Application of intramolecular 1,3-dipolar cyclic addition of azide and olefin; Construction of (pyrrolidine-2-ylidene)glycinate and glycinamides

Article abstract of DOI:10.1248/cpb.53.529

Oxopropyl E-(pyrrolidine-2-ylidene)glycinamide (5c) and allyl E-(pyrrolidine-2-ylidene)glycinate (5d) were effectively synthesized from 2,3,5-tri-O-benzyl-4-O-tert-butyldimethylsilyl(TBDMS)-D-arabinal (7) using intramolecular 1,3-dipolar cyclic reaction o

Full text of DOI:10.1248/cpb.53.529

May 2005
Chem. Pharm. Bull. 53(5) 529—536 (2005)
529
Application of Intramolecular 1,3-Dipolar Cyclic Addition of Azide and
Olefin; Construction of (Pyrrolidine-2-ylidene)glycinate and Glycinamides
Yaeko KONDA-YAMADA, ,a Keiko ASANO,a Takahiro SATOU,a Souichi MONMA,a Masataka SAKAYANAGI,a
*
a
Noriko SATOU,a Kazuyoshi TAKEDA,b and Yoshihiro HARIGAYA
a School of Pharmaceutical Sciences, Kitasato University; Shirokane, Minato-ku, Tokyo 108–8641, Japan: and
b Center for Advanced Technology EBARA Reseach Co., Ltd.; 4–2–1 Honfujisawa, Fujisawa 251–8502, Japan.
Received January 5, 2005; accepted February 15, 2005; published online February 22, 2005
Oxopropyl E-(pyrrolidine-2-ylidene)glycinamide (5c) and allyl E-(pyrrolidine-2-ylidene)glycinate (5d) were
effectively synthesized from 2,3,5-tri-O-benzyl-4-O-tert-butyldimethylsilyl(TBDMS)-D-arabinal (7) using in-
tramolecular 1,3-dipolar cyclic reaction of azide and olefin as a key reaction. These results proved this cyclic re-
action should be applicable for the synthesis of various (pyrrolidine-2-ylidene)glycinate and glycinamide. In ad-
dition, the development of a synthetic route for the precursor of an unsaturated cyclic dehydro amino acid in-
volved in azinomycins (carzinophilin) using relating glycinate, methyl E-(pyrrolidine-2-ylidene)glycinate (5a) was
described.
Key words cyclic addition; azide; olefin; (pyrrolidine-2-ylidene)glycinate; azinomycin
The 1-azabicyclo[3.1.0]-hex-2-ylidene)glycinate system Results and Discussion
like 3 is an important fragment involved in antitumor antibi-
Our synthetic strategy for 5c and 5d is described below
otics, azinomycins1,2) A (1), B (2) (carzinophilin3,4)). We al- (Chart 1). Compound 8, which was already synthesized via
ready reported5) an efficient synthetic method for (pyrrolidin- aldehyde 7 according to the procedure described in our previ-
2-ylidene)glycinates 5a and 5b, which are the basic skeleton ous paper,5) would afford unsaturated carboxylic acid 9
of unique unsaturated cyclic dehydro amino acid 3, by in- by hydrolysis of the methyl ester 8. Acid 9 would be con-
tramolecular-1,3-dipolar cyclic addition of azide and olefin verted to the amide 10, which would give the alcohol 11.
as a key reaction using azide 4a and 4b. Recently, several Compound 11 would be converted to (pyrrolidine-2-yli-
synthetic studies6,7) and investigation of biological properties dene)glycinamide 5c conveniently via azide by intramolecu-
of carzinophilin and its related synthetic products have been lar 1,3-dipolar cyclic addition of azide olefin in a similar
reported8) and it is mentioned there that a five-membered un- manner as described in a preliminary report.5) Acid 9 would
saturated dehydro amino acid part like 3 has an important also afford allyl ester 12, which would give the alcohol 13.
role in the biological activity of carzinophilin. Our work con- Compound 13 would be cyclized to (pyrrolidine-2-
cerning the intramolecular 1,3-dipolar cyclic addition of ylidene)glycinate 5d via azide in a similar way as described
azide and olefin would serve to construct (pyrrolidine-2-yli- in Chart 1.
dene)glycinates, which are the key compounds for 3.
One important step in this strategy is removal of the tert-
In this paper, further application of this cyclic reaction was butyldimethylsilyl (TBS) group from 10 (Z) and 12 (Z), be-
investigated to see if this method could be widely used to
synthesize other (pyrrolidin-2-ylidene)glycinate and glycin-
amide. We chose newly an amide 4c which has an azino-
mycin A related functional group (RꢀNHCH2COCH3) and
another ester 4d as substrates of azide. Intramolecular cyclic
reaction of azide and olefin occurred in both cases of 4c and
4d and afforded cyclic dehydro amino acid 5c and 5d in high
yield. Considering both the results obtained in a preliminary
report5) and that obtained in this paper, this reaction was re-
vealed to be applicable for various esters 4a, 4b, 4d
(RꢀOMe, OtBu, allyl) and also amide 4d (RꢀNHCOCH3).
It is remarkable that the reaction occurred in the amide 4d,
which is presumed to have poor reactivity in this cyclic reac-
tion considering the already described reaction mechanism,5)
because the amide group does not have enough electron-
withdrawing force, hence it is difficult to construct the triazo-
line ring which is an important intermediate5) for intramolec-
ular 1,3-dipolar cyclic addition of azide and olefin.
In addition, the conversion of methyl (E)-(pyrrolidine-2-
ylidene)glycinate 5a, which was already synthesized by us,5)
to the key compound 6a and 6b for the precursor of aziridine
construction for 3 was developed. These results will serve for
the construction of 3.
Fig. 1
∗ To whom correspondence should be addressed. e-mail: konday@pharm.kitasato-u.ac.jp
© 2005 Pharmaceutical Society of Japan

530
Vol. 53, No. 5
cause isomerization of the geometry resulting in unsaturated isopropylamine [EtN(i-Pr)2] for neutralization of HCl in
alcohol 11 and 13 would occur as already described in our CH2Cl2 gave an amide alcohol 15 as a mixture of diastere-
previous paper.5) Another is, if the amide 11 cyclizes by in- omers in 85% yield. Oxidation of alcohol 15 with Dess–Mar-
tramolecular 1,3-dipolar cyclic addition of azide olefin via tin reagent10) afforded the desired ketone 10 in 95% yield. In
azide 4c to give 5c, and optimization of its cyclic reaction the removal of the TBS group, pyridine was used as a mixed
should be required. The cyclic reaction of ester 13 is ex- solvent to prevent Z-E isomerization by strong acid hydrogen
pected to give 5d via azide 4d similarly as methyl and tert- fluoride (HF). The TBS group was removed by using HF-
butyl ester (4a, 4b) (Chart 1).
pyridine in a mixed solvent (tetrahydrofuran (THF):
The synthesis of azide 4c and its cyclic reaction for 5c is pyridineꢀ1:1) to provide conformational isomers 11a and
initially described as follows (Chart 2). Horner–Emmons re- 11b in 89%, 9.0% yields, respectively (Chart 2).
action of aldehyde 75) with Horner reagent 145,9) using DBU
A proof of the 11a and 11b as conformational isomers was
as a base in CH2Cl2 afforded the desired Z-olefine 8a in 67% given by NMR techniques of nOes and long-range selective
yield and the E-isomer 8b in 10% yield. Stereo structures of proton decoupling experiments (LSPD) (Fig. 2). In both iso-
8a and 8b were determined by comparison with the NMR mers, 5.8% and 2.7% nOes were observed at H-4 respec-
data obtained in our previous work.5) Hydrolysis of 8a by tively, when 2-NH was irradiated. These results show 11a
treatment with aqueous 1 N NaOH in dioxane afforded acid 9 and 11b are both Z-form. C13–H1 coupling constants between
quantitatively as a single product. Condensation of 9 and 1- H-3 and C-1 in 11a and 11b showed the values of 8.5, 7.5
amino-2-propanol using 1-ethyl-3-(3-dimethylaminopropyl)- Hz, respectively, by LSPD (Fig. 2). In the coupling constant
3
3
carbodiimide hydrochloride (EDCI·HCl) and 1-hydroxyben- of JCH, an equation of JCH (trans)ꢁ3JCH (cis) should be ap-
3
3
zotriazole (HOBt) as condensing reagents under N-ethyldi- plied and the difference between JCH (trans) and JCH (cis)
should be fairly large according to the literature.5,11) The val-
3
3
ues of JCH in 11a and JCH in 11b are close to each other
(8.5, 7.5Hz), though the values are unexpectedly fairly large.
These results indicate 11a and 11b are the conformational
Chart 1. Strategy for 5c and 5d
Fig. 2. NOE and LSPD Data of 11a and 11b
Chart 2

May 2005
531
isomers and not the geometrical isomers around the olefinic chloromethanesulfonyl (Mc) group, which is a much stronger
structure and both should have Z-configuration (Fig. 2). It is leaving group than the mesyl group, was carried out. The al-
assumed that 11a and 11b are rotational isomers to the axis cohol 11a was converted into Mc derivative13) 18 in 85%
of C2-NHCbz, because strong nOe between 2-NH and 5-ben- yield by treatment with Mc-Cl in the presence of triethyl-
zyl-CH2 (8.5%) was observed in 11a and no nOe was de- amine in pyridine. Transformation of Mc derivative 18 into
tected in 11b.
azide 4c was carried out by treatment with NaN3 in the pres-
Investigation of optimal conditions for intramolecular 1,3- ence of benzyltriethylammonium bromide in DMF. The reac-
dipolar cyclic addition of azide olefin using 11a was carried tion did not proceed under the conditions at room tempera-
out (Chart 3). We initially adopted OTf as a leaving group. ture. However, when the reaction temperature was raised to
The desired alcohol 11a was first converted to triflate 16 by 50°C, intramolecular 1,3-dipolar cyclic addition of azide
treatment with triflic anhydride under 2,6-lutidine as a base olefin occurred successfully and 18 was directly transformed
in CH2Cl2, followed by conversion to its azide using NaN3 into (pyrrolidin-2-ylidene)glycinate 5c in 71% yield from 18
under benzyltriethylanmmonium bromide in N,N-dimethyl- presumably via azide 4c though 4c was not trapped as an in-
formamide (DMF) according to a similar way as described in termediate. NOe experiment showed 5c has the desired E-
our previous paper.5) Formation of the triflate 16 could be de- geometry because 2.3% nOe was observed at 3-H when a-
tected; however, further conversion to azide did not occur.
NH was irradiated. The inversion of configuration at C-5 was
Then, the investigation by using another leaving group for confirmed because nOe was observed between 6-CH2 and 3-
conversion of 11a to azide was carried out. The alcohol 11a H. This result shows 18 was once converted to azide 4c by
was next transformed to methanesulfonyl (Ms) derivative 17 SN2 reaction, then 4c was cyclized immediately to afford
by treatment with mesylchloride in the presence of triethyl- pyrrolidine 5c (Fig. 3). Total yield of 5c from 9 is 43.4%.
amine in CH2Cl2 in 93% yield. But the conversion of 17 into
Generally, intramolecular 1,3-dipolar cyclic addition of
azide 4c did not occur by treatment with NaN3 under either azide and olefin via triazoline occurs between azide dipole
condition with BnEt3NꢂBrꢃ as a phase catalyst in DMF or and electron-deficient dipolarphile such as olefin having an
15-crown-5 in HMPA.12) Further examination using a mono- electron-withdrawing group (such as COOMe) to provide a
heterocyclic compound successfully.14,15) It has been scarcely
reported that this cyclic reaction occurs between azide dipole
and olefin dipolarphile having an amide group. In this mean-
ing, our report should expand the application of azide olefin
cyclic reaction to construct new heterocyclic compounds.
As described in the previous paper,5) azide olefin cyclic re-
action proceeded successfully, using Me ester 4a and OtBu
ester 4b as a substrate. In this paper, further examination was
carried out using allyl ester 4d as a substrate. Synthetic pro-
cedure for azide 4d and its cyclic reaction for 5d is described
as follows (Chart 4).
Fig. 3. NOE Data of 5c
Chart 3
Chart 4

532
Vol. 53, No. 5
Fig. 4. NOE and LSPD Data of 13a and 13b
Fig. 6. NOE Data of 5d
Fig. 5. LSPD Data of t-Butyl Ester5)
Condensation of acid 9 with allyl alcohol by using EDCI,
HOBt, EtN(i-Pr)2 in CH2Cl2 gave the allyl ester 12 in 85%
yield in a similar way as the synthesis of amide 15. Removal
of the TBS group by HF-pyridine in THF-pyridine gave the
Z-alcohol 13a (78%) and E-alcohol 13b (14%), respectively,
as stereoisomers. The stereostructures were determined by
the measurement of nOe and LSPD (Fig. 4).
In the isomer 13a, 4.4% nOe was observed at 4-H when 2-
NH was irradiated, hence 13a has Z-configuration. In the iso-
mer 13b, the signal of 2-NH could not be observed due to
overlapping with the signals of the phenyl group, so nOe
measurement was impossible. Then, examination by LSPD
was carried out (Fig. 4). The C13–H1 coupling constants be-
tween H-3 and C-1 in 13a and 13b showed the values of
Jꢀ4.0, 7.0Hz, respectively. According to the literature,11) it
Fig. 7. Heat of Formation Values of 11a,11b and 13a,13b by PM3 Calcu-
lation
mechanism as shown in Fig. 7, which is the same as previ-
ously reported.5) After removal of the TBDMS group,
Michael addition of the generated hydroxyl group at the b-
position of the a,b-unsaturated ester would occur to afford a
furan ring. In this addition, the hydroxyl group would attack
from both sides of the re and si planes to afford b and a
forms, and each form is accompanied with two isomers, Z
and E forms, to give four stereoisomers of furans, b (Z), b
(E), a (Z), a (E). And if the reaction proceeds under condi-
tions of thermodynamic control, furan intermediates would
accumulate to the more stable isomer having the smallest
heat of formation (Hf) with the isomeric rearrangement;
thus, they would return to 11a and 13a or isomerize to 11b
and 13b.
The heats of formation were calculated by PM3 calcula-
tion with two pairs of isomers, 11a and 11b, 13a and 13b. Hf
of 11a and 11b exhibited ꢃ195.2311, ꢃ194.3613kcal/mol,
respectively. These results explain 11a (Z-form) is more sta-
bilized than 11b (E-form) with the difference of 0.87
kcal/mol; accordingly, thermodynamic equilibrium would
proceed to produce the Z-form. These calculation data were
coincident with our experimental data producing only Z-iso-
mers 11a and 11b. The respective Hf of 13a and 13b exhib-
ited ꢃ177.8207, ꢃ177.5021kcal/mol, respectively, which
explains 13a is also more stabilized than 13b and thermo-dy-
namic equilibrium would proceed to produce the Z-form.
These results coincide with the experimental result, which
showed the ratio of the Z and E-isomers (13a:13bꢀ5.7:1).
Conversion of the (Pyrrolidin-2-ylidene)glycinate 5a to
Precursors 6a and 6b toward 3 Initially, the conversion of
5a to 6a for the purpose of the synthesis of aziridine deriva-
tive 3a was investigated (Chart 5). Considering the require-
3
is said that the value of JCH (trans) is much larger than that
3
of JCH (cis) and their reference are fairly large. In fact, t-
3
butyl esters exhibited the values of JCH (cis)ꢀ4.0Hz and
3JCH (trans)ꢀ8.0Hz, respectively, as described in our previ-
ous report.5) (Fig. 5). This rule can be also applied to the iso-
mers 13a and b.
From these results, it is considered that 13a and 13b are
the geometrical isomers and 13a is the desired Z-olefin and
13b is E-olefin. Treatment of the desired 13a with triflic an-
hydride and 2,6-lutidine in CH2Cl2 at ꢃ40°C provided tri-
flate 19 which was immediately followed by transformation
to the azide 4d by adding DMF, NaN3 and benzene-triethy-
lammonium bromide directly in the reaction mixture of tri-
flate at ꢃ40°C for 30min, followed at ꢃ20°C for 19h to af-
ford the azide 4d. Then, the azide 4d was heated in THF at
60°C for 2h to provide (pyrrolidine-2-ylidene)glycinate 5d
in 59% yield from 13a. The stereostructure of 5d was deter-
mined by nOe measurement (Fig. 6). 1.8% nOe was observed
at 3-H when a-NH was irradiated. This result shows 5d has
the desired E configuration. Total yield of 5d from 9 was
40%.
Consideration on the Stereoselectivity in the Alcohols
11 and 13 by Heat of Formation (Hf) Using PM3 Calcu-
lated Method As described above, in the removal of the
TBDMS group by HF-pyridine from amide 10 and allyl ester
12, isomerization of geometry is expected, which is a similar
case as shown in our previous paper.5) Amide 10 afforded
both Z-alcohols 11a (89%) and 11b (9.0%) but did not pro-
vide E-form, while allyl ester 12 afforded 13a (Z, 78%) and
13b (E, 14%), respectively. We proposed the isomerization

May 2005
533
ester.
In conclusion, pyrrolidine-2-ylidene glycin-amide (5c) and
glycinate (5d) were effectively obtained from the alcohol 11
and 13 via azide 4c and 4d, respectively, by using intramole-
cular 1,3-dipolar cyclic reactions of azide and olefin. These
results proved this cyclic reaction should be applicable for
the synthesis of various pyrrolidine-2-ylidene glycinate and
glycinamide.
Experimental
Melting points were taken on a Yanagimoto hot-stage and are uncorrected.
Optical rotations were measured on a JASCO model DPI-1000 digital po-
1
larimeter. H- and 13C-NMR were recorded on a Varian VXR-300 (75Hz),
UNITY-400 (100.6MHz) spectrometers. All the NMR spectra were taken
using CDCl3 as a solvent unless otherwise described. The signals were as-
signed by H–1H COSY, DEPT, HMQC, HMBC experiments. Mass spectra
were obtained on a JEOL JMS-DX300 mass spectrometer (low-resolution
mass spectrometry) and JEOL JMS-AX505 HA mass spectrometer (high-
resolution mass spectrometry). Rf values and preparative TLC were done on
1
Chart 5
ment of the subsequent removal of the benzyl group, the Cbz
group of 5a should be interchanged to a Boc group. Thus, a Silica gel 60 PF254 (Merck). Flash column chromatography was done using
Silica gel 60 (art. 1.09385, Merck).
The PM3 calculation was performed by the program CAChe WorkSystem
(Ver. 4.9.3 for Machintosh) produced by Fujitsu using Machintosh G4
OS.9.2). Fifteen models were selected within conformers (625) by searching
Boc group was introduced to 5a using Boc2O in the presence
of Et3N, DMAP to provide 20 in 88% yield. It was deter-
mined that the Boc group was located in the same nitrogen
1
having the Cbz group, because in nOe experiment by H-
NMR measurement, irradiation at 1-NH caused 5% nOe at 5-
H. The removal of the benzyl group in 20 by Pd (OH)2/C
under hydrogen gave successively a triol 21 in 83% yield. Se-
lective mesylation by treatment with mesyl chloride in the
presence of Et3N at ꢃ40°C afforded 22 (57%). The location
of the mesyl group was determined because the chemical
shift value of 6-Ha in 22 exhibited more low field shift (d
4.02→4.49) than 3-H and 4-H. Acetylation of 22 provided
diacetate 6a. The low field shift of the chemical shift values
two points of dihedral angles, C-6,5,4,3 and C-5,4,3,2, which are concerned
with cyclic reaction. After further optimerization of each structural parame-
ter of fifteen models by MM2, the most stabilized structure was searched by
PM3.
Methyl (Z and E, 4R,5S,6R)-2-Benzyloxycarbonylamino-6-tert–butyl-
dimethylsiloxy-4,5,7-tribenzyloxy-2-heptenoate (8a, 8b) To a solution of
14 (510mg, 1.51mmol) in CH2Cl2 (5ml) was added DBU (226ml, 1.51
mmol). After the solution was allowed to stir for 20min, a solution of 7 (580
mg, 1.08mmol) in CH2Cl2 (5ml) was added and stirred for further 24h. The
reaction mixture was neutralized with aqueous 1N-H2SO4 and diluted with
AcOEt (100ml), washed with saturated NaHCO3 (4mlꢄ2), saturated NaCl
(4mlꢄ2). The organic layer was dried over Na2SO4 and concentrated in
vacuo. Purification of the resulting yellow oil (910mg) by flash column
chromatography (n-hexane/AcOEtꢀ7:1) afforded 8a (Z-form, 540mg,
67.3%) and 8b (E-form, 80.0mg, 10.3%), respectively. 8a: Rfꢀ0.44 (n-
hexane/AcOEtꢀ5:1). [a]D24 ꢃ11.60° (cꢀ0.50, CHCl3). 1H-NMR (300MHz)
d: ꢃ0.01, 0.05 (each 3H, s, Si(CH3)2), 0.83 (9H, s, C(CH3)3), 3.39 (1H, dd,
Jꢀ9.0, 5.0Hz, 7-Ha), 3.68 (1H, dd, Jꢀ9.0, 6.0Hz, 7-Hb), 3.74 (1H, dd,
1
of 3-H (d 4.93→6.03) and 4-H (d 4.57→5.36) in 6a by H-
NMR explained also the mesylation occurred at 6-OH in 21.
The construction of an aziridine ring using 6a by tetrabutyl-
ammonium fluoride (TBAF) and potassium bis(trimethylsi-
lyl) amide (KHMDS) was attempted. However, the desired
3a was not obtained and also the starting material was not re- Jꢀ7.0, 3.0Hz, 5-H), 3.77 (3H, brs, COOCH3), 3.91—3.98 (1H, m, 6-H),
4.36, 4.58 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.43, 4.48 (each 1H, d,
Jꢀ12.5Hz, OCH2Ph), 4.43 (1H, dd, Jꢀ8.5, 7.0Hz, 4-H), 4.67, 4.72 (each
1H, d, Jꢀ11.0Hz, OCH2Ph), 5.03, 5.10 (each 1H, d, Jꢀ12.0Hz,
COOCH2Ph), 6.14 (1H, dd, Jꢀ8.5, 1.0Hz, 3-H), 7.20—7.31 (20H, m,
covered. Only complicated by-products were obtained which
is the same result as shown in the recent literature,7) in which
this result is explained by the base-induced elimination of the
3-OAc, producing imine, which decomposes or polymerizes.
Next, we changed the target of the precursor for 3 and
planned the synthesis of the mesylbenzylether 6b, because
benzyl ethers should tolerate a strong anion such as Fꢃ or a
strong base such as KHMDS (Chart 5). Selective deprotec-
tion of tri-benzyl ether 20 was performed by catalytic reduc-
tion using Pd(OH)2/C under hydrogen giving dibenzyl ether
24 in 39% yield. Mesylation by MsCl in the presence of Et3N
afforded mono mesyl derivative 6b in 73% yield. The loca-
tion of the mesyl group was determined by comparing the
1H-NMR data of 24 and 6b, which exhibited the low field
shift of 6-Ha, 6-Hb in 6b (6-Ha: 3.54→4.35; 6-Hb:
3.63→4.38). These results confirmed at the same time that
the benzyl group at C-6 in 20 was selectively removed suc-
cessively by reduction. Thus, a facile route to 6b from 5a
was established.
OCH2Phꢄ4), 7.53 (1H, brs, NHCO). HR-FAB-MS m/z: 762.3444
[MꢂNa]ꢂ Calcd for C43H53O8NSiNa: 762.3438 [MꢂNa]. 8b: Rfꢀ0.51 (n-
hexane/AcOEtꢀ5:1). [a]D24 ꢂ11.20° (cꢀ0.50, CHCl3). 1H-NMR (400MHz)
d: 0.07, 0.10 (each 3H, s, Si(CH3)2), 0.91 (9H, s, C(CH3)3), 3.65 (1H, dd,
Jꢀ10.0, 5.5Hz, 7-Ha), 3.65 (3H, brs, COOCH3), 3.73 (1H, dd, Jꢀ5.0, 4.5
Hz, 5-H), 3.74 (1H, dd, Jꢀ10.0, 3.0Hz, 7-Hb), 4.14 (1H, ddd, Jꢀ5.5, 5.0,
3.0Hz, 6-H), 4.42, 4.62 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.48, 4.51 (each
1H, d, Jꢀ12.0Hz, OCH2Ph), 4.69, 4.72 (each 1H, d, Jꢀ12.3Hz, OCH2Ph),
5.09 (1H, dd, Jꢀ9.5, 4.5Hz, 4-H), 5.14, 5.19 (each 1H, d, Jꢀ12.5Hz,
COOCH2Ph), 6.82 (1H, brs, NHCO), 6.85 (1H, brd, Jꢀ9.5Hz, 3-H), 7.22—
7.41 (20H, m, OCH2Phꢄ4). HR-FAB-MS m/z: 762.3424 [MꢂNa]ꢂ, Calcd
for C43H53O8NSiNa: 762.3438 [MꢂNa].
(Z,4R,5S,6R)-2-Benzyloxycarbonylamino-6-tert-butyldimethylsiloxy-
4,5,7-tribenzyloxy-2-heptenoic Acid (9) To a solution of 8a (482.4mg,
0.653mmol) in dioxane (3.6ml) was added an aqueous solution of 1N-
NaOH (1.0ml, 0.98mmol). After the mixture was allowed to stir for 19.5h,
the reaction mixture was acidified with 10% HCl and extracted with CHCl3
(100mlꢄ2). The combined organic layer was dried over Na2SO4, and con-
centrated in vacuo to afford 9 (474mg, 100%) as colorless oil. Compound 9
was used for the next reaction without purification. Rfꢀ0.40
(CHCl3/MeOHꢀ10:1). [a]D24 ꢂ5.2° (cꢀ1.08, CHCl3). IR (KBr) cmꢃ1: 1720
Compounds 5c and 5d described previously should also
afford their monomesyl esters 25a and 25b (Fig. 1) in a simi-
lar way as shown in Chart 5. We are now going to examine
construction of an aziridine ring system using the precursor
6b and also the conversion of 5c and 5d to their monomesyl
1
(NHCOO), 1710 (COO), 1655 (CꢀC). H-NMR (400MHz) d: 0.00 (6H, s,
Si(CH3)2), 0.84 (9H, s, C(CH3)3), 3.41 (1H, dd Jꢀ9.5, 5.0Hz, 7-Ha), 3.69
(1H, dd, Jꢀ9.5, 6.0Hz, 7-Hb), 3.77 (1H, dd, Jꢀ6.5, 3.0Hz, 5-H), 3.97 (1H,
ddd, Jꢀ6.0, 5.0, 3.0Hz, 6-H), 4.37, 4.58 (each 1H, d, Jꢀ12.0Hz, OCH2Ph),

534
Vol. 53, No. 5
4.44, 4.49 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.46 (1H, dd, Jꢀ8.0, 6.5Hz,
Hz, 5-H), 3.93 (1H, m, 6-H), 4.17 (2H, brs, 1ꢅ-CH2), 4.33, 4.54 (each 1H, d,
4-H), 4.67, 4.72 (each 1H, d, Jꢀ11.0Hz, OCH2Ph), 5.04, 5.10 (each 1H, d, Jꢀ11.5Hz, OCH2Ph), 4.41 (1H, dd, Jꢀ7.0, 4.0Hz, 4-H), 4.48, 4.52 (each
Jꢀ12.0Hz, COOCH2Ph), 6.38 (1H, d, Jꢀ8.5Hz, 3-H), 7.20—7.32 (20H, m, 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.52, 4.58 (each 1H, d, Jꢀ11.0Hz, OCH2Ph),
OCH2Phꢄ4), 7.55 (1H, brs, NH). 13C-NMR (100MHz) d: ꢃ4.99, ꢃ4.68 (q, 5.01, 5.06 (each 1H, d, Jꢀ12.0Hz, COOCH2Ph), 6.00 (1H, d, Jꢀ7.0Hz, 3-
Si(CH3)2), 18.04 (s, C(CH3)3), 25.82 (q, C(CH3)3), 67.25 (t, COOCH2Ph), H), 6.62 (1H, brs, CONH), 7.19—7.34 (20H, m, OCH2Phꢄ4), 7.44 (1H, br
70.60 (t, 7-C), 71.47 (t, OCH2Ph), 72.04 (d, 6-C), 73.29, 75.06 (each t, s, NHCOO). 13C-NMR (100MHz) d: 27.32 (q, 3ꢅ-C), 50.04 (t, 1ꢅ-C), 67.36
OCH2Phꢄ2), 75.40 (d, 4-C), 83.78 (d, 5-C), 127.58 (d, 3-C), 127.53, 127.66, (t, COOCH2Ph), 70.29 (d, 6-C), 70.49 (t, 7-C), 71.63, 73.45, 74.60 (each t,
127.87, 127.94, 127.98, 128.09, 128.17, 128.22, 128.34, 128.45 (each d, OCH2Phꢄ3), 75.56 (d, 4-C), 80.80 (d, 5-C), 122.97 (d, 3-C), 127.85, 127.88,
OCH2Phꢄ4), 129.64 (s, 2-C), 135.84 (s, COOCH2Ph-1ꢅ-C),137.51, 137.79, 128.0, 128.13, 128.21, 128.39, 128.42, 128.44, 128.47 (each d,
138.32 (each s, OCH2Ph-1ꢅ-Cꢄ3), 154.17 (s, NHCO), 167.02 (s, COOH). OCH2Phꢄ4), 133.53 (s, 2-C), 135.71 (s, COOCH2Ph), 137.29, 137.31,
HR-FAB-MS m/z: 748.3281 [MꢂNa]ꢂ. Calcd for C42H51O8NSiNa: 137.61 (each s, OCH2Phꢄ3), 153.96 (s, NHCOO), 164.16 (s, CONH),
748.3282 [MꢂNa].
202.39 (s, 2ꢅ-C). HR-FAB-MS m/z: 689.2829 [MꢂNa]ꢂ, Calcd for
(Z,4R,5S,6R)-N-2ꢀ-Hydroxypropyl-2-benzyloxycarbonylamino-6-tert- C39H42O8N2Na: 689.2839 [MꢂNa]. 11b: Rfꢀ0.24 (n-hexane/AcOEtꢀ1:2).
butyldimethyl-siloxy-4,5,7-tribenzyloxy-2-heptenamide (15) To a solu- [a]D24 ꢂ93.44° (cꢀ0.63, CHCl3). H-NMR (400MHz) d: 2.19 (3H, s, 3ꢅ-
1
tion of 9 (652.5mg, 0.90mmol) in CH2Cl2 (9ml) were added EDCI·HCl
(346.2mg, 1.80mmol), HOBt (121.9mg, 0.90mmol), EtN(i-Pr)2 (315ml,
1.80mmol), 1-amino-2-propanol (84ml, 1.08mmol) under argon and stirred
for 23.5h. The reaction mixture was diluted with CHCl3 (100ml), washed
with H2O (30ml). The organic layer was dried over Na2SO4, and concen-
CH3), 2.82 (1H, brs, 6-OH), 3.46 (1H, dd, Jꢀ9.5, 5.5Hz, 7-Ha), 3.55 (1H,
dd, Jꢀ9.5, 3.0Hz, 7-Hb), 3.56 (1H, brs, 6-H), 3.84 (1H, dd, Jꢀ8.5, 3.2Hz,
5-H), 4.17 (2H, brs, 1ꢅ-CH2), 4.38, 4.63 (each 1H, d, Jꢀ12.0Hz, OCH2Ph),
4.41, 4.48 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.52 (1H, dd, Jꢀ9.0, 3.2Hz,
4-H), 4.53, 4.86 (each 1H, d, Jꢀ11.0Hz, OCH2Ph), 5.06, 5.12 (each 1H, d,
trated in vacuo. Purification of the resulting yellow oil by flash column chro- Jꢀ12.0Hz, COOCH2Ph), 6.12 (1H, d, Jꢀ9.0Hz, 3-H), 6.64 (1H, brs,
matography (n-hexane/AcOEtꢀ3:2) afforded 15 (599mg, 85.1%). Rfꢀ0.49
CONH), 7.20—7.35 (20H, m, OCH2Phꢄ4), 7.59 (1H, brs, NHCOO). 13C-
NMR (100MHz) d: 27.33 (q, 3ꢅ-C), 50.05 (t, 1ꢅ-C), 67.35 (t, COOCH2Ph),
70.23 (t, 7-C), 70.74 (d, 6-C), 71.39, 73.34, 74.81 (each t, OCH2Phꢄ3),
(CHCl3/MeOHꢀ10:1). [a]D23 ꢃ6.41° (cꢀ1.28, CHCl3). IR (KBr) cmꢃ1
:
1
1720 (NHCOO), 1660 (CONH), 1640 (CꢀC), 1250 (OH), 1090 (OH). H-
NMR (400MHz, DMSO-d6) d: ꢃ0.01, 0.00 (each 3H, s, Si(CH3)2), 0.81 75.92 (d, 4-C), 80.34 (d, 5-C), 123.71 (d, 3-C), 134.13 (s, 2-C), 135.84,
(9H, s, C(CH3)3), 1.01 (3H, d, Jꢀ6Hz, 3ꢅ-CH3), 3.07 (2H, m, 1ꢅ-H2), 3.47 137.49, 137.93 (each s, OCH2Phꢄ4), 154.07 (s, NHCOO), 164.04 (s,
(1H, dd, Jꢀ10.0, 6.5Hz, 7-Ha), 3.62 (1H, dd, Jꢀ5.5, 2.5Hz, 5-H), 3.65 (1H,
m, 7-Hb), 3.68 (1H, m, 2ꢅ-H), 4.00, 4.15 (total 1H, each dt, Jꢀ6.0, 2.0 Hz; C39H42O8N2Na: 689.2839 [MꢂNa].
CONH), 202.44 (s, 2ꢅ-C). HR-FAB-MS m/z: 689.2860 [MꢂNa]ꢂ, Calcd for
fifth, Jꢀ3.0Hz, 6-H), 4.38, 4.39 (each 1H, d, Jꢀ13.0Hz, OCH2Ph), 4.54,
4.58 (each 1H, d, Jꢀ12.5Hz, OCH2Ph), 4.26, 4.49 (each 1H, d, Jꢀ12.0Hz,
OCH2Ph), 4.44 (H, dd, Jꢀ9.0, 7.0Hz, 4-H), 4.64, 4.65 (total 1H, each d,
Jꢀ3.5Hz, 2ꢅ-OH), 5.99, 6.24 (total 1H, J=9.0Hz, 3-H), 7.87, 7.90 (total 1H,
(Z,4R,5S,6R)-N-2ꢀ-Oxopropyl-2-benzyloxycarbonylamino-6-methane-
sulfonyl-4,5,7-tribenzyloxy-2-heptenamide (17) To a solution of 11a
(23.8mg, 0.036mmol) in CH2Cl2 (1.0ml) were added triethylamine (15.0
ml) and MsCl (3.0ml, 0.0396mmol) at 0°C under argon. After the reaction
each t, Jꢀ6.0Hz, CONH), 7.10—7.60 (20H, m, OCH2Phꢄ4), 8.45, 8.65 mixture was stirred for 10min at 0°C, it was diluted with H2O (10ml) and
(total 1H, each br, NHCOO). HR-FAB-MS m/z: 805.3884 [MꢂNa]ꢂ. Calcd
for C45H58O8N2SiNa: 805.3860 [MꢂNa].
extracted by CHCl3 (50mlꢄ2). The combined organic layer was dried over
Na2SO4 and concentrated in vacuo. Purification of the resulting oil (31.5mg)
(Z,4R,5S,6R)-N-2ꢀ-Oxopropyl-2-benzyloxycarbonylamino-6-tert-butyl- by preparative TLC (silica gel, n-hexane/AcOEtꢀ1:2) afforded 17 (25.0mg,
1
dimethylsiloxy-4,5,7-tribenzyloxy-2-heptenamide (10) To a solution of
15 (9.3mg, 0.012mmol) in CH2Cl2 (1.0ml) was added Dess–Martin reagent
(26mg, 0.06mmol) under argon. After the reaction mixture was stirred for
40min at room temperature, Dess–Martin reagent (5.1mg, 0.012mmol) was
further added and stirred for 20min. The reaction mixture was diluted with
93.3%) as a colorless oil. Rfꢀ0.40 (n-hexane/AcOEtꢀ1:2). H-NMR (400
MHz) d: 2.20 (3H, s, 3ꢅ-CH3), 2.92 (3H, s, SO2CH3), 3.75 (1H, dd, Jꢀ11.0,
7.0Hz, 7-Ha), 3.83 (1H, dd, Jꢀ11.0, 3.5Hz, 7-Hb), 3.90 (1H, t, Jꢀ4.0Hz,
5-H), 4.16 (2H, brs, 1ꢅ-CH2), 4.36 (1H, dd, Jꢀ7.0, 4.0Hz, 4-H), 4.38, 4.51
(each 1H, d, Jꢀ11.5Hz, OCH2Ph), 4.50 (2H, s, OCH2Ph ), 4.62, 4.68 (each
CHCl3 (15ml), washed with H2O (5ml). The organic layer was dried over 1H, d, Jꢀ11.0Hz, OCH2Ph), 4.80, 5.05 (each 1H, d, Jꢀ12.0Hz, OCH2Ph),
Na2SO4, and concentrated in vacuo. Purification of the residue by prepara-
tive TLC (CHCl3/MeOHꢀ30:1) afforded 10 (8.9mg, 95.1%) as colorless
5.51 (1H, m, 6-H), 5.92 (1H, d, Jꢀ7.0Hz, 3-H), 6.65 (1H, brt, Jꢀ4.0Hz, 1-
NH), 7.20—7.40 (20H, m, OCH2Phꢄ4). HR-FAB-MS m/z: 767.2594 [M]ꢂ,
oil. Rfꢀ0.53 (CHCl3/MeOHꢀ20:1). [a]D24 ꢂ30.27° (cꢀ1.13, CHCl3). IR Calcd for C40H44O10N2SNa: 767.2594 [M]. m/z: 767.2594 [M]ꢂ, Calcd for
1
(KBr) cmꢃ1: 1735 (NHCOO), 1725 (CO), 1660 (CONH), 1640 (CꢀC). H-
NMR (300MHz) d: ꢃ0.02, ꢃ0.01 (each 3H, s, Si(CH3)2), 0.82 (9H, s,
C(CH3)3), 2.21 (3H, s, 3ꢅ-H3), 3.37 (1H, dd, Jꢀ9.0, 4.0Hz, 7-Ha), 3.69 (1H,
C40H44O10N2SNa: 767.2614 [M].
(Z,4R,5S,6R)-N-2ꢀ-Oxopropyl-2-benzyloxycarbonylamino-6-mono-
chrolomethane sulfonyl-4,5,7-tribenzyloxy-2-heptenamide (18) To a so-
dd, Jꢀ9.0, 7.0Hz, 7-Hb), 3.71 (1H, dd, Jꢀ6.5, 2.5Hz, 5-H), 3.92 (1H, ddd, lution of 11a (134.2mg, 0.202mmol) in pyridine (2ml), was added McCl
Jꢀ7.0, 4.0, 2.5Hz, 6-H), 4.17 (2H, brs, 1ꢅ-H2), 4.38, 4.56 (each 1H, d, (90ml, 1.01mmol) at 0°C under argon and stirred for 30min at room tem-
Jꢀ12.0Hz, OCH2Ph), 4.39 (1H, dd, Jꢀ8.5, 6.5Hz, 4-H), 4.44, 4.48 (each
perature. The reaction mixture was diluted with H2O (10ml), extracted by
1H, d, Jꢀ12.0Hz, OCH2Ph), 4.70, 4.74 (each 1H, d, Jꢀ11.0Hz, OCH2Ph), CHCl3 (20mlꢄ3). The combined CHCl3 layer was dried over Na2SO4, and
4.96, 5.06 (each 1H, d, Jꢀ12.0Hz, COOCH2Ph), 5.92 (1H, d, Jꢀ8.5Hz, 3-
H), 6.63 (1H, brs, CONH), 7.10—7.60 (20H, m, OCH2Phꢄ4), 7.82 (1H, br
s, NHCOO). 13C-NMR (100MHz) d: ꢃ4.78, ꢃ4.63 (each q, Si(CH3)2),
18.09 (s, C(CH3)3), 25.83 (q, C(CH3)3, 3ꢅ-CH3), 67.20 (t, COOCH2Ph),
concentrated in vacuo to afford a yellow oil (223.8mg). Purification of the
residue by flash column chromatography (n-hexane/AcOEtꢀ1:2) provided
the desired product 18 (133.1 mg, 87.4%) as a colorless oil. Rfꢀ0.36 (n-
hexane/AcOEtꢀ1:2). [a]D24 ꢂ5.08° (cꢀ1.30, CHCl3). IR (KBr) cmꢃ1: 1725
1
71.69 (t, 7-C), 71.80 (t, OCH2Ph), 72.22 (d, 6-C), 73.25 (t, OCH2Ph), 74.28 (CO, NHCOO), 1650 (CONH), 1640 (CꢀC), 1370 (OSO2). H-NMR (400
(d, 4-C), 74.42 (t, OCH2Ph), 83.67 (d, 5-C), 127.48 (d, 3-C), 127.59, 127.95, MHz) d: 2.21 (3H, s, 3ꢅ-CH3), 3.75 (1H, dd, Jꢀ11.5, 7.0Hz, 7-Ha), 3.86
128.04, 128.10, 128.19, 128.27, 128.30, 128.40, 128.43, 128.56 (each d, (1H, dd, Jꢀ11.5, 3.0Hz, 7-Hb), 3.99 (1H, t, Jꢀ4.0Hz, 5-H), 4.16 (2H, brs,
OCH2Phꢄ4), 133.55 (s, 2-C), 135.87 (s, COOCH2Ph), 137.35, 137.70, 1ꢅ-CH2), 4.37 (1H, dd, Jꢀ7.5, 4.0Hz, 4-H), 4.38, 4.51 (each 1H, d, Jꢀ11.0
138.00 (s, OCH2Phꢄ3), 153.90 (s, NHCOO), 164.06 (s, CONH), 202.43 (s, Hz, OCH2Ph), 4.50, 4.62 (each 1H, d, Jꢀ12.5Hz, OCH2Ph), 4.50 (2H, s,
2ꢅ-C). HR-FAB-MS m/z: 803.3705 [MꢂNa]ꢂ, Calcd for C45H56O8N2SiNa:
803.3704 [MꢂNa].
SO2CH2Cl), 4.60, 4.67 (each 1H, d, Jꢀ11.0Hz, OCH2Ph), 4.98, 5.06 (each
1H, d, Jꢀ12.0Hz, COOCH2Ph), 5.12 (1H, ddd, Jꢀ7.0, 4.0, 3.0Hz, 6-H),
(Z,4R,5S,6R)-N-2ꢀ-Oxopropyl-2-benzyloxycarbonylamino-6-hydroxy- 5.90 (1H, d, Jꢀ7.5Hz, 3-H), 6.62 (1H, brt, Jꢀ4.0Hz, CONH), 7.20—7.40
4,5,7-tribenzyloxy-2-heptenamide (11a, 11b) To a mixture of 10 (99.9mg,
0.128mmol) in THF (0.7ml) and dry pyridine (0.7ml) was added HF-pyri-
dine (820ml) dropwise during 7min under argon at 0°C and stirred for 73.5
(20H, m, OCH2Phꢄ4). 13C-NMR (100MHz) d: 27.30 (q, 3ꢅ-C), 50.02 (t, 1ꢅ-
C), 54.15 (t, SO2CH2Cl), 67.50 (t, COOCH2Ph), 68.68 (d, 6-C), 71.79 (t, 7-
C), 73.61, 75.07, 75.12 (each t, OCH2Phꢄ3), 80.29 (d, 4-C), 83.18 (d, 5-C),
h. The reaction mixture was adjusted to pH 7—8 with saturated NaHCO3 so- 121.44 (d, 3-C), 127.50—129.40 (each d, OCH2Phꢄ4), 133.93 (s, 2-C),
lution, then extracted with CHCl3 (100mlꢄ3). The combined organic layer 135.63 (s, COOCH2Ph), 136.62, 136.98, 137.12 (each s, OCH2Phꢄ3),
was dried over Na2SO4, and concentrated in vacuo. Purification of the
residue by preparative TLC (n-hexane/AcOEtꢀ1:2) afforded 11a (76.0mg,
89.2%) and 11b (7.7mg, 9.0%), respectively, as a yellow oil. 11a: Rfꢀ0.16
(n-hexane/AcOEtꢀ1:2). [a]D24 ꢂ2.15° (cꢀ1.21, CHCl3). 1H-NMR (400
153.73 (s, NHCOO), 164.08 (s, CONH), 202.32 (s, 2ꢅ-C). HR-FAB-MS m/z:
801.2255 [MꢂNa]ꢂ, Calcd for C40H43O10N2ClSNa: 801.2225 [MꢂNa].
(E,3R,4R,5S)-N-Benzyloxycarbonyl-Nꢀ-2ꢀ-oxopropyl-a-(5-benzyl-
oxymethyl-3,4-dibenzyl-oxypyrrolidine-2-ylidene)glycinamide (5c) To a
MHz) d: 2.21 (3H, s, 3ꢅ-CH3), 2.62 (1H, brs, 6-OH), 3.55 (1H, dd, Jꢀ9.5, solution of 18 (133.1mg, 0.17mmol) in DMF (1.7ml) were added
5.0Hz, 7-Ha), 3.59 (1H, dd, Jꢀ9.5, 4.0Hz, 7-Hb), 3.70 (1H, dd, Jꢀ7.0, 4.0 BnEt3NꢂBrꢃ (23.3mg, 0.09mmol), NaN3 (119.9mg, 1.71mmol) under

May 2005
535
argon. After the solution was stirred for 19.5h at 50°C, it was diluted with
4.54, 4.86 (each 1H, d, Jꢀ11.0Hz, benzyl-CH2), 4.58 (1H, dd, Jꢀ9.0, 3.0
H2O (7ml) and extracted with a mixture of solvents (n-hexane/AcOEtꢀ1:1) Hz, 4-H), 4.66 (2H, br, OCH2), 5.10, 5.14 (each 1H, d, Jꢀ12.0Hz, COOBn-
(15mlꢄ3). The combined organic layer was dried over Na2SO4 and concen- CH2), 5.23 (1H, brd, Jꢀ10.0Hz, AllylꢀCH2-cis), 5.33 (1H, brd, Jꢀ17.0Hz,
trated in vacuo. Purification of the resulting yellow oil (135.6mg) by flash AllylꢀCH2-trans), 5.91 (1H, m, Allyl-CHꢀ), 6.37 (1H, d, Jꢀ9.0Hz, 3-H),
column chromatography (n-hexane/AcOEtꢀ1:2) afforded 5c (80.5mg,
7.20—7.37 (20H, m, OCH2Ph). HR-FAB-MS m/z: 674.2730 [MꢂNa]ꢂ,
71.0%) as a yellow oil. Rfꢀ0.40 (n-hexane/AcOEtꢀ1:2). [a]D24 ꢂ20.98° Calcd for C39H41O8NNa: 674.2730.
(cꢀ1.02, CHCl3). IR (KBr) cmꢃ1: 1720 (NHCO), 1710 (CO), 1655
(CONH), 1645 (CꢀC). H-NMR (400MHz) d: 2.15 (3H, s, 3ꢅ-CH3), 3.54 loxy-2-heptenoate (4d) To a solution of 13a (1.238g, 1.90mmol) in
Allyl (Z,4R,5R,6)-6-Azido-2-benzyloxycarbonylamino-4,5,7-tribenzy-
1
(1H, dd, Jꢀ9.5, 6.5Hz, 6-Ha), 3.63 (1H, dd, Jꢀ9.5, 4.0Hz, 6-Hb), 4.04,
4.45 (each 1H, m, 1ꢅ-CH2), 4.10 (1H, br, 5-H), 4.11 (1H, brs, 4-H), 4.44,
4.54 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.46, 4.49 (each 1H, d, Jꢀ11.0Hz,
OCH2Ph), 4.48, 4.51 (each 1H, d, Jꢀ11.5Hz, OCH2Ph), 4.58 (1H, brs, 3-
H), 5.05 (1H, d, Jꢀ12.0Hz, COOCH2Ph-Ha), 5.15 (1H, brs, COOCH2Ph-
Hb), 5.86 (1H, brs, NHCOO), 6.39 (1H, brs, CONH), 7.15—7.40 (20H, m,
OCH2Phꢄ4), 8.34 (1H, brs, 1-H). 13C-NMR (100MHz) d: 27.18 (q, 3ꢅ-C),
CH2Cl2 (19ml) were added 2,6-lutidine (1.1ml, 9.50mmol), Tf2O (1.6ml,
9.50mmol) at ꢃ40°C under argon. After the mixture was allowed to stir for
55min, BnEt3NꢂBrꢃ (262.7mg, 0.96mmol), NaN3 (1.24g, 19.10mmol)
were added and stirred for 30min at ꢃ40°C after which it was allowed to
warm to ꢃ20°C, stirred for 19h. The resulting mixture was diluted with
H2O (100ml) and extracted with n-hexane/AcOEt (1:1) (250mlꢄ3). The
combined organic phase was dried over Na2SO4 and concentrated in vacuo
49.58 (t, 1ꢅ-C), 59.57 (d, 5-C), 67.15 (t, COOCH2Ph), 69.15 (t, 6-C), 72.31, to provide light brown oil 4d (2.16g) as a crude substance, which was used
73.46 (each t, OCH2Phꢄ3), 80.43, (d, 4-C) 83.29 (d, 3-C), 94.22 (s, a-C),
directly in the next reaction because of its instability. Rfꢀ0.58 (toluene/ace-
127.0—129.5 (each d, OCH2Phꢄ4), 136.33 (s, COOCH2Ph), 137.20, toneꢀ10:1). IR (KBr) cmꢃ1: 3400 (NH), 2100 (N3), 1730 (COO, NHCOO),
137.32, 137.93 (s, OCH2Phꢄ3), 156.429 (s, 2-C), 156.76 (s, NHCOO), 1675 (CHꢀCH2), 1620 (CꢀC).
168.48 (s, CONH), 203.89 (s, 2ꢅ-C). HR-FAB-MS m/z: 664.3025 [MꢂNa]ꢂ,
Calcd for C39H42O7N3: 664.3023 [MꢂNa].
Allyl (E,3R,4R,5S)-N-Benzyloxycarbonyl-N-tert-butoxycarbonyl-a-(5-
benzyloxymethyl-3,4-dibenzyloxypyrrolidin-2-ylidene)glycinate (5d)
Allyl
(Z,4R,5S,6R)-2-Benzyloxycarbonyamino-6-tert-butyldimethyl- Compound 4d was dissolved in THF (38ml) and stirred for 2h at 60°C
siloxy-4,5,7-tribenzyloxy-2-heptenoate (12) To a solution of 9 (511.4mg,
0.71mmol) in CH2Cl2 (7ml) were added EDCI·HCl (406.0mg, 2.12mmol),
HOBt (145.7mg, 1.06mmol), EtN (i-Pr)2 (370ml, 2.12mmol), allyl alcohol
(96ml, 1.41mmol) under argon. After the solution was stirred for 19.5h at
room temperature, it was partitioned between H2O (80ml) and CHCl3 (120
ml) and the aqueous layer was further extracted with CHCl3 (120mlꢄ2).
The combined organic layer was dried over Na2SO4 and concentrated in
vacuo. The resulting yellow oil (615.5mg) was purified by flash column
chromatography (n-hexane/AcOEtꢀ12:1) to provide 12 (458.7mg, 85.1%)
as a yellow oil. Rfꢀ0.30 (n-hexane/AcOEtꢀ5:1). [a]D24 ꢃ3.33° (cꢀ0.40,
under argon. After that, the solvent was removed and the resulting residue
was purified by flash column chromatography (silica gel, toluene/ace-
toneꢀ50:1) to afford 5d (729.9mg, 59.3% from 13a as a light yellow oil.
Rfꢀ0.43 (toluene/acetoneꢀ10:1). [a]D25 ꢂ10.3° (cꢀ1.05, CHCl3). IR (KBr)
cmꢃ1: 1735 (COO), 1720 (NHCO), 1680 (CHꢀCH2), 1610 (CꢀC). 1H-
NMR (400MHz) d: 3.59 (1H, dd, Jꢀ9.5, 8.0Hz, 6-Ha), 3.66 (1H, Jꢀ9.5,
4.0Hz, 6-Hb), 4.06 (1H, brs, 4-H), 4.18 (1H, m, 5-H), 4.40, 4.52 (each 1H,
d, Jꢀ12.0Hz, 4-OCH2Ph), 4.45, 4.49 (each 1H, d, Jꢀ11.0Hz, 3-OCH2Ph),
4.50, 4.57 (each 1H, d, Jꢀ11.5Hz, 6-OCH2Ph), 4.61 (2H, brd, Jꢀ5.0Hz, 1ꢅ-
H2), 4.67 (1H, brs, 3-H), 5.12, 5.15 (each 1H, d, Jꢀ12.0Hz, COOCH2Ph),
CHCl3). IR (KBr) cmꢃ1: 1735 (COO), 1725 (NHCO), 1655 (CHꢀCH2), 5.16 (1H, brd, Jꢀ11.0Hz, 3ꢅ-cis-H), 5.28 (1H, brd, Jꢀ17.0Hz, 3ꢅ-trans-H),
1
1635 (CꢀC). H-NMR (300MHz) d: ꢃ0.01 (6H, s, Si(CH3)2), 0.83 (9H, s, 5.68 (1H, brs, NHCO), 5.89 (1H, ddd, Jꢀ17.0, 11.0, 5.0Hz, 2ꢅ-H), 7.18—
C(CH3)3), 3.39 (1H, dd, Jꢀ9.0, 4.5Hz, 7-Ha), 3.69 (1H, dd, Jꢀ9.0, 6.5Hz,
7-Hb), 3.74 (1H, dd, Jꢀ6.5, 3.0Hz, 5-H), 3.94 (1H, ddd, Jꢀ6.5, 4.5, 3.0Hz,
7.45 (20H, m, OCH2Phꢄ4), 7.90 (1H, brs, 1-H). 13C-NMR (100MHz) d:
60.48 (d, 5-C), 64.25 (t, 1ꢅ-C), 66.78 (t, COOCH2Ph), 68.99 (t, 6-C), 72.05
6-H), 4.38, 4.59 (each 1H, d, Jꢀ11.5Hz, OCH2Ph), 4.44, 4.48 (each 1H, d, (t, 4-OCH2Ph), 72.68 (3-OCH2Ph), 73.47 (t, 6-OCH2Ph), 79.94 (d, 4-C),
Jꢀ11.5Hz, OCH2Ph), 4.45 (1H, dd, Jꢀ8.5, 6.5Hz, 4-H), 4.68 (2H, m, 1ꢅ- 82.54 (d, 3-C), 92.37 (s, a-C), 117.10 (t, 3ꢅ-C), 127.69, 127.82, 127.98,
H2), 4.68, 4.72 (each 1H, d, Jꢀ11.0Hz, OCH2Ph), 5.03, 5.09 (each 1H, d, 128.17, 128.30, 128.40, 128.47 (each d, OCH2Phꢄ4), 132.92 (d, 2ꢅ-C),
Jꢀ12.0Hz, COOCH2Ph), 5.24 (1H, dd, Jꢀ10.0, 1.0Hz, 3ꢅ-cis-H), 5.34 (1H,
136.75 (s, COOCH2Ph), 137.34, 137.83 (s, OCH2Phꢄ3), 156.28 (s, NHCO),
dd, Jꢀ17.0, 1.0Hz, 3ꢅ-trans-H), 5.91 (1H, ddt, Jꢀ17.0, 10.0, 5.5Hz, 2ꢅ-H), 159.83 (s, 2-C), 167.47 (s, COOAllyl). HR-FAB-MS m/z: 671.2754
6.18 (1H, d, Jꢀ8.5Hz, 3-H), 7.16—7.35 (20H, m, OCH2Phꢄ4), 7.54 (1H, [MꢂNa]ꢂ, Calcd for C39H40O7N2Na: 671.2733 [MꢂNa].
brs, NH). 13C-NMR (75.0MHz) d: ꢃ4.97, ꢃ4.65 (q, Si(CH3)2), 18.20 (s,
C(CH3)3)25.78 (q, C(CH3)3), 66.06 (t, 1ꢅ-C), 67.22 (t, COOCH2Ph), 70.49 (t,
Methyl (E,3R,4R,5S)-N-Benzyloxycarbonyl-N-tert-butoxycarbonyl-a-
(3,4-dibenzyloxy-5-benzyloxymethylpyrrolidin-2-ylidene)glycinate (20)
7-C), 71.34 (t, OCH2Ph), 71.91 (d, 6-C), 73.24, 75.04 (each t, OCH2Phꢄ2), To a solution of 5a (37.0mg, 0.06mmol) in CH2Cl2 (0.8ml) were added
75.30 (d, 4-C), 83.88 (d, 5-C), 118.41 (t, 3ꢅ-C), 127—129 (each d, DMAP (3.7mg, 0.03mmol), Et3N (4ml, 0.03mmol), Boc2O (1.4ml, 0.06
OCH2Phꢄ4), 130.41 (d, 3-C), 130.86 (s, 2-C), 131.80 (d, 2ꢅ-C), 135.91 (s,
mmol). After the solution was stirred for 1h at 0°C under argon, further
COOCH2Ph), 137.48, 137.87, 138.38 (each s, OCH2Phꢄ3), 153.73 (s, reagents, DMAP (3.7mg), Et3N (4ml), Boc2O (1.4ml) were added and
NHCO), 163.57 (s, COOallyl). HR-FAB-MS m/z: 788.3602 [MꢂNa]ꢂ, stirred for additional 4h, then the solvent was removed in vacuo. Resulted
Calcd for C45H55O8NSiNa : 788.3595 [MꢂNa].
yellow oil (63.5mg) was purified by preparative TLC (silica gel, n-
Allyl (Z and E,4R,5S,6R)-2-Benzyloxycarbonylamino-6-hydroxy-4,5,7- hexane/AcOEtꢀ1:1) to give 20 (37.6mg, 88%) as a light yellow oil.
tribenzyloxy-2-heptenoate (13a, 13b) To a solution of 12 (636.9mg, 0.83
mmol) in the solvent of THF–pyridine (1:1) (8ml) was added HF–pyridine
(5.6ml) during 30min at 0°C under argon. After the solution was allowed to
stir for 19.8h at 0°C, it was adjusted to pH 8—9 with saturated NaHCO3
Rfꢀ0.32 (n-hexane/AcOEtꢀ2:1). [a]D24 ꢂ5.40° (cꢀ1.00, CHCl3). 1H-NMR
(400MHz) d: 1.38 (9H, s, C(CH3)3), 3.55 (1H, dd, Jꢀ9.6, 7.8Hz, 6-Ha),
3.58 (3H, s, COOCH3), 3.67 (1H, dd, Jꢀ9.6, 5.0Hz, 6-Hb), 4.06 (1H, dd,
Jꢀ5.0, 2.7Hz, 4-H), 4.18 (1H, dt, Jꢀ7.8, 5.0Hz, 5-H), 4.37, 4.47 (each 1H,
dropwise and extracted with CHCl3 (150mlꢄ3). The combined organic d, Jꢀ11.4Hz, OCH2Ph), 4.45, 4.50 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.50,
layer was dried over Na2SO4 and concentrated in vacuo. The resulting yel- 4.56 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.54 (1H, d, Jꢀ2.7Hz, 3-H), 4.72,
low oil (634mg) was purified by flash column chromatography (n- 5.07 (each 1H, d, Jꢀ12.5Hz, COOCH2Ph), 7.12—7.40 (20H, m,
hexane/AcOEtꢀ3:1) to give 13a (Z-form, 422.7mg, 77.9%) and 13b (E- OCH2Phꢄ4), 7.98 (1H, brs, 1-H). 13C-NMR d: 27.89 (q, C(CH3)3), 50.80
form, 74.2mg, 13.7%) as a colorless oil, respectively. 13a Rfꢀ0.27 (n- (q, COOCH3), 60.38 (d, 5-C), 67.57 (t, COOCH2Ph), 69.15 (t, 6-C), 72.24,
hexane/AcOEtꢀ2:1). [a]D24 0.00° (cꢀ0.50, CHCl3). 1H-NMR (300MHz,
CDCl3) d: 2.82 (1H, d, Jꢀ5.5Hz, 6-OH), 3.61 (1H, dd, Jꢀ5.0, 10.0Hz, 7-
CHa), 3.65 (1H, dd, Jꢀ3.5, 10.0Hz, 7-CHb), 3.81 (1H, dd, Jꢀ3.2, 7.0Hz, 5-
OH), 4.00 (1H, m, 6-H), 4.39 (1H, d, Jꢀ10.5Hz, benzyl-CHa), 4.53—4.65
(5H, m, benzyl-CHb), 4.54 (1H, m, 4-H), 4.72 (2H, d, Jꢀ5.3Hz, Allyl-
72.85, 73.53 (each t, OCH2Phꢄ3), 79.89 (d, 4-C), 82.95 (s, C(CH3)3), 83.00
(d, 3-C), 96.20 (s, a-C), 127.62, 127.65, 127.67, 127.70, 127.74, 127.82,
127.91, 127.95, 128.17, 128.01, 128.26, 128.30, 128.33, 128.35, 128.40,
128.46 (each d, OCH2Phꢄ4), 136.00 (s, COOCH2Ph-1ꢅ-C), 137.15, 137.26,
137.81 (each s, OCH2Ph-1ꢅ-Cꢄ3), 152.09 (s, NHCO), 153.82 (s,
OCH2), 5.09, 5.13 (each 1H, d, Jꢀ12.0Hz, benzyl-CH2), 5.29 (1H, dq, COOCH2Ph), 158.40 (s, 2-C), 167.70 (s, COOCH3). HR-FAB-MS m/z:
Jꢀ10.5, 1.0Hz, AllylꢀCH2-cis), 5.38 (1H, dq, Jꢀ16.0, 1.0Hz, AllylꢀCH2- [MꢃH]ꢂ 721.3127, Calcd for C42H45O9N2Na: 721.3125.
trans), 5.95 (1H, m, Allyl-CHꢀ), 6.43 (1H, d, Jꢀ8.0Hz, 3-H), 7.22—7.45
(20H, m, OCH2Ph). HR-FAB-MS m/z: 674.2730 [MꢂNa]ꢂ, Calcd for
Methyl (E,3R,4R,5S)-N-tert-Butoxycarbonyl-a-(3,4-dihydroxy-5-hy-
droxymethyl-pyrrolidine-2-ylidene)glycinate (21) To a solution of 20
C39H41O8NNa: 674.2730. 13b Rfꢀ(hexane:AcOEtꢀ2:1). [a]D24 ꢂ127.99° (472mg, 0.654mmol) in MeOH (20ml) was added Pd(OH)2/C (377.8mg) in
(cꢀ0.50, CHCl3). 1H-NMR (300MHz, CDCl3) d: 3.46 (1H, dd, Jꢀ10.0, 5.5 MeOH (11ml). After the mixture was stirred under hydrogen gas for 2.5h at
Hz, 7-Ha). 3.56 (1H, dd, Jꢀ10.0, 3.0Hz, 7-Hb), 3.59 (1H, ddd, Jꢀ8.5, 5.5, room temperature, the reaction mixture was evaporated in vacuo. Resulting
3.0Hz, 6-H), 3.85 (1H, dd, Jꢀ8.5, 3.0Hz, 5-H), 4.37, 4.66 (each 1H, brd,
yellow oil (222.5mg) was purified by flash column chromatography (silica
Jꢀ12.0Hz, benzyl-CH2), 4.42, 4.48 (each 1H, d, Jꢀ11.5Hz, benzyl-CH2), gel, n-hexane/AcOEtꢀ2:1) to provide 21 (172.3mg, 83%) as a light yellow

536
Vol. 53, No. 5
oil. Rfꢀ0.11 (n-hexane/AcOEtꢀ1:5), IR (KBr) cmꢃ1: 3400 (OH, NH),
(1H, brs, NHCO), 7.83 (1H, brs, 1-H). 13C-NMR d: 28.16 (q, C(CH3)3),
1670 (COO, NHCOO), 1590 (CꢀC), 1480, 1430 (Ph). [a]D24 ꢃ47.8° 50.36 (q, COOCH3), 59.76 (d, 6-C), 63.31 (t, 5-C), 70.74, 71.14 (each t,
1
(cꢀ1.00, CHCl3). H-NMR (400MHz) d: 1.48 (9H, s, C(CH3)3), 3.71 (3H, OCH2Phꢄ2), 77.61 (s, C(CH3)3), 79.15 (d, 4-C), 80.83 (d, 3-C), 92.30 (s, a-
s, COOCH3), 3.97 (1H, dd, Jꢀ12.0, 5.0Hz, 6-Ha), 4.02 (1H, dd, Jꢀ12.0, 4.0 C), 127.52, 127.63, 127.68 127.79 127.97, 128.14 (each d, OCH2Phꢄ2),
Hz, 6-Hb), 4.17 (1H, dt, Jꢀ5.0, 4.0Hz, 5-H), 4.32 (1H, dd, Jꢀ4.0Hz, 4-H),
137.87 (each, s, OCH2Ph-1ꢅ-Cꢄ2), 155.67 (s, NHCO), 159.49 (s, 2-C),
4.66 (1H, br, 3-H), 5.63 (1H, brs, NHCO), 7.69 (1H, brs, 1-H). 13C-NMR d: 168.05 (s, COOCH3). HR-FAB-MS m/z: 498.2367 [M]ꢂ, Calcd for
28.27 (q, C(CH3)3), 51.22 (q, COOCH3), 60.77 (d, 6-C), 62.63 (d, 5-C), C27H34O7N2: 498.2366.
74.87 (d, 4-C), 78.63 (s, 3-C), 91.24 (s, C(CH3)3), 99.23 (s, a-C), 158.73 (s,
2-C), 158.75 (s, COOC(CH3)3), 162.99 (s, NHCO), 168.63 (s, COOCH3). methanesulfonyloxymethyl-pyrrolidine-2-ylidene)glycinate (6b) To
HR-FAB-MS m/z: 318.1431 [M]ꢂ, Calcd for C13H22O7N2: 318.1427.
solution of 24 (94.6mg, 0.19mol) in CH2Cl2 (60ml) were added Et3N (80ml,
Methyl (E,3R,4R,5S)-N-tert-Butoxycarbonyl-a-(3,4-dihydroxy-5- 0.51mmol), MsCl (22ml, 0.28mmol ). After the solution was stirred for 1.2
Methyl (E,3R,4R,5S)-N-tert-Butoxycarbonyl-a-(3,4-dibenzyloxy-
a
methanesulfonyloxymethyl-pyrrolidine-2-ylidene)glycinate (22) To
a
h under argon at ꢃ78°C, the reaction mixture was diluted with CHCl3 (60
ml), washed with saturated NaHCO3 (2ml), saturated NaCl (2ml), dried
over Na2SO4, concentrated in vacuo. Resulting yellow oil (174mg) was puri-
fied by preparative TLC (silica gel, n-hexane/AcOEtꢀ1:2) to provide 6b
solution of 21 (24.5mg, 0.08mmol) in CH2Cl2 (60ml) were added Et3N (44
ml, 0.32mmol), MsCl (9ml, 0.08mmol). After the solution was stirred for 16
h under argon at ꢃ40°C, Et3N (66ml, 0.48mmol), MsCl (9ml, 0.12mmol)
were further additioned and stirred for 4h. The reaction mixture was diluted
with CHCl3 (20ml), washed with saturated NaHCO3 (1mlꢄ2), saturated ꢃ13.60° (cꢀ1.00, CHCl3). H-NMR (300MHz, DMSO-d6) d: 1.34 (9H, s,
NaCl (1ml), dried over Na2SO4, evaporated in vacuo. The residue (51.8mg)
(79.7mg, 73%) as a light yellow oil. Rfꢀ0.35 (n-hexane/AcOEtꢀ1:1). [a]D26
1
C(CH3)), 3.17 (3H, s, SO2Me), 3.56 (3H, s, COOCH3), 4.12 (1H, d, Jꢀ5.0,
was purified by preparative TLC (silica gel, n-hexane/AcOEtꢀ1:10) to af- 1.5Hz, 4-H), 4.20 (1H, td, Jꢀ5.5, 5.0, 5-H), 4.35, 4.38 (each 1H, dd,
ford 22 (17.5mg, 57%) as a light yellow oil. Rfꢀ0.44 (n-hexane/AcOEtꢀ1: Jꢀ12.5, 5.5, 6-H2), 4.45, 5.51 (each 1H, d, Jꢀ11.4Hz, OCH2Ph), 4.53, 4.58
10). [a]D24 ꢃ49.20° (cꢀ1.00, CHCl3). H-NMR (400MHz) d: 1.48 (9H, s, (each 1H, d, Jꢀ11.5Hz, OCH2Ph), 4.66 (1H, d, Jꢀ1.5Hz, 3-H), 7.20—7.42
1
C(CH3)3), 3.09 (3H, s, SO2CH3), 3.72 (3H, s, COOCH3), 4.28 (1H, dd, (10H, m, OCH2Phꢄ2), 7.56 (1H, brs, NHCO), 7.85 (1H, brs, 1-H). HR-
Jꢀ10.5, 7.5Hz, 6-Ha), 4.38 (1H, m, 5-H), 4.49 (1H, dd, Jꢀ10.5, 3.2Hz, 6-
Hb), 4.57 (1H, dd, Jꢀ8.5, 3.0Hz, 4-H), 4.93 (1H, brd, Jꢀ3.0Hz, 3-H), 5.64
(1H, s, NHCO), 7.84 (1H, brs, 1-H). HR-FAB-MS m/z: 419.1119 [MꢂNa]ꢂ,
Calcd for C14H24O9N2SNa: 419.1120.
FAB-MS m/z: 576.2156 [M]ꢂ, Calcd for C28H36O9N2S: 576.2141.
References
1) Nagaoka K., Matsumoto M., Oono, J., Yokoi K., Ishizeki S.,
Nakashima T., J. Antibiot., 39, 1527—1532 (1986).
2) Yokoi K., Nagaoka K., Nakashima T., Chem. Pharm. Bull., 34, 4554—
4561 (1986).
3) Hata T., Koga F., Kanamori K., Matsumae A., Sugawara R., Shima T.,
Ito S., Tomizawa S., J. Antibiot. Ser. A, 7, 107—112 (1954).
4) Moran E. J., Armstrong R. W., Tetrahedron Lett., 32, 3807—3810
(1991).
5) Konda Y., Satou T., Tsushima K., Dodo M., Kusunoki A., Sakayanagi
M., Satou N., Takeda K., Harigaya Y., Tetrahedron, 55, 12723—12740
(1999).
6) Coleman R. S., Li J., Navarro A., Angew. Chem. Int. Ed., 2001,
1736—1739 (2001).
7) Hashimoto M., Sugiura M., Terashima S., Tetrahedron, 59, 3063—
3087 (2003).
8) Hashimoto M., Matsumoto M., Yamada K., Terashima S., Tetrahedron,
59, 3087—3097 (2003).
9) Schmidt U., Lieberknecht A., Synthesis, 1984, 53—60 (1984).
10) Dess D. B., Martin J. C., J. Am. Chem. Soc., 113, 7277—7287 (1991).
11) Natsumori N., Murata M., Tachibana K., Tetrahedron, 51, 12229—
12238 (1995).
Methyl (E,3R,4R,5S)-N-tert-Butoxycarbonyl-a-(3,4-diacetoxy-5-
methanesulfonyloxymethyl-pyrrolidine-2-ylidene)glycinate (6a) To
a
solution of 22 (24.1mg, 0.06mmol) in dry pyridine (0.7mg) were added
dimethylaminopyridine (DMAP) (2.4mg, 0.06mmol), Ac2O (14ml, 0.15
mmol). After the mixture was stirred for 13h at 0°C, EtOH was added to
quench Ac2O and stirred for 5min. The solvent was removed in vacuo to
give a yellow oil (37.2mg), which was purified by preparative TLC (silica
gel, n-hexane/AcOEtꢀ1:3) to give 6a (23.5mg, 80%) as a light yellow oil.
Rfꢀ0.50 (n-hexane/AcOEtꢀ1:3). [a]D24 ꢃ14.60° (cꢀ1.00, CHCl3). 1H-
NMR (400MHz) d: 1.42 (9H, s, C(CH3)3), 2.08, 2.12 (each 3H, s,
OCOCH3ꢄ2), 3.11 (3H, s, OSO2CH3), 3.70 (3H, s, COOCH3), 4.20 (1H, dd,
Jꢀ10.0, 6.0Hz, 6-Ha), 4.37 (1H, dd, Jꢀ10.0, 5.0Hz, 6-Hb), 4.38 (1H, m, 5-
H), 5.30 (1H, s, NHCO), 5.36 (1H, dd, Jꢀ5.0, 3.5Hz, 4-H), 6.03 (1H, d,
Jꢀ3.5Hz, 3-H), 7.98 (1H, brs, 1-H). HR-FAB-MS m/z: 480.1415 [M]ꢂ,
Calcd for C18H28O11N2S: 480.1413.
Methyl (E,3R,4R,5S)-N-tert-Butoxycarbonyl-a-(3,4-dibenzyloxy-5-hy-
doxymethylpyrrolidin-2-ylidene)glycinate (24) To a solution of 20 (93.5
mg, 0.129mol) in MeOH (20ml) was added Pd(OH)2/C (37.4mg) in MeOH
(1ml). The mixture was stirred for 45min under hydrogen gas at room tem-
perature, after that it was filtered off, evaporated in vacuo. Resulted oil (69.9
mg) was purified by preparative TLC (silica gel, n-hexane/AcOEtꢀ1:3) to 12) Nakamura Y., Shin C., Chemistry Lett., 49—52 (1992).
obtain 24 (25.3mg, 39%) as light yellow oil. Rfꢀ0.38 (n- 13) Shimizu T., Hiranuma S., Nakata T., Tetrahedron Lett., 39, 8313—
hexane/AcOEtꢀ1:4). [a]D24 ꢃ47.60° (cꢀ1.00, CHCl3). 1H-NMR (400MHz,
8316 (1998).
a
DMSO-d6) d: 1.34 (9H, s, C(CH3)3), 3.55 (3H, s, COOCH3), 3.54 (1H, td, 14) Kolsaker P., Ellingsen P. O., Woien G., Acta Chem. Scand., B32, 683—
Jꢀ11.0, 6.5Hz, 6-Ha), 3.63 (1H, td, Jꢀ11.0, 5.0Hz, 6-Hb), 3.99 (1H, m, 5-
H), 3.99 (1H, dd, Jꢀ4.5, 1.0Hz, 4-H), 4.36, 4.46 (each 1H, d, Jꢀ11.5Hz,
OCH2Ph), 4.52, 4.58 (each 1H, d, Jꢀ12.0Hz, OCH2Ph), 4.61 (1H, brd,
Jꢀ1.0Hz, 3-H), 4.91 (1H, dd, 6-OH), 7.23—7.37 (10H, m, OCH2Ph), 7.52
686 (1978).
15) Wade P. A., “Conprehensive Organic Synthesis,” Vol. 4, Chap. 4, ed.
by Semmelhack M. F., Pergamon Press, Oxford, 1991, pp. 1157—
1158.