Stereospecific reaction of α-carbamoyloxy-2-alkenylboronates and α-carbamoyloxy-alkylboronates with grignard reagents - Synthesis of highly enantioenriched secondary alcohols

Article abstract of DOI:10.1055/s-2004-832835

Highly enantioenriched secondary alcohols were synthesized by treatment of α-carbamoyloxy-2-alkenylboronates and α-carbamoyloxy-alkylboronates with Grignard reagents. An intermediary boronate complex was transformed stereospecifically to the corresponding secondary 2-alkenyl- and alkylboronates by migration of an introduced residue. Oxidative workup furnished the enantioenriched secondary alcohols.

Full text of DOI:10.1055/s-2004-832835

LETTER
2275
Stereospecific Reaction of a-Carbamoyloxy-2-alkenylboronates and
a-Carbamoyloxy-alkylboronates with Grignard Reagents – Synthesis of
Highly Enantioenriched Secondary Alcohols
Synthesis of
H
ig
d
hly Enantio
i
enriche
t
d
Seco
h
ndary
A
lcohols Beckmann, Vidya Desai, Dieter Hoppe*
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstr. 40, 48149 Münster, Germany
Fax +49(251)8336531; E-mail: dhoppe@uni-muenster.de
Received 29 July 2004
ton is abstracted preferentially5 resulting in the S-configu-
red lithium species 4, which is configurationally stable at
–78 °C. Reaction with triisopropyl borate followed by
acidic workup and transesterification with pinacol led to
Abstract: Highly enantioenriched secondary alcohols were synthe-
sized by treatment of a-carbamoyloxy-2-alkenylboronates and a-
carbamoyloxy-alkylboronates with Grignard reagents. An interme-
diary boronate complex was transformed stereospecifically to the
corresponding secondary 2-alkenyl- and alkylboronates by migra- the desired a-carbamoyloxy-alkylboronate (5).6
tion of an introduced residue. Oxidative workup furnished the enan-
The a-carbamoyloxy-substituted boronates 2 and 5 were
tioenriched secondary alcohols.
subjected to a stereospecific substitution reaction by treat-
Key words: boron, asymmetric synthesis, alcohols, chirality,
ment with Grignard reagents.
stereoselectivity
Enantioenriched secondary alcohols are important inter-
N
mediates in organic chemistry. They are key structures in
N
HS
HR
the synthesis of several natural products.1
sec-BuLi,
(−)-sparteine
Ph
Ph
Li
N
So far, several methods have been developed for the syn-
thesis of enantioenriched secondary alcohols such as
enantioselective reduction of the corresponding ketones2
or addition of organometallic compounds to aldehydes us-
ing chiral ligands or chiral Lewis acids.3
(S)
3
OCb
Et2O, −78 °C
O
O
4
O
Herein we report a new method for the synthesis of enan-
tioenriched secondary alcohols starting from simple pri-
mary alcohols, which are transformed to highly
enantioenriched a-carbamoyloxy-substituted boronates.
1) B(OiPr)3, Et2O, −78 °C
Ph
B
O
(S)
2) pinacol, p-TsOH,
MgSO4, CH2Cl2
O
O
5
90%, >95% ee
N
a-Carbamoyloxy-crotylboronate (2, Scheme 1) can be
synthesized from the enantioenriched g-stannylated alke-
nyl carbamate 1.4
Scheme 2
Ts
N
Organoborane chemistry offers the possibility of ste-
reospecific ligand migration from boron to carbon, which
is of great value in asymmetric synthesis.7–9 In general, a-
halogenated alkylboranes 6 (Scheme 3) react with Grig-
nard reagents stereospecifically in a nucleophilic substitu-
tion process. The Grignard reagent adds to borane 6
forming borate complex 7, which rearranges by migration
of a ligand R1 from boron to an electron deficient carbon
via transition state 8 to form product 9. The leaving group
X is replaced by the ligand R1 under inversion of config-
uration.7
1)
B
Cl
O
B
, CH2Cl2, 0 °C
N
Bu3Sn
OCb
O
Ts
OCb
80%, 85% ee
1
2
88% ee
2) HCl/H2O
3) pinacol, p-TsOH
MgSO4, CH2Cl2
Scheme 1
The analoguous a-carbamoyloxy-alkylboronate (5) was
synthesized from the corresponding alkyl carbamate 3 by
enantioselective deprotonation with the chiral base sec-
butyllithium/(–)-sparteine (Scheme 2). The pro-(S)-pro-
There are many examples for the utility of this efficient
process, especially for chain extension of a-halo-boronic
esters developed by Matteson et al.8,9
This method has also been utilized in asymmetric synthe-
sis employing chiral boronates 10 (Scheme 4).10 Upon
treatment of 10 with dichloromethyllithium the ate-com-
plex 11 is formed. This was treated with zinc chloride to
SYNLETT 2004, No. 13, pp 2275–2280
Advanced online publication: 24.09.2004
DOI: 10.1055/s-2004-832835; Art ID: G29804ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
4

2276
E. Beckmann et al.
LETTER
L
The resulting secondary allylic boronates 14 were prone
to hydrolysis on the attempt of purification and, thus, were
directly oxidized to the corresponding secondary allylic
alcohols 1512 (Scheme 5) with retention of configura-
tion.13 The reaction proceeds under complete stereotrans-
fer and in 58–62% yield with respect to the
carbamoyloxy-alkenylboronate (1, Table 1).
X
L
L
X
L
B
R1
R2
R3
B
C
R2
R1M
+
R3
6
7
L
L
L
R2
R3
X
B
C
B
C
R2
+
X
L
R1
R3
Table 1 Preparation of Enantioenriched Secondary Allylalcohols
R1
9
8
Entry Grignard
reagent
Product
Yield ee
(%)a
(%)
Scheme 3
1
2
3
PrMgCl
62
85b
84c
85d
OH
CHCl2
CH2
O
O
O
LiCHCl2
B
CH2
B
*
*
15a
15b
−100 °C
O
R
R
BnMgCl
C6H11MgBr
58
62
OH
OH
11
10
Ph
Cl
O
ZnCl2, 20 °C
B
CH2R
*
*
O
H
12
Scheme 4
15c
15d
4
C8H15MgCl
60
85b
OH
form the diastereomeric homologation product 12 which
can be further transformed to several highly enantioen-
riched products. However, without addition of zinc chlo-
ride to the reaction mixture, the homologation reaction
proceeds very slowly and inefficiently.10
a Yield based on 2.
b Determined by 1H NMR shift experiment with 40 mol% of Eu(hfc)3.
c Determined by chiral HPLC (column: chiragrom 2, 60 × 2 mm;
solvent: i-PrOH–hexane = 1:600).
For this kind of reaction an electron deficient carbon with
a leaving group in a-position to the boron is required. As
we found out, these conditions are fulfilled by the a-car-
bamoyloxy-substituted boronates 2 and 5.
d Determined by comparison of optical rotation.14
The allylic boronates 14 can also be employed in a stereo-
selective addition to aldehydes (Scheme 6). The reaction
with benzaldehyde via transition state 16a or 16b furnish-
es the anti-(E)- and (Z)-homoallylic alcohols 17of oppo-
site absolute configuration.15 This was already found for
17a (Table 2, entry 1).16 However, separation of (E)- and
(Z)-17 on a preparative scale turned out to be difficult.
O
O
Et2O
O
B
R1MgX
+
O
B
R1
−78 °C
OCb
2
OCb
85% ee
13
The assumption, that a larger substituent R1 could im-
prove the E:Z ratio, could not be verified (Table 2). How-
ever, the enantioenrichment of the starting material is
completely transferred to the product 17.
25 °C
H2O2, NaOH
THF
O
B
OH
− OCb
O
R1
15
R1
If an organolithium reagent such as n-butyllithium
(Table 2, entry 2) is used for the preparation of allylboro-
nate 14 the yield drops dramatically. This is consistent
with the observations of Matteson et al. for the reaction of
organolithium reagents with boronates.10 Obviously, the
typical features of Grignard reagents play an important
role in this reaction which is also underlined by the fact
that two equivalents are needed for a smooth reaction.11
Presumably one Grignard reagent acts as a Lewis acid
making the carbamoyloxy moiety a better leaving group,
which results in a higher reaction rate.
14
84–85% ee
Scheme 5
a-Carbamoyloxy-crotylboronate (2) was treated with
Grignard reagents at –78 °C to form the boronate complex
13 (Scheme 5). Upon warming to room temperature the
substituent R1 migrates to the electron deficient a-carbon
atom with substitution of the carbamoyloxy moiety under
inversion of configuration at the chiral centre.11
Synlett 2004, No. 13, 2275–2280 © Thieme Stuttgart · New York

LETTER
Synthesis of Highly Enantioenriched Secondary Alcohols
2277
O
B
O
N
O
N
1) B(OiPr)3, Et2O,
−78 °C
R1
Ph
B
14
O
Ph
Li
N
2) pinacol, pTsOH,
MgSO4, CH2Cl2
OCb
PhCHO
toluene, 60 °C
5
O
O
4
>95% ee
R1MgX
Et2O, −78 °C
O
B
O
B
R1
O
R1
O
+
O
O
Ph
O
O
Ph
B
25 °C
Ph
Ph
B
O
R1
O
16b
16a
OCb
18
R1
19
H2O2, NaOH,
THF
OH
OH
R1
Ph
OH
R1
Ph
Ph
84–85% ee
CH3 R1
CH3
(Z)-17
(E)-17
20
Scheme 6
Scheme 7
Table 2 Preparation of Enantioenriched Homoallylic Alcohols
Entry
1
Organometal reagent Main producta
Yield (%)b
51
E:Z
ee (%) c
84
MeMgBr
20:80
OH
Ph
CH3 CH3
17a
2
3
n-BuLi
28
57
25:75
85
83
OH
Ph
17b
C6H11MgBr
33:67
OH
Ph
H3C
17c
4
5
PhMgBr
46
59
89:11
28:72
84
85
OH
Ph
Ph
CH3
17d
t-BuMgCl
OH
Ph
CH3
17e
a From all unknown compounds, correct CHN analyses were obtained.
b Yield based on 2.
c The ee value of the main product; determined by chiral HPLC (column: chiragrom 2, 250 × 2 mm; solvent: i-PrOH–hexane = 1:400).
Synlett 2004, No. 13, 2275–2280 © Thieme Stuttgart · New York

2278
E. Beckmann et al.
LETTER
The reaction of a-carbamoyloxy-alkylboronate (5) with chiral secondary alcohols, since the alkylation reaction of
Grignard reagents proceeds in the same way as described 4 is limited to few primary alkyl iodides5c and 2-alkenyl
above. Formation of the boronate complex 18 (Scheme 7) halides.18
leads to migration of the substituent R1 to the electron-de-
For the synthesis of the opposite enantiomers, less avail-
ficient a-carbon upon warming to room temperature. The
carbamoyloxy moiety is replaced stereospecifically, and
subsequent oxidation of the hydrolytically labile interme-
diate 19 furnishes the secondary alcohols 20 in greater
than 95% ee and 50–70% overall yield (Table 3).17
able (+)-sparteine would be required.19 Here, the use of a
(+)-sparteine surrogate, developed by O’Brien et al. can
close the gap.20
Acknowledgment
Table 3 Preparation of Enantioenriched Secondary Alcohols
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 424) and by the Fonds der Chemischen Industrie. V. D. grate-
fully acknowledges a fellowship of the Alexander von Humboldt
Foundation.
Entry Grignard
reagent
Product
Yield ee
(%)a
(%)b
1
PrMgCl
50
>95
OH
OH
References
Ph
20a
(1) Review: Hoffmann, R. W. Stereoselective Synthesis of
Polyketide Natural Products – Achievements and Future
Development, In Stereocontrolled Organic Synthesis; Trost,
B. M., Ed.; Blackwell: Oxford (UK), 1994, 259.
2
C6H11MgBr
70
61
>95
Ph
(2) (a) Sibi, M. P.; Cook, G. R.; Liu, P. Tetrahedron Lett. 1999,
40, 2477. (b) Chiodi, O.; Fotiadu, F.; Sylvestre, M.; Buono,
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Angew. Chem., Int. Ed. Engl. 1995, 34, 2005; Angew. Chem.
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1993, 34, 6041. (e) Corey, E. J.; Bakshi, R. K.; Shibata, S.;
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H. Tetrahedron Lett. 1979, 19, 4565. (g) Locatelli, M.;
Cozzi, P. G. Angew. Chem. Int. Ed. 2003, 42, 4928; Angew.
Chem. 2003, 115, 5078. (h) Review: Noyori, R.; Kitamura,
M.; Ohkuma, T. Proc. Natl. Acad. Sci. 2004, 101, 5356.
(3) (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763.
(b) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.
20b
Ph
3
C8H15MgCl
>95
OH
20c
4
5
i-PrMgCl
t-BuMgCl
56
64
>95
>95
OH
OH
Ph
20d
Ph
Tetrahedron 2001, 57, 835. (c) Weber, B.; Seebach, D.
Tetrahedron 1994, 50, 7473. (d) Noyori, R.; Suga, S.;
Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988,
60, 1597. (e) Corey, E. J.; Hannon, F. J. Tetrahedron Lett.
1987, 28, 5233.
20e
a Yield based on 5.
b Determined by chiral HPLC (column: chiragrom 2, 250 × 2 mm; sol-
vent: i-PrOH–hexane = 1:400).
(4) Beckmann, E.; Hoppe, D. Synthesis, submitted.
(5) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed.
Engl. 1990, 29, 1422; Angew. Chem. 1990, 102, 1457.
(b) Beak, P.; Zajdel, W. J. J. Am. Chem. Soc. 1984, 106,
1010. (c) For reviews see: Hoppe, D.; Hense, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2282; Angew. Chem. 1997,
109, 2376. (d) Marr, F.; Brüggemann, M.; Hoppe, D.
Enantioselective Synthesis by Lithiation Adjacent to Oxygen
and Electrophile Incorporation, In Topics in
In summary, we have developed a method for the synthe-
sis of highly enantioenriched secondary alcohols, which
should be applicable to a diversity of a-carbamoyloxy-
alkylboronates and a-carbamoyloxy-2-alkenylboronates.
With this approach it is even possible to synthesize sec-
ondary alcohols with very similar substituents in high
enantiomeric excess, which is not possible by enantiose-
lective reduction.
Organometallic Chemistry, Vol. 5; Hodgson, D. M., Ed.;
Springer: Berlin, 2003, 61.
(6) Experimental Procedure: The amount of 1.315 g (5.0
mmol, 1.0 equiv) of 3 and 1.490 g (6.0 mmol, 1.2 equiv) of
(–)-sparteine were dissolved in 10 mL of anhyd Et2O and the
mixture was cooled to –78 °C. To this mixture 5.0 mL (6.0
mmol, 1.2 equiv) of a 1.2 M solution of sec-butyllithium in
cyclohexane were added slowly within 15 min with a syringe
pump. After a deprotonation time of 5 h 1.410 g (7.5 mmol,
1.5 equiv) triisopropyl borate were added at –78 °C and the
reaction mixture was stirred for an additional hour. The
reaction was quenched with 5 mL of 2 M HCl at –78 °C and
the layers were separated. The aqueous layer was extracted
with Et2O (3 × 5 mL), the combined organic extracts were
dried with MgSO4 and the solvent was removed in vacuum.
An additional advantage is the fact that starting from one
enantioenriched precursor a wide variety of products is
accessible by simply changing the Grignard reagent.
There is no loss of stereoinformation as the reaction oc-
curs via the intermediary borate complex, which rearrang-
es with loss of the carbamoyloxy group. The displacement
proceeds with inversion of configuration at the chiral cen-
ter.
This method significantly broadens the scope of applica-
tion of lithiated alkyl carbamates 4 for the synthesis of
Synlett 2004, No. 13, 2275–2280 © Thieme Stuttgart · New York

LETTER
The crude product was dissolved in 10 mL of CH2Cl2 and
Synthesis of Highly Enantioenriched Secondary Alcohols
2279
NMR (75 MHz, CDCl3): d = 19.5 (CH3), 25.7, 29.6, 30.0,
37.8 [CH2 (oct)], 42.3 [CH(oct)], 75.2 [CH(OH)], 127.0,
133.8 (CH=CH) ppm. Anal. Calcd for C12H22O (182.17): C,
79.06; H, 12.16. Found: C, 78.67; H, 12.44. The ee was
determined by 1H NMR shift experiment with 40 mol% of
Eu(hfc)3.
added to a flask charged with 885 mg (7.5 mmol, 1.5 equiv)
of pinacol, 0.050 g of p-toluenesulfonic acid and MgSO4.
This mixture was stirred at r.t. for 24 h, the solid material
was filtered off and the solvent was removed. After
purification of the crude product by flash column
chromatography (SiO2, cyclohexane–EtOAc = 5:1) we
obtained 1.788 g (4.5 mmol, 90%) of compound 5 as a
colorless oil. The ee was determined by 1H NMR shift
experiment using 30 mol% of Eu(hfc)3. Rf = 0.24 (Et2O–
pentane = 1:1); [a]D20 +36.7 (c 0.97, CH2Cl2). 1H NMR (300
MHz, CDCl3): d = 1.27 [s, 12 H, CH3 (pinacol)], 1.29–1.35
[m, 12 H, CH3 (Cb)], 1.94–2.19 (m, 2 H, CH2), 2.75–2.98 (m,
2 H, CH2), 3.85, 4.14 [sep, 2 H, CH(Cb), 3J = 7.0 Hz)], 3.92
(dd, 1 H, CH, 3J = 4.2 Hz, 3J = 10.3 Hz), 7.21–7.38 [m, 5 H,
CH(Ar)] ppm. 13C NMR (75 MHz, CDCl3): d = 20.2, 20.3,
20.6 [CH3 (pinacol) + CH3(Cb)], 26.9 (CH2), 33.3 (CH2),
46.7, 48.4 [CH(Cb)], 79.8 (CH), 125.6 [Cq(pinacol)], 128.2,
128.5 [CH(Ar)], 142.5 [Cq(Ar)], 162.7 [C=O(Cb)] ppm.
Anal. Calcd for C22H36BNO4 (389.27): C, 67.87; H, 9.32; N,
3.60. Found: C, 67.76; H, 9.36; N, 3.85.
(13) (a) Hoffmann, R. W.; Hölzer, B.; Knopff, O. Org. Lett. 2001,
12, 1945. (b) Hoffmann, R. W.; Hölzer, B.; Knopff, O.;
Harms, K. Angew. Chem. Int. Ed. 2000, 39, 3072; Angew.
Chem. 2000, 112, 3206.
(14) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2001, 66, 5552.
(15) The crude product 14 was dissolved in 5 mL of anhyd
toluene and 106 mg (1.0 mmol, 2.0 equiv) of benzaldehyde
were added. The mixture was heated to 60 °C for 12 h and
then cooled to r.t. The toluene was removed in vacuo, the
residue was dissolved in 5 mL of Et2O, and 90 mg (0.6
mmol, 1.2 equiv) of triethanolamine were added. After one
hour of stirring at r.t. the precipitate was filtered off and the
solvent was removed. Flash column chromatography of the
crude product (SiO2, Et2O–pentane = 1:5) furnished the
homoallyl alcohols 17 as colorless liquids. The E:Z-ratios of
the compounds were determined by 1H NMR of the crude
products. The ee were determined by HPLC using a chiral
column (chiragrom 2, 250 × 2 mm) and the solvent mixture
i-PrOH–hexane = 1:400. Compound 17a: E:Z = 80:20;
Rf = 0.54 (Et2O–pentane = 1:1); [a]D20 +24.3 (c 0.67,
CHCl3). Compound 17b: E:Z = 25:75; Rf = 0.57 (Et2O–
pentane = 1:1); [a]D20 +4.7 (c 0.50, CHCl3). Compound 17c:
E:Z = 33:67; Rf = 0.69 (Et2O–pentane = 1:1); [a]D20 +26.5 (c
1.12, CHCl3). Compound 17d: E:Z = 89:11; Rf = 0.58
(Et2O–pentane = 1:1); [a]D20 +30.1 (c 1.00, CHCl3).
Compound 17e: E:Z = 28:72; Rf = 0.69 (Et2O–pentane =
1:1); [a]D20 +74.2 (c 1.21, CHCl3). Compound (E)-17e: 1H
NMR (300 MHz, CDCl3): d = 0.83 (d, 3 H, CH3, 3J = 6.9
Hz), 1.01 (s, 9 H, CH3), 2.17 (d, 1 H, OH, 3J = 2.4 Hz), 3.36–
3.49 [m, 1 H, CH(CH3)], 4.27 [dd, 1 H, CH(OH), 3J = 2.4
Hz, 3J = 7.9 Hz], 5.25 (dd, 1 H, CH, 3J = 8.6 Hz, 3J = 15.9
Hz), 5.63 (d, 1 H, CH, 3J = 15.9 Hz), 7.23–7.35 [m, 5H,
CH(Ar)] ppm. Compound (Z)-17e: 1H NMR (300 MHz,
CDCl3): d = 0.77 (d, 3 H, CH3, 3J = 6.8 Hz), 1.14 (s, 9 H,
CH3), 2.14 (d, 1 H, OH, 3J = 1.7 Hz), 2.97–3.10 [m, 1 H,
CH(CH3)], 4.23 [dd, 1 H, CH(OH), 3J = 1.7 Hz, 3J = 8.4 Hz],
5.09 (dd, 1 H, CH, 3J = 11.0 Hz, 3J = 11.9 Hz), 5.59 (d, 1 H,
(7) Matteson, D. S. Stereodirected Synthesis with
Organoboranes; Springer: Berlin, 1995.
(8) (a) Matteson, D. S.; Majumdar, D. Organometallics 1983, 2,
230. (b) Tsai, D. J. S.; Matteson, D. S. Organometallics
1983, 2, 236.
(9) (a) Matteson, D. S.; Mah, R. W. H. J. Am. Chem. Soc. 1963,
85, 2599. (b) Matteson, D. S.; Mah, R. W. H. J. Org. Chem.
1963, 28, 2171.
(10) (a) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am.
Chem. Soc. 1986, 108, 810. (b) Tripathy, P. B.; Matteson,
D. S. Synthesis 1990, 200.
(11) Experimental Procedure: The amount of 163 mg (0.5
mmol, 1.0 equiv) of 2 was dissolved in 5 mL of anhyd Et2O
and cooled to –78 °C. To this mixture 1.0 mmol (2.0 equiv)
of the Grignard reagent as solution in Et2O was slowly
added. The mixture was stirred for 1 h at –78 °C and then
warmed to r.t. for an additional hour. The solution was
quickly filtered over ca. 5 g of silica gel with pentane and the
solvent was removed carefully at 800 mbar to furnish the
crude product 14, which was subjected to the subsequent
reactions without further purification.
(12) The crude product 14 was dissolved in 5.00 mL of THF. At
r.t., 1.20 mL (0.6 mmol, 1.2 equiv) of 0.5 M NaOH was
added dropwise and after 5 min, 0.07 mL (0.7 mmol, 1.4
equiv) H2O2 (35%) was added. The mixture was stirred for
30 min at r.t., then diluted with 5.00 mL of H2O and the
layers were separated. The aqueous layer was extracted with
Et2O (3 × 5 mL), the combined organic extracts were
washed with sat. FeSO4 solution to destroy the peroxides and
then dried with MgSO4. After removal of the solvent in
vacuum the crude product was purified by flash column
chromatography (SiO2, Et2O–pentane = 1:6) to furnish the
alcohols 15 as colorless liquids. Compound 15a:21 Rf = 0.44
(Et2O–pentane = 1:1); [a]D20 –8.3 (c 0.85, CHCl3). The ee
was determined by 1H NMR shift experiment with 40 mol%
of Eu(hfc)3. Compound 15b:22 Rf = 0.46 (Et2O–
CH, 3J = 11.9 Hz), 7.23–7.35 [m, 5 H, CH(Ar)] ppm. 13
C
NMR (75 MHz, CDCl3): d = 17.6 [CH(CH3)], 29.8, 31.6,
33.5 (CH3), 41.2 [CH(CH3)], 79.0 [CH(OH)], 127.0, 127.1,
127.7, 128.2, 130.5 [CH(Ar), CH], 142.4 (CH), 143.1
[Cq(Ar)] ppm. Anal. Calcd for C15H22O (218.17): C, 82.52;
H, 10.16. Found: C, 82.17; H, 10.22.
(16) Andersen, M. W.; Hildebrandt, B.; Köster, G.; Hoffmann, R.
W. Chem. Ber. 1989, 122, 1777.
(17) Experimental Procedure: The amount of 195 mg (0.5
mmol, 1.0 equiv) of 5 was dissolved in 5.00 mL of anhyd
Et2O and the solution was cooled to –78 °C. To this mixture
1.0 mmol (2.0 equiv) of the Grignard reagent as solution in
Et2O was slowly added. The mixture was stirred for 1 h at
–78 °C and then warmed to r.t. for an additional hour. The
solution was quickly filtered over ca. 5 g of silica gel with
pentane and the solvent was removed carefully at 800 mbar.
The residue was dissolved in 5.00 mL of THF. At r.t. 1.20
mL (0.6 mmol, 1.2 equiv) of 0.5 M NaOH were added
dropwise and after 5 min 0.07 mL (0.7 mmol, 1.4 equiv)
H2O2 (35%) were added. The mixture was stirred for 30 min
at r.t., then diluted with 5.00 mL of H2O and the layers were
separated. The aqueous layer was extracted with Et2O (3 ×
5 mL), the combined organic extracts were washed with sat.
FeSO4 solution to destroy the peroxides and then dried with
pentane = 1:1); [a]D20 –7.4 (c 0.76, CHCl3). The ee was
determined by chiral HPLC (column: chiragrom 2, 60 × 2
mm; solvent: i-PrOH–hexane = 1:600). Compound 15c:
Rf = 0.52 (Et2O–pentane = 1:1); [a]D20 –11.8 (c 2.4, EtOH).
The ee was determined by comparison of optical rotation.14
Compound 15d: Rf = 0.59 (Et2O–pentane = 1:1); [a]D20 –3.3
(c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3): d = 1.19–1.71
[m, 19 H, CH2 (oct), CH(oct), CH3, OH], 3.81 [t, 1 H,
CH(OH), 3J = 6.2 Hz], 5.46 (ddq, 1 H, CH, 4J = 1.0 Hz,
3J = 7.0 Hz, 3J = 15.2 Hz), 5.63 (ddq, 1 H, CH) ppm. 13
C
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2280
E. Beckmann et al.
LETTER
MgSO4. After removal of the solvent in vacuum the crude
product was purified by flash column chromatography
(SiO2, Et2O–pentane = 1:6) to furnish the alcohols 20. The
ee were determined by HPLC using a chiral column
(chiragrom 2, 250 × 2 mm) and the solvent mixture i-PrOH–
hexane = 1:400. Compound 20a:23 colorless liquid;
CHCl3). Compound 20e:26 colorless liquid; Rf = 0.55 (Et2O–
pentane = 1:1); [a]D20 +50.0 (c 1.15, CHCl3).
(18) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2002, 4, 119.
(19) (a) Ebner, T.; Eichelbaum, M.; Fischer, P.; Meese, C. O.
Arch. Pharm. 1989, 322, 399. (b) Clemo, G. R.; Raper, R.;
Short, W. S. J. Chem. Soc. 1949, 663.
(20) (a) Harrison, J. R.; O’Brien, P.; Porter, D. W.; Smith, N. M.
Chem. Commun. 2001, 1202. (b) Dearden, M. J.; Firkin, C.
R.; Hermet, J.-P. R.; O’Brien, P. J. Am. Chem. Soc. 2002,
124, 11870.
Rf = 0.43 (Et2O–pentane = 1:1); [a]D20 +11.9 (c 1.00,
CHCl3). Compound 20b:24 white solid; mp 96 °C; Rf = 0.53
(Et2O–pentane = 1:1); [a]D20 +28.7 (c 0.91, CHCl3).
Compound 20c: colorless liquid; Rf = 0.55 (Et2O–
pentane = 1:1); [a]D20 +15.8 (c 0.92, CHCl3). 1H NMR (300
MHz, CDCl3): d = 1.29–1.82 [m, 16 H, CH2 (oct), CH(oct),
OH], 2.67 (ddd, 2 H, CH2, 3J = 7.0 Hz, 3J = 9.4 Hz, 3J = 13.5
Hz), 2.86 (ddd, 2 H, CH2, 3J = 5.7 Hz, 3J = 9.4 Hz, 3J = 13.5
Hz), 3.48 [m, 1 H, CH(OH)], 7.17–7.34 [m, 5 H, CH(Ar)]
ppm. 13C NMR (75 MHz, CDCl3): d = 27.1, 27.5, 26.0, 30.0,
32.7 [CH2(oct), CH2], 36.47 (CH2), 48.1 [CH(oct)], 75.0
[CH(OH)], 127.9, 128.4, 130.0 [CH(Ar)], 141.1 [Cq(Ar)]
ppm. Anal. Calcd for C17H26O (246.20): C, 82.87; H, 10.64.
Found: C, 82.51; H, 10.86. Compound 20d:25 colorless
liquid; Rf = 0.54 (Et2O–pentane = 1:1); [a]D20 +27.5 (c 0.85,
(21) Al-Hassan, M. I.; Miller, R. B. Synth. Commun. 2001, 31,
3641.
(22) Yanagisawa, A.; Namura, N.; Naritake, Y.; Yamamoto, H.
Synthesis 1991, 12, 1130.
(23) Hoffmann, R. W.; Herold, T. Chem. Ber. 1981, 114, 375.
(24) Ujikawa, O.; Inanaga, J.; Yamaguchi, H. Tetrahedron Lett.
1989, 30, 2837.
(25) Soai, K.; Hayasa, T.; Takai, K.; Sugiyana, T. J. Org. Chem.
1994, 59, 7908.
(26) Borden, W. T. J. Am. Chem. Soc. 1970, 92, 4898.
Synlett 2004, No. 13, 2275–2280 © Thieme Stuttgart · New York