Synthesis of medium ring ethers. 5. The synthesis of (±)-laurencin

Article abstract of DOI:10.1021/ja9709132

The enantioselective synthesis of (+)-laurencin 1 has been achieved in 27 steps from (R)-malic acid 20. The key steps involved methylenation of the lactone 49 followed by intramolecular hydrosilation of the enol ether 14 (Scheme 11) and one carbon homologation of the diol 13 to give the key ethyl substituted cyclic ether 59 (Scheme 13). The lactone 49 was obtained by two efficient routes, namely a Claisen ring expansion (Scheme 3) followed by cl-hydroxylation (Scheme 6) and a Yamaguchi lactonization (Scheme 11). Elaboration of the (E)-pentenynyl side chain (Scheme 18) and introduction of bromine (Scheme 19) completed the synthesis of (+)-laurencin 1.

Full text of DOI:10.1021/ja9709132

J. Am. Chem. Soc. 1997, 119, 7483-7498
7483
Synthesis of Medium Ring Ethers. 5. The Synthesis of
(+)-Laurencin
Jonathan W. Burton, J. Stephen Clark, Sam Derrer, Thomas C. Stork,
Justin G. Bendall, and Andrew B. Holmes*
Contribution from the Department of Chemistry, UniVersity Chemical Laboratory,
Lensfield Road, Cambridge CB2 1EW U.K.
ReceiVed March 21, 1997X
Abstract: The enantioselective synthesis of (+)-laurencin 1 has been achieved in 27 steps from (R)-malic acid 20.
The key steps involved methylenation of the lactone 49 followed by intramolecular hydrosilation of the enol ether
14 (Scheme 11) and one carbon homologation of the diol 13 to give the key ethyl substituted cyclic ether 59 (Scheme
13). The lactone 49 was obtained by two efficient routes, namely a Claisen ring expansion (Scheme 3) followed by
R-hydroxylation (Scheme 6) and a Yamaguchi lactonization (Scheme 11). Elaboration of the (E)-pentenynyl side
chain (Scheme 18) and introduction of bromine (Scheme 19) completed the synthesis of (+)-laurencin 1.
Introduction
and subsequent functionalization of the enol ether double
bond.8-12 Other notable approaches have been reported by
Murai,17 Overman,18-21 Palenzuela,22 Nicolaou23 and others,24-26
and these are summarized in a series of recent review articles.27-29
The eight-membered medium ring ether natural product (+)-
laurencin 1 is the prototypical member of a growing family of
marine natural product cyclic ethers isolated from red algae and
those marine organisms which feed on Laurencia species.
Laurencin was first isolated from L. glandulifera by Irie and
Masamune and co-workers.1,2 Its structure was assigned by
chemical degradation, spectroscopic analysis, and X-ray crystal-
lography,3,4 and the absolute configuration was determined by
the Prelog atrolactic acid method on a side-chain degradation
product. Racemic laurencin was synthesized by Masamune and
co-workers in an epic assault reported in the late 1970s.5-7 In
recent years we and a number of others have developed new
synthetic methodology to prepare medium ring ethers by ring
expansion methods. Our own approach has been based on ring
expansion reactions of cyclic ketones and vinyl-substituted
ketene acetals to produce, respectively, saturated8-12 and
unsaturated medium ring lactones13-16 which have been elabo-
rated to 2,n-disubstituted cyclic ethers by Tebbe methylenation
Results and Discussion
Synthesis of (+)-Octahydrodeacetyldebromolaurencin 2.
Our previous experience with the hydroboration of exocyclic
enol ethers derived from saturated eight-membered lactones
demonstrated a preference for the cis-2,8-disubstitution pat-
tern,11,12 but we needed unambiguous chemical confirmation
of the relative and absolute configuration of the products.
Octahydrodeacetyldebromolaurencin 21,2 offered an excellent
opportunity to synthesize a known degradation product of
laurencin, confirm the cis-disubstitution pattern, and assign the
absolute stereochemistry of the degradation product.9 The
Baeyer-Villiger, Tebbe methylenation, hydroboration strategy
has been well documented in previous publications.8-12 Scheme
1 summarizes the application of the route to the synthesis of 2.
X Abstract published in AdVance ACS Abstracts, July 15, 1997.
(1) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron Lett. 1965, 1091.
(2) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193.
(3) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. J.
Chem. Soc., Chem. Commun. 1965, 638.
(4) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Robertson, J. M. J.
Chem. Soc. (B) 1969, 559.
(5) Murai, A.; Murase, H.; Matsue, H.; Masamune, T. Tetrahedron Lett.
1977, 2507.
(6) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc. Jpn. 1979,
52, 127.
(7) Masamune, T.; Murase, H.; Matsue, H.; Murai, A. Bull. Chem. Soc.
Jpn. 1979, 52, 135.
(8) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1986,
565.
(17) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345.
(18) Blumenkopf, T. A.; Bratz, M.; Castan˜eda, A.; Look, G. C.; Overman,
L. E.; Rodriguez, D.; Thompson, A. S. J. Am. Chem. Soc. 1990, 112, 4386.
(19) Blumenkopf, T. A.; Look, G. C.; Overman, L. E. J. Am. Chem.
Soc. 1990, 112, 4399.
(9) Clark, J. S.; Holmes, A. B. Tetrahedron Lett. 1988, 29, 4333.
(10) Carling, R. W.; Curtis, N. R.; Holmes, A. B. Tetrahedron Lett. 1989,
30, 6081.
(11) Carling, R. W.; Clark, J. S.; Holmes, A. B. J. Chem. Soc., Perkin
Trans. 1 1992, 83.
(12) Carling, R. W.; Clark, J. S.; Holmes, A. B.; Sartor, D. J. Chem.
Soc., Perkin Trans. 1 1992, 95.
(13) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1986,
325.
(20) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110,
2248.
(21) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am.
Chem. Soc. 1995, 117, 5958.
(22) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J. A. Synlett
1996, 983.
(23) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589.
(24) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 916.
(25) Isobe, M.; Hosokawa, S.; Kira, K. Chem. Lett. 1996, 473.
(26) Gre´e, D. M.; Martelli, J. T.; Gre´e, R. L. J. Org. Chem. 1995, 60,
2316.
(14) Curtis, N. R.; Holmes, A. B.; Looney, M. G. Tetrahedron 1991,
47, 7171.
(15) Congreve, M. S.; Holmes, A. B.; Hughes, A. B.; Looney, M. G. J.
Am. Chem. Soc. 1993, 115, 5815.
(16) Fuhry, M. A. M.; Holmes, A. B.; Marshall, D. R. J. Chem. Soc.,
Perkin Trans. 1 1993, 2743.
(27) Moody, C. J.; Davies, M. J. In Studies in Natural Product Chemistry;
Atta-ur-Rahman, Ed.; Elsevier Science: 1992; Vol. 10, pp 201-239.
(28) Elliott, M. C. Contemp. Org. Synth. 1994, 1, 457.
(29) Rousseau, G. Tetrahedron 1995, 51, 2777.
S0002-7863(97)00913-X CCC: $14.00 © 1997 American Chemical Society

7484 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Burton et al.
Scheme 1. Synthesis of Octahydrodeacetyldebromolaurencin
(R)-2-Ethylcycloheptanone 5 was prepared by Enders30,31 alky-
lation of the azaenolate derived from the SAMP-hydrazone 3.
The alkylation product 4 was obtained with a de of 90% [1H
NMR, 90 MHz, Eu(fod)3] and was converted into 5 by
ozonolysis. The Baeyer-Villiger oxidation was carried out by
addition of the ketone 5 to a buffered solution of trifluoroper-
acetic acid in order to minimize racemization. Tebbe methyl-
enation, followed by hydroboration with the bulky diisoamyl-
borane, afforded only one diastereoisomeric alcohol which was
subsequently shown to be the cis-product 8. This was oxidized
with PCC, and the resulting aldehyde was treated with pentyl-
magnesium bromide at 0 °C to afford a 1.5:1 mixture of the
alcohols 2 and 9, favoring the required material. Attempts to
improve selectivity by chelation control using magnesium
bromide or mixed cuprates such as pentylcoppermagnesium
iodide or bromide were unsuccessful.32,33 Oxidation of the
diastereoisomeric mixture 2 and 9 gave the ketone 10 which
was reduced diastereoselectively with L-Selectride in a Felkin-
Anh sense to afford exclusively the octahydrodeacetyldebro-
molaurencin 2. This exhibited a specific rotation [R]D21 +19.6
(c 1.52, CHCl3) and was identical in all respects (TLC, 1H NMR,
a related molecule, laurenyne,35 had to be revised after its total
synthesis by Overman.20
Previous Syntheses of 1. The first enantioselective synthesis
of (+)-laurencin was reported by Murai and co-workers and
relied on a novel ring expansion reaction of a four-membered
ring fused to a tetrahydropyran.17 The resulting lactone was
elaborated to the key intermediate 12 (P ) TBS) (see Scheme
2) which serves as a natural focus for the ring synthesis.
Overman and colleagues described the second enantioselective
synthesis of laurencin using their intramolecular oxacarbenium
ion cyclization procedure.21 This was followed by Palenzuela’s
formal synthesis involving an intramolecular alkylation of an
R-lithiosulfone.22 It is noteworthy that the latter two syntheses
demonstrated that ring closure of unconstrained acyclic precur-
sors to eight-membered ring ethers is entirely feasible under
certain circumstances.24-26
Retrosynthetic Analysis of 1. The purpose of this paper is
to report our own synthesis of (+)-laurencin36 and to demon-
strate some interesting aspects of the functionalization of eight-
membered lactones. The retrosynthetic analysis of laurencin
(Scheme 2) depends on the late introduction of bromine by
displacement with inversion of configuration of the correspond-
ing alcohol 11, a process which has precedent from all the earlier
reported syntheses. The introduction of the pentenynyl side
chain was planned by alkylation of the aldehyde 12. The
synthesis of the medium ring 2,8-disubstituted tetrahydro-oxocin
13 relied on elaboration of the corresponding lactone precursor
15 by methylenation and enol ether 14 functionalization.
Considerable previous experience encouraged us to prepare the
lactone 16 by [3,3]-sigmatropic rearrangement of the vinyl-
substituted ketene acetal 17 which was to be generated in situ
by selenoxide elimination of the precursor 18. The synthesis
therefore relied on a preparation of the triol derivative 19 from
(R)-malic acid 20. In the event this strategy was realized. An
alternative approach to 15 by an intramolecular ring closure
(lactonization) has also been developed. Furthermore, we have
18
13C NMR, IR, MS) with an authentic sample [R]D +21.6 (c
1.86, CHCl3).1,2,34 The enantiomeric purity of 2 could not be
assayed by the Mosher ester method, but based on the specific
rotation it was judged to be of 91% ee. The highly diastereo-
selective reduction of the side-chain carbonyl group has
subsequently been applied by Murai17 and by us in the synthesis
of (+)-laurencin 1 itself. The synthesis of (+)-2 based on the
well precedented Enders method for preparing (R)-5 indepen-
dently establishes the absolute configuration of (+)-1. This is
an important correlation because although the absolute config-
uration had previously been determined by X-ray methods, the
previous assignment by X-ray of the absolute configuration of
(30) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933.
(31) Enders, D.; Frey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173.
(32) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. Tetrahedron Lett. 1986,
27, 4011.
(33) Sato, F.; Kobayashi, Y.; Takahashi, O.; Chiba, T.; Takeda, Y.;
Kusakabe, M. J. Chem. Soc., Chem. Commun. 1985, 1636.
(34) Authentic 2 was kindly supplied by Dr A. Fukuzawa, who degraded
natural (+)-laurencin 1 to obtain the sample.
(35) Falshaw, C. P.; King, T. J.; Imre, T. J.; Islimyeli, S.; Thomson, R.
H. Tetrahedron Lett. 1980, 21, 4951.
(36) Burton, J. W.; Clark, J. S.; Bendall, J.; Derrer, S.; Stork, T.; Holmes,
A. B. J. Am. Chem. Soc. 1996, 118, 6806.

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7485
Scheme 2. Retrosynthesis of (+)-Laurencin 1
Oxidation of the selenides 25 to the selenoxides 18, followed
by selenoxide elimination in refluxing xylene in the presence
of DBU is presumed to have generated the intermediate vinyl-
substituted ketene acetal 17 which underwent [3,3]-sigmatropic
rearrangement to the lactone 16 in good yield. The fact that
high yields were consistently obtained for this rearrangement
is indirect evidence that both diastereoisomeric ketene acetals
rearranged almost equally well. 1H NMR analysis of a later
intermediate, the hydroxy lactone 15 (J5,6 ) 11.0 Hz) indicated
that the lactone 16 contained a cis-double bond. Such Claisen
ring expansions were first used by Petrzilka41 to prepare a 10-
membered lactone. We have used this procedure to obtain
seven-, eight- and nine-membered lactones, and almost without
exception the (Z)-alkene is produced in the smaller rings.13-16
However we have seen occasional exceptions, and a recent
example reported by Pearson also yielded a nine-membered
lactone with mainly the (E)-double bonded product.42 In the
synthesis of the lactone 16 the results are consistent with the
involvement of all chair-like transition states (Figure 2) for the
1,3-anti diol-derived precursor TS1, while the 1,3-syn-diol
precursor is able to invert one of the rings to a less hindered
conformation TS2 to relieve the strain arising from the OTPS
substituent.
Conversion of the Lactone 16 into a 2,8-Disubstituted
Tetrahydrooxocin. Methylenation of the racemic lactone (()-
16 with the Tebbe reagent43,44 gave the enol ether 26 in good
yield (Scheme 4). The conformational rigidity owing to the
presence of the endocyclic double bond in 26 meant that it was
sufficiently stable to be chromatographed on silica gel in the
presence of triethylamine and a suitable solvent. All attempts
at hydroborating the enol ether 26 with a variety of organobo-
ranes were uniformly unsuccessful. Either the exocyclic double
bond resisted attack, or under more forcing conditions ring-
opening of the intermediate organoborane occurred together with
competing hydroboration of the endocyclic double bond. It was
therefore decided to attempt phenylselenoacetalization of the
enol ether, according to well established precedent for simple
enol ethers.41 The enol ether 26 reacted efficiently with
benzeneselenenyl chloride in methanol in the presence of
triethylamine to give a 6:1 mixture of methoxy acetals 27a and
27b. The relative stereochemistry of these isomers was not
assigned, but precedent would suggest that the major isomer
was 27a, because most examples of nucleophilic attack on eight-
membered oxacarbenium ions favor the incoming reagent being
trans to existing substituents.8-12 In keeping with this observa-
tion, reduction of the major methoxy-acetal with alane afforded
mainly the cis-phenylselenomethyl derivative 28a plus a trace
of the trans-isomer 28b; the harsh reducing conditions resulted
in cleavage of the silyl protecting group. These were each
converted into the corresponding 3,5-dinitrobenzoates 29a and
29b, respectively. The major product formed crystals suitable
for X-ray structure determination, and the structure is shown
in Figure 3.45
found two different methods of elaborating the lactone 16 to
2,8-disubstituted oxocane derivatives.
Claisen Route to the Lactone 16. The optimum route to
the lactone 16 was developed from our racemic synthesis
(Scheme 3).13 (R)-Malic acid 20 was esterified37 and selectively
reduced38,39 to the diol 21 which was protected as the acetonide
22. Reduction of the ester 22 with DIBAL-H at low temperature
to minimize acetonide cleavage, followed by addition of
vinylmagnesium chloride to the aldehyde 23 in the presence of
thoroughly dried cerium(III) chloride,40 afforded the allylic
alcohol 24. Vinylmagnesium bromide will also add to the
aldehyde 23, but the reagent becomes less efficient with age,
and the most reproducible yields of 24 are obtained with
vinylmagnesium chloride. The allylic alcohol 24 was obtained
as an approximate 1:1 mixture of diastereoisomers, both of
which appeared to undergo the subsequent Claisen rearrange-
ment without difficulty, and the mixture was always carried
through the synthesis without separation of the isomers. Ac-
etonide hydrolysis followed by selective silylation of the primary
alcohol afforded the TPS ether 19 which was converted with
phenylselenoacetaldehyde diethyl acetal41 into the mixture of
acetals 25. No attempt was made to separate these isomers,
but the spectroscopic evidence from a number of investigations
would imply that the major isomers present were 25a, 25b, and
25c (Figure 1).
This is the first crystal structure of a synthetic ∆5,6-2,8-
disubstituted-tetrahydro-2H-oxocin.26 An examination of the
ring conformation of 29a showed that it represents a global
minimum characteristic of the ring conformation of the eight-
(42) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546.
(43) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(44) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem.
Soc. 1980, 102, 3270.
(37) Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933.
(38) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu,
S.; Moriwake, T. Chem. Lett. 1984, 1389.
(39) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067.
(40) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(45) Compound 29a, C22H22O7Se, MW 505.39, was obtained as yellow
crystals, space group P1h (No. 2), a ) 8.574(1) Å, b ) 11.434(1) Å, c )
12.702(1) Å, R ) 114.14(1)°, â ) 92.33(1)°, γ ) 103.39(1)°, V ) 1092.6
Å3, Z ) 2, Dcalcd ) 1.54 g cm-3, F(000) ) 516, λ (Cu KR) 1.5418 Å, µ
(41) Petrzilka, M. HelV. Chim. Acta 1978, 61, 3075.
(Cu KR) 27.67 cm-1
.

7486 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Scheme 3. Synthesis of the Lactone 16
Burton et al.
Scheme 4. Elaboration of the Lactone 16
Figure 1. Diastereoisomeric acetals 25.
Figure 2. Claisen transition states.
membered unsaturated Laurencia metabolites laurencin3,4 1,
trans-pinnatifidenyne46 30, and bermudenynol47 31 (Figure 4).
The cis-phenylselenomethyl derivative 28a was protected and
then readily transformed by Pummerer rearrangement into the
R-acetoxy derivative 32 and then by reduction into the hy-
droxymethyl derivative 33 (Scheme 5). This sequence therefore
established an alternative to hydroboration for the conversion
of enol ethers into functionalized eight-membered ring ethers.
r-Hydroxylation of the Lactone 16. Before applying a
methylenation sequence to the laurencin precursor itself it was
necessary to introduce an R-hydroxyl substituent adjacent to
the lactone carbonyl group of 16 in anticipation of the need
ultimately to replace this substituent by bromine at the end of
the synthesis. We were attracted to the possibility of using the
Davis oxaziridine reagents to oxidize the lactone enolate
diastereoselectively.48
Formation of the potassium enolate derived from the lactone
16, as a solution in THF at -78 °C followed by addition of
trans-(()-2-(phenylsulfonyl)-3-phenyloxaziridine 3449,50 gave
the hydroxy lactones 15 and 35 as a 1:1 mixture of diastereo-
isomers in 22% yield (Scheme 6).
(46) Gonza´lez, A. G.; Mart´ın, J. D.; Mart´ın, V. S.; Norte, M.; Pe´rez, R.;
Ruano, J. Z.; Drexler, S. A.; Clardy, J.Tetrahedron 1982, 38, 1009.
(47) Cardellina II, J.; Horsley, S. B.; Clardy, J.; Leftow, S. R.; Meinwald,
J. Can. J. Chem. 1982, 60, 2675.
(48) Davis, F. A.; Chen, B. C. Chem. ReV. 1992, 92, 919.

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7487
Scheme 5. Pummerer Rearrangement of 28a
Figure 4. Chem3D representations of the crystal structures of the
dinitrobenzoate 29a, laurencin 1, trans-pinnatifidenyne 30, and ber-
mudenynol 31 taken from the Cambridge Crystallographic Database
to show the comparison of the oxocane ring conformation (viewed along
the 3-C-4-C bond). For clarity, the side chains have been deleted from
all the models.
Scheme 6. Enolate Hydroxylation of 16
4.61, m, 1H); irradiation of the signal due to 3-H did not lead
to enhancement of 8-H. These experiments indicated that 3-H
and 8-H were in a trans-relationship. Molecular modeling
(Monte Carlo conformational search54 using the MM2 force
field55 in MacroModel version 5.556) provided a unique global
minimum conformation for the analogous lactone 35a. This
model fitted the NOE data very well and indicated that 8-H
and 6-H were in close proximity (3.31 Å apart).
Figure 3. The X-ray crystal structure of the dinitrobenzoate 29a.
Reaction of a THF solution of the potassium enolate derived
from the lactone 16 with 1(R)-(-)-(10-camphorsulfonyl)-
oxaziridine 37 at -78 °C provided the hydroxy lactones 15 and
35 as a 5.3:1 mixture of diastereoisomers (11%). The structure
of the 3(R)-alcohol 15 was established Via 1D gradient NOE
measurements51,52 which fit well with the results obtained from
molecular modeling of the analogous lactone 15a (Figure 6).
In particular strong reciprocal NOEs were observed in the H
NMR spectra between the signals due to 3-H (δ 4.40-4.36, m,
1H) and 8-H (δ 4.62, m, 1H).
Performing the above experiments using toluene as the solvent
provided the hydroxy lactones in reasonable yield (see Table
1). The desired 3(R)-alcohol 15 could be obtained in an
optimum yield of 26% (entry 9) but not as the exclusive product.
We have subsequently shown that both 15 and 35 could, in
principle, be employed in a synthesis of laurencin, but alternative
higher yielding routes to 15 became desirable.
The selectivities observed in the above reactions are hard to
account for and do not appear to fit the recent model put forward
by Bach and Davis57 for oxidation of ketone enolates using the
chlorocamphorsulfonyl oxaziridine 38. We relied, in part, on
The poor selectivity indicated that the remote CH2OTPS
substituent in the enolate derived from 16 provided insufficient
conformational bias to favor the required 3(R)-alcohol 15 for
the proposed synthesis of (+)-laurencin. It was clear that
reagent control would be required to control the diastereose-
lectivity of attack. Davis48 has advocated the use of the (10-
camphorsulfonyl)oxaziridines 36 and 37 to perform diastereo-
selective enolate oxidations. The use of 36 in THF at -78 °C
with the potassium enolate derived from 16 afforded only the
3(S)-alcohol 35 in 7% yield. The configuration of the 3(S)-
alcohol 35 was rigorously established Via 1H NMR 1D gradient
NOE measurements51,52 (Figure 5) and Mosher ester analysis53
(see Supporting Information). Irradiation of 8-H (δ 4.82-4.78,
m, 1H) led to an enhancement of the signal due to 6-H (δ 5.82,
dt, J ) 11.0, 7.7, 1H) but no enhancement of 3-H (δ 4.64-
1
(49) Davis, F. A.; Stringer, O. D. J. Org. Chem. 1982, 47, 1774.
(50) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth. 1988,
66, 203.
(54) Chang, G.; Guida, W. C.; Still, W. C. J. Am. Chem. Soc. 1989,
111, 4379.
(51) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am. Chem.
Soc. 1994, 116, 6037.
(52) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A. J. J.
Am. Chem. Soc. 1995, 117, 4199.
(55) Allinger, N. L. J. Am. Chem. Soc. 1977, 99, 8127.
(56) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput.
Chem. 1990, 11, 440.
(53) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
(57) Bach, R. D.; Andre´s, J. L.; Davis, F. A. J. Org. Chem. 1992, 57,
613.

7488 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Burton et al.
Scheme 7. Retrosynthesis of the Lactone 15
Figure 5. Chem3D representation of the global minimum conformation
(Macromodel, MM2 force field, Monte Carlo conformational search)
of 35a (TPS group modeled as TMS group) analogous to the hydroxy
lactone 35 and 1D gradient NOE data for 35.
Scheme 8. Synthesis of the Phosphonium Salt 40
Scheme 9. Synthesis of the Aldehyde 41
Scheme 10. Synthesis of the seco-Acid 39
Figure 6. Chem3D representation of the global minimum conformation
(MacroModel, MM2 force field, Monte Carlo conformational search)
of 15a (TPS modeled as TMS group) analogous to the hydroxy lactone
15 and 1D gradient NOE data for 15.
Table 1. Oxidation of the Enolate Derived from 16
yield 15
and 35
ratio
15:35
entry solvent oxaziridine
base
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
toluene
toluene
toluene
34
36
37
36
36
36
34
36
37
KHMDS
KHMDS
KHMDS
LiHMDS
LDA
NaHMDS
KHMDS
KHMDS
KHMDS
22
7
11
trace
trace
20
64
65
1:1
4.5:95.5
5.3:1
nda
nda
nda
1:4
1:2
1:1
52
a Not determined is abbreviated as nd.
the previous model put forward by Davis for ketone enolates
in our original incorrect assignment of the structure of 15,
although one reported example of a lactone enolate hydrox-
ylation does seem more consistent with our own findings.48
Therefore we conclude that the application of this model to
chiral lactone enolates should be exercised with caution. Given
that our original hydroxy lactone was compound 35 and not
15, we concluded that we could not have synthesized laurencin;
the original paper was therefore withdrawn, and the synthetic
sequence was repeated using authentic 15.36 The alternative
route to 15 is described below.
We note in passing that the major byproduct from the
oxaziridine oxidations was the ring opened hydroxy acid,
suggesting that the involvement of ketene intermediates may
well explain the poor yields of hydroxy lactones isolated.
Yamaguchi Lactonization Route to the r-Hydroxy Lac-
tone 15. The recent promising advances in ring closure of seco-
acids to eight-membered lactones58 suggested the direct lac-
tonization of the hydroxy acid 39. The cis-double bond in 39
implies a Wittig disconnection to provide the phosphonium salt
40 and the aldehyde 41, both available from (R)-malic acid 20
(Scheme 7).
The known bromide 4259-61 was treated with molten tri-
phenylphosphine under lithium iodide catalysis to provide the
phosphonium salt 40 which could be crystallized by sonication
with ether (Scheme 8).
The aldehyde 41 was prepared by ethanolysis of the known
BOM-protected lactone 4362 and Swern oxidation63 of the
resulting primary alcohol (Scheme 9).
Wittig reaction of the ylid derived from the phosphonium
salt 40 (BuLi, THF, -78 °C to 0 °C) with the aldehyde 41
(59) Mori, K.; Watanabe, H. Tetrahedron Lett. 1984, 25, 6025.
(60) Barth, M.; Bellamy, F. D.; Renaut, P.; Samreth, S.; Schuber, F.
Tetrahedron 1990, 46, 6731.
(61) Meyers, A. I.; Lawson, J. P.; Walker, D. G.; Linderman, R. J. J.
Org. Chem. 1986, 51, 5111.
(62) Collum, D. B.; McDonald III, J. H.; Still, W. C. J. Am. Chem. Soc.
1980, 102, 2118.
(58) Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994, 116,
5511.
(63) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480.

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7489
provided the alkene 44 (73%) (Scheme 10). The geometry of
the alkene 44 was assigned as (Z) according to precedent and
was later confirmed by the measurement of a 10.9 Hz coupling
between 5-H and 6-H in the lactone 47. A small quantity of
the dienes [predominantly the 2(E),4(Z) isomer 45, J2,3 ) 15.3
Scheme 11. Yamaguchi Lactonization and Hydrosilation
Studies
Hz, J4,5 ) 10.9 Hz] was obtained from the Wittig reaction (the
structure of the minor geometrical isomer could not be proved).
Standard protecting group manipulations on the alkene 44
provided the lactonization precursor 39 in good overall yield.
Corey-Nicolaou64-66 lactonization of the seco-acid 39 gave
the required lactone 47 in moderate yield. However, 47 could
be prepared in excellent yield using the Yamaguchi lactonization
conditions (Scheme 11).67,68 A small quantity of the nine-
membered lactone 46 (ratio 47:46, 10:1) was also obtained,
owing to silyl group migration from primary to secondary
hydroxyl groups before lactonization. The nine-membered
lactone 46 was not separated at this stage but was removed by
flash chromatography of a later intermediate. Deprotection of
69
the BOM ether from the lactones 46 and 47 with BCl3‚SMe2
afforded the corresponding hydroxy lactones from which 15
could be separated by HPLC for analytical purposes. The
hydroxy lactone 15 synthesized Via the seco-acid 39 was
identical to the major diastereoisomer formed by Davis oxidation
of the potassium enolate of the lactone 16 with the oxaziridine
37 (Table 1, Entry 3). Trimethylsilylation of the hydroxy
lactones allowed quantitative separation of the nine-membered
lactone 48 by flash chromatography.
Methylenation and Intramolecular Hydrosilation Studies.
Methylenation of the eight-membered lactone 49 with the Petasis
reagent,70,71 which is more convenient to prepare than Tebbe’s
reagent,43 gave the enol ether 50 which was converted into the
silane 14 (Scheme 11).72 The intramolecular hydrosilation of
acyclic enol ethers has been developed by Tamao73 and has
subsequently been exploited by us in an approach to the nine-
membered cyclic ether obtusenyne.74 The key intramolecular
hydrosilation reaction of 14 was carried out with the catalyst
bis(1,3-divinyl-1,1,3,3-tetramethyldisiloxane)platinum(0)
[Pt(DVS)2].75-77 This reagent has been shown to operate Via a
mechanism that involves reduction of the ligands on platinum
followed by the formation of colloids which then act as the
catalyst for the reaction.78,79 The best result obtained in the
hydrosilation of 14 involved the portionwise addition of 8 mol
% of the catalyst (0.1 M in toluene) to the neat silane 14 under
an atmosphere of dry air, followed by oxidation with basic
hydrogen peroxide.72,77 This provided the diols 13 and 51 as a
58:42 mixture in 86% yield. However, the reaction was
capricious and generally favored the trans-isomer 51. Although
control of the stereochemistry of the hydrosilation of 14 is a
highly desirable objective, we have been able to use both 13
and 51 in the present route to (+)-laurencin (Vide infra). Larger
scale hydrosilation reactions (860 µmol, see Experimental
Section) provided the diols in substantially lower yield, which
may be due to the development of oxygen deficiency which
results in irreversible colloid agglomeration and a consequent
loss of catalytic activity.78
Conversion of the diols 51 and 13 into the corresponding
p-methoxybenzylidene acetals 52 and 53 allowed assignment
of the stereochemistry at 2-C and 3-C. The acetal 52, derived
from the trans-diol 51, exhibited a 9.0 Hz coupling constant
between 3-H and 2-H in the 1H NMR spectrum, which is
consistent with a trans-diaxial relationship between 2-H and
3-H in a six-membered ring, whereas the acetal 53, derived from
the cis-diol 13 exhibited a 2.0 Hz coupling constant between
3-H and 2-H. This is consistent with an axial-equatorial
coupling in a six-membered ring. Other coupling constants were
(64) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
(65) Corey, E. J.; Brunelle, D. J.; Stork, P. J. Tetrahedron Lett. 1976,
38, 3405.
(66) Gerlach, H.; Thalmann, A. HelV. Chim. Acta 1974, 57, 2661.
(67) Inanaga, J.; Hirata, K.; Hiroko, S.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(68) Mulzer, J.; Kirstein, H. M.; Buschmann, J.; Lehmann, C.; Luger,
P. J. Am. Chem. Soc. 1991, 113, 910.
(69) Congreve, M. S.; Davison, E. C.; Fuhry, M. A. M.; Holmes, A. B.;
Payne, A. N.; Robinson, R. A.; Ward, S. E. Synlett 1993, 663.
(70) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(71) Petasis, N. A.; Lu, S. P.; Bzowej, E. I.; Fu, D. K.; Staszewski, J.
P.; Akritopoulou-Zanze, I.; Patane, M. A.; Hu, Y. H. Pure Appl. Chem.
1996, 68, 667.
(72) Tamao, K.; Nakagawa, Y.; Arai, H.; Higuchi, N.; Ito, Y. J. Am.
Chem. Soc. 1988, 110, 3712.
(73) Tamao, K.; Nakagawa, Y.; Ito, Y. Organometallics 1993, 12, 2297.
(74) Curtis, N. R.; Holmes, A. B. Tetrahedron Lett. 1992, 33, 675.
(75) Karstedt, B. D. (General Electric Co.), U.S. Appl. 226,928, 16 Feb
1972. Chem. Abstr. 1974, 80, P16134j.
(76) Karstedt, B. D. (General Electric Co.), Ger. Offen., 2,307,085, 23
Aug 1973. Chem. Abstr. 1974, 80, P16134j.
(77) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694.
(78) Lewis, L. N. J. Am. Chem. Soc. 1990, 112, 5998.

7490 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Burton et al.
Scheme 12. Organocuprate Studies
Scheme 13. Organocuprate Studies
Figure 7. Chem3D representations of the ground state conformations
(MacroModel, MM2 force field, Monte Carlo conformational search)
of 53a and 52a (TPS group modeled as TMS group) analogous to 53
and 52 with predicted coupling constants from Macromodel and
1
coupling constants measured by 500 MHz H NMR for 53 and 52.
also in good agreement with those predicted Via computer
modeling (Figure 7).
Introduction of the Ethyl Side Chain. For the synthesis
of (+)-laurencin it was necessary to convert the hydroxymethyl
group of 13 into an ethyl substituent. This could be achieved
by displacement of a sulfonate ester with an organocuprate. The
monotosylate 54 (Scheme 12), formed from the diol 13, showed
a large cross-peak between 2-H and 8-H in the 1H NMR NOESY
spectrum, lending strength to the structural assignment for the
cis-diol 13 given above. However, treatment of 54 with Me2-
CuCNLi2 afforded the oxetane 55 (85%) and not the required
ethyl-substituted oxocane 56 (Scheme 12). Formation of 55
further demonstrates the cis-relationship of 2-H and 3-H. The
oxetane 55 failed to react with methyllithium in the presence
of BF3‚OEt2 to afford 5680 and therefore it was necessary to
protect the 3-hydroxyl group to prevent intramolecular cycliza-
tion.
Me2CuLi in an ether/benzene solvent system82 provided the
required ethyl-substituted oxocane 59 in 19% yield. Reaction
of the corresponding triflate 60 under the same conditions
provided 59 in an improved 60% yield. If benzene was omitted
from these reactions, then no product was observed. This
observation can probably be attributed to solvation of the PMB
group of 58 and 60 by benzene, which allows reaction to occur.
Use of the more reactive Me2CuCNLi2 in the above reactions
provided substantial amounts of the alcohol 57 arising Via attack
of the organocuprate at sulfur. Removal of the silyl protecting
group followed by tetrapropylammonium per-ruthenate(VII)
Cleavage of the previously formed acetal 53 with DIBAL-
H81 afforded the primary alcohol 57 which was converted into
the corresponding tosylate 58 (Scheme 13). Reaction of 58 with
(79) Lewis, L. N.; Lewis, N. J. Am. Chem. Soc. 1986, 108, 7228.
(80) Elis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. Soc. 1984, 106,
3693.
(82) Pougny, J. R. Tetrahedron Lett. 1984, 25, 2363.
(83) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(81) Schreiber, S. L.; Wang, Z.; Schulte, G. Tetrahedron Lett. 1988, 29,
4085.

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7491
Scheme 15. Model Side Chain Studies
Scheme 14. Epimerization Studies
This result is in contrast to the work of Yamamoto who
demonstrated complete retention of alkene geometry for allyl-
ations involving a large number of allylbarium reagents; the
reason for the loss of stereochemistry is not clear. The
ultimately successful strategy for side-chain introduction in-
volved a samarium(II) iodide Barbier-type reductive coupling
reaction.17,88 The reaction was first tested on some model
oxocanes. Treatment of the racemic aldehydes 749 or 7511 with
the bromide 6989 in the presence of samarium(II) iodide provided
the corresponding alcohols 76 and 77 and 78 and 79 as 1:1
mixtures of diastereoisomers in 68% and 71% yield, respectively
(Schemes 16 and 17).
The structural assignment of all these products is discussed
below. Similarly, reaction of 61 with 69 in the presence of
samarium(II) iodide provided the alcohols 70 and 71 as a 1:1
mixture of diastereoisomers in 63% yield (Scheme 18).
The geometry of the side-chain alkene was confirmed by
coupling constant analysis (for 70 J3′,4′ ) 15.9 Hz, for 71 J3′,4′
) 16.0 Hz). However, a small amount of the (Z)-enyne side
chain was also observed in all the unpurified reaction mixtures
(for 72 J3′,4′ ) 10.9 Hz), along with the side-chain dimer 73
arising from cross-coupling of the side-chain bromide 69. In
all reactions no control of the newly formed stereocenter could
be realized, as expected from the synthesis of octahy-
drodeacetyldebromolaurencin 2.
(TPAP) oxidation83,84 gave the aldehyde 61 in good yield in
readiness for introduction of the pentenynyl side chain.
In order to make use of the trans-diol 51 in the synthesis of
(+)-laurencin it was necessary to epimerize the 2-C stereocenter
(Scheme 14). Treatment of the trans-diol 51 under standard
tosylation conditions provided the monotosylate 62 (46%) along
with starting material (43%). Reaction of the tosylate 62 with
Me2CuCNLi2 in ether gave the ethyl-substituted product 63.
TPAP oxidation83,84 of 63 afforded the ketone 64 in good yield
(85%). Epimerization at 2-C was then accomplished by
treatment with potassium carbonate in methanol providing the
desired 2-C epimer 65 (71%). This epimerization is precedented
from the work of Murai17 and Palenzuela.22 Reduction of the
ketone 65 with L-Selectride in THF17 followed by PMB
protection afforded the oxocane 59, identical to that previously
synthesized, indicating that the reduction had occurred in the
expected sense.17,22
Introduction of the Pentenynyl Side Chain. All that
remained for the synthesis of (+)-laurencin was the introduction
of the unsaturated side chain and replacement of the 3-C oxygen
with bromine. The proposed route for introduction of the
unsaturated side-chain involved the addition of a pentenynyl
anion to the corresponding aldehyde 61. A large number of
model studies were conducted in order to realize this plan. For
example, reaction of the pentenynyl chloride 6685 with barium
metal, formed by the reduction of barium(II) iodide, followed
by addition of hexanal yielded the (E)-67 and (Z)-alkenes 68
as a 1:1.5 mixture in 48% overall yield (Scheme 15).86,87
Octahydrodeacetyldebromolaurencin 2 and the 1′-epimer 9
exhibited two major distinguishing features in the H NMR
spectrum; in the 1′(R)-alcohol 2 the three hydrogens next to
oxygen appeared as a single multiplet [δ 3.42-3.27 (m, 3H, 2
× CHOR, CH1′OH)] and the OH resonance was broad [δ 2.71
(br, 1H, OH)]. For the 1′(S)-alcohol 9 the hydrogens next to
1
(84) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625.
(85) This reagent was prepared from (E)-pent-2-en-4-yn-1-ol; (a) BuLi,
TMSCl, THF then HCl (93%); (b) Me2S, N-chlorosuccinimide, CH2Cl2
(80%).
(88) Souppe, J.; Namy, J. L.; Kagan, H. B. Tetrahedron Lett. 1982, 23,
3497.
(86) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am. Chem. Soc. 1991,
113, 8955.
(87) Yanagisawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H. J. Am. Chem.
Soc. 1994, 116, 6130.
(89) This reagent was prepared from (E)-5-trimethylsilylpent-2-en-4-yn-
1-ol,85 (CH3)2NC(Br)dC(CH3)2, CH2Cl2 (58%); Bendall, J. G.; Payne, A.
N.; Screen, T. E. O.; Holmes, A. B. J. Chem. Soc., Chem. Commun. 1997,
1067.

7492 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Scheme 16. Barbier-Type Coupling
Burton et al.
Scheme 17. Barbier-Type Coupling
Scheme 18. Side-Chain Introduction
oxygen appeared as two separate multiplets [δ 3.60-3.56 (m,
1H, CHOR) and 3.41-3.35 (m, 2H, CHOR, CH1′OH)], and
the OH resonance was also broad [δ 2.04-2.03 (br, 1H, OH)].
Each diastereomer of the three pairs synthesized by the
samarium(II) iodide mediated reductive coupling fitted the
pattern of spectral data observed for octahydrodeacetyldebro-
molaurencin 2 and its 1′-epimer 9. For one of the pair, the two
protons R to the oxocane oxygen and the CH1′OH appeared as
an overlapping multiplet (approximately δ 3.55-3.30), and the
OH appeared in the range δ 2.80-2.60. For the other, the two
protons R to the oxocane oxygen and the CH1′OH appeared as
distinct multiplets, and the OH appeared at higher field
(approximately δ 2.20-2.00) (see tables). The OH signal was
well defined in these cases, suggesting that it may be involved
in an intramolecular hydrogen bond with the oxocane oxygen,
which fixes the ring conformation and produces chemical shifts
indicative of the side-chain alcohol configuration. The structural
assignment of all these alcohols was therefore made on the basis
of the 1H NMR chemical shift of the OH proton and, to a lesser
extent, on the shift of the protons R to oxygen. It was also
found that the 1′(R)-alcohols were all less polar than the
corresponding 1′(S)-alcohols.
Following the precedent observed for octahydrodeacetylde-
bromolaurencin 2, recycling of the 1′(S)-alcohol 71 was achieved
by oxidation with the Dess-Martin reagent90-92 to give the
corresponding ketone in good yield; this was reduced with
L-Selectride to yield the 1′(R)-alcohol 70 as the sole product
(as judged by 250 MHz 1H NMR) in accordance with previous
experience.9,17 The best procedure required separation of the
alcohols 70 and 71 by HPLC, followed by the oxidation/
(90) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(91) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(92) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7493
was freeze-thaw degassed (three cycles) and cooled to -78 °C.
Butyllithium (10.3 cm3 of a 1.6 M solution in hexanes, 16.5 mmol)
was added dropwise over a period of 5 min causing the reaction mixture
to change from colorless to dark red. The reaction mixture was stirred
at this temperature for 5 min after which the cooling bath was removed,
and the reaction mixture was allowed to warm to room temperature
and was stirred for 1 h whereupon nearly all the salt had dissolved.
The reaction mixture was recooled to -78 °C, and a concentrated
solution of the aldehyde 41 (2.21 g, 8.30 mmol) in THF (9 cm3, 3 cm3
rinse) (obtained by Swern oxidation of the alcohol resulting from
ethanolysis of 4362) was slowly added. During the addition of the
aldehyde most of the color was discharged. The reaction mixture was
stirred for 1 min and then allowed to warm to room temperature.
Stirring was continued for 5 min, and then the reaction was quenched
by the addition of half-saturated ammonium chloride solution (100 cm3).
EtOAc (150 cm3) was added and the organic phase separated. The
aqueous phase was further extracted with EtOAc (2 × 150 cm3), and
the organic phases were combined, washed with brine (200 cm3), and
dried (MgSO4). The solvent was removed in Vacuo, and purification
by flash chromatography (light petroleum:EtOAc, 5:1) yielded the diene
45 (52 mg) and the alkene 44 (2.28 g, 6.03 mmol, 72% based on
Scheme 19. Completion of the Synthesis
26
aldehyde) as clear and colorless oils; [R]D +17.3 (c 0.44, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ 7.33-7.26 (m, 5H), 5.61-5.53 (m,
2H), 4.83 (d, J ) 7.2 Hz, 1H), 4.81 (d, J ) 7.2 Hz, 1H), 4.64 (d, J )
12.3 Hz, 1H), 4.62 (d, J ) 12.3 Hz, 1H), 4.23 (dd, J ) 6.8, 5.8 Hz,
1H), 4.16 (q, J ) 7.1 Hz, 2H), 4.12 (dq, J ) 6.5, 6.0 Hz, 1H), 4.02
(dd, J ) 8.0, 6.0 Hz, 1H), 3.57-3.54 (dd, J ) 8.0, 6.5 Hz, 1H), 2.58-
2.52 (m, 2H), 2.41 (dt, J ) 14.1, 6.5 Hz, 1H), 2.31 (dt, J ) 14.2, 6.5
Hz, 1H), 1.42, 1.35 (2 × s, 2 × 3H), 1.25 (t, J ) 7.1 Hz, 3H); 13C
NMR (50 MHz, CDCl3) δ 172.0, 137.6, 128.4, 127.8, 127.6, 126.5,
109.0, 94.2, 75.4, 75.3, 70.0, 69.0, 60.9, 31.6, 31.0, 26.8, 25.6, 14.2;
IR (CDCl3) 1741 (CO) cm-1; MS (CI, NH3) m/z (rel intensity) 396
[100, (M + NH4)+], 379 [12, (M + H)+]; HRMS (CI, NH3) m/z
379.2121 (379.2121 calcd for C21H31O6, MH). Anal. Calcd for
C21H30O6: C, 66.7; H, 8.0. Found: C, 66.9; H, 7.9.
reduction sequence to convert the 1′(S)-alcohol 71 into the 1′-
(R)-alcohol 70.
Introduction of Bromine and Completion of the Synthesis.
The free hydroxyl group of 70 was acetylated under standard
conditions, and the PMB group was removed on exposure to
BCl3‚SMe2 according to the method of Congreve69 to yield the
alcohol 80 (Scheme 19).
The bromine atom was successfully introduced by treatment
of the alcohol 80 with freshly purified carbon tetrabromide and
freshly distilled trioctylphosphine in hot toluene.17 This resulted
in a very clean reaction to form trimethylsilyl-laurencin 81 in
69% yield. The spectra of 81 were essentially identical to those
of the corresponding triisopropylsilyl analog reported by Over-
man.21
2(E),4(Z),(R)-Ethyl-6-(2,2-dimethyl-1,3-dioxolan-4-yl)-hex-2,4-di-
enoate 45. The diene 45 was isolated in various quantities from the
26
Wittig reactions attempted, the major isomer being 2(E),4(Z); [R]D
-25.2 (c 0.575, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.55 (ddd, J
) 15.3, 11.6, 1.0 Hz, 1H), 6.24 (dddt, J ) 11.6, 10.9, 1.6, 0.7 Hz,
1H), 5.90 (d, J ) 15.3 Hz, 1H, 2-H), 5.84 (dddt, J ) 10.9, 7.8, 1.0, 1.0
Hz, 1H), 4.21 (q, 2H), 4.17 (m, 1H), 4.04 (dd, J ) 8.1, 6.1 Hz, 1H),
3.58 (dd, J ) 8.1, 6.9 Hz, 1H), 2.59 (m, 2H), 1.43, 1.35 (2 × s, 2 ×
3H), 1.29 (t, J ) 7.1 Hz, 3H); δC (100 MHz, CDCl3) 167.0, 138.7,
135.1, 128.8, 122.4, 109.2, 75.0, 68.8, 60.4, 32.4 (C-6), 26.8, 25.5,
Treatment of TMS-laurencin 81 with a cold solution of TBAF
in THF afforded (+)-laurencin 1 {[R]D20 +70 (c 0.05 in CHCl3),
27
lit.1 [R]D +70.2 (c 1.00 in CHCl3)} in 98% yield. The
synthetic sample was isolated as a white gum, and therefore a
melting point could not be obtained. However, in all other
respects (1H NMR, 13C NMR, IR, [R]D, MS) the synthetic
sample had characteristics in accordance with the data supplied
by Professor Murai for a natural and a synthetic sample.
14.3; IR (CDCl3) 1706 (CO), 1638 (CdC), 1607 (CdC) cm-1
.
Satisfactory mass spectral data could not be obtained on this compound
probably due to its instability.
(Z),2(R),7(R)-Ethyl-2-[[(benzyloxy)methyl]oxy]-7,8-dihydroxy-
oct-4-enoate and (Z),2(R),7(R)-Ethyl-2-[[(benzyloxy)methyl]oxy]-8-
[(tert-butyldiphenylsilyl)oxy]-7-hydroxy-oct-4-enoate. The alkene 44
(2.35 g, 6.2 mmol) was dissolved in 80% aqueous acetic acid (75 cm3),
and the resulting solution was heated to 55 °C for 20 min with stirring.
The solvent was removed in Vacuo, and the residual solvent was
removed by coevaporation with toluene (3 × 50 cm3) to yield the
deprotected material (Z),2(R),7(R)-ethyl-2-[[(benzyloxy)methyl]oxy]-
7,8-dihydroxy-oct-4-enoate as a clear and colorless oil which was
directly used for the next reaction without purification. For charac-
terization purposes purification by flash chromatography gave homo-
geneous material; [R]D26 +40.4 (c 0.47, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.36-7.27 (m, 5H), 5.62-5.54 (m, 2H), 4.84 (d, J ) 7.1
Hz, 1H), 4.81 (d, J ) 7.1 Hz, 1H), 4.64 (s, 2H), 4.27 (dd, J ) 12.1,
6.0 Hz, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 3.78-3.72 (brm, 1H), 3.65
(brd, J ) 11.0 Hz, 1H), 3.50 (dd, J ) 11.0, 6.5 Hz, 1H), 2.62-2.54
(m, 2H), 2.54-2.46 (br, 1H), 2.34-2.22 (m, 2H), 2.22-2.12 (br, 1H),
1.26 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.0, 137.4,
128.4, 127.8, 126.7, 94.1, 74.9, 71.4, 70.1, 66.1, 61.1, 31.4, 30.7, 14.2;
IR (CDCl3) 3593 (OH), 1742 (CO) cm-1; MS (CI, NH3) m/z (rel
intensity) 356 [40, (M + NH4)+], 339 [20, (M + H)+]; HRMS (CI,
NH3) m/z 356.2070 (356.2073 calcd for C18H30O6N, MNH4). Anal.
Calcd for C18H26O6: C, 63.9; H, 7.7. Found: C, 63.6; H, 7.8.
Conclusion
In summary, this work has demonstrated that medium-ring
ether natural products can be obtained from the corresponding
lactone precursors by methylenation and subsequent enol-ether
functionalization. The Claisen ring expansion route is a
convenient method for the preparation of medium-ring lactones,
but efficient lactonization of seco-acid precursors is equally
effective.
Experimental Section
For general experimental techniques see Supporting Information.
(Z),2(R)-Ethyl-2-[[(benzyloxy)methyl]oxy]-6-[(R)-2,2-dimethyl-
1,3-dioxolan-4-yl]-hex-4-enoate 44. The phosphonium salt 40 (4.51
g, 9.57 mmol) was freshly prepared from the bromide 4259-61 and was
dried in Vacuo (<0.5 mmHg) for 48 h. The vacuum was quenched
with argon and THF (140 cm3) was added. The resulting suspension
(93) Organocopper Reagents A Practical Approach; Taylor, R. J. K.,
Ed.; Oxford University Press: Oxford, 1994; pp 105-110.
(94) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693.

7494 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Burton et al.
The residue was dissolved in DMF (20 cm3), imidazole (2.28 g, 17.4
mmol) and tert-butylchlorodiphenylsilane (2.22 g, 8.1 mmol) were
added, and the reaction was stirred at ambient temperature overnight.
The reaction mixture was poured into water (100 cm3). The aqueous
phase was extracted with EtOAc (3 × 50 cm3), and the combined
organic phases washed with brine (50 cm3). The organic phase was
dried (MgSO4), and purification by flash chromatography (light
petroleum:EtOAc, 2:1) yielded (Z),2(R),7(R)-ethyl-2-[[(benzyloxy)-
methyl]oxy]-8-[(tert-butyldiphenylsilyl)oxy]-7-hydroxy-oct-4-enoate (2.9
g, 5 mmol, 81% from the acetonide 44) as a clear and colorless oil;
[R]D +26.0 (c 0.75, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.67-
7.65 (m, 4H), 7.43-7.27 (m, 11H), 5.59-5.51 (m, 2H), 4.79 (d, J )
7.1 Hz, 1H), 4.77 (d, J ) 7.1 Hz, 1H), 4.60 (s, 2H), 4.21 (t, J ) 6.2
Hz, 1H), 4.14 (q, J ) 7.2 Hz, 2H), 3.75-3.74 (brm, 1H), 3.65 (dd, J
) 10.1, 4.1 Hz, 1H), 3.56 (dd, J ) 10.1, 6.9 Hz, 1H), 2.56-2.51 (m,
3H), 2.31-2.21 (m, 2H), 1.22 (t, J ) 7.2 Hz, 3H), 1.07 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 172.0, 137.6, 135.5, 133.2, 129.8, 128.4,
127.8, 127.7, 126.2, 94.1, 75.1, 71.5, 70.0, 67.5, 61.0, 31.1, 30.8, 26.8,
19.2, 14.2; IR (CHCl3) 3566 (OH), 1731 (CO) cm-1; MS (CI, NH3)
m/z (rel intensity) 594 [65, (M + NH4)+]; HRMS (CI, NH3) m/z
594.3250 (594.3251 calcd for C34H48O6SiN, MNH4). Anal. Calcd for
C34H44O6Si: C, 70.8; H, 7.7. Found: C, 70.8; H, 7.6.
intensity) 548 [10, (M + NH4)+]; HRMS (CI, NH3) m/z 548.2830
(548.2832 calcd for C32H42O5SiN, MNH4). Anal. Calcd for C32H38O5-
Si: C, 72.4; H, 7.2. Found: C, 72.4; H, 7.1.
8(R),3(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-2-
oxo-3,4,7,8-tetrahydro-(2H)-oxocin 15. To a stirred solution of the
lactone 47 (2.33 g, 4.40 mmol) in CH2Cl2 (150 cm3) was added boron
trichloride-methyl sulfide complex (4.39 cm3 of a 2.0 M solution in
CH2Cl2, 8.80 mmol). Stirring was continued for 1 min, and the reaction
was rapidly quenched by pouring onto a vigorously stirred solution of
saturated sodium bicarbonate (130 cm3). THF (50 cm3) was im-
mediately added, and vigorous stirring was continued for 0.5 h. The
organic layer was separated, and the aqueous phase was extracted with
CH2Cl2 (2 × 100 cm3). The organic phases were combined and dried
(MgSO4), and purification by flash chromatography (CH2Cl2) yielded
the title compound 15 (1.67 g 93%) as a clear and colorless oil which
was identical to the material prepared by the oxidation of 16 with 37
26
1
23
(see Supporting Information); [R]D -13.3 (c 0.59, CHCl3); δH(500
MHz, CDCl3) 7.67-7.66 (m, 4H), 7.46-7.39 (m, 6H), 5.79 (dt, J )
11.0, 8.1 Hz, 1H), 5.70 (dt, J ) 11.0, 7.1 Hz, 1H), 4.66-4.62 (m, 1H),
4.40-4.36 (m, 1H), 3.91 (dd, J ) 10.8, 5.8 Hz, 1H), 3.78 (dd, J )
10.8, 5.7 Hz, 1H), 2.87 (d, J ) 7.2 Hz, 1H), 2.67-2.62 (m, 1H), 2.49-
2.43 (m, 2H), 2.34 (dt, J ) 15.3, 8.2 Hz, 1H), 1.07 (9H, s); 13C NMR
(50 MHz, CDCl3) δ 176.3, 135.6, 129.9, 128.9, 127.8, 77.5, 73.2, 65.2,
34.0, 30.1, 26.8, 19.2; IR (CDCl3) 3551 (OH), 1743 (CO) cm-1; MS
(CI, NH3) m/z (rel intensity) 428 [80, (M + NH4)+], 411 [18, (M +
H)+]; HRMS (CI, NH3) m/z 411.1992 (411.1992 calcd for C24H31O4-
Si, MH).
(Z),2(R),7(R)-2-[[(Benzyloxy)methyl]oxy]-8-[(tert-butyldiphenyl-
silyl)oxy]-7-hydroxy-oct-4-enoic Acid 39. Lithium hydroxide mono-
hydrate (924 mg, 22 mmol) was added to a stirring suspension of
(Z),2(R),7(R)-ethyl-2-[[(benzyloxy)methyl]oxy]-8-[(tert-butyldiphenyl-
silyl)oxy]-7-hydroxy-oct-4-enoate (2.54 g, 4.4 mmol) in THF and water
(1:1, 160 cm3). The milky reaction mixture was stirred for 4.5 h
whereupon it became clear. The reaction mixture was acidified to pH
2 (pH paper) with 2 M hydrochloric acid (20 cm3), and the THF was
removed in Vacuo. Water (100 cm3) was added, and the aqueous phase
extracted with EtOAc (3 × 100 cm3). The combined organic phases
were washed with brine (100 cm3) and dried (MgSO4), and the solvent
was removed in Vacuo. Purification by flash chromatography (EtOAc:
light petroleum:acetic acid, 200:200:1) followed by coevaporation with
toluene (3 × 30 cm3) yielded the acid 39 (2.18 g, 3.97 mmol, 90%) as
a clear and colorless oil; [R]D20 +2.89 (c 0.87, CH2Cl2); 1H NMR (400
MHz, CDCl3) δ 7.67-7.65 (m, 4H), 7.44-7.33 (m, 6H), 7.33-7.28
(m, 4H), 5.62-5.51 (m, 2H), 4.81 (d, J ) 7.1 Hz, 1H), 4.77 (d, J )
7.1 Hz, 1H), 4.61 (s, 2H), 4.27 (t, J ) 6.0 Hz, 1H), 3.77-3.74 (m,
1H), 3.65 (dd, J ) 10.1, 4.1 Hz, 1H), 3.56 (dd, J ) 10.1, 6.9, 1H),
2.57-2.54 (m, 2H), 2.29-2.24 (m, 2H), 1.07 (s, 9H); 13C NMR (50
MHz, CDCl3) δ 175.9, 137.3, 135.5, 133.1, 129.8, 128.8, 128.4, 127.8,
126.0, 94.2, 75.0, 71.6, 70.2, 67.4, 31.0, 30.5, 26.8, 19.2; IR (CDCl3)
3600-2500 (broad OH), 1764 (CO), 1722 (CO) cm-1; MS (CI, NH3)
m/z (rel intensity) 548 [10, (M + NH4 - H2O)+]. Anal. Calcd for
C32H40O6Si: C, 70.0; H, 7.4. Found: C, 69.9; H, 7.4.
3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-[(trimethyl-
silyl)oxy]-2-oxo-3,4,7,8-tetrahydro-(2H)-oxocin 49 and 3(R),8(R)-
8-[(tert-Butyldiphenylsilyl)oxy]-3-[(trimethylsilyl)oxy]-2-oxo-3,4,7,8,9-
pentahydro-(2H)-oxonin 48. To a stirred solution of the alcohols
prepared by deprotection of a 10:1 mixture of 47 and 46 (1.35 g, 3.29
mmol) in THF (50 cm3) was added triethylamine (0.5 cm3). Chloro-
trimethylsilane (2.5 cm3) and triethylamine (2.5 cm3) were mixed in a
sealed centrifuge tube and centrifuged for 3 min. A portion of the
supernatant liquid (5 cm3) was added to the reaction mixture, and a
white precipitate was formed immediately. After 1 h the reaction was
quenched by the addition of pH 7 buffer (50 cm3) and ether (50 cm3).
The organic layer was separated, and the aqueous phase was extracted
with ether (2 × 50 cm3). The organic phases were combined, washed
with brine (50 cm3), and dried (MgSO4). Purification by flash
chromatography (light petroleum:ether, 10:1) gave the nine-ring lactone
48 (142 mg, 0.29 mmol, 9%) as a clear and colorless oil; [R]D20 -17.6
1
(c 1.4, CH2Cl2); H NMR (200 MHz, CDCl3) δ 7.72-7.62 (m, 4H),
7.44-7.33 (m, 6H), 5.69-5.48 (m, 1H), 5.43-5.24 (brm, 1H), 4.67
(dd, J ) 11.2, 5.8 Hz, 1H), 4.46 (brt, J ) 4.0, Hz, 1H), 4.12-4.00 (m,
1H), 3.80 (dd, J ) 11.2, 5.8 Hz, 1H), 2.85-2.73 (brm, 1H), 2.58-
2.47 (brm, 1H), 2.27-2.13 (brm, 1H), 2.07-1.97 (brm, 1H), 1.09 (s,
9H), 0.14 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 173.3, 135.8, 135.7,
133.7, 133.5, 129.9, 129.9, 127.8, 127.7, 125.5, 112.6, 70.9, 70.5, 68.5,
34.0, 33.3, 27.0, 19.1, -0.2; IR (CDCl3) 1757 (CO) cm-1; MS (CI,
NH3) m/z (rel intensity) 483 [20, (M + H)+]; HRMS (CI, NH3) m/z
483.2375 (483.2387 calcd for C27H39O4Si2, MH).
8(R),3(R)-3-[[(Benzyloxy)methyl]oxy]-8-[[(tert-butyldiphenylsilyl)-
oxy]methyl]-2-oxo-3,4,7,8-tetrahydro-(2H)-oxocin 47. The lactone
47 was prepared using the Yamaguchi lactonization procedure described
by Mulzer.67,68 To a stirred solution of the acid 39 (1.0 g, 1.82 mmol)
in THF (40 cm3) was added triethylamine (0.381 cm3, 276 mg, 2.74
mmol). After 10 min 2,4,6-trichlorobenzoyl chloride (0.328 cm3, 512
mg, 2.09 mmol) was added, and the solution was stirred for 2 h. The
resulting cloudy reaction mixture was transferred Via cannula into
toluene (500 cm3, 50 cm3 rinse) in a pressure equalizing dropping
funnel. This solution was added dropwise, down a Vigreux column,
heated by refluxing toluene, into refluxing toluene (550 cm3) containing
DMAP (3.12 g, 25.5 mmol) over a period of 4 h. The reaction was
heated under reflux for a further 0.5 h and then allowed to cool. The
solvent was removed in Vacuo, and purification by flash chromatog-
raphy (CH2Cl2:light petroleum, 4:1) gave the title compound 47 (806
Further elution of the column gave the eight-ring lactone 49 (1.28
g, 2.66 mmol, 81%) as a clear and colorless oil; [R]D18 +27.8 (c 0.27,
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.69-7.63 (m, 4H), 7.45-
7.38 (m, 6H), 5.84 (dt, J ) 10.7, 8.1 Hz, 1H), 5.66 (dt, J ) 10.7, 7.5
Hz, 1H), 4.70-4.68 (m, 1H), 4.19 (dd, J ) 9.8, 5.3 Hz, 1H), 3.93 (dd,
J ) 10.5, 5.4 Hz, 1H), 3.80 (dd, J ) 10.5, 5.9 Hz, 1H), 2.75 (q, J )
10.5 Hz, 1H), 2.53-2.47 (m, 1H), 2.36 (ddd, J ) 12.2, 6.9, 5.4 Hz,
1H), 2.27 (ddd, J ) 13.8, 8.3, 1.7 Hz, 1H), 1.08 (s, 9H), 0.17 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 175.6, 135.6, 135.6, 133.3, 133.2, 130.3,
129.7, 128.1, 127.7, 78.7, 75.7, 65.2, 34.7, 30.7, 26.7, 19.2, -0.3; IR
(CDCl3) 1745 (CO) cm-1; MS (CI, NH3) m/z (rel intensity) 500 [18,
(M + NH4)+], 483 [10, (M + H)+]; HRMS (CI, NH3) m/z 483.2387
(483.2387 calcd for C27H39O4Si2, MH). Anal. Calcd for C27H38O4Si2:
C, 67.2 H, 7.9. Found: C, 67.6; H, 7.9.
23
1
mg, 1.52 mmol, 84%); [R]D +28.8 (c 0.6, CH2Cl2); H NMR (500
MHz, CDCl3) δ 7.67-7.63 (m, 4H), 7.45-7.26 (m, 11H), 5.86 (dt, J
) 10.9, 8.0 Hz, 1H), 5.70-5.64 (m, 1H), 4.81 (d, J ) 7.0 Hz, 1H),
4.78 (d, J ) 7.0 Hz, 1H), 4.75-4.72 (m, 1H), 4.66 (d, J ) 12.0 Hz,
1H), 4.54 (d, J ) 12.0 Hz, 1H), 4.13 (dd, J ) 9.8, 5.3 Hz, 1H), 3.85
(dd, J ) 10.5, 5.9 Hz, 1H), 3.76 (dd, J ) 10.5, 6.2 Hz, 1H), 2.82-
2.75 (m, 1H), 2.54-2.50 (m, 1H), 2.48-2.43 (m, 1H), 2.33-2.29 (m,
1H), 1.06 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 174.8, 137.4, 135.6,
133.2, 130.5, 129.8, 128.3, 127.7, 94.3, 80.4, 78.3, 69.9, 65.1, 31.7,
30.6, 26.7, 19.3; IR (CDCl3) 1744 (CO) cm-1; MS (CI, NH3) m/z (rel
3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-2-methylene-3-
[(trimethylsilyl)oxy]-3,4,7,8-tetrahydro-(2H)-oxocin 50 and 3(R),8(R)-
8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-2-methylene-
3,4,7,8-tetrahydro-(2H)-oxocin. To a stirred solution of the silylether
49 (1.41 g, 2,93 mmol) in toluene (100 cm3) was added dimethylti-

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7495
tanocene (14.6 cm3 of a 50 mg/cm3 solution in toluene, 3.5 mmol),
and the resultant orange solution was heated under reflux, in the dark,
for 35 min. The reaction mixture was allowed to cool, and the solvent
was removed in Vacuo. The resulting orange oil was taken up in
EtOAc, and the crude reaction mixture was preadsorbed onto UG1
alumina (previously deactivated by the addition of 6% w/w water).
Purification by gravity chromatography on deactivated UG1 alumina
(light petroleum:ether, 20:1) yielded the impure enol ether 50. For
analytical purposes the enol ether could be purified further by
chromatography in the same solvent system. Data for 50; Rf 0.8 (light
petroleum:ether, 1:1); [R]D26 +9.2 (c 0.13, EtOAc); 1H NMR (500 MHz,
CDCl3) δ 7.70-7.67 (m, 4H), 7.43-7.37 (m, 6H), 5.85-5.73 (m, 1H),
5.64-5.59 (m, 1H), 4.49 (s, 1H), 4.46 (s, 1H), 4.18, (dd, J ) 10.7, 4.9
Hz, 1H), 3.92 (dd, J ) 10.2, 6.0 Hz, 1H), 3.81-3.76 (m, 1H), 3.65
(dd, J ) 10.2, 6.5 Hz, 1H), 2.74 (q, J ) 11.0 Hz, 1H), 2.40-2.34 (m,
1H), 2.23 (ddd, J ) 13.8, 8.3, 0.9 Hz, 1H), 2.12 (ddd, J ) 11.9, 6.6,
5.0 Hz, 1H), 1.09 (s, 9H), 0.13 (s, 9H); 13C NMR (50 MHz, CDCl3) δ
165.4, 135.6, 135.6, 133.6, 129.6, 129.6, 129.2, 127.6, 100.3, 85.9,
76.2, 66.4, 33.2, 30.8, 26.8, 19.2, -0.2; IR (CDCl3) 1646 (enol ether)
cm-1; HRMS (+FAB) m/z 480.2479 (480.2516 calcd for C28H40O3Si2,
M).
(0.2 cm3, 200 µmol), and stirring was continued for 2 h. Dry hexane
(15 cm3) and ethylenediaminetetraacetic acid, disodium salt dihydrate
(615 mg, 1.65 mmol) were added, and the resulting suspension was
stirred for 1 h. The reaction mixture was filtered through a pad of
Celite, and the filter cake was washed with dry hexane. The solvent
was removed in Vacuo to furnish a brown oil. This residue was taken
up in THF/MeOH (1:1, 16 cm3) to which a 15% solution of potassium
hydroxide (0.43 cm3) and 30% H2O2 (0.64 cm3, 6.0 mmol) were added.
The reaction mixture was stirred for 1.25 h whereupon further potassium
hydroxide solution (0.05 cm3) and H2O2 (0.06 cm3) were added. After
0.5 h the reaction was quenched by the addition of powdered sodium
thiosulfate (1.89 g, 12 mmol), and stirring was continued overnight.
The suspension was diluted with EtOAc (25 cm3), dried (MgSO4), and
filtered through a pad of Celite. The solvent was removed in Vacuo,
and purification by flash chromatography (CH2Cl2:MeOH, 97:3) yielded
the enol ether 3(R),8(R)-8-[[(tert-butyldiphenylsilyl)oxy]methyl]-3-
hydroxy-2-methylene-3,4,7,8-tetrahydro-(2H)-oxocin (121 mg, 0.3
mmol, 29%). Further elution of the column furnished 13 (70 mg) as
a clear and colorless oil; Rf 0.4 (CH2Cl2:MeOH, 95:5); [R]D20 -18.2 (c
1
0.22, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.72-7.67 (m, 4H),
7.46-7.38 (m, 6H), 5.80-5.70 (m, 2H), 3.90-3.86 (brm, 1H), 3.85-
3.78 (brm, 1H), 3.72 (ddd, J ) 9.0, 3.5, 2.0 Hz, 1H), 3.69-3.65 (m,
2H), 3.63-3.58 (m, 1H), 3.51-3.45 (m, 1H), 2.97 (d, J ) 9.5 Hz,
1H), 2.56 (dt, J ) 12.5, 9.5 Hz, 1H), 2.36-2.30 (m, 1H), 2.27-2.20
(m, 1H), 2.02-1.97 (ddd, J ) 14.5, 8.4, 1.5 Hz, 1H), 1.66 (d, J ) 9.0
Hz, 1H), 1.07 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 135.6, 135.6,
132.9, 129.9, 129.4, 128.7, 127.8, 83.4, 82.1, 73.1, 67.7, 64.1, 33.6,
30.4, 26.7, 19.0; IR (CHCl3) 3478 (OH) cm-1; MS (CI, NH3) m/z (rel
intensity) 444 [60, (M + NH4)+], 427 [8, (M + H)+]; HRMS (CI, NH3)
m/z 444.2570 (444.2570 calcd for C25H38O4SiN, MNH4).
The impure enol ether 50 was dissolved in methanol (20 cm3) and
cooled to 0 °C, and solid potassium carbonate was added (150 mg).
The reaction mixture was stirred vigorously, allowed to warm to
ambient temperature over a 0.5 h period, and filtered. Purification by
gravity chromatography on deactivated UG1 alumina (light petroleum:
ether, 2:1) yielded the hydroxy-enol ether 3(R),8(R)-8-[[(tert-butyl-
diphenylsilyl)oxy]methyl]-3-hydroxy-2-methylene-3,4,7,8-tetrahydro-
20
(2H)-oxocin (863 mg, 2.1 mmol, 72% from 49); [R]D +3.3 (c 0.22,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.69-7.68 (m, 4H), 7.44-
7.39 (m, 6H), 5.75-5.64 (m, 2H), 4.58 (d, J ) 1.5 Hz, 1H), 4.55 (d,
J ) 1.5 Hz, 1H), 4.19 (m, 1H), 3.91 (ddt, J ) 12.2, 6.1, 4.1 Hz, 1H),
3.85 (dd, 10.3, 6.1 Hz, 1H), 3.66 (dd, J ) 10.3, 6.1 Hz, 1H), 2.61 (dt,
J ) 12.7, 9.0 Hz, 1H), 2.34-2.32 (m, 2H), 2.27 (ddd, J ) 12.7, 6.3,
3.9 Hz, 1H), 1.97 (d, J ) 8.2 Hz, 1H), 1.08 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 164.0, 135.6, 135.6, 133.5, 133.4, 129.7, 129.2, 129.0,
127.7, 99.3, 84.1, 75.4, 65.7, 33.0, 29.5, 26.6, 19.2; IR (CH2Cl2) 3593
(OH), 1649 (enol ether) cm-1; MS (CI, NH3) m/z (rel intensity) 426
[17, (M + NH4)+], 409 [7, (M + H)+]; HRMS (CI, NH3) m/z 409.2199
(409.2199 calcd for C25H33O3Si, MH).
Further elution of the column gave mixed fractions which were
repurified by flash chromatography (CH2Cl2:MeOH, 97:3) to yield 13
(140 mg total, 0.33 mmol, 32%) and 51 (120 mg, 0.28 mmol, 27%);
Rf 0.3 (CH2Cl2:MeOH, 95:5); [R]D20 -15.9 (c 0.23, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.70-7.68 (m, 4H), 7.50-7.38 (m, 6H), 5.83
(dt, J ) 10.3, 7.9 Hz, 1H), 5.68-5.63 (m, 1H), 3.96 (dd, J ) 11.8, 9.3
Hz, 1H), 3.98-3.94 (br, 1H), 3.73-3.65 (m, 4H), 3.60-3.59 (brm,
1H), 3.48 (dd, J ) 11.8, 3.3 Hz, 1H), 2.44-2.32 (m, 2H), 2.17-2.07
(m, 1H), 1.90 (ddd, J ) 14.2, 7.2, 3.4 Hz, 1H), 1.57 (br, 1H), 1.07 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 135.6, 135.6, 132.7, 130.0, 129.9,
128.2, 127.9, 76.9, 76.2, 72.2, 65.0, 64.3, 35.4, 28.2, 26.7, 19.1; IR
(CHCl3) 3452 (OH) cm-1; MS (CI, NH3) m/z (rel intensity) 444 [20,
(M + NH4)+], 427 [40, (M + H)+]; HRMS (CI, NH3) m/z 444.2570
(444.2570 calcd for C25H38O4SiN, MNH4).
3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-[(Dimethyl-
silyl)oxy]-2-methylene-3,4,7,8-tetrahydro-(2H)-oxocin 14. To a stirred
solution of the enol ether 3(R),8(R)-8-[[(tert-butyldiphenylsilyl)oxy]-
methyl]-3-hydroxy-2-methylene-3,4,7,8-tetrahydro-(2H)-oxocin (160
mg, 0.39 mmol) in 1,1,3,3-tetramethyldisilazane (0.8 cm3) was added
solid ammonium chloride (4 mg), and the reaction mixture was heated
to 60 °C and stirred at that temperature overnight. The reaction mixture
was allowed to cool, dry hexane was added, and filtration through a
cotton wool plug followed by removal of the solvent in Vacuo gave
the required silane 14 (182 mg, 0.39 mmol, 99%) as a very unstable
oil; 1H NMR (400 MHz, CDCl3) δ 7.71-7.67 (m, 4H), 7.41-7.37 (m,
6H), 5.78 (dt, J ) 10.3, 7.8 Hz, 1H), 5.63 (dt, J ) 10.3, 6.9 Hz, 1H),
4.67 (sp, J ) 2.8 Hz, 1H), 4.53 (d, J ) 0.8 Hz, 1H), 4.51 (d, J ) 0.8
Hz, 1H), 4.18 (dd, J ) 10.7, 4.9 Hz, 1H), 3.93 (dd, J ) 10.1, 6.0, 1H),
3.83-3.78 (m, 1H), 3.66 (dd, J ) 10.1, 6.4 Hz, 1H), 2.77 (q, J ) 10.8
Hz, 1H); 2.42-2.34 (m, 1H), 2.27-2.17 (m, 2H), 1.08 (s, 9H), 0.23
(d, J ) 2.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 164.7, 135.6,
135.6, 133.6, 133.5, 129.6, 129.1, 127.6, 100.7, 85.9, 77.8, 66.4, 32.7,
30.8, 26.8, 19.2, -1.0, -1.0; IR (CDCl3) 2960, 2932, 2859, 2120 (SiH),
2(R),3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-
2-(hydroxymethyl)-3,4,7,8-tetrahydro-(2H)-oxocin p-Methoxyben-
zylidene Acetal 53. To a stirred solution of the diol 13 (190 mg, 0.45
mmol) in benzene (10 cm3) was added freshly distilled anisaldehyde
(81 µL, 91 mg, 0.67 mmol), PPTS (5 mg), and MgSO4 (50 mg). The
reaction mixture was heated to reflux for 5.5 h and then allowed to
cool. The solvent was then removed in Vacuo, and purification by
preparative layer chromatography (CH2Cl2:MeOH, 99:1) yielded the
20
title compound 53 (200 mg, 82%) as a clear and colorless oil; [R]D
1
-27.5 (c 0.375, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.72-7.70
(m, 4H), 7.45-7.35 (m, 8H), 6.86 (d, J ) 9.0 Hz, 2H), 5.94-5.89 (m,
1H), 5.70 (ddt, J ) 10.3, 6.6, 1.8 Hz, 1H), 5.45 (s, 1H), 4.23 (dd, J )
12.0, 2.0 Hz, 1H, CHHOCHAr), 3.98 (ddd, J ) 11.5, 5.0, 2.0 Hz, 1H,
3-H), 3.95 (dd, J ) 12.0, 2.0 Hz, 1H, CHHOCHAr), 3.83 (dd, J )
10.0, 5.5, Hz, 1H), 3.79 (s, 3H), 3.60 (dd, J ) 10.0, 6.5, 1H), 3.49-
3.39 (m, 1H), 3.35 (q, J ) 2.0 Hz, 1H, 2-H), 2.86 (q, J ) 11.5 Hz, 1H,
4-H), 2.44-2.37 (m, 1H), 2.35-2.27 (m, 2H, 4-H, 7-H), 1.07 (s, 9H);
13C NMR (62.5 MHz, CDCl3) δ 159.9, 135.7, 133.7, 133.6, 131.0,
129.6, 129.6, 127.7, 127.6, 127.3, 113.5, 100.9, 83.6, 79.9, 73.3, 72.2,
67.3, 55.3, 31.5, 30.1, 26.8, 19.2; IR (CDCl3) 2932, 2858, 1615, 1589,
1517 cm-1; MS (CI, NH3) m/z (rel intensity) 562 [35, (M + NH4)+],
545 [100, (M + H)+]; HRMS (CI, NH3) m/z 545.2720 (545.2723 calcd
for C33H41O5Si, MH).
1647 (enol ether) cm-1
. Due to the instability of this compound
satisfactory mass spectral data was not obtained.
2(R),3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-
2-(hydroxymethyl)-3,4,7,8-tetrahydro-(2H)-oxocin 13 and 2(S),3(R),
8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-2-(hy-
droxymethyl)-3,4,7,8-tetrahydro-(2H)-oxocin 51. Note: This reac-
tion must be carried out under dry air. The silane 14 (487 mg, 1.03
mmol) was dried in Vacuo for 48 h. The vacuum was purged with air,
a stirrer flea was added, and the reaction flask was fitted with a drying
tube (CaCl2). The platinum catalyst Pt(DVS)2 (0.52 cm3 of a 0.1 M
solution in toluene, 5.2 µmol) was added Via syringe. The reaction
mixture immediately became yellow and gradually turned dark red as
gas was evolved. After stirring for 2 h, further catalyst was added
2(S),3(R),8(R)-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-
2-(hydroxymethyl)-3,4,7,8-tetrahydro-(2H)-oxocin p-Methoxyben-
zylidene Acetal 52. Compound 52 was prepared in an analogous
19
fashion to compound 53 (97% yield); [R]D -2.0 (c 0.61, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ 7.69-7.65 (m, 4H), 7.46-7.38 (m,

7496 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Burton et al.
8H), 6.88 (d, J ) 9.0 Hz, 2H), 5.97-5.87 (m, 1H), 5.76-5.71 (m,
1H), 5.40 (s, 1H), 4.18 (dd, J ) 11.0, 5.5 Hz, 1H, CHHOCHAr), 3.88
(ddd, J ) 10.0, 9.0, 5.5 Hz, 1H, 2-H), 3.82 (dd, J ) 11.0, 6.4 Hz, 1H),
3.79 (s, 3H), 3.70 (dd, J ) 11.0, 4.7 Hz, 1H), 3.65-3.59 (m, 1H),
3.59 (dd, J ) 11.0, 10.0 Hz, 1H, CHHOCHAr), 3.52 (ddd, J ) 10.9,
9.0, 3.2 Hz, 1H, 3-H), 2.52-2.45 (m, 2H, 7-H, 4-H), 2.40 (ddd, J )
13.5, 8.4, 3.2 Hz, 1H, 4-H), 2.05 (ddd, J ) 13.9, 7.1, 3.0 Hz, 1H),
1.09 (9H, s); δC(100 MHz, CDCl3) 160.0, 135.6, 133.1, 130.4, 129.5,
128.8, 127.8, 127.4, 113.7, 100.7, 80.4, 76.0, 70.3, 67.7, 65.4, 55.3,
mixture was allowed to warm to 0 °C, whereupon the reaction mixture
became homogeneous. The reaction mixture was stirred at this
temperature for 3 h and was then quenched by the addition of a saturated
solution of ammonium chloride and stirred until all the solid had
dissolved. The organic phase was separated, and the aqueous phase
was extracted with ether (2 × 5 cm3). The organic phases were
combined and dried (MgSO4). Purification by flash chromatography
(light petroleum:ether, 3:2) gave the ethyl-substituted oxocane 59 (10.9
mg, 20.0 µmol, 60%) as a clear and colorless oil; [R]D20 +8.6 (c 0.09,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J ) 7.6 Hz, 4H), 7.41-
7.34 (m, 6H), 7.23 (d, J ) 8.5 Hz, 2H), 6.84 (d, J ) 8.5 Hz, 2H),
5.87-5.81 (m, 1H), 5.71-5.65 (m, 1H), 4.60 (d, J ) 11.8 Hz, 1H),
4.38 (d, J ) 11.8 Hz, 1H), 3.81 (dd, J ) 10.0, 5.0 Hz, 1H), 3.79 (s,
3H), 3.51 (dd, J ) 10.0, 8.0 Hz, 1H), 3.43-3.34 (m, 3H), 2.66 (q, J )
11.0 Hz, 1H), 2.44-2.39 (m, 1H), 2.35-2.27 (m, 2H), 1.68-1.61 (m,
1H), 1.33-1.23 (m, 1H), 1.05 (s, 9H), 0.78 (t, J ) 7.4 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3) δ 159.0, 135.6, 133.8, 133.7, 130.9, 130.1,
129.6, 129.5, 129.2, 127.6, 113.6, 83.2, 82.4, 80.7, 70.7, 66.8, 55.2,
31.6, 29.1, 26.9, 25.7, 19.2, 10.8; IR (CDCl3) 2932, 1612 cm-1; MS
(CI, NH3) m/z (rel intensity) 562 [20, (M + NH4)+]; HRMS (CI, NH3)
m/z 562.3353 (562.3352 calcd for C34H48O4SiN, MNH4). Further
elution of the column yielded the starting alcohol 57 (7.3 mg, 13.3
µmol, 40%).
32.9, 28.2, 26.8, 19.2; IR (CH2Cl2) 2933, 2859, 1615, 1518 cm-1
;
HRMS (+FAB) m/z 545.2692 (545.2723 calcd for C33H41O5Si, MH).
2(R),3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-2-(hy-
droxymethyl)-3-[(p-methoxybenzyl)oxy]-3,4,7,8-tetrahydro-(2H)-
oxocin 57. To a stirred solution of 53 (190 mg, 0.35 mmol) in CH2Cl2
(20 cm3) at -78 °C was added DIBAL-H (1.57 cm3 of 1.0 M solution
in CH2Cl2, 1.57 mmol). The resulting solution was stirred for 10 min
at -78 °C and then for 1 h at -50 °C before being quenched with
MeOH (3 cm3). The reaction mixture was allowed to warm to ambient
temperature, and a saturated solution of ammonium chloride (2.5 cm3)
and 1 M sodium potassium tartrate (2.5 cm3) were added. The resulting
gel was stirred until dissolution occurred. The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2 (2 × 5
cm3). The organic phases were combined and dried (MgSO4), and the
solvent was removed in Vacuo. Purification by flash chromatography
(light petroleum:ether, 2:1) gave the title compound 57 (98 mg, 0.18
mmol, 51%) as a clear and colorless oil; Rf 0.2 (light petroleum:ether,
2(R),3(R),8(R)-2-Ethyl-8-(hydroxymethyl)-3-[(p-methoxybenzyl)-
oxy]-3,4,7,8-tetrahydro-(2H)-oxocin. To a stirred solution of the
oxocane 59 (43 mg, 79 µmol) in THF (6 cm3) at 0 °C was added TBAF
(0.4 cm3 of a 1.0 M solution in THF, 0.40 mmol). The resulting
solution was stirred at 0 °C for 5 min and then stirred at ambient
temperature for 1.5 h. The solvent was removed in Vacuo and
purification by preparative layer chromatography (EtOAc:light petro-
leum, 2:1) yielded the title compound (23 mg, 75 µmol, 96%) as a
17
1
2:1); [R]D -1.3 (c 0.32, CH2Cl2); H NMR (500 MHz, CDCl3) δ
7.73-7.66 (m, 4H), 7.43-7.37 (m, 6H), 7.25 (d, J ) 8.6 Hz, 2H),
6.88 (d, J ) 8.6 Hz, 2H), 5.81-5.76 (m, 1H), 5.70-5.65 (m, 1H),
4.60 (d, J ) 11.8 Hz, 1H), 4.36 (d, J ) 11.8 Hz, 1H), 3.99 (t, J ) 10.1
Hz, 1H), 3.81 (s, 3H), 3.76-3.71 (m, 2H), 3.60-3.55 (m, 2H), 3.49-
3.41 (m, 2H), 3.36 (d, J ) 11.7 Hz, 1H), 2.69 (q, J ) 11.0 Hz, 1H),
2.42-2.37 (m, 1H), 2.30-2.24 (m, 1H), 1.85 (dd, J ) 14.0, 8.4 Hz,
1H), 1.05 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 159.2, 135.7, 135.6,
132.8, 132.7, 130.3, 129.8, 129.6, 129.5, 128.6, 127.8, 113.7, 84.8,
83.3, 79.1, 70.2, 68.2, 64.5, 55.3, 30.7, 29.1, 26.7, 18.9; IR (CDCl3)
3478 (OH) cm-1; MS (CI, NH3) m/z (rel intensity) 564 [10, (M +
NH4)+], 547 [1, (M + H)+ ]; HRMS (CI, NH3) m/z 564.3140 (564.3145
calcd for C33H46O5SiN, MNH4).
19
1
clear and colorless oil; [R]D -25.8 (c 0.26, CH2Cl2); H NMR (250
MHz, CDCl3) δ 7.27 (d, J ) 8.6 Hz, 2H), 6.86 (d, J ) 8.6 Hz, 2H),
5.87-5.61 (m, 2H), 4.65 (d, J ) 11.7 Hz, 1H), 4.41 (d, J ) 11.7 Hz,
1H), 3.80 (s, 3H), 3.57-3.37 (m, 5H), 2.65 (q, J ) 10.5 Hz, 1H), 2.44-
2.35 (m, 2H), 2.31-2.22 (m, 1H), 1.96 (ddd, J ) 14.0, 8.2, 1.1 Hz,
1H), 1.81-1.63 (m, 1H), 1.50-1.39 (m, 1H), 0.87 (t, J ) 7.4 Hz, 3H);
13C NMR (62.5 MHz, CDCl3) δ 159.2, 130.5, 129.7, 129.4, 129.2,
113.7, 82.9, 82.5, 80.1, 71.1, 66.1, 55.3, 30.9, 29.0, 25.7, 10.7; IR
(CDCl3) 3685 (OH) cm-1; MS (CI, NH3) m/z (rel intensity) 324 [21,
(M + NH4)+], 307 [5, (M + H)+]; HRMS (CI, NH3) m/z 307.1915
(307.1909 calcd for C18H27O4, MH).
2(R),3(R),8(R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-[(p-meth-
oxybenzyl)oxy]-2-[[(trifluoromethanesulfonyl)oxy]methyl]-3,4,7,8-
tetrahydro-(2H)-oxocin 60 and 2(R),3(R),8(R)-[[(tert-butyldiphen-
ylsilyl)oxy]methyl]-2-ethyl-3-[(p-methoxybenzyl)oxy]-3,4,7,8-tet-
rahydro-(2H)-oxocin 59. Trifluoromethanesulfonic anhydride (20 µL,
33 mg, 118 µmol) was added to a stirred solution of the alcohol 57
(18.4 mg, 33.6 µmol) in CH2Cl2 (1 cm3) containing pyridine (0.15 cm3)
at -15 °C. The solution was stirred for 10 min and then quenched by
the addition of a saturated solution of sodium bicarbonate (2 cm3). The
liquid phases were extracted with CH2Cl2 (3 × 5 cm3). The organic
phases were combined, washed with 1 M hydrochloric acid (10 cm3)
and a saturated solution of sodium bicarbonate (10 cm3), and dried
(MgSO4). The solvent was removed in Vacuo to yield the unstable
triflate 60; 1H NMR (500 MHz, THF-d8) δ 7.68-7.66 (m, 4H), 7.39-
7.33 (m, 6H), 7.19 (d, J ) 8.6 Hz, 2H), 6.83 (d, J ) 8.6, 2H), 5.91-
5.86 (m, 1H), 5.73-5.68 (m, 1H), 4.54 (d, J ) 11.2 Hz, 1H), 4.51-
4.47 (m, 2H), 4.27 (d, J ) 11.2 Hz, 1H), 4.00 (dt, J ) 7.6, 3.6 Hz,
1H), 3.80 (dd, J ) 9.1, 4.0 Hz, 1H), 3.72 (s, 3H), 3.65 (ddd, J ) 11.2,
5.0, 3.1 Hz, 1H), 3.52-3.45 (m, 2H), 2.64 (q, J ) 11.0 Hz, 1H), 2.48-
2.39 (m, 3H), 1.02 (s, 9H).
2(R),3(R),8(R)-8-Carboxaldehyde-2-ethyl-3-[(p-methoxybenzyl)-
oxy]-3,4,7,8-tetrahydro-(2H)-oxocin 61, 2(R),3(R),8(R)-2-Ethyl-8-
[(E),(R)-1-hydroxy-6-(trimethylsilyl)-3-hexen-5-ynyl]-3-[(p-methox-
ybenzyl)oxy]-3,4,7,8-tetrahydro-(2H)-oxocin 70, 2(R),3(R),8(R)-2-
Ethyl-8-[(E),(S)-1-hydroxy-6-(trimethylsilyl)-3-hexen-5-ynyl]-3-[(p-
methoxybenzyl)oxy]-3,4,7,8-tetrahydro-(2H)-oxocin 71 and (E)-2-
Ethenyl-1,8-bis(trimethylsilyl)-oct-5-en-1,7-diyne 73.17 To a stirred
solution of the alcohol 2(R),3(R),8(R)-2-ethyl-8-(hydroxymethyl)-3-[(p-
methoxybenzyl)oxy]-3,4,7,8-tetrahydro-(2H)-oxocin (20 mg, 65 µmol)
in CH2Cl2 (1.5 cm3) was added 4-methylmorpholine N-oxide (23 mg,
0.20 mmol) and powdered 4Å molecular sieves, and the mixture was
stirred for 5 min. TPAP (1.1 mg, 3.3 µmol) was added, and the
suspension was stirred for 20 min. The reaction mixture was diluted
with EtOAc and filtered through a plug of silica gel with EtOAc
washing. The solvent was removed in Vacuo to yield the aldehyde 61
(20 mg, 65 µmol, 100%) as a clear and colorless oil which was not
characterized and was used in the following reaction.
The cuprate displacement was performed according to the procedure
of Pougny.82 The triflate 60 was coevaporated with toluene (2 × 2
cm3) and put under an argon atmosphere. Recrystallized copper(I)
iodide93 (67 mg, 0.35 mmol) was placed in a round-bottomed flask
which was then purged with argon. Ether (1 cm3) was added, and the
grey suspension was cooled to -78 °C. Methyllithium (530 µL of a
1.3 M solution in ether, 0.70 mmol) was added quickly, while the
suspension was stirred vigorously. The cooling bath was removed,
and the reaction mixture was allowed to warm to 0 °C and was stirred
at that temperature for 1 min to yield a grey, almost homogeneous,
solution. The reaction mixture was recooled to -78 °C, and the triflate,
prepared above, was added as a solution in benzene (1 cm3, 2 × 0.5
cm3 rinse). The cooling bath was removed, and the heterogeneous
An oven dried magnetic stirrer bar was placed in a 50 cm3 oven
dried Schlenk tube which was sealed with a new septum. The system
was placed under vacuum and heated with a heat-gun for approximately
2 min. The vacuum was quenched with oxygen-free argon, and the
system was allowed to cool. The drying procedure was then repeated.
A dry gas-tight syringe was flushed with freshly prepared samarium
diiodide94 and then used to transfer samarium diiodide (1.68 cm3 of a
0.1 M solution in THF, 0.17 mmol) to the Schlenk tube. The Schlenk
tube was then sealed completely, and the solution of samarium diiodide
was allowed to stir for 10 min at ambient temperature to ensure that
the system was oxygen free. The Schlenk tube was cooled to -70 °C
(2-propanol/dry ice bath). A solution of the aldehyde 61 (17 mg, 56
µmol) and the enyne 69 (16 mg, 73 µmol) in THF (1 cm3) was added

Synthesis of Medium Ring Ethers. 5
J. Am. Chem. Soc., Vol. 119, No. 32, 1997 7497
to the cooled solution of samarium diiodide Via cannula with rinsing
(0.5 cm3). The dry ice was removed from the cold bath, and the system
was allowed to warm to 0 °C over a 2 h period. The reaction mixture
was quenched by the addition of 0.1 M hydrochloric acid (4 cm3) and
ether. The mixture was extracted with ether (3 × 10 cm3). The organic
phases were combined, washed with 1 M sodium thiosulfate solution
(15 cm3) and a saturated solution of sodium bicarbonate (15 cm3), and
dried (MgSO4). Purification by flash chromatography (ether:light
petroleum, 1:1) yielded the impure side-chain dimer 73 (4.5 mg, 16
µmol) as a clear and colorless oil; 1H NMR (250 MHz, CDCl3) δ 6.20
(dt, J ) 15.9, 7.3 Hz, 1H), 5.74 (ddd, J ) 16.9, 10.0, 5.7 Hz, 1H),
5.57 (dt, J ) 15.9, 1.3 Hz, 1H), 5.32 (dt, J ) 16.9, 1.3 Hz, 1H), 5.12
(dt, J ) 10.0, 1.3, 1H), 3.19-3.11 (m, 1H), 2.35 (dt, J ) 7.2, 1.3 Hz,
1H), 0.17, 0.18 (2 × s, 2 × 9H); HRMS (electrospray) m/z 275.1656
(275.1651 calcd for C16H27Si2, MH). Further elution of the column
yielded a 1:1 mixture of the epimeric alcohols 70 and 71 (15.5 mg, 35
µmol, 63%) which could be separated by HPLC (CH2Cl2:MeOH, 200:
1).
intensity) 502 [17, (M + NH4)+], 485 [1, (M + H)+]; HRMS (CI, NH3)
m/z 502.2990 (502.2989 calcd for C28H44O5SiN, MNH4).
2(R),3(R),8(R)-8-[(E),(R)-1-Acetoxy-6-(trimethylsilyl)-3-hexen-5-
ynyl]-2-ethyl-3-hydroxy-3,4,7,8-tetrahydro-(2H)-oxocin 80. To a
stirred solution of the acetate 2(R),3(R),8(R)-8-[(E),(R)-1-acetoxy-6-
(trimethylsilyl)-3-hexen-5-ynyl]-2-ethyl-3-[(p-methoxybenzyl)oxy]-
3,4,7,8-tetrahydro-(2H)-oxocin (7 mg, 14.9 µmol) in CH2Cl2 (1 cm3)
was added boron trichloride-methyl sulfide complex (37.4 µL, 74.7
µmol).69 The solution was stirred for 5 min and then quenched by the
addition of a saturated solution of sodium bicarbonate (1 cm3). The
reaction mixture was diluted with water, and the mixture was extracted
with CH2Cl2 (3 × 5 cm3). The organic phases were combined and
dried (MgSO4). The solvent was removed in Vacuo, and purification
by flash chromatography (light petroleum:ether, 3:2) gave the title
compound 80 (5 mg, 13.7 µmol, 92%) as a clear and colorless oil;
24
1
[R]D -25.0 (c 0.04, CH2Cl2); H NMR (500 MHz, CDCl3) δ 6.11
(dt, J ) 16.0, 7.2 Hz, 1H), 5.77-5.74 (m, 2H), 5.58 (d, J ) 16.0 Hz,
1H), 4.96 (dt, J ) 8.0, 4.6 Hz, 1H), 3.73-3.65 (m, 1H), 3.47-3.45
(m, 1H), 3.41-3.39 (m, 1H), 2.54-2.49 (m, 2H), 2.44-2.38 (m, 1H),
2.37-2.31 (m, 1H), 2.17-2.12 (m, 1H), 2.08 (s, 3H), 1.66-1.58 (m,
2H), 0.93 (t, J ) 7.4 Hz, 3H), 0.18 (s, 9H); 13C NMR (62.5 MHz,
CDCl3) δ 170.5, 140.3, 129.5, 128.8, 112.7, 103.4, 93.8, 83.1, 80.5,
74.4, 73.6, 34.1, 33.5, 29.8, 25.5, 21.1, 10.4, -0.1; IR (CDCl3) 1734
(CO) cm-1; MS (CI, NH3) m/z (rel intensity) 382 [17, (M + NH4)+],
365 [12, (M + H)+]; HRMS (CI, NH3) m/z 365.2148 (365.2148 calcd
for C20H33O4Si, MH).
Data for the less polar compound 70; Rf 0.3 (ether:light petroleum,
25
1
1:1); [R]D -41.0 (c 0.105, CH2Cl2); H NMR (500 MHz, CDCl3) δ
7.27 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 6.28 (dt, J ) 15.9,
7.2 Hz, 1H), 5.83-5.78 (m, 1H), 5.72-5.67 (m, 1H), 5.58 (d, J )
15.9 Hz, 1H), 4.64 (d, J ) 11.6 Hz, 1H), 4.40 (d, J ) 11.6 Hz, 1H),
3.81 (s, 3H), 3.53-3.42 (m, 3H, 2-H, 3-H, CHOH), 3.12 (dd, J ) 9.1,
6.7 Hz, 1H, 8-H), 2.80 (brd, J ) 2.8 Hz, 1H, OH), 2.65 (q, J ) 11.0
Hz, 1H), 2.49-2.37 (m, 3H), 2.29-2.23 (m, 1H), 2.06 (dd, J ) 13.6,
8.4 Hz, 1H), 1.66-1.62 (m, 1H), 1.60-1.55 (m, 1H), 0.83 (t, J ) 7.4
Hz, 3H), 0.18 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 159.3, 141.8,
130.4, 129.6, 129.4, 129.3, 113.7, 111.9, 103.8, 93.2, 84.2, 83.3, 79.6,
73.1, 71.1, 55.3, 37.1, 30.9, 28.9, 25.3, 10.5, -0.1; IR (CDCl3) 3566
(OH) cm-1; MS (CI, NH3) m/z (rel intensity) 460 [15, (M + NH4)+],
443 [3, (M + H)+]; HRMS (CI, NH3) m/z 460.2883 (460.2883 calcd
for C26H42O4SiN, MNH4).
2(R),3(S),8(R)-8-[(E),(R)-1-Acetoxy-6-(trimethylsilyl)-3-hexen-5-
ynyl]-3-bromo-2-ethyl-3,4,7,8-tetrahydro-(2H)-oxocin, TMS-Lau-
rencin 81.17 To a stirred solution of the alcohol 80 (4.0 mg, 10.9 µmol)
in toluene (1 cm3) was added carbon tetrabromide (18.2 mg, 55 µmol)
that had been purified by sublimation followed by dissolution in CH2Cl2
and passage down a column of UG1 alumina and dried over potassium
hydroxide pellets in Vacuo. Trioctylphosphine (24.5 µL, 55 µmol),
that had been purified by distillation at reduced pressure (Kugelrohr,
0.1 mmHg, 175 °C), was added Via syringe, and the resulting solution
was heated to 70 °C for 2 h. The reaction mixture was allowed to
cool, and the solvent was removed in Vacuo. Purification by flash
chromatography (hexane:EtOAc, 40:1 increasing the polarity to 35:1)
yielded the title compound 81 as a clear and colorless oil (3.2 mg, 7.5
The more polar alcohol 71 contained signals at δ 6.16 (dt, J ) 10.8,
7.4 Hz, SiC≡CCHdCH) assigned to 72 as a slight impurity. Data for
22
the more polar compound 71; Rf 0.3 (ether:light petroleum, 1:1); [R]D
-47.0 (c 0.1, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.27 (d, J ) 8.5
Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 6.23 (dt, J ) 16.0, 7.3 Hz, 1H),
5.82 (dt, J ) 10.1, 7.9 Hz, 1H), 5.71-5.65 (m, 1H), 5.60 (d, J ) 16.0
Hz, 1H), 4.63 (d, J ) 11.7 Hz, 1H), 4.39 (d, J ) 11.7 Hz, 1H), 3.80
(s, 3H), 3.71-3.68 (m, 1H, CHOH), 3.49-3.46 (m, 1H, 2-H), 3.44-
3.41 (m, 1H, 3-H), 3.18 (dd, J ) 9.1, 5.1 Hz, 1H, 8-H), 2.65 (q, J )
10.8 Hz, 1H), 2.50-2.43 (m, 2H), 2.40-2.36 (m, 1H), 2.30-2.22 (m,
1H), 2.20-2.15 (m, 2H, 7-H, OH), 1.68-1.63 (m, 1H), 1.52-1.48 (m,
1H), 0.82 (t, J ) 7.4 Hz, 3H), 0.17 (s, 9H); 13C NMR (62.5 MHz,
CDCl3) δ 159.2, 142.1, 130.6, 129.8, 129.6, 129.2, 113.7, 112.4, 103.7,
93.4, 84.2, 83.3, 80.0, 73.3, 71.0, 55.3, 36.8, 29.4, 28.9, 25.5, 10.7,
-0.1; IR (CDCl3) 3586 (OH) cm-1; MS (CI, NH3) m/z (rel intensity)
460 [5, (M + NH4)+], 443 [1, (M + H)+]; HRMS (CI, NH3) m/z
460.2883 (460.2883 calcd for C26H42O4SiN, MNH4).
18
µmol, 69%); [R]D +37.1 (c 0.035, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 6.10 (dt, J ) 15.9, 7.5 Hz, 1H), 5.95-5.86 (m, 2H), 5.57 (d,
J ) 15.9 Hz, 1H), 4.98 (dt, J ) 8.6, 4.3 Hz, 1H), 4.07 (dt, J ) 9.9, 3.5
Hz, 1H), 3.43 (ddd, J ) 9.9, 7.2, 2.5 Hz, 1H), 3.39 (dd, J ) 10.5, 4.4
Hz, 1H), 3.15 (ddd, J ) 13.7, 8.6, 3.5 Hz, 1H), 2.52-2.44 (m, 2H),
2.41-2.31 (m, 2H), 2.11-2.05 (m, 1H), 2.08 (s, 3H), 1.95 (ddq, J )
14.5, 7.5, 2.5 Hz, 1H), 1.57 (dqu, J ) 14.5, 7.5 Hz, 1H), 0.98 (t, J )
7.5 Hz, 3H), 0.18 (s, 9H); 13C NMR (62.5 MHz, CDCl3) δ 170.4, 140.2,
129.3, 128.9, 112.7, 103.3, 93.8, 84.5, 81.3, 74.2, 55.9, 33.7, 32.3, 29.7,
25.8, 21.1, 9.2, -0.1; IR (CHCl3) 1734 (CO) cm-1; HRMS (electro-
spray) m/z 427.1279 (427.1305 calcd for C20H32O3Si79Br, MH).
2(R),3(R),8(R)-8-[(E),(R)-1-Acetoxy-6-(trimethylsilyl)-3-hexen-5-
ynyl]-2-ethyl-3-[(p-methoxybenzyl)oxy]-3,4,7,8-tetrahydro-(2H)-oxo-
cin. To a stirred solution of the alcohol 70 (7 mg, 15.8 µmol) in CH2Cl2
(2 cm3) containing pyridine (5 drops) at 0 °C was added DMAP (5
mg) and acetic anhydride (3 drops). The solution was stirred for 5 h
and then quenched by the addition of 1 M hydrochloric acid (5 cm3).
The mixture was extracted with EtOAc (2 × 5 cm3). The organic
phases were combined, washed with a saturated solution of sodium
bicarbonate (5 cm3), and dried (MgSO4). The solvent was removed in
Vacuo, and purification by flash chromatography (light petroleum:ether,
5:1) gave the title compound (7 mg, 14.4 µmol, 95%) as a clear and
colorless oil; [R]D -15.2 (c 0.105, CH2Cl2); H NMR (250 MHz,
CDCl3) δ 7.27 (d, J ) 8.4 Hz, 2H), 6.86 (d, J ) 8.5 Hz, 2H), 6.10 (dt,
J ) 15.9, 7.6 Hz, 1H), 5.83-5.61 (m, 2H), 5.56 (d, J ) 15.9 Hz, 1H),
4.96 (dt, J ) 8.7, 4.0 Hz, 1H), 4.62 (d, J ) 11.7 Hz, 1H), 4.39 (d, J
) 11.7 Hz, 1H), 3.80 (s, 3H), 3.49-3.30 (m, 3H), 2.72-2.47 (m, 2H),
2.44-2.22 (m, 5H), 2.17-1.97 (m, 1H), 2.06 (s, 3H), 1.68-1.46 (m,
2H), 0.84 (t, J ) 7.4 Hz, 3H), 0.18 (s, 9H); 13C NMR (62.5 MHz,
CDCl3) δ 170.5, 159.2, 140.8, 130.7, 129.6, 129.4, 129.3, 113.7, 112.5,
103.6, 93.5, 84.2, 81.4, 79.9, 74.8, 70.8, 55.3, 33.5, 29.9, 28.8, 25.3,
21.1, 10.6, -0.1; IR (CDCl3) 1734 (CO) cm-1; MS (CI, NH3) m/z (rel
2(R),3(S),8(R)-8-[(E),(R)-1-Acetoxy-3-hexen-5-ynyl]-3-bromo-2-
ethyl-3,4,7,8-tetrahydro-(2H)-oxocin, (+)-Laurencin 1. To a stirred
solution of TMS-laurencin 81 (3.2 mg, 7.5 µmol) in THF (2 cm3) at
-13 °C was added TBAF (34 µL of a 1.1 M solution in THF, 37 µmol),
and the reaction mixture was stirred for 2.5 min. The reaction was
quenched by the addition of brine (2 cm3) and ether (2 cm3). The
mixture was extracted with ether (10 cm3) and dried (MgSO4).
Purification by flash chromatography (hexane:EtOAc, 15:1) yielded
20
(+)-laurencin 1 (2.6 mg, 7.3 µmol, 98%) as a white gum; [R]D +70
27
1
(c 0.05, CHCl3), {lit.1 [R]D +70.2 (c 1.00, CHCl3)}; H NMR (500
MHz, CDCl3) δ 6.16 (dt, J ) 16.0, 7.2 Hz, 1H, C≡CCHdCH), 5.96-
5.86 (m, 2H, 5-H, 6-H), 5.53 (dd, J ) 16.0, 1.5 Hz, 1H, C≡CCHdCH),
5.00 (dt, J ) 8.7, 4.4 Hz, 1H, AcOCH), 4.07 (dt, J ) 9.9, 3.4 Hz, 1H,
3-H), 3.43 (ddd, J ) 9.9, 7.4, 2.6 Hz, 1H, 2-H), 3.39 (dd, J ) 10.5,
4.4 Hz, 1H, 8-H), 3.16 (ddd, J ) 14.0, 8.5, 3.4 Hz, 1H, 4-H), 2.82 (d,
J ) 1.5 Hz, 1H, C≡CH), 2.53-2.33 (m, 4H, 4-H, 7-H, C≡CCHd
CHCH2), 2.10-2.06 (m, 1H, 7-H), 2.08 (s, 3H, CH3COO), 1.95 (ddq,
J ) 14.4, 7.4, 2.6 Hz, 1H, CHHCH3), 1.57 (dqu, J ) 14.4, 7.4, 1H,
CHHCH3), 0.98 (t, J ) 7.4 Hz, 3H, CH2CH3); 13C NMR (62.5 MHz,
CDCl3) δ 170.3, 141.1, 129.2, 129.0, 111.6, 84.6, 81.8, 81.4, 76.7, 74.1,
56.0, 33.8, 32.3, 29.7, 25.8, 21.0, 9.3; IR (CHCl3) 3304 (C≡CH), 2927,
25
1

7498 J. Am. Chem. Soc., Vol. 119, No. 32, 1997
Burton et al.
2855, 1734 (CO) cm-1; HRMS (electrospray) m/z 355.0909 (355.0909
of the accompanying paper and Prof. J. Palenzuela for spectra
of the benzyl analog of 59. Further acknowledgments appear
in the Supporting Information.
calcd for C17H24O379Br, MH).
Acknowledgment. We thank the Engineering and Physical
Sciences Research Council (EPSRC) UK for a research grant,
Pfizer Central Research, and Corpus Christi College Cambridge
for the award of a studentship and a Junior Research Fellow
ship (J.W.B.), the Cambridge European Overseas Trust, Ciba
(Novartis) and the Swiss Foundation for Gifted Students
(scholarship to S.D.), and the Commission of the European
Communities (TMR award to T.C.S.) for generous financial
support. We thank Dr. G. M. Williams for assistance in the
preparation of 40 and 41, Dr. S. Bunkhall for the X-ray analysis
of compound 29a, Prof. L. E. Overman for spectra of TIPS-
laurencin, Prof. A. Murai for spectra of natural and synthetic
laurencin, and Dr. J. M. Goodman for advice on molecular
modeling. We thank Prof. R. Hoffmann (Marburg) for a preprint
Supporting Information Available: Experimental proce-
dures for the synthesis of 2-10, 16-19, 21-29, 32-35, 40-
43, 54-56, 58, 62-69, and 76-79 and the procedure for the
conversion of 71 into 70; details of the X-ray crystal structure
determination; tables of atomic coordinates, isotropic displace-
ment parameters, anisotropic displacement parameters, bond
lengths, and bond angles for 29a (this data has been deposited
1
with the Cambridge Crystallographic Database); H and 13C
NMR spectra of synthetic (+)-laurencin 1 (58 pages). See any
current masthead page for ordering information and Internet
access instructions.
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