A Demonstration of the Synthetic Potential of Pyridinium Salt Photochemistry by Its Application to a Stereocontrolled Synthesis of (+)-Mannostatin A

Full text of DOI:10.1021/jo980855i

6
072
J . Org. Chem. 1998, 63, 6072-6076
A Dem on str a tion of th e Syn th etic P oten tia l
of P yr id in iu m Sa lt P h otoch em istr y by Its
Ap p lica tion to a Ster eocon tr olled Syn th esis
of (+)-Ma n n osta tin A1
Sch em e 1
Rong Ling and Patrick S. Mariano*
Department of Chemistry, University of New Mexico,
Albuquerque, New Mexico 87131-1096
Received May 6, 1998
In tr od u ction
2
3
Earlier, we demonstrated how an old, yet understud-
Sch em e 2
4
ied, pyridinium salt photochemical reaction can be used
in versatile, stereocontrolled routes to highly function-
alized aminocyclopentenes 1 (Scheme 1). Remarkably
high levels of functional and stereochemical complexity
are introduced in these reactions of pyridinium salts
which proceed by sequential photoelectrocyclization, nu-
cleophilic addition, and aziridine ring-opening pathways.
As a consequence of these features, a number of interest-
ing applications of this chemistry to complex molecule
synthesis can be envisaged.
Part of our continuing investigations of this process
focuses on the development of procedures for enantiose-
lective synthesis of functionalized aminocyclopentenes 1
and applications of this methodology to the preparation
of biomedically relevant cyclic and acyclic targets. In this
note, we describe preliminary results of this effort which
shows (1) that the acetoxyaminocyclopentenol 3 (Scheme
which yields an amino-diol that is converted without
isolation to its amido-diacetate derivative 2. The yield
7
of this process is photon limited, and, in our hands
crystalline 2 is produced in ca. 1-g quantities by use of a
2
0 h irradiation period. Amido-diacetate 2 is structurally
2
) can be prepared in nonracemic form by using a
similar to substrates which have been converted to
combination of pyridinium salt photochemistry and en-
nonracemic acetoxy-alcohols by electric eel acetylcho-
zymatic desymmetrization and (2) that 3 can be trans-
linesterase (EEACE) catalyzed hydrolysis.8 Reaction of
5
formed via a short route to the R-mannosidase inhibitor
2
with EEACE in pH 6.9 NaH
chromatographic purification, the crystalline monoalcohol
([R]25
+ 69.7°, c 3.5, CHCl ) in a 68% yield and 80%
2 4
PO buffer provides, after
(
+)-mannostatin A (4).6
3
D
3
Resu lts a n d Discu ssion
The route developed to generate 3 begins with pho-
1
ee (by Mosher ester H NMR and chiral HPLC analysis).
Owing to the unpredictability of the stereochemical
course of this esterase reaction, a Mosher ester H NMR
method10 was used to confirm that hydrolysis occurs at
the pro-R acetate center.
9
1
tolysis of pyridinium perchlorate in 0.7% aqueous HClO
4
(1) A portion of these studies was conducted in the Department of
Chemistry and Biochemistry, University of Maryland, College Park,
MD 20742.
The acetoxy-amido alcohol 3 contains an array of
diverse functionality which can be exploited in stereo-
controlled syntheses of cyclic and acyclic amino-polyol
targets. In the current context, we have explored an
approach to (+)-mannostatin A which takes advantage
of the existing and/or latent R-amido alcohol, allylic
(
2) Ling, R.; Yoshida, M.; Mariano, P. S. J . Org. Chem. 1996, 61,
4
439.
(
3) Kaplan, L.; Pavlick, J . W.; Wilzbach, K. E. J . Am. Chem. Soc.
1
972, 94, 3283.
(
4) Yoon, U. C.; Quillen, S. L.; Mariano, P. S.; Swanson, R.;
Stavinoha, J . L.; Bay, E. J . Am. Chem. Soc. 1983, 16, 130.
5) (a) For the structure determination of (+)-mannostatin A, see:
(
carbonate, and olefin groups in 3 to perform C
1
hydroxyl
Morishima, H.; Kojiri, K.; Yamamoto, T.; Aoyagi, T.; Nakamura, H.;
Iitaka, Y. J . Antibiot. 1989, 42, 1008. (b) For the isolation and biological
evaluation of (+)-mannostatin A, see: Aoyagi, T.; Yamamoto, T.; Kojiri,
K.; Morishima, H.; Nagai, M.; Hamada, M.; Takeuchi, T.; Umezawa,
H. J . Antibiot. 1989, 42, 883. Tropea, J . E.; Kaushal, G. P.; Pastuszak,
I.; Mitchell, M.; Aoyagi, T.; Molyneux, R. J .; Elbein, A. D. Biochemistry
inversion and C methylthio and C -C diol introduction.
4
2
3
Two routes, differing in the timing of OH-inversion and
MeS-introduction, have been explored for synthesis of 4.
In the less efficient sequence (Scheme 3) alcohol 3 is
1
990, 29, 10062.
6) For previous total synthesis, see: (a) King, S. B.; Ganem, B. J .
(
(7) In a typical photoreaction irradiation is conducted on a solution
of 2 g of pyridinium perchlorate in 0.7% aqueous perchloric acid for
20 h by using circular reactor with 16 × 254 nm lamps.
(8) (a) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth.
1995, 73, 25. (b) Deardorff, D. R.; Matthews, A. J .; McMeekin, D. S.;
Craney, C. L. Tetrahedron Lett. 1986, 27, 1255.
(9) Griffith, D. A.; Danishefsky, S. J . J . Am. Chem. Soc. 1991, 113,
5863.
(10) (a) Ohtani, I.; Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H.
Tetrahedron Lett. 1989, 30, 3147. (b) Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J . Org. Chem. 1991, 56, 1296. (c) Kusumi, T.; Ohtani,
I.; Inouye, Y.; Kakisawa, H. Tetrahedron Lett. 1988, 29, 4731.
Am. Chem. Soc. 1994, 116, 562. (b) Knapp, S.; Dhar, T. G. M. J . Org.
Chem. 1991, 56, 4096. (c) Ganem, B.; King, S. B. J . Am. Chem. Soc.
1
Soc. 1991, 113, 6317. (e) Ogawa, S.; Yuming, Y. J . Chem. Soc., Chem.
Commun. 1991, 890. (f) Trost, B. M.; Van Vranken, D. L. J . Am. Chem.
Soc. 1993, 115, 444. (g) Li, C.; Fuchs, P. L.Tetrahedron Lett. 1994, 35,
991, 113, 5089. (d) Trost, B. M.; Van Vranken, D. L. J . Am. Chem.
5
121. (h) Ogawa, S.; Kimura, H.; Vehida, C.; Ohashi, T. J . Chem. Soc.,
Perkin Trans. I 1995, 1695. For previous syntheses of analogues, see:
i) Nishimura, Y.; Umezawa, Y.; Adachi, H.; Kondo, S.; Takeuchi, T.
(
J . Org. Chem. 1996, 61, 480. (j) Ingall, A. H.; Moore, P. R.; Roberts, S.
M. Tetrahedron: Asymmetry 1994, 5, 2155.
S0022-3263(98)00855-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/24/1998

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6073
Sch em e 3a
The route developed for synthesis of (+)-mannostatin
A, in addition to highlighting the preparative utility of
pyridinium salt photochemistry, is modestly concise and
economical. Also, it appears to possess the flexibility
required to prepare a variety of regiochemical and
stereochemical analogues of the natural product which
6
a,i
themselves may be of biomedical significance.
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectra were recorded by
using CDCl solutions unless specified otherwise, and chemical
3
1
3
shifts are reported in ppm relative to CHCl (δ 7.24 ppm for H
and δ 77.0 ppm for 13C). C NMR resonance assignments were
aided by the use of the DEPT-135 technique to determine
numbers of attached hydrogens. IR spectral vibrational fre-
13
-
1
a
quencies are expressed in wavenumbers (cm ). Column chro-
matography was performed with EM type 60 (230-400 mesh)
silica gel, type F-20 alumina (neutral, 80-200 mesh), or Fluorisil
Burgess reagent, THF, reflux; 0.3 N HCl; K2CO3, pH 9.5 (56%);
b) TBDMSCl, imidazole, CH2Cl2, 25 °C (100%); (c) NaOCH3,
(
CH3OH, 25 °C (100%); (d) EtOCOCl, Py, DMAP, THF (92%); (e)
(
100-200 mesh) absorbants. Preparative TLC was performed
(dba)3Pd2CHCl3, dppp, TMSSCH3, THF, reflux (61%).
on 20 × 20 cm plates coated with EM type 60 GF-254 silica gel.
Sch em e 4a
Mass spectra are either low resolution (LRMS) or high resolution
(HRMS) by using electron impact ionization unless specified as
chemical ionization (CI). All reactions were run under a dry N
2
atmosphere unless otherwise noted. Organic extracts obtained
following workup of reaction mixtures were dried over anhydrous
2 4 4
Na SO or MgSO . The enantiomeric purity of alcohol interme-
1
diates were determined by H NMR analysis of their Mosher
ester derivatives or chiral HPLC (Dynamax SD 200) analysis.
All compounds prepared in this study were judged by NMR to
be >90% pure unless otherwise noted.
Preparative photochemical reactions were conducted with a
Rayonet photochemical chamber reactor (RPR-100) using a bank
of 254 nm lamps. The photolysis solutions were purged with
2
N both before and during irradiation. The progress of each
preparative photochemical reaction was monitored by UV ab-
sorption spectrometry to determine percent conversions, TLC,
and/or 1H NMR spectroscopy.
4
-Acyla m in o-3,5-a cetoxycyclop en ten e (2). A N
solution of pyridinium perchlorate (2.00 g, 11.13 mmol) and
perchloric acid (70%, 6.0 mL) in H O (600 mL) was irradiated
for 20 h. The photolyzate was neutralized by sodium bicarbonate
5.5 g) and concentrated under reduced pressure below 45 °C,
2
-purged
a
TBDMSCl, imidazole, DMF 25 °C (97%); (b) NaOCH3, CH3OH,
2
5 °C (100%); (c) EtOCOCl, Py, DMAP, THF (90%); (d) (dba)3Pd2-
CHCl3, dppp, TMSSCH3, THF, reflux (91%); (e) HF (48%), 25 °C
100%); (f) Burgess reagent, THF, reflux; 0.3 N HCl, K2CO3, pH
.5 (65%); (g) OsO4, TMEDA, CH2Cl2, -78 °C (74%); (h) 6 N HCl,
00 °C (100%).
2
(
9
1
(
and the residue was transferred to a 250 mL flask with acetone.
The residue was concentrated in vacuo to yield diol (100%
conversion as indicated by UV). Without further purification,
a solution of diol and 4-DMAP (0.200 g, 1.64 mmol) in anhydrous
pyridine (60 mL) was stirred, and acetic anhydride (6.00 mL,
subjected to Wipf11 inversion to produce the C
. TBDMS protection, ester hydrolysis, and carbonate
1
epimer
5
formation then set the stage for implementation of
Trost’s12 palladium-catalyzed methylthiolation procedure.
As a consequence of the mechanism of the latter process
and the low level of steric discretion on the R-face of the
of the π-allyl Pd intermediate, this process yields an
undesirable mixture of 9 and 10 in a 2:1 ratio.
6
3.65 mmol) was then added dropwise. The solution was stirred
at 25 °C under N2 for 24 h. The reaction mixture was poured
into ice-water, neutralized with NaHCO , and extracted with
CHCl The extracts were concentrated in vacuo to give a
3
3
.
residue which was subjected to column chromatography (silica
gel, 1:1 acetone:hexanes) to yield 1.12 g (42%) of 4-acylamido-
3
1
,5-acetoxycyclopentene (2) as a crystalline material (mp 167-
In contrast, 3 can be transformed to the carbonate 13
directly which, as expected, is converted to a single
methylthioether 14 (Scheme 4) under the Trost meth-
ylthiolation conditions. Wipf inversion of the liberated
alcohol 15 yields the cis-amido alcohol 16 which is then
subjected to directed dihydroxylation13 to afford amido-
triol 17. Acid-catalyzed hydrolysis of 17 yields the
1
71 °C): H NMR 5.93 (s, 2H, vinyl), 5.56 (d, J ) 5.2 Hz, 2H,
H , H ), 4.22 (dt, J ) 5.2 Hz, J ) 7.6 Hz, 1H, H ), 2.05 (s, 6H,
3
5
4
1
3
2CO
2
CH
3
), 1.95 (s, 3H, NHCOCH
, C ), 62.6 (C
); IR (neat) 3301, 3072, 2950, 1738, 1656, 1547, 1228,
020; MS (CI) m/z (rel intensity) 242 (M + 1, 5), 241 (1), 198
16
5), 182 (13), 139 (100), 97 (81); HRMS(CI) calcd m/z for C11H -
3
); C NMR 170.8, 170.7 (Cd
O), 132.9 (CHdCH), 80.1 (C
NHCOCH
1
3
5
4
), 23.2, 20.9 (CO CH
2
3
,
3
(
NO
5
242.1028, found 242.1040.
2
5
hydrochloride salt of (+)-mannostatin A (4-HCl, [R]
D
(
1R,4S,5S)-4-Acetoxy-5-a cyla m in o-2-cyclop en ten -1-ol (3).
6
c
+
5.4°, c 1.0, CH
3
OH, lit. +5.9°) which has spectroscopic
To a suspension solution of amido diacetate 2 (1.002 g, 4.15
mmol) in NaH PO buffer solution (50 mL, 0.58 M, pH ) 6.92)
in a 50 mL flask was added electric eel acetyl cholinesterase
properties (except for optical rotation) that are identical
to those previously reported for the naturally occurring
2
4
3
substance.6
a,g
(EEACE) (44 mg, 20 × 10 units, Sigma). The resulting mixture
was stirred gently at 15-20 °C for 5 h. The reaction is
terminated when only a trace of triacetate remains and the
corresponding diol begins to appear. The resulting mixture was
concentrated in vacuo and extracted with CHCl3. The combined
(11) (a) Wipf, P.; Miller, C. P. J . Org. Chem. 1993, 58, 1575. (b) Wipf,
P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907. (c) Wipf, P.; Miller,
C. P. Tetrahedron Lett. 1992, 33, 6267.
2 4
organic extracts were dried over anhydrous Na SO and con-
centrated in vacuo to yield a yellow residue which was subjected
to column chromatography (silica gel, 1:1 hexanes:acetone) to
(
(
12) Trost, B. M.; Scanlan, T. S. Tetrahedron Lett. 1986, 27, 4141.
13) Donohoe, T. J .; Moore, P. R.; Waring, M. J . Tetrahedron Lett.
1
997, 38, 5027.

6
074 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
give 0.562 g (68% yield) monoalcohol 3: mp 121-123 °C; [R]25
(0.146 mL, 1.530 mmol) dropwise with stirring for 12 h at 25 °C
D
+
69.7° (c 3.5, CHCl
3
); 78-80% enantiomeric excess (ee% was
under an atmosphere of N
with water and extracted with CHCl
dried over MgSO and concentrated in vacuo to give a colorless
2
. The reaction mixture was quenched
1
determined by both H NMR analysis of its Mosher ester
3
. The organic extracts were
1
derivatives and chiral HPLC analysis); H NMR 6.50 (brs, 1H,
4
NH), 6.01 (ddd, J ) 5.9, 1.6, 1.6 Hz,1H, vinyl), 5.72 (ddd, J )
residue which was subjected to column chromotography (silica
5
.9, 1.6, 1.6 Hz, 1H, vinyl), 5.45 (ddd, J ) 6.0, 3.1, 1.6 Hz, 1H,
gel, 3:1 hexanes:acetone) to afford the carbonate 8 (0.241 g, 92%
yield): mp 52.8-54.6 °C; [R]25
+76.2° (c 1.6, CHCl
); H NMR
1
H
2
1
4
), 4.56 (ddd, J ) 6.6, 3.0, 1.6 Hz, 1H, H
.08 (s, 3H, OCOCH ), 2.02 (s, 3H, NCOCH
72.4 (CdO), 136.3, 128.3 (CHdCH), 80.9 (C
), 22.9, 20.9 (COCH ); IR (neat) 3310, 2924, 2847, 1739, 1654,
242, 1065; CIMS m/z (rel intensity) 200 (M + 1, 31), 182 (4),
39 (71), 97 (100); HRMS calcd m/z for C N 200.0923 (M
1), found 200.0918.
1S,4S,5S)-4-Acetoxy-5-acylam in o-2-cyclopen ten e-1-ol (5).
A solution of monoalcohol 3 (0.635 g, 3.19 mmol) in 30 mL of
dry THF was flushed with N and treated with Burgess reagent
0.912 g, 3.83 mmol). The resulting mixture was heated to 75
1
), 3.67 (m, 1H, H
3
5
),
); C NMR 173.0,
), 80.2 (C ), 69.6
D
3
1
3
3
6.06 (d, J ) 7.5 Hz, 1H, NH), 5.97 (appd, 2H, vinyl), 5.52 (dd J
) 5.0, 2.0 Hz, 1H, H ), 4.78 (dd, J ) 7.0, 2.0, Hz, 1H, H ), 4.39
(ddd, J ) 9.0, 7.0, 5.0 Hz, 1H, H ), 4.15 (q, J ) 7.5 Hz, 2H, CH
CH ), 1.96 (s, 3H, COCH ), 1.27 (t, J ) 7.5 Hz, 3H, CH CH
0.87 (s, 9H, C(CH ), 0.05 (s, 3H, Si(CH )), 0.04 (s, 3H, Si(CH
C NMR 169.8 (COCH ), 154.8 (COOC ) 132.9, 136.8 (CHd
CH), 85.2 (C ), 73.9 (C ), 64.2 (CH ), 56.4 (C ), 25.7 (C(CH ),
23.3 (COCH ), 18.1 (C(CH ), 14.2 (CH CH ), -4.7, -5.1 (Si-
(CH ); IR (neat) 3061, 2988, 2956, 1742, 1659, 1264, 1078; MS
m/z (rel intensity) 343 (5), 328 (3), 286 (100), 196 (82); HRMS
calcd m/z for C16 NSi 343.1815, found 343.1811.
4
1
5
3
(C
5
3
4
2
-
1
1
+
3
3
2
3
),
));
9
H
14
O
4
3
)
3
3
3
1
3
3
2 5
H
(
5
3
2
4
3 3
)
3
3
)
3
2
3
2
3 2
)
(
°
C for 3 h, treated with 30 mL of aqueous 0.6 M HCl solution,
29 5
H O
and stirred for 30 min at 25 °C. The pH of the solution was
adjusted to 9.5 by addition of a saturated K CO solution. The
reaction mixture was stirred at 25 °C for 10 h. The THF and
water were evaporated, and the residue was extracted with
(3S,4S,5S)-4-Acyla m in o-5-ter t-bu tyld im eth ylsilyloxy-3-
m eth ylth io-1-cyclop en ten e (9). Allyl carbonate 8 (0.220 g,
0.64 mmol) and methylthiotrimethylsilane (0.453 mL, 3.20
mmol) were dissolved in 15 mL of dry THF and placed under
2
3
CHCl3. The combined organic extracts were dried over MgSO
4
an atmosphere of N
etone)-dipalladium(0)-chloroform adduct ((dba)
g, 0.048 mmol) and 1,3-bis(diphenylphosphino)propane (dppp)
(0.120 g, 0.288 mmol) were dissolved in 3.0 mL of dry THF under
2
. In a separate flask, tris(dibenzylideneac-
Pd CHCl ) (0.051
and concentrated in vacuo to give a yellow oil which was
subjected to column chromatography (silica gel, 1:1 hexanes:
acetone) to give 0.356 g (56% yield) of monoalcohol 5 as a
3
2
3
2
5
1
colorless oil: [R]
D
+97.2° (c 1.5, CHCl
3
); H NMR 6.50 (br s,
2
N . When this solution sustained a yellow color (10 min), it was
1
5
1
1
5
1
H, NH), 6.11 (m, 1H, vinyl), 5.89 (dd, J ) 6.1, 1.7 Hz, 1H, vinyl),
added via syringe to the allyl carbonate solution in three
portions. The reaction mixture was stirred at 65 °C for 48 h
and concentrated in vacuo to give a brown-yellow residue which
was subjected to column chromatography (silica gel, 2:1 ether:
hexanes). Then 0.117 g of silyl ether 9 (61% yield) and 0.054 g
.72 (m, 1H, H
4
), 4.86 (m, 1H, H
1
), 4.15 (dd, J ) 12.2, 5.9 Hz,
), 2.01 (s, 3H, COCH
1
3
H, H ), 2.07 (s, 3H, COCH
5
3
3
); C NMR
), 73.6 (C ),
); IR (neat) 3320, 2914, 2846, 1737,
658, 1239, 1065; MS m/z (rel intensity) 199 (0.4), 139 (63), 97
N 199.0845, found 199.0849.
3S,4R,5S)-5-Acetoxy-4-a cyla m in o-3-ter t-bu tyld im eth yl-
silyloxy-1-cyclop en ten e (6). To a solution of secondary alcohol
(0.175 g, 0.880 mmol) in 5 mL of dry CH Cl were added
71.5, 171.1 (CdO), 135.6, 134.2 (CHdCH), 81.8 (C
8.3 (C ), 23.3, 21.0 (COCH
4
1
5
3
of regioisomer 10 (28% yield) were provided as colorless oils.
9: [R]25
+86.0° (c 1.2, CHCl
); H NMR 6.17 (d, J ) 6.6 Hz,
1
(
100); HRMS calcd m/z for C
9
H
13
O
4
D
3
(
1H, NH), 5.81 (ddd, J ) 5.7, 2.2, 1.0 Hz, 1H, H
5.7, 1.6, 1.6 Hz, 1H, H ), 4.88 (ddd, J ) 6.6, 2.2, 1.6 Hz, 1H, H
4.30 (ddd, J ) 6.6, 6.6, 3.3 Hz, 1H, H ), 3.62 (ddd, J ) 3.3, 1.6,
1.0 Hz, 1H, H ), 2.17 (s, 3H, SCH ), 1.94 (s, 3H, COCH ), 0.86
(s, 9H, C(CH ), 0.04 (s, 3H, Si(CH )), 0.05 (s, 3H, Si(CH
NMR 169.8 (CdO), 134.1, 133.8 (CHdCH), 74.9 (C ), 56.9, 55.4
(C and C ), 25.7 (C(CH ), 23.3 (COCH ), 18.0 (C(CH ), 13.9
(SCH ), -4.8, -5.1 (Si(CH ); IR (neat) 2926, 2905, 1630, 1461,
1249, 1067; MS m/z (rel intensity) 301 (1), 245 (24), 244 (57),
1
), 5.73 (ddd J )
2
5
),
5
2
2
4
imidazole (0.167 g, 2,46 mmol) and tert-butyldimethylsilyl
chloride (0.184 g, 1.23 mmol). The resulting mixture was stirred
3
3
3
1
3
3
)
3
3
3
));
C
at 25 °C for 14 h, diluted with water, and extracted with CHCl
3
.
5
The combined organic extracts were dried over MgSO and
4
3
4
3
)
3
3
3 3
)
concentrated in vacuo to give a yellow residue which was
subjected to column chromatography (silica gel, 3:1 hexanes:
acetone) to provide 0.275 g (100% yield) silyl ether 6: mp 84.7-
3
3 2
)
212 (17), 169 (79), 116 (100); HRMS calcd m/z for C14
27 2
H O NSSi
2
5
1
8
5.4 °C; [R]
Hz, 1H, NH), 5.93 (m, 1H, H
), 5.62 (dd, J ) 5.2, 1.5 Hz, 1H, H
.7 Hz, 1H, H ), 4.33 (ddd, J ) 12.5, 6.0, 5.2 Hz, 1H, H
s, 3H, OCOCH ), 1.93 (s, 3H, NCOCH ), 0.84 (s, 9H, C(CH
.03 (s, 3H, Si(CH )), 0.02 (s, 3H, Si(CH
CdO), 135.8, 133.7 (CHdCH), 81.7 (C ), 73.7 (C
C(CH ), 23.2, 21.0 (COCH ), 18.0 (C(CH ), -4.6, -5.1 (Si-
CH ); IR (neat) 2915, 2848, 1739, 1684, 1240, 1079; MS m/z
rel intensity) 313 (3), 298 (3), 256 (82), 195 (61), 154 (37); HRMS
NSi 313.1709, found 313.1705.
1S,4S,5R)-5-Acyla m in o-4-ter t-bu tyld im eth ylsilyloxy-2-
cyclop en ten e-1-ol (7). To a solution of acetate 6 (0.275 g, 0.880
mmol) in 20 mL of CH OH at 25 °C was added sodium methoxide
0.010 g, 0.180 mmol) in 1.6 mL of CH OH. The reaction was
D
+93.5° (c 2.2, CHCl
), 5.89 (dd, J ) 6.0, 1.5 Hz, 1H,
), 4.69 (ddd, J ) 6.0, 1.7,
), 2.01
),
)); C NMR 170.9, 169.8
), 56.4 (C ), 25.6
3
); H NMR 6.10 (d, J ) 12.5
301.1532, found 301.1529.
10: [R]25
-62.3° (c 4.8, CHCl
); H NMR 5.96 (d, J ) 7.7 Hz,
1
2
D
3
H
1
(
0
(
(
(
(
1
5
1H, NH), 5.74 (s, 2H, vinyl), 4.98 (m, 1H, H
1.5 Hz, 1H, H ), 3.51 (m, 1H, H ), 2.00 (s, 3H, SCH
3H, COCH ), 0.89 (s, 9H, C(CH ), 0.11 (s, 3H, Si(CH
(s, 3H, Si(CH )); C NMR 169.4 (CdO), 132.9, 131.1 (CHdCH),
77.5 (C ), 57.3, 56.3 (C and C ), 25.7 (C(CH ), 23.4(COCH ),
18.1 (C(CH3)3), 13.0 (SCH ), -4.5, -5.0 (Si(CH ); IR (neat)
2927, 2850, 1651, 1469, 1254, 1102; MS m/z (rel intensity) 301
4
), 4.25 (dd, J ) 5.9,
), 1.96 (s,
)), 0.09
3
4
5
3
3
3
3
3
)
3
3
3
)
3
3
1
3
13
3
3
3
5
3
4
4
3
5
3
)
3
3
3
)
3
3
3
)
3
3
3 2
)
3 2
)
(1), 245 (57), 244 (46), 212 (19); HRMS calcd m/z for C14
NSSi 301.1532, found 301.1532.
(1S,4S,5S)-5-Acyla m in o-4-m eth ylth io-2-cyclop en ten e-1-
ol (16). Meth od 1 (from silyl ether 9). To a solution of silyl
27 2
H O -
calcd m/z for C15
H
27
O
4
(
3
ether 9 (0.101 g, 0.34 mmol) in CH
mL of an HF aqueous solution (48%). The reaction mixture was
stirred at 25 °C for 1.5 h, neutralized with NaHCO , and
extracted with CHCl The organic extracts were combined,
dried over MgSO , and concentrated in vacuo to give 51 mg of
monoalcohol 16 (81% yield) as a clear oil: [R]
3
CN (6 mL) was added 0.2
(
3
stirred for 10 h at 25 °C and concentrated in vacuo to give a
yellow residue which was subjected to column chromatography
3
3
.
(
silica gel, 2:1 hexanes:acetone) to give the allyl alcohol 7 (0.238
4
2
5
25
g, 100% yield): mp 98.3-99.7 °C; [R]
D
+29.5° (c 1.3, CHCl
3
);
),
D
+80.4° (c 1.9,
); H NMR 6.39 (d, J ) 7.8 Hz, 1H, NH), 5.91 (dd, J )
5.9, 1.8 Hz, 1H, H ), 5.88 (dd, J ) 5.9, 1.5 Hz, 1H, H ), 4.82 (dt,
J ) 6.0, 1.8 Hz, 1H, H ), 4.29 (ddd, J ) 7.8, 6.0, 5.0 Hz, 1H, H ),
3.66 (m, 1H, H ), 2.09 (s, 3H, SCH
NMR 171.1 (CdO), 135.4, 133.6 (CHdCH), 74.3 (C
(C and C ), 23.3 (COCH ), 13.0 (SCH ); IR (neat) 3300, 2895
1
1
H NMR 6.04 (br s, 1H, NH), 6.00 (dd, J ) 6.0, 1.5 Hz, 1H, H
2
CHCl
3
5
2
1
3
1
2
3
.83 (ddd, J ) 6.0, 2.0, 2.0 Hz, 1H, H
.0 Hz, 1H, H ), 4.68 (m, 1H, H ), 3.81 (m, 1H, H
H, OH), 2.01 (s, 3H, COCH ), 0.88 (s, 9H, C(CH
H, Si(CH )), 0.06 (s, 3H, Si(CH
32.4 (CHdCH), 82.3 (C ), 74.6 (C
2.9 (COCH ), 18.1 (C(CH ), -4.1, -5.0 (Si(CH
305, 2955, 2862, 1658, 1254, 1076; MS m/z (rel intensity) 271
4), 256 (4), 214 (16), 213 (100); HRMS calcd m/z for C13
3
), 4.76 (ddd, J ) 6.6, 2.0,
), 3.78 (br s,
), 0.09 (s,
)); C NMR 171.9 (CdO), 137.5,
), 61.2 (C ), 25.7 (C(CH ),
); IR (neat)
2
3
4
1
5
1
5
1
3
3
3
)
3
4
3
), 2.01 (s, 3H, COCH
3
);
C
1
3
3
3
1
), 57.2, 54.3
4
1
5
3
)
3
4
5
3
3
3
3
)
3
3
)
2
2853, 1638, 1441, 1249; CIMS m/z (rel intensity) 188 (1), 169
(67), 140 (17), 127 (48), 98 (20), 81 (100); HRMS calcd m/z for
(
H
25
O
3
-
C
8
H
14
O
2
NS 188.0745 (M+1), found 188.0748.
Meth od 2 (from monoalcohol 15). A solution of monoalcohol
15 (0.020 g, 0.11 mmol) in 2 mL of dry THF was flushed with
2
N and treated with Burgess reagent (0.030 g, 0.13 mmol). The
NSi 271.1604, found 271.1615.
(
3S,4R,5S)-4-Acyla m in o-3-ter t-bu tyld im eth ylsilyloxy-5-
eth oxyca r bon yloxy-1-cyclop en ten e (8). To a solution of allyl
alcohol 7 (0.207 g, 0.765 mmol) and pyridine (0.247 mL, 3.06
mmol) in 10 mL of dry THF was added ethyl chloroformate
resulting mixture was heated to 75 °C for 3 h, treated with 2
mL of an aqueous 0.6 M HCl solution, and stirred for 30 min at

Notes
J . Org. Chem., Vol. 63, No. 17, 1998 6075
2
5 °C. The pH of the solution was adjusted to 9.5 by addition
of a saturated K CO solution. The reaction mixture was stirred
at 25 °C for 2 h. The mixture was extracted with CHCl . The
combined organic extracts were dried over MgSO and concen-
O), 133.9, 133.7 (CHdCH), 78.6 (C
4
), 77.3 (C
1
), 70.1 (C
5
3
), 25.7
); IR
2
3
(C(CH ), 23.0 (COCH ), 17.9 (C(CH
3
)
3
3
3
)
3
), -4.6 (Si(CH
)
2
3
(neat) 3294, 2911, 2848, 1652, 1048; MS m/z (rel intensity) 271
(0.3), 256 (3), 214 (100), 172 (9), 122 (16); HRMS calcd m/z for
4
trated in vacuo to give a yellow oil which was subjected to column
chromatography (silica gel, 1:1 hexanes:acetone) to give 0.013 g
C
13
H
25
O
3
NSi 271.1604, found 271.1624.
(3R,4R,5S)-4-Acyla m in o-3-ter t-bu tyld im eth ylsilyloxy-5-
(
65% yield) of monoalcohol 16 as a colorless oil.
1R,2R,3R,4S,5R)-4-Acylam in o-5-m eth ylth iocyclopen tan e-
,2,3-tr iol (17). A solution of monoalcohol 16 (0.041 g, 0.22
Cl (20 mL)
, and a solution of osmium
tetroxide (0.066 g, 0.26 mmol) in CH Cl (0.35 mL) was added
eth oxyca r bon yloxy-1-cyclop en ten e (13). To a solution of
allyl alcohol 12 (0.081 g, 0.300 mmol) and pyridine (0.036 mL,
0.450 mmol) in 4 mL of dry THF was added ethyl chloroformate
(0.057 mL, 0.60 mmol) dropwise with stirring for 12 h at 25 °C
(
1
mmol) and TMEDA (0.039 mL, 0.26 mmol) in CH
was cooled to -78 °C under N
2
2
2
under an atmosphere of N
with water and extracted with CHCl
dried over MgSO and concentrated in vacuo to give a colorless
2
. The reaction mixture was quenched
2
2
3
. The organic extracts were
dropwise. The reaction was stirred at -78 °C for 1.5 h and then
warmed to 25 °C. The solvent was removed in vacuo and
replaced with THF (10 mL), water (0.5 mL), and sodium
m-bisulfite (1.5 g). The mixture was heated at 65 °C for 5 h
and then filtered through Celite. The filterate was dried over
4
residue which was subjected to column chromotography (silica
gel, 3:1 hexanes:acetone) to afford the carbonate 13 (0.093 g,
90% yield) as a colorless oil: [R]25
-7.54° (c 4.0, CHCl
);
1
H
D
3
NMR 6.10 (d, J ) 7.5 Hz, 1H, NH), 5.86 (m, 2H, vinyl), 5.52 (d
J ) 5.6 Hz, 1H, H ), 4.89 (d, J ) 5.2 Hz, 1H, H ), 4.13 (q, J )
7.5 Hz, 2H, CH CH ), 3.71 (m, 1H, H ), 1.97 (s, 3H, COCH ),
1.27 (t, J ) 7.5 Hz, 3H, CH CH ), 0.84 (s, 9H, C(CH ), 0.03 (s,
); C NMR 170.6 (COCH ), 154.8 (COOC ) 137.8,
129.4 (CHdCH), 82.4 (C ), 77.4 (C ), 67.0 (CH ), 64.0 (C ), 25.7
(C(CH ), 23.4 (COCH ), 18.0 (C(CH ), 14.2 (CH CH ), -4.7,
-4.8(Si(CH ); IR (neat) 2949, 2865, 1741, 1652, 1254, 1044;
MS m/z (rel intensity) 343 (4), 328 (8), 286 (43), 354 (35), 196
MgSO
4
and concentrated under reduced pressure to give a
5
3
colorless oil which was subjected to column chromotography
(
2
3
4
3
silica gel, 1:1 acetone:hexanes, and then acetone) to yield 36
2
3
3 3
)
H
2 5
2
5
13
mg of 17 (74%) as a colorless oil: [R]
D
+8.8° (c 1.0, CH
, and H ), 3.85 (t, J )
), 2.02 (s, 3H, SCH ),
external reference)
), 56.6, 56.6 (C and
3
OH);
6H, Si(CH
3
)
2
3
1
H NMR (D
2
O) 4.03-3.93 (m, 3H, H
1
, H
2
3
5
3
2
4
5
1
1
C
1
.6 Hz, 1H, H
.92 (s, 3H, COCH
76.5 (CdO), 76.3, 73.9, 73.0 (C
), 24.3 (COCH ), 14.8 (SCH
470, 1075; MS m/z (rel intensity) 221 (2), 185 (60), 148 (80);
HRMS calcd m/z for C NS 221.0722, found 221.0741.
+)-Man n ostatin A Mon oh ydr och lor ide (4-HCl). A stirred
4
), 2.89 (t, J ) 7.0 Hz, 1H, H
5
3
3
)
3
3
3
)
3
2
3
1
3
3
); C NMR (D
2
O, CDCl
, and C
3
3
3 2
)
1
, C
2
4
5
3
3
); IR (neat) 3340, 2914, 2850, 1651,
29 5
(37), 122 (100); HRMS calcd m/z for C16H O NSi 343.1815, found
343.1835.
(3S,4S,5R)-4-Acyla m in o-5-ter t-bu tyld im eth ylsilyloxy-3-
m eth ylth io-1-cyclop en ten e (14). Allyl carbonate 13 (0.210
g, 0.61 mmol) and methylthiotrimethylsilane (0.430 mL, 3.10
mmol) were dissolved in 15 mL of dry THF and placed under
8
H
15
O
4
(
solution of triol 17 (0.010 g, 0.040 mmol) in an (6 M, 1 mL)
aqueous solution of HCl was heated at 100 °C for 12 h. The
solvent was removed in vacuo, and the remaining oil was washed
an atmosphere of N
acetone)-dipalladium(0)-chloroform adduct ((dba)
(0.032 g, 0.030 mmol) and 1,3-bis(diphenylphosphino)propane
(dppp) (0.075 g, 0.180 mmol) were dissolved in 2.0 mL of dry
2
. In a separate flask, tris(dibenzylidene-
3
Pd CHCl )
with ether (2 × 1 mL) and CHCl
3
(1 mL). The residue was dried
3
2
in vacuo to afford (+)-mannostatin A monohytrochloride (4-HCl)
2
5
(
0.010 g, 100% yield) as a clear oil: [R]
D
3
+5.4° (c 1.0, CH OH).
The spectroscopic data of this compound were consistent with
those reported:
H
H
2
7
2
THF under N . When this solution sustained a yellow color (10
6
a,g 1
H NMR (D
2
O) 4.16 (dd, J ) 6.5, 3.9 Hz, 1H,
), 3.89 (dd, J ) 7.6, 4.8 Hz, 1H,
), 3.00 (t, J ) 7.4 Hz, 1H, H ),
O, CDCl external reference)
), 57.6 (C ), 54.3 (C ), 14.5 (SCH );
min), it was added via syringe to the allyl carbonate solution in
three portions. The reaction mixture was stirred at 65 °C for
20 h and concentrated in vacuo to give a brown-yellow residue
which was subjected to column chromatography (silica gel, 2:1
ether:hexanes) to yield 83 mg (60% conversion) of recoved
starting material 13 and 0.101 g (91% yield based upon recoved
2
), 3.98 (t, J ) 4.4 Hz, 1H, H
), 3.43 (t, J ) 6.7 Hz, 1H, H
.03 (s, 3H, SCH
6.3, 74.6, 70.8 (C
3
1
4
5
1
3
3
); C NMR (D
, C , and C
2
3
1
2
3
4
5
3
IR (neat) 3302, 2913, 2050, 1596, 1126, 1077; FABMS m/z (rel
intensity) 180 (M + 1, 100); HRMS calcd m/z for C NS
80.0694 (M + 1), found 180.0681.
3R,4R,5S)-5-Acetoxy-4-a cyla m in o-3-ter t-bu tyld im eth yl-
2
5
6
H
14
O
3
starting material) of silyl ether 14: [R]
D
+116.1° (c 2.5, CHCl
H NMR 6.17 (br s, 1H, NH), 5.70-5.76 (m, 2H, vinyl), 4.83 (m,
1H, H ), 3.80 (ddd, J ) 6.6, 6.6, 3.3 Hz, 1H, H ), 3.70 (m, 1H,
), 2.03 (s, 3H, SCH ), 1.99 (s, 3H, COCH ), 0.86 (s, 9H,
C(CH ), 0.05 (s, 3H, Si(CH )), 0.04 (s, 3H, Si(CH
170.1 (CdO), 134.7, 132.8 (CHdCH), 80.3 (C ), 65.8, 52.5 (C
and C ), 25.8 (C(CH ), 23.5 (COCH ), 18.0 (C(CH ), 11.9
(SCH ), -4.7, -4.8 (Si(CH ); IR (neat) 2930, 2911, 1652, 1552,
3
);
1
1
(
5
4
silyloxy-1-cyclop en ten e (11). To a solution of secondary
alcohol 3 (0.100 g, 0.50 mmol) in 1.5 mL of dry DMF were added
imidazole (0.085 g, 1.25 mmol) and tert-butyldimethylsilyl
chloride (0.090 g, 0.60 mmol). The resulting mixture was stirred
at 25 °C for 12 h, diluted with water, and extracted with CHCl
The combined organic extracts were dried over MgSO and
concentrated in vacuo to give a yellow residue which was
subjected to column chromatography (silica gel, 1:1 hexanes:
acetone) to provide 0.152 g (97% yield) of silyl ether 11 as a
H
3
3
3
1
3
3
)
3
3
3
)); C NMR
5
3
4
3
)
3
3
3 3
)
3
.
3
3 2
)
4
1369, 1097; MS m/z (rel intensity) 301 (0.5), 286 (5), 254 (32),
244 (80), 169 (44), 127 (24), 122 (51); HRMS calcd m/z for
C
14
H
27
O
2
NSSi 301.1532, found 301.1527.
(1R,4S,5S)-5-Acyla m in o-4-m et h ylt h io-2-cyclop en t en -1-
ol (15). To a solution of silyl ether 14 (0.030 g, 0.10 mmol) in
CH CN (3 mL) was added 60 µL of a HF aqueous solution (48%).
The reaction mixture was stirred at 25 °C for 45 min, neutralized
with NaHCO , and extracted with CHCl . The organic extracts
were combined, dried over MgSO , and concentrated in vacuo
to give 19 mg of monoalcohol 15 (100% yield) as a clear oil: [R]
2
5
1
colorless oil: [R]
D
+14.0° (c 0.8, CHCl
.0 Hz, 1H, NH), 5.82 (dt, J ) 6.1, 1.5 Hz,1H, H
.1, 1.5 Hz, 1H, H ), 5.40 (dd, J ) 5.6, 1.2 Hz, 1H, H
H, H ), 3.90 (ddd, J ) 8.0, 6.1, 5.6 Hz, 1H, H ), 1.98 (s, 3H,
), 1.92 (s, 3H, NCOCH ), 0.82 (s, 9H, C(CH ), 0.02 (s,
H, Si(CH )), 0.00 (s, 3H, Si(CH )); C NMR 170.8, 170.5 (Cd
O), 137.3, 129.8 (CHdCH), 79.7 (C ), 78.1 (C ), 66.0 (C ), 25.6
), 17.9 (C(CH ), -4.8, -5.0 (Si-
); IR (neat) 2916, 2845, 1736, 1646, 1233, 1083; CIMS m/z
rel intensity) 314 (3), 256 (62), 196 (21), 182 (18), 122 (70);
NSi 314.1788, found 314.1811.
1S,4R,5R)-5-Acyla m in o-4-ter t-bu tyld im eth ylsilyloxy-2-
cyclop en ten e-1-ol (12). To a solution of silyl ether 11 (0.174
g, 0.56 mmol) in 20 mL of CH OH at 25 °C was added sodium
methoxide (0.054 g, 0.100 mmol) in 1.0 mL of CH OH. The
3
); H NMR 6.54 (d, J )
), 5.73 (dt, J )
), 4.73 (m,
8
6
1
2
3
1
5
3
4
3
3
OCOCH
3
3
3
3
)
3
4
1
3
25
3
3
D
1
5
3
4
+140.2° (c 0.8, CHCl
1H, H ), 5.67 (m, 1H, H
3.50 (m, 1H, H ), 2.04 (s, 3H, SCH
NMR 172.9 (CdO), 134.4, 131.9 (CHdCH), 81.8 (C
52.4 (C ), 22.9 (COCH ), 11.2 (SCH ); IR (neat) 3275, 3085, 1636,
3
); H NMR 6.32 (br s, 1H, NH), 5.87 (m,
), 4.64 (m, 1H, H ), 3.78 (m, 1H, H ),
), 2.02 (s, 3H, COCH
), 65.8(C
(
(
(
C(CH
CH
3
)
3
), 23.2, 21.0 (COCH
3
3
)
3
2
3
1
5
3
1
3
)
2
4
3
3
);
C
4
),
1
HRMS calcd m/z for C15
H
28
O
4
5
3
3
(
1337, 1091; FABMS m/z (rel intensity) 188 (M + 1, 65), 170 (50),
149 (42), 128 (50); HRMS calcd m/z for C
+ 1), found 188.0756.
8 14 2
H O NS 188.0745 (M
3
3
En a n tiom er ic P u r ity An a lysis of Alcoh ol 3. Mosh er
Ester P r ep a r a tion . To a solution of monoalcohol 3 (10 mg,
0.050 mmol) and 4-DMAP (2 mg, 0.016 mmol) in 1 mL of
pyridine was added a solution of (S)-MTPACl (19 mg, 0.075
reaction was stirred at 25 °C for 10 h and concentrated in vacuo
to give a yellow residue which was subjected to column chro-
matography (silica gel, 2:1 hexanes:acetone) to give the allyl
2
5
alcohol 12 (0.151 g, 100% yield) as a colorless oil: [R]
D
-38.1°
); H NMR 6.04 (br s, 1H, NH), 5.84 (dt, J ) 6.0,
.5 Hz, 1H, H ), 5.72 (dt, J ) 6.0, 1.5 Hz, 1H, H ), 4.57 (m, 1H,
), 4.47 (m, 1H, H ), 3.70 (m, 1H, H ), 2.04 (s, 3H, COCH ),
), 0.07 (s, 6H, Si(CH ); C NMR 172.4 (Cd
mmol) in CH
°C under an atmosphere of N
quenched with water and extracted with CHCl
extracts were dried over Na SO and concentrated in vacuo to
give 21 mg (100% yield) of crude (S)-Mosher ester diastereomers
2
Cl
2
(0.5 mL) dropwise with stirring for 12 h at 25
The reaction mixture was
. The organic
1
(c 1.1, CHCl
3
2
.
1
H
0
2
3
3
4
1
5
3
2
4
1
3
.87 (s, 9H, C(CH
3
)
3
3 2
)

6
076 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
as a 89:11 mixture (78% ee) based upon 1H NMR integration of
extracts were dried over Na
SO
and concentrated in vacuo to
2
4
diastereomeric H signals. Subjection of crude Mosher ester to
4
give a residue which was subjected to column chromotography
(silica gel, 1:1 hexanes:acetone) to yield 20 mg (59% conversion)
of recoved starting material 3 and 11 mg (46% yield based upon
recoved starting material) of racemic monoalcohol 5 as a white
crystal.
a preparative TLC (silica gel, 1:1 hexanes:acetone) did not affect
diastereomeric ratios and gave pure Mosher ester 17 mg in 82%
1
yield: H NMR (mixture of diastereomers) 7.35-7.54 (m, 10H,
aromatic, A and B), 6.05 (br s, 4H, vinyl, A and B), 5.90 (d J )
4
4
7
3
.8 Hz, 1H, H
.8 Hz, 1H, H
.2, 4.8 Hz, 1H, H
.57 (s, 3H, OCH
3
, A), 5.85 (d, J ) 4.8 Hz, 1H, H
3
, B), 5.66 (d, J )
, B), 4.25 (dt, J )
, B), 4.06 (dt, J ) 7.2, 4.8 Hz, 1H, H , A),
, B), 3.52 (s, 3H, OCH , A), 2.04 (s, 6H,
, B), 1.98 (s, 3H,
En a n tiom er ic P u r ity An a lysis of Alcoh ol 3 by a Ch ir a l
5
, A), 5.60 (d, J ) 4.8 Hz, 1H, H
5
HP LC. A Chiralcel OJ semipreparative column (1 cm × 25 cm)
4
4
(
5
Chiral Technologies, Inc., Exton, PA) preceded by a 0.46 cm ×
3
3
cm Chiracel OJ guard column was used. The racemic
OCOCH
NCOCH
3
, A and B), 1.99 (s, 3H, NCOCH
, A).
3
monoalcohol 3 and the enantioenriched monoalcohol 3 dissolved
in a HPLC grade hexanes:2-propanol mixtures (85:15) and
chromatography using the same mobile phase at ambient
temperature with a flow rate of 2.0 mL/min. The UV detector
was at 230 nm. This gives the individual enantiomers of 5. (+)-
3
To a solution of monoalcohol 3 (12 mg, 0.060 mmol) and
4
-DMAP (2 mg, 0.016 mmol) in 1 mL of pyridine was added a
solution of (R)-MTPACl (23 mg, 0.090 mmol) in CH
dropwise with stirring for 12 h at 25 °C under an atmosphere
of N The reaction mixture was quenched with water and
extracted with CHCl The organic extracts were dried over
Na SO and concentrated in vacuo to give 25 mg (100% yield)
of crude (R)-Mosher ester diastereomers as an 89:11 mixture
2 2
Cl (0.5 mL)
5
:
t
R
) 15.4 min. (-)-5:
t
R
) 16.5 min. An 80% ee was
2
.
1
determined by HPLC, which is consistent with H NMR analysis
of its Mosher ester derivatives.
3
.
2
4
1
Ack n ow led gm en t. The studies described above
were conducted with financial support provided by the
NIH (GM-27251) and a generous gift from Dojindo
Laboratories. Preliminary investigations carried out in
an expert fashion by Drs. Mutsuo Yoshida and Noriaki
Nakayama on the enzymatic resolution process are
greatly appreciated.
(
78% ee) based upon H NMR integration of diastereomeric H
4
or OCH signals. Subjection of crude Mosher ester to a prepara-
3
tive TLC plate (silica gel, 1:1 hexanes:acetone) did not affect
diastereomeric ratios and gave pure Mosher ester 21 mg in 83%
1
yield: H NMR (mixture of diastereomers) 7.24-7.52 (m, 10H,
aromatic, A and B), 6.18 (d, J ) 7.2 Hz, 2H, NH, A and B), 5.91
(
m, 4H, vinyl, A and B), 5.87 (m, 2H, H
3
, A and B), 5.65 (d, J )
, A), 4.25 (dt, J )
, A), 4.05 (dt, J ) 7.2, 4.8 Hz, 1H, H , B),
, A), 3.49 (s, 3H, OCH , B), 2.04 (s, 6H,
, A), 1.98 (s, 3H,
4
7
3
.8 Hz, 1H, H
.2, 4.8 Hz, 1H, H
.56 (s, 3H, OCH
5
, B), 5.62 (d, J ) 4.8 Hz, 1H, H
5
4
4
1
H and 13C NMR
3
3
Su p p or t in g In for m a t ion Ava ila b le:
OCOCH
NCOCH
3
, A and B), 1.99 (s, 3H, NCOCH
, B).
3
data for all new compounds prepared in this work (34 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
3
P r ep a r a t ion of R a cem ic Mon oa lcoh ol 3. A solution of
amido diacetate 2 (49 mg, 0.201 mmol) and sodium hydride (8
mg, 0.201 mmol) in 1.0 mL of dry DMF was stirred for 5 h at 25
°
C under an atmosphere of N
2
.
The reaction mixture was
. The organic
quenched with water and extracted with CHCl
3
J O980855I