Toward the development of a general chiral auxiliary. A remarkable, highly diastereoselective, auxiliary-mediated substitution: Application to an enantioselective synthesis of the cyclohexene subunit of (+)-tetronolide

Full text of DOI:10.1021/jo961585b

7238
J . Org. Chem. 1996, 61, 7238-7239
Sch em e 1
Tow a r d th e Develop m en t of a Gen er a l
Ch ir a l Au xilia r y. A Rem a r k a ble, High ly
Dia ster eoselective, Au xilia r y-Med ia ted
Su bstitu tion : Ap p lica tion to a n
En a n tioselective Syn th esis of th e
Cycloh exen e Su bu n it of (+)-Tetr on olid e
Robert K. Boeckman, J r.,* and Stephen T. Wrobleski
Sch em e 2
Department of Chemistry, University of Rochester,
Rochester, New York 14627-0216
Received August 15, 1996
The development of methods allowing the diastereo-
facially selective construction of carbon-carbon bonds is
one of the important thrusts of modern synthetic organic
chemistry.1 In our studies, several camphor-derived lac-
tams have been found useful as auxiliaries for Diels-
Alder, [2 + 2] cycloaddition, alkylation, and aldol con-
densation reactions.2 Ongoing efforts directed toward the
enantioselective construction of (+)-tetronolide (1),3-6 the
aglycon of the stereochemically complex natural antitu-
mor tetrocarcins required methodology for the construc-
tion of enantiomerically pure hydroxy ester 2. Prior stud-
ies from our laboratories have realized significant progress
toward 1, including the development of a sequence that
afforded (()-2.7-9 We hoped to take advantage of the
Sch em e 3a
a
Key: (a) n-BuLi (1.1 equiv), KO-t-Bu (1.1 equiv), THF, -78 °C,
then n-Bu3SnCl; (b) n-BuLi (1 equiv), THF, -78 °C then CO2(g);
(c) 10 (2 equiv), PhSO2Cl (1.5 equiv), TMEDA (4.8 equiv), THF,
-78 °C, then lithio 7 [from 7 and n-BuLi (1 equiv)], THF, 0 °C; (d)
Br2 (1 equiv), Na2CO3, CH2Cl2, -78 °C; (e) AgOTf (1 equiv), 12
(1.3 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2, slow addition of
solution of 6 (1 equiv), -78 °C f rt.
general strategy employed previously, in which (()-2
was derived via bicyclic acetal 3 from mixed acetal 4 by
means of an exo selective intramolecular [4 + 2] cyclo-
addition (Scheme 1).8 Thus, the problem was reduced
to the enantioselective construction of mixed acetal 4.
Since no suitable methodology existed, we developed
the first such methodology based on a novel enantiose-
lective synthesis of the key mixed acetal (R)-4 using a
chiral auxiliary-mediated substitution via neighboring
group participation.10
Incorporation of bicyclic lactam (1R)-7,2 into key di-
bromo ether precursor 6 should permit formation of
diastereomerically pure mixed acetal 5 (Scheme 2).
Participation of one of the imide carbonyl groups of the
controller unit should rigidify the reacting array of atoms
restricting the conformations available, and serve to
differentiate the faces of the reacting center during the
coupling.
As depicted in Scheme 3, preparation of dibromo ether
6 begins with divinyl ether (8). Metalation of 8 with
n-BuLi and KO-t-Bu (Schlosser’s base) followed by trap-
ping with n-Bu3SnCl affords the useful vinylstannane 9
in 98% yield.11 Subsequent transmetalation of 9 with
n-BuLi followed by carboxylation with CO2(g) provided
the lithium carboxylate salt 10 in 89% yield.12 Exposure
of 10 to PhSO2Cl in the presence of TMEDA generates
the related symmetrical anhydride, which is condensed
in situ with the lithium salt of 7 to afford the enol
(1) (a) Furuta, K.; Maruyama, T.; Yamamoto, H. J . Am. Chem. Soc.
1991, 113, 1041. (b) Parmee, E. R.; Tempkin, O.; Masamune, S. J . Am.
Chem. Soc. 1991, 113, 9365 and references cited therein.
(2) (a) Boeckman, R. K., J r.; Connell, B. J . J . Am. Chem. Soc. 1995,
117, 12368. (b) Boeckman, R. K., J r.; J ohnson, A. T.; Musselman, R.
A. Tetrahedron Lett. 1994, 35, 8521. (c) Boeckman, R. K., J r.; Nelson,
S. G.; Gaul, M. D. J . Am. Chem. Soc. 1992, 114, 2258.
(3) Structure of tetronolide: (a) Hirayama, H.; Kasai, M.; Shirahata,
K., Ohashi, Y.; Sasada, Y.; Bull. Chem. Soc. J pn. 1982, 55, 2984. (b)
Hirayama, H.; Kasai, M.; Shirahata, K. Tetrahedron Lett. 1980, 21,
2559.
(4) Total synthesis of tetronolide: (a) Takeda, T.; Kawanishi, E.;
Nakamura, H.; Yoshii, E. Tetrahedron Lett. 1991, 32, 4925. (b) Takeda,
K.; Urahata, M.; Yoshii, E.; Takayanagi, H.; Oqura, H. J . Org. Chem.
1986, 51, 4735. (c) Takeda, K.; Kobayashi, T.; Saito, K.; Yoshii, E. J .
Org. Chem. 1988, 53, 1092.
(5) Synthetic studies toward tetronolide: (a) Roush, W. R.; Brown,
B. B. J . Am. Chem. Soc. 1993, 115, 2268 and references therein. (b)
Roush, W. R.; Koyama, K. Tetrahedron Lett. 1992, 33, 6227.
(6) Synthetic studies toward structurally related spiro tetronic
acids: (a) Roush, W. R.; Sciotti, R. J . J . Am. Chem. Soc. 1994, 116,
6457. (b) Reference 5a and references therein. (c) Marshall, J . A.; Xie,
S. J . Org. Chem. 1992, 57, 2987.
(7) Boeckman, R. K., J r.; Barta, T. E.; Nelson, S. G. Tetrahedron
Lett. 1991, 32, 4091.
(8) Boeckman, R. K., J r.; Estep, K. M.; Nelson, S. G. Tetrahedron
Lett. 1991, 32, 4095.
(9) Boeckman, R. K., J r.; Walters, M. A.; Koyano, H. Tetrahedron
Lett. 1989, 30, 4787.
(10) March, J . Advanced Organic Chemistry, 3rd ed.; McGraw-Hill,
Inc.: New York, 1985; pp 272-286.
(11) (a) Schlosser, M.; Strunk, S. Tetrahedron Lett. 1984, 25, 741.
(b) Schlosser, M. J . Organomet. Chem. 1967, 8, 9. (c) Schlosser, M. J .
Organomet. Chem. 1967, 8, 419.
S0022-3263(96)01585-X CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 21, 1996 7239
Sch em e 4a
Sch em e 5
8
8
a
Key: (a) Ti(OEt)4, PhCH3, rt, 4 h; (b) (R)-(+)-1-PhEtNCO,
Et3N, THF, ∆.
pure (+)-2 having [R]25 34.4° (c 2.9, CH2Cl2) as previ-
D
ously described.8
pyruvate imide 11 in 77% overall yield.13 Regioselective
addition of Br2 to the more electrophilic vinyl ether
affords the key, highly sensitive, dibromo ether 6 (5-6:1
ratio of diastereomers) in greater than 95% yield.14 The
neat oily dibromo ether 6 was found to be very sensitive
to presumably acid catalyzed epimerization affording an
∼1:1 mixture of diastereomers on standing at ambient
temperature.
The magnitude of the diastereoselectivity observed in
the condensation to afford triene (R)-5, as described, is
particularly noteworthy considering the distal relation-
ship of the controller unit with respect to the newly
formed chiral center. This result certainly suggests an
intimate participation of the controller unit within the
transition state(s) possibly as proposed in Scheme 5. The
transition state(s) lacking nonbonded interactions be-
tween the bromomethyl group and controller unit or side
chain are favored with nucleophilic attack by the alcohol
anti to the participating chiral auxiliary. Formation of
the desired R isomer of 5 in an overall double inversion
was obtained as is typically observed in cases of neigh-
boring group participation.10 This model is consistent
with the absolute stereochemistry observed for 5 as
confirmed by the results of X-ray analysis of carbamate
14 and is supported by the isolation of 15 and 16 as minor
byproducts of the condensation.
Thus, for the crucial coupling, the CH2Cl2 solution of
the crude dibromo ether 6 is immediately added slowly
to a CH2Cl2 solution of AgOTf (1 equiv), dienol ester 12
(1.3 equiv),8 and 2,6-lutidine (1.5 equiv) at -78 °C
followed by gradual warming to room temperature.
Under these carefully defined conditions, the desired
mixed bromo acetal 5 was obtained as a 96:4 mixture of
diastereomers in 64% yield. At this juncture, the con-
figuration of the newly created asymmetric center at the
mixed acetal carbon could not be readily discerned from
spectroscopic data. Therefore, the mixture of bromo
acetals 5 was transformed via triene ester 4 to the allylic
alcohol 13 as depicted in Scheme 4. Unfortunately,
mixed acetal imide 5 has, up to now, proven unsuitable
for use in the Diels-Alder cycloaddition owing to its
instability to a variety of Lewis acids. Consequently, 5
was smoothly converted to ester 4 in 92% yield upon
treatment with Ti(OEt)4 (3 equiv) in toluene at 25 °C with
near-quantitative recovery of the lactam 7. Using the
sequence previously documented for the racemic series,
enantiomerically enriched bromo acetal ester 4 was
efficiently transformed to allylic alcohol 13 by [4 + 2]
cycloaddition and epoxidation, followed by exposure to
DBU.8 Allylic alcohol 13 afforded, upon treament with
(R)-(+)-R-methylbenzyl isocyanate, a crystalline carbam-
Efforts to extend this novel approach to other useful
complex acetals as well as synthetic studies directed
toward the completion of the enantioselective total
synthesis of tetronolide will be reported in due course.
1
ate 14 as a single detectable diastereomer (500 MHz H
NMR). Single-crystal X-ray analysis of 14 unambigu-
ously determined the configuration at the acetal center
in the major diastereomer of mixed bromo acetal 5 to be
R as is required for conversion to (+)-2.15 Alcohol 13 was
then efficiently converted in five steps to enantiomerically
Ack n ow led gm en t. We are extremely grateful to the
National Institute of General Medical Sciences (NIGMS)
and the National Cancer Institute (NCI) of the National
Institutes of Health for research grants (GM-29290, GM-
30345, and CA-29108) in support of these studies.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 3-6, 9-11,
13, 14 and an Ortep drawing of the X-ray model for 14 (7
pages).
(12) Boeckman, R. K., J r.; Charette, A. B.; Asberom, T.; J ohnston,
B. H. J . Am. Chem. Soc. 1991, 113, 5337.
(13) Boeckman, R. K., J r.; Weidner, C. H.; Perni, R. B.; Napier, J .
J . J . Am. Chem. Soc. 1989, 111, 8036.
(14) Owing to the sensitivity of the dibromide 6, handling is
minimized. The methylene chloride solution of 6 is filtered and partially
concentrated prior to direct addition to the coupling reaction. Dibro-
mide 6 was found to rapidly epimerize upon concentration to a neat
liquid. Care is taken to avoid exposure of the solution of 6 to moisture
as traces of HBr apparently catalyze rapid equilibration of 6.
J O961585B
(15) The details of the single-crystal X-ray analysis of carbamate
14 will be published as part of a full account of these studies.