.3 Hz, 1
H), 3.41 (s, 3 H), 3.58 (dd, J = 5.6, 2.1 Hz, 2 H), 3.63–3.74 (m, 5 H),
3.72 (s, 3 H), 3.84 (app t, J = 8.1 Hz, 1 H), 3.93 (dd, J = 10.2, 9 Hz,
1 H), 4.32 (d, J = 10.2 Hz, 1 H), 4.72 (s, 2 H), 7.06 (d, J = 8.3 Hz, 1
H), 7.34 (d, J = 8.3 Hz, 1 H).
t-BuLi (1.7M in pentane, 0.94 mL, 1.59 mmol) was added dropwise
to a solution of 2-bromopropene (92 L, 1.03 mmol) in anhyd THF
(6 mL) at –78 °C. After stirring for 15 min, a solution of oxazoline
6a in anhyd THF (2 mL) was added and the reaction mixture was
stirred for 15 min at –78 °C. Anhyd HMPA (227 L, 1.59 mmol)
was added and the solution was allowed to stir another 20 min at
–78 °C. Iodide 27 (358 mg, 1.19 mmol) was added and after 5 min,
the reaction was stopped by addition of sat. aq NH4Cl (10 mL). Af-
ter addition of EtOAc (6 mL), the phases were separated. The or-
ganic layer was washed with brine, dried (Na2SO4), filtered and
concentrated. The crude material was purified by flash chromatog-
raphy (5% EtOAc–hexanes and 15% EtOAc–hexanes) to give 370
mg (86%) of 28 as a single diastereomer and as a viscous, light yel-
low oil; [ ]D25 –157 (c = 0.42, CHCl3).
13C NMR (CDCl3, 75 MHz): = 15.5, 21, 23.8, 24.1, 25.8, 26.2,
27.42, 33.5, 34.2, 43.3, 45.1, 59, 60.5, 66.7, 67.3, 67.7, 71.8, 75.8,
94.8, 123.1, 123.4, 125.3, 130.6, 135.1, 138.9, 139.2, 154.7, 167.3.
HRMS (FAB+): m/z Calcd for C31H47NO5 (M + H)+ 513.3454.
Found: 513.3444.
IR (neat): 1652 cm–1.
1H NMR (CDCl3, 300 MHz): = 0.92 (s, 9 H), 1.24 (d, J = 6.6 Hz,
3 H), 1.25 (d, J = 6.6 Hz, 3 H), 1.45 (ddd, J = 14.7, 6.6, 6.6 Hz, 1
H), 1.75 (s, 3 H), 1.79–1.84 (m, 1 H), 1.96 (ddd, J = 14.7, 6.6, 6.6
Hz, 1 H), 2.35–2.68 (m, 5 H), 3.14 (br d, J = 16.5 Hz, 1 H), 3.31
(sept, J = 6.9 Hz, 1 H), 3.43 (s, 3 H), 3.56–3.59 (m, 2 H), 3.69–3.8
(m, 3 H), 3.76 (s, 3 H), 3.92 (app t, J = 8.1 Hz, 1 H), 3.99 (s, 3 H),
4.05 (app t, J = 9.5 Hz, 1 H), 4.7 (s, 2 H), 4.84 (s, 1 H), 4.91 (s, 1
H), 4.95 (s, 1 H), 5.01 (s, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 7.04 (d,
J = 8.4 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 20.9, 23.7, 23.9, 24.4, 25.1, 26.1,
27.6, 34.1, 35.3, 46.4, 47.4, 59, 60.7, 66.8, 68.1, 70.1, 71.8, 74.9,
94.6, 111.4, 114.4, 123.2, 123.9, 131.2, 136.6, 138.7, 145.8, 146,
154.8, 170.7.
(4S)-4-tert-Butyl-2-[(4aS,10aR)-7-isopropyl-8-methoxy-1-meth-
yl-3,9,10,10a-tetrahydro-4H-phenanthren-4a-yl]oxazoline (20)
A tandem addition was carried out with oxazoline 6a, 2-lithiopro-
pene, and 4-bromobut-1-ene to give the adduct 19 in a similar man-
ner as with compounds 10 and 28. To a degassed solution of
oxazoline adduct 19 (60 mg, 0.142 mmol) in CH2Cl2 (14 mL) was
added Grubbs’ catalyst (A, 5 mg). The brown solution was refluxed
for 24 h adding additional catalyst (3 5 mg) every 6–8 h. The sol-
vent was removed and the residue was purified by flash chromatog-
raphy to give 51 mg (90%) of 20.
1H NMR (CDCl3, 300 MHz): = 0.84 (s, 9 H), 1.24 (d, J = 7.5 Hz,
3 H), 1.27 (d, J = 7.5 Hz, 3 H), 1.28–1.33 (m, 1 H), 1.69–1.82 (m, 4
H), 2.05–2.49 (m, 4 H), 2.66–2.86 (m, 2 H), 2.98–3.10 (m, 1 H),
3.30 (sept, J = 7.5 Hz, 1 H), 3.66–3.76 (m, 1 H), 3.72 (s, 3 H), 3.88
(app t, J = 8.4 Hz, 1 H), 3.94 (app t, J = 9.3 Hz, 1 H), 5.28 (br s, 1
H), 7.07 (d, J = 8.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H).
HRMS (FAB+): m/z Calcd for C33H52NO5 (M + H)+ 542.3845.
Found: 542.3839.
(4S)-4-tert-Butyl-2-[(1S,2R)-2-isopropenyl-6-isopropyl-5-meth-
oxy-1-(4-methylpent-4-enyl)-1,2,3,4-tetrahydronaphthalen-1-
yl]oxazoline (10)
The compound was obtained in a similar manner to adduct 28 from
1-iodo-4-methylpent-4-ene to give 10 as a single diastereomer;
white solid (76%); mp 104–105 °C; [ ]D25 –258 (c = 0.71, MeOH).
HRMS (FAB+): m/z Calcd for C26H37NO2 (M + H)+ 396.2902.
Found: 396.2896.
[(4aS,10aR)-7-Isopropyl-8-methoxy-2-(2-methoxyethoxy-
methoxymethyl)-1-methyl-3,9,10,10a-tetrahydro-4H-phenan-
thren-4a-yl]methanol (30); Representative Example of
IR (film): 2859, 1651, 1480, 1450 cm–1.
1H NMR (CDCl3, 300 MHz): = 0.73–0.93 (m, 1 H), 0.86 (s, 9 H),
1.17 (d, J = 6.9 Hz, 3 H), 1.19 (d, J = 6.9 Hz, 3 H), 1.20–1.35 (m, 1
H), 1.55 (s, 3 H), 1.64–1.67 (m, 1 H), 1.72 (s, 3 H), 1.91 (m, 2 H),
2.18 (dd, J = 9.1, 7.5 Hz, 2 H), 2.29 (qd, J = 12.6, 4.46 Hz, 1 H),
2.46–2.62 (m, 2 H), 3.08 (dq, J = 10.7, 2.5 Hz, 1 H), 3.27 (hept,
J = 6.9 Hz, 1 H), 3.68–3.74 (m, 1 H), 3.70 (s, 3 H), 3.86 (t, J = 8.1
Hz, 1 H), 3.98 (dd, J = 10.3, 8.7 Hz, 1 H), 4.55 (s, 1 H), 4.61 (s, 1
H), 4.76 (s, 1 H), 4.88 (s, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 6.97 (d,
J = 8.3 Hz, 1 H).
Conversion of an Oxazoline to a Carbinol
The oxazoline 29 (69 mg, 0.13 mmol) was dissolved in CH2Cl2 (1
mL), then chilled to 0 °C, and CaH2 ( 5 mg) was added. To this was
added methyl triflate (30 L, 0.27 mol), and the solution was stirred
overnight, and allowed to warm to r.t. After filtration through a plug
of cotton, the solution was concentrated and the residue was dis-
solved in THF–H2O (4:1, 2.5 mL). The mixture was chilled to 0 °C
and NaBH4 (15 mg, 0.39 mmol) was added portionwise. After chill-
ing for 30 min, aq 1 N NaOH ( 2 mL) was added and the mixture
was stirred for an additional 3 h. The solution was extracted with
EtOAc (3 10 mL), dried (Na2SO4), filtered and concentrated. The
crude oxazolidine was dissolved in THF/H2 (4:1, 2 mL), and oxalic
acid dihydrate (82 mg, 0.65 mmol) was added. The solution was re-
fluxed for 6 h. After cooling, sat. aq NaHCO3 (2 mL) was added,
and the solution was extracted with EtOAc (3 10 mL). The organ-
ic phase was washed with brine (10 mL), dried (Na2SO4), filtered
and concentrated to yield the crude aldehyde which was generally
used without further purification. To a solution of the crude alde-
hyde in THF–H2O (1:1, 2.5 mL) at 0 °C was slowly added NaBH4
(12.5 mg, 0.33 mmol). The reaction mixture was stirred for 30 min
at 0 °C and then diluted with aq 1 N NaOH (5 mL). After stirring for
3 h, the mixture was extracted with EtOAc (3 8 mL) and washed
13C NMR (CDCl3, 75 MHz): = 21.1, 21.7, 22.2, 23.6, 23.9, 24.4,
25.2, 26.0, 26.2, 34.0, 36.6, 38.0, 46.5, 47.5, 60.6, 67.9, 74.9, 109.8,
114.1, 123.3, 123.7, 131.1, 137.0, 138.4, 145.8, 146.1, 154.7, 170.9.
Anal. Calcd for C30H45NO2: C, 79.77; H, 10.04. Found: C, 79.52; H,
10.13.
(4S)-4-tert-Butyl-2-[(4aS,10aR)-7-isopropyl-8-methoxy-2-(2-
methoxyethoxymethoxymethyl)-1-methyl-3,9,10,10a-tetrahy-
dro-4H-phenanthren-4a-yl]oxazoline (29)
The following procedure was performed using standard Schlenk-
line techniques. A solution of oxazoline adduct 28 (250 mg, 0.46
mmol) in benzene (5 mL), which had been degassed via freeze/
pump/thaw cycles (liquid N2, 4 ), was added by cannula to
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Chiral Dihydronaphthyloxazolines
2073
with brine (10 mL). The EtOAc solution was dried (Na2SO4), fil-
tered and concentrated. Flash chromatography (25% and 50%
EtOAc–hexanes) gave 42 mg, (75%) of carbinol 30 as a light yellow
oil from oxazoline 29; [ ]D25 +4.8 (c = 1.2, CHCl3).
2.83 (ddd, J = 18.9, 9.9, 8.9 Hz, 1 H), 3.01 (dd, J = 17.4, 7.2 Hz, 1
H), 3.30 (sept, J = 6.6 Hz, 1 H), 3.74 (s, 3 H), 5.43 (br s, 1 H), 7.07
(d, J = 7.8 Hz, 1 H), 7.11 (d, J = 7.8 Hz, 1 H).
HRMS (FAB+): m/z Calcd for C20H29O (M + H)+ 285.2218, Found:
IR (neat): 3478 cm–1 (br).
285.2213.
1H NMR (CDCl3, 300 MHz): = 1.04 (dd, J = 8.7, 5.1 Hz, 1 H),
1.22 (d, J = 3 Hz, 3 H), 1.24 (d, J = 3 Hz, 3 H), 1.44–1.7 (m, 2 H),
1.78 (s, 3 H), 2.18–2.44 (m, 4 H), 2.65 (br d, J = 12 Hz, 1 H), 2.94
(ddd, J = 18.3, 18.3, 9.5 Hz, 1 H), 3.01 (ddd, J = 18.3, 18.3, 8 Hz, 1
H), 3.31 (sept, J = 6.8 Hz, 1 H), 3.41 (s, 3 H), 3.52–3.61 (m, 3 H),
3.67–3.76 (m, 3 H), 3.74 (s, 3 H), 4.00 (d, J = 10.8 Hz, 1 H), 4.27
(d, J = 10.8 Hz, 1 H), 4.74 (s, 2 H), 7.10 (d, J = 8.2 Hz, 1 H), 7.16
(d, J = 8.2 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): = 15.7, 20.3, 23.3, 23.9, 26.2, 28.4,
29.7, 40.5, 43.9, 59, 60.5, 64.6, 66.8, 67.7, 71.8, 94.8, 121.2, 123.5,
127.3, 129.7, 132.9, 139.4, 141.3, 155.6.
HRMS (FAB+): m/z Calcd for C25H39O5 (M + H)+ 419.2797.
Found: 419.2799.
(4aS,10aR)-4a-(N,N,N ,N -Tetramethylphosphorodiamidatyl)-
7-isopropyl-8-methoxy-1-methyl-3,4,4a,9,10,10a-hexahydro-
phenanthrene-2-carboxylic Acid (38)
To a solution of the phosphorodiamidate 31 (5 mg, 0.01 mmol) in
CH2Cl2 (0.8 mL) was added a catalytic amount of CaH2 and the so-
lution was chilled to –78 °C. BBr3 (0.3 M in CH2Cl2, 40 L) was
slowly added, and the solution was stirred 10 min at –78 °C. The
mixture was diluted with aq 1 N NaOH, warmed to r.t., and extract-
ed with CH2Cl2 (5 mL). The phases were separated, and the organic
layer was dried (Na2SO4), filtered and concentrated. The crude al-
cohol 36 was dissolved in CH2Cl2 (1 mL) and MnO2 ( 20 mg) was
added. After 2 h, the mixture was filtered through a plug of Celite
and concentrated. The crude aldehyde 37 was dissolved in dioxane–
H2O (1:1, 0.8 mL), and sulfamic acid [0.1 M in dioxane–H2O (1:1),
274 L] and NaClO2 [0.2 M in dioxane–H2O (1:1), 144 L] were
added sequentially. After stirring 3 h at r.t., the solvent was re-
moved, and the residue was dissolved in CH2Cl2 (5 mL) and washed
with brine (5 mL). The organic phase was dried (Na2SO4), filtered
and concentrated. The residue was subjected to flash chromatogra-
phy (C-18 silica gel, MeCN) to give 38, partially purified, ( 2.5 mg)
as a colorless film.
[(4aS,10aR)-7-Isopropyl-8-methoxy-2-(2-methoxyethoxy-
methoxymethyl)-1-methyl-3,9,10,10a-tetrahydro-4H-phenan-
thren-4a-yl]methanol-N,N,N ,N -tetramethylphosphoro-
diamidate (31); Representative Example of Phosphorodiami-
date Formation
To a solution of carbinol 30 (23 mg, 0.055 mmol, dried via toluene
azeotrope) in THF (1.2 mL) at 0 °C was added MeLi (0.5 M in Et2O,
145 L, 0.072 mmol). After stirring for 10 min, HMPA (15 L, 0.11
mmol) was added and the solution was stirred for an additional 20
min at 0 °C. To this was added N,N-dimethylphosphoramidic
dichloride (8 L, 0.067 mmol). The solution was allowed to warm
to r.t. and stirred for 30 min. After being rechilled to 0 °C, dime-
thylamine ( 1 mL) was added and the solution was stirred for 30
min. H2O (5 mL) was added and the mixture was extracted with
CH2Cl2 (3 5 mL), then washed with brine (5 mL). Flash chroma-
tography on neutral alumina (EtOAc and 2% MeOH–EtOAc) gave
26 mg (85%) of 31 as a light yellow oil; [ ]D25 –8.2 (c = 1, CHCl3).
1H NMR (CDCl3, 300 MHz).19
13C NMR (CDCl3, 75 MHz): = 18.3, 20, 23.1, 23.6, 24.1, 26.1,
28.3, 29.7, 36.2, 36.3, 44.9, 60.6, 67.3, 122.1, 123.2, 125.7, 129.1,
139.5, 141, 143.6, 155.1, 171.3.
HRMS (FAB+): m/z Calcd for C25H40N2O5P (M + H)+ 479.2675.
Found: 479.2680.
Supplementary Material
See Ref.19 for information on supplementary material.
IR (neat): 1044, 993 cm–1.
1H NMR (CDCl3, 300 MHz): = 1.14 (d, J = 7.2 Hz, 3 H), 1.22 (d,
J = 7.2 Hz, 3 H), 1.52–1.67 (m, 2 H), 1.74 (s, 3 H), 2.25 (s, 3 H),
2.28 (s, 3 H), 2.20–2.43 (m, 4 H), 2.50 (s, 3 H), 2.53 (s, 3 H), 2.61–
2.68 (m, 2 H), 2.85–3.09 (m, 2 H), 3.29 (sept, J = 6.8 Hz, 1 H), 3.4
(s, 3 H), 3.56–3.61 (m, 2 H), 3.71 (s, 3 H), 3.69–3.76 (m, 2 H), 3.88
(d, J = 11.1 Hz, 1 H), 4.0 (dd, J = 9.6, 3 Hz, 1 H), 4.27 (d, J = 11.1
Hz, 1 H), 4.73 (s, 2 H), 7.04 (d, J = 8.4 Hz, 1 H), 7.15 (d, J = 8.4 Hz,
1 H).
13C NMR (CDCl3, 75 MHz): = 15.7, 20.3, 23, 23.6, 24.3, 25.8,
26.1, 28.5, 36.2, 36.4, 39.4, 43.9, 59, 60.5, 66.8, 67.5, 71.8, 94.8,
122.1, 122.8, 127.2, 129.1, 132.6, 141.4, 155.
HRMS (FAB+): m/z Calcd for C29H50N2O6P (M + H)+ 553.3407.
Found: 553.3393.
Acknowledgment
The authors are grateful to the National Science Foundation (USA)
for financial support of this work.
References
(1) For reviews on the use of chiral oxazolines in synthesis, see:
(a) Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991.
(b) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(c) Reumann, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(2) Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc.
1987, 109, 5446.
(3) Andrews, R. C.; Teague, S. J.; Meyers, A. I. J. Am. Chem.
Soc. 1988, 110, 7854.
(4aR,10aR)-7-Isopropyl-8-methoxy-1,4a-dimethyl-
3,4,4a,9,10,10a-hexahydrophenanthrene (40d)
(4) Meyers, A. I.; Willemsen, J. J. Chem. Commun. 1997, 1573.
(5) Rawson, D. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2292.
(6) (a) Barner, B. A.; Meyers, A. I. J. Am. Chem. Soc. 1984, 106,
1865. (b) Meyers, A. I.; Lutomski, K. A.; Laucher, D.
Tetrahedron 1988, 44, 3107. (c) Meyers, A. I.; Roth, G. P.;
Hoyer, D.; Barner, B. A.; Laucher, D. J. Am. Chem. Soc.
1988, 110, 4611.
(7) Takaishi, Y.; Shishido, K.; Wariishi, N.; Shibuya, M.; Goto,
K.; Kido, M.; Takai, M.; Ono, Y. Tetrahedron Lett. 1992,
33, 7177.
Oxazoline tricycle 20 (100 mg, 0.25 mmol) was treated in a similar
manner as compound 29 to give the required phosphorodiamidate
39 (56 mg, 0.13 mmol), which was then dissolved in THF (1 mL).
To this was added a solution of lithium naphthalenide (0.3 M in
THF) and the reaction mixture was stirred for 30 min at r.t. H2O (1
mL) was added and the resulting mixture was extracted with Et2O
(20 mL). The extract was washed with brine, dried (MgSO4), fil-
tered and concentrated. The residue was purified by flash chroma-
tography (2% EtOAc–hexanes) to give 20 mg (54%) of 40d.
(8) Xu, J.; Ikekawa, T.; Ohkawa, M.; Yokota, I.; Hara, N.;
Fujimoto, Y. Phytochemistry 1997, 44, 1511.
1H NMR (CDCl3, 300 MHz): = 1.04 (s, 3 H), 1.20 (d, J = 7 Hz, 3
H), 1.25 (d, J = 7 Hz, 3 H), 1.54–1.72 (m, 5 H), 2.10–2.30 (m, 5 H),
Synthesis 2002, No. 14, 2064–2074 ISSN 0039-7881 © Thieme Stuttgart · New York

2074
L. F. Basil et al.
PAPER
(9) Niwa, M.; Nakamura, N.; Kitajima, K.; Ueda, M.;
Tsutsumishita, Y.; Futaki, S.; Takaishi, Y. Biochem.
Biophys. Res. Commun. 1997, 239, 367.
(15) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.;
DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112,
3875.
(10) Shishido, K.; Goto, K.; Miyoshi, S.; Takaishi, Y.; Shibuya,
M. J. Org. Chem. 1994, 59, 406.
(11) Meyers, A. I.; Robichaud, A. J.; McKennon, M. J.
Tetrahedron Lett. 1992, 33, 1181.
(12) Compound 12 was prepared as described in the
experimental.
(16) The yield of this reaction was dependent upon the quality of
the catalyst (purchased from Strem Chemical Company) as
evidenced by its often dark color.
(17) (a) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J. Am.
Chem. Soc. 1972, 94, 5098. (b) Liu, H.-J.; Shang, X.
Tetrahedron Lett. 1998, 39, 367.
(13) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
1996, 118, 100.
(18) Liu, H.-J.; Lee, S. P.; Chan, W. H. Can. J. Chem. 1977, 55,
3797.
(14) Attempts were made to use a vinyl bromide into the tandem
product below. However, the electrophilic step in the tandem
addition failed. Presumably, the azaenolate, formed upon the
addition of the 2-lithiopropene, is too basic and causes
elimination of HBr from 1,3-dibromobut-3-ene
(Scheme 11).
(19) 300 MHz 1H NMR spectra of 32–34 and 38 are included in
the supplementary material.
(20) (a) Yus, M.; Alonso, E.; Ramón, D. J. Tetrahedron 1997, 53,
14355. (b) Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett.
1997, 38, 2253.
(21) McKillop, A.; Fiaud, J.-C.; Hug, R. P. Tetrahedron 1974, 30,
1379.
Li
1.
N
O
Br
N
O
2.
(I)Br
Br
OMe
OMe
(-)-6
Scheme 11
Synthesis 2002, No. 14, 2064–2074 ISSN 0039-7881 © Thieme Stuttgart · New York