Synthetic and mechanistic studies of the retro-Claisen rearrangement. 3. A route to enantiomerically pure vinyl cyclobutane diesters via a highly diastereoselective syn S(N)2' reaction and their rearrangement to enantiomerically pure dihydrooxacenes

Full text of DOI:10.1021/jo9712254

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J . Org. Chem. 1997, 62, 6456-6457
Syn th etic a n d Mech a n istic Stu d ies of th e
Retr o-Cla isen Rea r r a n gem en t. 3. A Rou te
to En a n tiom er ica lly P u r e Vin yl
Cyclobu ta n e Diester s via a High ly
Dia ster eoselective Syn SN2′ Rea ction a n d
Th eir Rea r r a n gem en t to En a n tiom er ica lly
P u r e Dih yd r ooxa cen es
Robert K. Boeckman, J r.* and Michael R. Reeder
Department of Chemistry, University of Rochester,
Rochester, New York 14627-0216
Two routes to the required acyclic substrates have been
established. The first, which utilizes a [2,3] Wittig
rearrangement,9 begins with an R-alkoxymethoxy vinyl
ketone such as 10 obtained from ethyl lactate.10 Chela-
tion controlled reduction of 10 with Zn(BH4)2 followed by
alkylation with (iodomethyl)tributylstannane affords the
anti bis ether 11 in 86% overall yield (Scheme 1).9,11
Exposure of 11 to nBuLi at -78°C affords homoallylic
alcohol 12 in ∼45% yield. Alcohol 12 was routinely trans
formed to the allylic phenyl carbonate (S)-(-)-7 via
malonate 13 in 40-50% overall yield. This route was
limited by the modest yields obtained in the [2,3] rear-
rangement. Thus, as outlined in Scheme 2, we generally
employed an enzymatic resolution of the related racemic
allylic alcohols. The known aldehyde 1412 was coverted
to the enones 15-17 and the related allylic alcohols (()-
18-20 using standard methods in 65-75% overall yields.
The corresponding (S) alcohols 18-20 were isolated in
∼85-90% yield (of theoretical) upon exposure to Lipase
PS3013 and shown to be enantiomerically pure (>99% ee)
upon conversion to the related Mosher ester.14 The
corresponding phenyl carbonates (S)-(-)-7 and (S)-(-)-
21-22 were prepared as before (>95% yield). Enanti-
oselective reduction of the precursor enones 15-17 has,
thus far, not afforded material of high enantiomeric
purity.
Received J uly 8, 1997
As part of a program to investigate the retro-Claisen
rearrangement1,2 and its application to the synthesis of
biologically interesting natural molecules (e.g. Methy-
mycin and Laurencin),3 we required an efficient enanti-
oselective route to the precursor vinyl cyclobutane di-
esters such as 1. Realization of a general enantioselective
synthesis of 1 should then make possible preparation of
the related enantiomerically pure medium ring ethers
like dihydrooxacene 2 for which few general synthetic
routes exist.4
Prior efforts had led to the preparation of enantiomeri-
cally pure dihydrooxepins such as 3 via retro-Claisen
rearrangement of 4. In turn, 4 and related structures
are accessible from the cyclopropane diesters 5 obtainable
from acyclic precursors 6 using π-allyl palladium chem-
istry.2 However, this methodology had not been utilized
to prepare cyclobutane derivatives like 1 with the excep-
tion of two cases.5,6 Our investigations into the use of
π-allyl palladium chemistry to prepare cyclobutane di-
esters 1 from acyclic precursors 7 revealed that this route
is generally not feasible.7 Unfortunately, cyclization of
acyclic substrates such as 7, via intramolecular SN2′
alkylation, did not initially appear attractive since our
work established that cyclization of the acyclic diester 8
proceeded with poor facial discrimination.2,8
We initially examined cyclization of (S)-(-)-7. Surpris-
ingly, exposure of (S)-(-)-7 to NaH in THF failed to
provide the expected cyclobutane diester 23. Similar
behavior was observed in a variety of solvents including
tBuOCH3 and DMF and for several leaving groups (e.g.
OAc, OBz). The only products resulted from deacylation
to (S)-(-)-18 accompanied by recovered (S)-(-)-7 in some
cases. Quite remarkably, when cyclization was attempted
using NaH in toluene at 50-60 °C, smooth cyclization
In this paper, we report development of a general
highly enantioselective route to the cyclobutane diesters
1 via a highly π facially selective syn SN2′ ring closure of
acyclic substrates such as 7 and rearrangement of the
derived dialdehyde 9 to dihydrooxacenes 2.
(1) Boeckman, R. K., J r.; Shair, M. D.; Vargas, J . R.; Stolz, L. A. J .
Org. Chem. 1993, 58, 1295.
was observed to afford cyclobutane diester (+)-23, [R]25
D
(2) Boeckman, R. K., J r. New Methodology And Applications to the
Synthesis of Antibiotics and Other Bioactive Complex Molecules. In
Antibiotic and Antiviral Compounds: Chemical Synthesis and Modi-
fication; Krohn, K., Kirst, H., Maas, H., Eds.; VCH: Weinheim, 1993;
pp 15-30.
136 (c ) 1.7, CHCl3), in ∼75% yield and >99% ee,
accompanied by some recovered (S)-(-)-18. The enan-
tiomeric purity of (+)-23 was established by GLC analysis
of the bis Mosher ester obtained by reduction of (+)-23
with LAH and derivatization.14 The absolute configura-
tion of (+)-23 was established by chemical correlation
with cyclohexene diester (R)-(-)-24 ([R]25D -183 (c ) 1.7,
CHCl3)) obtained by acylation of the known ester (3R,4S)-
(-)-25.15 Cyclobutane diester (+)-23 was then treated
(3) For related studies of the retro-Claisen rearrangement, see:
Hofmann, B.; Reissig, H.-U. Synlett 1993, 27.
(4) Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D. A.; Abe,
Y.; Bal Reddy, K.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Conley,
S. R.; Rutjes, F. P. J . T. J . Am. Chem. Soc. 1995, 117, 10227 and
subsequent papers. Overman, L. E.; Matthisa, B.; Bullock, W. H.;
Takemoyo, T. J . Am. Chem. Soc. 1995, 117, 5958. Holms, A. B.;
Robinson, R. A.; Clark, J . S. J . Am. Chem. Soc. 1993, 115, 10400.
Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc. J pn 1979,
52, 135.
(5) Trost, B. M.; Verhoven, T. R. J . Org. Chem. 1976,41, 3125. Trost,
B. M.; Weber, L. J . Am. Chem. Soc. 1975, 97, 1611.
(6) Malacria, M.; Le Bideau, F.; Zucco, M. Tetrahedron Lett. 1995,
36, 2487.
with Pd(dppe)2 affording (S)-(+)-25 ([R]25 183 (c ) 1.8,
D
CHCl3)), a process known to proceed via overall retention,
thus establishing the configuration of (+)-23 as R.16
This cyclization appears general, proceeding under the
same conditions for the related substrates 21 and 22 to
(7) Boeckman, R. K., J r.; Reeder, M. R. Manuscript in preparation.
Reeder, M. R. Ph. D. Dissertation, University of Rochester, Rochester,
NY, 1996.
(8) Boeckman, R. K., J r.; Vargas, J . R. Unpublished results, 1989.
(9) Kallmerten, J .; Tong, X. Synlett 1992, 845. Kallmerten, J .;
Ballstra, M. Tetrahedron Lett. 1988, 29, 6901. Mikami, K.; Nakai, T.
Synthesis 1991, 594 and the reference cited therein. Mikami, K.; Nakai,
T. Chem Rev. 1986, 86, 8.
(11) Oishi, T.; Tanaka, T.; Nakata, T. Tetrahedron Lett. 1983, 24,
2653.
(12) Warner, D. T.; Moe, O. A. J . Am. Chem. Soc. 1948, 70, 3470.
(13) Enzymes in Synthetic Organic Chemistry; Whitesides, G. M.,
Wong, C. H., Eds.; Pergamon Press: New York, 1994.
(14) Mosher, H. S.; Dale, J . A.; Dull, D. L. J . Org. Chem. 1969, 34,
2543.
(10) Rapoport, H.; Palkowitz, A. D.; Knudsen, C. G.; Maurer, P. J .
J . Org. Chem. 1985, 50, 325.
(15) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am. Chem. Soc.
1988, 110, 1238.
S0022-3263(97)01225-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 19, 1997 6457
Sch em e 1
occur syn to the departing group. While syn substitution
has been commonly observed for both cyclic and acyclic
substrates,19,20 SN2′ substitutions are known to occur via
both syn and anti pathways depending on the substrate,
substrate substitution, nucleophile, and leaving group.19-21
The high degree of fidelity seen for the syn pathway in
these cases is noteworthy, especially in light of our prior
observation that ring closure of 8 to 5 proceeds with much
poorer facial discrimination (84:16 syn/ anti).2,8
Given the high stereoselectivity seen in the SN2′
cyclizations of 7 and related substrates and the unusual
solvent dependence, we attempted to determine the
mechanism of this process. When the base was changed
to KH or LDA, only deacylation products were observed,
even in toluene. Addition of 18-crown-6 to the anion
prepared from 7 using NaH in toluene at rt gave no ring
closure upon heating, giving unreacted 7 (short time) and
deacylation upon prolonged heating. Thus, it would
appear that both the malonate anion and the leaving
group must be associated with the counterion to observe
cyclization in the nonpolar medium. Within the geomet-
ric constraints, this outcome is consistent with previous
theoretical models.19,22 A preorganized complex such as
33 could account for the observed results, since such a
complex is geometrically constrained to afford only syn
Sch em e 2
substitution. Such a complex cannot as readily form in
the case of the lower homolog 8, and in this case,
cyclization may ensue from aggregates with less prefer-
ence for syn or anti substitution.23 Isolated examples of
highly stereoselective intramolecular SN2′ reactions of
carbon nucleophiles have been reported in which both
syn and anti substitution pathways have been ob-
served.19,21 The most closely analogous cases where both
syn and anti pathways are geometrically possible have
been considered to be proceding by such an associative
mechanism,24 although such counterion assistance in the
departure of the leaving group in alkylation reactions
carried out in nonpolar media has been invoked on
numerous occasions.23
Ta ble 1
Applications to the Laurencia group are in progress.
Ack n ow led gm en t. We are grateful to the NIGMS
and the NCI of the NIH for research grants (GM-29290,
GM-30345, and CA-29108) in support of these studies.
Thanks to Dr. J . Ramon Vargas for performing some of
the cyclization experiments involving 8.
afford the expected cyclobutane diesters (R)-(+)-26 and
(R)-(+)-27 in 72 and 78% yields, respectively (Table 1).
The cyclobutane diesters 23, 26, and 27 were smoothly
transformed to the dihydrooxacenes using our general
protocol.1 Reduction of 23, and 26, and 27 with LAH in
Et2O at 0 °C afforded the diols 28-30 in 84-95% yields.
Subsequent oxidation with 3 equiv of Dess-Martin
periodinane17 in CH2Cl2 buffered with 8 equiv of pyridine
afforded the dihydrooxacenes (R)-(+)-2, (R)-(+)-31, and
(R)-(+)-32 in 70-85% yields and >99% ee, indicating
complete chirality transfer as expected.1 The enantio-
meric purity of (R)-(+)-2, (R)-(+)-31, and (R)-(+)-32 were
established by NMR and GLC analysis of the Mosher
esters of the alcohols obtained by reduction of 2 and 31
and 32 with NaBH4.14,18
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for compounds 2, 7, 21-32
(12 pages).
J O9712254
(19) Magid, R. M. Tetrahedron 1980, 36, 1901. Altenbach, H.-J .
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 6, pp 830-832. March, J . Advanced Organic
Chemistry, 4th ed.; J . Wiley & Sons: New York, 1992; pp 327-330.
(20) Stork, G.; White, W. N. J . Am. Chem. Soc. 1959, 78, 4609. Stork,
G.; White, W. N. J . Am. Chem. Soc. 1956, 78, 4619.
(21) Schultz, A. G.; Godfrey, J . D.; Arnold, E. V.; Clardy, J . J . Am.
Chem. Soc. 1979, 101, 1276. Stork, G.; Kreft, A. F., III. J . Am. Chem.
Soc. 1977, 99, 3850, 3851.
The stereochemical outcome observed for the cycliza-
tions to 23, 26, and 27 requires that the SN2′ substitution
(22) Yates, R. L.; Epiotis, N. D.; Bernardi, F. J . Am. Chem. Soc.
1975, 97, 6615 and references therein.
(23) Williams, R. M.; Glinka, T.; Kwast, E. J . Am. Chem. Soc. 1988,
110, 5927. Martel, J .; Blade-Font, A.; Marie, C.; Vivat, M.; Toromanoff,
E.; Buendia, J . Bull. Soc. Chim. Fr. 1978, II-131. Martel, J .; Toro-
manoff, E.; Mathieu, J .; Nomine´, G. Tetrahedron Lett. 1983, 24, 2653.
(24) Caine, D. Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 3, pp 12-18.
(16) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
(17) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155.
(18) In contrast to the dihydrooxepines such as 3,1 reduction of the
formyldihydrooxacenes 2, 31, and 32 afforded only the dihydrooxacene
alcohols which were converted to the related Mosher ester for analysis.