An asymmetric aldol - Ring-closing metathesis strategy for the enantioselective construction of oxygen heterocycles: An efficient approach to the enantioselective synthesis of (+)-laurencin

Article abstract of DOI:10.1021/ja990421k

A strategy is described for the enantioselective construction of medium- ring cyclic ethers by merging the asymmetric aldol addition of glycolates with a ring-closing metathesis reaction. Cyclic ethers of seven-, eight-, and nine-membered rings are readil

Full text of DOI:10.1021/ja990421k

J. Am. Chem. Soc. 1999, 121, 5653-5660
5653
An Asymmetric Aldol-Ring-Closing Metathesis Strategy for the
Enantioselective Construction of Oxygen Heterocycles: An Efficient
Approach to the Enantioselective Synthesis of (+)-Laurencin
Michael T. Crimmins* and Allison L. Choy
Contribution from the Venable and Kenan Laboratories of Chemistry, The UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599-3290
ReceiVed February 9, 1999
Abstract: A strategy is described for the enantioselective construction of medium-ring cyclic ethers by merging
the asymmetric aldol addition of glycolates with a ring-closing metathesis reaction. Cyclic ethers of seven-,
eight-, and nine-membered rings are readily available through a ring-closing metathesis without cyclic
conformational constraints, by exploiting the acyclic conformational bias of the gauche effect. A short formal
synthesis of the eight-membered ether (+)-laurencin, a red algae metabolite, has been accomplished utilizing
the aldol-metathesis combination.
Medium-ring ethers are found in a number of marine natural
products, such as brevetoxin A1 and B,2 yessotoxin,3 ciguatoxin,4
and maitotoxin.5 In addition, several other marine natural
products containing medium-ring ethers, including laurencin,6
prelaureatin,7 pannosallene,8 isolaurallene,9 and neolaurallene10
(Figure 1), have been isolated from red algae and species which
feed on Laurencia sp.11 Laurencin, a representative member of
the red algae oxocenes, has been the subject of significant
synthetic effort and has been prepared by several different
strategic approaches.12,13
* Corresponding author. Phone: (919) 966-5177. Fax: (919) 962-2388.
E-mail: mtc@net.chem.unc.edu.
(1) Shimizu, Y.; Chou, H. N.; Bando, H.; Van Duyne, G.; Clardy, J. C.
J. Am. Chem. Soc. 1986, 108, 514-515. Pawlak, J.; Tempesta, M. S.; Golik,
J.; Zagorski, M. G.; Lee, M. S.; Nakanishi, K.; Iwashita, T.; Gross, M. L.;
Tomer, K. B. J. Am. Chem. Soc. 1987, 109, 1144-1150. Shimizu, Y.;
Bando, H.; Chou, H.-N.; Van Duyne, G.; Clardy, J. C. J. Chem. Soc., Chem.
Commun. 1986, 1656-1658.
Figure 1.
A General Strategy for the Asymmetric Synthesis of
Unsaturated Medium-Ring Ethers. We sought to develop a
flexible approach to the synthesis of unsaturated medium-ring
ethers14 which would allow the preparation of a variety of ring
sizes and stereochemical substitution patterns. The strategy we
pursued was based on the recognition that many of the red algae
medium-ring ether natural products were substituted on both
carbons flanking the ether linkage. In addition, one or both of
the carbons adjacent to the ether linked carbons were substituted,
(2) Lin, Y. Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.; Golik,
J.; James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773-6775.
(3) Murata, M.; Kumagai, M.; Lee, J. S.; Yasumoto, T. Tetrahedron Lett.
1987, 28, 5869-5872. Takahashi, H.; Kusumi, T.; Kan, Y.; Satake, M.;
Yasumoto, T. Tetrahedron Lett. 1996, 37, 7087-7090. Murata, M.; Legrand,
A. M.; Ishibashi, Y.; Yasumoto, T. J. Am. Chem. Soc. 1989, 111, 8929-
8931.
(4) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T. J. Am.
Chem. Soc. 1989, 111, 8929-8931. Murata, M.; Legrand, A. M.; Ishibashi,
Y.; Fukui, M.; Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380-4386.
(5) Nonomura, T.; Sasaki, M.; Matsumori, N.; Murata, M.; Tachibana,
K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1675-1678.
Sasaki, M.; Matsumori, N.; Maruyama, T.; Nonomura, T.; Murata, M.;
Tachibana, K.; Yasumoto, T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1672-
1675.
(12) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J. G.;
Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483-7498.
(13) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33, 4345-4348.
Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem.
Soc. 1995, 117, 5958-5966. Mujica, M. T.; Afonso, M. M.; Galindo, A.;
Palenzuela, J. A. Synlett 1996, 983-984. Kru¨ger, J.; Hoffmann, R. W. J.
Am. Chem. Soc. 1997, 119, 7499-7504. Mujica, M. T.; Afonso, M. M.;
Galindo, A.; Palenzuela, J. A. J. Org. Chem. 1998, 63, 9728-9738.
(14) For a review on the synthesis of medium-ring cyclic ethers, see:
Moody, C. J.; Davies, M. J. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, A., Ed.; Elsevier Science Publishers: New York 1992; Vol
10. For more recent examples, see: Berger, D.; Overman, L. E.; Renhowe,
P. A. J. Am. Chem. Soc. 1997, 119, 2446-2452. Rychnovsky, S. D.;
Dahanukar, V. H. J. Org. Chem. 1996, 61, 7648-7649. Overman, L. E.;
Thompson, A. S. J. Am. Chem. Soc. 1988, 110, 2248-2256. Nicolaou, K.
C.; Yang, Z.; Ouellette, M.; Shi, G.-Q.; Ga¨rtner, P.; Gunzner, J. L.; Agrios,
K. A.; Huber, R.; Chadha, R.; Huang, D. H. J. Am. Chem. Soc. 1997, 119,
8105-8106.
(6) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193-
4205. Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Monteath Robertson,
J. J. Chem. Soc., Chem. Commun. 1965, 638.
(7) Fukuzawa, A.; Takasugi, Y.; Murai, A. Tetrahedron Lett. 1991, 32,
5597-5598.
(8) Suzuki, M.; Takahashi, Y.; Matsuo, Y.; Masuda, M. Phytochemistry
1996, 41, 1101-1103.
(9) Kurata, K.; Furusaki, A.; Suehiro, K.; Katayama, C.; Suzuki, T. Chem.
Lett. 1982, 1031-1034.
(10) Notaro, G.; Piccialli, V.; Sica, D.; Mayol, L.; Giordano, F. J. Nat.
Prod. 1992, 55, 626-632.
(11) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113-158. Faulkner, D. J.
Nat. Prod. Rep. 1997, 14, 259-302. Faulkner, D. J. Nat. Prod. Rep. 1996,
13, 75-125 and earlier reviews in the same series.
10.1021/ja990421k CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/27/1999

5654 J. Am. Chem. Soc., Vol. 121, No. 24, 1999
Crimmins and Choy
Scheme 1
Scheme 2
and in particular, substituted with an oxygen group cis or a
halide trans on the â-carbon to the ether oxygen. This observa-
tion suggested a functional precursor such as diol 2 for laurencin;
similar precursors can be imagined for the other aforementioned
medium-ring ether natural products. Diol 2, a key intermediate
in Holmes’s recently reported synthesis of laurencin,12 was
envisioned to arise from the reduction of an asymmetric aldol
product such as 3, followed by a ring-closing metathesis reaction
of the diene to form the ∆-4-oxocene. The aldol product 3 could
be prepared from acid 4 by attachment to a chiral auxiliary prior
to a boron- or titanium enolate-mediated aldol addition (Scheme
1).
Scheme 3
There were two key reactions to the success of the above
strategy: the auxiliary-mediated asymmetric aldol addition of
a glycolate imide and the ring-closing metathesis reaction to
construct the ∆-4-oxocene. While some precedent existed for
the aldol addition in reports by Evans,15 at the time we began
this work16 no examples of construction of eight-membered
cyclic ethers by olefin metathesis had been reported. In fact,
there was evidence that formation of eight-membered cyclic
ethers might not be achievable by ring-closing metathesis
without an internal cyclic constraint.17 Since we began this
investigation, reports of the formation of medium-ring ethers
both with18 and without19 cyclic conformational constraints have
appeared. However, at the outset, the uncertainty of the ring-
closing metathesis to form the ∆-4-oxocene prompted an
investigation of the synthesis of simpler analogues to test the
proposed strategy.
An approach to the synthesis of seven-, eight-, and nine-
membered cyclic ethers was undertaken using the asymmetric
aldol-olefin metathesis sequence. The general strategy for the
asymmetric construction of the required dienes is illustrated in
Scheme 2 for the preparation of cyclic ether 10. Treatment of
3-buten-1-ol with sodium hydride and bromoacetic acid in THF
gave the alkoxyacetic acid in quantitative yield. Subsequent
exposure of the acid to pivaloyl chloride and triethylamine
provided the mixed anhydride in situ. Acylation of the lithium
salt of (S)-2-benzyloxazolidinone with the mixed anhydride
provided the acyl oxazolidinone 6 in 82% yield. Formation of
the dibutylboron enolate according to the standard Evans20
protocol and addition of acrolein gave the syn aldol product 7
as single detectable isomer by 300-MHz NMR spectroscopy.
Reductive removal of the chiral auxiliary (LiBH4, THF, MeOH)
afforded the diol 8 in excellent yield. Acylation of the diol with
acetic anhydride produced the required diene 9 in five synthetic
steps in good overall yield (>99% ee). Exposure of diene 9 to
ring-closing metathesis conditions ([(C6H11)3P]2Cl2RudCHPh,
CH2Cl2, 0.1 M, 40 °C) resulted in predominant formation of a
dimer accompanied by less than 20% of the desired oxepene.
Fortunately, when the concentration was lowered (0.003 M
CH2Cl2, 40 °C, 5 mol % catalyst), the reaction resulted in
exclusive formation of the oxepene 10 in 95% yield after 2 h.
With the successful ring closure of diene 9 to oxepene 10 with
the Grubbs catalyst, the Schrock molybdenum catalyst was not
investigated, since is it difficult to handle and also more difficult
to prepare because of oxygen sensitivity.
The corresponding eight-membered ring precursor 15 was
constructed by a similar route, starting with 4-penten-1-ol, as
illustrated in Scheme 3. Exposure of diene 15 to 7 mol % of
the Grubbs catalyst in dichloromethane (0.003 M) at 40 °C
resulted in the formation of 73% of the oxocene 16, ac-
companied by 17% of a dimer. This result was particularly
gratifying in light of earlier reports of failed attempts to close
(15) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799-802.
(16) For a preliminary communication on the synthesis of medium-ring
ethers by an asymmetric aldol-metathesis strategy, see: Crimmins, M. T.;
Choy, A. L. J. Org. Chem. 1997, 62, 7548-7549.
(17) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108-2109.
(18) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123-126.
Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 127-130. Delgado,
M.; Martin, J. D. Tetrahedron Lett. 1997, 38, 6299-6300. Clark, J. S.;
Hamelin, O.; Hufton, R. Tetrahedron Lett. 1998, 39, 8321-8324.
(19) Linderman, R. J.; Siedlecki, J.; O’Neill, S. A.; Sun, H. J. Am. Chem.
Soc. 1997, 119, 6919-6920.
(20) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.

EnantioselectiVe Synthesis of (+)-Laurencin
J. Am. Chem. Soc., Vol. 121, No. 24, 1999 5655
Scheme 4
Scheme 6
able synthesis of 3-butenal was needed. Double allylation of
glyoxal with allyl bromide and tin metal in aqueous media23,24
gave 1,7-octadiene-3,4-diol in 85% yield. Cleavage of the diol
with sodium periodate in a dichloromethane-pH 4 buffer
biphase provided excellent yields of 3-butenal in solution form.
The resultant dichloromethane solution of 3-butenal was used
directly in the aldol addition.
Scheme 5
A recent modification of the Evans procedure was exploited
in the aldol addition. We recently discovered that chlorotitanium
enolates of acyloxazolidinethiones undergo rapid, highly selec-
tive syn aldol additions when the enolates are formed with
titanium tetrachloride using (-)-sparteine as the base.25 Here
we demonstrate that R-alkoxy acyloxazolidinones and R-alkoxy
acyloxazolidinethiones also function well in this reaction. Aldol
addition of the titanium enolates of 6 and 12 to 3-butenal as
described above produced 19 and 23, respectively, with excellent
stereoselectivity. Subsequent removal of the auxiliary and
acylation of the resultant diols gave the diene-diacetates 21 and
25.
eight-membered rings by olefin metathesis without cyclic
constraints. Hoveyda had reported a successful ring-closing
metathesis reaction on a sulfonamide linked diene 17 but also
reported that the diene ether 18 produced only dimers and
oligomers.21 The successful ring-closing metathesis of diene 15
The diene 21 was converted to the ∆-4-oxocene 22 in 94%
yield in 30 min by exposure to 7 mol % of the Grubbs catalyst.
The remarkable ease of the ring closure of diene 21 in contrast
to the partial dimerization of the isomeric diene 15 can be
rationalized on the basis of the relative energies of the products.
The position of the double bond has a dramatic effect on the
relative energy of the oxocene. Oxocene 22 was calculated26 to
be on the order of 3-4 kcal lower in energy than oxocene 16.
This difference in energy is presumably reflected in the transition
states for formation of the metallocyclobutane intermediates
which lead to the ring-closed products.
in contrast to 18 suggests that the vicinal stereogenic centers in
diene 15 provide access to conformations where the olefinic
chains are gauche, which are required to facilitate ring closure
by virtue of the gearing due to the known gauche effect of 1,2-
dioxygen substitution. The stabilization which results from the
gauche disposition of the two oxygens contributes substantially
to the stabilization of one of the conformations with the olefinic
chains gauche. The lack of the vicinal oxygen dipolar effect in
diene 18 apparently allows dimerization and oligomerization
to compete.
The nine-membered cyclic ether 26 was also readily formed
by ring-closing metathesis of diene 25. While Clark has shown
that nine-membered cyclic ethers can be prepared by ring-
closing metathesis with the Schrock molybdenum carbene
complex,18 the closure of diene 25 to ether 26 is the first example
of the formation of a nine-membered ring by an olefin
metathesis without a cyclic conformational constraint. The
remarkable efficiency of this process portends well for its
application in the synthesis of marine natural products such as
isolaurallene.
The isomeric ∆-4-oxocene 22 and the nine-membered
analogue 26 were prepared (Schemes 4 and 6) from the
asymmetric aldol reaction of 6 and 12. The use of 3-butenal or
a 3-butenal equivalent as the aldehyde was required to incor-
porate the correct number of carbons and position the alkene
correctly in the ∆-4-oxocene after the olefin metathesis. While
4-tert-butyldiphenylsilyloxybutanal had been used as a 3-butenal
equivalent in the earlier model studies because of initial
problems with generating and purifying 3-butenal, the need to
convert the primary silyl ether to a terminal olefin was
cumbersome. Thus, a procedure for the simple preparation of
3-butenal was required. A survey of the literature and attempted
execution of some known methods22 for the preparation of
3-butenal met with unsatisfactory results. An alternative, work-
Formal Synthesis of (+)-Laurencin. After we demonstrated
the feasibility of the basic strategy for the construction of
(23) Einhorn, C.; Luche, J.-L. J. Organomet. Chem. 1987, 322, 177-
183.
(24) Crimmins, M. T.; Wells, A. J.; Kirincich, S. J.; Choy, A. L. Synth.
Commun. 1998, 28, 3675-3679.
(21) Visser, M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda,
A. H. J. Am. Chem. Soc. 1996, 118, 4291-4298.
(22) Kasahara, A.; Izumi, T.; Yanai, H. Chem. Ind. 1983, 898. Kritchev-
sky, D. J. Am. Chem. Soc. 1943, 65, 487. Trost, B. M.; Dumas, J.; Villa,
M. J. Am. Chem. Soc. 1992, 114, 9836-9845.
(25) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883-7884.
(26) Molecular mechanics calculations were made using the MM2 force
field.

5656 J. Am. Chem. Soc., Vol. 121, No. 24, 1999
Crimmins and Choy
Scheme 7
Figure 2.
no influence on the selectivity of the asymmetric aldol addition
in either case. The chiral auxiliary was readily removed by
reduction of 3a or 3b with lithium borohydride in methanol-
ether to produce the diol 29 in greater than 80% yield.
Acetylation of the diol gave diacetate 30. The critical ring-
closing metathesis reaction proceeded smoothly with 5 mol %
(Cy3P)2RuCl2dCHPh in dichloromethane (0.003 M) at reflux
to give 97% of the eight-membered ether 31.
The stereochemistry of the ∆-4-oxocene 31 which resulted
was confirmed by inspection of the NOESY spectrum. A
substantial cross-peak was observed between H7 and H13,
indicating a cis relationship on the ∆-4-oxocene (see Figure
2). A significant interaction was also observed for H12 and H13,
indicating their cis relationship.
The diacetate 31 was converted to the Holmes intermediate
2 by DDQ cleavage of the benzyl ether,30 protection of the
primary alcohol as its tert-butyldiphenylsilyl ether, and meth-
anolysis of the two acetates. The diol 2 was identical in all
respects (1H NMR, 13C NMR, IR, and [R]25D) to that reported
by Holmes et al.12 The strategy presented here for the asym-
metric construction of medium-ring cyclic ethers by merging
the asymmetric aldol addition of glycolates with a ring-closing
metathesis reaction should provide efficient entry to a variety
of cyclic ethers. Application of this strategy to the synthesis of
various marine metabolites is in progress.
medium-ring ethers, the application of the asymmetric aldol-
olefin metathesis sequence to the synthesis of (+)-laurencin was
undertaken. Diol 2 was chosen as the initial target, since its
conversion to laurencin had been successfully completed by
Holmes et al.12 A precursor to the C7 (laurencin numbering)
side chain would be incorporated at an early stage of the
synthesis prior to the asymmetric aldol reaction. The synthesis
of the required alkoxy acetic acid 4 is shown in Scheme 7. Ring-
opening of commercially available (R)-benzyl glycidyl ether with
vinylmagnesium bromide in the presence of catalytic copper(I)
iodide gave 92% of the secondary alcohol 27. Exposure of the
alcohol 27 and bromoacetic acid to sodium hydride produced
the desired alkoxyacetic acid 4 in 71% yield. The acid 4 was
treated with oxalyl chloride, and the resultant acid chloride was
added to (S)-4-benzyloxazolidine-2-thione and triethylamine to
provide the acyloxazolidinethione 28a in 73% overall yield. The
corresponding acyl oxazolidinone 28b was prepared similarly
by exposure of the acid chloride to the lithium salt of (S)-4-
benzyloxazolidine-2-one.
Enolization of acyloxazolidinethione 28a with TiCl4 and (-)-
sparteine25 at -78 °C, followed by addition of freshly prepared
3-butenal solution, produced the aldol adduct 3a with excellent
diastereoselectivity (>98:2 ds, 90% yield at 30% conversion),
thus establishing the C12 and C13 stereogenic centers for (+)-
laurencin. Alternatively, the acyloxazolidinone 28b could be
enolized29 with TiCl4 and Hunig’s base followed by aldol
reaction with 3-butenal to give 65% yield of the aldol adduct
3b after purification. The C7 stereogenic center appears to have
Experimental Section
Materials and Methods: General. Infrared (IR) spectra were
obtained using a Mattson FT-IR 5000 Galaxy series infrared spectrom-
eter. Proton and carbon nuclear magnetic resonance (1H and 13C NMR)
spectra were recorded on the following instruments: Bruker model AC-
200 (1H at 200 MHz; 13C at 50 MHz), Bruker model WM-250 (1H at
250 MHz), and Varian model XL-400 (1H at 400 MHz, 13C at 100
MHz). Optical rotations were determined using a Perkin-Elmer 241
polarimeter. Elemental analyses were performed by Atlantic Microlab,
Inc., Norcross, GA. Diethyl ether, tetrahydrofuran (THF), and dichloro-
methane were dried by being passed through a column of neutral
alumina under nitrogen immediately prior to use. Alkylamines, chloro-
trimethylsilane, and acetonitrile were distilled from calcium hydride
immediately prior to use.
(R)-1-(Benzyloxymethyl)but-3-enyl-1-oxyacetic Acid (4). Sodium
hydride (60% dispersion in mineral oil, 2.80 g, 70 mmol) was washed
three times with dry hexanes and suspended in 50 mL of THF, and the
mixture was cooled to 0 °C. The appropriate alcohol (70 mmol; 3-buten-
1-ol for acid 5; 4-penten-1-ol for acid 11; and alcohol 2727 for acid 4)
was added dropwise over 15 min. The resulting mixture was stirred at
0 °C for 15 min, warmed to 25 °C for 15 min, and then recooled to 0
°C. In a second flask, sodium hydride (60% dispersion in mineral oil,
2.80 g, 70 mmol) was washed three times with dry hexanes and
suspended in 25 mL of THF, and the mixture was cooled to 0 °C.
Bromoacetic acid (70 mmol) dissolved in 25 mL of THF was cannulated
into the second flask, and the mixture was stirred at 0 °C for 5 min.
The sodium alkoxide of the alcohol was then cannulated into the flask
containing the sodium carboxylate of bromoacetic acid. The resultant
mixure was warmed to 25 °C and stirred for 3 h. The reaction was
(27) Takano, S.; Sekiguchi, Y.; Sato, N.; Ogasawara, K. Synthesis 1987,
139-141.
(28) Gravestock, M. B.; Knight, D. W.; Lovell, J. S.; Thornton, S. R. J.
Chem. Soc., Perkin Trans. 1 1994, 1661-1663.
(29) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047-1049.
(30) Schreiber, S. L.; Ikemoto, N. J. Am. Chem. Soc. 1992, 114, 2524-
2536.

EnantioselectiVe Synthesis of (+)-Laurencin
J. Am. Chem. Soc., Vol. 121, No. 24, 1999 5657
quenched with water, and the THF was removed in vacuo. The aqueous
layer was washed with ether, acidified with concentrated H2SO4, and
then extracted three times with ether. The extracts were washed with
water, dried over Na2SO4, filtered, and concentrated in vacuo. The
known28 alkoxyacetic acid 4 was obtained in 71% yield and was used
without further purification: 1H NMR (CDCl3) δ 7.33 (m, 5H), 5.74
(m, 1H), 5.11 (m, 2H), 4.60 (ABq, J ) 12.0 Hz, ∆νAB ) 7.2 Hz, 2H),
4.17 (ABq, J ) 17.5 Hz, ∆νAB ) 56.9 Hz, 2H), 3.59 (m, 1H), 3.47
(m, 2H), 2.25 (m, 2H); 13C NMR (CDCl3) δ 35.7, 67.5, 71.7, 73.1
79.8, 117.8, 127.5, 127.6, 128.2, 133.1, 136.9, 173.4; IR (film) 3600-
and the combined extracts were washed with saturated NaHCO3 and
brine, dried over Na2SO4, and concentrated in vacuo. Purification by
flash chromatography gave 2.15 g (40%) of alcohol 7 and 1.80 g (80%
brsm) of acyloxazolidinone 6: 1H NMR (CDCl3) δ 7.26 (m, 5H), 5.87
(m, 2H), 5.38-5.02 (m, 4H), 5.13 (d, J ) 3.0 Hz, 1H), 4.67 (m, 1H),
4.36 (m, 1H), 4.22 (m, 2H), 3.73 (ddd, J ) 9.0, 6.6, 6.6 Hz, 1H), 3.46
(ddd, J ) 9.0, 6.9, 6.9 Hz, 1H), 3.33 (dd, J ) 13.4, 3.5 Hz, 1H), 2.82
(dd, J ) 13.4, 9.6 Hz, 1H), 2.64 (d, J ) 7.9 Hz, 1H), 2.39 (m, 2H);
13C NMR (CDCl3) δ 34.0, 37.7, 55.6, 66.9, 70.4, 73.6, 80.3, 116.9,
117.0, 127.4, 129.0, 129.4, 134.5, 134.9, 136.5, 153.5, 170.3; IR (film)
3720-3000 (br), 1770, 1700, 1390, 1210, 1100 cm-1; [R]25D ) +38.6°
(c 0.27, CH2Cl2). Anal. Calcd for C19H23O5N1: C, 66.07; H, 6.71.
Found: C, 65.79; H, 6.84.
2700 (br), 1760, 1360, 1120 cm-1; [R]25 ) -31.4 (c 0.41, CH2Cl2).
D
1
3-Butenyl-1-oxyacetic acid (5): 100% yield; H NMR (CDCl3) δ
5.80 (m, 1H), 5.10 (m, 2H), 4.12 (s, 2H), 3.62 (t, J ) 6.6 Hz, 2H),
2.39 (m, 2H); 13C NMR (CDCl3) δ 33.6, 67.5, 70.9, 116.7, 134.2, 175.2;
IR (film) 3720-2200 (br), 1740, 1430, 1130, 910 cm-1; Anal. Calcd
for C6H10O3: C, 55.37; H, 7.74. Found: C, 55.30; H, 7.86.
(4S)-3-[(2S,3R)-1-Oxo-2-(pent-4-enyl-1-oxy)-3-hydroxy-4-pen-
tenyl]-4-benzyl-2-oxazolidinone (13). By the same procedure described
above, 6.84 g of acyloxazolidinone 12 provided 3.64 g (45%) of 13
and 2.74 g (85% brsm) of acyloxazolidinone 12: 1H NMR (CDCl3) δ
7.28 (m, 5H), 5.87 (m, 2H), 5.40-5.17 (m, 2H), 5.10 (d, J ) 3.0 Hz,
1H), 5.08-4.93 (m, 2H), 4.67 (m, 1H), 4.37 (m, 1H), 4.23 (m, 2H),
3.67 (ddd, J ) 9.0, 6.3, 6.3 Hz, 1H), 3.44 (ddd, J ) 9.0, 6.6, 6.6 Hz,
1H), 3.34 (dd, J ) 13.3, 3.5 Hz, 1H), 2.82 (dd, J ) 13.3, 9.6 Hz, 1H),
2.56 (d, J ) 7.9 Hz, 1H), 2.15 (m, 2H), 1.72 (m, 2H); 13C NMR (CDCl3)
δ 28.7, 30.0, 37.7, 55.5, 66.9, 70.6, 73.4, 80.3, 115.0, 116.8, 127.4,
128.9, 129.3, 134.9, 136.6, 137.9, 153.4, 170.4; IR (film) 3700-3140
1
4-Pentenyl-1-oxyacetic acid (11): 100% yield; H NMR (CDCl3)
δ 5.79 (m, 1H), 5.00 (m, 2H), 4.10 (s, 2H), 3.56 (t, J ) 6.6 Hz, 2H),
2.13 (dt, J ) 7.3, 6.5 Hz, 2H), 1.73 (m, 2H); 13C NMR (CDCl3) δ
28.5, 30.0, 67.7, 71.3, 115.1, 137.8, 180.2; IR (film) 3700-2500 (br),
1740, 1440, 1140, 910 cm-1. Anal. Calcd for C7H12O3: C, 58.32; H,
8.39. Found: C, 58.05; H, 8.11.
(S)-3-[1-Oxo-2-(but-3-enyl-1-oxy)]-4-benzyl-2-oxazolidinone (6).
A solution of the alkoxyacetic acid 5 (5.48 g, 42.1 mmol) and
triethylamine (6.2 mL, 44.2 mmol) in 350 mL of ether were added to
a flask fitted with a mechanical stirrer, and the mixture was cooled to
-78 °C. Pivaloyl chloride (5.44 mL, 44.2 mmol) was added slowly
over 15 min, and the resultant mixture was stirred for 5 min at -78 °C
and then warmed to 0 °C for 1 h. In a separate flask, (S)-4-benzyl-2-
oxazolidinone (7.46 g, 42.1 mmol) in 50 mL of THF was cooled to
-78 °C, and n-BuLi (26.0 mL, 42.5 mmol) was added dropwise. After
addition was complete, the mixture was stirred at -78 °C for 10 min.
The solution of mixed anhydride was recooled to -78 °C, and the
lithiated oxazolidinone was then cannulated into the mixed anhydride.
After being stirred for 15 min at -78 °C, the mixture was warmed to
0 °C for 30 min. The reaction was quenched with water and warmed
to 25 °C. The aqueous layer was extracted with ether, and the combined
extracts were washed with brine, dried over Na2SO4, and concentrated
in vacuo. Purification by flash chromatography provided 10.0 g (82%)
of acyloxazolidinone 6: 1H NMR (CDCl3) δ 7.27 (m, 5H), 5.85 (m,
1H), 5.10 (m, 2H), 4.66 (m, 3H), 4.24 (m, 2H), 3.64 (t, J ) 7.0 Hz,
2H), 3.32 (dd, J ) 13.5, 3.2 Hz, 1H), 2.79 (dd, J ) 13.5, 9.5 Hz, 1H),
2.43 (m, 2H); 13C NMR (CDCl3) δ 34.0, 37.7, 54.8, 67.2, 70.7, 71.2,
116.7, 127.4, 129.0, 129.3, 134.7, 134.9, 153.4, 170.2; IR (film) 2920,
(br), 2920, 1770, 1700, 1390, 1210, 1100 cm-1; [R]25 ) +42.3° (c
D
0.18, CH2Cl2). Anal. Calcd for C20H25O5N1: C, 66.83; H, 7.01.
Found: C, 66.58; H, 7.09.
(2R,3R)-2-(But-3-enyl-1-oxy)-4-pentene-1,3-diol (8). Alcohol 7
(0.16 g. 0.5 mmol), 5 mL of THF, and anhydrous methanol (0.04 mL)
were cooled to 0 °C. Lithium borohydride (2.0 M in THF, 0.51 mL,
1.0 mmol) was added dropwise, and the mixture was stirred for 1 h at
0 °C. The reaction was quenched with 15% NaOH and then concen-
trated in vacuo. The aqueous layer was extracted with ether, and the
combined extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography gave 0.052
g (66%) of diol 8: 1H NMR (CDCl3) δ 5.83 (m, 2H), 5.40-5.04 (m,
4H), 4.18 (m, 1H), 3.68 (m, 4H), 3.27 (ddd, J ) 6.2, 4.4, 4.4 Hz, 1H),
2.58 (d, J ) 4.0 Hz, H), 2.34 (m, 2H), 2.01 (t, J ) 6.1 Hz, 1H); 13C
NMR (CDCl3) δ 34.4, 61.3, 70.3, 72.8, 82.6, 117.2, 117.3, 135.1, 136.9;
IR (film) 3700-3040 (br), 2880, 1640, 1430, 1100, 920 cm-1; [R]25
D
) +2.3° (c 0.17, CH2Cl2). Anal. Calcd for C9H16O3: C, 62.77; H, 9.36.
Found: C, 62.99; H, 9.30.
(2R,3R)-2-(Pent-4-enyl-1-oxy)-4-pentene-1,3-diol (14). By the same
procedure described above, 0.323 g of alcohol 13 provided 0.149 g
(89%) of diol 14: 1H NMR (CDCl3) δ 5.83 (m, 2H), 5.41-4.94 (m,
4H), 4.20 (m, 1H), 3.78 (m, 1H), 3.70-3.50 (m, 3H), 3.26 (ddd, J )
5.8, 4.4, 4.4 Hz, 1H), 2.50 (d, J ) 4.0 Hz, 1H), 2.13 (m, 2H), 1.90 (t,
J ) 6.0 Hz, 1H), 1.70 (m, 2H).; 13C NMR (CDCl3) δ 29.0, 30.2, 61.1,
70.4, 72.6, 82.1, 114.9, 116.9, 137.0, 138.0; IR (film) 3700-3120 (br),
1770, 1720, 1390, 1260, 1210, 1130 cm-1; [R]25 ) +79.3° (c 0.24,
D
CH2Cl2). Anal. Calcd for C16H19O4N1: C, 66.42; H, 6.62. Found: C,
66.14; H, 6.63.
(S)-3-[1-Oxo-2-(pent-4-enyl-1-oxy)]-4-benzyl-2-oxazolidinone (12).
By the same procedure described above, 5.45 g of alkoxyacetic acid
11 provided 9.20 g (80%) of acyloxazolidinone 12: 1H NMR (CDCl3)
δ 7.26 (m, 5H), 5.82 (m, 1H), 5.00 (m, 2H), 4.67 (m, 3H), 4.24 (m,
2H), 3.58 (t, J ) 6.6 Hz, 2H), 3.31 (dd, J ) 13.5, 3.1 Hz, 1H), 2.79
(dd, J ) 13.5, 9.5 Hz, 1H), 2.16 (m, 2H), 1.75 (m, 2H); 13C NMR
(CDCl3) δ 28.7, 30.1, 37.7, 54.8, 67.2, 70.6, 71.4, 114.9, 127.4, 129.0,
129.4, 134.9, 138.0, 153.4, 170.3; IR (film) 2920, 1770, 1710, 1390,
1350, 1260, 1210, 1140 cm-1; [R]25D ) +65.4° (c 0.19, CH2Cl2). Anal.
Calcd for C17H21O4N1: C, 67.31; H, 6.98. Found: C, 67.05; H, 7.01.
(4S)-3-[(2S,3R)-1-Oxo-2-(but-3-enyl-1-oxy)-3-hydroxy-4-pentenyl]-
4-benzyl-2-oxazolidinone (7). Acyloxazolidinone 6 (4.5 g, 15.6 mmol)
and 30 mL of dichloromethane were cooled to -40 °C in a flask
equipped with a low-temperature thermometer. Neat dibutylboron
triflate (4.3 mL, 17.1 mmol) was added dropwise, followed by dropwise
addition of triethylamine (2.6 mL, 18.7 mmol). The solution was stirred
at -40 to -30 °C for 1 h and then cooled to -78 °C. Freshly distilled
acrolein (1.3 mL, 18.7 mmol) was added dropwise, and the mixture
was stirred at -78 °C for 1.5 h and then warmed to 0 °C for 30 min.
The reaction was quenched at 0 °C by the sequential dropwise addition
of pH 7 buffer (1.2 mL/mmol of oxazolidinone), methanol (4 mL/mmol
of oxazolidinone), and 30% H2O2 (1.2 mL/mmol of oxazolidinone).
The mixture was stirred for 1 h at 0 °C and then concentrated in vacuo.
The aqueous layer was extracted three times with dichloromethane,
2940, 1640, 1420, 1100, 910 cm-1; [R]25 ) +4.2° (c 0.22, CH2Cl2).
D
Anal. Calcd for C10H18O3: C, 64.49; H, 9.74. Found: C, 64.61; H,
9.77.
(2R,3R)-2-(But-3-enyl-1-oxy)-5-hexene-1,3-diol (20). By the same
procedure described above, 0.300 g of alcohol 19 provided 0.106 g
(68%) of diol 20: 1H NMR (CDCl3) δ 5.82 (m, 2H), 5.09 (m, 4H),
3.85-3.50 (m, 5H), 3.24 (dd, J ) 9.3, 4.5 Hz, 1H), 2.55 (d, J ) 4.7
Hz, 1H), 2.29 (m, 5H); 13C NMR (CDCl3) δ 34.5, 37.8, 61.5, 70.1,
71.1, 81.3, 117.1, 117.7, 134.4, 135.1; IR (film) 3720-3100 (br), 2900,
1640, 1430, 1080, 910 cm-1; [R]25 ) -6.5° (c 0.28, CH2Cl2). Anal.
D
Calcd for C10H18O3: C, 64.49; H, 9.74. Found: C, 64.35; H, 9.52.
(2R,3R)-2-(Pent-4-enyl-1-oxy)-5-hexene-1,3-diol (24). By the same
procedure described above, 0.253 g of alcohol 23 provided 0.116 g
(85%) of diol 24: 1H NMR (CDCl3) δ 5.82 (m, 2H), 5.05 (m, 4H),
3.80 (m, 2H), 3.66 (m, 2H), 3.50 (ddd, J ) 9.2, 6.5, 6.5 Hz, 1H), 3.24
(dd, J ) 9.0, 4.6 Hz, 1H), 2.43-2.04 (m, 6H), 1.70 (m, 2H); 13C NMR
(CDCl3) δ 29.1, 30.3, 38.0, 61.6, 70.2, 71.2, 81.0, 115.1, 117.8, 134.5,
138.1; IR (film) 3700-3100 (br), 2940, 1640, 1440, 1090, 910 cm-1
;
[R]25D ) -6.5° (c 0.20, CH2Cl2). Anal. Calcd for C11H20O3: C, 65.97;
H, 10.07. Found: C, 66.10; H, 9.98.
(2R,3R)-2-[(R)-1-(Benzyloxymethyl)but-3-enyl-1-oxy]-5-hexene-
1,3-diol (29). The same procedure described above was used except

5658 J. Am. Chem. Soc., Vol. 121, No. 24, 1999
Crimmins and Choy
that the alcohol 3b (770 mg) was diluted with 17 mL of ether instead
of with THF. An 80% yield of diol 29 (400 mg) was realized.
(7R,8R)-7-Acetoxy-8-(acetoxymethyl)-2,3,7,8-tetrahydro-(4H)-
oxocin (16). By the same procedure desribed above, 0.046 g of diene
15 provided 0.030 g (73%) of oxocin 16 and 17% of a dimer: 1H NMR
(CDCl3) δ 5.90 (m, 1H), 5.68 (m, 1H), 5.53 (ddd, J ) 11.0, 7.0, 1.0
Hz, 1H), 4.26 (dd, J ) 11.2, 3.2 Hz, 1H), 4.10 (ddd, J ) 12.4, 3.9, 3.9
Hz, 1H), 3.93 (m, 2H), 3.52 (ddd, J ) 12.4, 10.7, 3.1 Hz, 1H), 2.43
(m, 1H), 2.14 (m, 1H), 2.06 (s, 3H), 2.05 (s, 3H), 1.94-1.53 (m, 2H);
13C NMR (CDCl3) δ 20.9, 25.7, 30.5, 63.5, 69.6, 77.2, 78.1, 126.3,
133.8, 170.1, 170.9; IR (film) 2940, 1740, 1370, 1230, 1100, 1040
(2R,3R)-2-(But-3-enyl-1-oxy)-4-pentene-1,3-diol Bis(acetate) (9).
Diol 8 (0.172 g, 1.0 mmol) and 5 mL of dichloromethane were cooled
to 0 °C. Triethylamine (0.35 mL, 2.5 mmol) was added dropwise, and
the mixture was stirred for 10 min. Acetic anhydride (0.28 mL, 3.0
mmol) was added dropwise, and then a catalytic amount of 4-(di-
methylamino)pyridine (0.012 g, 0.10 mmol) was added. The reaction
was warmed to 25 °C and stirred for 2-4 h. After the reaction was
quenched with 5% HCl, the layers were quickly separated. The organic
layer was washed with saturated NaHCO3 and brine, dried over Na2SO4,
and concentrated in vacuo. Purification by flash chromatography
afforded 0.180 g (70%) of diacetate 9: 1H NMR (CDCl3) δ 5.81 (m,
2H), 5.44-4.98 (m, 5H), 4.10 (AB portion of ABX, JAB ) 11.8 Hz,
JAX ) 6.9 Hz, JBX ) 4.1 Hz, ∆νAB ) 44.8 Hz, 2H), 3.63 (m, 3H), 2.30
(m, 2H), 2.08 (s, 3H), 2.05 (s, 3H); 13C NMR (CDCl3) δ 20.9, 21.1,
34.3, 63.3, 71.0, 73.3, 78.3, 116.6, 118.5, 132.2, 134.9, 169.9, 170.8;
cm-1; [R]25 ) +22.6° (c 0.80, CH2Cl2); MS m/z 182 (M+ - CH3-
D
CO2H). Anal. Calcd for C12H18O5: C, 59.49; H, 7.49. Found: C, 59.21;
H, 7.33.
(2R,3R)-3-Acetoxy-2-(acetoxymethyl)-3,4,7,8-tetrahydro-(2H)-
oxocin (22). By the same procedure desribed above, 0.039 g of diene
21 provided 0.033 g (94%) of oxocin 22 in 30 min with no detectable
dimerization: 1H NMR (CDCl3) δ 5.82 (m, 2H), 4.98 (ddd, J ) 11.2,
5.6, 2.4 Hz, 1H), 4.13 (ddd, J ) 12.2, 3.7, 3.7 Hz, 1H), 3.95 (m, 3H),
3.39 (m, 1H), 2.64 (m, 2H), 2.33 (m, 1H), 2.07 (s, 3H), 2.06 (m, 1H),
2.02 (s, 3H); 13C NMR (CDCl3) δ 20.8, 21.0, 28.9, 29.8, 64.1, 72.9,
74.6, 78.2, 127.7, 131.6, 170.4, 170.7; IR (film) 2940, 1740, 1370,
IR (film) 1750, 1370, 1230, 1050 cm-1; [R]25 ) +25.2° (c 0.63,
D
CH2Cl2).
(2R,3R)-2-(Pent-4-enyl-1-oxy)-4-pentene-1,3-diol Bis(acetate) (15).
By the same procedure described above, 0.05 g of diol 14 provided
0.066 g (91%) of diacetate 15: 1H NMR (CDCl3) δ 5.81 (m, 2H),
5.33 (m, 3H), 4.99 (m, 2H), 4.10 (AB portion of ABX, JAB ) 11.8 Hz,
JAX ) 6.8 Hz, JBX ) 4.1 Hz, ∆νAB ) 37.0 Hz, 2H), 3.56 (m, 3H), 2.09
(s, 3H), 2.09 (m, 2H), 2.05 (s, 3H), 1.64 (m, 2H); 13C NMR (CDCl3)
δ 20.8, 21.0, 29.1, 30.0, 63.3, 70.8, 73.4, 78.3, 114.8, 118.4, 132.3,
1230 cm-1; [R]25 ) -41.0° (c 1.27, CH2Cl2); MS m/z 182 (M+
-
D
CH3CO2H). Anal. Calcd for C12H18O5: C, 59.49; H, 7.49. Found: C,
59.66; H, 7.80.
(2R,3R)-3-Acetoxy-2-(acetoxymethyl)-∆5,6-oxonene (26). By the
same procedure described above, 0.020 g of diene 25 provided 0.016
g (89%) of oxocene 26 in 1 h and 10% of a dimer: 1H NMR (CDCl3)
δ 5.66 (ddd, J ) 11.0, 11.0, 6.0 Hz, 1H), 5.46 (ddd, J ) 11.0, 11.0,
6.0 Hz, 1H), 5.01 (ddd, J ) 10.0, 6.0, 3.0 Hz, 1H), 4.08 (m, 3H), 3.55
(ddd, J ) 7.3, 5.7, 2.9 Hz, 1H), 3.26 (ddd, J ) 10.4, 10.4, 5.1 Hz,
1H), 2.85 (dd, J ) 22.9, 11.2 Hz, 1H), 2.69 (m, 1H), 2.29 (m, 1H),
2.06 (s, 3H), 2.02 (s, 3H), 2.00 (m, 2H), 1.58 (m, 1H); 13C NMR
(CDCl3) δ 20.8, 21.8, 27.4, 28.1, 64.1, 72.4, 72.7, 79.3, 124.7, 132.9,
138.0, 169.9, 170.7; IR (film) 1750, 1370, 1230, 1100, 1050 cm-1
;
[R]25 ) +24.5° (c 0.96, CH2Cl2).
D
(2R,3R)-2-(But-3-enyl-1-oxy)-5-hexene-1,3-diol Bis(acetate) (21).
By the same procedure described above, 0.861 g of diol 20 provided
0.465 g (88%) of diacetate 21: 1H NMR (CDCl3) δ 5.77 (m, 2H),
5.08 (m, 5H), 4.12 (AB portion of ABX, JAB ) 11.5 Hz, JAX ) 6.5
Hz, JBX ) 4.9 Hz, ∆νAB ) 15.3 Hz, 2H), 3.62 (m, 3H), 2.39 (m, 4H),
2.05 (s, 6H); 13C NMR (CDCl3) δ 20.8, 21.0, 34.3, 34.4, 63.1, 70.9,
71.9, 77.2, 116.6, 118.0, 133.4, 134.8, 170.4, 170.7; IR (film) 2950,
170.4, 170.7; IR (film) 2960, 1740, 1370, 1230, 1040 cm-1; [R]25
)
D
-31.7° (c 0.60, CH2Cl2); MS m/z 136 (M+ - 2CH3CO2H). Anal. Calcd
for C13H20O5: C, 60.92; H, 7.87. Found: C, 61.09; H, 7.56.
(2R,3R,8R)-8-(Benzyloxymethyl)-3-acetoxy-2-(acetoxymethyl)-
3,4,7,8-tetrahydro-(2H)-oxocin (31). A solution of diene 30 (24 mg,
0.062 mmol) in dichloromethane (0.003 M) was heated to reflux, and
then 4 mg of (Cy3P)2Cl2RudCHPh (7 mol %) was added in one portion.
The mixture was heated at reflux for 2 h and then cooled to 25 °C.
After the mixture was diluted with dichloromethane, air was bubbled
through the mixture for several hours. Purification by flash chroma-
tography gave 22 mg (97%) of oxocin 31 with no detectable
dimerization: 1H NMR (CDCl3) δ 7.30 (m, 5H), 5.80 (m, 2H), 4.98
(ddd, J ) 11.0, 5.3, 2.8 Hz, 1H), 4.53 (s, 2H), 4.12 (dd, J ) 12.2, 10.0
Hz, 1H), 3.95 (dd, J ) 12.2, 5.1 Hz, 1H), 3.95 (m, 1H), 3.53 (m, 2H),
3.40 (m, 1H), 2.70 (dt, J ) 11.0, 11.0 Hz, 1H), 2.32 (m, 3H), 2.06 (s,
3H), 1.92 (s, 3H); 13C NMR (CDCl3) δ 20.7, 21.1, 28.8, 31.6, 64.1,
73.2, 73.3, 74.6, 78.0, 82.3, 127.6, 127.9, 128.3, 130.7, 138.1, 170.5,
170.7; IR (film) 3020, 2980, 1740, 1450, 1370, 1230, 1090, 1040, 730,
690 cm-1; [R]25D ) -7.3 (c 0.26, CH2Cl2). Anal. Calcd for C20H26O6:
C, 66.28; H, 7.23. Found: C, 66.35; H, 7.29.
(4S)-3-[1-Oxo-2-[(R)-1-(benzyloxymethyl)but-3-enyl-1-oxy]-4-
benzyl-1,3-oxazolidinone-2-thione (28a). A solution of the alkoxy-
acetic acid 4 (0.25 g, 1 mmol), 5 mL of dichloromethane, catalytic
dimethylformamide (0.1 mmol), and 2.0 M oxalyl chloride in dichlo-
romethane (0.6 mL, 1.2 mmol) was stirred for 2 h at 25 °C. The mixture
was concentrated in vacuo, and the resultant acid chloride (0.27 g, 1
mmol) was diluted with 2 mL of dichloromethane and cooled to 0 °C.
In a separate flask, triethylamine (0.33 mL, 2.4 mmol) was added
dropwise to (S)-4-benzyloxazolidine-2-thione (0.155 g, 0.8 mmol) in
3 mL of dichloromethane. The mixture was stirred for 5 min at 25 °C
and then slowly cannulated into the solution of acid chloride. The
resultant mixture was stirred at 0 °C for 1 h, warmed to 25 °C, and
stirred for 12 h. The reaction was quenched with water, the aqueous
layer was extracted with dichloromethane, and the combined extracts
were washed with 10% H2SO4, dried over Na2SO4, and concentrated
in vacuo. Purification by flash chromatography afforded 0.250 g (73%)
of acyloxazolidinethione 28a: 1H NMR (CDCl3) δ 7.25 (m, 10H), 5.88
(m, 1H), 5.25 (ABq, J ) 18.0 Hz, ∆νAB ) 18.8 Hz, 2H), 5.10 (m,
2H), 4.86 (m, 1H), 4.53 (s, 2H), 4.26 (m, 2H), 3.77 (m, 1H), 3.62 (m,
1750, 1370, 1225, 1050 cm-1; [R]25 ) +4.8° (c 0.11, CH2Cl2).
D
(2R,3R)-2-(Pent-4-enyl-1-oxy)-5-hexene-1,3-diol Bis(acetate) (25).
By the same procedure described above, 0.170 g of diol 24 provided
0.095 g (89%) of diacetate 25.: 1H NMR (CDCl3) δ 5.74 (m, 2H),
5.02 (m, 5H), 4.10 (AB portion of ABX, JAB ) 11.3 Hz, JAX ) 10.8
Hz, JBX ) 1.3 Hz, ∆νAB ) 15.8 Hz, 2H), 3.55 (m, 3H), 2.37 (m, 2H),
2.04 (m, 2H), 2.03 (s, 6H), 1.65 (m, 2H); 13C NMR (CDCl3) δ 20.8,
21.0, 29.1, 30.1, 34.4, 63.1, 70.8, 71.9, 77.2, 114.9, 118.0, 133.4, 138.0,
170.4, 170.8; IR (film) 1750, 1380, 1230 cm-1; [R]25D ) +4.9° (c 0.18,
CH2Cl2).
(2R,3R)-2-[(R)-1-(Benzyloxymethyl)but-3-enyl-1-oxy]-5-hexene-
1,3-diol Bis(acetate) (30). By the same procedure described above,
0.043 g of diol 29 provided 0.036 g (67%) of diacetate 30: 1H NMR
(CDCl3) δ 7.29 (m, 5H), 5.76 (m, 2H), 5.05 (m, 5H), 4.51 (s, 2H),
4.13 (AB portion of ABX, JAB ) 11.5 Hz, JAX ) 4.5 Hz, JBX ) 3.5
Hz, ∆νAB ) 22.1 Hz, 2H), 3.73 (m, 2H), 3.45 (app d, J ) 5.5 Hz, 2H),
2.48 (m, 1H), 2.41-2.18 (band, 3H), 2.03 (s, 3H), 1.98 (s, 3H); 13C
NMR (CDCl3) δ 20.8, 21.0, 34.0, 36.8, 63.4, 72.1, 72.4, 73.3, 76.5,
79.0, 117.5, 117.8, 127.5, 128.3, 133.6, 134.3, 138.2, 170.4, 170.7; IR
(film) 1740, 1370, 1230, 1100 cm-1; [R]25D ) -0.2 (c 0.56, CH2Cl2).
(2R,3R)-3-Acetoxy-2-(acetoxymethyl)-2,3,6,7-tetrahydrooxepin (10).
A solution of diene 9 (0.061 g, 0.24 mmol) in 80 mL of dichloromethane
(0.003 M) was heated to reflux, and then 0.014 g of (Cy3P)2Cl2Rud
CHPh (7 mol %) was added in one portion. The mixture was heated at
reflux for 2 h and then cooled to 25 °C. After dilution with
dichloromethane, air was bubbled through the mixture for several hours.
Purification by flash chromatography gave 0.052 g (95%) of oxepin
10: 1H NMR (CDCl3) δ 5.93 (m, 2H), 5.24 (dd, J ) 6.5, 1.5 Hz, 1H),
4.10 (m, 3H), 3.88 (ddd, J ) 7.4, 6.1, 1.6 Hz, 1H), 3.62 (ddd, J )
12.4, 10.2, 2.6 Hz, 1H), 2.58 (m, 1H), 2.26 (m, 1H), 2.07 (s, 3H), 2.05
(s, 3H); 13C NMR (CDCl3) δ 20.8, 20.9, 31.4, 63.6, 70.0, 71.1, 78.1,
127.3, 134.9, 170.4, 170.7; IR (film) 1740, 1380, 1230, 1050 cm-1
;
[R]25 ) -181.5° (c 0.81, CH2Cl2); MS m/z168 (M+ - CH3CO2H).
D
Anal. Calcd for C11H16O5: C, 57.89; H, 7.07. Found: C, 57.68; H,
7.15.

EnantioselectiVe Synthesis of (+)-Laurencin
J. Am. Chem. Soc., Vol. 121, No. 24, 1999 5659
2H), 3.25 (dd, J ) 13.2, 3.3 Hz, 1H), 2.64 (dd, J ) 13.2, 10.1 Hz,
1H), 2.41 (m, 2H); 13C NMR (CDCl3) δ 36.3, 37.2, 59.6, 71.1, 71.6,
72.9, 73.2, 78.7, 117.3, 127.2, 127.3, 127.4, 128.2, 128.8, 129.2, 134.1,
135.0, 138.0, 171.3, 184.6; IR (film) 2900, 1710, 1360, 1320, 1200,
cannulated into the deprotonated oxazolidinone. The reaction mixture
was stirred for 30 min at -78 °C and then warmed to 25 °C and stirred
for 15 min. The reaction was quenched with saturated NH4Cl and then
concentrated in vacuo. The aqueous layer was extracted with ether,
and the combined extracts were washed with saturated NH4Cl and brine,
dried over Na2SO4, and concentrated in vacuo. Purification by flash
1120, 960, 740, 690 cm-1; [R]25 ) +75.1 (c 0.49, CH2Cl2). Anal.
D
Calcd for C24H27O4N1S1: C, 67.74; H, 6.39. Found: C, 67.68; H, 6.43.
(4S)-3-[(2S,3R)-1-Oxo-2-[(R)-1-(benzyloxymethyl)but-3-enyl-1-
oxy]-3-hydroxy-5-hexenyl]-4-benzyl-1,3-oxazolidine-2-thione (3a).
The acyloxazolidinethione 28a (0.627 g, 1.47 mmol) and 7 mL of
dichloromethane were cooled to -78 °C. Titanium tetrachloride (0.16
mL, 1.47 mmol) was added dropwise, and the mixture was stirred for
10 min at -78 °C. (-)-Sparteine (0.85 mL, 3.68 mmol) was added
dropwise, and the mixture was stirred at -78 °C for 1 h. A solution of
3-butenal (7.35 mmol) in dichloromethane was added dropwise, and
the reaction was stirred for 1 h at -78 °C. The reaction was quenched
at -78 °C with half-saturated NH4Cl and warmed to 25 °C. The solution
was filtered through Celite, and the salts were washed with dichloro-
methane. The aqueous layer was extracted with dichloromethane, and
the combined extracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Purification by flash chromatography afforded
0.194 g of alcohol 3a (27%) and 0.396 g (90% brsm) of acyloxazoli-
dinethione 28a: 1H NMR (CDCl3) δ 7.21 (m, 10H), 6.34 (d, J ) 2.0
Hz, 1H), 5.87 (m, 2H), 5.12 (m, 4H), 4.74 (m, 1H), 4.48 (ABq, J )
12.0 Hz, ∆νAB ) 10.6 Hz, 2H), 4.16 (m, 2H), 4.07 (dt, J ) 7.0, 2.0
Hz, 1H), 3.83 (m, 1H), 3.67 (dd, J ) 10.3, 7.3 Hz, 1H), 3.50 (dd, J )
10.3, 2.9 Hz, 1H), 3.20 (dd, J ) 13.2, 3.3 Hz, 1H), 2.50-2.27 (band,
5H), 2.05 (dd, J ) 13.2, 11.0 Hz, 1H); 13C NMR (CDCl3) δ 36.5,
36.8, 38.8, 61.0, 70.7, 72.3, 73.1, 73.5, 79.9, 79.9, 117.6, 118.0, 127.0,
127.2, 127.5, 128.4, 128.4, 128.8, 128.9, 129.3, 134.2, 134.4, 135.5,
138.0, 172.1, 185.1; IR (film) 3700-3040 (br), 2900, 1710, 1360, 1320,
1
chromatography afforded 2.09 g (89%) of acyloxazolidinone 28b: H
NMR (CDCl3) δ 7.24 (m, 10H), 5.88 (m, 1H), 5.09 (m, 2H), 4.87 (s,
2H), 4.60 (m, 1H), 4.52 (s, 2H), 4.15 (m, 2H), 3.75 (m, 1H), 3.60 (m,
2H), 3.28 (dd, J ) 13.5, 3.3 Hz, 1H), 2.61 (dd, J ) 13.5, 9.7 Hz, 1H),
2.41 (m, 2H); 13C NMR (CDCl3) δ 170.6, 153.4, 138.2, 135.1, 134.2,
129.4, 129.0, 128.4, 127.54, 127.47, 127.35, 117.4, 79.0, 73.3, 72.8,
70.0, 67.1, 54.8, 37.6, 36.3; IR (film) 3010-2800 (br), 1780, 1720,
1390, 1260, 1210, 1130 cm-1; [R]25D ) +67.5 (c 0.24, CH2Cl2). Anal.
Calcd for C24H27O5N1: C, 70.40; H, 6.65. Found: C, 70.38; H, 6.67.
(4S)-3-[(2S,3R)-1-Oxo-2-[(R)-1-(benzyloxymethyl)but-3-enyl-1-
oxy]-3-hydroxy-5-hexenyl]-4-benzyl-1,3-oxazolidinone (3b). The acyl-
oxazolidinone 28b (0.38 g, 0.93 mmol) and 6 mL of dichloromethane
were cooled to -78 °C. Titanium tetrachloride (0.11 mL, 1.02 mmol)
was added dropwise, and the mixture was stirred for 10 min at -78
°C. Diisopropylethylamine (0.40 mL, 2.32 mmol) was diluted with 0.4
mL of dichloromethane and then added very slowly dropwise. After
complete addition, the mixture was stirred at -78 °C for 2.5 h. A
solution of 3-butenal (4.64 mmol) in dichloromethane was added
dropwise, and the reaction was stirred for 1.5 h at -78 °C. The reaction
was quenched at -78 °C with half-saturated NH4Cl and warmed to 25
°C. The aqueous layer was extracted with dichloromethane, and the
combined extracts were dried over Na2SO4 and concentrated in vacuo.
Purification by flash chromatography afforded 0.288 g of alcohol 3b
(65%): 1H NMR (CDCl3) δ 7.20 (m, 10H), 5.88 (m, 2H), 5.38 (d, J )
2.0 Hz, 1H), 5.14 (m, 4H), 4.47 (m, 1H), 4.46 (ABq, J ) 12.0 Hz,
∆νAB ) 18.4 Hz, 2H), 4.05 (m, 1H), 3.86 (m, 3H), 3.68 (dd, J ) 10.3,
7.7 Hz, 1H), 3.49 (dd, J ) 10.3, 3.0 Hz, 1H), 3.22 (dd, J ) 13.3, 3.1
Hz, 1H), 2.39 (m, 4H), 1.74 (dd, J ) 13.3, 11.0 Hz, 1H); 13C NMR
(CDCl3) δ 171.2, 153.5, 138.2, 135.7, 134.4, 134.3, 129.3, 128.9, 128.4,
127.5, 127.1, 127.0, 118.1, 117.5, 80.10, 80.11, 74.1, 73.0, 72.3, 66.8,
55.8, 38.9, 36.9, 36.5; IR (film) 3700-3020 (br), 3010-2800 (br), 1775,
1190, 910, 730, 690 cm-1; [R]25 ) +15.3 (c 0.30, CH2Cl2). Anal.
D
Calcd for C28H33O5N1S1: C, 67.85; H, 6.71; N, 2.83. Found: C, 67.41;
H, 6.78; N, 2.66.
(4S)-3-[(2S,3R)-1-Oxo-2-(but-3-enyl-1-oxy)-3-hydroxy-5-hexenyl]-
4-benzyl-2-oxazolidinone (19). By the same procedure described above,
1.45 g of acyloxazolidinone 6 provided 0.845 g (47%) of alcohol 19
and 0.608 g (89% brsm) of acyloxazolidinone 6: 1H NMR (CDCl3) δ
7.27 (m, 5H), 5.85 (m, 2H), 5.18-5.04 (m, 4H), 5.03 (d, J ) 2.0 Hz,
1H), 4.68 (ddd, J ) 12.5, 6.0, 3.2 Hz, 1H), 4.22 (m, 2H), 3.95 (m,
1H), 3.76 (ddd, J ) 8.8, 6.5, 6.5 Hz, 1H), 3.42 (ddd, J ) 8.8, 7.0, 7.0
Hz, 1H), 3.35 (dd, J ) 13.2, 3.1 Hz, 1H), 2.81 (dd, J ) 13.2, 9.5 Hz,
1H), 2.41 (m, 4H), 2.25 (d, J ) 9.5 Hz, 1H); 13C NMR (CDCl3) δ
34.0, 37.6, 38.7, 55.6, 67.0, 70.1, 71.6, 79.6, 116.8, 117.6, 127.3, 128.9,
129.3, 134.1, 134.6, 134.9, 153.4, 170.7; IR (film) 3720-3120 (br),
1710, 1390, 1350, 1300-1180 (br), 1180-950 (br), 910 cm-1; [R]25
D
) +0.4 (c 0.25, CH2Cl2). Anal. Calcd for C28H33O6N: C, 70.13; H,
6.94. Found: C, 70.11; H, 6.90.
(2R,3R)-2-[(R)-1-(Benzyloxymethyl)but-3-enyl-1-oxy]-5-hexene-
1,3-diol (29). Alcohol 3 (0.097 g, 0.196 mmol), 1 mL of ether, and 16
mL of anhydrous methanol (0.392 mmol) were cooled to 0 °C. A 2.0
M solution of lithium borohydride in THF (0.20 mL, 0.392 mmol) was
added dropwise, and the reaction was stirred for 2 h at 0 °C. After
15% NaOH was added, the mixture was warmed to 25 °C for 15 min
to deprotonate the free (S)-4-benzyloxazolidine-2-thione. The aqueous
layer was separated, and the organic layer was washed six times with
15% NaOH. The organic layer was then washed with brine, dried over
Na2SO4, and concentrated in vacuo to afford 51.4 mg of diol 29 (86%),
which was used without further purification: 1H NMR (CDCl3) δ 7.34
(m, 5H), 5.81 (m, 2H), 5.10 (m, 4H), 4.55 (s, 2H), 3.88-3.42 (band,
7H), 3.37 (dt, J ) 5.7, 2.7 Hz, 1H), 2.74 (d, J ) 2.9 Hz, 1H), 2.27 (m,
4H); 13C NMR (CDCl3) δ 36.9, 37.7, 62.4, 71.3, 72.7, 73.6, 77.9, 81.8,
117.4, 118.3, 127.8, 128.0, 128.5, 133.7, 134.5, 137.1; IR (film) 3720-
2920, 1770, 1700, 1640, 1390, 1210, 1110, 910, 730, 690 cm-1; [R]25
D
) +33.3° (c 0.24, CH2Cl2). Anal. Calcd for C20H25O5N1: C, 66.83; H,
7.01. Found: C, 66.59; H, 6.98.
(4S)-3-[(2S,3R)-1-Oxo-2-(pent-4-enyl-1-oxy)-3-hydroxy-5-hexenyl]-
4-benzyl-2-oxazolidinone (23). By the same procedure described above,
0.556 g of acyloxazolidinone 12 provided 0.325 g (48%) of alcohol
23 and 0.238 g (90% brsm) of acyloxazolidinone 12: 1H NMR (CDCl3)
δ 7.26 (m, 5H), 5.84 (m, 2H), 5.16-4.94 (m, 4H), 5.01 (d, J ) 3.0
Hz, 1H), 4.68 (ddd, J ) 13.0, 7.0, 3.3 Hz, 1H), 4.22 (m, 2H), 3.95 (m,
1H), 3.68 (ddd, J ) 9.0, 6.3, 6.3 Hz, 1H), 3.40 (ddd, J ) 9.0, 6.7, 6.7
Hz, 1H), 3.34 (dd, J ) 13.5, 3.3 Hz, 1H), 2.81 (dd, J ) 13.5, 9.5 Hz,
1H), 2.43 (dt, J ) 7.0, 1.1 Hz, 2H), 2.23 (d, J ) 9.5 Hz, 1H), 2.17 (m,
2H), 1.75 (m, 2H); 13C NMR (CDCl3) δ 28.8, 30.1, 37.7, 38.8, 55.7,
67.0, 70.4, 71.6, 79.6, 115.0, 117.7, 127.4, 129.0, 129.4, 134.1, 135.0,
138.0, 153.4, 170.9; IR (film) 3720-3140 (br), 2920, 1780, 1700, 1640,
3100 (br), 2920, 1090, 910, 730, 690 cm-1; [R]25 ) -20.8 (c 0.65,
D
CH2Cl2). Anal. Calcd for C18H26O4: C, 70.56; H, 8.55. Found: C, 70.89;
H, 8.69.
(2R,3R,8R)-8-(Hydroxymethyl)-3-acetoxy-2-(acetoxymethyl)-3,4,7,8-
tetrahydro-(2H)-oxocin (32). Oxocin 31 (0.030 g, 0.083 mmol) was
dissolved in 3 mL of dichloromethane and 0.3 mL of pH 7 buffer (10:1
dichloromethane/buffer). Recrystallized DDQ (0.075 g, 0.332 mmol)
was added in one portion, and the reaction was stirred for 12 h at 25
°C. An additional 4 equiv of DDQ (0.075 g) and 0.15 mL of pH 7
buffer were then added, and the reaction was stirred for another 12 h.
The reaction was quenched by the dropwise addition of saturated
NaHCO3 and diluted with dichloromethane. The organic layer was
washed with saturated NaHCO3, dried over Na2SO4, and concentrated
in vacuo. Purification by flash chromatography afforded 13.3 mg (60%)
of oxocin 32: 1H NMR (CDCl3) δ 5.87 (m, 1H), 5.73 (m, 1H), 5.01
(ddd, J ) 11.1, 5.3, 2.8 Hz, 1H), 4.11 (m, 2H), 3.97 (m, 1H), 3.51 (m,
1390, 1210, 1100, 910, 690 cm-1; [R]25 ) +37.4° (c 0.17, CH2Cl2).
D
Anal. Calcd for C21H27O5N1: C, 67.54; H, 7.29. Found: C, 66.87; H,
7.41.
(4S)-3-[1-Oxo-2-[(R)-1-(benzyloxymethyl)but-3-enyl-1-oxy]-4-
benzyl-1,3-oxazolidinone (28b). The alkoxyacetic acid 4 (1.43 g, 5.7
mmol), 25 mL of dichloromethane, catalytic dimethylformamide (0.6
mmol), and 2.0 M oxalyl chloride in dichloromethane (3.4 mL, 6.8
mmol) were stirred for 2 h at 25 °C. The mixture was concentrated in
vacuo to afford a quantitative yield of the acid chloride. In a separate
flask, (S)-4-benzyl-2-oxazolidinone (1.11 g, 6.3 mmol) was dissolved
in 25 mL of THF and then cooled to -78 °C. After the mixture was
stirred for 15 min at -78 °C, the acid chloride in 50 mL of THF was

5660 J. Am. Chem. Soc., Vol. 121, No. 24, 1999
Crimmins and Choy
3H), 2.68 (dt, J ) 11.0, 11.0 Hz, 1H), 2.35 (m, 3H), 2.08 (s, 3H), 2.05
(s, 3H); 13C NMR (CDCl3) δ 20.8, 21.1, 28.9, 30.7, 64.8, 66.1, 74.7,
78.3, 84.9, 127.8, 130.3, 170.3, 171.0; IR (film) 3800-3060 (br), 2940,
1730, 1650, 1380, 1260, 1050, 800, 730 cm-1; [R]25D ) -18.1 (c 0.41,
CH2Cl2). Anal. Calcd for C13H20O6: C, 57.34; H, 7.40. Found: C, 57.07;
H, 7.44.
stirred for 2 h at 25 °C. The mixture was diluted with water and
concentrated in vacuo. The aqueous layer was extracted with dichlo-
romethane, and the combined extracts were dried over Na2SO4.
Purification by flash chromatography afforded 6.6 mg (97%) of 2,
identical in all respects to that reported by Holmes et al.:12 1H NMR
(400 MHz, CDCl3) δ 7.67 (m, 4H), 7.41 (m, 6H), 5.73 (m, 2H), 3.86
(m, 1H), 3.80 (m, 1H), 3.71 (ddd, J ) 9.1, 3.3, 2.2 Hz, 1H), 3.66 (m,
2H), 3.60 (m, 1H), 3.48 (dd, J ) 15.3, 8.4 Hz, 1H), 3.03 (d, J ) 10.1
Hz, 1H), 2.55 (dt, J ) 12.1, 9.6 Hz, 1H), 2.32 (m, 1H), 2.21 (m, 1H),
1.96 (ddd, J ) 14.0, 8.2, 1.2 Hz, 1H), 1.65 (d, J ) 8.7 Hz, 1H), 1.04
(s, 9H); 13C NMR (CDCl3) δ 19.0, 26.7, 30.4, 33.6, 64.1, 67.7, 73.1,
82.1, 83.4, 127.7, 127.8, 128.7, 129.3, 129.8, 132.9, 135.6, 135.6; IR
(film) 3700-3120 (br), 2920, 2860, 1430, 1110, 1070, 820, 800, 740,
(2R,3R,8R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-acetoxy-2-
(acetoxymethyl)-3,4,7,8-tetrahydro-(2H)-oxocin (33). The oxocin 32
(6.4 mg, 0.024 mmol), 0.12 mL of dimethylformamide, imidazole (3.6
mg, 0.053 mmol), and tert-butylchlorodiphenylsilane (7 µL, 0.026
mmol) were stirred for 1 h at 25 °C. The reaction was quenched with
water, and the aqueous layer was extracted three times with ethyl
acetate. The combined extracts were washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. Purification by flash chro-
matography afforded 8.1 mg (66%) of oxocin 33: 1H NMR (CDCl3)
δ 7.66 (m, 4H), 7.38 (m, 6H), 5.91 (m, 1H), 5.73 (m, 1H), 4.97 (ddd,
J ) 11.0, 5.5, 2.3 Hz, 1H), 3.97 (m, 3H), 3.75 (dd, J ) 9.7, 5.1 Hz,
1H), 3.53 (dd, J ) 9.7, 7.3 Hz, 1H), 3.44 (m, 1H), 2.68 (dt, J ) 11.0,
11.0 Hz, 1H), 2.37 (m, 3H), 2.05 (s, 3H), 1.88 (s, 3H), 1.04 (s, 9H).;
13C NMR (CDCl3) δ 19.2, 20.7, 21.1, 26.8, 28.8, 31.3, 63.9, 66.6, 74.5,
77.7, 83.6, 127.6, 127.9, 129.7, 131.0, 133.4, 133.6, 135.5, 135.6, 170.5,
700 cm-1; [R]25 ) -14.7 (c 0.33, CH2Cl2).
D
Acknowledgment. Financial support of our programs by the
NIH and the NSF is acknowledged with thanks. Thanks are
also due to the Department of Education and Eastman Chemical
Co. for fellowships for A.L.C.
170.6; IR (film) 2940, 2860, 1750, 1430, 1370, 1240, 1110, 700 cm-1
;
Supporting Information Available: Experimental details
for the 1,7-octadiene-4,5-diol, 3-butenal, and the dimers from
olefin metathesis of dienes 9 and 15 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
[R]25 ) +2.1 (c 0.40, CH2Cl2).
D
(2R,3R,8R)-8-[[(tert-Butyldiphenylsilyl)oxy]methyl]-3-hydroxy-2-
(hydroxymethyl)-3,4,7,8-tetrahydro-(2H)-oxocin (2). The oxocin 33
(8.1 mg, 0.016 mmol), methanol (1.3 uL, 0.033 mmol), water (0.2 µL,
8:1 MeOH/H2O), and potassium carbonate (4.6 mg, 0.033 mmol) were
JA990421K