Total synthesis of (-)-ephedradine A: An efficient construction of optically active dihydrobenzofuran-ring via C-H insertion reaction

Article abstract of DOI:10.1016/j.tet.2004.06.144

The stereocontrolled total synthesis of (-)-ephedradine A (1) has been accomplished. Construction of optically active dihydrobenzofuran-ring was performed by a novel asymmetric C-H insertion reaction. After an intramolecular ester-amide exchange reaction and a Sharpless asymmetric aminohydroxylation reaction, construction of the complex macrocyclic ring was performed by Ns-strategy and an intramolecular aza-Wittig reaction. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.06.144

Tetrahedron 60 (2004) 9615–9628
Total synthesis of (K)-ephedradine A: an efficient construction
of optically active dihydrobenzofuran-ring
via C–H insertion reaction
*
Wataru Kurosawa, Hideki Kobayashi, Toshiyuki Kan and Tohru Fukuyama
Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan Science and Technology Corporation, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received 7 May 2004; revised 4 June 2004; accepted 5 June 2004
Available online 24 August 2004
Abstract—The stereocontrolled total synthesis of (K)-ephedradine A (1) has been accomplished. Construction of optically active
dihydrobenzofuran-ring was performed by a novel asymmetric C–H insertion reaction. After an intramolecular ester–amide exchange
reaction and a Sharpless asymmetric aminohydroxylation reaction, construction of the complex macrocyclic ring was performed by
Ns-strategy and an intramolecular aza-Wittig reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
platform for the preparation of 1. Introduction of b-amino
ester moiety of 4 would be achieved by Heck reaction and
Sharpless aminohydroxylation reaction of 5, therefore, the
construction of optically active dihydrobenzofuran 5 would
be important task for the total synthesis. Since the
(K)-Ephedradine A (orantine, 1) is a complex macrocyclic
spermine alkaloid isolated by Hikino and co-workers in
1979 as one of the hypotensive components of the Chinese
traditional drug ‘mao-kon’.1,2 While synthesis of racemic
O-methylated orantine (2) was achieved by Wasserman and
co-workers in 1985,3 total synthesis of 1 has not been
reported to date. Clearly, construction of the two macro-
cyclic rings in the presence of a labile dihydrobenzofuran
moiety constitutes the major challenge in the total synthesis
of 1. Recently we have developed a highly efficient method-
ology for the construction of medium- and large-sized cyclic
amines via 2-nitrobenzenesulfonamides (Ns-strategy).4,5
We envisioned this strategy being applied to the construc-
tion of the macrocyclic ring of 1. Herein we report an
efficient total synthesis of (K)-ephedradine A (1) by the
stereocontrolled synthesis of optically active intermediate 4
and the subsequent construction of the macrocyclic poly-
amine ring by the Ns-strategy.6
The heart of our synthetic plan is illustrated in Scheme 1.
Construction of the macrocyclic lactam and the secondary
amine of 1 would be performed in the precursor 3. Since 3
would be derived from 4 by stepwise incorporation of
the polyamine chains, the dihydrobenzofuran containing the
b-amino ester moiety 4 was envisaged as an appropriate
Keywords: Dihydrobenzofuran-ring; Asymmetric C–H insertion reaction;
Ns-strategy; Macrocyclization; Aza-Wittig reaction.
* Corresponding author. Tel.: C81-3-5802-4777; fax: C81-3-5802-8694;
e-mail: fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1. Retrosynthetic analysis of ephedradine A (1).
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.144

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W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
dihydrobenzofuran derivatives are often found in bioactive
compounds and pharmaceuticals, an efficient synthesis has
attracted much interest. Although many synthetic efforts
have been reported to date, including a biomimetic
oxidative dimerization of cinnamic acid derivatives,7 there
are still only a few examples of enantioselective synthesis.8
Recently, asymmetric C–H insertion reactions of metal-
carbenoids have been the subject of intensive investigation.9
Furthermore, Davies has recently reported that a chiral
rhodium-carbenoid, derived from an aryl diazoester, under-
went inter- or intramolecular asymmetric C–H insertion
reaction.10,11 We envisioned that intramolecular C–H
insertion of the carbenoid generated from 6 would provide
the optically active 5.12
Scheme 3. Transformation of cis-dihydrobenzofuran 13 to trans-isomer 14.
the predominant formation of the trans-isomer 14. During
the transformation, the a-position of the ester 14 was
unaffected based on the fact that no deuterium incorporation
was observed in 14 when 13 was treated with CF3CO2D in
CD2Cl2. However, the enantiomeric excess of the trans-
isomer was 32%. In order to improve the enantioselectivity,
the incorporation of the chiral auxiliary to the ester moiety
of 10a was investigated (Scheme 4).
2. Results and discussion
As shown in Scheme 2, the C–H insertion precursor 10a was
Scheme 4. Incorporation of chiral auxiliary 15b and c into the carboxylic
acid 9. Reagents and conditions: (a) ROH (15b, c), WSCD$HCl, DMAP,
CH2Cl2; (b) p-AcNHC6H4SO2N3, DBU, CH3CN (75% for 10b and 73% for
10c in 2 steps).
Davies reported earlier that high diastereoselectivity of
intermolecular Rh-carbenoid-mediated cyclopropanation
was achieved by using a-hydroxy ester derivatives as the
chiral auxiliaries.14 Similarly, we have observed high
diastereoselectivity in the C–H insertion reaction when
10b and 10c were employed. Thus, carboxylic acid 9 was
coupled with methyl (S)-lactate (15b) and pyrrolidinyl (S)-
lactamide15 (15c) followed by the diazo transfer reaction to
give the cyclization precursors 10b and 10c, respectively
(Scheme 3).
Scheme 2. Preparation of diazoester 10a and the C–H insertion reaction.
Reagents and conditions: (a) allyl bromide, K2CO3, DMF, 60 8C (99%); (b)
diethylaniline, 210 8C (88%); (c) K2CO3, 4-(benzyloxy)benzyl chloride,13
DMF, 60 8C (95%); (d) O3, CH2Cl2/MeOH, K78 8C; Me2S, K78 8C to rt;
(e) NaClO2, 2-methyl-2-butene, NaH2PO4$2H2O, t-BuOH/H2O (77% in 2
steps); (f) CH2N2, Et2O (81%); (g) p-AcNHC6H4SO2N3, DBU, CH3CN
(71%); (h) Rh2(S-DOSP)4 (5 mol%), CH2Cl2 (72%, 11a:12aZ5:1).
readily prepared in a seven-step sequence from 4-bromo-
phenol (7). Thus, allylation of phenol 7, Claisen rearrange-
ment, and subsequent introduction of a 4-(benzyloxy)benzyl
group13 to the resultant phenol provided 8. Ozonolysis of the
double bond in 8 followed by treatment with NaClO2
furnished the carboxylic acid 9. After esterification of 9,
diazotransfer reaction was carried out by treatment with
p-acetamidobenzenesulfonyl azide and DBU. With the
requisite diazoester 10a in hand, the C–H insertion reaction
by chiral rhodium catalyst was next investigated. Upon
treatment of 10a with 5 mol% of Davies’ catalyst, Rh2(S-
DOSP)4, the reaction proceeded smoothly to afford the
dihydrobenzofuran in 72% yield as a 5:1 mixture of 11a and
12a. Fortunately, the undesired 2,3-cis-benzofuran was
readily converted to the thermodynamically more stable
trans-isomer as shown in Scheme 3. After the removal of
the benzyl group, the treatment of 13 with TFA resulted in
Upon treatment with rhodium catalyst (5 mol%), the C–H
insertion reactions of 10b and 10c proceeded smoothly to
afford exclusively the trans-dihydrobenzofurans 12b and
12c (Table 1). Presumably, the increased bulk of the ester
moiety is responsible for the high trans-selectivity.
Table 1. Diastereoselectivity of the Rh-carbenoid-mediated intramolecular
C–H insertion reaction of 10b and 10c
Run
Cat. Rha
12bb
12cb
1
2
3
Rh2(Oac)4
Rh2(S-DOSP)4
Rh2(R-DOSP)4
7:2
5:2
7:1
3:1
8:1
13:1
a
All reactions were carried out in CH2Cl2 using 5 mol% of Rh catalyst.
Diastereoselectivity was determined by 1H NMR.
b

W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
9617
Furthermore, it is interesting to note that the C–H insertion
products 12b and c possessed the same configuration
(2S,3S) regardless of the chirality of the catalyst (run 2
and 3). Thus, the asymmetric induction was strongly
dependent on the chiral auxiliaries and not on the catalyst.16
The high diastereoselectivities of 12b and c indicate that the
carbenoid intermediate might have strong interaction with
the carbonyl group of the chiral auxiliary as illustrated in
Figure 1. The highest diastereoselectivity was attained by
combination of the diazoester 10c and Rh2(R-DOSP)4 to
afford 12c in 84% yield and 86% de. However, the
treatment of the diazoester 10c containing the pyrrolidinyl
(S)-lactamide chiral auxiliary with Rh2(R-DOSP)4 gave the
(2S,3S)-dihydrobenzofuran 12c, the stereochemistry of
which was opposite to (K)-ephedradine A. In order to
obtain the (2R,3R)-dihydrobenzofuran 12c, the combination
of the inversion of the chiral auxiliary and the use of Rh2(S-
DOSP)4 were necessary.
dihydrobenzofuran ring brought about by activation of the
carboxylic acid 18. After numerous efforts to construct the
amide bond, an intramolecular ester–amide exchange
reaction of 21 was found to be suitable for the synthesis
of 23. Upon treatment of 18 and the alcohol 195 with DEAD
and PPh3, the condensation reaction proceeded smoothly to
give 20 (Scheme 6). Removal of the Ns group of 20 and
subsequent treatment of the secondary amine 21 with
dimethylaluminum chloride18,19 in refluxing CH2Cl2 gave
the amide 23 in 67% yield. The amide formation would be
promoted by the dual activation of the aluminum which
coordinate both of the ester-group and the secondary amine
in 22.
Figure 1.
As shown in Scheme 5, the cyclization precursor 16 was
prepared by condensation of carboxylic acid 9 with the
lactamide-type chiral auxiliary 15c under Mitsunobu
conditions17 and subsequent diazo transfer reaction. Upon
treatment of 16 with 0.3 mol% of the Davies catalyst,10 the
C–H insertion reaction proceeded smoothly to afford
exclusively the trans-dihydrobenzofuran 17 in 63% yield
(2 steps) and high diastereoselective manner (13:1).
Removal of the chiral auxiliary by hydrolysis and subse-
quent recrystallization gave the optically pure carboxylic
acid 18.
Scheme 6. Synthesis of key intermediate 23. Reagents and conditions: (a)
19, PPh3, DEAD, toluene (96%); (b) PhSH, K2CO3, DMF/CH3CN, 50 8C
(88%); (c) Me2AlCl, CH2Cl2, reflux, (67%).
Next we turned our attention to the construction of the
b-amino ester moiety. Acetylation of the alcohol 23
followed by a conventional Heck reaction20 of 24 with
methyl acrylate furnished the cinnamate derivative 25.
Facile and diastereoselective incorporation of the nitrogen
atom in 25 was achieved by the Sharpless asymmetric
aminohydroxylation reaction21 to afford 26 as the predomin-
ant product (12:1). After conversion of the hydroxyl group
of 26 to the corresponding chloride by treatment with PPh3
and CCl4, removal of the chlorine of 27 under transfer
hydrogenation conditions provided the b-amino ester with
concomitant cleavage of the Cbz group and benzyl ether.
Selective protection of the resultant phenol with the benzyl
group under Mitsunobu conditions and subsequent intro-
duction of the Ns group on the primary amine 28 furnished
the sulfonamide 29 Scheme 7.
Direct condensation of 18 with secondary amine derivatives
of 19 was unsuccessful due to the decomposition of the
The next challenge in the synthesis was the crucial
construction of the 16-membered polyamine ring
(Scheme 8). Coupling between the sulfonamide 29 and the
alcohol 3022 under Mitsunobu conditions to afforded 31.
Since the undesired b-elimination of the alkylsulfonamide
31 occurred readily, the protecting group was switched from
the Ns to the corresponding N-Cbz derivative yielded 32.
Acid-catalyzed selective deprotection of the TBS group of
32, coupling with NsNH2 under Mitsunobu conditions and
subsequent cleavage of the TBDPS ether furnished the
Scheme 5. Construction of dihydrobenzofuran ring 18. Reagents and
conditions: (a) 15c, PPh3, DEAD, toluene (80%); (b) AcNHC6H4SO2N3,
DBU, CH3CN; (c) Rh2(S-DOSP)4 (0.3 mol%), CH2Cl2 (63% in 2 steps); (d)
Ba(OH)2$8H2O, THF/MeOH/H2O (90%).

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W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
macrolactam ring. The cyclization precursor 38 bearing an
activated ester was prepared from 35 in a five-step sequence
involving deprotection of the acetyl group, mesylation of
the alcohol, displacement of the mesylate with NaN3, basic
hydrolysis of the methyl ester and condensation of the
resultant carboxylic acid with pentafluorophenol. While
generation of the amine moiety from the azide 38 under
hydrogenation conditions resulted in exclusive dimeriza-
tion, treatment with PPh3 in refluxing toluene under high-
dilution conditions (7.0 mM) successfully afforded the
13-membered iminoether 40 via the Staudinger23 and the
intramolecular aza-Wittig reactions.24,25 Subsequent
hydrolysis of 40 by refluxing in CH3CN–H2O afforded the
desired 13-membered macrolactam 41 in 73% yield (2
steps).26 Removal of the Ns group and simultaneous
cleavage of the Cbz group and benzyl ether with BCl3
yielded (K)-ephedradine A (1), the spectral data of which
(1H NMR, 13C NMR, IR, and HRMS) were in full
agreement with those of the natural product Scheme 9.1
Scheme 7. Synthesis of b-amino ester 29. Reagents and conditions: (a)
Ac2O, pyr (88%); (b) methyl acrylate, Pd(OAc)2 (6 mol%), P(o-tol)3
(18 mol%), Et3N, DMF, 100 8C (84%); (c) CbzNClNa, K2OsO2(OH)4
(6 mol%), (DHQD)2PHAL (8 mol%), n-PrOH/H2O (66%); (d) PPh3, CCl4,
toluene, 100 8C (87%); (e) Pd/C (20 mol%), HCO2NH4, MeOH, 60 8C; (f)
BnOH, PPh3, DEAD, toluene, 60 8C (61% in 2 steps); (g) NsCl, Na2CO3,
CH2Cl2/H2O (72%).
3. Conclusion
In conclusion, we have developed an efficient synthetic
method for the optically active transK2,3-dihydrobenzo-
furan derivatives by combination of Davies’ Rh catalyst and
pyrrolidinyl lactamide chiral auxiliary. This protocol would
be amenable to large-scale preparations of the dihydro-
benzofuran derivative. Additionally, Sharpless’ asymmetric
aminohydroxylation reaction was suitable for the prepar-
ation of the desired b-amino ester 29. Furthermore, our
synthesis features the construction of all the secondary
amines using Ns-strategy including macrocyclization and
formation of the two amide bonds by the intramolecular
ester–amide exchange reaction and the aza-Wittig reaction.
cyclization precursor 34. Upon treatment of 34 with DEAD
and PPh3 in 0.05 M solution of toluene at room temperature,
the desired cyclization reaction proceeded smoothly to
afford 35 in 77% yield.
With the desired macrocyclic polyamine in hand, we next
focused on the construction of the 13-membered
Scheme 8. Construction of 16-membered polyamine ring. Reagents and conditions: (a) 30, PPh3, DEAD, toluene, 60 8C (95%); (b) PhSH, KOH, CH3CN, 60 8C
(93%); (c) CbzCl, NaHCO3, CH2Cl2/H2O (91%); (d) CSA, MeOH (94%); (e) NsNH2, DEAD, PPh3, toluene/THF (quant.); (f) aq. HF, CH3CN (84%); (g) PPh3,
DEAD, toluene (77%).

W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
9619
heated at 60 8C for 50 min. After cooling, the reaction
mixture was poured into water, and extracted with Et2O.
The organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (10% AcOEt in n-hexane) to afford the
above allyl ether (244 g, 1.15 mol, 99%). IR (film, cmK1
)
3083, 2910, 2868, 1648, 1590, 1578, 1489, 1285, 1242,
1
1072, 821. H NMR (CDCl3, 400 MHz) d 7.37 (d, JZ
9.1 Hz, 2H), 6.80 (d, JZ9.1 Hz, 2H), 5.98–6.08 (m, 1H),
5.40 (dq, JZ17.2, 1.6 Hz, 1H), 5.29 (dq, JZ10.6, 1.4 Hz,
1H), 4.51 (dt, JZ5.1, 1.6 Hz, 2H); 13C NMR (CDCl3,
100 MHz) d 157.5, 132.7, 132.0, 117.6, 116.3, 112.7, 68.7;
HRMS (FAB) Calcd for C9H9BrO (MC) 211.9837, found
211.9830.
4.1.2. 2-Allyl-4-bromo-phenol. The allyl ether (244 g,
1.15 mol) was dissolved in 600 ml of N,N-diethylaniline,
and the mixture was heated at 210 8C for 9 h. After cooling,
the reaction mixture was poured into 3 N aqueous HCl, and
extracted with AcOEt. The extracts were washed with
water, followed by saturated aqueous NaCl, dried over
anhydrous MgSO4, and concentrated under reduced press-
ure. The residue was purified by flash chromatography (20%
AcOEt in n-hexane) to afford 25 (216 g, 1.01 mol, 88%). as
an oil. IR (film, cmK1) 3465, 3079, 2978, 2911, 1637, 1584,
1492, 1413, 1319, 1264, 809; 1H NMR (CDCl3, 400 MHz) d
7.20–7.27 (m, 2H), 6.70 (d, JZ6.8 Hz, 1H), 5.92–6.03 (m,
1H), 5.14–5.21 (m, 2H), 5.00 (s, 1H), 3.37 (d, JZ6.3 Hz,
2H); 13C NMR (CDCl3, 100 MHz) d 153.1, 135.4, 132.9,
130.5, 127.7, 117.5, 117.1, 112.8, 34.7; HRMS (FAB) Calcd
for C9H9BrO (MC) 211.9837, found 211.9837.
Scheme 9. Total synthesis of (K)-ephedradine A (1). Reagents and
conditions: (a) K2CO3, MeOH/THF (96%); (b) MsCl, Et3N, CH2Cl2, 0 8C;
(c) NaN3, DMF, 60 8C (82% in 2 steps); (d) LiOH, MeOH/THF/H2O
(97%); (e) pentafluorophenol, WSCD$HCl, CH2Cl2 (93%); (f) PPh3,
toluene, reflux; (g) CH3CN/H2O, reflux (73% in 2 steps); (h) PhSH, KOH,
CH3CN, 50 8C (75%); (i) BCl3, CH2Cl2, K78 to 0 8C (73%).
4.1.3. 1-(4-Benzyloxy-benzyloxy)-2-allyl-4-bromo-benzene
(8). To a mixture of the above phenol (216 g, 1.01 mol) and
K2CO3 (206 g, 1.49 mol, 1.5 equiv.) in DMF (600 ml) was
added 4-benzyloxy-benzyl chloride (252 g, 1.08 mol,
1.1 equiv.), and the mixture was heated at 60 8C. After
3 h, 4-benzyloxy-benzyl chloride (11.7 g, 0.0504 mol,
0.050 equiv.) and K2CO3 (14.0 g, 0.101 mol, 0.10 equiv.)
were added, and the mixture was stirred at 60 8C for 2hr. After
cooling, the reaction mixture was poured into water, and
extracted with Et2O. The organic layer was washed with
saturated aqueous NaCl, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was purified
by flash chromatography (10% AcOEt in n-hexane) to afford 8
(394 g, 0.966 mol, 95%) as an oil. IR (film, cmK1): 3343,
2933, 2859, 1543, 1413, 1364, 1339, 1165, 1126, 1059, 853,
783, 741. 1H NMR (400 MHz, CDCl3) d: 1.30 (4H, m), 1.50
(2H, m), 1.53(4H, m), 3.09(2H), 3.63(2H), 5.25(1H, m), 7.75
(2H, m), 7.87 (1H, m), 8.14 (1H, m). 13C NMR (100 MHz,
CDCl3) d: 25.5, 26.4, 28.8, 29.5, 32.5, 43.8, 62.9, 125.4, 131.1,
132.8, 133.5, 133.8, 149.8. FAB-MS: 317 (MHC); HRMS
(FAB): 317.1180 (C13H21O2N5S, MHC). Exact mass
317.1177 (MHC).
4. Experimental
4.1. General methods
Unless otherwise noted, solvents and reagents were reagent
grade and used without purification. Dichloromethane
(CH2Cl2) and toluene were distilled from calcium hydride.
IR spectra were recorded on a JASCO FT/IR-410
1
spectrophotometer. H NMR and 13C NMR spectra were
obtained as solutions in CDCl3 unless otherwise indicated,
and chemical shifts are reported in parts per million (ppm, d)
downfield from internal standard tetramethylsilane (TMS),
which were taken on a JEOL JNM-LA400. Coupling
constants are reported in hertz (Hz). Spectra splitting
patterns are designated as s, singlet; br, broad; d, doublet;
t, triplet; m; multiplet. Mass spectra (MS) and high-
resolution mass spectra (HRMS) were measured with a
JEOL JMS-GCmate instrument.
4.1.4. [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-
acetic acid (9). To a solution of 8 (170 g, 0.416 mol) in
CH2Cl2 (1500 ml) and MeOH (500 ml) was bubbled ozone
at K78 8C for 7.5 h. To the mixture was bubbled Ar gas,
then added dimethyl sulfide (190 ml, 2.59 mol, 6.2 equiv.)
at the same temperature. The mixture was allowed to reach
ambient temperature, and stirred for 1 h. The reaction
4.1.1. 1-Allyloxy-4-bromo-benzene. To a mixture of 4-
bromophenol (7) (200 g, 1.16 mol) and K2CO3 (207 g,
1.50 mol, 1.3 equiv.) in DMF (600 ml) was added allyl
bromide (110 ml, 1.27 mol, 1.1 equiv.), and the mixture was

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W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
mixture was concentrated under reduced pressure to give
the crude aldehyde, which was used in the next reaction
without further purification. To a mixture of the crude
aldehyde, 2-methyl-2-butene (200 ml, 1.89 mol, 4.5 equiv.)
and NaH2PO4$2H2O (64.8 g, 0.415 mol, 1.0 equiv.) in
t-butanol (1000 ml) and water (200 ml) was slowly added
sodium chlorite (79%, 166 g, 1.45 mol, 3.5 equiv.) at 0 8C.
The mixture was allowed to room temperature, and stirred
for 72 h. To the mixture were added NaH2PO4$2H2O
(64.8 g, 0.415 mol, 1.0 equiv.) and sodium chlorite (79%,
47.4 g, 0.414 mol, 1.0 equiv.), then the mixture was stirred
for further 12 h. The reaction mixture was quenched with
NaHSO3 (303 g, 7.0 equiv.) at 0 8C, poured into 10% citric
acid, and extracted with AcOEt. The organic layer was
washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The
residue was purified by flash chromatography (40% AcOEt
in n-hexane), then crystallized with AcOEt/n-hexane to
afford 9 (137 g, 0.321 mol, 77% in 2 steps) as a white
powder; IR (film, cmK1) 3033, 2924, 2869, 1710, 1612,
CDCl3) d: 166.1, 159.1, 153.4, 138.7, 132.2, 130.8, 130.3,
129.3, 129.0, 128.6, 128.1, 128.0, 127.5, 115.1, 115.0,
114.2, 70.4, 70.0, 52.1; HRMS (FAB): 439.0547
(C23H20O4Br, MHCKN2). Exact mass 439.0544 (MHCK
N2).
4.1.7. 2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-
benzofuran-3-carboxylic acid methyl ester (11a, 12a).
To a stirred solution of 10a (42 mg, 0.090 mmol) in CH2Cl2
(0.90 ml) was added Rh2(S-DOSP)4 (10 mg, 0.0053 mmol,
0.058 equiv.). The mixture was stirred for 10 min, and the
residue was evaporated under reduced pressure. The ratio of
cis:trans was determined by 1H NMR.
4.1.8. 2-{[2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-
acetoxy}-propionic acid methyl ester. To a stirred solution
of 9 (260 mg, 0.63 mmol) in CH2Cl2 (2.5 ml) was added
WSCD$HCl (250 mg, 1.30 mmol, 2.07 equiv.) and (S)-
methyl lactate (0.085 ml, 0.90 mmol, 1.43 equiv.) and
DMAP (5 mg, 0.041 mmol, 0.07 equiv.) at 0 8C. The
mixture was allowed to room temperature, and stirred for
1.5 h. The reaction mixture was partitioned between CH2Cl2
and H2O, washed with brine, dried over MgSO4, filtered,
and evaporated under reduced pressure. The residue was
purified by flash chromatography as a yellow oil (290 mg,
0.565 mmol, 90%). IR (film, cmK1) 2951, 1745, 1612,
1514, 1491, 1242, 1174, 1012, 810, 742. 1H NMR
(400 MHz, CDCl3) d: 7.24–7.44 (m, 9H), 6.97 (d, JZ
8.0 Hz, 2H), 6.78 (d, JZ8.4 Hz, 1H), 5.08 (s, 2H), 4.97 (s,
2H), 4.29 (q, JZ7.2 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 2H), 1.42
(d, JZ7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) d 176.0,
171.1, 158.5, 155.7, 136.8, 133.5, 131.1, 128.7, 128.5,
127.9, 127.3, 125.1, 114.8, 113.4, 112.6, 70.0, 68.8, 66.6,
52.2, 35.2, 16.7; HRMS (FAB) Calcd for C26H26BrO6 (MC
HC) 513.0912, found 513.0929.
1
1585, 1512, 1489, 1382, 1241, 1128, 808, 738; H NMR
(CDCl3, 400 MHz) d 7.50–8.09 (br, 1H), 7.19–7.44 (m, 9H),
6.91 (d, JZ8.3 Hz, 2H), 6.74 (d, JZ8.5 Hz, 1H), 4.99 (s,
2H), 4.91 (s, 2H), 3.59 (s, 2H); 13C NMR (CDCl3,
100 MHz) d 177.1, 158.6, 155.7, 136.9, 133.7, 131.3,
128.8, 128.7, 128.6, 128.0, 127.5, 125.2, 114.9, 113.6,
112.8, 70.1, 70.0, 35.8; HRMS (FAB) Calcd for
C22H20BrO4 (MCH)C 427.0544, found 427.0531.
4.1.5. [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-
acetic acid methyl ester. To a stirred solution of the
carboxylic acid 9 (250 mg, 0.60 mmol) in Et2O added
diazomethane which was generated from N-methyl-N-
nitrosourea in KOH/Et2O dropwise at 0 8C. The reaction
mixture was allowed to room temperature, and stirred for
2 h. When the reaction was completed, AcOH was added
into the mixture. Then the mixture was evaporated with
toluene as a white solid (214 mg, 0.486 mmol, 81%). IR
(film, cmK1) 3059, 2949, 1739, 1612, 1587, 1514, 1490,
1437, 1242, 1174, 1119, 1011, 808, 745, 721, 696. 1H NMR
(400 MHz, CDCl3) d: 7.67–7.65 (3H, m), 7.57–7.28 (6H,
m), 7.00 (2H, JZ8.4 Hz), 6.79 (1H, JZ8.4 Hz), 5.07 (2H,
s), 4.97 (2H, s), 3.63 (3H, s), 3.58 (2H, s) 13C NMR
(100 MHz, CDCl3) d: 171.8, 156.0, 137.0, 133.8, 132.3,
132.2, 132.1, 129.0, 128.8, 128.6, 128.2, 127.6, 125.8,
115.1, 113.7, 70.3, 70.2, 52.1, 35.9; HRMS (FAB) Calcd for
C23H22BrO4 (MHC) 441.0701, found 441.0693.
4.1.9. 2-{[2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-
diazo-acetoxy}-propionic acid methyl ester (10b). To
a stirred solution of the above ester (280 mg, 0.545 mmol),
and p-acetoamidobenzenesulfonylazide (170 mg, 0.708 mmol,
1.30 equiv.) in MeCN (5.0 ml) were added DBU (0.20 ml,
1.34 mmol, 2.45 equiv.). The mixture was stirred for 1 h.
Then the mixture was quenched with NH4Cl aq, partitioned
between Et2O and NH4Cl aq. Organic layers were washed
with brine, dried over Na2SO4, filtered, and evaporated
under reduced pressure. The residue was purified by flash
chromatography as a yellow solid (235 mg, 0.436 mmol,
80%). IR (film, cmK1): 2955, 2106, 1755, 1703, 1612, 1514,
1
1491, 1246, 1155, 1097, 1007, 823, 741, 696. H NMR
4.1.6. [2-(4-Benzyloxy-benzyloxy)-5-bromo-phenyl]-
diazo-acetic acid methyl ester (10a). To a stirred solution
of the above methyl ester (151 mg, 0.343 mol), and p-aceto-
amidobenzenesulfonylazide (111 mg, 0.463 mol, 1.35 equiv.)
in MeCN (3.4 ml) were added DBU (0.15 ml, 1.01 mmol,
2.94 equiv.). The mixture was stirred for 4 h. Then the
mixture was quenched with NH4Cl aq, partitioned between
Et2O and NH4Cl aq. Organic layers were washed with brine,
dried over Na2SO4, filtered, and evaporated under reduced
pressure. The residue was purified by flash chromatography
as a yellow solid (114 mg, 0.243 mmol, 71%). IR (film,
cmK1): 2104, 1741, 1703, 1612, 1514, 1487, 1381, 1244,
(400 MHz, CDCl3) d: 1.51 (3H, d, JZ7.6 Hz), 3.76 (3H, s),
4.99 (2H, s), 5.07 (2H, s), 5.22 (1H, q, JZ7.2 Hz), 6.82 (1H,
d, JZ8.4 Hz), 6.98 (2H, d, JZ8.4 Hz), 7.27–7.44 (8H, m),
7.77 (1H, d, JZ2.8 Hz); 13C NMR (CDCl3, 100 MHz) d
171.2, 158.9, 153.3, 136.8, 132.0, 129.4, 129.3, 128.6,
128.0, 127.9, 127.4, 115.8, 114.9, 113.7, 70.8, 70.0, 69.0,
52.4; HRMS (FAB) Calcd for C26H24BrO6N2 (MCH)C
539.0817, found 539.0840.
4.1.10. 2-(4-Benzyloxy-phenyl)-5-bromo-2,3-dihydro-
benzofuran-3-carboxylic acid 1-methoxycarbonyl-ethyl
ester (12b). To a stirred solution of 10b (11.5 mg,
0.021 mmol) in CH2Cl2 (0.40 ml) was added Rh2(S-
DOSP)4 (1.9 mg, 0.001 mmol, 0.048 equiv.). The mixture
1
1174, 1018, 812, 742, 696. H NMR (400 MHz, CDCl3) d:
7.73 (s, 1H), 7.25–7.44 (m, 8H), 6.83 (d, JZ9.2 Hz, 1H),
5.07 (s, 2H), 4.99 (s, 2H), 3.82 (s, 3H), 13C NMR (100 MHz,

W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
9621
was stirred for 10 min, and the residue was evaporated under
reduced pressure. The ratio of cis:trans was determined by
1H NMR.
54.9, 46.1, 46.1, 26.2, 23.9, 16.5; HRMS (FAB) Calcd for
C29H28BrNO5 (MC) 549.1151, found 549.1140.
4.1.13. (2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-
dihydro-benzofuran-3-carboxylic acid (18). To a solution
of 17 (5.10 g, 9.27 mmol) in THF (40 ml) and MeOH
(40 ml) was added Ba(OH)2$8H2O (3.21 g, 10.2 mmol,
1.1 equiv.) at 0 8C. The mixture was allowed to room
temperature, and stirred for 3 h. The reaction mixture was
poured into 10% citric acid, and extracted with AcOEt. The
organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (4% MeOH in CH2Cl2) to afford 18
(3.55 g, 8.35 mmol, 90%). [a]2D6K758 (cZ1.1, CHCl3); IR
(film, cmK1) 2910, 1715, 1613, 1587, 1514, 1472, 1417,
1381, 1237, 1175, 827, 737; 1H NMR (CDCl3, 400 MHz) d
9.46–10.67 (br, 1H), 7.51 (s, 1H), 7.26–7.42 (m, 8H), 6.95
(d, JZ8.8 Hz, 2H), 6.75 (d, JZ8.8 Hz, 2H), 6.01 (d, JZ
7.6 Hz, 1H), 5.04 (s, 2H), 4.28 (d, JZ7.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 176.2, 159.0, 158.3, 136.6, 132.7,
131.9, 128.6, 128.3, 128.0, 127.4, 127.2, 125.4, 115.2,
112.7, 111.5, 85.7, 70.0, 55.1; HRMS (FAB) Calcd for
C22H17BrO4 (MC) 424.0310, found 424.0324.
4.1.11. (10R)-[2-(4-Benzyloxy-benzyloxy)-5-bromo-phe-
nyl]-acetic acid 10-methyl-20-oxo-20-pyrrolidin-10-yl-
ethyl ester. To a mixture of 9 (180 g, 0.422 mol), 15c
(72.3 g, 0.506 mol, 1.2 equiv.) and triphenylphosphine
(132 g, 0.504 mol, 1.2 equiv.) in toluene (500 ml) was
added DEAD (40% in toluene, 210 ml, 0.463 mol,
1.1 equiv.) for 2 h at 0 8C. The mixture was allowed to
room temperature, and stirred for further 2 h. The reaction
mixture was filtered through a pad of Celite, and
concentrated under reduced pressure. The residue was
purified by flash chromatography (60% AcOEt in n-hexane)
to afford the above ester (186 g, 0.337 mol, 80%) as a
colorless oil; [a]D27C198 (cZ0.75, CHCl3); IR (film, cmK1
)
3064, 3033, 2976, 2875, 1739, 1654, 1513, 1490, 1457,
1434, 1242, 1174, 1033, 810, 742; 1H NMR (CDCl3,
400 MHz) d 7.24–7.45 (m, 9H), 6.97 (d, JZ8.6 Hz, 2H),
6.76 (d, JZ8.8 Hz, 1H), 5.14 (q, JZ6.7 Hz, 1H), 5.05 (s,
2H), 4.96 (s, 2H), 3.74 (d, JZ16.5 Hz, 1H), 3.63 (d, JZ
16.5 Hz, 1H), 3.54 (dt, JZ9.8, 6.7 Hz, 1H), 3.48 (dt, JZ
12.2, 6.8 Hz, 1H), 3.39 (dt, JZ12.2, 6.8 Hz, 1H), 3.27 (dt,
JZ9.8, 6.7 Hz, 1H), 1.89 (ddt, JZ6.7, 6.7, 6.6 Hz, 2H),
1.78 (ddt, JZ6.8, 6.8, 6.6 Hz, 2H), 1.35 (d, JZ6.7 Hz, 3H);
13C NMR (CDCl3, 100 MHz) d 170.8, 168.5, 158.4, 155.6,
136.7, 133.6, 131.1, 128.8, 128.6, 128.5, 127.9, 127.3,
125.2, 114.7, 113.4, 112.7, 69.9, 69.9, 68.7, 45.9, 45.9, 35.2,
26.0, 23.8, 16.3; HRMS (FAB) Calcd for C29H30BrNO5
(MC) 551.1307, found 551.1326.
4.1.14. (2R,3R)-2-(40-Benzyloxy-phenyl)-5-bromo-2,3-
dihydro-benzofuran-3-carboxylic acid 3-[[40-(tert-butyl-
diphenyl-silanyloxy)-butyl]-(20-nitro-benzenesulfonyl)-
amino]-propyl ester (20). To a mixture of 18 (35.0 g,
82.4 mmol), 19 (55.8 g, 97.9 mmol, 1.2 equiv.) and tri-
phenylphosphine (23.7 g, 90.5 mmol, 1.1 equiv.) in toluene
(200 ml) and THF (10 ml) was added DEAD (40% in
toluene, 41.0 ml, 90.5 mmol, 1.1 equiv.) at 0 8C. The
mixture was allowed to room temperature, and stirred for
30 min. The reaction mixture was filtered through a pad of
Cellite, and concentrated under reduced pressure. The
residue was purified by flash chromatography (50%
AcOEt in n-hexane) to afford the above ester 20 (77.4 g,
79.1 mmol, 96%). [a]D27K378 (cZ0.72, CHCl3); IR (film,
cmK1) 3070, 2931, 2859, 1732, 1613, 1588, 1540, 1513,
1471, 1373, 1236, 1162, 1111, 824, 736; 1H NMR (CDCl3,
400 MHz) d 7.90–7.93 (m, 1H), 7.51–7.68 (m, 7H), 7.23–
7.45 (m, 15H), 6.95 (d, JZ8.8 Hz, 2H), 6.74 (d, JZ8.5 Hz,
1H), 6.03 (d, JZ7.6 Hz, 1H), 5.04 (s, 2H), 4.23 (d, JZ
8.5 Hz, 1H), 4.20 (t, JZ6.3 Hz, 2H), 3.61 (t, JZ6.0 Hz,
2H), 3.39 (dt, JZ7.1, 7.6 Hz, 2H), 3.30 (t, JZ7.6 Hz, 2H),
1.90–1.99 (m, 2H), 1.44–1.65 (m, 4H), 1.01 (s, 9H); 13C
NMR (CDCl3, 100 MHz) d 170.0, 159.0, 158.4, 148.0,
136.7, 135.5, 133.7, 133.4, 133.3, 132.4, 132.3, 131.5,
130.6, 129.6, 128.5, 128.1, 127.9, 127.6, 127.4, 127.2,
126.1, 124.1, 115.1, 112.5, 111.4, 86.0, 70.0, 63.1, 62.9,
55.2, 47.5, 44.2, 29.4, 27.6, 26.8, 24.6, 19.1; HRMS (FAB)
Calcd for C51H53BrN2NaO9SSi (MCNa)C 999.2322, found
999.2294.
4.1.12. (10R,2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-
2,3-dihydro-benzofuran-3-carboxylic acid 10-methyl-20-
oxo-20-pyrrolidin-10-yl-ethyl ester (17). To a mixture of
the above ester (8.12 g, 14.7 mmol) and p-acetamido-
benzenesulfonyl azide (4.24 g, 17.7 mmol, 1.2 equiv.) in
CH3CN (70 ml) was slowly added DBU (2.90 ml,
19.4 mmol, 1.3 equiv.) at 0 8C. The mixture was allowed
to room temperature, and stirred for 10 h. The reaction
mixture was poured into 10% citric acid, and extracted with
AcOEt. The organic layer was washed with saturated
aqueous NaCl, dried over anhydrous MgSO4, and concen-
trated under reduced pressure. The residue was purified by
flash chromatography (50% AcOEt in n-hexane) to afford
desired diazoester and inseparable co-products. To the
mixture in CH2Cl2 (50 ml) was added Rh2(S-DOSP)4
(83.7 mg, 0.0440 mmol, 0.0030 equiv.) at 0 8C. After
stirring for 30 min at the same temperature, the reaction
mixture was concentrated under reduced pressure. The
residue was purified by flash chromatography (50% AcOEt
in n-hexane) to afford 17 (5.10 g, 9.27 mmol, 63% in 2
steps) as a colorless powder; [a]2D6K538 (cZ0.18, CHCl3);
IR (film, cmK1) 3066, 3033, 2977, 2952, 2876, 1740, 1656,
1
1514, 1472, 1433, 1236, 1175, 1025, 829, 737; H NMR
4.1.15. (2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-
dihydro-benzofuran-3-carboxylic acid 3-[4-(tert-butyl-
diphenyl-silanyloxy)-butylamino]-propyl ester (21). To
a mixture of the above ester 20 (56.9 g, 58.2 mmol) and
K2CO3 (16.2 g, 117 mmol, 2.0 equiv.) in DMF (80 ml) and
CH3CN (100 ml) was added thiophenol (7.80 ml,
76.4 mmol, 1.3 equiv.), and the mixture was heated at
50 8C for 40 min. After cooling, the reaction mixture was
(CDCl3, 400 MHz) d 7.37 (s, 1H), 7.11–7.29 (m, 8H), 6.80
(d, JZ8.8 Hz, 2H), 6.60 (d, JZ8.8 Hz, 1H), 5.95 (d, JZ
7.3 Hz, 1H), 5.08 (q, JZ6.7 Hz, 1H), 4.88 (s, 2H), 4.24 (d,
JZ7.3 Hz, 1H), 1.61–1.83 (m, 4H), 1.36 (d, JZ6.7 Hz,
3H); 13C NMR (CDCl3, 100 MHz) d 170.1, 168.2, 159.0,
158.6, 136.8, 136.8, 132.5, 132.4, 128.6, 128.5, 128.0,
127.4, 127.3, 126.0, 115.1, 112.5, 111.4, 86.0, 70.0, 69.6,

9622
W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
poured into 5% NaCl in water, and extracted with AcOEt.
The organic layer was washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (100% AcOEt) to afford 21 (40.7 g,
51.4 mmol, 88%). [a]D27K458 (cZ0.53, CHCl3); IR (film,
cmK1) 3392, 3069, 2931, 2858, 1739, 1613, 1587, 1513,
1471, 1428, 1372, 1237, 1112, 824, 737; 1H NMR (CDCl3,
400 MHz) d 7.64–7.68 (m, 4H), 7.24–7.47 (m, 15H), 6.95
(d, JZ8.6 Hz, 2H), 6.78 (d, JZ3.9 Hz, 1H), 6.05 (d, JZ
7.4 Hz, 1H), 5.05 (s, 2H), 4.20 (d, JZ7.4 Hz, 1H), 4.15–
4.33 (m, 2H), 3.66 (t, JZ5.9 Hz, 2H), 2.67 (t, JZ7.2 Hz,
2H), 2.59 (t, JZ6.8 Hz, 2H), 1.86 (tt, JZ6.8, 6.8 Hz, 2H),
1.51–1.62 (br, 4H), 1.04 (s, 9H); 13C NMR (CDCl3,
100 MHz) d 170.2, 159.0, 158.4, 136.7, 135.6, 135.5,
134.0, 132.5, 132.3, 129.5, 128.6, 128.6, 128.2, 128.0,
127.6, 127.4, 127.3, 126.3, 115.2, 112.6, 111.5, 86.0, 70.0,
64.1, 63.8, 55.4, 49.7, 46.2, 30.3, 29.0, 26.9, 26.2, 19.2;
HRMS (FAB) Calcd for C45H51BrNO5Si (MCH)C
792.2720, found 792.2770.
88%). [a]2D6K518 (cZ1.1, CHCl3); IR (film, cmK1) 3069,
2931, 2858, 1739, 1651, 1613, 1587, 1514, 1471, 1385,
1243, 1174, 1111, 824, 738; 1H NMR (CDCl3, 400 MHz) d
7.66 (d, JZ7.8 Hz, 4H!1/3), 7.60 (d, JZ6.8 Hz, 4H!2/3),
7.23–7.41 (m, 14H), 7.10 (s, 1H), 6.95 (d, JZ8.6 Hz, 2H!
1/3), 6.89 (d, JZ8.8 Hz, 2H!2/3), 6.76 (d, JZ8.5 Hz, 1H),
6.02 (d, JZ9.3 Hz, 1H!2/3), 6.04 (d, JZ9.3 Hz, 1H!1/3),
5.04 (s, 2H!1/3), 4.95 (s, 2H!2/3), 4.49 (d, JZ9.3 Hz,
1H!1/3), 4.45 (d, JZ9.3 Hz, 1H!2/3), 3.69–4.10 (m, 8H),
2.03 (s, 3H!2/3), 1.87 (s, 3H!1/3), 1.89–1.95 (br, 2H),
1.52–1.80 (br, 2H), 1.22–1.44 (br, 2H), 1.06 (s, 9H!1/3),
1.00 (s, 9H!2/3); 13C NMR (CDCl3, 100 MHz) d 170.8,
170.4, 169.9, 169.8, 158.9, 136.6, 135.4, 133.8, 133.5,
132.0, 131.9, 131.8, 129.7, 129.5, 129.0, 128.5, 127.9,
127.6, 127.3, 127.1, 126.5, 115.1, 112.6, 111.5, 88.7, 69.9,
63.4, 62.9, 62.0, 60.8, 53.5, 48.1, 46.3, 44.7, 43.8, 29.8,
29.2, 28.6, 27.1, 26.7, 26.0, 24.3, 20.8, 20.6, 19.2, 19.0;
HRMS (FAB) Calcd for C47H53BrNO6Si (MCH)C
834.2826, found 834.2847.
4.1.18. (20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-
acrylic acid methyl ester (25). To a mixture of the above
acetate (12.7 g, 15.2 mmol), tris(o-tolyl)phosphine (833 mg,
2.74 mmol, 0.18 equiv.) and methyl acrylate (8.20 ml,
91.1 mmol, 6.0 equiv.) in DMF (50 ml) was added palla-
dium acetate (205 mg, 0.915 mmol, 0.060 equiv.), and the
mixture was heated at 100 8C for 24 h. After cooling, the
reaction mixture was concentrated under reduced pressure.
The residue was purified by flash chromatography (40%
AcOEt in n-hexane) to afford 25 (10.7 g, 12.7 mmol, 84%).
[a]2D4K808 (cZ0.96, CHCl3); IR (film, cmK1) 3069, 2950,
2858, 1715, 1650, 1606, 1514, 1488, 1385, 1239, 1111, 823,
4.1.16. (2R,3R)-2-(4-Benzyloxy-phenyl)-5-bromo-2,3-
dihydro-benzofuran-3-carboxylic acid [40-(tert-butyl-
diphenyl-silanyloxy)-butyl]-(30-hydroxy-propyl)-amide
(23). To a solution of 21 (21.0 g, 26.5 mmol) in CH2Cl2
(200 ml) was added dimethylaluminium chloride (0.98 M in
CH2Cl2, 35.1 ml, 34.4 mmol, 1.3 equiv.) at 0 8C, and the
mixture was allowed to room temperature. After 1 h, the
mixture was heated at reflux for 3 h. After cooling, the
reaction mixture was carefully poured into cold saturated
aqueous NaHCO3, and extracted with CH2Cl2. The organic
layer was washed with saturated aqueous NaCl, dried over
anhydrous Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography
(40% AcOEt in n-hexane) to afford 23 (14.1 g, 17.8 mmol,
67%). [a]2D6K508 (cZ0.90, CHCl3); IR (film, cmK1) 3435,
3069, 2932, 2858, 1960, 1888, 1629, 1587, 1513, 1381,
1240, 1174, 1111, 824, 738; 1H NMR (CDCl3, 400 MHz) d
7.57–7.67 (m, 4H), 7.23–7.42 (m, 14H), 7.09 (s, 1H), 6.95
(d, JZ8.6 Hz, 2H!1/4), 6.89 (d, JZ8.8 Hz, 2H!3/4), 6.77
(d, JZ8.6 Hz, 1H!3/4), 6.74 (d, JZ8.5 Hz, 1H!1/4), 6.09
(d, JZ9.3 Hz, 1H!1/4), 6.00 (d, JZ9.0 Hz, 1H!3/4), 5.04
(s, 2H!1/4), 4.96(s, 2H!3/4), 4.69(d, JZ9.3 Hz, 1H!1/4),
4.49 (d, JZ9.0 Hz, 1H!3/4), 3.05–3.71 (m, 8H), 1.53–1.85
(m, 4H), 1.21–1.45 (m, 2H), 1.05 (s, 9H!1/4), 1.00 (s,
9H!3/4); 13C NMR (CDCl3, 100 MHz) d 171.4, 170.0,
159.0, 136.6, 135.4, 133.8, 133.5, 132.2, 131.8, 131.5,
129.6, 128.9, 128.5, 127.9, 127.6, 127.3, 126.4, 115.1,
112.6, 111.6, 88.9, 88.7, 69.9, 63.4, 62.9, 58.2, 53.7, 52.9,
47.9, 46.0, 44.1, 42.5, 31.2, 30.5, 29.9, 29.2, 26.8, 26.0,
24.2, 19.0; HRMS (FAB) Calcd for C45H51BrNO5Si (MC
H)C 792.2720, found 792.2744.
1
738; H NMR (CDCl3, 400 MHz) d 7.59–7.68 (m, 5H),
7.24–7.44 (m, 14H), 7.20 (s, 1H), 6.96 (d, JZ8.5 Hz, 1H),
6.89 (d, JZ8.6 Hz, 2H), 6.28 (d, JZ15.8 Hz, 1H!2/3),
6.26 (d, JZ15.9 Hz, 1H!1/3), 6.08 (d, JZ8.8 Hz, 1H!1/2),
6.08 (d, JZ9.0 Hz, 1H!1/2), 5.05 (s, 2H!1/3), 4.96 (s,
2H!2/3), 4.50 (d, JZ9.0 Hz, 1H!1/3), 4.49 (d, JZ
8.8 Hz, 1H!2/3), 4.03–4.21 (m, 1H), 3.80–3.99 (m, 1H),
3.78 (s, 3H!2/3), 3.75 (s, 3H!1/3), 3.60–3.73 (m, 2H),
3.12–3.57 (m, 4H), 2.04 (s, 3H!6/11), 2.03 (s, 3H!2/11),
1.87 (s, 3H!3/11), 1.90–1.97 (br, 2H), 1.53–1.84 (br, 2H),
1.28–1.45 (br, 2H), 1.06 (s, 9H!1/3), 1.00 (s, 9H!2/3);
13C NMR (CDCl3, 100 MHz) d 171.0, 170.5, 170.2, 170.1,
167.7, 167.6, 161.8, 161.7, 159.1, 159.0, 144.6, 144.6,
136.7, 135.5, 135.4, 133.8, 133.5, 133.5, 132.0, 131.8,
130.5, 129.7, 129.6, 128.6, 128.5, 128.0, 128.0, 127.9,
127.9, 127.8, 127.7, 127.6, 127.4, 127.4, 127.3, 127.2,
123.3, 115.2, 115.1, 115.1, 110.5, 110.4, 89.0, 70.0, 69.9,
63.4, 63.0, 62.0, 60.9, 53.3, 53.3, 51.6, 48.2, 46.4, 44.9,
43.7, 29.9, 29.3, 28.7, 27.2, 26.9, 26.8, 26.1, 24.3, 20.9,
20.7, 19.2, 19.1; HRMS (FAB) Calcd for C51H57NO8Si
(MC) 839.3853, found 839.3887.
4.1.17. (20R,30R)-Acetic acid 3-{[20-(400-benzyloxy-phenyl)-
50-bromo-20,30-dihydro-benzofuran-30-carbonyl]-[40-
(tert-butyl-diphenyl-silanyloxy)-butyl]-amino}-propyl
ester (24). To a solution of 23 (27.1 g, 34.2 mmol) in
pyridine (80 ml) was added acetic anhydride (4.20 ml,
44.6 mmol, 1.3 equiv.) at 0 8C. The mixture was allowed to
room temperature, and stirred for 8 h. The reaction mixture
was concentrated under reduced pressure, and the residue
was purified by flash chromatography (30% AcOEt in
n-hexane) to afford the above acetate 24 (25.1 g, 30.1 mmol,
4.1.19. (2S,3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-
(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-
(4-benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-3-
benzyloxycarbonylamino-2-hydroxy-propionic acid
methyl ester (26). To a solution of benzyl carbamate
(7.42 g, 49.1 mmol, 3.2 equiv.) in n-propyl alcohol (40 ml)
at room temperature was added 1.6 M NaOH (29.7 ml,

W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
9623
47.5 mmol, 3.1 equiv.), followed by a freshly prepared
solution of t-butyl hypochrorite (5.35 ml, 47.6 mmol,
3.1 equiv.). After 15 min, a solution of the ligand (DHQD)2-
PHAL (95%, 1.00 g, 1.22 mmol, 0.080 equiv.) in n-propyl
alcohol (1 ml) was added. To the mixture was added 25
29.4, 28.7, 27.2, 26.9, 25.9, 24.3, 20.9, 19.2; HRMS (FAB)
Calcd for C59H65ClN2O10Si (MC) 1024.4097, found
1024.4128
4.1.21. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-3-
amino-propionic acid methyl ester (28). A mixture of
cholide 27 (230 mg, 0.225 mmol), ammonium formate
(141 mg, 2.24 mmol, 10 equiv.) and 10% palladium on
carbon (47.5 mg, 0.0446 mmol, 0.20 equiv.) in MeOH
(3.0 ml) was heated at 60 8C for 75 min. After cooling, the
reaction mixture was filtered through a pad of Celite, and
concentrated under reduced pressure. The residue was
poured into saturated aqueous NaHCO3, and extracted with
CH2Cl2. The organic layer was washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The crude product was used
in the next reaction without further purification. To a
mixture of the crude product, benzyl alcohol (30.0 ml,
0.290 mmol, 1.3 equiv.) and triphenylphosphine (71.0 mg,
0.271 mmol, 1.2 equiv.) in toluene (2.0 ml) was added
DEAD (40% in toluene, 0.120 ml, 0.264 mmol, 1.2 equiv.)
at 0 8C. The mixture was allowed to room temperature, then
heated at 60 8C for 2 h. The reaction mixture was filtered
through a pad of Celite, and concentrated under reduced
pressure. The residue was purified by flash chromatography
(5% MeOH in AcOEt) to afford the above amine 28
(118 mg, 0.138 mmol, 61% in 2 steps). [a]2D7K538 (cZ1.1,
CHCl3); IR (film, cmK1) 3380, 3305, 3068, 2931, 2858,
1732, 1651, 1514, 1487, 1384, 1243, 1111, 824, 740, 703;
1H NMR (CDCl3, 400 MHz) d 7.64–7.66 (m, 2H), 7.59–
7.61 (m, 2H), 7.24–7.45 (m, 13H), 7.15–7.21 (m, 1H), 7.05
(s, 1H), 6.95 (d, JZ4.3 Hz, 1H), 6.87 (d, JZ13.7 Hz, 2H!
1/2), 6.85 (d, JZ13.4 Hz, 2H!1/2), 6.03 (d, JZ9.0 Hz,
1H!2/3), 6.02 (d, JZ8.9 Hz, 1H!1/3), 5.05 (s, 2H!1/3),
4.95 (s, 2H!2/3), 4.48 (d, JZ8.9 Hz, 1H!1/3), 4.46 (d,
JZ9.0 Hz, 1H!2/3), 4.36 (dd, JZ13.3, 6.7 Hz, 1H), 3.80–
4.13 (m, 2H), 3.68 (s, 3H!2/3), 3.66 (s, 3H!1/3), 3.40–
3.56 (m, 2H), 3.10–3.37 (m, 2H), 2.60–2.63 (m, 2H), 2.02
(s, 3H!2/3), 1.88 (s, 3H!1/3), 1.75–1.97 (m, 4H), 1.52–
1.72 (m, 2H), 1.22–1.44 (m, 2H), 1.04 (s, 9H!1/3), 1.00 (s,
9H!2/3); 13C NMR (CDCl3, 100 MHz) d 172.6, 171.0,
170.6, 159.1, 137.6, 136.8, 135.5, 133.7, 132.5, 129.8,
128.6, 128.0, 127.7, 127.4, 121.4, 115.1, 110.0, 88.4, 70.1,
63.5, 63.1, 62.1, 61.0, 53.8, 52.4, 51.7, 48.2, 46.4, 44.9,
44.2, 43.6, 29.9, 29.5, 28.8, 27.2, 26.9, 26.1, 24.3, 20.9,
19.2; HRMS (FAB) Calcd for C51H60N2NaO8Si (MCNa)C
879.4017, found 879.3998.
(12.9 g, 15.4 mmol), followed by
a solution of
K2OsO2(OH)4 (339 mg, 0.920 mmol, 0.060 equiv.) in H2O
(1.0 ml), and the mixture was stirred for 4 h. The reaction
mixture was quenched with NaHSO3 (16.0 g, 10 equiv.),
poured into 10% citric acid, then extracted with AcOEt. The
organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (60% AcOEt in n-hexane) to afford 26
(10.2 g, 10.1 mmol, 66%). [a]2D6K468 (cZ1.0, CHCl3); IR
(film) 3363, 3068, 2952, 2858, 1731, 1644, 1587, 1514,
1384, 1239, 1111, 824, 739 cmK1 1H NMR (CDCl3,
;
400 MHz) d 7.66 (d, JZ6.8 Hz, 4H!3/10), 7.60 (dd, JZ
6.6, 1.0 Hz, 4H!7/10), 7.16–7.43 (m, 20H), 6.92–7.14 (m,
1H), 6.79–6.90 (m, 2H), 5.94–6.13 (m, 1H), 5.67–5.90 (br,
1H), 5.04 (s, 2H!1/3), 4.97–5.25 (br, 3H), 4.93 (s, 2H!2/3),
4.34–4.66 (br, 2H), 3.04–4.19 (br, 11H), 1.82–2.08 (br, 5H),
1.50–1.75 (br, 2H), 1.18–1.40 (br, 2H), 1.05 (s, 9H!1/3),
1.01 (s, 9H!2/3); 13C NMR (CDCl3, 100 MHz) d 173.0,
171.4, 170.5, 159.4, 158.9, 156.4, 155.7, 136.7, 136.3,
135.4, 133.6, 132.1, 129.6, 128.4, 127.9, 127.6, 127.3,
122.6, 115.1, 109.8, 88.5, 88.2, 73.5, 69.9, 66.8, 63.4, 62.9,
62.0, 60.9, 60.1, 59.7, 56.4, 53.7, 52.8, 52.5, 47.9, 46.3,
44.7, 42.9, 42.3, 29.8, 29.3, 28.6, 26.8, 25.8, 24.2, 20.8,
20.6, 19.1; HRMS (FAB) Calcd for C59H66N2NaO11Si
(MCNa)C 1029.4334, found 1029.4352.
4.1.20. (2R,3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-
(tert-butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-
(400-benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-
3-benzyloxycarbonylamino-2-chloro-propionic acid
methyl ester (27). To a mixture of 26 (3.01 g, 2.99 mmol)
and triphenylphosphine (1.56 g, 5.95 mmol, 2.0 equiv.) in
toluene (10 ml) was added carbon tetrachloride (4.31 ml,
44.9 mmol, 15 equiv.), and the mixture was heated at
100 8C for 2 h. After cooling, the reaction mixture was
concentrated under reduced pressure. The residue was
purified by flash chromatography (40% AcOEt in n-hexane)
to afford the above chloride 27 (2.68 g, 2.61 mmol, 87%).
[a]2D6K558 (cZ1.2, CHCl3); IR (film, cmK1) 3419, 3321,
3068, 2952, 2858, 1732, 1650, 1587, 1456, 1242, 1111, 824,
1
737; H NMR (CDCl3, 400 MHz) d 7.66 (d, JZ6.8 Hz,
4H!1/3), 7.60 (d, JZ6.6 Hz, 4H!2/3), 7.21–7.45 (m,
19H), 7.08–7.18 (m, 1H), 6.95 (d, JZ8.3 Hz, 1H), 6.87 (d,
JZ8.3 Hz, 2H!2/3), 6.82 (d, JZ8.0 Hz, 2H!1/3), 6.51
(brd, JZ8.6 Hz, 1H), 6.07 (d, JZ9.0 Hz, 1H!3/4), 6.01 (d,
JZ8.6 Hz, 1H!1/4), 5.22–5.37 (br, 1H), 5.05 (s, 2H!1/3),
5.01–5.15 (br, 2H), 4.92 (s, 2H!2/3), 4.71 (brd, JZ5.1 Hz,
1H!1/2), 4.55–4.66 (br, 1H!1/2), 4.47 (d, JZ8.6 Hz,
1H!1/4), 4.45 (d, JZ9.0 Hz, 1H!3/4), 3.67 (s, 3H!2/3),
3.63 (s, 3H!1/9), 3.61 (s, 3H!2/9), 3.56–4.20 (br, 3H),
3.35–3.55 (br, 3H), 3.01–3.25 (m, 2H), 1.82–2.06 (m, 3H),
1.51–2.06 (br, 4H), 1.21–1.39 (br, 2H), 1.05 (s, 9H!2/7),
1.00 (s, 9H!5/7); 13C NMR (CDCl3, 100 MHz) d 171.6,
170.4, 168.4, 159.9, 159.0, 155.7, 136.7, 136.3, 135.5,
133.9, 133.6, 132.0, 129.7, 129.1, 128.5, 128.1, 127.7,
127.4, 122.3, 115.2, 110.0, 88.7, 70.0, 67.1, 63.5, 63.0, 62.0,
61.0, 58.8, 57.3, 53.7, 53.1, 47.9, 46.4, 44.9, 42.7, 29.8,
4.1.22. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-5-yl]-3-(2-
nitro-benzenesulfonylamino)-propionic acid methyl
ester (29). To a mixture of the amine 28 (3.78 g,
4.41 mmol) and Na2CO3 (935 mg, 8.82 mmol, 2.0 equiv.)
in CH2Cl2 (20 ml) and water (15 ml) was added 2-nitro-
benzensulfonyl chloride (1.26 g, 5.70 mmol, 1.3 equiv.),
and the mixture was stirred for 4 h. The reaction mixture
was poured into water, and extracted with CH2Cl2. The
organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash

9624
W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
chromatography (40% AcOEt in n-hexane) to afford 29
(3.33 g, 3.20 mmol, 72%). [a]2D6K1138 (cZ0.26, CHCl3);
IR (film, cmK1) 3314, 3069, 2932, 2858, 1737, 1646, 1612,
1541, 1513, 1490, 1362, 1241, 1171, 1112, 1046, 854, 824,
37.6, 33.5, 30.0, 29.4, 28.7, 27.1, 26.9, 26.8, 25.9, 25.8,
24.3, 21.0, 20.7, 19.2, 19.2, 18.2, K5.4; HRMS (FAB)
Calcd for C66H83N3NaO13SSi2 (MCNa)C 1236.5083,
found 1236.5085
1
740; H NMR (CDCl3, 400 MHz) d 7.51–7.80 (m, 8H),
4.1.24. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-3-
[30-(tert-butyl-dimethyl-silanyloxy)-propylamino]-pro-
pionic acid methyl ester. To a mixture of 31 (3.66 g,
3.01 mmol) and thiophenol (1.62 ml, 15.9 mmol,
5.3 equiv.) in CH3CN (20 ml) was added 5.0 M aqueous
KOH (1.58 ml, 7.90 mmol, 2.6 equiv.), and the mixture was
heated at 60 8C for 2 h. After cooling, the reaction mixture
was filtered through a pad of Celite, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (5% MeOH in AcOEt) to afford the amine
(2.88 g, 2.80 mmol, 93%). [a]2D6K438 (cZ0.31, CHCl3); IR
(film, cmK1) 3336, 3070, 3034, 2930, 2857, 1739, 1651,
7.19–7.47 (m, 14H), 6.37–7.05 (m, 5H), 5.86 (d, JZ9.6 Hz,
1H!2/3), 5.84 (d, JZ10.0 Hz, 1H!1/3), 5.04 (s, 2H),
4.88–4.98 (m, 1H), 4.30 (d, JZ10.0 Hz, 1H!1/3), 4.29 (d,
JZ9.6 Hz, 1H!2/3), 4.13 (t, JZ6.8 Hz, 2H), 3.61 (s, 3H),
3.09–4.03 (m, 6H), 2.79–2.99 (m, 2H), 2.09 (s, 3H!2/3),
1.90 (s, 3H!1/3), 1.75–2.07 (m, 2H), 1.52–1.68 (br, 2H),
1.22–1.37 (br, 2H), 1.06 (s, 9H!1/3), 1.01 (s, 9H!2/15),
0.99 (s, 9H!8/15); 13C NMR (CDCl3, 100 MHz) d 171.7,
170.7, 170.6, 169.7, 169.6, 159.3, 159.3, 158.9, 147.2,
136.7, 135.5, 135.5, 134.1, 133.9, 133.9, 133.6, 133.6,
133.1, 133.0, 132.6, 132.2, 132.2, 132.0, 131.7, 131.6,
131.5, 130.6, 130.5, 129.8, 129.6, 129.0, 128.6, 128.5,
128.1, 128.0, 127.7, 127.7, 127.5, 127.4, 127.4, 127.2,
127.2, 127.0, 125.9, 125.6, 121.5, 121.1, 115.2, 115.0,
109.3, 109.2, 88.6, 88.5, 70.0, 69.9, 63.4, 63.0, 62.2, 61.2,
55.2, 53.4, 53.3, 51.9, 48.3, 46.6, 45.0, 43.5, 41.6, 41.5,
30.0, 29.4, 28.9, 27.3, 26.9, 26.8, 26.0, 24.4, 21.0, 20.7,
19.3, 19.1; HRMS(FAB) Calcd for C57H63N3NaO12SSi
(MCNa)C 1064.3799, found 1064.3848.
1
1612, 1513, 1485, 1362, 1245, 1173, 1111, 835, 740; H
NMR (CDCl3, 400 MHz) d 7.66 (d, JZ6.4 Hz, 4H!1/3),
7.60 (dd, JZ6.4, 1.5 Hz, 4H!2/3), 7.26–7.45 (m, 14H),
7.19 (br, 1H!1/2), 7.17 (br, 1H!1/2), 6.95 (d, JZ8.6 Hz,
2H!1/2), 6.88 (d, JZ8.6 Hz, 2H!1/2), 6.84 (d, JZ
8.3 Hz, 1H), 6.06 (d, JZ9.0 Hz, 1H!2/3), 6.03 (d, JZ
9.0 Hz, 1H!1/3), 5.05 (s, 2H!1/3), 4.94 (s, 2H!2/3), 4.46
(d, JZ9.0 Hz, 1H!1/3), 4.44 (d, JZ9.0 Hz, 1H!2/3),
3.62 (s, 3H!2/3), 3.59 (s, 3H!1/3), 3.57–4.15 (br, 7H),
3.50 (brt, JZ5.9 Hz, 2H), 3.11–3.38 (m, 2H), 2.46–2.70 (m,
4H), 2.03 (s, 3H!2/3), 1.88 (s, 3H!1/3), 1.79–2.00 (br,
2H), 1.53–1.69(br, 4H), 1.24–1.43(br, 2H), 1.05(s, 9H!2/5),
1.00 (s, 9H!3/5), 0.87 (s, 9H), 0.023 (s, 6H!3/5), 0.019 (s,
6H!2/5); 13C NMR (CDCl3, 100 MHz) d 172.3, 172.3,
171.0, 170.5, 170.4, 159.1, 159.1, 158.9, 158.8, 136.8,
135.6, 135.5, 135.5, 133.9, 133.9, 133.6, 132.6, 132.5,
129.7, 129.6, 128.6, 128.5, 128.0, 128.0, 127.7, 127.7,
127.4, 127.4, 127.3, 127.2, 126.8, 122.2, 122.0, 115.1,
115.0, 109.9, 88.3, 88.2, 70.0, 69.9, 63.5, 63.1, 62.1, 61.6,
61.0, 59.2, 53.8, 53.7, 51.6, 48.2, 46.4, 44.9, 44.5, 43.7,
43.1, 43.1, 33.0, 32.9, 29.9, 29.4, 28.7, 27.2, 26.9, 26.8,
26.0, 25.9, 24.3, 20.9, 20.7, 19.2, 19.1, 18.3, 14.4, K5.3;
HRMS (FAB) Calcd for C60H81N2O9Si2 (MCH)C
1029.5481, found 1029.5527.
4.1.23. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-3-
{(200-nitro-benzenesulfonyl-[30-(tert-butyl-dimethyl-
silanyloxy)-propyl]-amino)-propionic acid methyl ester
(31). To a mixture of 29 (3.31 g, 3.18 mmol), 30 (905 mg,
4.76 mmol, 1.5 equiv.) and triphenylphosphine (1.08 g,
4.12 mmol, 1.3 equiv.) in toluene (20 ml) was added
DEAD (40% in toluene, 1.87 ml, 4.12 mmol, 1.3 equiv.)
at 0 8C. The mixture was allowed to room temperature, and
heated at 60 8C for 1 h. After cooling, the reaction mixture
was filtered through a pad of Celite, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (30% AcOEt in n-hexane) to afford 31
(3.66 g, 3.01 mmol, 95%). [a]2D7K658 (cZ1.8, CHCl3); IR
(film, cmK1) 3073, 2953, 2930, 2894, 2857, 1739, 1648,
1613, 1588, 1544, 1513, 1490, 1429, 1372, 1241, 1172,
1
1111, 835, 742; H NMR (CDCl3, 400 MHz) d 7.86–7.93
(m, 1H), 7.54–7.70 (m, 7H), 7.25–7.44 (m, 14H), 7.07–7.23
(m, 1H), 6.96 (d, JZ8.6 Hz, 2H!1/3), 6.89 (d, JZ8.8 Hz,
2H!2/3), 6.75 (d, JZ8.3 Hz, 1H!2/3), 6.73 (d, JZ
8.6 Hz, 1H!1/3), 6.12 (d, JZ9.0 Hz, 1H!2/3), 6.08 (d,
JZ9.0 Hz, 1H!1/3), 5.42–5.50 (m, 1H), 5.06 (s, 2H!1/3),
4.95 (s, 2H!2/3), 4.43 (d, JZ9.0 Hz, 1H!1/3), 4.40 (d,
JZ9.0 Hz, 1H!2/3), 4.11 (t, JZ6.3 Hz, 2H!1/2), 4.11 (t,
JZ6.3 Hz, 2H!1/2), 3.54 (s, 3H!5/8), 3.53 (s, 3H!3/8),
3.41–4.00 (m, 6H), 3.10–3.40 (m, 5H), 2.81–2.96 (m, 1H),
2.04 (s, 3H!2/3), 1.88 (s, 3H!1/3), 1.25–1.71 (br, 8H),
1.05 (s, 9H!1/3), 1.01 (s, 9H!2/3), 0.91 (s, 9H!1/8), 0.88
(s, 9H!7/8), 0.02 (s, 6H!2/3), 0.01 (s, 6H!1/3); 13C
NMR (CDCl3, 100 MHz) d 171.1, 170.6, 170.4, 170.3,
170.0, 159.8, 159.7, 158.9, 158.9, 147.9, 136.7, 135.5,
135.5, 133.9, 133.9, 133.9, 133.8, 133.7, 133.3, 132.3,
132.2, 131.7, 131.4, 131.4, 129.8, 129.7, 129.6, 128.6,
128.5, 128.3, 128.2, 128.0, 128.0, 127.7, 127.7, 127.5,
127.4, 127.2, 127.1, 124.3, 124.1, 123.9, 115.2, 115.0,
109.6, 88.5, 88.3, 70.0, 69.9, 63.5, 63.0, 62.2, 61.1, 60.5,
57.3, 57.3, 53.4, 53.3, 52.0, 48.1, 46.5, 44.9, 43.6, 43.6,
4.1.25. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-3-
{benzyloxycarbonyl-[30-(tert-butyl-dimethyl-silanyloxy)-
propyl]-amino}-propionic acid methyl ester (32). To a
mixture of the amine (2.88 g, 2.80 mmol) and NaHCO3
(800 mg, 9.52 mmol, 3.4 equiv.) in CH2Cl2 (20 ml) and
water (15 ml) was added benzyl chloroformate (0.680 ml,
4.78 mmol, 1.7 equiv.), and the mixture was stirred for 1 h
at room temperature. The reaction mixture was poured into
saturated aqueous NaHCO3, and extracted with CH2Cl2.
The organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (30% AcOEt in n-hexane) to afford the
above silyl ether (2.95 g, 2.54 mmol, 91%). [a]2D7K508 (cZ
1.8, CHCl3); IR (film, cmK1) 3069, 3033, 2952, 2857, 1736,
1698, 1648, 1612, 1586, 1513, 1362, 1246, 1174, 1110, 834,
776, 739; 1H NMR (CDCl3, 400 MHz) d 7.63–7.68 (m, 2H),

W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
9625
7.58–7.62 (m, 2H), 7.25–7.44 (m, 19H), 7.01–7.20 (br, 1H),
6.94 (d, JZ8.6 Hz, 2H!1/3), 6.87 (d, JZ8.8 Hz, 2H!2/3),
6.82 (d, JZ8.3 Hz, 1H), 6.01–6.08 (br, 1H), 5.47–5.65 (br,
1H), 5.14 (s, 2H), 5.05 (s, 2H!1/3), 4.93 (s, 2H!2/3),
4.35–4.49 (br, 1H), 4.00–4.14 (m, 2H), 3.60 (s, 3H!2/3),
3.57 (s, 3H!1/3), 3.29–3.96 (m, 8H), 2.89–3.27 (m, 6H),
2.02 (s, 3H!1/2), 1.85 (s, 3H!1/2), 1.49–1.75 (br, 4H),
1.19–1.43 (br, 2H), 1.05 (s, 9H!1/3), 1.00 (s, 9H!2/3),
0.86 (s, 9H), K0.01 (s, 6H); 13C NMR (CDCl3, 100 MHz) d
171.2, 171.1, 171.0, 170.5, 170.2, 159.4, 159.4, 158.9,
158.9, 136.8, 136.7, 135.5, 135.5, 133.9, 133.9, 133.6,
132.4, 132.3, 132.2, 129.7, 129.6, 128.6, 128.5, 128.4,
128.0, 128.0, 127.9, 127.7, 127.7, 127.4, 127.4, 127.3,
127.2, 115.1, 115.0, 109.7, 88.5, 88.3, 70.0, 69.9, 67.0, 63.4,
63.0, 62.1, 60.9, 53.6, 53.5, 51.8, 48.0, 46.4, 44.8, 43.7,
42.7, 37.5, 32.7, 29.9, 29.4, 28.6, 27.1, 26.9, 26.8, 25.9,
24.2, 20.9, 20.7, 19.2, 19.1, 18.2, K5.4; HRMS (FAB)
Calcd for C68H86N2NaO11Si2 (MCNa)C 1185.5668, found
1185.5679.
Celite, and concentrated under reduced pressure. The
residue was purified by flash chromatography (50%
AcOEt in n-hexane) to afford the sulfonamide (2.43 g,
1.97 mmol, quant.). [a]2D6K538 (cZ1.3, CHCl3); IR (film,
cmK1) 3258, 3068, 3030, 2952, 2932, 2897, 2856, 1739,
1696, 1643, 1542, 1514, 1491, 1428, 1365, 1243, 1171,
1
1113, 825, 741; H NMR (CDCl3, 400 MHz) d 7.98–8.10
(br, 1H), 7.55–7.79 (br, 7H), 7.19–7.46 (br, 19H), 6.29–7.10
(br, 4H), 5.59–5.86 (br, 2H), 5.15 (brs, 2H), 5.05 (s, 2H!3/7),
4.98 (s, 2H!4/7), 4.60 (brd, JZ8.5 Hz, 1H!1/3), 4.55
(brd, JZ8.5 Hz, 1H!2/3), 4.17–4.25 (br, 1H), 4.01–4.12
(br, 1H), 3.84–4.00 (br, 1H), 3.63–3.78 (br, 1H), 3.43–3.62
(br, 4H), 3.24–3.39 (br, 1H), 2.68–3.21 (br, 8H), 2.03 (s,
3H!1/2), 1.87 (s, 3H!1/2), 1.21–1.76 (br, 8H), 1.05 (s,
9H!1/3), 0.99 (s, 9H!2/3); 13C NMR (CDCl3, 100 MHz)
d 171.1, 170.6, 159.8, 159.7, 159.2, 159.1, 147.9, 136.6,
136.6, 135.5, 135.4, 133.9, 133.6, 133.1, 132.3, 131.7,
130.7, 129.7, 129.6, 128.6, 128.5, 128.5, 128.0, 127.7,
127.6, 127.6, 127.4, 127.4, 124.7, 124.6, 122.3, 122.1,
115.3, 115.2, 110.2, 89.3, 89.1, 70.0, 69.9, 63.5, 62.9, 62.2,
62.0, 61.0, 54.1, 51.8, 48.0, 43.5, 41.3, 29.8, 29.4, 28.2,
27.0, 26.9, 26.8, 25.7, 24.0, 20.9, 20.7, 19.2, 19.1, 14.4;
HRMS (FAB) Calcd for C68H77N4O14SSi (MCH)C
1233.4926, found 1233.4966.
4.1.26. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-50-yl]-3-
[benzyloxycarbonyl-(30-hydroxy-propyl)-amino]-pro-
pionic acid methyl ester. To a solution of silyl ether 32
(344 mg, 0.296 mmol) in MeOH (2.0 ml) was added CSA
(6.00 mg, 0.0283 mmol, 0.10 equiv.), and the mixture was
stirred for 20 min at room temperature. The reaction
mixture was quenched with triethylamine (13.0 mml,
0.0930 mmol, 0.30 equiv.), and concentrated under reduced
pressure. The residue was purified by flash chromatography
(5% MeOH in CH2Cl2) to afford the alcohol (293 mg,
0.279 mmol, 94%). [a]D26K748 (cZ0.39, CHCl3); IR (film,
cmK1) 3463, 2952, 2859, 1739, 1694, 1644, 1587, 1513,
1366, 1243, 1174, 1112, 824, 769, 738.1H NMR (CDCl3,
400 MHz) d 7.57–7.69 (m, 4H), 7.25–7.46 (m, 19H), 6.77–
7.22 (br, 4H), 5.63–6.03 (br, 2H), 5.19 (brs, 2H), 5.05 (s,
2H!2/5), 4.96 (s, 2H!3/5), 4.42–4.58 (br, 1H), 4.01–4.13
(br, 2H), 3.56 (s, 3H), 2.91–3.95 (br, 14H), 2.03 (s, 3H!1/2),
1.88 (s, 3H!1/4), 1.70 (s, 3H!1/4), 1.21–1.69 (br, 6H),
1.05 (s, 9H!2/5), 1.00 (s, 9H!3/5); 13C NMR (CDCl3,
100 MHz) d 171.1, 170.5, 159.7, 159.7, 159.2, 159.1, 136.6,
136.6, 135.5, 135.5, 133.8, 133.8, 133.6, 133.6, 131.9,
131.8, 129.8, 129.6, 128.6, 128.6, 128.5, 128.1, 128.0,
127.7, 127.7, 127.5, 127.4, 127.4, 127.3, 122.1, 122.0,
115.3, 115.2, 110.3, 89.0, 88.9, 70.0, 69.9, 63.4, 63.0, 62.9,
62.0, 61.9, 61.0, 55.6, 55.5, 53.9, 51.8, 48.1, 46.5, 44.8,
43.7, 41.0, 29.8, 29.4, 28.5, 27.1, 26.9, 26.8, 25.9, 24.2,
20.9, 20.7, 19.2, 19.1; HRMS (FAB) Calcd for C62H72N2
NaO11Si (MCNa)C 1071.4803, found 1071.4781.
4.1.28. (3R,20R,30R)-3-[30-[(300-Acetoxy-propyl)-(400-
hydroxy-butyl)-carbamoyl]-20-(400-benzyloxy-phenyl)-
20,30-dihydro-benzofuran-5-yl]-3-{benzyloxycarbonyl-
[30-(200-nitro-benzenesulfonylamino)-propyl]-amino}-
propionic acid methyl ester (34). To a solution of above
sulfonamide (2.43 g, 1.97 mmol) in CH3CN (20 ml) was
added HF (48 wt% solution in H2O, 1.20 ml, 28.8 mmol,
15 equiv.), and the mixture was stirred for 90 min. The
reaction mixture was carefully poured into cold saturated
aqueous NaHCO3, and extracted with CH2Cl2. The organic
layer was washed with saturated aqueous NaCl, dried over
anhydrous MgSO4, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography (5%
MeOH in AcOEt) to afford 34 (1.65 g, 1.66 mmol, 84%).
[a]2D4K688 (cZ0.69, CHCl3); IR (film, cmK1) 3464, 3092,
3065, 3033, 2948, 1738, 1694, 1634, 1542, 1492, 1366,
1341, 1243, 1171, 1125, 830, 739 ; 1H NMR (CDCl3,
400 MHz) d 8.05 (brs, 1H), 7.74–7.81 (m, 1H), 7.64–7.73
(m, 2H), 7.28–7.46 (m, 14H), 7.00 (d, JZ8.6 Hz, 2H!1/2),
6.99 (d, JZ8.8 Hz, 2H!1/2), 6.80 (brd, JZ7.3 Hz, 1H),
5.84 (d, JZ9.0 Hz, 1H!2/3), 5.83 (d, JZ8.8 Hz, 1H!1/3),
5.63–5.73 (br, 1H), 5.11–5.20 (br, 2H), 5.09 (s, 2H!1/2),
5.08 (s, 2H!1/2), 4.54–4.64 (br, 1H), 2.77–4.14 (br, 17H),
2.05 (s, 3H), 1.30–1.83 (br, 8H); 13C NMR (CDCl3,
100 MHz) d 171.2, 170.6, 159.8, 159.2, 155.9, 147.9,
136.7, 136.6, 133.3, 132.4, 131.9, 130.8, 128.6, 128.5,
128.1, 127.6, 127.5, 124.8, 122.4, 115.3, 115.3, 110.3, 89.2,
89.0, 70.1, 62.3, 62.0, 61.0, 54.0, 53.9, 51.9, 51.9, 48.1,
45.8, 44.6, 43.7, 41.5, 41.5, 29.7, 29.5, 28.3, 27.0, 26.1,
24.1, 21.0, 20.7; HRMS (FAB) Calcd for C52H59N4O14S
(MCH)C 995.3749, found 995.3709.
4.1.27. (3R,20R,30R)-3-[30-{(300-Acetoxy-propyl)-[400-(tert-
butyl-diphenyl-silanyloxy)-butyl]-carbamoyl}-20-(400-
benzyloxy-phenyl)-20,30-dihydro-benzofuran-5-yl]-3-
{benzyloxycarbonyl-[30-(200-nitro-benzenesulfonyl-
amino)-propyl]-amino}-propionic acid methyl ester (33).
To a mixture of the above alcohol (2.17 g, 1.97 mmol),
2-nitrobenzenesulfonamide (996 mg, 4.93 mmol, 2.5 equiv.)
and triphenylphosphine (672 mg, 2.56 mmol, 1.3 equiv.) in
toluene (15 ml) and THF (7.5 ml) was added DEAD (40%
in toluene, 1.16 ml, 2.56 mmol, 1.3 equiv.) at 0 8C. The
mixture was allowed to room temperature, and stirred for
40 min. The reaction mixture was filtered through a pad of
4.1.29. (13R,19R,20R)-3-(30-Acetoxy-propyl)-19-(40-ben-
zyloxy-phenyl)-13-methoxycarbonylmethyl-8-(20-nitro-
benzenesulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo
[12.5.2.00,0]heneicosa-14(21),15,17(20)-triene-12-car-
boxylic acid benzyl ester (35). To a mixture of 34 (1.65 g,
1.66 mmol) and triphenylphosphine (564 mg, 2.15 mmol,

9626
W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
1.3 equiv.) in toluene (33 ml) was added DEAD (40% in
toluene, 0.970 ml, 2.14 mmol, 1.3 equiv.) at 0 8C. The
mixture was allowed to room temperature, and stirred for
40 min. The reaction mixture was filtered through a pad of
Celite, and concentrated under reduced pressure. The
residue was purified by flash chromatography (70%
AcOEt in n-hexane) to afford 35 (1.24 g, 1.27 mmol,
77%) as a yellow oil. [a]2D7K868 (cZ0.57, CHCl3); IR
(film, cmK1) 3091, 3066, 3032, 2951, 2870, 1739, 1695,
1644, 1612, 1546, 1513, 1492, 1455, 1372, 1241, 1173, 986,
851, 830, 750; 1H NMR (CDCl3, 400 MHz) d 7.53–7.90 (m,
4H), 7.25–7.50 (m, 13H), 6.95 (d, JZ8.8 Hz, 2H), 6.85–
7.24 (m, 2H), 6.13 (d, JZ8.3 Hz, 1H), 5.48–5.65 (br, 1H),
5.16 (s, 2H), 5.04–5.11 (br, 2H), 4.43–4.56 (br, 1H), 3.63–
4.35 (br, 4H), 3.61 (s, 3H), 2.66–3.49 (br, 10H), 1.88 (s, 3H),
1.39–2.00 (br, 8H); 13C NMR (CDCl3, 100 MHz) d 171.4,
171.0, 170.8, 170.6, 159.6, 159.0, 155.5, 148.3, 136.7,
136.5, 133.5, 132.4, 132.3, 131.6, 130.4, 128.6, 128.5,
128.0, 128.0, 127.8, 127.5, 127.4, 127.1, 126.9, 126.8,
124.1, 120.3, 115.3, 115.2, 110.8, 88.2, 70.0, 67.3, 62.0,
60.8, 56.3, 53.5, 51.9, 49.2, 47.4, 44.2, 37.6, 30.8, 29.4,
28.4, 26.9, 26.7, 26.4, 25.3, 25.0, 21.0, 20.7; HRMS (FAB)
Calcd for C52H56N4O13S (MC) 976.3565, found
976.3542.
oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-
14(21),15,17(20)-triene-12-carboxylic acid benzyl ester
(37). To a mixture of the above alcohol 36 (93.0 mg,
0.0995 mmol) and triethylamine (20.0 ml, 0.144 mmol,
1.5 equiv.) in CH2Cl2 (0.80 ml) at 0 8C was added
methanesulfonyl chloride (9.0 ml, 0.117 mmol, 1.2 equiv.),
and the mixture was stirred at the same temperature for
20 min. The reaction mixture was poured into saturated
aqueous NaHCO3, and extracted with CH2Cl2. The organic
layer was washed with saturated aqueous NaCl, dried over
anhydrous MgSO4, and concentrated under reduced pres-
sure. To a solution of crude product in DMF (0.80 ml) was
added sodium azide (20.0 mg, 0.308 mmol, 3.1 equiv.), and
the mixture was heated at 60 8C for 30 min. After cooling,
the reaction mixture was poured into 5% NaCl in water, and
extracted with AcOEt. The organic layer was washed with
saturated aqueous NaCl, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was
purified by flash chromatography (70% AcOEt in n-hexane)
to afford the above mesylate (77.9 mg, 0.0811 mmol, 82%
in 2 steps). as a yellow oil. [a]2D6K838 (cZ0.34, CHCl3); IR
(film, cmK1) 3089, 3062, 3033, 2948, 2873, 2100, 1739,
1693, 1643, 1612, 1548, 1513, 1493, 1454, 1242, 1173, 985,
1
851, 830, 772, 735; H NMR (CDCl3, 400 MHz) d 7.73–
7.91 (br, 1H), 7.53–7.70 (m, 3H), 7.24–7.48 (m, 13H), 6.98
(d, JZ8.8 Hz, 2H), 6.93–7.24 (br, 1HC1H!1/2), 6.86 (d,
JZ8.3 Hz, 1H!1/2), 6.19 (d, JZ7.4 Hz, 1H!1/10), 6.13
(d, JZ8.6 Hz, 1H!4/5), 5.87 (d, JZ10.0 Hz, 1H!1/10),
5.43–5.66 (br, 1H), 5.17 (s, 2H), 5.05–5.10 (br, 2H), 4.48–
4.58 (br, 1H), 4.23–4.33 (br, 1H), 3.62 (s, 3H), 2.63–3.83
(br, 13H), 1.33–1.90 (br, 8H); 13C NMR (CDCl3, 100 MHz)
d 171.0, 159.6, 159.0, 155.5, 148.3, 136.8, 136.5, 133.6,
133.5, 133.4, 132.4, 132.2, 131.6, 131.6, 130.7, 130.4,
130.3, 128.6, 128.5, 128.2, 128.1, 128.0, 128.0, 127.8,
127.5, 127.5, 127.4, 127.2, 127.2, 126.8, 124.1, 120.3,
115.3, 115.2, 110.9, 88.4, 70.0, 67.3, 56.3, 53.5, 52.0, 49.1,
48.0, 47.2, 44.1, 28.3, 25.0; HRMS (FAB) Calcd for
C50H54N7O11S (MCH)C 960.3602, found 960.3563.
4.1.30. 19-(4-Benzyloxy-phenyl)-3-(3-hydroxy-propyl)-
13-methoxycarbonylmethyl-8-(2-nitro-benzenesul-
fonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]-
heneicosa-14(21),15,17(20)-triene-12-carboxylic acid
benzyl ester (36). To a solution of 35 (1.24 g, 1.27 mmol)
in MeOH (12 ml) and THF (3.0 ml) was added K2CO3
(228 mg, 1.65 mmol, 1.3 equiv.), and the mixture was
stirred at room temperature for 1 h. The reaction mixture
was poured into 10% citric acid, and extracted with CH2Cl2.
The organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (5% MeOH in AcOEt) to afford the
above alchohol (1.14 g, 1.22 mmol, 96%).as a colorless
oil; [a]2D6K648 (cZ0.40, CHCl3); IR (film, cmK1) 3382,
3060, 2949, 1739, 1694, 1643, 1588, 1546, 1514, 1494,
1436, 1372, 1241, 1173, 1120, 1059, 986, 851, 830, 772,
4.1.32. 3-(3-Azido-propyl)-19-(4-benzyloxy-phenyl)-13-
carboxymethyl-8-(2-nitro-benzenesulfonyl)-2-oxo-18-
oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]heneicosa-14(21),
15,17(20)-triene-12-carboxylic acid benzyl ester. To a
solution of the above methyl ester (77.9 mg, 0.0811 mmol)
in MeOH (1.0 ml) and THF (0.10 ml) was added 2.0 M
lithium hydroxide (0.240 ml, 0.480 mmol, 6.0 equiv.), and
the mixture was stirred for 5 h. The reaction mixture was
poured into 10% citric acid, and extracted with AcOEt. The
organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (5% MeOH in CH2Cl2) to afford the
above carboxylic acid (74.3 mg, 0.0785 mmol, 97%).
[a]2D4K808 (cZ0.28, CHCl3); IR (film, cmK1) 3091, 3063,
3033, 2941, 2871, 2100, 1696, 1645, 1612, 1543, 1514,
1
735; H NMR (CDCl3, 400 MHz) d 7.51–7.94 (m, 4H),
7.26–7.50 (m, 13H), 6.96 (d, JZ8.8 Hz, 2H), 6.82–7.21 (m,
2H), 6.23 (d, JZ6.8 Hz, 1H!1/7), 6.18 (d, JZ8.6 Hz,
1H!5/7), 5.87 (d, JZ10.3 Hz, 1H!1/7), 5.50–5.70 (br,
1H), 5.29 (s, 2H!2/5), 5.17 (s, 2H!3/5), 5.05–5.09 (m,
2H), 4.58–4.78 (br, 1H), 4.19–4.34 (m, 2H), 3.68–3.88 (m,
2H), 3.62 (s, 3H!1/6), 3.61 (s, 3H!1/6), 3.60 (s, 3H!2/3),
2.61–3.50 (m, 12H), 1.41–2.00 (m, 6H); 13C NMR (CDCl3,
100 MHz) d 172.3, 171.5, 171.1, 159.6, 159.2, 158.8, 158.8,
155.6, 148.3, 136.7, 136.5, 133.7, 133.5, 133.3, 132.9,
132.6, 132.4, 132.1, 132.0, 132.0, 132.0, 131.9, 131.6,
131.6, 131.0, 130.7, 130.4, 130.2, 128.6, 128.6, 128.5,
128.5, 128.2, 128.0, 128.0, 127.8, 127.5, 127.4, 127.4,
127.1, 127.0, 124.1, 124.1, 120.4, 115.3, 115.1, 110.8,
109.6, 89.5, 88.2, 70.1, 70.0, 67.3, 58.3, 58.1, 56.2, 54.7,
53.5, 53.0, 52.8, 52.0, 52.0, 49.1, 47.0, 43.6, 42.1, 37.7,
31.0, 29.9, 29.3, 26.5, 25.4, 25.0; HRMS (FAB) Calcd for
C50H55N4O12S (MCH)C 935.3537, found 935.3573.
1
1492, 1455, 1373, 1242, 1173, 984, 830, 737; H NMR
(CDCl3, 400 MHz) d 7.71–7.97 (br, 1H), 7.50–7.69 (br, 3H),
7.00–7.50 (m, 14H), 6.97 (d, JZ8.5 Hz, 2H), 6.83 (d, JZ
7.8 Hz, 1H), 6.12 (d, JZ8.6 Hz, 1H), 5.29–5.70 (br, 1H),
5.13 (brs, 2H), 5.05 (brs, 2H), 4.47–4.61 (br, 1H), 4.20–4.33
(br, 1H), 2.60–3.86 (br, 13H), 1.21–1.90 (br, 8H); 13C NMR
(CDCl3, 100 MHz) d 174.8, 171.5, 159.6, 159.0, 155.7,
148.3, 136.8, 136.4, 133.5, 132.3, 132.2, 132.1, 131.6,
4.1.31. 3-(3-Azido-propyl)-19-(4-benzyloxy-phenyl)-13-
methoxycarbonylmethyl-8-(2-nitro-benzenesulfonyl)-2-

W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
9627
131.2, 130.6, 130.3, 130.2, 128.6, 128.5, 128.0, 128.0,
127.8, 127.5, 127.5, 127.5, 127.2, 126.9, 124.1, 120.4,
115.3, 115.2, 110.8, 88.5, 70.0, 67.4, 60.4, 56.1, 53.4, 49.1,
48.0, 47.1, 44.1, 43.6, 37.7, 29.3, 28.3, 26.5, 25.0, 21.1;
HRMS (FAB) Calcd for C49H52N7O11S (MCH)C
946.3446, found 946.3463.
5.4 Hz, 1H), 5.16–5.30 (m, 2H), 5.07 (s, 2H), 4.45 (d, JZ
10.8 Hz, 1H), 1.40–4.38 (m, 22H); 13C NMR (CDCl3,
100 MHz) d 171.5, 169.2, 159.6, 159.0, 156.6, 156.0, 148.2,
136.8, 133.0, 132.6, 131.9, 131.8, 131.4, 130.7, 130.6,
130.1, 128.6, 128.6, 128.1, 128.0, 127.8, 127.7, 127.5,
125.9, 123.9, 123.5, 115.0, 110.4, 87.9, 70.0, 67.3, 60.1,
53.9, 48.5, 46.7, 45.4, 45.1, 42.9, 37.8, 29.7, 28.3, 26.8,
24.8; HRMS (FAB) Calcd for C49H52N5O10S (MCH)C
902.3435, found 902.3466.
4.1.33. 3-(3-Azido-propyl)-19-(4-benzyloxy-phenyl)-13-
pentfluororphenoxycarbonylmethyl-8-(2-nitro-benzene-
sulfonyl)-2-oxo-18-oxa-3,8,12-triaza-tricyclo[12.5.2.00,0]-
heneicosa-14(21),15,17(20)-triene-12-carboxylic acid
benzyl ester (38). To a mixture of the above acid
(83.0 mg, 0.0877 mmol) and pentafluorophenol (24.2 mg,
0.132 mmol, 1.5 equiv.) in CH2Cl2 (2.0 ml) was added
WSCD$HCl (41.9 mg, 0.219 mmol, 2.5 equiv.) at 0 8C. The
mixture was allowed to room temperature, and stirred for
30 min. The reaction mixture was poured into 10% citric
acid, and extracted with AcOEt. The organic layer was
washed with saturated aqueous NaCl, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The
residue was purified by flash chromatography (50% AcOEt
in n-hexane) to afford 38 (90.9 mg, 0.082 mmol, 93%) as a
4.1.35. O-Benzyloxy-N1-benzyloxycarbonyl-ephedra-
dine-A. To a mixture of 41 (75.9 mg, 0.0841 mmol) and
thiophenol (34.0 ml, 0.333 mmol, 4.0 equiv.) in CH3CN
(4.0 ml) was added 5.0 M aqueous KOH (42.0 ml,
0.210 mmol, 2.5 equiv.), and the reaction mixture was
heated at 50 8C for 70 min. After cooling, the reaction
mixture was filtered through a pad of Celite, and
concentrated under reduced pressure. The residue was
purified by flash chromatography (i-PrNH2/MeOH/
AcOEtZ1/1/8) to afford the above amine (45.3 mg,
0.0632 mmol, 75%) as a colorless as a colorless oil;
[a]2D2K948 (cZ0.43, CHCl3); IR (film, cmK1) 3309, 3062,
3034, 2954, 2932, 2871, 1690, 1645, 1513, 1496, 1454,
1414, 1241, 1130, 1114, 828, 736; 1H NMR (CDCl3,
400 MHz) d 7.27–7.53 (m, 13H), 7.15 (d, JZ8.2 Hz, 1H),
6.97 (d, JZ8.8 Hz, 2H), 6.83 (d, JZ8.2 Hz, 1H), 6.43 (d,
JZ10.2 Hz, 1H!2/3), 6.33 (d, JZ10.7 Hz, 1H!1/3), 5.54
(brs, 1H), 5.21 (s, 2H!1/2), 5.20 (s, 2H!1/2), 5.07 (s, 2H),
4.44 (d, JZ10.0 Hz, 1H), 1.36–4.23 (m, 22H); 13C NMR
(CDCl3, 100 MHz) d 173.0, 171.4, 169.4, 169.1, 159.3,
159.0, 158.9, 136.9, 136.8, 132.7, 132.5, 132.0, 130.7,
128.6, 128.5, 128.0, 128.0, 127.9, 127.8, 127.7, 127.7,
127.5, 127.4, 124.9, 124.3, 115.0, 111.1, 110.3, 87.4, 70.0,
67.1, 57.6, 56.0, 54.1, 49.1, 49.0, 47.6, 47.1, 47.0, 41.4,
41.0, 37.4, 30.2, 29.7, 28.5, 28.0, 27.4, 23.6, 22.8, 22.2;
HRMS (FAB) Calcd for C43H48N4O6 (MCH)C 717.3653,
found 717.3649.
colorless oil; [a]D26K618 (cZ0.28, CHCl3); IR (film, cmK1
)
3064, 3034, 2936, 2101, 1787, 1697, 1645, 1612, 1586,
1546, 1520, 1456, 1373, 1244, 1173, 1101, 996, 830, 773,
738; H NMR (CDCl3, 400 MHz) d 7.75–7.90 (br, 1H),
1
7.54–7.70 (m, 3H), 7.14–7.45 (m, 13H), 7.07 (s, 1H), 6.98
(d, JZ8.8 Hz, 2H), 6.90 (d, JZ8.3 Hz, 1H), 6.20 (d, JZ
7.1 Hz, 1H!1/7), 6.14 (d, JZ8.3 Hz, 1H!6/7), 5.61–5.73
(br, 1H), 5.19 (s, 2H), 5.05–5.10 (br, 2H), 4.57 (d, JZ
8.3 Hz, 1H!6/7), 4.53 (d, JZ7.1 Hz, 1H!1/7), 4.21–4.33
(br, 1H), 2.96–3.84 (br, 11H), 2.61–2.90 (br, 2H), 1.32–1.90
(br, 8H); 13C NMR (CDCl3, 100 MHz) d 171.4, 166.5,
160.0, 159.1, 155.5, 148.3, 142.2, 140.8, 139.8, 139.1,
138.4, 136.8, 136.6, 136.3, 133.5, 133.4, 132.3, 132.2,
131.6, 130.4, 129.7, 128.6, 128.1, 128.0, 127.9, 127.5,
127.4, 127.1, 124.1, 120.2, 115.3, 115.2, 115.2, 111.1, 88.5,
70.0, 67.5, 53.4, 49.3, 47.9, 44.1, 30.7, 29.7, 28.4, 27.1,
26.4, 25.0; HRMS (FAB) Calcd for C55H51F5N7O11S (MC
H)C 1112.3287, found 1112.3262
4.1.36. Ephedradine-A (1). To a solution of the above
amine (16.2 mg, 0.0226 mmol) in CH2Cl2 (0.60 ml) was
added BCl3 (1.0 M in CH2Cl2, 0.090 ml, 0.090 mmol,
4.0 equiv.) at K78 8C, and the mixture was stirred for
30 min at the same temperature. The mixture was allowed to
0 8C, and stirred for 90 min. The reaction mixture was
poured into saturated aqueous NaHCO3, and extracted with
10% MeOH in CH2Cl2. The organic layer was washed with
saturated aqueous NaCl, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue was
purified by PTLC (i-PrNH2/MeOH/CH2Cl2 Z5/5/90) to
afford Ephedradine A (1) (8.17 mg, 0.0166 mmol, 73%) as a
colorless oil; [a]2D5K728 (cZ0.25, CHCl3/MeOHZ9/1); IR
4.1.34. O-Benzyloxy-N1-benzyloxycarbonyl-N2-nitro-
benzensulfonyl-ephedradine-A (41). To a solution of
triphenylphosphine (69.0 mg, 0.263 mmol, 2.5 equiv.) in
toluene (10 ml) at reflux was added a solution of 38
(117 mg, 0.105 mmol) in toluene (5.0 ml) via syringe pump
for 4 h. After the addition, the mixture was heated at the
same temperature for 4 h. After cooling, the reaction
mixture was concentrated under reduced pressure. The
residue was dissolved in CH3CN (5.0 ml) and water
(1.0 ml), and heated at reflux for 60 h. The reaction mixture
was poured into water, and extracted with CH2Cl2. The
organic layer was washed with saturated aqueous NaCl,
dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by flash
chromatography (5% MeOH in AcOEt) to afford 41
(69.3 mg, 0.0768 mmol, 73%) as a colorless as a colorless
oil; [a]2D3K608 (cZ0.21, CHCl3); IR (film, cmK1) 3413,
3353, 3089, 3065, 3033, 2932, 2873, 1691, 1649, 1544,
1513, 1454, 1372, 1173, 1125, 828, 736; 1H NMR (CDCl3,
400 MHz) d 7.76–7.93 (m, 1H), 7.28–7.72 (m, 16H), 7.09
(brd, JZ8.2 Hz, 1H), 6.98 (d, JZ8.8 Hz, 2H), 6.85 (d, JZ
8.2 Hz, 1H), 6.36 (d, JZ10.8 Hz, 1H), 5.86 (dd, JZ5.6,
1
(film, cmK1) 3287 (br), 2929, 1641, 1519, 1488; H NMR
(CD3OD, 400 MHz) d 7.29 (d, JZ8.7 Hz, 2H), 7.21 (brs,
1H), 7.13 (dd, JZ8.0, 1.0 Hz, 1H), 6.78 (d, JZ8.7 Hz, 2H),
6.77 (d, JZ8.0 Hz, 1H), 6.01 (d, JZ11.3 Hz, 1H), 4.59 (d,
JZ11.3 Hz, 1H), 4.13 (dd, JZ13.9, 8.5 Hz, 1H), 3.62–3.98
(m), 2.52–3.00 (m), 2.04–2.45 (m), 1.43–1.92 (m); 13C
NMR (CD3OD, 100 MHz) d 173.6, 171.7, 160.2, 159.4,
136.8, 131.1, 130.7, 129.1, 129.1, 127.3, 123.7, 116.5,
116.5, 110.0, 89.5, 61.6, 54.7, 49.7, 48.5, 47.8, 47.1, 44.9,
43.1, 38.4, 29.5, 27.7, 27.6, 25.8; HRMS (FAB) Calcd for
C28H36N4O4 (MCH)C 493.2816, found 493.2824.

9628
W. Kurosawa et al. / Tetrahedron 60 (2004) 9615–9628
(d) Baker, R.; Cooke, N. G.; Humphrey, G. R.; Wright,
Acknowledgements
S. H. B.; Hirshfield, J. J. Chem. Soc., Chem. Commun. 1987,
1102–1104.
We thank Professor Yoshiteru Oshima (Tohoku University)
for providing spectral data of the natural product. The
authors also thank Dr. H. Naoki (Suntory Institute for
Bioorganic Research) for kindly measuring the HRMS. This
work was financially supported by CREST, JST, and a
Grant-in-Aid from the Ministry of Education, Science,
Sports, Culture and Technology, Japan.
9. For a review on asymmetric intermolecular C–H activation,
see: Davies, H. M. L.; Antoulinakis, E. G. J. Organomet.
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10. Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett.
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12. Kurosawa, W.; Kan, T.; Fukuyama, T. Synlett 2003,
1028–1030.
13. Since the 4-(benzyloxy)benzyl chloride was not commercially
available, it was prepared from 4-(hydroxy)benzaldehyde in
the following three-step sequence: (a) K2CO3, BnBr, DMF,
60 8C, quant; (b) NaBH4, THF/H2O, 99%; (c) SOCl2, CH2Cl2,
98%.
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