Formal total synthesis of (+)-trehazolin. Application of an asymmetric aldol-olefin metathesis approach to the synthesis of functionalized cyclopentenes

Article abstract of DOI:10.1021/jo015568k

An asymmetric synthesis of the aminocyclopentitol pseudosugar of trehazolin has been completed. The synthesis hinges on an asymmetric aldol-ring closing metathesis strategy to construct the five-membered ring with control of both the relative and absolute stereochemistry.

Full text of DOI:10.1021/jo015568k

4012
J . Org. Chem. 2001, 66, 4012-4018
F or m a l Tota l Syn th esis of (+)-Tr eh a zolin . Ap p lica tion of a n
Asym m etr ic Ald ol-Olefin Meta th esis Ap p r oa ch to th e Syn th esis of
F u n ction a lized Cyclop en ten es
Michael T. Crimmins* and Elie A. Tabet
Venable and Kenan Laboratories of Chemistry, The University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received February 13, 2001
An asymmetric synthesis of the aminocyclopentitol pseudosugar of trehazolin has been completed.
The synthesis hinges on an asymmetric aldol-ring closing metathesis strategy to construct the five-
membered ring with control of both the relative and absolute stereochemistry.
Glycosyl transferases and glycosidases control the
biosynthesis of various glycoconjugates such as glycolip-
ids, glycoproteins, and oligosaccharides. As such, these
enzymes have a profound effect on a variety of biological
functions including signal transduction and cell recogni-
tion.1 Glycosidases are enzymes that catalyze the hy-
drolysis of glycosidic bonds; thus, glycosidase inhibitors
can be of importance in the study of processes controlled
by glycoconjugates and as potential clinical agents to
control disease caused by malfunction of glycoconjugates.
A diverse collection of naturally occurring glycosidase
inhibitors is known, many of which contain an aminocy-
clopentitol unit. Included in the aminocyclopentitol gly-
cosidases are trehazolin,2 the mannostatins,3 and the
allosamidins.4 The biological activity and synthetic ap-
proaches to these aminocyclopentitol glycosidases have
been extensively studied.5
Trehalase is a glycosidase that catalyzes the break-
down of R,R-trehalose to glucose. As a result, specific and
potent inhibitors of trehalase might be used as insecti-
cides because trehalose is the principal blood sugar found
in insects and is used to support various energy-requiring
functions.6 Trehazolin 1 and trehalostatin 2 (Figure 1),
isolated by Ando and co-workers2 in 1991 and Nakayama
and co-workers7 in 1991, respectively, fit the above
criteria and thus have attracted much interest from the
synthetic community. Trehazolin was isolated from a
culture broth of Micromonospora strain SANK 62390,
while trehalostatin from Amycolatopsis trehalostatica.
The absolute configuration of trehazolin was established
F igu r e 1. Trehalase inhibitors.
through the synthetic efforts of Shiozaki and co-workers.8a
It was also determined through the synthetic studies of
Ogawa and co-workers that the structure of trehalostatin
was incorrect and that in fact trehazolin and trehalosta-
tin are the same compound.8b
Several total syntheses of trehazolin8 have been re-
ported since the seminal work of Shiozaki and Ogawa.
All the syntheses rely on the coupling of trehazolamine
or a protected form of trehazolamine with a glucose
derivative near the end of the synthesis. As such, any
synthesis of trehazolamine constitutes a formal synthesis
of the natural product, trehazolin. For comparison, the
efficiency to trehazolamine or a protected form are
discussed below. The most recent synthesis of trehazola-
mine, by Al-Abed,8I utilizes a ring-closing metathesis of
a diene derived from arabinose to construct the five-
membered carbocycle in nine steps from 2′,3′,5′-tri-O-
benzyl-D-arabinose. The syntheses by Chiara8g,h and
Giese8f rely on a pinacol coupling of a hydroxylamine
derived from either mannose or glucose to prepare the
five-membered ring. The Chiara and Giese approaches
produce trehazolamine in 12 and 11 steps, respectively,
from the appropriate natural carbohydrate. Knapp’s8c 15-
step approach to trehazolamine utilized ribonolactone as
the starting point for preparation of the carbocyclic sugar.
(1) Elbein, A. Annu. Rev. Biochem. 1987, 56, 497-534.
(2) Ando, O.; Satake, H.; Itoi, K.; Sato, A.; Nakajima, M.; Takahashi,
S.; Haruyama, H. J . Antibiot. 1991, 44, 1165-1168.
(3) Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Morishima, H.; Nagai, M.;
Hamada, M.; Takcuchi, T.; Umezawa, H. J . Antibiot. 1989, 42, 883-
889.
(4) (a) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A.; Koseki, K.
Tetrahedron Lett. 1986, 27, 2475-2478. (b) Sakuda, S.; Isogai, A.;
Matsumoto, S.; Suzuki, A. J . Antibiot. 1987, 40, 296-300.
(5) (a) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev.
1999, 99, 779-844. (b) Kobayashi, Y. Carbohydr. Res. 1999, 315, 3-15.
(6) Elbein, A. D. Adv. Carbohydr. Chem. Biochem. 1974, 30, 227-
256.
(7) (a) Murao, S.; Sakai, T.; Gibo, H.; Nakayama, T.; Shim, T. Agric.
Biol. Chem. 1991, 55, 895-897. (b) Nakayama, T.; Amachi, T.; Murao,
S.; Sakai, T.; Shin, T.; Kenny, P. T. M.; Iwashita, T.; Zagorski, M.;
Komura, H.; Nomoto, K. J . Chem. Soc., Chem. Commun. 1991, 919-
921.
(8) (a) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J . Org. Chem. 1994,
59, 813-822. (b) Uchida, C.; Yamagishi, T.; Ogawa, S. J . Chem. Soc.,
Perkin Trans. 1 1994, 589-602. (c) Knapp, S.; Purandare, A.; Pupitz,
K.; Withers, S. G. J . Am. Chem. Soc. 1994, 116, 7461-7462. (d)
Ledford, B. E.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117, 11811-
11812. (e) Li, J .; Lang, F.; Ganem, B. J . Org. Chem. 1998, 63, 3403-
3410. (f) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J . Org. Chem. 1998,
63, 5877-5882. (g) Storch de Gracia, I.; Dietrich, H.; Bobo, S.; Chiara,
J . L. J . Org. Chem. 1998, 63, 5883-5889. (h) Storch do Gracia, I.; Bobo,
S.; Martin-Ortega, M. D.; Chiara, J . L. Org. Lett. 1999, 1, 1705-1708.
(i) eepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2001, 42, 1471-1473.
10.1021/jo015568k CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/09/2001

Total Synthesis of (+)-Trehazolin
J . Org. Chem., Vol. 66, No. 11, 2001 4013
Sch em e 1
Sch em e 2
The Ganem8e and Carreira8d approaches began with
cyclopentadiene as the synthon for the carbocycle and
produced a trehazolamine derivative in 12 and 14 steps,
respectively.
After our initial total synthesis of the carbocyclic
nucleosides carbovir and abacavir using an asymmetric
aldol-metathesis strategy9 to access a functionalized
cyclopentene derivative, it was decided to apply this
strategy to the total synthesis of trehazolin, which
contains a heavily functionalized cyclopentane ring.
Retrosynthetically, trehazolin can arise from the cou-
pling of aminocyclopentitol 3 and the R-D-glucosyl isothio-
cyanate 48d following precedented work of others (Scheme
1).8 The aminocyclitol can arise from cyclopentene 5
through a series of functional group manipulations. An
electrophilic cyclization-elimination sequence could pro-
vide the aminocyclopentene 5 from cyclopentenol deriva-
tive 6, which is the product of a ring-closing metathesis
of diene 7. Diene 7 is the obvious product of an asym-
metric aldol addition reaction.
The acylated oxazolidinone 8a was subjected to the
Evans dialkyl boron triflate10 protocol using 3-butenal11
to yield the syn aldol product 7a in 63% yield as shown
in Scheme 2. Similarly, but in slightly higher yield (75%),
the N-acyloxazolidinethione 8b delivered the aldol adduct
7b when enolized with TiCl4-(-)-sparteine12 and then
treated with 3-butenal. To our knowledge, this is the first
example of an asymmetric crotonyl aldol addition through
the use of a chlorotitanium enolate. Attempted ring
closing metathesis13 on diene 7a or 7b led to incomplete
conversion to the desired cyclopentene (56:44 ratio of
starting material to product) presumably due to the
coordination of the homoallylic alcohol to the metal center
in the intermediate alkylidine. As a result, the secondary
alcohol was protected to circumvent the problem. Protec-
Sch em e 3
tion of the alcohol as the tert-butyldimethylsilyl ether
provided 9a or 9b in high yield and exposure of the diene
9a and 9b to the Grubbs catalyst14 generated cyclopen-
tene 10a or 10b in 85% yield over two steps. Reductive
removal of the chiral auxiliary followed by treatment of
the resultant alcohol with trichloroacetonitrile gave
imidate 11. It was anticipated that an electrophilic
cyclization of the imidate on the cyclopentene olefin
would be used to introduce the amine at C1′ stereose-
lectively. Treatment of imidate 11 with phenylselenyl
chloride or N-(phenylseleno)phthalimide15 gave no reac-
tion; however, N-iodosuccinimide-promoted cyclization
smoothly produced the iodide 12. Unfortunately, elimina-
tion using DBU resulted in the undesired cyclopentene
regioisomer 13.
The electrophilic cyclization developed by Hirama and
Ito16 was next investigated in an attempt to generate the
desired cyclopentene after elimination of the halide
(Scheme 3). Treatment of the alcohol 6 with p-toluene-
sulfonyl isocyanate followed by cyclization with iodine
(9) Crimmins, M. T.; King, B. W. J . Org. Chem. 1996, 61, 4192-
4193.
(10) Evans, D. A.; Sjogren, E. B.; Bartroli, J .; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957-4960.
(11) Crimmins, M. T.; Kirincich, S. J .; Wells, A. J .; Choy, A. L. Synth.
Commun. 1998, 28, 3675-3679.
(12) Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc.
1997, 119, 7883-7884. Crimmins, M. T.; King, B. W.; Tabet, E. A.,
Chaudhary, K. J . Org. Chem. 2001, 65, 894-902.
(13) (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem. Res. 1995,
28, 446-452. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-
4450. (c) Blechert, S. Pure Appl. Chem. 1999, 71, 1393-1399.
(14) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100-110.
(15) Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P.
J . Am. Chem. Soc. 1979, 101, 3704-3706.
(16) Hirama, M.; Iwashita, M.; Yamazaki, Y.; Ito, S. Tetrahedron
Lett. 1984, 25, 4963-4964.

4014 J . Org. Chem., Vol. 66, No. 11, 2001
Crimmins and Tabet
Sch em e 4
of the less hindered face of the alkene using dimethyl-
dioxirane19 gave 74% of epoxide 19 as the only detectable
isomer. Acid-promoted nucleophilic opening of the ep-
oxide by the neighboring carbamate carbonyl oxygen
generated oxazolidinone 20 in 83% yield. Finally, intro-
duction of the stereocenter at C5′ was accomplished.
Deprotection of the acetate under basic conditions pro-
vided the primary alcohol which was converted to the
primary selenide using the protocol developed by Grieco
(70% overall).20 Thus, treatment of alcohol 21 with
2-nitrophenylselenocyanate21 and tributylphosphine gave
the intermediate selenide 22 which was immediately
oxidized with hydrogen peroxide to give the exocyclic
olefin 23. Osmylation of the alkene gave 75% of triol 24
as a single observable diastereomer. Exposure of oxazo-
lidinone 24 to aqueous base followed by peracetylation
with acetic anhydride gave ester 25 which was spectro-
scopically identical (1H NMR, 13C NMR, IR, [R]D) to that
previously reported. Ester 25 has been taken on to
trehazolin as described by Shiozaki.8a
An asymmetric aldol ring closing metathesis approach
has been applied to the synthesis of the carbocyclic sugar
trehazolamine. The synthesis was completed in 18 steps
form the N-acyloxazolidinethione 8b. While the synthesis
is not as efficient as some previous approaches, it
demonstrates the power and flexibility of the general
strategy of combining reactions which control acyclic
stereochemistry with the ring-closing metathesis reac-
tion.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Gen er a l P r oced u r es. Infrared
(IR) spectra were obtained using a Perkin-Elmer 283 infrared
spectrometer. Proton and carbon nuclear magnetic resonance
(1H and 13C NMR) spectra were recorded on the following
instrument: Bruker Model Avance 400 (1H at 400 MHz; 13C
at 100 MHz). Optical rotations were determined using a
Perkin-Elmer 241 polarimeter. Elemental analyses were per-
formed by Atlantic Microlab, Inc., Norcross, GA. Thin-layer
chromatography (TLC) was conducted on silica gel F254 TLC
plates purchased from Scientific Adsorbents, Inc. Flash chro-
matography was carried out using silica gel (32-63 µm)
purchased from Scientific Adsorbents, Inc. Diethyl ether,
tetrahydrofuran (THF), and dichloromethane were dried by
being passed through a column of neutral alumina under
nitrogen immediately prior to use. Alkylamines, and benzene
were distilled from calcium hydride immediately prior to use.
1,2-dimethoxyethane was distilled from sodium immediately
prior to use. All air and water sensitive reactions were
performed in flasks flame dried under a positive flow of argon
and conducted under an argon atmosphere.
generated iodide 14 in 77% overall yield. Elimination of
the halide with DBU yielded 91% of the cyclopentene 15.
With the successful introduction of the stereocenter at
C1′, efforts were next directed toward the incorporation
of the C2′ and C3′ centers, which effectively required a
selective anti dihydroxylation of the alkene. A neighbor-
ing group directed nucleophilic opening of the cyclopen-
tene â-epoxide was envisioned as a possible solution.
Reduction of the cyclic carbamate 15 with LiBH4-gener-
ated alcohol 16. Reductive removal of the sulfonamide
with sodium and ammonia led to scrambling of the tert-
butyldimethylsilyl ether. Consequently, a new strategy,
as shown in Scheme 4, was investigated to circumvent
the silyl transfer.
(4R)-Ben zyl-3-((3S)-h yd r oxy-(2R)-vin ylh ex-5-en oyl)ox-
a zolid in -2-on e (7a ). A solution of the acyloxazolidinone 8a 10
(13.17 g, 54 mmol) in 280 mL of CH2Cl2 was cooled to -78 °C.
Bu2BOTf (14.7 mL, 59 mmol) was diluted in 15 mL of CH2Cl2
and then added dropwise slowly. The mixture was stirred for
5 min at -78 °C. Et3N (10.5 mL, 75 mmol) was diluted with
10 mL of CH2Cl2 and then added dropwise slowly. After
complete addition, the mixture was stirred at -78 °C for 1 h.
The mixture was gradually warmed to 0 °C, stirred for 15 min,
and then recooled to -78 °C. A solution of 3-butenal (277
mmol) in 100 mL of CH2Cl2 was cooled to -78 °C and added
to the enolate solution via cannula. The reaction was stirred
for 1 h at -78 °C, gradually warmed to 0 °C, and stirred for 1
Hydrolysis of the cyclic carbamate was next attempted
using the protocol developed by Kunieda.17 Reductive
removal of the sulfonamide of alkene 15 using sodium
naphthalide18 followed by acylation of the nitrogen with
di-tert-butyl dicarbonate generated cyclic carbamate 17
in 88% yield. Attempted epoxidation of cyclopentene 17
led to formation of the epoxide in only 26% yield due to
the formation of an enone as a side product. Thus,
epoxidation was attempted after hydrolysis of the car-
bamate. Cesium carbonate mediated hydrolysis of the
carbamate, and protection of the alcohol with acetic
anhydride gave ester 5 in 95% overall yield. Epoxidation
(19) Murray, R. W. Chem. Rev. 1989, 89, 1187-1201.
(20) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.
(21) Sharpless, K. B.; Young, M. W. J . Org. Chem. 1975, 40, 947-
949.
(17) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185-
4188.
(18) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Clossom,
W. D. J . Am. Chem. Soc. 1967, 89, 5311-5312.

Total Synthesis of (+)-Trehazolin
J . Org. Chem., Vol. 66, No. 11, 2001 4015
h. The reaction was quenched with 1 M NaHSO4 and warmed
to 25 °C. The layers were separated, and the aqueous layer
was extracted once with CH2Cl2. The combined organic layers
were washed with brine and concentrated in vacuo. The
residue was dissolved in 360 mL of Et2O and cooled to 0 °C. A
solution of pH 7 buffer (53 mL) was added followed by dropwise
addition of H2O2 (53 mL of a 30% solution in H2O) while the
temperature was maintained around 0 °C. The mixture was
stirred for 1 h. Water was added, and the layers were
separated. The aqueous layer was extracted twice with ether.
The combined extracts were washed with saturated NaHCO3,
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography afforded 3.58 g of
acyloxazolidinone and 10.7 g of alcohol 7a (63%; 90% based
on recovered starting material): 1H NMR (CDCl3, 400 MHz)
δ 7.33-7.25 (m, 3H), 7.19-7.16 (m, 2H), 6.00 (ddd, J ) 17.6,
9.6, 9.2 Hz, 1H), 5.81 (dddd, J ) 16.8, 10.4, 6.8, 6.8 Hz, 1H),
5.43-5.39 (m, 2H), 5.14-5.09 (m, 2H), 4.70 (dddd, J ) 9.2,
7.6, 3.2, 3.2 Hz, 1H), 4.58 (dd, J ) 9.2, 3.6 Hz, 1H), 4.17 (AB
portion of ABX, J AB ) 8.8 Hz, J AX ) 21.2 Hz, J BX ) 7.6 Hz,
∆νAB ) 9 Hz, 2H), 4.09-4.04 (m, 1H), 3.22 (dd, J ) 13.2, 3.2
Hz, 1H), 2.97 (d, J ) 2 Hz, 1H), 2.73 (dd, J ) 13.6, 9.6 Hz,
1H), 2.35-2.20 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 173.8,
152.8, 134.8, 134.2, 131.0, 129.4, 128.9, 127.3, 121.7, 117.9,
70.9, 65.9, 55.0, 51.5, 38.6, 37.5; IR (film) 3500 (br), 3080, 1775,
mL of ether was cooled to 0 °C. Lithium borohydride (24 mL
of a 2.0 M solution in THF, 48 mmol) was added dropwise,
and the reaction was stirred for 2 h at 0 °C and 1 h at 25 °C.
The mixture was recooled to 0 °C and quenched with the
dropwise addition of 1 M NaOH. The mixture was warmed to
25 °C, and the layers were separated. The aqueous layer was
extracted three times with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatog-
raphy afforded 6.1 g of alcohol 6 (83.4%): 1H NMR (CDCl3,
400 MHz) δ 5.74 (dddd, J ) 6.0, 2.4, 2.4, 2.4 Hz, 1H), 5.57
(dddd, J ) 6.0, 2.0, 2.0, 2.0 Hz, 1H), 4.67 (ddd, J ) 7.4, 7.4,
5.6 Hz, 1H), 3.74 (d, J ) 4.8 Hz, 1H), 3.72 (d, J ) 4.8 Hz, 1H),
2.91 (dd, J ) 6.4, 6.4 Hz, 1H), 2.81-2.77 (m, 1H), 2.58-2.51
(m, 1H), 2.34-2.27 (m, 1H), 0.89 (s, 9H), 0.10 (s, 3H), 0.08 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 130.2, 129.9, 75.3, 62.2,
50.6, 41.4, 25.8, 17.9, -4.6, -5.2; IR (film) 3420 (br) cm-1
;
[R]24 ) -17.7 (c 0.81, CH2Cl2). Anal. Calcd for C12H24O2Si:
D
C, 63.10; H, 10.59. Found: C, 63.16; H, 10.59.
1-[(4R )-4-Ben zyl-2-t h ioxooxa zolid in -3-yl]b u t -2-en -1-
on e (8b). To a cooled solution (-78 °C) of (R)-4-benzyl-2-
oxazolidinethione (2.05 g, 10.6 mmol) and Et3N (1.92 mL, 14.0
mmol) in 75 mL of CH2Cl2 was added dropwise trans-crotonyl
chloride (1.22 mL, 12.7 mmol). The mixture was stirred for 30
min and quenched with H2O. The layers were separated, and
the organic layer was washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 2.33 g of acylated thione 8b (84%):
1H NMR (CDCl3, 400 MHz) δ 7.72 (dq, J ) 15.2, 1.6 Hz, 1H),
7.34-7.09 (m, 6H), 4.90 (dddd, J ) 13.6, 6.4, 3.6, 2.8 Hz, 1H),
4.33-4.27 (m, 2H), 3.34 (dd, J ) 13.2, 3.2 Hz, 1H), 2.78 (dd,
J ) 13.2, 10.0 Hz, 1H), 1.99 (dd, J ) 6.8, 1.6 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 185.5, 166.0, 146.4, 135.2, 129.3, 128.9,
1685 cm-1; [R]24 ) -22.8 (c 1.47, CH2Cl2). Anal. Calcd for
D
C
18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.42; H,
6.69; N, 4.29.
(4R)-Ben zyl-3-[(3S)-(ter t-bu tyldim eth ylsilan yloxy)-(2R)-
vin ylh ex-5-en oyl]oxa zolid in -2-on e (9a ). To a cooled solu-
tion (0 °C) of alcohol 7a (12.1 g, 38 mmol) in 300 mL of CH2Cl2
was added 2,6-lutidine (17.9 mL, 150 mmol) followed by
dropwise addition of TBSOTf (15.4 mL, 67 mmol) diluted in
15 mL of CH2Cl2. The reaction was stirred for 2 h and
quenched with saturated NaHCO3. The layers were separated,
and the organic layer was washed with 1 M HCl, saturated
NaHCO3, and brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. Purification by flash chromatography afforded
15.02 g of diene 9a (92%): 1H NMR (CDCl3, 400 MHz) δ 7.33-
7.23 (m, 3H), 7.19-7.17 (m, 2H), 6.01 (ddd, J ) 17.4, 10.4, 9.2
Hz, 1H), 5.81 (dddd, J ) 17.0, 10.4, 7.2, 7.2 Hz, 1H), 5.30-
5.22 (m, 2H), 5.04-4.97 (m, 2H), 4.60 (dddd, J ) 9.6, 6.8, 3.2,
3.2 Hz, 1H), 4.50 (dd, J ) 9.2, 5.6 Hz, 1H), 4.16-4.10 (m, 3H),
3.24 (dd, J ) 13.2, 3.2 Hz, 1H), 2.73 (dd, J ) 13.6, 9.6 Hz,
1H), 2.35-2.29 (m, 2H), 0.87 (s, 9H), 0.03 (s, 3H), -0.02 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 172.4, 152.8, 135.2, 134.4,
133.4, 129.5, 128.9, 127.3, 119.6, 117.3, 72.4, 65.9, 55.5, 53.2,
40.6, 37.5, 25.8, 18.0, -4.2, -4.8; IR (film) 3080, 1780, 1695,
127.2, 123.2, 70.4, 60.0, 37.4, 18.5; IR (film) 1680, 1640 cm-1
;
[R]24 ) -109.3 (c 0.91, CH2Cl2). Anal. Calcd for C14H15NO2S:
D
C, 64.34; H, 5.79; N, 5.36. Found: C, 64.44; H, 5.68; N, 5.38.
(2R,3S)-1-[(4R)-4-Ben zyl-2-th ioxooxa zolid in -3-yl]-3-h y-
d r oxy-2-vin ylh ex-5-en -1-on e (7b). A solution of the acylox-
azolidinethione 8b (1.16 g, 4.46 mmol) in 30 mL of CH2Cl2 was
cooled to -78 °C. Titanium tetrachloride (0.51 mL, 4.68 mmol)
was added dropwise slowly. The mixture was stirred for 5 min
at -78 °C. (-)-Sparteine (2.56 mL, 11 mmol) was then added
dropwise slowly. After complete addition, the mixture was
stirred at -78 °C for 2 h. A solution of 3-butenal (31 mmol) in
14 mL of CH2Cl2 was cooled to -78 °C and added to the enolate
solution via cannula. The reaction was stirred for 1 h at -78
°C, gradually warmed to 0 °C, and stirred for 1 h. The reaction
was quenched with half-saturated NH4Cl and warmed to 25
°C. The layers were filtered through Celite, separated, and the
aqueous layer was extracted twice with CH2Cl2. The combined
extracts were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatog-
raphy afforded 1.10 g of alcohol 7b (75%): 1H NMR (CDCl3,
400 MHz) δ 7.34-7.24 (m, 3H), 7.20-7.18 (m, 2H), 6.03 (ddd,
J ) 17.2, 10.4, 8.8 Hz, 1H), 5.81 (dddd, J ) 16.8, 10.0, 7.2, 7.2
Hz, 1H), 5.58 (dd, J ) 8.8, 4.0 Hz, 1H), 5.44-5.38 (m, 2H),
5.15-5.10 (m, 2H), 4.95 (dddd, J ) 13.6, 3.6, 3.4, 3.2 Hz, 1H),
4.32-4.25 (m, 2H), 4.13-4.08 (m, 1H), 3.23 (dd, J ) 13.2, 3.2
Hz, 1H), 2.74 (d, J ) 2.8 Hz, 1H), 2.72 (dd, J ) 13.2, 10.0 Hz,
1H), 2.32-2.27 (m, 2H),; 13C NMR (CDCl3, 100 MHz) δ 184.9,
174.5, 134.9, 134.0, 130.9, 129.3, 129.0, 127.4, 121.5, 118.1,
1640 cm-1; [R]24 ) -45.1 (c 0.88, CH2Cl2). Anal. Calcd for
D
C
24H35NO4Si: C, 67.10; H, 8.21; N, 3.26. Found: C, 67.16; H,
8.22; N, 3.31.
(4R)-Ben zyl-3-[(1R,5S)-5-(ter t-bu tyldim eth ylsilan yloxy)-
cyclop en t-2-en eca r bon yl]oxa zolid in -2-on e (10a ). A solu-
tion of diene 9a (14.56 g, 34 mmol) in 300 mL of CH2Cl2 was
heated to reflux. Grubbs’ metathesis catalyst [Cl2(Cy3P)2Rud
CHPh; 1.39 g, 1.7 mmol] was added in one portion and the
reaction was stirred for 2 h at reflux. After cooling to 25 °C,
the mixture was stirred open to air overnight and concentrated
in vacuo. Purification by flash chromatography gave 12.56 g
of alkene 10a (92%): 1H NMR (CDCl3, 400 MHz) δ 7.34-7.20
(m, 5H), 5.92 (dddd, J ) 6.4, 2.4, 2.2, 2.0 Hz, 1H), 5.72 (dddd,
J ) 6.0, 2.0, 2.0, 2.0 Hz, 1H), 4.92 (ddd, J ) 7.0, 7.0, 2.8 Hz,
1H), 4.82 (dddd, J ) 7.2, 4.0, 2.0, 2.0 Hz, 1H), 4.61 (dddd, J )
10.0, 7.6, 3.2, 3.2 Hz, 1H), 4.14 (AB portion of ABX, J AB ) 2.8
Hz, J AX ) 9.2 Hz, J BX ) 9.2 Hz, ∆νAB ) 14 Hz, 2H), 3.34 (dd,
J ) 13.6, 3.2 Hz, 1H), 2.74 (dd, J ) 13.2, 9.6 Hz, 1H), 2.67-
2.60 (m, 1H), 2.38-2.32 (m, 1H), 0.80 (s, 9H), 0.01 (s, 3H),
-0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.9, 153.3,
135.5, 131.6, 129.4, 128.9, 127.2, 127.0, 73.0, 65.9, 56.0, 55.4,
71.2, 70.1, 59.9, 51.1, 38.8, 37.3; IR (film) 3480 (br), 1685 cm-1
;
[R]24 ) -64.2 (c 1.3, CH2Cl2). Anal. Calcd for C19H21NO3S:
D
C, 65.23; H, 6.39; N, 4.23. Found: C, 65.27; H, 6.25; N, 4.22.
(2R,3S)-1-[(4R)-4-Ben zyl-2-th ioxooxazolidin -3-yl]-3-(ter t-
bu tyld im eth ylsila n yloxy)-2-vin ylh ex-5-en -1-on e (9b). To
a cooled solution (0 °C) of alcohol 7b (440 mg, 1.33 mmol) in
10 mL of CH2Cl2 was added 2,6-lutidine (0.62 mL, 5.3 mmol)
followed by TBSOTf (0.46 mL, 2.00 mmol). The reaction was
stirred for 1.5 h and quenched with saturated NaHCO3. The
layers were separated, and the organic layer was washed with
1 M HCl, saturated NaHCO3, and brine, dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 414 mg of diene 9b (70%): 1H NMR
(CDCl3, 400 MHz) δ 7.34-7.19 (m, 5H), 6.06 (ddd, J ) 17.4,
42.5, 38.1, 25.5, 17.6, -4.5, -5.4; IR (film) 1785, 1705 cm-1
;
[R]24 ) -47.2 (c 0.90, CH2Cl2). Anal. Calcd for C22H31NO4Si:
D
C, 65.80; H, 7.78; N, 3.49. Found: C, 65.52; H, 7.96; N, 3.47.
[(1S,5S)-5-(ter t-Bu tyld im eth ylsila n yloxy)cyclop en t-2-
en yl]m eth a n ol (6). A solution of alkene 10a (12.85 g, 32
mmol) in anhydrous methanol (1.94 mL, 48 mmol) and 300

4016 J . Org. Chem., Vol. 66, No. 11, 2001
Crimmins and Tabet
10.4, 8.8 Hz, 1H), 5.81 (dddd, J ) 16.8, 10.0, 7.2, 7.2 Hz, 1H),
5.40 (dd, J ) 8.8, 5.2 Hz, 1H), 5.32 (dd, J ) 10.4, 1.6 Hz, 1H),
5.27-5.23 (m, 1H), 5.04-4.98 (m, 2H), 4.85-4.79 (m, 1H), 4.28
(dd, J ) 9.6, 2.0 Hz, 1H), 4.26-4.16 (m, 2H), 3.27 (dd, J )
13.6, 3.2 Hz, 1H), 2.71 (dd, J ) 13.2, 10.4 Hz, 1H), 2.39-2.26
(m, 2H), 0.86 (s, 9H), 0.03 (s, 3H), -0.03 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 184.6, 173.2, 135.3, 134.3, 133.1, 129.4,
129.0, 127.4, 119.7, 117.5, 72.9, 69.8, 60.6, 52.9, 40.7, 37.2, 25.7,
9.6, 0.8 Hz, 1H), 4.76 (ddd, J ) 9.6, 8.6, 6.0 Hz, 1H), 4.55 (dd,
J ) 11.2, 1.2 Hz, 1H), 4.12 (d, J ) 6.0 Hz, 1H), 4.01 (dd, J )
11.2, 4.4 Hz, 1H), 2.95 (ddd, J ) 9.0, 9.0, 3.2 Hz, 1H), 2.43 (s,
3H), 2.18 (dd, J ) 14.8, 6.0 Hz, 1H), 1.84 (ddd, J ) 14.6, 10.0,
6.0 Hz, 1H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 150.6, 145.6, 135.0, 129.6, 129.3, 72.4,
67.6, 64.8, 44.8, 40.6, 25.6, 24.8, 21.7, 17.9, -4.7, -5.1; IR (film)
1740 cm-1; [R]24 ) -22.4 (c 1.9, CH2Cl2). Anal. Calcd for
D
18.0, -4.1, -4.7; IR (film) 1695 cm-1; [R]24 ) -62.2 (c 2.6,
C
20H30INO5SSi: C, 43.56; H, 5.48; N, 2.54. Found: C, 43.93;
D
H, 5.57; N, 2.59.
CH2Cl2). Anal. Calcd for C24H35NO3SSi: C, 64.68; H, 7.92; N,
3.14. Found: C, 64.55; H, 8.03; N, 3.21.
[8R,9S]-(5S)-(ter t-Bu tyld im eth ylsila n yloxy)-1-(tolu en e-
4-su lfon yl)-4,4a ,5,7a -t et r a h yd r o-1H -cyclop en t a [d ][1,3]-
oxa zin -2-on e (15). To a solution of iodide 14 (12.19 g, 22
mmol) in 200 mL of benzene was added DBU (6.6 mL, 44
mmol). The mixture was heated at reflux for 1 h, cooled to 25
°C, and filtered. Purification by flash chromatography afforded
8.5 g of alkene 15 (91%): 1H NMR (CDCl3, 400 MHz) δ 7.94
(ddd, J ) 8.4, 2.0, 2.0 Hz, 2H), 7.31 (d, J ) 8 Hz, 2H), 6.01
(ddd, J ) 6.0, 1.6, 1.6 Hz, 1H), 5.85 (ddd, J ) 5.6, 1.6, 1.6 Hz,
1H), 5.10 (dddd, J ) 7.6, 2.0, 1.8, 1.6 Hz, 1H), 4.90 (dddd, J )
6.8, 1.6, 1.6, 1.6 Hz, 1H), 4.22 (dd, J ) 11.6, 8.4 Hz, 1H), 4.14
(dd, J ) 11.2, 5.2 Hz, 1H), 3.03-2.96 (m, 1H), 2.42 (s, 3H),
0.86 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ 150.4,
145.1, 136.8, 135.2, 131.6, 129.4, 129.1, 75.0, 65.5, 62.4, 41.2,
25.6, 21.6, 18.0, -4.8, -5.1; IR (film) 1740 cm-1; [R]24D ) -77.1
(c 1.37, CH2Cl2). Anal. Calcd for C20H29NO5SSi: C, 56.71; H,
6.90; N, 3.31. Found: C, 56.65; H, 6.94; N, 3.26.
[(4R)-4-Ben zyl-2-th ioxooxa zolid in -3-yl]-[(1R,5S)-5-(ter t-
b u t yld im et h ylsila n yloxy)cyclop en t -2-en yl]m et h a n on e
(10b). A solution of diene 9b (105 mg, 0.24 mmol) in 5 mL of
CH2Cl2 was heated to reflux. Grubbs’ metathesis catalyst (10
mg, 0.01 mmol) was added in one portion, and the reaction
was stirred for 2.5 h at reflux. After being cooled to 25 °C, the
mixture was stirred open to air overnight and concentrated
in vacuo. Purification by flash chromatography gave 90 mg of
alkene 10b (91%): 1H NMR (CDCl3, 400 MHz) δ 7.34-7.21
(m, 5H), 5.91 (dddd, J ) 6.0, 2.4, 2.4, 2.4 Hz, 1H), 5.86-5.82
(m, 1H), 5.73 (dddd, J ) 6.0, 2.4, 2.2, 2.0 Hz, 1H), 5.05 (ddd,
J ) 7.2, 7.0, 2.8 Hz, 1H), 4.88-4.83 (m, 1H), 4.30 (dd, J ) 9.2,
2.0 Hz, 1H), 4.20-4.16 (m, 1H), 3.33 (dd, J ) 13.2, 3.2 Hz,
1H), 2.74 (dd, J ) 13.2, 10.4 Hz, 1H), 2.71-2.64 (m, 1H), 2.40-
2.34 (m, 1H), 0.78 (s, 9H), 0.03 (s, 3H), -0.02 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 185.3, 171.8, 135.5, 131.2, 129.4, 129.0,
127.3, 127.2, 73.1, 69.8, 60.4, 56.2, 42.8, 37.8, 25.6, 17.7, -4.4,
-4.9; IR (film) 1700 cm-1; [R]24D ) +15.9 (c 0.75, CH2Cl2). Anal.
Calcd for C22H31NO3SSi: C, 63.27; H, 7.48; N, 3.35. Found:
C, 63.60; H, 7.43; N, 3.30.
[(1S,5S)-5-(ter t-Bu tyld im eth ylsila n yloxy)cyclop en t-2-
en yl]m et h a n ol (6). A solution of alkene 10b (86 mg, 0.21
mmol) in anhydrous methanol (0.02 mL, 0.4 mmol) and 3 mL
of ether was cooled to 0 °C. Lithium borohydride (0.20 mL of
a 2.0 M solution in THF, 0.4 mmol) was added dropwise, and
the reaction was stirred for 1.5 h 0 °C. The mixture was
quenched with the dropwise addition of 1 M NaOH. The
mixture was warmed to 25 °C, and the layers were separated.
The aqueous layer was extracted once with Et2O. The com-
bined organic layers were washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 35 mg (75%) of alcohol 6 identical
to that prepared above.
[8R,9S]-(5S)-(ter t-Bu t yld im et h ylsila n yloxy)-2-oxo-4,-
4a ,5,7a -tetr a h yd r ocyclop en ta [d ][1,3]oxa zin e-1-ca r boxy-
lic Acid ter t-Bu tyl Ester (17). To a solution of naphthalene
(13.1 g, 102 mmol) in 88 mL of 1,2-dimethoxyethane was added
sodium (2.07 g, 90 mmol). The mixture was sonicated for 2 h
to give a dark green solution.22
A solution of alkene 15 (8.87 g, 20.9 mmol) in 180 mL of
THF was cooled to -78 °C. Sodium naphthalenide (68 mL of
a 1 M solution, 68 mmol) was added dropwise, and the mixture
was stirred for 15 min. The reaction was quenched with
saturated NH4Cl and warmed to 25 °C. The layers were
separated, and the aqueous layer was extracted three times
with ethyl acetate. The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Purification by flash chromatography afforded 5.21 g
of oxazolidinone (92.4%): 1H NMR (CDCl3, 400 MHz) δ 6.58
(s, 1H), 5.75 (ddd, J ) 6.0, 1.2, 1.2 Hz, 1H), 5.72 (ddd, J ) 5.6,
1.6, 1.6 Hz, 1H), 4.96 (dddd, J ) 6.8, 1.6, 1.6, 1.6 Hz, 1H),
4.27 (dddd, J ) 6.8, 1.6, 1.4, 1.2 Hz, 1H), 4.19 (dd, J ) 11.6,
5.6 Hz, 1H), 4.05 (dd, J ) 11.6, 11.6 Hz, 1H), 2.93-2.86 (m,
1H), 0.87 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 156.5, 134.7, 132.2, 76.3, 65.4, 56.9, 39.0, 25.7,
[8S,9S]-(5S)-(ter t-Bu tyld im eth ylsila n yloxy)-(7S)-iod o-
1-(tolu en e-4-su lfon yl)h exah ydr ocyclopen ta[d][1,3]oxazin -
2-on e (14). To a stirred solution of alcohol 6 (6.1 g, 27 mmol)
in 200 mL of THF was added p-toluenesulfonyl isocyanate
(4.47 mL, 29 mmol). The mixture was stirred for 12 h and
concentrated in vacuo. Purification by flash chromatography
afforded 10.7 g of alkene (94.5%): 1H NMR (CDCl3, 400 MHz)
δ 7.91 (ddd, J ) 8.4, 2.0, 2.0 Hz, 2H), 7.31 (d, J ) 8.4 Hz, 2H),
7.31 (br s, 1H), 5.72 (dddd, J ) 6.0, 2.4, 2.2, 2.0 Hz, 1H), 5.48
(dddd, J ) 6.0, 2.0, 2.0, 2.0 Hz, 1H), 4.46 (ddd, J ) 6.8, 6.8,
4.4 Hz, 1H), 4.30 (dd, J ) 10.8, 6.4 Hz, 1H), 4.08 (dd, J ) 10.4,
7.2 Hz, 1H), 2.83-2.76 (m, 1H), 2.52-2.45 (m, 1H), 2.42 (s,
3H), 2.24-2.19 (m, 1H), 0.80 (s, 9H), -0.01 (s, 3H), -0.03 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 150.5, 144.9, 135.5,,130.4,
129.5, 129.2, 128.3, 72.3, 66.4, 48.3, 41.8, 25.7, 21.6, 17.9, -4.8,
18.0, -4.9, -5.1; IR (film) 3320, 1670 cm-1; [R]24 ) -6.5 (c
D
0.53, CH2Cl2). Anal. Calcd for C13H23NO3Si: C, 57.96; H, 8.60;
N, 5.20. Found: C, 57.98; H, 8.64; N, 5.38.
To a cooled solution (0 °C) of oxazolidinone (5.21 g, 19 mmol)
in 160 mL of THF were added Et3N (2.7 mL, 19 mmol), di-
tert-butyl dicarbonate (8.89 mL, 39 mmol), and 4-(dimethyl-
amino)pyridine (0.473 g, 3.9 mmol). The reaction was warmed
to 25 °C, stirred for 12 h, and concentrated in vacuo. Purifica-
tion by column chromatography afforded 6.85 g of alkene 17
(96%): 1H NMR (CDCl3, 400 MHz) δ 5.86 (ddd, J ) 5.6, 1.6,
1.6 Hz, 1H), 5.83 (ddd, J ) 6.0, 1.2, 1.2 Hz, 1H), 4.94-4.89
(m, 2H), 4.23 (dd, J ) 10.8, 6.8 Hz, 1H), 4.10 (dd, J ) 11.2,
5.2 Hz, 1H), 2.96 (dddd, J ) 8.0, 7.2, 7.2, 4.8 Hz, 1H), 1.52 (s,
9H), 0.88 (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ
152.6, 152.0, 136.8, 130.5, 83.6, 75.6, 64.8, 60.9, 41.0, 27.9, 25.7,
-5.2; IR (film) 3240, 1730, 1600 cm-1; [R]24 ) -39.3 (c 0.77,
D
CH2Cl2). Anal. Calcd for C20H31NO5SSi: C, 56.44; H, 7.34; N,
3.29. Found: C, 56.67; H, 7.26; N, 3.29.
To a solution of alkene (11.37 g, 27 mmol) in 220 mL of ether
was added K2CO3 (9.23 g, 67 mmol). The mixture was cooled
to 0 °C, and iodine (13.56 g, 53 mmol) was added. The mixture
was warmed to 25 °C and stirred for 36 h. The reaction was
quenched with 10% Na2SO3, and the mixture was stirred until
both layers were colorless. The layers were separated, and the
aqueous layer was extracted with CH2Cl2. The organic layers
were separately washed with saturated Na2SO3 and brine,
dried over Na2SO4, filtered, and concentrated in vacuo. Puri-
fication by flash chromatography afforded 12.08 g of iodide 14
(82%): 1H NMR (CDCl3, 400 MHz) δ 8.01 (ddd, J ) 8.4, 2.0,
2.0 Hz, 2H), 7.34 (ddd, J ) 8.6, 2.4, 2.0 Hz, 2H), 5.31 (dd, J )
18.1, -4.7, -5.0; IR (film) 1740 cm-1; [R]24 ) -97.4 (c 0.65,
D
CH2Cl2). Anal. Calcd for C18H31NO5Si: C, 58.51; H, 8.46; N,
3.79. Found: C, 58.64; H, 8.51; N, 3.94.
[(1R,4S,5S)-4-(ter t-Bu tyldim eth ylsilan yloxy)-5-h ydr oxy-
m eth ylcyclop en t-2-en yl]ca r ba m ic Acid ter t-Bu tyl Ester
(18). To a cooled solution (0 °C) of alkene 17 (3.24 g, 8.8 mmol)
in 80 mL of MeOH was added Cs2CO3 (0.571 g, 1.8 mmol).
(22) Azuma, T.; Yanagida, S.; Sakurai, H. Synth. Commun. 1982,
12, 137-140.

Total Synthesis of (+)-Trehazolin
J . Org. Chem., Vol. 66, No. 11, 2001 4017
The reaction was warmed to 25 °C and stirred for 48 h. The
reaction was quenched with saturated NH4Cl, and the aqueous
layer was extracted four times with CH2Cl2. The combined
organic layers were washed with saturated NaHCO3, brine,
dried over Na2SO4, filtered, and concentrated in vacuo. Puri-
fication by flash chromatography afforded 2.82 g of alcohol 18
(93.6%): 1H NMR (CDCl3, 400 MHz) δ 5.91 (dd, J ) 6.0, 2.0
Hz, 1H), 5.86 (ddd, J ) 5.6, 1.6, 1.6 Hz, 1H), 5.17 (d, J ) 10
Hz, 1H), 4.77-4.75 (m, 1H), 4.72-4.68 (m, 1H), 3.86 (ddd,
J ) 12.2, 5.2, 2.4 Hz, 1H), 3.66 (ddd, J ) 11.6, 11.6, 3.2 Hz,
1H), 2.89 (dd, J ) 11.2, 2.8 Hz, 1H), 2.54-2.48 (m, 1H), 1.43
(s, 9H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3 H); 13C NMR (CDCl3,
100 MHz) δ 156.3, 135.5, 135.1, 79.5, 76.9, 60.2, 55.8, 47.1,
(4S,5R,6R,7S,8S)-5-(ter t-Bu t yld im et h ylsila n yloxy)-6-
h yd r oxy-4-h yd r oxym eth ylh exa h yd r ocyclop en ta oxa zol-
2-on e (21). To a solution of alcohol 20 (1.47 g, 4.24 mmol) in
40 mL of MeOH was added K2
CO3 (0.59 g, 4.24 mmol). The
reaction was stirred for 2 h. The reaction was quenched with
saturated NH4Cl. The aqueous layer was extracted five times
with ethyl acetate, and the combined organic layers were
washed with brine and concentrated in vacuo. Purification by
flash chromatography afforded 1.26 g of diol 21 (98%): 1H
NMR (CD3CN, 400 MHz) δ 5.70 (s, 1H), 4.66 (dd, J ) 8.0, 1.2
Hz, 1H), 4.29 (dd, J ) 7.2, 7.2 Hz, 1H), 4.02 (d, J ) 3.6 Hz,
2H), 3.77-3.69 (m, 2H), 3.35 (d, J ) 3.6 Hz, 1H), 2.61 (t, J )
4.8, 4.8 Hz, 1H), 2.25 (dddd, J ) 7.5, 7.5, 5.0, 4.0 Hz, 1H),
0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (CD3CN, 100
MHz) δ 159.7, 86.7, 81.2, 79.6, 58.9, 57.8, 49.8, 26.4, 19.0, -4.3,
28.3, 25.7, 17.9, -4.5, -5.1; IR (film) 3420 (br, 1700 cm-1
;
[R]24 ) +50.3 (c 1.05, CH2Cl2). Anal. Calcd for C17H33NO4Si:
D
-4.9; IR (KBr) 3350 (br), 1710 cm-1; [R]24 ) -7.5 (c 0.86,
C, 59.44; H, 9.68; N, 4.08. Found: C, 59.55; H, 9.69; N, 4.03.
D
MeOH); mp 201-203 °C. Anal. Calcd for C13H25NO5Si: C,
51.46; H, 8.30; N, 4.62. Found: C, 51.23; H, 8.45; N, 4.59.
(5R,6R,7S,8S)-5-(ter t-Bu t yld im et h ylsila n yloxy)-6-h y-
dr oxy-4-m eth ylen eh exah ydr ocyclopen taoxazol-2-on e (23).
To a solution containing diol 21 (1.26 g, 4.16 mmol) and
2-nitrophenyl selenocyanate (2.36 g, 10.4 mmol) in 40 mL of
THF was added freshly distilled tri-n-butylphosphine (3.11
mL, 12.0 mmol) dropwise. The reaction was stirred for 12 h
and quenched with saturated NaHCO3. The aqueous layer was
extracted four times with ethyl acetate, and the combined
organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 1.8 g of selenide, which was used
immediately in the next reaction.
Acetic Acid (1S,2R,5S)-2-ter t-Bu toxyca r bon yla m in o-5-
(ter t-bu tyldim eth ylsilan yloxy)cyclopen t-3-en ylm eth yl Es-
ter (5). To a cooled solution (0 °C) of alcohol 18 (2.82 g, 8.2
mmol) in 75 mL of CH2Cl2 were added Et3N (3.43 mL, 25
mmol), Ac2O (1.16 mL, 12 mmol), and 4-(dimethylamino)-
pyridine (0.05 g, 0.41 mmol). The reaction was warmed to 25
°C and stirred for 6 h. The reaction was quenched with 1 M
HCl. The layers were separated, and the aqueous layer was
washed with CH2Cl2. The combined organic layers were
washed with saturated NaHCO3 and brine, dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by flash
chromatography afforded 3.02 g of ester 5 (95.3%): 1H NMR
(CDCl3, 400 MHz) δ 5.98 (dd, J ) 5.6, 2.4 Hz, 1H), 5.96 (dd,
J ) 5.6, 2.4 Hz, 1H), 4.67 (ddd, J ) 10.4, 6.8, 2.0 Hz, 1H),
4.55 (dd, J ) 5.6, 2.0 Hz, 1H), 4.37 (d, J ) 10.4 Hz, 1H), 4.21
(dd, J ) 11.2, 6.8 Hz, 1H), 4.16 (dd, J ) 11.2, 8.0 Hz, 1H),
2.44-2.37 (m, 1H), 2.02 (s, 3H), 1.41 (s, 9H), 0.86 (s, 9H), 0.05
(s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.9, 154.9,
135.9, 135.1, 79.2, 74.5, 61.0, 54.8, 44.9, 28.2, 25.7, 20.9, 17.9,
To a cooled solution (0 °C) of the selenide (1.8 g) in 50 mL
of THF was added H2O2 (4.8 mL of a 30% solution in H2O)
dropwise. The reaction was warmed to 25 °C and stirred for
12 h. The reaction was quenched with H2O and the aqueous
layer was extracted three times with ethyl acetate. The
combined organic layers were washed with saturated Na2SO3
and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Purification by flash chromatography afforded 0.94 g
of alkene 23 (79% over two steps): 1H NMR (CDCl3, 400 MHz)
δ 5.88 (s, 1H), 5.34 (dd, J ) 2.0, 2.0 Hz, 1H), 5.24 (dd, J ) 1.6,
1.6 Hz, 1H), 4.76 (ddd, J ) 8.6, 3.6, 0.8 Hz, 1H), 4.53-4.50
(m, 1H), 4.26 (ddd, J ) 6.0, 1.6, 1.2 Hz, 1H), 4.06 (ddd, J )
6.0, 4.0, 4.0 Hz, 1H), 2.42 (d, J ) 4.4 Hz, 1H), 0.89 (s, 9H),
0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 159.1,
149.0, 113.2, 83.7, 81.1, 77.7, 55.2, 25.7, 18.1, -4.7, -4.8; IR
-4.4, -5.2; IR (film) 3450, 3360, 1720 cm-1; [R]24 ) +32.6 (c
D
1.48, CH2Cl2). Anal. Calcd for C19H35NO5Si: C, 59.19; H, 9.15;
N, 3.63. Found: C, 59.45; H, 9.14; N, 3.61.
Acet ic Acid (1R,2S,3S,4R,5R)-2-ter t-Bu t oxyca r bon yl-
am in o-4-(ter t-bu tyldim eth ylsilan yloxy)-6-oxabicyclo[3.1.0]-
h ex-3-ylm eth yl Ester (19). Ester 5 (3.02 g, 7.8 mmol) was
dissolved in dimethyldioxirane (218 mL of a 0.05 M solution
in acetone, 10.9 mmol). The reaction was stirred for 5 h and
concentrated in vacuo. Purification by flash chromatography
afforded 2.34 g of epoxide 19 (74.3%): 1H NMR (CDCl3, 400
MHz) δ 4.74 (d, J ) 10.4 Hz, 1H), 4.33 (dd, J ) 10.4, 6.0 Hz,
1H), 4.25 (d, J ) 4.0 Hz, 1H), 4.17 (dd, J ) 10.8, 6.8 Hz, 1H),
4.06 (dd, J ) 10.8, 8.8 Hz, 1H), 3.48 (d, J ) 2.0 Hz, 1H), 3.37
(d, J ) 2.4 Hz, 1H), 2.20-2.16 (m, 1H), 2.02 (s, 3H), 1.40 (s,
9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 170.7, 155.0, 79.5, 71.2, 59.4, 56.7, 56.3, 50.6, 40.8,
(film) 3370, 1745 cm-1; [R]24 ) -33.6 (c 1.8, MeOH). Anal.
D
Calcd for C13H23NO4Si: C, 54.71; H, 8.12; N, 4.91. Found: C,
54.34; H, 8.04; N, 4.79.
(4R,5R,6R,7S,8R)-5-(ter t-Bu tyld im eth ylsila n yloxy)-4,6-
dih ydr oxy-4-h ydr oxym eth ylh exah ydr ocyclopen taoxazol-
2-on e (24). To a solution of alkene 23 (0.63 g, 2.21 mmol) and
n-methylmorpholine n-oxide (0.60 g of NMO‚H2O, 4.4 mmol)
in 30 mL of acetone and 10 mL of H2O was added OsO4 (1.4
mL of a 0.01 g/mL solution, 0.06 mmol). The mixture was
stirred for 12 h. The reaction was quenched with saturated
Na2SO3 and stirred for 1 h, and the aqueous layer was
extracted five times with ethyl acetate. The combined organic
layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatog-
raphy afforded 0.53 g of triol 24 (75%): 1H NMR (CD3CN, 400
MHz) δ 5.95 (s, 1H), 4.86 (d, J ) 8.8 Hz, 1H), 4.10 (d, J ) 8.0
Hz, 1H), 4.02 (d, J ) 6.0 Hz, 1H), 3.87 (d, J ) 1.6 Hz, 1H),
3.75-3.66 (m, 4H), 2.93 (s, 1H), 0.86 (s, 9H), 0.10 (s, 3H), 0.09
(s, 3H); 13C NMR (CD3CN, 100 MHz) δ 159.2, 86.9, 85.9, 82.6,
28.1, 25.6, 20.8, 17.7, -4.6, -5.5; IR (film) 3440, 1725 cm-1
;
[R]24 ) +17.1 (c 1.37, CH2Cl2). Anal. Calcd for C19H35NO6Si:
D
C, 56.83; H, 8.78; N, 3.49. Found: C, 57.06; H, 8.83; N, 3.52.
Acetic a cid (4S,5R,6R,7S,8S)-5-(ter t-Bu tyld im eth ylsi-
la n yloxy)-6-h yd r oxy-2-oxoh exa h yd r ocyclop en ta oxa zol-
4-ylm eth yl Ester (20). To a solution of epoxide 19 (2.34 g,
5.8 mmol) in 60 mL of CH2Cl2 was added (1S)-(+)-10-cam-
phorsulfonic acid (0.136 g, 0.58 mmol). The reaction was stirred
for 12 h. The reaction was quenched with saturated NaHCO3,
and the layers were separated. The aqueous layer was
extracted three times with CH2Cl2, and the combined organic
layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo. Purification by flash chromatog-
raphy afforded 1.67 g of alcohol 20 (83%): 1H NMR (CDCl3,
400 MHz) δ 5.58 (s, 1H), 4.80 (dd, J ) 7.6, 1.2 Hz, 1H), 4.43
(dd, J ) 11.2, 9.2 Hz, 1H), 4.29 (dd, J ) 6.8, 6.8 Hz, 1H), 4.24-
4.20 (m,2H), 4.11 (d, J ) 3.6 Hz, 1H), 2.50-2.43 (m, 2H), 2.05
(s, 3H), 0.85 (s, 9H), 0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 171.5, 158.6, 85.9, 79.4, 78.6, 60.7, 56.7, 45.7, 25.5,
82.3, 64.6, 62.9, 26.3, 18.9, -4.3, -4.8; IR (KBr) 1735 cm-1
;
[R]24 ) +13.5 (c 0.34, MeOH); mp 215-216 °C. Anal. Calcd
D
for C13H25NO6Si: C, 48.88; H, 7.89; N, 4.38. Found: C, 48.63;
H, 7.88; N, 4.29.
[1R-(1r,2â,3r,4â,5â)]-5-Acet a m id o-1,2,3,4-t et r a cet oxy-
1-(a cetoxym eth yl)cyclop en ta n e (25). Triol 24 (30.5 mg,
0.095 mmol) in 5 mL of ethanol and 2 mL of 2 N KOH was
heated at reflux for 12 h. The mixture was concentrated in
vacuo by azeotroping with several aliquots of methanol. To the
mixture was added 2 mL of pyridine, 3 mL of acetic anhydride,
and 15 mg of 4-(dimethylamino)pyridine. The mixture was
20.9, 17.9, -4.8, -5.5; IR (KBr) 3410, 1740, 1720 cm-1
;
[R]24 ) -11.5 (c 0.96, MeOH); mp 196-198 °C. Anal. Calcd
D
for C15H27NO6Si: C, 52.15; H, 7.88; N, 4.05. Found: C, 52.19;
H, 7.82; N, 3.91.

4018 J . Org. Chem., Vol. 66, No. 11, 2001
Crimmins and Tabet
stirred for 12 h, filtered, and concentrated in vacuo. Purifica-
tion by flash chromatography afforded 33 mg of ester 258a (80%
over two steps): 1H NMR (CDCl3, 400 MHz) δ 5.89 (d, J ) 9.6
Hz, 1H), 5.77 (d, J ) 5.6 Hz, 1H), 5.34 (dd, J ) 7.6, 4.8 Hz,
1H), 5.29 (dd, J ) 9.2, 8.2 Hz, 1H), 5.21 (t, J ) 5.2, 5.2 Hz,
1H), 4.58 (d, J ) 12.0 Hz, 1H), 4.52 (d, J ) 12.0 Hz, 1H), 2.10
(s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H),
1.98 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.4, 169.9, 169.7,
169.5, 168.93, 168.90, 86.6, 78.9, 76.4, 73.3, 59.5, 52.7, 23.1,
21.6, 20.9, 20.7, 20.6, 20.5; IR (film) 3320, 3000, 1750, 1670,
1530, 1435, 1375, 1225, 1045, 895 cm-1; [R]24 ) +4.1 (c 1.57,
D
CHCl3).
Ack n ow led gm en t. This work was supported by a
research grant from the National Institutes of Health.
Burroughs-Wellcome and Bost Fellowships for E.A.T.
are gratefully acknowledged.
J O015568K