Synthesis and Lewis acid-catalyzed nucleophilic substitution of chiral 1-alkoxyalkyl carboxylates

Full text of DOI:10.1021/ja970153v

J. Am. Chem. Soc. 1997, 119, 4541
4541
Table 1. Bayer-Villiger Reaction of Optically Active R-Alkoxy
Ketones
Synthesis and Lewis Acid-Catalyzed Nucleophilic
Substitution of Chiral 1-Alkoxyalkyl Carboxylates
Hiroshi Matsutani, Satsuki Ichikawa, Jayamma Yaruva,
Tetsuo Kusumoto,* and Tamejiro Hiyama†
Sagami Chemical Research Center
Nishiohnuma, Sagamihara, Kanagawa 229, Japan
Research Laboratory of Resources Utilization
Tokyo Institute of Technology
Nagatsuta, Yokohama, Kanagawa 226, Japan
ReceiVed January 17, 1997
Chiral acetals are versatile building blocks for the synthesis
of biologically active agents and functional materials.1 The
acetal is usually rendered chiral due to the dissymmetric
environment induced by a stereogenic center near the acetal
carbon or by a chiral glycol moiety.1 In contrast, few optically
pure acetals are known whose acetal carbon only is chiral.2 The
mechanism of the Lewis acid-mediated nucleophilic substitution
of acetals is also a recent topic of interest.3 Denmark reported
that sterically unhindered aliphatic acetals underwent intramo-
lecular SN2-type substitution with the aid of a mild Lewis acid.3a
In contrast, Sammakia observed that dimethyl acetals underwent
intermolecular allylation Via an oxocarbenium ion using any
kind of Lewis acid.3c We report herein that the Baeyer-Villiger
reaction of optically active R-alkoxy ketones 1 affords optically
active 1-alkoxyalkyl carboxylates 2. The resulting acetals 2
undergo substitution with lithium dialkylcuprate(I) in the
presence of boron trifluoride etherate4 to give optically active
alkoxyalkane 3 with inversion of configuration.
The syntheses of optically active 1-alkoxyalkyl carboxylates
2a-g5 were readily achieved by the Baeyer-Villiger oxidation
of optically active R-alkoxy ketones 1a-g6 shown in Table 1.
The reaction proceeded smoothly in good yields (46-92%) from
ketones 1a-g (84-100% ee), and the resulting acetals 2a-g
had high anantiomeric excess (ee) (81-97%).7 Due to the steric
effect of the t-Bu group, longer reaction time was needed for
1g to give 2g and the yield was rather low (Table 1, entry 7).
It is worth noting that the oxidation is highly regioselective;
the regioisomeric R-alkoxyalkanoate was not produced in the
oxidation. Thus, the migratory aptitude is demonstrated to be
1-alkoxyalkyl . alkyl, in accord with the order recently dis-
closed.8 In line with well-established results,9 we can state that
the stereochemical course of the Baeyer-Villiger reaction is
retention. This conclusion is substantiated by further elaboration
(Vide infra).
We next studied the stereochemical course of the Lewis acid-
catalyzed C-C bond-forming reactions, using the optically
active 1-alkoxyalkyl carboxylates 2. The chiral acetals 2 should
be advantageous reagents over cyclic diastereomeric acetals,1,3,10
since their structure is simple and the stereochemical outcome
is easily assayed. In our preliminary experiments, the reaction
of 2a with allyltrimethylsilane in the presence of boron
† Tokyo Institute of Technology.
(1) (a) Fujioka, H.; Kita, Y. In Studies in Natural Products Chemistry;
Rahman, A.-u., Ed.; Elsevier: Amsterdam, The Netherlands, 1994; Vol.
14, pp 469-516. (b) Ferrier, R. J.; Blattner, R.; Furneaux, R. H.; Tyler, P.
C.; Wightman, R. H.; Williams, N. R. In Carbohydrate Chemistry; The
Royal Society of Chemistry: Cambridge, 1991; Vol. 23, Chapter 7. (c)
Seebach, D.; Imwinkelried, R.; Weber, T. In Modern Synthetic Methods
1986; Scheffold, R., Ed.; Springer Verlag: Berlin, Heidelberg, 1986; Vol.
4, pp 125-259. (d) Whitesell, J. K. Chem. ReV. 1989, 89, 1581-1590. (e)
Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-1054.
(2) Synthesis of an optically active 1-alkoxy-2,2,2-trichloroethyl ester
is achieved enzymatically: Cheˆnevert, R.; Desjardins, M.; Gagnon, R. Chem.
Lett. 1990, 33-34.
(3) For the mechanism on the Lewis acid-catalyzed nucleophilic substitu-
tion of acetals, see: (a) Denmark, S. E.; Almstead, N. G. J. Am. Chem.
Soc. 1991, 113, 8089-8110. (b) Denmark, S. E.; Almstead, N. G. J. Org.
Chem. 1991, 56, 6485-6487. (c) Sammakia, T.; Smith, R. S. J. Am. Chem.
Soc. 1994, 116, 7915-7616. (d) Sammakia, T.; Smith, R. S. J. Am. Chem.
Soc. 1992, 114, 10998-10999. (e) Mori, I.; Ishihara, K.; Flippin, L. A.;
Nozaki, K.; Yamamoto, H.; Bartlett, P. A.; Heathcock, C. H. J. Org. Chem.
1990, 55, 6107-6115. (f) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 477-511.
trifluoride etherate10b,d gave a homoallylic ether, with the
acyloxyl group behaving as the leaving group, but with complete
racemization. All attempts to prevent the racemization by tuning
the Lewis acid catalyst (TiCl4, Ti-blend,11 TMSOTf, ZnCl2, or
(4) Organocopper or cuprate reagents associated with boron trifluoride
cleave acetals: Ghribi, A.; Alexakis, A.; Normat, J. F. Tetrahedron Lett.
1984, 25, 3075-3078.
(7) Enantiomeric excess (ee) was analyzed by HPLC with CHIRALCEL
or CHIRALPAK (Daicel columns).
(5) To a dichloromethane solution of 1 were added sodium hydrogen
carbonate (1.3 equiv) and m-chloroperbenzoic acid (m-CPBA, 1.5 equiv).
The resulting mixture was stirred at 0 °C to room temperature. Excess
m-CPBA was quenched with aqueous sodium sulfite solution, and the
resulting mixture was extracted with chloroform. Organic layer was
separated, washed first with aqueous sodium hydrogen carbonate and then
with aqueous sodium chloride, dried, and concentrated. The residue was
distilled to give 2. Upon standing in a glass tube for several days or upon
silica gel chromatography, 2 racemized gradually. Thus, 2 was used for
further reaction immediately after isolation by distillation.
(6) Ketone 1a was obtained from (2R,3R)-2,3-butanediol, 1b-f were
synthesized from R-amino acids, and 1g was prepared from L-lactic acid.
Details of the synthesis and spectral data are listed in Supporting
Information.
(8) (a) The migratory aptitude of a substituent in a pyranose system is
reported to be C-OCH2Ph > C-OMe > C(OR)2 . C-OCOR ∼ C-CH3 >
C-H. Chida, N.; Tobe, T.; Ogawa, S. Tetrahedron Lett. 1994, 35, 7249-
7252. (b) Only cyclic ketones were used as the substrate. Tsang, R.; Fraser-
Reid, B. J. Org. Chem. 1992, 57, 1065-1067.
(9) Krow, G. R. In Organic Reactions; John Wiley & Sons: New York,
1993; Vol. 43, pp 251-798.
(10) For studies on the reaction of cyclic diastereomeric 1-alkoxyalkyl
carboxylates, see: (a) Seebach, D.; Imwinkelried, R.; Stucky, G. Ang. Chem.,
Int. Ed. Engl. 1986, 25, 178-180. (b) Seebach, D.; Imwinkelried, R.; Stucky,
G. HelV. Chim. Acta 1987, 70, 448-464. (c) Schreiber, S. L.; Reagan, J.
Tetrahedron Lett. 1986, 27, 2945-2948. (d) Boons, G.-J.; Eveson, R.; Smith,
S.; Stauch, T. Synlett 1996, 536-538. (e) Dahanukar, V. H.; Rychnovsky,
S. D. J. Org. Chem. 1996, 61, 8317-8320.
S0002-7863(97)00153-4 CCC: $14.00 © 1997 American Chemical Society

4542 J. Am. Chem. Soc., Vol. 119, No. 19, 1997
Communications to the Editor
Table 2. Nucleophilic Substitution of Optically Active
1-Alkoxyalkyl Carboxylates Using Organocopper Reagents
Scheme 1
the reaction proceeded with high stereospecificity. Although
we attempted to reduce the amount of BF3‚OEt2 to 1.5 equiv
(entry 2), the observed ee of 3a was not improved. A similar
reaction was performed using Et2CuLi‚LiI instead of Bu2CuLi‚
LiI to give 3b with a slightly reduced ee as compared with 3a
(entry 3). To demonstrate the generality and scope of this reac-
tion, various 1-alkoxyalkyl carbonates were used as the substrate.
An acetal 2b gave ether 3c (entry 4) with inversion ratio of
76%. Although 2c reacted smoothly to give the corresponding
ether 3d (entry 5), (S)-1-phenoxyethyl acetate (2d) proved to
be inert (entry 6). The acetal 2e in which an isobutyl moiety is
attached at the acetal carbon (R2) gave 3e (65% ee) by the
reaction with Bu2CuLi‚LiI. The lower ee might be attributed
to the steric hindrance of the isobutyl group (entries 7 and 8).
The same substrate, upon reaction with Me2CuLi‚LiI/BF3‚OEt2,
gave 3f with high inversion ratio, particularly when the amount
of BF3‚OEt2 was reduced (entry 10). Whereas the reaction of
propanoate 2f also proceeded stereospecifically (entry 11), pi-
valate 2g reacted with Bu2CuLi‚LiI with complete loss of stereo-
chemical integrity. Thus, the steric bulk of the leaving group
affects significantly the stereochemical course of the reaction.
A plausible reaction pathway follows.3c The Lewis acid-aided
reactions of acetal 2a with allyltrimethylsilane should produce
an oxocarbenium ion (5a), which then reacts with a nucleophile
to give racemic 4a (Scheme 1, path A). In contrast, BF3‚OEt2-
aided alkylation of 2a with a cuprate reagent should proceed
Via a Lewis acid-substrate complex 5b (Scheme 1, path B) that
is responsible for the stereochemical course of the reaction Via
SN2-like displacement. The reaction through an alternative path
involving the oxocarbenium ion intermediate 5a should be
limited but not negligible. Our data show that SN2 type nucleo-
philic substitution of chiral acetal derivatives can be realized
by an appropriate combination of substrate, nucleophile, and
the Lewis acid.
a The absolute configuration was assigned on the basis of the optical
rotation of the corresponding authentic sample. b [R]20D ) +19° (c 1.0,
CHCl3). The (R)-isomer, prepared by benzylation of commercially
available (R)-2-hexanol, showed [R]20D ) -21° (c 1.1, CHCl3). c [R]20
D
) +23° (c 1.0, CHCl3). The (S)-isomer prepared from commercially
available (S)-2-butanol showed [R]20D ) +25° (c 1.0, CHCl3). d [R]20
D
) +14° (c 1.0, CHCl3). The (S)-isomer derived from commercially
available (S)-2-hexanol showed [R]20 ) +17° (c 1.0 CHCl3). e The
D
absolute configuration was estimated on the analogy of entries 1-4
and 11. f [R]20 ) +17° (c 1.0, CHCl3). g Reaction at -78 to -30 °C
D
for 1.5 h.
MgBr2‚OEt2) failed. The racemic products resulted again with
allyltributyltin3b,10e or enol sillyl ether10d (eq 1).
We then studied the reaction with an organocopper reagent.
Treatment of 2a with lithium dibutylcuprate(I) (Bu2CuLi‚LiI)
afforded 2-(benzyloxy)hexane in only 12% yield. However,
use of Bu2CuLi‚LiI and boron trifluoride etherate (BF3‚OEt2)
gave (S)-2-(benzyloxy)hexane12 (3a, 69% yield, 48% ee) starting
with 77% ee of (S)-1-(benzyloxy)ethyl acetate (2a). We were
delighted to find that, by slow addition of BF3‚OEt2 to a mixture
of 2a (92% ee) and Bu2CuLi‚LiI, ether 3a was obtained in 53%
yield with 86% ee (Table 2, entry 1).13 Thus, the BF3‚OEt2-
aided alkylation of 2a with Bu2CuLi‚LiI proceeds with inversion
of configuration. In addition, the yield of 3a was markedly
suppressed by using BuCu‚LiI/BF3‚OEt2, and racemic 3a
resulted by using Bu2CuLi‚LiI/AlCl3. Alkylation of various
acetals 2 with lithium dialkylcuprate(I) and boron trifluoride
etherate is summarized in Table 2. The inversion ratio, (% ee
of 3)/(% ee of 2), is shown in parentheses. Noteworthy is that
We have reported herein that the Baeyer-Villiger oxidation
of optically active R-alkoxyalkyl ketones 1a-g enables us to
obtain chiral 1-alkoxyalkyl carboxylates 2a-g of high optical
purity. The alkylation with lithium dialkylcuprate(I) and boron
trifluoride etherate gave stereospecifically alkylated products
with a high degree of inversion of configuration. This process
provides us with a new synthetic method for the synthesis of
optically active secondary alcohols and their derivatives.
Supporting Information Available: Experimental procedures and
characterization data for 1a-g, 2a-g, and 3a-f and their intermediates
(19 pages). See any current masthead page for ordering and Internet
access instructions.
JA970153V
(11) Johnson, W. S.; Crackett, P. H.; Elliott, J. D.; Jagodzinski, J. J.;
Lindell, S. D.; Natarajan, S. Tetrahedron Lett. 1984, 25, 3951-3954.
Allylation of 1a with “Ti-blend” as a catalyst according to the procedure
reported by Denmark3a gave a racemic allylated product.
(12) The absolute configuration of 3a-c was assigned by comparison
of the sign of the optical rotation with the those of the corresponding
authentic sample which was prepared by benzylation of the commercially
available optically active 2-alkanol. The absolute configuration of 3d-f
was estimated on the analogy of 3a-c in entries 1-4 and 11 of Table 2.
See Supporting Information for details.
(13) Butyllithium (6 equiv) in hexane was added at -30 °C to the
suspension of copper(I) iodide (3 equiv) in diethyl ether to prepare lithium
dibutylcuprate(I). To the reaction mixture were added dropwise the ester
2a at -78 °C and then an ethereal solution of boron trifluoride etherate (3
equiv). The reaction mixture was stirred at -78 °C for 0.5 h, and the reaction
was quenched with aqueous ammonium chloride. The insoluble material
was filtered through Celite, and the filtrate was extracted with diethyl ether.
The organic layer was separated, washed with aqueous sodium chloride
solution, dried, and concentrated. The residue was purified by silica gel
column chromatography.