Anionic ring-contraction reaction of cyclic acetal system: Stereoselective approach to multi-functionalized oxetanes

Article abstract of DOI:10.1055/s-2004-817772

The reaction of pantolactone derived bicyclic acetal 1 with alkyl lithiums provides 2,2,4-trisubstituted 3-hydroxy oxetane 2 with high diastereoselectivity.

Full text of DOI:10.1055/s-2004-817772

LETTER
651
Anionic Ring-Contraction Reaction of Cyclic Acetal System: Stereoselective
Approach to Multi-Functionalized Oxetanes
Stereoselective
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tanes i Suzuki, Katsuhiko Tomooka*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
Meguro-ku, Tokyo 152-8552, Japan
Fax +81(3)57343931; E-mail: ktomooka@apc.titech.ac.jp
Received 9 December 2003
from (–)-pantolactone in three steps: acetal formation
Abstract: The reaction of pantolactone derived bicyclic acetal 1
with alkyl lithiums provides 2,2,4-trisubstituted 3-hydroxy oxetane
2 with high diastereoselectivity.
with benzaldehyde dimethyl acetal, reduction with
DIBAL, and montmorillonite K10 promoted acetal ex-
change reaction7 (Scheme 2).
Key words: acetals, carbanions, stereoselective synthesis, oxe-
tanes, rearrangements
Functionalized oxetanes are an attractive synthetic inter-
mediate, which allow unique ring-opening reactions1 and
are present in a variety of biologically active natural prod-
ucts as a key skeleton.2 Although a number of methods for
the synthesis of functionalized oxetanes have been report-
ed, a more efficient approach needs to be developed.
Herein, we wish to report a stereoselective approach to the
highly functionalized chiral oxetanes B by anionic ring-
contraction reaction of cyclic acetal A (path a in
Scheme 1). We have found this novel reaction during the
course of study on the [1,2]-Wittig rearrangement.
Scheme 2
A reaction of acetal 1a (a/b = 39:61) was performed by
treatment with t-BuLi (4 equiv) in THF at –78 °C to 0 °C.
To our surprise, the reaction was found to yield unexpect-
ed oxetane 2a4 in 17% yield as a single diastereomer,5 but
did not give the expected [1,2]-rearrangement product 3
(Scheme 3). The stereochemistry of 2a was determined by
X-ray crystallography of its TBDPS ether 4a (Figure 1).8
Scheme 1
Scheme 3
Recently, we have developed the acetal [1,2]-Wittig re-
arrangement protocol by which O-glycosides (cyclic
acetals) can be converted to C-glycosides with high dia-
stereoselectivity.3 Thus, we envisioned that application of
the rearrangement protocol to acetal A could provide the
acyl C-glycoside C via deprotonation of Ha followed by a
ring contractive rearrangement (path b in Scheme 1). To
this end, we attempted the reaction of acetal 1a4,5 which
was successfully prepared as a mixture of C1¢ epimers6
This result means that the unanticipated sequential reac-
tions proceeded which include 1) cleavage of the O-C1¢
bond, 2) formation of a carbon-carbon bond between C1
and C1¢, 3) introduction of a t-Bu group derived from t-
BuLi to the C1¢ position, 4) ring-opening of five-mem-
bered acetal. To clarify the generality of this novel reac-
tion, next we examined a similar reaction of 1a with
MeLi, n-BuLi and s-BuLi. As shown in Scheme 4, all of
these reactions provide the corresponding oxetanes 2b–
d4,5,8–11 in moderate to good yield with excellent dia-
stereoselectivity.
SYNLETT 2004, No. 4, pp 0651–0654
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9.
0
3.
2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-817772; Art ID: U27303ST
© Georg Thieme Verlag Stuttgart · New York

652
M. Suzuki, K. Tomooka
LETTER
A plausible mechanism of this oxetane formation reaction
is shown in Scheme 7. The mechanism most likely in-
volves the carbene intermediate B which is formed by the
O-C1¢ bond cleavage in acetal anion A.13,14 Then, the re-
sulting carbene B inserts into alkyl lithium14 to form the
lactol alkoxide C which then isomerizes into aldehyde D.
At the end, aldehyde D undergoes an intramolecular nu-
cleophilic addition reaction to form oxetane E.15 The key
to this process is the generation of the lactol alkoxide C,
which acts as a masked aldehyde, and reacts only with an
intramolecular nucleophile but does not react with the
alkyl lithium reagent.
Figure 1
Scheme 4
Scheme 7
Furthermore, we have found that a similar reaction can
occur in the propargyl acetal system. A reaction of
propargylic acetal 1b12 (81% dr at C1¢) with MeLi in THF
gave alkynyl substituted oxetane 2e4–6 in 45% yield, also
as a single diastereomer (Scheme 5).
To confirm the postulated reaction pathway from lactol
alkoxide C to oxetane E, we examined the reaction of
pantolactol derived benzyl ether 55,16 with excess amount
of n-BuLi (Scheme 8). As expected, the reaction gave
oxetane 64,5,17 (>95% dr) as a major product, albeit in
moderate chemical yield.
Scheme 5
Scheme 8
In order to gain insight into the steric course of the reac-
tion, next we examined the reaction of diastereochemical-
ly enriched a-1a and b-1a. As a result, reaction of a-1a
and b-1a provided the same stereoisomer of oxetane 2c,
and the yields are not significantly different (Scheme 6).
These results reveal that the stereochemistry of C1¢ of the
substrate does not affect the stereochemistry of the prod-
uct. In other words, the reaction is stereoselective, but is
not stereospecific at the acetal C1¢ chirality.
In summary, we have described a highly diastereoselec-
tive approach to multi-functionalized oxetane by the an-
ionic ring-contraction reaction of cyclic acetal. The
investigation into the scope and limitation, detailed reac-
tion mechanism as well as its synthetic applications are
under way in our laboratory.
Acknowledgment
H
This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-Element Cy-
clic Molecules’, Basic Area (B) No. 14350473 and the 21st Century
COE Program ‘Creation of Molecular Diversity and Development
of Functionalities’ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
O
O
O
a
a
n-Bu
OH
O
O
H
Ph
(68%)
(74%)
O
O
OH
Ph
1'
1'
Ph
H
α-1a (>95% dr5)
2c (>95% dr5)
β-1a (>95% dr5)
Scheme 6 Reagents and conditions: a) n-BuLi (4 equiv), THF, –78
°C to 0 °C.
Synlett 2004, No. 4, 651–654 © Thieme Stuttgart · New York

LETTER
Stereoselective Approach to Multi-Functionalized Oxetanes
653
(7) (a) Trost, B. M.; Edstrom, E. D. Angew. Chem., Int. Ed.
Engl. 1990, 29, 520. (b) Tomooka, K.; Nakamura, Y.;
References
(1) Reviews: (a) Porco, J. A.; Schreiber, S. L. In Comprehensive
Organic Synthesis, Vol. 5; Trost, B. M.; Fleming, I., Eds.;
Pergamon: Oxford, 1991, 151–192. (b) Abe, M.; Nojima,
M. J. Synth. Org. Chem., Jpn. 2001, 59, 855.
(2) For example: (a) Thromboxane A2: Bhalgwat, S. S.; Still,
W. C. J. Am. Chem. Soc. 1985, 107, 6372. (b) Oxetin:
Kawata, Y.; Ikekawa, N.; Murata, M.; Omura, S. Chem.
Pharm. Bull. 1986, 34, 3102. (c) Oxetanocin: Nishiyama,
S.; Yamamura, S. J. Synth. Org. Chem., Jpn. 1991, 49, 670.
(d) Merrilactone A: Birman, V. B.; Danishefsky, S. J. J. Am.
Chem. Soc. 2002, 124, 2080.
Nakai, T. Synlett 1995, 321.
(8) Crystallographic data of 4a and 2b have been deposited with
the Cambridge Crystallographic Data Center as
supplementary publication no. CCDC 225890 and 225891,
respectively. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK [fax: +44 (1223)336033; e-mail:
deposit @ccdc.cam.ac.uk].
(9) The relative stereochemistry of 2c was determined by NOE
experiment of its acetal derivative as shown below
(Scheme 9).
(3) (a) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem.
Soc. 1996, 118, 3317. (b) Tomooka, K.; Yamamoto, H.;
Nakai, T. Angew. Chem. Int. Ed. 2000, 39, 4500.
(4) All new compounds were fully characterized by IR, 1H and
13C NMR analyses. Data for selected compounds are as
follows. Compound a-1a: 1H NMR (300 MHz, CDCl3): d =
7.55–7.52 (m, 2 H), 7.40–7.38 (m, 3 H), 5.98 (d, J = 3.9 Hz,
1 H), 5.85 (s, 1 H), 4.13 (d, J = 3.9 Hz, 1 H), 3.84 (d, J = 8.1
Hz, 1 H), 3.54 (d, J = 8.1 Hz, 1 H), 1.14 (s, 3 H), 1.07 (s, 3
H). 13C NMR (75 MHz, CDCl3): d = 137.0, 129.6, 128.4,
126.7, 106.2, 104.7, 88.0, 77.2, 43.0, 24.0, 17.9. Compound
b-1a: 1H NMR (300 MHz, CDCl3): d = 7.48–7.44 (m, 2 H),
7.40–7.37 (m, 3 H), 6.09 (s, 1 H), 6.03 (d, J = 3.6 Hz, 1 H),
4.23 (d, J = 3.6 Hz, 1 H), 3.78 (d, J = 8.6 Hz, 1 H), 3.69 (d,
J = 8.6 Hz, 1 H), 1.20 (s, 3 H), 1.07 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 137.5, 129.5, 128.4, 126.4, 106.0, 105.7,
88.1, 80.1, 43.0, 25.0, 18.9. IR (neat): 2963, 2873, 1460,
1393, 1222, 1074, 1027, 1008 cm–1. Anal. Calcd for
Scheme 9
(10) The substrate 2d consisted of a 1:1 mixture of two epimers
at the chirality center of s-Bu.
(11) General Procedure for the Ring-Contraction Reaction:
To a THF (9 mL) solution of 1a (72.4 mg, 0.33 mmol, 62%
dr) was added n-BuLi (1.04 mL, 1.27 M in hexane, 1.32
mmol) dropwise at –78 °C. After the addition, the solution
was stirred for 15 min at –78 °C, and the temperature was
allowed to rise to 0 °C over a period of 1 h. The resulting
mixture was stirred at 0 °C for 1 h, and then sat. NH4Cl aq
was added. The mixture was extracted with Et2O. The
combined organic phase was dried over Na2SO4, filtered and
the solvent was removed in vacuo. The residue was purified
by silica gel column chromatography (hexane/Et2O = 1:1) to
give the oxetane 2c (67.8 mg, 74%, >95% dr). In the case of
the reaction with MeLi, >10 equiv of MeLi was required to
drive the reaction to completion.
28
C13H16O3: C, 70.89; H, 7.32. Found: C, 71.16; H, 7.26. [a]D
+29.4 (c 3.67, CHCl3). Compound 2a: 1H NMR (300 MHz,
CDCl3): d = 7.61 (d, J = 7.8 Hz, 1 H), 7.41–7.36 (m, 1 H),
7.26–7.25 (m, 3 H), 5.10 (br s, 1 H), 4.92 (d, J = 7.4 Hz, 1
H), 4.44 (d, J = 7.4 Hz, 1 H), 3.63 (d, J = 10.4 Hz, 1 H), 3.00
(d, J = 10.4 Hz, 1 H), 1.60 (br s, 1 H), 0.96 (s, 12 H), 0.84 (s,
3 H). 13C NMR (75 MHz, CDCl3): d = 139.2, 128.8, 127.6,
127.2, 126.5, 125.9, 95.9, 88.7, 70.0, 66.7, 39.4, 37.4, 24.7,
24.4, 19.8. IR (reflection): 3235, 2925, 1473, 1391, 1364,
1169, 963, 709, 598 cm–1. Compound 2e: 1H NMR (300
MHz, CDCl3): d = 4.26 (d, J = 7.0 Hz, 1 H), 4.16 (dd,
J = 11.3, 7.0 Hz, 1 H), 3.55 (d, J = 11.1 Hz, 1 H), 3.40 (dd,
J = 11.1, 5.3 Hz, 1 H), 2.60 (d, J = 11.3 Hz, 1 H), 2.09 (br s,
1 H), 1.63 (s, 3 H), 0.99 (s, 3 H), 0.97 (s, 9 H), 0.93 (s, 3 H),
0.19 (s, 6 H). 13C NMR (75 MHz, CDCl3): d = 103.0, 95.1,
94.1, 82.8, 72.1, 70.0, 37.3, 26.5, 26.2, 20.0, 19.4, 16.6, –
4.39, –4.44. IR (neat): 3418, 2956, 2928, 2857, 1472, 1363,
1251, 1123, 835, 777 cm–1. Compound 6: 1H NMR (300
MHz, CDCl3): d = 7.43–7.29 (m, 5 H), 5.89 (br s, 1 H), 5.45
(dd, J = 2.7, 2.4 Hz, 1 H), 4.56 (br s, 2 H), 4.04 (d, J = 10.5
Hz, 1 H), 3.43 (d, J = 10.5 Hz, 1 H), 1.74 (br s, 1 H), 1.10 (s,
3 H), 1.01 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 141.0,
128.6, 128.3, 128.1, 125.5, 125.3, 91.4, 90.8, 74.4, 66.6,
39.6, 23.5, 20.2. IR (neat): 3332, 2958, 2929, 1454, 1134,
1047, 972, 698 cm–1.
(12) Acetal 1b was prepared from (–)-pantolactone in three steps
as shown below (Scheme 10).
Scheme 10
(5) The diastereomer ratio was determined by 1H NMR analysis.
(6) The relative stereochemistry of a-1a and 2e was determined
by NOE experiment as shown below (Figure 2).
(13) We cannot rule out the possibility that the reaction proceeds
via not a free carbene but a related carbenoid intermediate.
(14) The alkyl lithium-promoted carbene or a related carbenoid
formation in acetal system, followed by its insertion to alkyl
lithium has been reported, see: (a) Shiner, C. S.; Tsunoda,
T.; Goodman, B. A.; Ingham, S.; Lee, S.; Vorndam, P. E. J.
Am. Chem. Soc. 1989, 111, 1381. (b) Boche, G.; Bosold, F.;
Lohrenz, J. C. W.; Opel, A.; Zulauf, P. Chem. Ber. 1993,
126, 1873.
Figure 2
Synlett 2004, No. 4, 651–654 © Thieme Stuttgart · New York

654
M. Suzuki, K. Tomooka
LETTER
(15) The exact origin of the observed stereoselectivity is not
clear at present, while it might be considered as the result of
i) stereoselective formation of benzylic or propargylic chiral
carbanion by the diastereoselective carbene insertion to
alkyl lithium (B→C) and/or the efficient epimerization
(at C or D), followed by ii) diastereoselective addition
reaction via the chelation intermediate (D).
(17) The structure of 6 was determined by 1H NMR analysis and
IR analysis of its derivatives as shown below (Scheme 11).
It is known that the oxetane-3-one displays a carbonyl
absorption in the IR spectrum at about 1820 cm–1, see: Thijis,
L.; Cillissen, P. J. M.; Zwannenburg, B. Tetrahedron 1992,
48, 9985.
(16) The lactol 5 was prepared from pantolactone(racemic) in
two steps: benzylation of the hydroxy group with benzyl
bromide, half-reduction with DIBAL.
Ha
Ha
Hb
b
O
a
O
Hc
Hc
6
OAc
OTBDPS
O
OAc
Ph
Ph
Jac=4.7 Hz, 1819 cm–1 (C=O)
Jab=6.8 Hz,Jbc=5.7 Hz
Scheme 11 Reagents and conditions: a) Ac2O; b) TBDPSCl;
Dess–Martin periodinane.
Synlett 2004, No. 4, 651–654 © Thieme Stuttgart · New York