Asymmetric total synthesis of the gastroprotective microbial agent AI-77-B

Article abstract of DOI:10.1002/ejoc.200390125

An enantioselective total synthesis of the pseudopeptide microbial agent AI-77-B, which has shown potent antiulcerogenic properties, is described. The synthesis is convergent and involves the assembly of a dihydroisocoumarin fragment and a hydroxy amino acid. The dihydroisocoumarin derivative was synthesised by means of a Diels-Alder reaction between 1-methoxy-1,3-cyclohexadiene and an alkynyl ester derivative as the dienophile. The alkynyl ester was obtained stereoselectively by two different synthetic routes: (1) A stereoselective allylation of leucinal, and (2) a titanium enolate-mediated anti-aldol reaction with trichlorobutyraldehyde, a novel homopropargylaldehyde equivalent. The stereocentres of the hydroxy amino acid moiety were generated through a titanium enolate-mediated syn-aldol reaction, Curtius rearrangement, and application of Dondoni's aldehyde homologation. Condensation of the dihydroisocoumarin and hydroxy amino acid moieties and subsequent removal of the protecting groups furnished optically active AI-77-B. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200390125

FULL PAPER
Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B
Arun K. Ghosh,*[a] Alexander Bischoff,[a] and John Cappiello[a]
Keywords: Asymmetric synthesis / Natural products / Total synthesis / AI-77-B
An enantioselective total synthesis of the pseudopeptide mi-
crobial agent AI-77-B, which has shown potent antiulcerog-
enic properties, is described. The synthesis is convergent and
ated anti-aldol reaction with trichlorobutyraldehyde, a novel
homopropargylaldehyde equivalent. The stereocentres of the
hydroxy amino acid moiety were generated through a tita-
involves the assembly of a dihydroisocoumarin fragment and nium enolate-mediated syn-aldol reaction, Curtius re-
a hydroxy amino acid. The dihydroisocoumarin derivative
was synthesised by means of a Diels−Alder reaction between
1-methoxy-1,3-cyclohexadiene and an alkynyl ester derivat-
arrangement, and application of Dondoni’s aldehyde homo-
logation. Condensation of the dihydroisocoumarin and hy-
droxy amino acid moieties and subsequent removal of the
ive as the dienophile. The alkynyl ester was obtained stereo- protecting groups furnished optically active AI-77-B.
selectively by two different synthetic routes: (1) A stereose- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
lective allylation of leucinal, and (2) a titanium enolate-medi-
Germany, 2003)
Introduction
dification of AI-77-B. These efforts culminated in the devel-
opment of a number of orally active prodrug analogues
possessing both antiinflammatory and antiulcer activit-
ies.[7,8] To date, several total syntheses of AI-77-B have been
reported, as well as synthetic approaches to either the dihy-
droisocoumarin or the hydroxy amino acid fragment.[9Ϫ24]
The majority of these previously described syntheses ut-
ilised chirality derived from -ribose,[9] -leucine,[10Ϫ16] -
aspartic acid[10,11,13,14] and -glutamic acid.[15,16] We have
recently reported a stereoselective route to AI-77-B in
which four of the five stereogenic centres were set by asym-
metric synthesis.[25,26] Here we now describe a convergent
and stereocontrolled total synthesis of AI-77-B in which all
five stereogenic centres have been constructed by asymmet-
ric synthesis.
The 3,4-dihydroisocoumarin derivatives are common
structural features of numerous natural products and ex-
hibit a wide range of important biological properties.[1,2]
One such natural product, AI-77-B (1, Figure 1), which
contains a 3,4-dihydroisocoumarin linked to a dihydroxy β-
amino acid side chain, has shown significant antiulcerog-
enic properties. AI-77-B (1) has been isolated from the cul-
ture broth of Bacillus pumilus AI-77.[3]
Results and Discussion
Figure 1. Structure of AI-77-B
Our synthetic plan for AI-77-B (1) is based upon coup-
ling the dihydroisocoumarin fragment 2 and the protected
hydroxy amino acid 3 and subsequent conversion of the ter-
minal olefin into a carboxylic acid at the final stage of the
synthesis. As outlined in Figure 2, the dihydroisocoumarin
skeleton would be constructed by means of a thermal
DielsϪAlder reaction between dienophile 4 and 1-methoxy-
1,3-cyclohexadiene. This reaction generally proceeds with
extrusion of ethylene, providing convenient access to
aromatic compounds.[27Ϫ29] Alkyne derivative 4 should be
accessible from anti-aldol product 5 through Curtius re-
arrangement and base-catalysed elimination of the trihalo-
alkane functionality. Both stereogenic centres in 4 would
be derived by the diastereoselective anti-aldol methodology
recently developed by our group.[30,31] Alternatively, con-
AI-77-B is a highly fluorescent pseudopeptide, the struc-
ture and absolute configuration of which were determined
by Shimojima and co-workers by spectroscopic and X-ray
crystallographic techniques.[4Ϫ6] It exhibits potent antiul-
cerogenic and simultaneous antiinflammatory activity to-
ward stress ulcers without anticholinergic and antihistam-
inergic side effects.[4Ϫ6] The therapeutic potential of AI-77-
B is, however, limited by its poor oral absorption properties.
Because of its intriguing biological properties, there has
been significant interest in the synthesis and structural mo-
[a]
Department of Chemistry, University of Illinois at Chicago,
845 West Taylor Street, Chicago, Illinois 60607, USA
E-mail: arunghos@uic.edu
Eur. J. Org. Chem. 2003, 821Ϫ832  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0305Ϫ0821 $ 20.00ϩ.50/0
821

A. K. Ghosh, A. Bischoff, J. Cappiello
FULL PAPER
struction of alkyne derivative 4 could be carried out by the corresponding methyl trichlorobutyrate in 32% yield
starting with leucinal, through stereoselective allylation fol- after distillation.[35]
lowed by conversion of the allyl group into a terminal al-
kyne derivative. The synthesis of hydroxy amino acid frag-
ment 3 should be achievable from isopropylidene derivative
6 through Dondoni’s homologation procedure,[32Ϫ34] and
the 1,2-amino alcohol functionality in 6 should be derivable
from syn-aldol product 7 by use of a Curtius rearrangement
as the key step. Our recently developed highly diastereo-
selective syn-aldol reaction can be employed to provide 7,[26]
therefore four of the five stereogenic centres in AI-77-B can
be efficiently constructed by means of our ester-derived tita-
nium enolate-based aldol reactions.
Scheme 1. (a) NaOH, BnEt3NCl, CHCl3, H2O, 0 °C, 2 h (32%); (b)
DIBAL, CH2Cl2, Ϫ78 °C, 1.5 h (95%); (c) 4-methylvaleric acid,
EDCI, DMAP, 23 °C, 2 h (99%); (d) TiCl4, iPr2NEt, 0 to 23 °C, 1 h,
then 8, Ϫ78 °C, 10 min (90%, 90% de); (e) LiOH, H2O2, THF, H2O,
room temp., 12 h (97%); (f) DPPA, Et3N, CH2Cl2, reflux, 12 h, (94%);
(g) Boc2O, DMAP, Et3N, THF, room temp., 3 h, then NaOH, EtOH,
H2O, room temp., 5 min (91%); (h) DMP, TsOH, CH2Cl2, 23 °C,
15 min (97%); (i) nBuLi, TMEDA, THF, Ϫ78 °C, 20 min, then
ClCO2Me (85%); (j) nBuLi, THF, Ϫ78 °C, 10 min (88%)
Subsequent reduction of the ester with DIBAL in
CH2Cl2 at Ϫ78 °C afforded aldehyde 8 in 95% yield. For
the ester enolate aldol reaction, the requisite optically active
indanyl ester 11 was prepared by esterification of the known
N-tosyl-1-amino-2-indanol[36] 10 with 4-methylvaleric acid
in the presence of EDCI for 2 h at 23 °C, which furnished
11 in near quantitative yield. The preparation of ester 11
Figure 2. Retrosynthesis of AI-77-B
was also accomplished in a one-pot procedure, by consecut-
It was intended that initial assembly of dihydroisocouma- ive tosylation and acylation of the commercially available
rin fragment 2 should be carried out prior to the construc- (1S,2R)-1-aminoindan-2-ol with TsCl and 2 equiv. of
tion of hydroxy amino acid moiety 3. We planned to use an DMAP in CH2Cl2 at 0 °C for 1 h, followed by esterification
ester-derived titanium enolate-mediated anti-aldol reaction with 4-methylvaleric acid in the presence of EDCI for 2 h
to construct both stereocentres of aldolate 5.[30] The ter- at 23 °C, to afford 11 in 99% yield. The aldol condensation
minal trichloroalkyl group in 5 was designed to provide al- of 11 was carried out by initial treatment of 11 with TiCl4
kyne functionality through a base-catalysed elimination re- and iPr2NEt in CH2Cl2 at 0 to 23 °C for 1 h. The resulting
action. As shown in Scheme 1, the requisite trichlorobutyr- titanium enolate was then cooled to Ϫ78 °C and treated
aldehyde (8) is a homopropargyl aldehyde (9) equivalent. with aldehyde 8 at Ϫ78 °C for 10 min to give aldolate 12 as
1
Multigram quantities of aldehyde 8 were prepared by the major product (anti/syn ϭ 19:1 by H and 13C NMR
Michael addition of chloroform to methyl acrylate under analysis) in 90% yield after silica gel chromatography. Sa-
catalytic phase-transfer conditions with NaOH and ponification of 12 with aqueous LiOH and H2O2 in THF/
BnEt3NCl in CHCl3/water (1:1) at 0 °C for 2 h to provide water (3:1) for 12 h at 23 °C provided the corresponding
822
Eur. J. Org. Chem. 2003, 821Ϫ832

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B
FULL PAPER
acid. The chiral auxiliary was recovered in 95% yield after
column chromatography. Curtius rearrangement[37Ϫ39] of
the resulting acid was carried out with diphenylphosphoryl
azide and triethylamine in CH2Cl2 at reflux for 12 h, to fur-
nish oxazolidinone derivative 13 as a single diastereomer in
94% yield.[40] Treatment of oxazolidinone 13 with Boc2O
and Et3N in the presence of a catalytic amount of DMAP
in THF at 23 °C for 3 h, followed by treatment with aque-
ous NaOH in EtOH/water (1:1) for 5 min, afforded the cor-
responding N-Boc-protected amino alcohol. Subsequent
protection of the resulting amino alcohol with 2,2-dime-
thoxypropane and p-TsOH in CH2Cl2 for 15 min at 23 °C
provided isopropylidene derivative 14 in 88% yield. Our
synthetic strategy now called for the conversion of the trich-
loro moiety of 14 into an alkyne, resulting in 17, the dien-
ophile for the key DielsϪAlder reaction. Our initial attempt
to generate the terminal alkyne functionality by treatment
of 14 with nBuLi (3Ϫ6 equiv.) in THF at Ϫ78 °C furnished
only a trace amount of terminal alkyne 15, together with
mostly undesired by-products. However, treatment of 14
with 1.5 equiv. of nBuLi in THF at Ϫ78 °C for 10 min gave
dichloroolefin 16 in excellent yield. Treatment of 14 with
nBuLi (4 equiv.) and TMEDA (3 equiv.) afforded the alkyne
derivative 15 in 88% yield. Subsequently, trichloro derivat-
ive 14 was converted into dienophile 17 in a one-pot pro-
cedure, 14 being treated at Ϫ78 °C first with nBuLi (1.5
equiv.), and then with TMEDA (3 equiv.) and nBuLi (3
equiv.). The resulting reaction mixture was quenched with
methyl chloroformate to provide the required dienophile 17
in 85% yield.
Scheme 2. (a) SnCl4, allyltributyltin, Ϫ78 °C, 1 h (94%, 92% de);
(b) HCϵCCH2Br, Zn, DMF/Et2O (1:1), 0 to 23 °C, 12 h (67%,
84% de); (c) DMP, TsOH, DCM, 23 °C, 1 h (99%); (d) O3, PPh3,
DCM, Ϫ78 °C (97%); (e) CH3COC(N2)PO(OMe)2, Cs2CO3,
iPrOH, 0 °C, 1 h, 23 °C, 11 h (97%); (f) nBuLi, ClCO2Me, THF,
Ϫ78 °C, 10 min (99%)
1
20 as the major product, in 67% yield. H and 13C NMR
analysis revealed a diastereomeric ratio of 92:8. The de-
picted stereochemical identity of the major isomer 20 was
established after its conversion into the isopropylidene de-
rivative 21 and subsequent NOE experiments.
The stereochemical outcome of the allyltributyltin addi-
tion to 18 can be explained on the basis of the chelated
transition state model shown in Figure 3. In this model,
SnCl4 forms a conformationally constrained chelated com-
plex in which the presence of the bulky isobutyl group con-
trols the direction of the incoming nucleophile. Preferential
Si-face attack thus results in the observed syn stereoselectiv-
ity. Similar allylmetal addition to α-aminoaldehydes has
previously been studied by Kiyooka et al. and Rich et
al.[43,44]
An alternative synthesis of dienophile 17 was also ac-
complished by means of a diastereoselective allylmetal ad-
dition to N-Boc-leucinal 18.[26] This was prepared in multig-
ram quantities from the commercial N-Boc--leucine by
formation and reduction of the corresponding Weinreb
amide.[41,42] Rich and Prasad have shown that the SnCl4-
mediated, highly diastereoselective allylsilane addition to 18
provides the threo isomer 19.[43] In a modified procedure,
the use of allyltributyltin in place of allylsilane provided
further improvements in the yield of and selectivity for threo
isomer 19. As shown in Scheme 2, treatment of 18 with
SnCl4 at Ϫ78 °C, followed by dropwise addition of allyltri-
butyltin in CH2Cl2, provided homoallylic alcohol 19 as a
1
major product (96:4 mixture by H NMR analysis).
The presence of tin impurities, however, greatly complic-
ated the purification of pure diastereomer 19. This problem
was circumvented by reduction of the crude product with
NaBH4 in MeOH for 2 min at 23 °C, which presumably
reduced the chloroalkylstannane impurities in the crude
Figure 3. Stereochemical model for allylmetal addition
For the synthesis of dienophile 17, homoallylic alcohol
product to alkylstannane derivatives.[45] This procedure sig- 19 was treated with 2,2-dimethoxypropane in the presence
nificantly simplified the chromatographic separation, and of a catalytic amount of p-TsOH at 23 °C for 1 h, followed
diastereomer 19 was isolated in 90% yield. For the stereose- by ozonolytic cleavage of the resulting olefin at Ϫ78 °C to
lective synthesis of the corresponding terminal alkyne deriv- provide 22 in 96% yield. Treatment of aldehyde 22 with di-
ative of 19, we have also investigated the addition to 18 methyl (1-diazo-2-oxopropyl)phosphonate[46Ϫ49] in the
of organozinc reagents derived from propargyl bromide.[26] presence of Cs2CO3 in 2-propanol at 0Ϫ23 °C for 11 h pro-
Treatment of N-Boc-leucinal with 4 equiv. of propargyl vided alkyne derivative 15 in 97% yield. The terminal al-
bromide in DMF/diethyl ether (1:1), followed by slow addi- kyne was deprotonated with nBuLi in THF at Ϫ78 °C for
tion of zinc dust at 0 °C, afforded homopropargyl alcohol 10 min and the resulting lithium acetylide was quenched
Eur. J. Org. Chem. 2003, 821Ϫ832
823

A. K. Ghosh, A. Bischoff, J. Cappiello
FULL PAPER
with methyl chloroformate at Ϫ78 °C to furnish the alkynyl
ester 17 in near quantitative yield.
With an efficient synthesis of dienophile 17 now available,
we next planned to carry out the key DielsϪAlder step. As
shown in Scheme 3, the DielsϪAlder reaction between 17
and excess 1-methoxy-1,3-cyclohexadiene (10 equiv.) was
carried out in toluene in a sealed tube at 175 °C bath tem-
perature for 72 h. The cycloaddition presumably proceeded
to form cycloadduct 23, which then underwent a retro-
DielsϪAlder reaction with the extrusion of ethylene. This
provided benzoate derivative 24 in 76% yield after silica gel
chromatography. Treatment of 24 with a catalytic amount
of p-TsOH and water in CH2Cl2 for 20 min at 23 °C
furnished 3,4-dihydroisocoumarin fragment 2 in 97%
yield.[26]
Scheme 4. (a) 4-Pentenoic acid, EDCI, DMAP, CH2Cl2, 23 °C, 4 h
(99%); (b) TiCl4, iPr2NEt, 0 to 23 °C, 1 h, then BnOCH2CHO, Ϫ78
°C, 20 min (97%); (c) LiOH, H2O2, THF/H2O (3:1), 23 °C, 12 h
(96%); (d) DPPA, Et3N, CH2Cl2, reflux, 12 h (92%); (e) Boc2O,
Et3N, DMAP, THF, 23 °C, 2 h, then aqueous NaOH/EtOH (1:1)
(96%); (f) DMP, p-TsOH, CH2Cl2, 23 °C, 6 h (92%); (g) Li/NH3,
THF, Ϫ78 °C, 5 min (95%); (h) (COCl)2, DMSO, Et3N, CH2Cl2,
Ϫ78 to 0 °C (95%)
Scheme 3. (a) 1-Methoxy-1,3-cyclobutadiene, toluene, 175 °C, 3 d
(76%); (b) TsOH, CH2Cl2, H2O, 23 °C, 20 min (97%)
amount of DMAP in THF at 23 °C for 2 h provided the
corresponding N-Boc-oxazolidinone derivative, which was
The synthesis of protected hydroxyamino acid fragment 3 hydrolysed with aqueous sodium hydroxide in EtOH/water
is shown in Scheme 4. We have recently developed practical (1:1) to furnish N-Boc-protected amino alcohol 28 in 96%
asymmetric methodologies for the preparation of optically yield. Treatment of 28 with 2,2-dimethoxypropane and a
active syn- and anti-aldols based upon ester-derived tita- catalytic amount of p-TsOH in CH2Cl2 at 23 °C afforded
nium enolate aldol reactions.[30,31] We planned to utilise our N,O-isopropylidene derivative 6 in 92% yield. Removal of
ester-derived titanium enolate-mediated syn-aldol con- the benzyl ether was effected by reduction of 6 with lithium
densation with benzyloxyacetaldehyde to generate the ste- in liquid ammonia at Ϫ78 °C for 5 min, and Swern oxida-
reocentres of aldolate 7. Thus, acylation of cis-1-toluenesul- tion of the resulting alcohol afforded aldehyde 29, which
fonamido-2-indanol 10 with 4-pentenoic acid in the pres- was subjected to Dondoni’s stereoselective homologation
ence of EDCI and DMAP afforded ester 25 in excellent procedure.[32Ϫ34]
yield.
As depicted in Scheme 5, treatment of aldehyde 29 with
The corresponding titanium enolate was generated by 2-(trimethylsilyl)thiazole in CH2Cl2 at 23 °C for 6 h fur-
treatment of ester 25 with TiCl4 and iPr2NEt in CH2Cl2 nished a 1:1 mixture of alcohol 30 and its trimethylsilyl
at 0Ϫ23 °C for 1 h. The resulting enolate was treated with ether derivative 31. Immediate exposure of the reaction
benzyloxyacetaldehyde at Ϫ78 °C to provide syn-aldolate mixture to nBu4NϩFϪ at 23 °C for 20 min afforded 30 in
26 as a single diastereomer in 97% yield after chromato- 85% yield. The determination of the isomer ratio by 1H
graphy. Aldolate 26 was converted into oxazolidinone 27 in NMR (CDCl3 or [D6]DMSO, including low-temperature
a two-step sequence. Saponification with lithium hydroxide experiments) was complicated by the presence of the N-
in the presence of hydrogen peroxide in THF/water (3:1) Boc-O-isopropylidene group, which resulted in rotational
provided the corresponding acid (97%), with recovery of the isomers at 23 °C. However, the level of diastereoselectivity
chiral auxiliary (92%). The Curtius rearrangement[37Ϫ39] of was determined unequivocally after protection of 30 as its
the resulting acid was carried out with diphenylphosphoryl benzyl ether 32 and subsequent removal of the isopropyl-
1
azide and triethylamine in CH2Cl2 at reflux for 12 h. This idene group to provide N-Boc derivative 33. The H and
afforded oxazolidinone 27 in 92% yield as a single isomer 13C NMR analysis of 33 revealed the presence of a single
by 1H and 13C NMR analysis.[40] Treatment of 27 with diastereomer. Our next synthetic plan required the conver-
Boc2O and triethylamine in the presence of a catalytic sion of the thiazole moiety of 32 into an aldehyde, followed
824
Eur. J. Org. Chem. 2003, 821Ϫ832

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B
FULL PAPER
by its oxidation to hydroxy amino acid fragment 3. The
thiazole group was first converted into an aldehyde in a
one-pot, three-step sequence developed by Dondoni et
al.[32Ϫ34] Accordingly, thiazole 32 was N-methylated by
treatment with methyl trifluoromethanesulfonate in the
presence of molecular sieves in acetonitrile at 23 °C for
30 min. The resulting thiazolinium CϭN bond was reduced
with sodium borohydride in MeOH at 0 °C for 30 min to
provide the corresponding thiazolidine. Subsequent treat-
ment of the thiazolidine with copper() oxide and copper()
chloride in a mixture of acetonitrile and water (10:1)
afforded the α-benzyloxyaldehyde in an overall yield of
82%. The more commonly used mercury() chloride pro-
cedure was less effective, as it converted the thiazolidine to
α-benzyloxyaldehyde in only modest yields (25Ϫ35%). The
α-benzyloxyaldehyde was oxidized with sodium chlorite in
tert-butyl alcohol/water (5:1) in the presence of 2-methyl-2-
Scheme 6. (a) TFA, CH2Cl2, 0 °C, 30 min, then 3, EDCI, DMAP,
CH2Cl2, room temp., 12 h (72%); (b) O3, CH2Cl2, Ϫ78 to 23 °C,
PPh3 (98%); (c) NaClO2, 2-methyl-2-butene, NaH2PO4·H2O,
tBuOH/H2O (5:1) (99%); (d) Cs2CO3, MeOH/H2O (5:1), 30 min,
then BnBr, DMF, 0 °C, 6 h (90%); (e) MgI2, THF, reflux, 5 min
(93%); (f) H2, 10% Pd/C, Dowex 50-X8, THF/MeOH (1:1), 23 °C,
12 h (75%)
butene to furnish 3 in 98% yield.
butyl alcohol and water (5:1) in the presence of 2-methyl-2-
butene, and (3) treatment of the resulting acid with cesium
carbonate and benzyl bromide to provide benzyl ester 35 in
87% yield over three steps. For clean O-demethylation, the
formation of benzyl ester 35 was critical, as attempted O-
demethylation of the corresponding acid with MgI2 in THF
resulted in numerous side products and a low yield
(15Ϫ25%) of the desired phenol derivative. Smooth O-de-
methylation was effected by treatment of 35 with MgI2 in
THF, followed by heating the resulting mixture at reflux for
5 min to afford phenol derivative 36 in 93% yield.[11]
The completion of the synthesis of AI-77-B now required
the removal of the remaining protecting groups. We initially
attempted sequential removal of the protecting groups, but
this proved to be more difficult than we had expected. After
much experimentation, we developed conditions that effec-
tively removed all three protecting groups in a one-pot pro-
cedure. Thus, phenol derivative 36 in THF/MeOH (1:1) was
treated with 10% Pd/C and Dowex 50-X8 resin at 23 °C
under hydrogen for 12 h. This resulted in clean removal of
the isopropylidene, tert-butoxycarbonyl and benzyl groups,
Scheme 5. (a) 2-TST, CH2Cl2, 23 °C, 6 h; (b) TBAF, THF, room
temp., 20 min (85%, 29 to 30); (c) NaH, BnBr, nBu4NI, THF, 12 h
(95%); (d) p-TsOH·H2O, MeOH, 23 °C, 24 h (95%); (e) i. MeOTf,
˚
4 A molecular sieves, MeCN, 23 °C, 30 min; ii. NaBH4, MeOH, 0
°C, 30 min; iii. CuO, CuCl2·H2O, MeCN/H2O (10:1), 23 °C, 10 min
(82%); (f) NaClO2, NaH2PO4·H2O, 2-methyl-2-butene, tBuOH/
H2O (5:1) (98%)
With the efficient synthesis of isocoumarin fragment 2
and hydroxyamino acid fragment 3 now accomplished, our
synthetic efforts were then focused on coupling these frag-
ments. As shown in Scheme 6, the free amine of isocouma-
rin 2 was generated by treatment with trifluoroacetic acid
in CH2Cl2 at 0 °C for 30 min, followed by concentration of
the reaction mixture to dryness. Since the free amine readily
transforms into the corresponding lactam upon standing,
the coupling reaction was carried out immediately with its
ammonium salt.[4] This was treated with acid 3 in the pres-
ence of EDCI and DMAP in CH2Cl2 at 23 °C for 12 h to
furnish the amide derivative 34 in 72% yield.
providing optically active AI-77-B in 75% yield {[α]D23
ϭ
Ϫ75.2 (c ϭ 0.11, MeOH); ref.[15,16] [α]2D2 ϭ Ϫ78.2 (c ϭ 0.08,
MeOH); m.p. 134Ϫ135 °C; ref.[4] m.p. 139.5 °C}. The spec-
tral data for synthetic AI-77-B are in full accordance with
the reported data for authentic samples.[4,10,11]
Conclusion
As shown, the terminal alkene in 34 was converted into
In summary, a stereocontrolled and convergent synthesis
the benzyl ester derivative by the following three-step se- of the gastroprotective substance AI-77-B has been achieved.
quence: (1) ozonolysis at Ϫ78 °C to furnish the correspond- A number of key features of this synthesis are noteworthy.
ing aldehyde, (2) oxidation of the resulting aldehyde to an All five stereogenic centres of AI-77-B were set up by asym-
acid by exposure to sodium chlorite in a mixture of tert- metric syntheses. The synthesis features highly diastereoselec-
Eur. J. Org. Chem. 2003, 821Ϫ832
825

A. K. Ghosh, A. Bischoff, J. Cappiello
FULL PAPER
(s) cmϪ1. HRMS (ES, m/z): calcd. C22H27NNaO4S [M ϩ Naϩ]
424.1559, found 424.1575.
tive ester-derived asymmetric syn- and anti-aldol reactions, a
regioselective DielsϪAlder reaction, and Dondini homologa-
tion. This synthesis should provide convenient access to a
variety of structural analogues of AI-77-B.
(2S,3S,1ЈS,2ЈR)-1Ј-Tosylaminoindan-2Ј-yl
6,6,6-Trichloro-3-hy-
droxy-2-isobutylhexanoate (12): TiCl4 (0.39 mL, 3.56 mmol) was
added at 0 °C to a solution of 11 (1.43 g, 3.56 mmol) in CH2Cl2
(50 mL). After the mixture had been stirred for 15 min, iPr2NEt
(2.17 mL, 12.5 mmol) was added dropwise at 0 °C and the resulting
mixture was stirred for 2 h at room temperature. It was then cooled
to Ϫ78 °C, and TiCl4 (0.78 mL, 7.12 mmol) was added in one por-
tion. Subsequently, 8 (0.63 g, 7.12 mmol) in CH2Cl2 (2 mL) was
added dropwise over a period of 5 min. After the mixture had been
stirred for 10 min at Ϫ78 °C, the reaction was quenched with satur-
ated aqueous NH4Cl and the organic phase was dried with
Na2SO4. Concentration in vacuo (crude NMR showed 90% de) and
chromatographic purification (silica, 30% EtOAc in hexanes)
yielded 12 (1.85 g, 90%) as a white solid. M.p. 185Ϫ188 °C (de-
comp.). [α]2D3 ϭ Ϫ14.1 (c ϭ 1.92, CHCl3). 1H NMR (CDCl3,
500 MHz): δ ϭ 7.84 (d, J ϭ 8.5 Hz, 2 H), 7.32 (d, J ϭ 8.5 Hz, 2
H), 7.29Ϫ7.19 (m, 4 H), 6.25 (d, J ϭ 10.0 Hz, 1 H), 5.42 (dd, J ϭ
5.0, 5.0 Hz, 1 H), 4.90 (dd, J ϭ 10.0, 5.0 Hz, 1 H), 3.72 (m, 1 H),
3.29 (d, J ϭ 7.0 Hz, 1 H), 3.12 (dd, J ϭ 17.5, 5.0 Hz, 1 H), 2.96
(ddd, J ϭ 14.5, 11.0, 4.5 Hz, 1 H), 2.93 (d, J ϭ 17.0 Hz, 1 H), 2.66
(ddd, J ϭ 15.0, 11.0, 4.5 Hz, 1 H), 2.57 (ddd, J ϭ 15.0, 6.5, 4.5 Hz,
1 H), 2.45 (s, 3 H), 1.95Ϫ1.86 (m, 2 H), 1.60 (ddd, J ϭ 13.5, 10.5,
4.5 Hz, 1 H), 1.47 (m, 1 H), 1.22 (ddd, J ϭ 13.5, 9.5, 4.5 Hz, 1 H),
0.91 (d, J ϭ 6.5 Hz, 3 H), 0.84 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C
NMR (CHCl3, 125 MHz): δ ϭ 173.3, 144.1, 140.3, 138.8, 138.0,
130.3, 128.9, 127.9, 127.6, 125.3, 124.8, 100.2, 75.8, 72.2, 60.1, 52.0,
51.0, 38.4, 37.7, 32.5, 26.7, 23.7, 22.2, 22.0 ppm. IR (film): ν˜ ϭ
3484 (br. s), 3273 (br. s), 1732 (s) cmϪ1. HRMS (ES, m/z): calcd.
C26H32Cl3NNaO5S [M ϩ Naϩ] 598.0964, found 598.0969.
Experimental Section
General: Melting points were recorded with a Thomas Hoover ca-
pillary melting point apparatus and are uncorrected. Anhydrous
solvents and reagents were obtained as follows: tetrahydrofuran
and diethyl ether, distillation from sodium and benzophenone;
dichloromethane, distillation from CaH2; triethylamine, distillation
from CaH2. All other solvents were HPLC grade. Column chroma-
tography was performed with Whatman 240Ϫ400 mesh silica gel
under low pressure of 5Ϫ10 psi. Thin-layer chromatography (TLC)
was carried out with E. Merck silica gel 60 F-254 plates.
4,4,4-Trichlorobutyraldehyde (8): A mixture of methyl acrylate
(2.00 g, 23.2 mmol), NaOH (10.0 g), BnEt3NCl (0.10 g), chloro-
form (20.0 g) and water (10.0 g) was vigorously stirred at 0 °C for
2 h. After addition of CH2Cl2 and water, the organic phase was
separated, washed with brine, dried with Na2SO4 and concentrated
in vacuo. Distillation of the residue furnished methyl 4,4,4-trichlo-
robutanoate (1.50 g, 32%) as a colourless liquid. b.p. 80 °C/1 Torr
(ref.[32Ϫ34] b.p. 80 °C/0.3 Torr). H NMR (CDCl3, 500 MHz): δ ϭ
1
3.74 (s, 3 H), 3.07 (m, 2 H), 2.82 (m, 2 H) ppm. 13C NMR (CHCl3,
125 MHz): δ ϭ 171.9, 98.9, 52.5, 50.3, 31.6 ppm. IR (film): ν˜ ϭ
1742 (s) cmϪ1. HRMS (ES, m/z): calcd. C5H7Cl3NaO2 [M ϩ Naϩ]
226.9409, found 226.9416. A solution of methyl 4,4,4-trichlorobut-
anoate (1.34 g, 6.54 mmol) in CH2Cl2 (80 mL) was cooled to Ϫ78
°C. DIBAL (1.0  in hexanes, 6.54 mL, 6.54 mmol) was added
dropwise and the reaction mixture was stirred for 1.5 h at Ϫ78 °C.
After the reaction had been quenched with aqueous potassium so-
dium tartrate, the organic layer was dried with Na2SO4 and concen-
trated in vacuo to give 8 (1.09 g, 95%) as a colourless liquid. 1H
NMR (CDCl3, 500 MHz): δ ϭ 9.81 (s, 1 H), 3.02 (m, 2 H), 2.97
(m, 2 H) ppm. 13C NMR (CHCl3, 125 MHz): δ ϭ 198.4, 98.8, 47.3,
40.9 ppm. IR (film): ν˜ ϭ 3439 (br. s), 1728 (s) cmϪ1. HRMS (ES,
m/z): calcd. C4H5Cl3NaO [M ϩ Naϩ] 196.9304, found 196.9295.
(4S,5S)-4-Isobutyl-5-(3Ј,3Ј,3Ј-trichloroprop-1Ј-yl)-1,3-oxazolidin-2-
one (13): A mixture of 12 (433 mg, 7.51 mmol), LiOH·H2O
(95.0 mg, 2.25 mmol) and H2O2 (30%, 153 µL, 4.50 mmol) in THF
(10 mL) and water (3 mL) was vigorously stirred for 12 h at 23 °C.
In order to obtain a biphase solution, saturated aqueous NaHCO3
(20 mL) and diethyl ether (20 mL) were added. The water layer
was acidified with concentrated HCl (pH ϭ 2) and extracted with
CH2Cl2. The organic layer was dried with Na2SO4, concentrated
in vacuo and chromatographically purified (silica, 40% EtOAc in
hexanes) to yield (2S,3S)-6,6,6-trichloro-3-hydroxy-2-isobutylhex-
anoic acid (212 mg, 97%) as a white solid. M.p. 145Ϫ147 °C.
(1ЈS,2ЈR)-1Ј-p-Tosylaminoindan-2Ј-yl 4-Methylpentanoate (11):
(1S,2R)-1-Aminoindan-2-ol (746 mg, 5.00 mmol) was dissolved in [α]2D3
ϭ
Ϫ21.7 (c
ϭ
1.57, MeOH). 1H NMR ([D4]MeOH,
CH2Cl2 (50 mL) and the solution was cooled to 0 °C. p-Toluenesul- 300 MHz): δ ϭ 4.94 (br. s), 3.77 (ddd, J ϭ 6.9, 2.7, 2.7 Hz, 1 H),
fonyl chloride (953 mg, 5.00 mmol) and DMAP (1.22 g, 10.0 mmol)
were added, and the mixture was stirred for 1 h at room temper-
3.00 (m, 1 H), 2.78 (m, 1 H), 2.53 (m, 1 H), 2.03 (m, 1 H), 1.85
(m, 1 H), 1.60 (m, 2 H), 1.25 (m, 1 H), 0.94 (d, J ϭ 1.4 Hz, 3 H),
ature to generate 10 in situ. 4-Methylvaleric acid (630 µL, 0.92 (d, J ϭ 1.5 Hz, 3 H) ppm. 13C NMR ([D4]MeOH, 75 MHz):
5.00 mmol) and EDCI {N-ethyl-NЈ-[3-(dimethylamino)propyl] car-
bodiimide hydrochloride} (959 mg, 5.00 mmol) were added, and
after 2 h of stirring at room temperature, the reaction mixture was
successively extracted with saturated aqueous NH4Cl and
NaHCO3. Drying of the organic layer with Na2SO4 and concentra-
δ ϭ 178.1, 101.4, 72.4, 53.0, 52.0, 38.8, 32.7, 27.6, 24.0, 22.0 ppm.
IR (film): ν˜ ϭ 3216 (br. s), 1705 (s) cmϪ1. HRMS (ES, m/z): calcd.
C9H15Cl3NaO3 [M ϩ Naϩ] 298.9984, found 298.9979. A solution
of
(2S,3S)-6,6,6-trichloro-3-hydroxy-2-isobutylhexanoic
acid
(135 mg, 4.63 mmol), diphenylphosphoryl azide (0.10 mL,
4.63 mmol) and triethylamine (0.13 mL, 9.26 mmol) in CH2Cl2 was
tion in vacuo yielded 11 (1.98 g, 99%) as a white solid. M.p.
115Ϫ116 °C. [α]2D3 ϭ Ϫ79.7 (c ϭ 0.74, CHCl3). H NMR (CDCl3, heated under reflux for 12 h. After evaporation of solvent, the res-
400 MHz): δ ϭ 7.80 (d, J ϭ 8.0 Hz, 2 H), 7.29 (d, J ϭ 8.0 Hz, 2 idue was chromatographically purified (silica, 30% EtOAc in hex-
1
H), 7.27Ϫ7.15 (m, 4 H), 5.47 (d, J ϭ 10.4 Hz, 1 H), 5.11 (ddd, J ϭ
4.0, 4.0, 0.8 Hz, 1 H), 4.97 (dd, J ϭ 10.0, 5.2 Hz, 1 H), 3.06 (dd,
anes) to yield 13 (126 mg, 94%) as a colourless oil. [α]2D3 ϭ Ϫ57.6
(c ϭ 1.63, CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ 6.87 (s, 1
J ϭ 17.2, 4.8 Hz, 1 H), 2.87 (d, J ϭ 17.2 Hz, 1 H), 2.43 (s, 3 H), H), 4.22 (m, 1 H), 3.59 (m, 1 H), 3.03 (m, 1 H), 2.78 (m, 1 H), 2.16
2.13 (dd, J ϭ 8.0, 8.0 Hz, 2 H), 1.46 (m, 1 H), 1.36 (dd, J ϭ 8.1,
8.1 Hz, 2 H), 0.83 (d, J ϭ 6.4 Hz, 3 H), 0.82 (d, J ϭ 6.3 Hz, 3 H)
ppm. 13C NMR (CHCl3, 100 MHz): δ ϭ 173.0, 143.8, 139.8, 138.7,
137.9, 129.9, 128.6, 127.4, 126.9, 125.0, 124.3, 74.6, 59.5, 37.5, 33.4,
(m, 2 H), 1.69 (m, 1 H), 1.55 (m, 1 H), 1.40 (m, 1 H), 0.97 (d, J ϭ
6.0 Hz, 3 H), 0.95 (d, J ϭ 5.8 Hz, 3 H) ppm. 13C NMR (CHCl3,
75 MHz): δ ϭ 159.3, 98.9, 81.3, 56.4, 50.8, 44.4, 31.6, 24.9, 23.2,
21.8 ppm. IR (film): ν˜ ϭ 3266 (br. s), 1755 (s) cmϪ1. HRMS (ES,
32.0, 27.6, 22.2, 21.6 ppm. IR (film): ν˜ ϭ : ν˜ ϭ 3280 (br. s), 1737 m/z): calcd. C10H17Cl3NO2 [M ϩ Hϩ] 288.0325, found 288.0330.
826
Eur. J. Org. Chem. 2003, 821Ϫ832

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B
FULL PAPER
(4S,5S)-tert-Butyl 4-Isobutyl-2,2-dimethyl-5-(3Ј,3Ј,3Ј-trichloropro-
Na2SO4. Evaporation of solvent and chromatographic purification
pyl)-1,3-oxazolidine-3-carboxylate (14): A solution of 13 (0.55 g, (silica, 10% EtOAc in hexanes) yielded 15 (3.24 g, 97%) as a colour-
1.91 mmol), Boc2O (0.57 mL, 2.48 mmol), DMAP (0.05 g,
0.38 mmol) and NEt3 (0.32 mL, 2.29 mmol) in THF (50 mL) was
stirred for 3 h at room temperature. NaOH (0.30 g, 7.62 mmol),
EtOH (50 mL) and water (50 mL) were added. The resulting mix-
ture was stirred for 5 min at room temperature, quenched with sat-
less oil. [α]2D3 ϭ ϩ44.3 (c ϭ 3.79, CHCl3). 1H NMR (CDCl3,
500 MHz): δ ϭ 3.94 (td, J ϭ 6.7, 1.6 Hz, 1 H), 3.89/3.77 (2 br. s,
1 H), 2.40 (m, 2 H), 1.98 (t, 4J ϭ 2.7 Hz, 1 H), 1.53Ϫ1.37 (m, 9
H), 1.40 (s, 9 H), 0.88 (d, J ϭ 6.4 Hz, 6 H) ppm. 13C NMR (CHCl3,
125 MHz): δ ϭ 152.0, 94.9/94.1, 80.6/80.0, 80.3, 79.5/78.9, 70.8,
urated aqueous NH4Cl and extracted with CH2Cl2. The organic 60.0, 43.6/42.4, 29.6/28.8, 28.8, 28.5/28.2, 26.2, 25.6, 24.4,
layer was dried with Na2SO4, concentrated in vacuo and chromato-
graphically purified (silica, 30% EtOAc in hexanes) to yield
(1S,2S)-tert-butyl 5,5,5-trichloro-2-hydroxy-1-isobutylpentylcarba-
mate (0.63 g, 91%) as a white solid. M.p. 78Ϫ82 °C. [α]2D3 ϭ Ϫ30.5
(c ϭ 1.67, CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ 4.74 (d, J ϭ
8.7 Hz, 1 H), 3.58 (br. s, 2 H), 3.05 (d, J ϭ 4.5 Hz, 1 H), 2.89 (m,
1 H), 2.77 (m, 1 H), 1.93 (m, 2 H), 1.64 (m, 1 H), 1.40 (m, 1 H),
1.42 (s, 9 H), 1.26 (m, 1 H), 0.92 (d, J ϭ 6.3 Hz, 6 H) ppm. 13C
NMR (CHCl3, 75 MHz): δ ϭ 156.6, 100.1, 79.7, 73.0, 52.9, 51.8,
40.9, 31.1, 28.3, 24.8, 23.3, 22.0 ppm. IR (film): ν˜ ϭ 3431 (br. s),
1787 (s) cmϪ1. HRMS (ES, m/z): calcd. C14H26Cl3NNaO3 [M ϩ
Naϩ] 384.0876, found 384.0885. A solution of (1S,2S)-tert-butyl
21.5 ppm. IR (film): ν˜ ϭ 2121 (w), 1700 (s) cmϪ1. LRMS (FAB):
m/z ϭ 296.2. HRMS (CI, m/z): calcd. C17H30NO3 [M ϩ Hϩ]
296.2226, found 296.2213.
(4S,5S)-tert-Butyl
5-(3,3-Dichloroprop-2-enyl)-4-isobutyl-2,2-di-
methyl-1,3-oxazolidine-3-carboxylate (16): n-Butyllithium (2.5  in
hexanes, 79.2 µL, 198 µmol) was added dropwise at Ϫ78 °C to a
solution of 14 (10.0 mg, 24.8 µmol) in THF (4 mL) and the mixture
was stirred at Ϫ78 °C for a further 10 min. The mixture was
quenched with saturated aqueous NH4Cl, diethyl ether was added,
and the organic phase was dried with Na2SO4. Evaporation of solv-
ent yielded 16 (8.0 mg, 88%) as a colourless film. [α]2D3 ϭ Ϫ9.5 (c ϭ
0.59, CHCl3). 1H NMR (CDCl3, 500 MHz): δ ϭ 5.85 (t, J ϭ
5.7 Hz, 1 H), 3.87 (ddd, J ϭ 9.7, 4.0, 2.5 Hz, 1 H), 3.76/3.64 (2 br.
s, 1 H), 2.42 (m, 1 H), 2.26 (m, 1 H), 1.90 (m, 1 H), 1.78 (m, 1 H),
1.65Ϫ1.44 (m, 16 H), 0.94 (d, J ϭ 6.3 Hz, 6 H) ppm. 13C NMR
(CHCl3, 125 MHz): δ ϭ 152.1, 127.6, 94.7/94.5, 80.2/79.6, 73.7,
61.5, 44.0/42.6, 40.3, 32.3/29.5, 28.9, 28.4/28.1, 26.1, 24.4,
5,5,5-trichloro-2-hydroxy-1-isobutylpentylcarbamate
2.65 mmol), 2,2-dimethoxypropane (1.63 mL,
(0.96 g,
13.2 mmol),
TsOH·H2O (0.05 g, 0.26 mmol) and Na2SO4 (0.50 g) in CH2Cl2
(30 mL) was stirred at room temperature for 15 min. The reaction
mixture was extracted with saturated aqueous NaHCO3, and the
organic layer was dried with Na2SO4 and concentrated in vacuo to
furnish 14 (1.03 g, 97%) as a colourless oil. [α]2D3 ϭ Ϫ7.8 (c ϭ 2.11,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ 3.90 (ddd, J ϭ 10.2,
3.9, 2.4 Hz, 1 H), 3.77/3.67 (2 br. s, 1 H), 2.95 (ddd, J ϭ 15.7, 11.1,
3.6 Hz, 1 H), 2.70 (ddd, J ϭ 15.9, 11.7, 4.8 Hz, 1 H), 2.10 (m, 1
21.8 ppm. IR (film): ν˜ ϭ 1700 (s) cmϪ1
.
(4S,5S)-tert-Butyl 4-Isobutyl-5-(3Ј-methoxycarbonylprop-2Ј-ynyl)-
2,2-dimethyl-1,3-oxazolidine-3-carboxylate (17). From 14: n-Butylli-
thium (2.5  in hexanes, 59.4 µL, 149 µmol) was added dropwise
at Ϫ78 °C to a solution of 14 (40.0 mg, 99.3 µmol) in THF (3 mL).
After the mixture had been stirred for 10 min at Ϫ78 °C,
N,N,NЈ,NЈ-tetramethylethylenediamine (50.0 µL, 298 µmol) and n-
butyllithium (119 µL, 298 µL) were added successively, and the
resulting mixture was stirred for another 10 min. Methyl chloro-
formate (23.0 µL, 298 µmol) was added in one portion, and the
reaction mixture was allowed to warm to room temperature over a
period of 10 min. The reaction was quenched with saturated aque-
ous NH4Cl, diethyl ether was added, and the organic phase was
dried with Na2SO4. Evaporation of solvent yielded 17 (26 mg, 85%)
as a white solid. From 15: n-Butyllithium (2.0  in hexanes,
4.10 mL, 8.12 mmol) was added at Ϫ78 °C to a solution of 15
(1.60 g, 5.42 mmol) in THF (150 mL), and the solution was stirred
for 10 min. Methyl chloroformate (1.26 mL, 16.3 mmol) was added
in one portion, and the reaction mixture was allowed to warm to
room temperature over a period of 10 min. The reaction was
quenched with saturated aqueous NH4Cl, diethyl ether was added,
and the organic phase was dried with Na2SO4. Evaporation of solv-
H), 1.94 (m, 1 H), 1.65Ϫ1.40 (m, 18 H), 0.93 (br. s, 6 H) ppm. 13
C
NMR (CHCl3, 75 MHz): δ ϭ 151.7, 99.7, 94.4/94.3, 79.9/79.2, 79.1/
78.7, 61.1, 51.6, 43.5/42.2, 33.0, 29.1/28.9, 28.5, 28.0/27.7, 25.7,
24.0, 21.4 ppm. IR (film): ν˜ ϭ 1702 (s) cmϪ1. HRMS (ES, m/z):
calcd. C17H30Cl3NNaO3 [M ϩ Naϩ] 424.1189, found 424.1195.
(4S,5S)-tert-Butyl
4-Isobutyl-2,2-dimethyl-5-prop-2Ј-ynyl-1,3-ox-
azolidine-3-carboxylate (15) from 22: A solution of TsCl (8.00 g,
42.0 mmol) and NaN3 (2.73 g, 42.0 mmol) in acetone (120 mL) and
H2O (120 mL) was stirred at 0 °C for 2 h. Acetone was evaporated,
the reaction mixture was extracted with diethyl ether, and the or-
ganic phase was dried with Na2SO4. Evaporation of solvent gave
tosyl azide (8.07 g, 97%) as a colourless oil. 1H NMR (CDCl3,
300 MHz): δ ϭ 7.75 (d, J ϭ 8.1 Hz, 2 H), 7.33 (d, J ϭ 8.1 Hz, 2
H), 2.39 (s, 3 H) ppm. 13C NMR (CHCl3, 75 MHz): δ ϭ 146.3,
135.4, 130.3, 127.5, 21.7 ppm. IR (film): ν˜ ϭ 2129 (s), 1171 (s)
cmϪ1. A solution of NaH (60% dispersion in mineral oil, 0.99 g,
41.5 mmol) in THF (100 mL) was cooled to 0 °C. Dimethyl (2-
oxopropyl)phosphonate (6.26 g, 37.7 mmol) in THF (100 mL) was
added dropwise, and the solution was stirred at 0 °C for 1 h. Tosyl
azide (8.18 g, 41.5 mmol) was then added in one portion and the
resulting mixture was stirred at 0 °C for 10 min. The reaction mix-
ture was quickly passed through a short column (silica, EtOAc) to
give dimethyl (1-diazo-2-oxopropyl)phosphonate (6.95 g, 96%) as a
colourless oil. Spectroscopic and analytical data are in agreement
with those reported.[48] 1H NMR (CDCl3, 300 MHz): δ ϭ 3.75 (s,
3 H), 3.71 (s, 3 H), 2.15 (s, 3 H) ppm. 13C NMR (CHCl3, 75 MHz):
δ ϭ 189.7, 115.6, 53.6, 53.5, 27.1 ppm. IR (film): ν˜ ϭ 2124 (s), 1659
(s), 1026 (s) cmϪ1. A solution of dimethyl (1-diazo-2-oxopropyl)-
ent yielded 17 (1.91 g, 99%) as a white solid. M.p. 65 °C. [α]2D3
ϭ
1
ϩ43.2 (c ϭ 2.70, CHCl3). H NMR (CDCl3, 400 MHz): δ ϭ 4.07
(t, J ϭ 6.3 Hz, 1 H), 3.90/3.82 (2 br. s, 1 H), 3.75 (s, 3 H), 2.62 (m,
2 H), 1.53Ϫ1.40 (m, 9 H), 1.48 (s, 9 H), 0.95 (d, J ϭ 6.2 Hz, 6 H)
ppm. 13C NMR (CHCl3, 100 MHz): δ ϭ 153.8, 151.6, 94.9/94.2,
85.0, 80.0, 78.3/77.5, 74.5, 60.5, 52.6, 43.2/42.0, 29.3/28.6, 28.5,
28.4/27.8, 26.1, 25.6, 24.0, 21.1 ppm. IR (film): ν˜ ϭ 1716 (s), 1700
(s) cmϪ1; LRMS (CI): m/z ϭ 354, 254. HRMS (FAB, m/z): calcd.
C19H31NNaO5 [M ϩ Naϩ] 376.2100, found 376.2102.
(1S,2S)-tert-Butyl
(2-Hydroxy-1-isobutylpent-4-enyl)carbamate
phosphonate (4.79 g, 24.9 mmol), 22 (3.39 g, 11.3 mmol) and (19): SnCl4 (1.0  in CH2Cl2, 102 mL, 102 mmol) was added at
Cs2CO3 (11.1 g, 34.0 mmol) in iPrOH (150 mL) was stirred at 0 °C Ϫ78 °C to a solution of N-Boc--leucinal (11.0 g, 51.0 mmol) in
for 1 h and then at room temperature for a period of 11 h. The
reaction mixture was quenched with saturated aqueous NH4Cl and
extracted with diethyl ether, and the organic phase was dried with
CH2Cl2 (300 mL) and the reaction mixture was stirred for 10 min.
Allyltributyltin (25.0 g, 76.0 mmol) was then added dropwise, and
the reaction mixture was stirred at Ϫ78 °C for 1 h. The reaction
Eur. J. Org. Chem. 2003, 821Ϫ832
827

A. K. Ghosh, A. Bischoff, J. Cappiello
FULL PAPER
was quenched with saturated aqueous NH4Cl, and the organic
layer was dried with Na2SO4 and concentrated in vacuo. The res-
ine-3-carboxylate (2.30 g, 99%) as a colourless oil. [α]2D3 ϭ ϩ6.2
(c ϭ 4.49, CH2Cl2). H NMR (CDCl3, 500 MHz): δ ϭ 5.80 (m, 1
1
idue was dissolved in MeOH (300 mL), NaBH4 (3.82 g, 0.10 mol) H), 5.13 (m, 2 H), 3.90 (t, J ϭ 6.4 Hz, 1 H), 3.79/3.68 (2 br. s, 1
was added in one portion, and the resulting mixture was vigorously
stirred for 2 min. After quenching and extraction with saturated
H), 2.42 (m, 1 H), 2.32 (m, 1 H), 1.62Ϫ1.45 (m, 9 H), 1.49 (s, 9
H), 0.94 (d, J ϭ 5.6 Hz, 6 H) ppm. 13C NMR (CHCl3, 125 MHz):
aqueous NaHCO3, the organic phase was dried with Na2SO4 and δ ϭ 152.2, 134.6, 118.2, 94.5/93.8, 80.9/79.9, 80.3, 60.4, 43.9/42.6,
concentrated in vacuo. The residue was purified by flash chromato-
graphy (silica, 20% EtOAc in hexanes) to give 19 (11.9 g, 90%) as
a colourless oil and the minor diastereomer (0.50 g, 4%). Major
Diastereomer: [α]2D3 ϭ Ϫ29.7 (c ϭ 3.30, MeOH). 1H NMR (CDCl3,
40.9/40.7, 29.5/28.8, 28.9, 28.4/28.1, 25.7, 24.4, 21.7 ppm. IR (film):
ν˜ ϭ 1701 (s), 1177 (s) cmϪ1; LRMS (CI): m/z ϭ 298.2, 198.3.
HRMS (CI, m/z): calcd. C17H32NO3 [M ϩ Hϩ] 298.2382, found
298.2370. A solution of (4S,5S)-tert-butyl 5-allyl-4-isobutyl-2,2-di-
400 MHz): δ ϭ 5.83 (m, 1 H), 5.15 (m, 2 H), 4.70 (d, J ϭ 9.5 Hz, methyl-1,3-oxazolidine-3-carboxylate (2.52 g, 8.46 mmol) in
1 H), 3.60 (m, 2 H), 2.31Ϫ2.16 (m, 3 H), 1.64 (m, 1 H), 1.48 (m, 1 CH2Cl2 (250 mL) was cooled to Ϫ78 °C. Ozone was passed
H), 1.42 (s, 9 H), 1.30 (m, 1 H), 0.92 (d, J ϭ 2.2 Hz, 3 H), 0.90 (s,
through the solution until the blue colour persisted. Oxygen and
J ϭ 2.2 Hz, 3 H) ppm. 13C NMR (CHCl3, 100 MHz): δ ϭ 156.2, nitrogen were successively passed through the solution for at least
134.7, 118.2, 79.1, 72.8, 52.0, 41.8, 39.1, 28.4, 24.8, 23.2, 22.2 ppm.
10 min each. PPh3 (2.33 g, 8.88 mmol) was added portionwise un-
der N2, and the reaction mixture was allowed to warm to room
IR (film): ν˜ ϭ 3436 (br. s), 1688 (s) cmϪ1; LRMS (CI): m/z ϭ 258.3,
202.1. HRMS (CI, m/z): calcd. C14H28NO3 [M ϩ Hϩ] 258.2069, temperature over a period of 1 h. Evaporation of solvent and chro-
found 258.2067. Minor Diastereomer: M.p. 101 °C. [α]2D3 ϭ Ϫ13.9
matographic purification (silica, 10% EtOAc in hexanes) of the res-
(c ϭ 0.36, MeOH). [α]2D3 ϭ Ϫ32.6 (c ϭ 4.54, CH2Cl2). 1H NMR idue yielded 22 (2.46 g, 97%) as a colourless oil. [α]2D3 ϭ ϩ8.3 (c ϭ
(CDCl3, 500 MHz): δ ϭ 5.86 (m, 1 H), 5.14 (m, 2 H), 4.67 (d, J ϭ 5.04, CH2Cl2). 1H NMR (CDCl3, 500 MHz): δ ϭ 9.82 (s, J ϭ
7.8 Hz, 1 H), 3.69 (br. s, 2 H), 2.68 (br. s, 1 H), 2.24Ϫ2.16 (m, 2
1.2 Hz, 1 H), 4.43 (t, J ϭ 5.8 Hz, 1 H), 3.81/3.67 (2 br. s, 1 H), 2.81
H), 1.65 (m, 1 H), 1.45 (s, 9 H), 1.36Ϫ1.29 (m, 2 H), 0.95 (d, J ϭ (br, 1 H), 2.71 (ddd, J ϭ 16.8, 6.1, 1.2 Hz, 1 H), 1.62Ϫ1.45 (m, 9
6.7 Hz, 3 H), 0.92 (s, J ϭ 7.2 Hz, 3 H) ppm. 13C NMR (CHCl3, H), 1.49 (s, 9 H), 0.96 (d, J ϭ 6.4 Hz, 6 H) ppm. 13C NMR (CHCl3,
125 MHz): δ ϭ 156.8, 135.4, 118.2, 79.9, 74.3, 53.5, 38.8, 38.4, 28.8, 125 MHz): δ ϭ 200.6, 152.1, 94.9/94.3, 80.3, 75.7/75.3, 61.4, 50.1,
25.2, 24.1, 22.0 ppm. IR (film): ν˜ ϭ 1707 (s), 1503 (s) cmϪ1
.
43.9/42.6, 29.5/28.9, 28.9, 28.4/28.0, 25.9, 23.1, 21.7 ppm. IR (film):
ν˜ ϭ 3365 (br. s), 1726 (m), 1698 (s) cmϪ1. LRMS (CI): m/z ϭ
300, 216. HRMS (CI, m/z): calcd. C16H30NO4 [M ϩ Hϩ] 300.2175,
found 300.2182.
(1S,2R)-tert-Butyl (2-Hydroxy-1-isobutylpent-4-ynyl)carbamate
(20): Zinc (46.0 mg, 0.70 mmol) was added portionwise at 0 °C,
over a period of 5 min, to a solution of 18 (50.0 mg, 0.23 mmol)
and propargyl bromide (80 w% in toluene, 37.5 mg, 0.26 mmol) in
diethyl ether (3 mL) and DMF (3 mL). The reaction mixture was
allowed to warm to room temperature, stirred for a further 12 h
and filtered through Celite, and the filtrate was concentrated in
vacuo. The residue was chromatographically purified (silica, 30%
EtOAc in hexanes) to give 20 (43.0 mg, 67%) as a colourless oil.
[α]2D3 ϭ Ϫ15.1 (c ϭ 0.08, CHCl3). 1H NMR (CDCl3, 400 MHz):
δ ϭ 4.60 (d, J ϭ 9.0 Hz, 1 H), 3.60 (m, 2 H), 2.39 (dd, 2 H, J ϭ
(4S,5S)-tert-Butyl 4-Isobutyl-5-(3-methoxy-2-methoxycarbonylben-
zyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (24): A mixture of
17 (1.00 g, 2.83 mmol), 1-methoxy-1,3-cyclobutadiene (65% tech.,
4.90 mL, 28.3 mmol) and toluene (5 mL) was vigorously stirred in
a sealed tube at 175 °C for 3 d. Chromatographic purification (sil-
ica, 10% EtOAc in hexanes) of the reaction mixture furnished 24
(0.94 g, 76%) as a colourless oil. [α]2D3 ϭ ϩ4.1 (c ϭ 1.47, CH2Cl2).
1H NMR (CDCl3, 400 MHz): δ ϭ 7.30 (dd, J ϭ 8.3, 8.0 Hz, 1 H),
6.89 (d, J ϭ 8.0 Hz, 1 H), 6.80 (d, J ϭ 8.3 Hz, 1 H), 4.09 (t, J ϭ
6.5 Hz, 1 H), 3.90/3.82 (2 br. s, 1 H), 3.90 (s, 3 H), 3.82 (s, 3 H),
2.93 (dd, J ϭ 13.6, 6.5 Hz, 1 H), 2.75 (dd, J ϭ 13.6, 6.5 Hz, 1 H),
1.68Ϫ1.63 (m, 3 H), 1.48Ϫ1.41 (m, 6 H), 1.46 (s, 9 H), 0.82 (d, J ϭ
6.6 Hz, 6 H) ppm. 13C NMR (CHCl3, 100 MHz): δ ϭ 168.9, 157.0,
152.2, 136.7, 130.8, 124.6, 123.0, 109.7, 94.8/94.1, 81.7/81.0, 80.3/
80.0, 60.5/60.2, 56.4, 52.7, 43.7/42.3, 40.2, 30.1/29.9, 28.9, 28.8/28.3,
25.8, 24.4, 21.1 ppm. IR (film): ν˜ ϭ 1733 (s), 1696 (s) cmϪ1. LRMS
(FAB): m/z ϭ 436, 336. HRMS (FAB, m/z): calcd. C24H37NNaO6
[M ϩ Naϩ] 458.2519, found 458.2521.
4
4
6.2, J ϭ 2.5 Hz), 2.36 (br. s, 1 H), 2.05 (t, J ϭ 2.5 Hz, 1 H), 1.67
(m, 1 H), 1.48 (s, 9 H), 1.34 (m, 2 H), 0.94 (d, J ϭ 6.6 Hz, 3 H),
0.91 (d, J ϭ 6.6 Hz, 3 H) ppm. 13C NMR (CHCl3, 100 MHz):
δ ϭ 156.6, 80.9, 79.8, 73.1, 70.7, 53.1, 38.8, 28.3, 24.8, 23.6, 23.4,
21.6 ppm. IR (film): ν˜ ϭ 1680 (s), 1530 (s) cmϪ1. HRMS (CI, m/
z): calcd. C14H25NNaO3 [M ϩ Hϩ] 278.1732, found 278.1725.
(4S,5R)-tert-Butyl
4-Isobutyl-2,2-dimethyl-5-prop-2Ј-ynyl-1,3-ox-
azolidine-3-carboxylate (21): A mixture of 20 (15.0 mg, 58.0 µmol),
2,2-dimethoxypropane (72.0 µL, 0.58 mmol), TsOH·H2O (1.7 mg,
10.0 µmol) and Na2SO4 (50.0 mg) in CH2Cl2 (2 mL) was stirred
for 1 h at room temperature. After the reaction mixture had been
quenched and extracted with saturated aqueous NaHCO3, the or-
ganic layer was dried with Na2SO4 and concentrated in vacuo to
give 21 (17.0 mg, 98%) as a colourless oil. [α]2D3 ϭ ϩ17.9 (c ϭ 0.04,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ ϭ 4.20Ϫ3.80 (m, 2 H),
2.58Ϫ2.35 (m, 2 H), 2.02 (s, 1 H), 1.73 (m, 1 H), 1.66Ϫ1.46 (m, 8
H), 1.47 (s, 9 H), 0.95 (d, J ϭ 6.2 Hz, 3 H), 0.94 (d, J ϭ 6.2 Hz, 3
(1S,3ЈS)-tert-Butyl
[1-(8Ј-Methoxy-1Ј-oxoisochroman-3Ј-yl)-3-
methylbutyl]carbamate (2): A mixture of 24 (560 mg, 1.28 mmol),
p-toluenesulfonic acid monohydrate (24.0 mg, 0.13 mmol), water
(30 µL) and CH2Cl2 (8 mL) was stirred for 20 min at ambient tem-
perature. The reaction mixture was quenched and extracted with
saturated aqueous NaHCO3, and the organic layer was dried with
Na2SO4 and concentrated in vacuo. Chromatographic purification
(silica, 20% EtOAc in hexanes) gave 2 (450 g, 97%) as a white solid.
M.p. 138Ϫ145 °C {ref.[19] m.p. 143.5Ϫ144.5 °C). [α]2D3 ϭ Ϫ151.7
H) ppm. IR (film): ν˜ ϭ 1685 (s) cmϪ1
.
(4S,5S)-tert-Butyl 4-Isobutyl-2,2-dimethyl-5-(2Ј-oxoethyl)-1,3-ox-
azolidine-3-carboxylate (22): A solution of 19 (2.00 g, 7.77 mmol), (c ϭ 1.32, CHCl3) (ref.[19] [α]2D3 ϭ Ϫ153.8 (c ϭ 0.86, CHCl3)}. [α]2D3
1
2,2-dimethoxypropane (19.1 mL, 155 mmol), TsOH·H2O (150 mg, ϭ Ϫ101.5 (c ϭ 2.10, MeOH). H NMR (CDCl3, 300 MHz): δ ϭ
0.77 mmol) and Na2SO4 (1.00 g) in CH2Cl2 (40 mL) was stirred
for 1 h at room temperature. After the reaction mixture had been
quenched and extracted with saturated aqueous NaHCO3, the or-
ganic layer was dried with Na2SO4 and concentrated in vacuo to
give (4S,5S)-tert-butyl 5-allyl-4-isobutyl-2,2-dimethyl-1,3-oxazolid-
7.42 (dd, J ϭ 8.4, 8.4 Hz, 1 H), 6.88 (d, J ϭ 8.4 Hz, 1 H), 6.80 (d,
J ϭ 8.4 Hz, 1 H), 4.81 (d, J ϭ 10.2 Hz, 1 H), 4.35 (d, J ϭ 12.6 Hz,
1 H), 3.92 (s, 3 H), 3.87 (d, J ϭ 10.2 Hz, 1 H), 3.06 (dd, J ϭ 15.9,
12.9 Hz, 1 H), 2.74 (dd, J ϭ 16.2, 1.8 Hz, 1 H), 1.75Ϫ1.60 (m, 2
H), 1.41 (s, 9 H), 1.39 (m, 1 H), 0.90 (d, J ϭ 6.6 Hz, 6 H) ppm.
828
Eur. J. Org. Chem. 2003, 821Ϫ832

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B
13C NMR (CHCl3, 75 MHz): δ ϭ 162.4, 161.0, 155.8, 142.2, 134.5, resulting mixture was acidified with concentrated HCl (pH ϭ 2).
FULL PAPER
119.4, 113.4, 110.6, 79.6, 79.4, 56.1, 50.4, 41.0, 31.7, 28.2, 24.6,
22.8, 22.0 ppm. IR (film): ν˜ ϭ 3344 (br. s), 1726 (s), 1694 (s) cmϪ1
LRMS (FAB): m/z 386. HRMS (FAB, m/z): calcd.
C20H29NNaO5 [M ϩ Naϩ] 386.1943, found 386.1964.
The organic layer was then dried with Na2SO4, concentrated in
vacuo and chromatographically purified (silica, 50% EtOAc in hex-
anes) to furnish (2S,1ЈS)-2-(2Ј-benzyloxy-1Ј-hydroxyethyl)pent-4-
enoic acid (3.74 g, 96%) as a white solid. M.p. 42 °C. [α]2D3 ϭ Ϫ5.9
.
ϭ
1
(c ϭ 4.10, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ 7.38Ϫ7.26
(1ЈS,2ЈR)-1Ј-p-Tosylaminoindan-2Ј-yl Pent-4-enoate (25): (1S,2R)-1-
Aminoindan-2-ol (1.69 g, 11.3 mmol) was dissolved in CH2Cl2
(50 mL) and the solution was cooled to 0 °C. p-Toluenesulfonyl
chloride (2.15 g, 11.3 mmol) and DMAP (2.76 g, 11.3 mmol) were
added and the mixture was stirred for 1 h at room temperature to
generate 10 in situ. 4-Pentenoic acid (1.13 g, 11.3 mmol), EDCI
(2.16 g, 11.3 mmol) and DMAP (1.38 g, 11.3 mmol) were added,
and the mixture was stirred for 4 h at room temperature. The reac-
tion mixture was extracted with saturated aqueous NH4Cl and
NaHCO3. The organic layer was dried with Na2SO4 and concen-
trated in vacuo to yield 25 (4.31 g, 99%) as a white solid. M.p.
(m, 5 H), 5.80 (dddd, 1 H, J ϭ 17.1, 10.2, 6.9, 6.6 Hz), 5.10 (d,
J ϭ 18.3 Hz, 1 H), 5.05 (d, J ϭ 11.4 Hz, 1 H), 4.55 (s, 2 H), 4.06
(br. s, 1 H), 3.54 (m, 2 H), 2.72 (m, 1 H), 2.47 (m, 2 H) ppm. 13C
NMR (CHCl3, 75 MHz): δ ϭ 178.8, 137.4, 134.8, 128.4, 127.9,
127.7, 117.2, 73.3, 71.6, 70.1, 48.0, 32.0 ppm. IR (film): ν˜ ϭ 3426
(br. s), 1710 (s) cmϪ1. LRMS (FAB, m/z): 251. HRMS (FAB, m/z):
calcd. C14H19O4 [M ϩ Hϩ] 251.1283, found 251.1289. A solution
of (2S,1ЈS)-2-(2Ј-benzyloxy-1Ј-hydroxyethyl)pent-4-enoic acid
(3.50 g, 14.0 mmol), diphenylphosphoryl azide (4.52 mL,
21.0 mmol) and triethylamine (2.92 mL, 21.0 mmol) in CH2Cl2
(150 mL) was stirred under reflux for 12 h. Removal of solvents
and chromatographic purification (silica, 50% EtOAc in hexanes)
1
120Ϫ121 °C. [α]2D3 ϭ Ϫ76.0 (c ϭ 1.59, CHCl3). H NMR (CDCl3,
400 MHz): δ ϭ 7.81 (d, J ϭ 8.2 Hz, 2 H), 7.31 (d, J ϭ 8.2 Hz, 2
H), 7.26Ϫ7.22 (m, 3 H), 7.17 (m, 1 H), 5.72 (m, 1 H), 5.38 (d, J ϭ
10.1 Hz, 1 H), 5.14 (ddd, J ϭ 5.2, 5.2, 1.0 Hz, 1 H), 4.96 (m, 3 H),
3.07 (dd, J ϭ 17.3, 5.0 Hz, 1 H), 2.88 (d, J ϭ 17.3 Hz, 1 H), 2.44
(s, 3 H), 2.23 (m, 4 H) ppm. 13C NMR (CHCl3, 100 MHz): δ ϭ
171.9, 143.8, 139.7, 138.6, 137.9, 136.4, 129.9, 128.6, 127.4, 127.0,
125.0, 124.3, 115.7, 74.8, 59.5, 37.5, 33.2, 28.6, 21.6 ppm. IR (film):
ν˜ ϭ 3283 (br. s), 1738 (s) cmϪ1. LRMS (FAB, m/z): 408. HRMS
(FAB, m/z): calcd. C21H23NNaO4S [M ϩ Naϩ] 408.1246, found
408.1256.
yielded 27 (3.18 g, 92%) as a white solid. M.p. 43Ϫ47 °C. [α]2D3
ϭ
Ϫ22.7 (c ϭ 6.11, CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ
7.37Ϫ7.25 (m, 5 H), 5.70 (dddd, 1 H, J ϭ 17.2, 10.3, 6.7, 6.4 Hz),
5.58 (br. s, 1 H), 5.17 (d, J ϭ 9.9 Hz, 1 H), 5.14 (d, J ϭ 17.1 Hz,
1 H), 4.77 (ddd, J ϭ 7.8, 6.2, 6.0 Hz, 1 H), 4.57 (s, 2 H), 3.90 (ddd,
J ϭ 10.2, 7.8, 3.9 Hz, 1 H), 3.71 (d, J ϭ 6.3 Hz, 2 H), 2.41 (dddd,
1 H, J ϭ 14.1, 3.9, 3.9, 4J ϭ 1.5 Hz), 2.20 (m, 1 H) ppm. 13C NMR
(CHCl3, 75 MHz): δ ϭ 158.4, 137.2, 133.0, 128.4, 127.9, 127.8,
119.3, 77.1, 73.7, 76.1, 53.7, 34.3 ppm. IR (film): ν˜ ϭ 3279 (br. s),
1754 (s) cmϪ1. LRMS (FAB, m/z): 248. HRMS (FAB, m/z): calcd.
C14H18O3N [M ϩ Hϩ] 248.1287, found 248.1277.
(2S,1ЈS,1ЈЈS,2ЈЈR)-1ЈЈ-p-Tosylaminoindan-2ЈЈ-yl 2-(2Ј-Benzyloxy-1Ј-
hydroxyethyl)pent-4-enoate (26): TiCl4 (1.43 mL, 13.0 mmol) was
added at 0 °C to a solution of 25 (5.02 g, 13.0 mmol) in CH2Cl2
(150 mL). After the mixture had been stirred for 15 min, iPr2NEt
(8.61 mL, 49.4 mmol) was added dropwise at 0 °C, and the re-
sulting mixture was stirred for 2 h at room temperature. It was then
cooled to Ϫ78 °C, and TiCl4 (2.85 mL, 26.0 mmol) was added in
one portion. Subsequently, benzyloxyacetaldehyde (1.83 mL,
26.0 mmol) was added dropwise over a period of 4 min. After stir-
ring for 1 h at Ϫ78 °C, the reaction mixture was quenched with
saturated aqueous NH4Cl and the organic layer was dried with
Na2SO4. Concentration in vacuo (crude NMR showed 98% de) and
chromatographic purification (silica, 20% EtOAc in hexanes)
(1S,1ЈS)-tert-Butyl [1-(2Ј-Benzyloxy-1Ј-hydroxyethyl)but-3-enyl]car-
bamate (28): A solution of 27 (3.00 g, 12.1 mmol), di-tert-butyl di-
carbonate (3.62 mL, 15.8 mmol), triethylamine (2.03 mL,
14.6 mmol) and 4-(dimethylamino)pyridine (0.30 g, 2.43 mmol) in
THF (100 mL) was stirred for 2 h at room temperature. Ethanol
(100 mL), water (100 mL) and sodium hydroxide (2.00 g,
50.0 mmol) were added, and the resulting mixture was stirred for
5 min at room temperature. Organic solvents were removed,
CH2Cl2 (200 mL) was added, and the aqueous phase was acidified
(pH ϭ 3) with concentrated HCl. The organic layer was dried with
Na2SO4 and concentrated in vacuo to yield 28 (3.75 g, 96%) as a
white solid. M.p. 50 °C. [α]2D3 ϭ ϩ4.07 (c ϭ 2.00, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ ϭ 7.38Ϫ7.26 (m, 5 H), 5.77 (dddd, 1 H, J ϭ
16.9, 10.2, 6.7, 6.2 Hz), 5.11Ϫ5.05 (m, 2 H), 4.82 (br. d, J ϭ 7.5 Hz,
1 H), 4.55 (s, 2 H), 3.77 (br. m, 2 H), 3.60Ϫ3.49 (m, 2 H), 2.69 (br.
s, 1 H), 2.30 (m, 2 H), 1.42 (s, 9 H) ppm. 13C NMR (CHCl3,
75 MHz): δ ϭ 156.0, 137.7, 134.4, 128.4, 127.8, 127.7, 117.7, 79.4,
73.5, 71.9, 71.7, 52.5, 35.1, 28.3 ppm. IR (film): ν˜ ϭ 3353 (br. s),
1684 (s), 1526 (s) cmϪ1. LRMS (FAB, m/z): 322. HRMS (FAB, m/
z): calcd. C18H28O4N [M ϩ Hϩ] 322.2018, found 322.2027.
yielded 26 (6.76 g, 97%) as a white solid. M.p. 165Ϫ167 °C. [α]2D3
ϭ
1
Ϫ61.2 (c ϭ 0.85, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ 7.81
(d, J ϭ 8.1 Hz, 2 H), 7.36Ϫ7.21 (m, 10 H), 7.14 (m, 1 H), 5.95 (d,
J ϭ 9.9 Hz, 1 H), 5.65 (dddd, 1 H, J ϭ 16.8, 10.2, 6.6, 6.6 Hz),
5.30 (dd, J ϭ 4.5, 4.4 Hz, 1 H), 4.99 (d, J ϭ 10.2 Hz, 1 H), 4.90
(d, J ϭ 16.2 Hz, 1 H), 4.89 (dd, J ϭ 9.5, 4.8 Hz, 1 H), 4.42 (s, 2
H), 4.01 (br. s, 1 H), 3.45 (dd, J ϭ 9.9, 4.2 Hz, 1 H), 3.37 (dd, J ϭ
9.6, 6.9 Hz, 1 H), 3.03 (dd, J ϭ 17.1, 4.2 Hz, 1 H), 2.95 (br. s, 1
H), 2.84 (d, J ϭ 17.1 Hz, 1 H), 2.60 (ddd, J ϭ 9.3, 5.4, 5.2 Hz, 1
H), 2.43 (s, 3 H), 2.27 (m, 2 H) ppm. 13C NMR (CHCl3, 75 MHz):
δ ϭ 172.3, 143.5, 139.9, 138.4, 137.9, 137.5, 135.2, 129.8, 128.4,
127.8, 127.3, 127.0, 124.7, 124.2, 117.2, 75.7, 73.3, 71.5, 70.4, 59.5,
48.3, 37.1, 30.8, 21.5 ppm. IR (film): ν˜ ϭ 3497 (br. s), 3286 (br. s),
1731 (s), 1449 (s) cmϪ1. HRMS (FAB, m/z): calcd. C30H34NO6S
[M ϩ Hϩ] 536.2107, found 536.2123.
(4S,5S)-tert-Butyl 4-Allyl-5-benzyloxymethyl-2,2-dimethyl-1,3-ox-
azolidine-3-carboxylate (6): A solution of 28 (3.50 g, 10.9 mmol),
2,2-dimethoxypropane (6.70 mL, 55.0 mmol), TsOH·H2O (210 mg,
1.09 mmol) and Na2SO4 (1.00 g) in CH2Cl2 (100 mL) was stirred
for 1 h at room temperature. Extraction of the reaction mixture
with saturated aqueous NaHCO3, drying with Na2SO4 and concen-
tration in vacuo furnished 6 (3.62 g, 92%) as a colourless oil.
[α]2D3 ϭ Ϫ17.0 (c ϭ 6.48, CHCl3). 1H NMR (CDCl3, 500 MHz):
(4S,5S)-4-Allyl-5-benzyloxymethyl-1,3-oxazolidin-2-one (27):
A
mixture of 26 (30%, 8.35 g, 15.6 mmol), hydrogen peroxide
(10.6 mL, 9.34 mmol) and LiOH·H2O (1.96 g, 4.67 mmol) in THF δ ϭ 7.37Ϫ7.29 (m, 5 H), 5.80 (m, 1 H), 5.03 (m, 2 H), 4.64 (dd,
(90 mL), ethanol (50 mL) and water (30 mL) was stirred for 3 h at
room temperature and subsequently quenched with aqueous
Na3SO3 (1.0 ). Aqueous NaOH was added (pH ϭ 12), organic
solvents were removed in vacuo, diethyl ether was added, and the
J ϭ 12.1, 5.3 Hz, 1 H), 4.52 (d, J ϭ 12.1 Hz, 1 H), 4.31 (dd, J ϭ
11.2, 5.5 Hz, 1 H), 4.11 (dd, J ϭ 11.2, 5.5 Hz, 1 H), 3.98 (dd, J ϭ
11.2, 5.4 Hz, 1 H), 3.63 (m, 2 H), 2.38 (m, 1 H), 2.29 (m, 1 H),
1.63/1.59 (2 s, 3 H), 1.57/1.54 (2 s, 3 H), 1.49/1.47 (2 s, 9 H) ppm.
Eur. J. Org. Chem. 2003, 821Ϫ832
829

A. K. Ghosh, A. Bischoff, J. Cappiello
FULL PAPER
13C NMR (CHCl3, 125 MHz): δ ϭ 152.5/152.0, 138.2/138.1, 135.8,
128.8, 128.4/128.2, 128.2/128.1, 117.2/117.0, 93.8/93.3, 80.4/80.0,
75.9, 74.0/73.9, 68.6/68.3, 58.4, 35.2/34.8, 28.9/28.8, 28.1/27.3, 25.4/
24.1 ppm. IR (film): ν˜ ϭ 1694 (s) cmϪ1. LRMS (FAB, m/z): 362.
HRMS (FAB, m/z): calcd. C21H32O4N [M ϩ Hϩ] 362.2331,
found 362.2345.
cmϪ1
.
LRMS (FAB, m/z): 355. HRMS (FAB, m/z): calcd.
C17H27O4N2S [M ϩ Hϩ] 355.1692, found 355.1702.
(allS)-tert-Butyl
4-Allyl-5-(1Ј-benzyloxy-1Ј-thiazol-2ЈЈ-ylmethyl)-
2,2-dimethyl-1,3-oxazolidine-3-carboxylate (32): Sodium hydride
(213 mg, 5.33 mmol) was added portionwise to a solution of 30
(1.57 g, 4.44 mmol), benzyl bromide (528 µL, 4.44 mmol) and tetra-
butylammonium iodide (1.80 g, 4.88 mmol) in THF (100 mL), and
the resulting mixture was heated under reflux for 1 h. After removal
of solvent, subsequent addition of brine and extraction with
CH2Cl2, the organic layer was dried with Na2SO4 and concentrated
in vacuo. Chromatographic purification (silica, 20% EtOAc in hex-
anes) gave 32 (1.87 g, 95%) as a colourless oil. [α]2D3 ϭ Ϫ15.2 (c ϭ
4.07, CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ 7.82 (d, J ϭ
3.0 Hz, 1 H), 7.44 (d, J ϭ 3.0 Hz, 1 H), 7.44Ϫ7.26 (m, 5 H), 5.86
(m, 1 H), 5.07Ϫ4.90 (m, 3 H), 4.42 (s, 2 H), 4.37 (m, 1 H), 4.18
(dd, J ϭ 10.8, 5.7 Hz, 1 H), 2.50Ϫ2.29 (m, 2 H), 1.54/1.50 (2 s, 3
H), 1.44 (s, 9 H), 1.43/1.40 (2 s, 3 H) ppm. 13C NMR (CHCl3,
75 MHz): δ ϭ 170.1, 152.0/151.6, 142.3, 137.1/136.9, 135.5, 128.4,
128.1/128.0, 127.8/127.6, 120.4, 116.4/116.0, 93.6/93.1, 79.9/79.6,
79.0/78.7, 76.1, 70.6/70.5, 58.0, 34.7/34.3, 28.3, 27.5/26.7, 24.6/
23.2 ppm. IR (film): ν˜ ϭ 1696 (s) cmϪ1. LRMS (FAB, m/z): 445.
HRMS (FAB, m/z): calcd. C24H33O4N2S [M ϩ Hϩ] 445.2161,
found 445.2184.
(4S,5S)-tert-Butyl 4-Allyl-5-formyl-2,2-dimethyl-1,3-oxazolidine-3-
carboxylate (29): A solution of 6 (3.62 g, 10.0 mmol) in THF
(25 mL) was added at Ϫ78 °C to a solution of lithium (236 mg,
34.1 mmol) in ammonia (50 mL). The resulting reaction mixture
was stirred for 5 min at Ϫ78 °C, quenched with solid NH4Cl and
allowed to warm to room temperature. Extraction with diethyl
ether and removal of solvent yielded (4S,5S)-tert-butyl 4-allyl-5-
hydroxymethyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (2.57 g,
95%) as a colourless oil. [α]2D3 ϭ Ϫ1.54 (c ϭ 3.25, CH2Cl2). 1H
NMR (CDCl3, 300 MHz): δ ϭ 5.79 (m, 1 H), 5.08 (d, J ϭ 17.1 Hz,
1 H), 5.03 (d, J ϭ 10.2 Hz, 1 H), 4.19 (dd, J ϭ 10.2, 5.4 Hz, 1 H),
4.06/3.94 (2 s, 1 H), 3.83Ϫ3.70 (m, 2 H), 2.35 (m, 1 H), 2.26 (br. s,
1 H), 2.08 (m, 1 H), 1.58/1.55 (2 s, 3 H), 1.52/1.51 (2 s, 3 H), 1.45
(s, 9 H) ppm. 13C NMR (CHCl3, 75 MHz): δ ϭ 152.5/152.2, 135.2,
117.1, 93.2/92.8, 80.0/79.7, 77.1, 60.9, 57.8, 34.7/34.1, 28.3, 27.7/
26.9, 24.8/23.5 ppm. IR (film): ν˜ ϭ 3454 (br. s), 1696 (s) cmϪ1
.
LRMS (FAB, m/z): 272. HRMS (FAB, m/z): calcd. C14H26O4N [M
ϩ Hϩ] 272.1862, found 272.1865. DMSO (3.92 mL, 55.3 mmol)
was added at Ϫ78 °C to a solution of oxalyl chloride (2.41 mL,
27.6 mmol) in CH2Cl2 (100 mL). The resulting reaction mixture
was stirred for 30 min at Ϫ78 °C, and a solution of (4S,5S)-tert-
butyl 4-allyl-5-hydroxymethyl-2,2-dimethyl-1,3-oxazolidine-3-carb-
oxylate (2.50 g, 9.21 mmol) in CH2Cl2 (10 mL) was then added
dropwise. After the mixture had been stirred for 45 min at Ϫ78 °C,
the reaction was completed by addition of triethylamine (12.8 mL,
92.1 mmol) and by allowing the reaction to warm to room temper-
ature over a period of 30 min. The mixture was extracted with sat-
urated aqueous NH4Cl, washed with brine, dried with Na2SO4 and
concentrated in vacuo to yield 29 (2.67 g, 95%) as a colourless oil.
[α]2D3 ϭ ϩ0.9 (c ϭ 1.00, MeOH). 1H NMR (CDCl3, 300 MHz): δ ϭ
9.73 (d, J ϭ 0.9 Hz, 1 H), 5.72 (m, 1 H), 5.08 (d, J ϭ 11.1 Hz, 1
H), 5.03 (dd, J ϭ 17.1, J ϭ 1.8 Hz, 1 H), 4.47 (dd, J ϭ 5.6, 0.9 Hz,
1 H), 4.41/4.29 (2 s, 1 H), 2.43 (m, 1 H), 2.32 (m, 1 H), 1.70 (s, 3
H), 1.52 (s, 3 H), 1.46 (s, 9 H) ppm. 13C NMR (CHCl3, 75 MHz):
δ ϭ 198.5, 151.5, 133.8, 118.7, 94.2, 80.6, 58.7, 35.1/34.9, 28.3, 27.2/
26.6, 24.7/23.5 ppm. IR (film): ν˜ ϭ 3406 (br. s), 1697 (s), 1674 (s)
(allS)-tert-Butyl [1-(2-Benzyloxy-1Ј-hydroxy-2Ј-thiazol-2ЈЈ-ylethyl)-
but-3-enyl]carbamate (33): A solution of 32 (27.0 mg, 60.7 µmol)
and p-TsOH·H2O (2.3 mg, 12.1 µmol) in MeOH (3 mL) was stirred
for 24 h at ambient temperature. Extraction with saturated aqueous
NaHCO3 and CH2Cl2, drying of the organic layer with Na2SO4
and concentration in vacuo gave 33 (22.5 mg, 95%) as a colourless
film. [α]2D3 ϭ Ϫ90.0 (c ϭ 0.50, CHCl3). 1H NMR (CDCl3,
500 MHz): δ ϭ 7.80 (d, J ϭ 3.2 Hz, 1 H), 7.41 (d, J ϭ 3.2 Hz, 1
H), 7.38Ϫ7.30 (m, 5 H), 5.75 (m, 1 H), 5.03 (m, 2 H), 4.77 (br. m,
1 H), 4.75 (d, J ϭ 7.1 Hz, 1 H), 4.58 (ABq, 2 H, J ϭ 11.5 Hz, ∆ν ϭ
111.1 Hz), 4.03 (br. m, 1 H), 3.92 (br. s, 1 H), 2.28 (m, 1 H), 2.22
(m, 1 H), 1.39 (s, 9 H) ppm. 13C NMR (CHCl3, 125 MHz): δ ϭ
171.6, 156.4, 142.8, 137.2, 135.3, 129.0, 128.8, 128.6, 120.6, 117.9,
79.9, 78.7, 76.3, 72.4, 52.3, 34.3, 28.7 ppm. IR (film): ν˜ ϭ 3400 (br.
s), 1707 (s) cmϪ1
.
(allS)-tert-Butyl 4-Allyl-5-(1Ј-benzyloxy-1Ј-carboxymethyl)-2,2-di-
˚
methyl-1,3-oxazolidine-3-carboxylate (3): Molecular sieves (4 A,
5.00 g) and methyl trifluoromethanesulfonate (0.55 mL,
4.83 mmol) were added to a solution of 32 (1.65 g, 3.71 mmol) in
MeCN (80 mL) and the resulting mixture was stirred at 23 °C for
30 min. The solvent was evaporated, the obtained residue was taken
cmϪ1
C14H24O4N [M ϩ Hϩ] 270.1705, found 270.1699.
. LRMS (FAB, m/z): 270. HRMS (FAB, m/z): calcd.
(allS)-tert-Butyl 4-Allyl-5-(1Ј-hydroxy-1Ј-thiazol-2ЈЈ-ylmethyl)-2,2- up into MeOH (150 mL), the mixture was cooled to 0 °C, sodium
dimethyl-1,3-oxazolidine-3-carboxylate (30): solution of 29 borohydride (210 mg, 5.57 mmol) was added, and the reaction mix-
(2.60 g, 9.65 mmol) in CH2Cl2 (70 mL) was cooled to 0 °C, and 2- ture was stirred for 30 min at 23 °C. Acetone (100 mL) was added
A
(trimethylsilyl)thiazole (1.54 mL, 9.65 mmol) was added. The reac-
tion mixture was stirred for 12 h at 23 °C and the solvent was
evaporated. In order to deprotect partially silylated product 31, the
residue was dissolved in THF (10 mL), tetrabutylammonium fluor-
ide (1.0 , 9.65 mL, 9.65 mmol) was added, and the mixture was
in order to quench excess hydride. The mixture was filtered through
a short path of Celite, which was subsequently rinsed with
MeOH, and the filtrate was concentrated in vacuo. The residue was
dissolved in MeCN (60 mL) and water (6 mL), followed by addi-
tion of copper() oxide (2.95 g, 37.1 mmol). With vigorous stirring,
stirred for 20 min at room temperature. Evaporation of solvent and copper() chloride dihydrate (0.63 g, 3.71 mmol) was added por-
chromatographic purification (silica, 30% EtOAc in hexanes) of the
tionwise over a period of 5 min. After a further 5 min, the mixture
residue afforded 30 (2.90 g, 85%) as a colourless oil. [α]2D3 ϭ ϩ8.6
was filtered through Celite and the filter cake was washed several
(c ϭ 1.17, MeOH). 1H NMR (CDCl3, 300 MHz): δ ϭ 7.74 (d, J ϭ times with CH2Cl2. The filtrate was dried with Na2SO4 and concen-
3.0 Hz, 1 H), 7.35 (d, J ϭ 3.0 Hz, 1 H), 5.93 (m, 1 H), 5.13Ϫ5.01 trated in vacuo to afford (allS)-tert-butyl 4-allyl-5-(1Ј-benzyloxy-2Ј-
(m, 3 H), 4.40Ϫ4.10 (m, 3 H), 2.65 (m, 1 H), 2.43 (m, 1 H), 1.61/
oxoethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.12 g, 82%)
1.57 (2 s, 3 H), 1.50/1.45 (2 s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR as a colourless oil. [α]2D3 ϭ Ϫ4.26 (c ϭ 3.40, CHCl3). 1H NMR
(CHCl3, 75 MHz): δ ϭ 170.4, 152.0/151.7, 141.2, 135.8/135.6,
120.2, 116.8/116.4, 94.1/93.5, 79.9/79.7, 78.5, 69.0, 58.1, 34.8/34.5,
28.3, 27.6/26.9, 24.9/23.6 ppm. IR (film): ν˜ ϭ 3387 (br. s), 1695 (s)
(CDCl3, 500 MHz): δ ϭ 9.73 (d, J ϭ 7.5 Hz, 1 H), 7.37 (m, 5 H),
5.82 (m, 1 H), 5.04 (m, 2 H), 4.57 (ABq, 2 H, J ϭ 11.7 Hz, ∆ν ϭ
54.0 Hz), 4.25Ϫ3.72 (m, 3 H), 2.43Ϫ2.28 (m, 2 H), 1.70/1.61 (2 s,
830
Eur. J. Org. Chem. 2003, 821Ϫ832

Asymmetric Total Synthesis of the Gastroprotective Microbial Agent AI-77-B
FULL PAPER
3 H), 1.57/1.52 (2 s, 3 H), 1.47 (s, 9 H) ppm. 13C NMR (CHCl3,
125 MHz): δ ϭ 200.9, 152.1/152.0, 137.1, 135.6, 129.0, 128.8, 128.4,
117.2/116.9, 94.5/93.9, 80.6, 80.5/80.3, 75.4/75.2, 72.8/72.6, 58.2,
35.2/34.8, 28.8, 28.0/27.3, 25.4/24.1 ppm. IR (film): ν˜ ϭ 1739 (s),
1696 (s) cmϪ1. LRMS (FAB, m/z): 390. HRMS (FAB, m/z): calcd.
C22H32O5N [M ϩ Hϩ] 390.2281, found 390.2287. A mixture of
(allS)-tert-butyl 4-allyl-5-(1Ј-benzyloxy-2Ј-oxoethyl)-2,2-dimethyl-
1,3-oxazolidine-3-carboxylate (0.42 g, 1.08 mmol), 2-methyl-2-but-
ene (4 mL), sodium chlorite (1.27 g, 14.0 mmol) and
NaH2PO4·H2O (1.93 g, 14.0 mmol) in tBuOH (25 mL) and water
(5 mL) was stirred for 2 h at room temperature. Saturated aqueous
NH4Cl was added, tBuOH was evaporated, and the aqueous layer
was extracted with CH2Cl2. The extract was dried with Na2SO4
and concentrated in vacuo to afford 3 (0.43 g, 98%) as a highly
viscous oil. [α]2D3 ϭ Ϫ13.2 (c ϭ 2.50, CHCl3). 1H NMR (CDCl3,
500 MHz): δ ϭ 7.35 (m, 5 H), 5.82 (m, 1 H), 5.01 (m, 2 H), 4.66
(d, J ϭ 11.0 Hz, 1 H), 4.46 (d, J ϭ 11.0 Hz, 1 H), 4.31 (m, 1.5 H),
4.12 (m, 1.5 H), 2.40Ϫ2.28 (m, 2 H), 1.60/1.57 (2 s, 3 H), 1.52/1.49
(2 s, 3 H), 1.48/1.45 (2 s, 9 H) ppm. 13C NMR (CHCl3, 125 MHz):
δ ϭ 174.9, 152.5/152.1, 136.9/136.8, 135.7, 128.9, 128.8, 128.5,
117.1/116.7, 94.4/93.9, 80.8/80.4, 76.5, 76.2/76.0, 72.8/72.6, 58.1,
35.1/34.7, 28.8, 28.0/27.3, 25.3/24.0 ppm. IR (film): ν˜ ϭ 1742 (m),
1670 (s) cmϪ1. LRMS (FAB, m/z): 406. HRMS (FAB, m/z): calcd.
C22H32O6N [M ϩ Hϩ] 406.2230, found 406.2244.
{benzyloxy[1ЈЈ-(8ЈЈЈ-methoxy-1ЈЈЈ-oxoisochroman-3ЈЈЈ-yl)-3ЈЈ-meth-
ylbutylcarbamoyl]methyl}-2,2-dimethyl-4-(2Ј-oxoethyl)-1,3-oxazol-
idine-3-carboxylate (294 mg, 98%) as a colourless oil. [α]2D3
ϭ
Ϫ105.8 (c ϭ 0.68, CHCl3). 1H NMR (CDCl3, 500 MHz): δ ϭ 9.60
(d, J ϭ 2.7 Hz, 1 H), 7.48 (dd, J ϭ 8.4, 7.6 Hz, 1 H), 7.37Ϫ7.22
(m, 5 H), 6.94 (d, J ϭ 8.5 Hz, 1 H), 6.78 (d, J ϭ 7.5 Hz, 1 H), 6.52
(m, 1 H), 4.68Ϫ4.08 (m, 6 H), 4.00 (m, 1 H), 3.98 (s, 3 H),
3.06Ϫ2.51 (m, 3 H), 1.89 (m, 2 H), 1.68 (m, 1 H), 1.48Ϫ1.30 (m,
16 H), 0.97 (d, J ϭ 8.3 Hz, 6 H) ppm. 13C NMR (CHCl3,
125 MHz): δ ϭ 200.1, 170.0/169.8, 162.5, 161.6, 151.7/150.7, 142.4,
136.5, 135.2, 129.5, 129.2, 129.0, 119.7, 113.7, 111.2, 94.4/94.0,
81.3/80.9, 80.0, 76.9, 76.6/76.1, 73.3/72.8, 56.7, 55.2, 49.2, 45.1,
41.0, 32.1, 28.7, 27.3/25.3, 25.1, 25.0/23.8, 23.5, 22.2 ppm. IR
(film): ν˜ ϭ 3311 (br), 1725 (s), 1690 (s) cmϪ1. LRMS (FAB, m/z):
653. HRMS (FAB, m/z) calcd. C36H49O9N2 [M ϩ Hϩ] 653.3438,
found 653.3458. A mixture of (allS)-tert-butyl 5-{benzyloxy-[1ЈЈ-
(8ЈЈЈ-methoxy-1ЈЈЈ-oxoisochroman-3ЈЈЈ-yl)-3ЈЈ-methylbutyl-
carbamoyl]methyl}-2,2-dimethyl-4-(2Ј-oxoethyl)-1,3-oxazolidine-3-
carboxylate (187 mg, 0.29 mmol), 2-methyl-2-butene (1 mL), so-
dium chlorite (335 mg, 3.70 mmol) and NaH2PO4·H2O (511 mg,
3.70 mmol) in tBuOH (10 mL) and water (2 mL) was stirred for 1 h
at room temperature. Saturated aqueous NH4Cl was added,
tBuOH was evaporated and the aqueous layer was extracted with
CH2Cl2. The extract was dried with Na2SO4 and concentrated in
vacuo to afford (allS)-tert-butyl 5-{benzyloxy-[1Ј-(8ЈЈ-methoxy-1ЈЈ-
oxoisochroman-3ЈЈ-yl)-3Ј-methylbutylcarbamoyl]methyl}-4-carb-
(allS)-tert-Butyl
4-Allyl-5-{benzyloxy[1Ј-(8ЈЈ-methoxy-1ЈЈ-oxoiso-
chroman-3ЈЈ-yl)-3Ј-methylbutylcarbamoyl]methyl}-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (34): Trifluoroacetic acid (10 mL) was
added at 0 °C to a solution of 2 in CH2Cl2 (40 mL). The reaction
mixture was stirred for 10 min at 0 °C and concentrated to com-
plete dryness in vacuo. A solution of 3 (402 mg, 1.00 mmol), EDCI
(190 mg, 1.00 mmol) and DMAP (484 mg, 3.96 mmol) in CH2Cl2
(25 mL) was added, and the mixture was stirred for 6 h at room
temperature. The reaction mixture was extracted with saturated
aqueous NH4Cl, dried with Na2SO4, concentrated in vacuo and
chromatographically purified (silica, 40% EtOAc in hexanes) to
give 34 (460 mg, 72%) as a white solid. M.p. 72 °C. [α]2D3 ϭ Ϫ95.4
(c ϭ 2.55, CHCl3). 1H NMR (CDCl3, 500 MHz): δ ϭ 7.48 (dd,
J ϭ 8.5, 7.5 Hz, 1 H), 7.37Ϫ7.27 (m, 4 H), 7.23 (m, 1 H), 6.93 (d,
J ϭ 8.5 Hz, 1 H), 6.78 (d, J ϭ 7.5 Hz, 1 H), 6.48 (m, 1 H), 5.81
(m, 1 H), 5.00 (m, 2 H), 4.63 (m, 1 H), 4.48 (m, 1 H), 4.43 (m, 2
H), 4.25 (m, 1.5 H), 4.06 (m, 0.5 H), 4.02 (d, J ϭ 7.9 Hz, 1 H),
3.98 (s, 3 H), 3.04 (dd, J ϭ 15.2, 13.4 Hz, 1 H), 2.72 (dd, J ϭ 15.1,
5.8 Hz, 1 H), 2.39Ϫ2.24 (m, 2 H), 1.90 (m, 1 H), 1.66 (m, 1 H),
1.48Ϫ1.31 (m, 16 H), 0.97 (m, 6 H) ppm. 13C NMR (CHCl3,
75 MHz): δ ϭ 169.9, 162.2, 161.0, 151.8/151.5, 142.0, 136.4/136.3,
135.4, 134.8, 128.7, 128.5, 128.3, 119.2, 116.5/116.1, 113.1, 110.7,
93.5/93.1, 79.9/79.7, 79.6, 76.6, 76.4/76.1, 72.3/72.1, 57.7/57.6, 56.1,
48.7, 40.5, 34.9/34.5, 31.6, 28.3, 27.5/26.8, 24.7, 24.6/23.3, 23.1,
21.7 ppm. IR (film): ν˜ ϭ 3313 (br), 1723 (s), 1691 (s) cmϪ1. LRMS
(FAB, m/z): 651. HRMS (FAB, m/z): calcd. C37H51O8N2 [M ϩ Hϩ]
651.3645, found 651.3695.
oxymethyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
(189 mg,
99%) as a viscous oil. [α]2D3 ϭ Ϫ97.5 (c ϭ 0.41, CHCl3). H NMR
(CDCl3, 500 MHz): δ ϭ 7.47 (dd, J ϭ 8.6, 7.5 Hz, 1 H), 7.32 (d,
J ϭ 7.4 Hz, 2 H), 7.23 (dd, J ϭ 7.4, 7.2 Hz, 2 H), 7.15 (m, 1 H),
6.93 (d, J ϭ 8.5 Hz, 1 H), 6.76 (d, J ϭ 7.5 Hz, 1 H), 6.71 (m, 1 H),
4.55Ϫ4.29 (m, 5 H), 4.19 (d, J ϭ 6.6 Hz, 1 H), 3.96 (s, 3 H), 3.65
(m, 1 H), 2.90 (m, 1 H), 2.69 (m, 2 H), 2.45 (m, 1 H), 1.87 (m, 1
H), 1.69 (m, 1 H), 1.48Ϫ1.26 (m, 16 H), 0.97 (d, J ϭ 8.3 Hz, 6 H)
ppm. 13C NMR (CHCl3, 125 MHz, 315 K): δ ϭ 174.3, 170.0,
162.7, 161.6, 151.7/150.7, 142.5, 136.9, 135.2, 128.9, 128.5, 119.7,
113.8, 111.3, 93.7, 80.9/80.7, 80.0, 76.8, 74.7/73.7, 72.3, 56.6, 56.3/
56.2, 49.5, 41.0, 35.9, 32.1, 28.7, 26.8/26.7, 25.2, 23.4, 23.2/23.1,
22.3 ppm. IR (film): ν˜ ϭ 3318 (br. w), 1710 (br. s) cmϪ1. LRMS
(FAB, m/z): 691. HRMS (FAB, m/z): calcd. C36H48O10N2Na [M ϩ
Naϩ] 691.3207, found 691.3230. A solution of (allS)-tert-butyl 5-
{benzyloxy[1Ј-(8ЈЈ-methoxy-1ЈЈ-oxoisochroman-3ЈЈ-yl)-3Ј-methyl-
butylcarbamoyl]methyl}-4-carboxymethyl-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (190 mg, 0.28 mmol) and Cs2CO3
(46.0 mg, 0.142 mmol) in MeOH (10 mL) and water (2 mL) was
stirred for 30 min at room temperature. Both solvents were evapor-
ated and the resulting residue was dissolved in DMF (20 mL).
Benzyl bromide (38.0 µg, 0.28 mmol) was added, and the reaction
mixture was stirred for 12 h at room temperature. EtOAc was ad-
ded and the mixture was washed with brine. The organic layer was
dried with Na2SO4, concentrated in vacuo and chromatographic-
ally purified (silica, 50% EtOAc in hexanes) to yield 35 (193 mg,
90%) a white solid. M.p. 74 °C. [α]2D3 ϭ Ϫ83.6 (c ϭ 1.35, CHCl3).
1H NMR (CDCl3, 500 MHz): δ ϭ 7.47 (dd, J ϭ 8.5, 7.5 Hz, 1 H),
7.34Ϫ7.17 (m, 10 H), 6.94 (d, J ϭ 8.5 Hz, 1 H), 6.77 (d, J ϭ 7.5 Hz,
1 H), 6.49 (m, 1 H), 5.05Ϫ4.30 (m, 8 H), 4.14 (m, 1 H), 3.98 (s, 3
H), 3.00Ϫ2.50 (m, 4 H), 1.86 (m, 1 H), 1.72 (m, 1 H), 1.52Ϫ1.35
(m, 16 H), 0.94 (m, 6 H) ppm. 13C NMR (CHCl3, 125 MHz): δ ϭ
171.3/170.9, 169.9, 162.6, 161.5, 152.1/151.5, 142.5, 136.9/136.8,
136.5/136.1, 135.2, 128.9Ϫ128.4, 119.7, 113.7, 111.2, 93.8/93.5,
80.9/80.6, 80.0/79.9, 76.8, 76.6/76.4, 73.1/72.6, 66.9/66.8, 56.7, 56.4/
56.2, 49.3, 40.9, 36.2/35.7, 32.1, 28.8, 28.2/27.2, 25.1, 25.0/23.8,
23.4, 22.4/22.3 ppm. IR (film): ν˜ ϭ 3326 (br. w), 1733 (s), 1694 (s)
1
(allS)-tert-Butyl 4-Benzyloxycarbonylmethyl-5-{benzyloxy[1Ј-(8ЈЈ-
methoxy-1ЈЈ-oxoisochroman-3ЈЈ-yl)-3Ј-methylbutylcarbamoyl]-
methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (35): A solution
of 34 (300 mg, 0.46 mmol) in CH2Cl2 (50 mL) was cooled to Ϫ78
°C. Ozone was passed through the solution until the blue colour
persisted. Oxygen and nitrogen were successively passed through
the solution for at least 10 min each. PPh3 (121 mg, 0.46 mmol)
was added portionwise under N2 and the reaction mixture was al-
lowed to warm to room temperature over a period of 1 h. Evapora-
tion of solvent and chromatographic purification (silica, 50%
EtOAc in hexanes) of the residue yielded (allS)-tert-butyl 5-
Eur. J. Org. Chem. 2003, 821Ϫ832
831

A. K. Ghosh, A. Bischoff, J. Cappiello
FULL PAPER
[7]
cmϪ1
. LRMS (FAB, m/z): 759. HRMS (FAB, m/z): calcd.
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C43H54O10N2Na [M ϩ Naϩ] 781.3676, found 781.3702.
[8]
[9]
(allS)-tert-Butyl 4-Benzyloxycarbonylmethyl-5-{benzyloxy[1Ј-(8ЈЈ-
hydroxy-1ЈЈ-oxoisochroman-3ЈЈ-yl)-3Ј-methylbutylcarbamoyl]-
methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (36): A solution
of 35 (106 mg, 0.14 mmol) and MgI2 (74.0 mg, 0.27 mmol) in THF
(5 mL) was heated to 40 °C for 30 min. The inorganic content was
precipitated by addition of hexane, the mixture was filtered through
a short path of silica, and the filter cake was rinsed with CH2Cl2.
The filtrate was concentrated in vacuo to yield 36 (97.0 mg, 93%)
as a colourless oil. [α]2D3 ϭ Ϫ43.0 (c ϭ 0.65, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ ϭ 10.90 (d, 4J ϭ 6.6 Hz, 1 H), 7.44 (dd, J ϭ
8.5, 7.5 Hz, 1 H), 7.40Ϫ7.14 (m, 10 H), 6.92 (d, J ϭ 8.5 Hz, 1 H),
6.67 (d, J ϭ 7.5 Hz, 1 H), 6.42 (m, 1 H), 5.03Ϫ4.80 (m, 2 H),
4.60Ϫ4.35 (m, 6 H), 4.19 (m, 1 H), 3.01Ϫ2.53 (m, 4 H), 1.71 (m,
1 H), 1.73 (m, 1 H), 1.47Ϫ1.34 (m, 16 H), 0.97 (m, 6 H) ppm.
13C NMR (CHCl3, 125 MHz): δ ϭ 171.4/171.0, 170.0/169.8, 162.6,
162.6, 152.1/151.4, 139.9, 137.0, 136.8, 136.4/136.0, 129.2Ϫ128.4,
118.5, 116.6, 108.4, 93.8/93.4, 81.8/81.7, 81.0/80.7, 76.9, 76.8/76.5,
73.3/72.8, 66.9/66.8, 56.3/56.1, 49.3, 41.1, 36.2/35.6, 30.6/30.1, 28.8,
28.0/27.0, 25.1, 25.0/23.8, 23.5, 22.3/22.2 ppm. IR (film): ν˜ ϭ 3341
(br. w), 1734 (s), 1686 (s) cmϪ1. HRMS (FAB, m/z): calcd.
C42H52O10N2Na [M ϩ Naϩ] 767.3520, found 767.3551.
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
AI-77-B (1): A mixture of 36 (32.0 mg, 43.0 µmol), Dowex 50 W-
X8-100 (2.00 g), palladium (10% on activated carbon, 4.0 mg),
THF (5 mL) and MeOH (5 mL) was stirred for 10 h at 23 °C under
hydrogen. Filtration through sand, evaporation of solvents and
chromatographic purification (silica, MeOH) gave 1 (13.7 mg, 75%)
as a white solid. M.p. 137Ϫ138 °C (ref.[10] m.p. 139.5Ϫ140 °C). [α]
[25]
[26]
[27]
ϭ Ϫ76.3 (c ϭ 0.09, MeOH) {ref.[16] [α]2D2 ϭ Ϫ78.2 (c ϭ 0.08,
23
D
[28]
[29]
[30]
MeOH)}. 1H NMR ([D4]MeOH, 400 MHz): δ ϭ 7.42 (dd, J ϭ 8.4,
7.7 Hz, 1 H), 6.81 (d, J ϭ 8.4 Hz, 1 H), 6.75 (d, J ϭ 7.6 Hz, 1 H),
4.62 (ddd, J ϭ 12.0, 3.2, 3.2 Hz, 1 H), 4.32 (ddd, J ϭ 10.4, 3.2,
3.2 Hz, 1 H), 4.09 (d, J ϭ 6.8 Hz, 1 H), 3.87 (dd, J ϭ 6.8, 4.4 Hz,
1 H), 3.54 (ddd, J ϭ 10.0, 4.4, 4.4 Hz, 1 H), 3.06 (dd, J ϭ 16.4,
12.4 Hz, 1 H), 2.89 (dd, J ϭ 16.4, 2.8 Hz, 1 H), 2.58 (dd, J ϭ 17.2,
4.0 Hz, 1 H), 2.46 (dd, J ϭ 16.8, 10.0 Hz, 1 H), 1.81 (ddd, J ϭ
14.0, 12.0, 7.6 Hz, 1 H), 1.68 (m, 1 H), 1.40 (ddd, J ϭ 14.0, 10.0,
4.0 Hz, 1 H), 0.95 (d, J ϭ 6.4 Hz, 3 H), 0.91 (d, J ϭ 6.4 Hz, 3 H)
ppm. 13C NMR ([D4]MeOH, 125 MHz): δ ϭ 177.2, 174.2, 170.0,
162.2, 140.5, 136.5, 118.5, 115.7, 108.4, 81.7, 72.2, 72.1, 51.6, 49.4,
39.7, 34.1, 29.8, 24.8, 22.8, 20.9 ppm. IR (film): ν˜ ϭ 3301 (br. s),
[31]
[32]
[33]
[34]
[35]
[36]
1672 (s) cmϪ1
.
[37]
[38]
[39]
Acknowledgments
Financial support by the National Institutes of Health is gratefully
acknowledged. We thank Dr. Geoff Bilcer and Mr. Gary Schiltz
for helpful discussions.
[40]
[41]
[42]
[43]
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