Asymmetric synthesis of stereodefined α-alkyl-γ-benzyloxymethyl-β-trimethylsilyl-γ- butyrolactones that serve as an efficient precursor for constructing carbon skeletons having a tertiary or quaternary stereogenic center

Article abstract of DOI:10.1016/S0040-4039(02)00770-0

The optically active lactone 1 can be transformed to a chiral building block or intermediate for constructing carbon skeletons containing either a tertiary or quaternary stereogenic center by taking advantage of the steric bulk as well as the reactivity o

Full text of DOI:10.1016/S0040-4039(02)00770-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4237–4239
Asymmetric synthesis of stereodefined
a-alkyl-g-benzyloxymethyl-b-trimethylsilyl-g-butyrolactones that
serve as an efficient precursor for constructing carbon skeletons
having a tertiary or quaternary stereogenic center
Kwangho Kim, Sentaro Okamoto, Yuuki Takayama and Fumie Sato*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 13 March 2002; accepted 12 April 2002
Abstract—The optically active lactone 1 can be transformed to a chiral building block or intermediate for constructing carbon
skeletons containing either a tertiary or quaternary stereogenic center by taking advantage of the steric bulk as well as the
reactivity of a trimethylsilyl group at the b-position of 1. © 2002 Elsevier Science Ltd. All rights reserved.
There are many natural and artificial biologically
important compounds that have a tertiary or quater-
nary stereogenic carbon center in their structure as the
main unit or a subunit, and thus, development of
asymmetric synthetic methodology that allows prepara-
tion of these skeletons is important. Herein we report
an easy method for synthesizing optically active g-ben-
zyloxymethyl-b-trimethylsilyl-g-butyrolactones 1 having
a variety of alkyl groups at the stereodefined a-position,
and show that they can serve as an efficient precursor
for preparing a chiral building block or intermediate for
constructing carbon skeletons containing either
a
tertiary1 or quaternary2 stereogenic center.
Our synthetic approach to 1, which is summarized in
Scheme 1, involves the synthesis of a-alkylidene lac-
tones 2 from readily available, optically active 3-
trimethylsilylglycidol benzyl ether (3) using, as a key
reaction, Ti(II)-mediated intramolecular nucleophilic
acyl substitution reaction (INAS reaction),3 and their
stereoselective reduction.
The epoxide 3 with 98% ee was prepared in 74% overall
yield by the Katsuki–Sharpless asymmetric epoxidation
of (E)-3-trimethylsilyl-2-propen-1-ol and the following
benzylation.4 The reaction of 3 with RCꢀCAlEt2 (2
equiv.) where R is Me, n-Bu, Ph and Si(CH3)3 in
hexane afforded the corresponding epoxide ring-open-
ing products exclusively in 93–96% yield.5 After conver-
sion of the hydroxy group of the products to ethyl
carbonate (:95% yield), the resulting carbonates 4
were reacted with a divalent titanium reagent Ti(O-i-
Pr)4/2i-PrMgCl6 to provide, after hydrolysis, the INAS
products 2 in high yield. The yield of 2 from 4 and their
[h]D values are summarized in Table 1. Conversion of 2
to 1 was carried out efficiently by reduction with a
Mg/CH3OH reagent under ultrasound irradiation,7,8
which proceeded with almost 100% stereoselectivity
except for 2d. In the case of 2d, 1d and its diastereomer
were produced in a ratio of 85:15; however, successive
Scheme 1.
Keywords: asymmetric synthesis; lactones; olefination; reduction; tita-
nium.
* Corresponding author. Tel.: +81-924-5787; fax: +81-45-924-5826;
e-mail: fsato@bio.titech.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00770-0

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K. Kim et al. / Tetrahedron Letters 43 (2002) 4237–4239
Table 1. Ti(II)-mediated INAS reactiona of 4 to 2 and its reductionb to 1
Entry
4
2
1
Yield (%)c
[h]D (c, CHCl3)
Yield (%)d
[h]D (c, CHCl3)
1
2
3
4
a; R=CH3
b; R=n-Bu
c: R=Ph
60
70
65
70
−107 (2.51)
−143 (1.10)
−117 (2.42)
−114 (1.22)
94
84
83
63e
−33.7 (0.90)
−45.6 (0.81)
−16.7 (1.13)
−60.1 (1.11)
d; R=(CH3)3Si
a The reaction was carried out in Et2O at −55 to −45°C for 3 h, with reactants ratio of 4:Ti(O-i-Pr)4:i-PrMgCl=1.0:1.5:3.0.
b 2:Mg turnings=1:10, rt, under ultrasound irradiation.
c Isolated yield by column chromatography after treatment of the crude reaction mixture with p-TsOH, which resulted in lactonization of the
corresponding a,b-unsaturated ester co-produced as a minor product.
d Isolated yield based on 2.
e Overall yield via two-step reaction of reduction with Mg/CH3OH and isomerization with [(CH3)3Si]2NK/t-BuOH (see text).
treatment of the diastereomeric mixture with
[(CH3)3Si]2NK (−78°C to 0°C, in THF) and t-BuOH
(−78°C to 0°C) resulted in complete isomerization of
the minor isomer, eventually providing pure 1d in 63%
overall yield. The structure of 1a–d shown in Scheme 1
was determined by their NOE experiments. The yield of
1 from 2 and their [h]D values are also summarized in
Table 1.
The compound 5 might find utility as a chiral building
block or intermediate for constructing carbon skeletons
containing a tertiary stereogenic center by taking
advantage of the versatile reactivity of the carboxyl and
(Z)-3-benzyloxy-1-propenyl groups embedded in it.
The compound 1 might serve as the precursor for
construction of a carbon skeleton containing a quater-
nary stereogenic center through stereoselective alkyla-
tion of the lactone enolate derived from 1, and the
following Peterson olefination reaction. We investigated
this possibility starting with 1b. Although the methyla-
tion of the enolate generated from 1b and
[(CH3)3Si]2NK with MeI proceeded with low
diastereoselectivity of 68:32, the allylation with
CH2ꢁCHCH2Br and benzylation with PhCH2Br pro-
ceeded with excellent diastereoselectivity to afford
exclusively the corresponding 8 and 9 as shown in
Scheme 3, the structure of which was, respectively,
confirmed by NOE experiments.12,13 The compounds 8
and 9 thus obtained could be readily converted to 10
and 11, respectively, by the reaction with n-Bu4NF.14
The easy synthesis of the compound of the type 10 is
especially noteworthy, since it might serve as a useful
chiral intermediate for constructing carbon skeletons
having a quaternary carbon center, because it has three
different functional groups at the stereogenic center, i.e.
allyl, carboxyl and (Z)-3-benzyloxy-1-propenyl groups
which might independently allow further elaboration.
Treatment of the lactones 1a–d with BF3·OEt2 (3
equiv.) resulted in smooth Peterson olefination
reaction9,10 to afford the corresponding 5a–d in excel-
lent yield as shown in Scheme 2. The enantiomeric
excess (ee) of 5b and 5c thus obtained was determined
1
to be 98 and 97% ee, respectively, by H NMR analysis
of the MTPA esters after converting to the correspond-
ing alcohol 6 as shown in Eq. (1). Meanwhile, the
absolute configuration of 5c was established by convert-
ing to known (R)-2-benzylvalerolactone (7)11 as also
shown in Eq. (1).
Scheme 2.
In the conversion of 2 to 1 and then to 5, 10 (via 8), or
11 (via 9) described above, the trimethylsilyl group
present in 2 plays indispensable dual roles which are the
control of the stereochemistry for constructing the ter-
tiary or quaternary carbon center, and the generation
of the double bond by Peterson olefination reaction.
With respect to the former role, we found that the
reduction of 12, which lacks a trimethylsilyl group at
the b-position, to 13 proceeded with 52:48 diastereose-
lectivity as shown in Scheme 4. Similarly, the kinetic
protonation or alkylation of the lactone enolate gener-
ated from 13 proceeded with 30:70 or 85:15 diastereose-
lectivity, respectively.
(1)

K. Kim et al. / Tetrahedron Letters 43 (2002) 4237–4239
4239
Scheme 3.
3. (a) Kasatkin, A.; Okamoto, S.; Sato, F. Tetrahedron Lett.
1995, 36, 6075–6078; (b) Okamoto, S.; Kasatkin, A.;
Zubaidha, P. K.; Sato, F. J. Am. Chem. Soc. 1996, 118,
2208–2216; (c) Mincheva, Z. P.; Gao, Y.; Sato, F. Tetra-
hedron Lett. 1998, 39, 7947–7950.
4. Kobayashi, Y.; Ito, T.; Yamakawa, I.; Urabe, H.; Sato,
F. Synlett 1991, 811–813.
5. Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.;
Nozaki, H. Tetrahedron Lett. 1982, 23, 3597–3600.
6. Reviews for synthetic reactions mediated by a Ti(O-i-
Pr)4/2i-PrMgX reagent: (a) Sato, F.; Urabe, H.;
Okamoto, S. Pure Appl. Chem. 1999, 71, 1511–1519; (b)
Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835–2886; (c) Sato, F.; Urabe, H.; Okamoto, S. Synlett
2000, 753–775; (d) Sato, F.; Okamoto, S. Adv. Synth.
Catal. 2001, 343, 759–784.
Scheme 4.
7. (a) Profitt, J. A.; Watt, D. S.; Corey, E. J. J. Org. Chem.
1975, 40, 127–128; (b) De Laszlo, S. E.; Ley, S. V.;
Porter, R. A. J. Chem. Soc., Chem. Commun. 1986,
344–346.
8. Hydrogenation of the alkene moiety of 2 in the presence
of a palladium or rhodium catalyst did not give 1 at all.
The reaction resulted in double bond migration into the
ring and/or the debenzylation of the benzyl ether.
9. Ager, D. J. Org. React. 1990, 38, 1–223.
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10. Use of n-BuN4F instead of BF3·OEt2 afforded a similar
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such as n-butyl iodide did not proceed.
13. The stereochemistry of the compound 8 and 9 was deter-
mined by NOE-difference experiments.
14. The reaction of the compound 8 and 9 with BF3·OEt2 did
not give the corresponding Peterson olefination product.