Stereocontrolled synthesis of the ABCDE ring moiety of ciguatoxin CTX3C

Article abstract of DOI:10.1016/j.tet.2004.07.010

The ABCDE ring moiety of ciguatoxin CTX3C, a major causative agent of ciguatera poisoning, was stereoselectively synthesized. The key transformations are a chiral auxiliary-based asymmetric alkylation and an asymmetric aldol condensation, which controlled

Full text of DOI:10.1016/j.tet.2004.07.010

Tetrahedron 60 (2004) 8375–8396
Stereocontrolled synthesis of the ABCDE ring moiety of
ciguatoxin CTX3C
Shoji Kobayashi, Yusuke Takahashi, Kazuo Komano, Babak H. Alizadeh, Yuuya Kawada,
†
Tohru Oishi, Shin-ichiro Tanaka, Yoshihiro Ogasawara, Shin-ya Sasaki and Masahiro Hirama
*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 16 June 2004; revised 2 July 2004; accepted 5 July 2004
Abstract—The ABCDE ring moiety of ciguatoxin CTX3C, a major causative agent of ciguatera poisoning, was stereoselectively
synthesized. The key transformations are a chiral auxiliary-based asymmetric alkylation and an asymmetric aldol condensation, which
controlled the formation of the C11 and C21-stereocenters, respectively. A highly practical and efficient route to the ABCD ring fragment, a
common precursor for the divergent synthesis of the left wings of ciguatoxins, was also established.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of the HIJKLM ring10 in terms of number of
synthetic steps, stereoselectivity, and overall yield.11 On the
other hand, preparation of the ABCDE ring moiety 512 was
yet to be optimized, especially with regard to stereocontrol.
In the original synthesis of 5, the stereoselectivity of the
coupling between AB ring 9 and E ring 8 was unsatisfac-
tory. Furthermore, E ring 8 was prepared from D-glucose via
a non-stereocontrolled aldol condensation. Therefore,
separation of undesired stereoisomers was required, fol-
lowed by repeated epimerization processes, to supply a
sufficient quantity of ring fragments for total synthesis. To
overcome these stereochemical disadvantages, an alterna-
tive approach featuring chiral auxiliary-based stereoselective
alkylation of 12 with 9 was developed to afford the ABCD
ring fragment 11.13 The intermediate 11 was expected to be
a common precursor for the divergent synthesis of the left
wings of 1, 2, 3 and 4. In our previous report,14 the fully
functionalized ABCDE ring moiety (10) of 4 was
synthesized from 11 through installation of the dihydroxy-
butenyl substituent at C5 in the A ring and the tetrahydro-
oxepin E ring. In this publication, we have developed a
stereocontrolled route to 5 from 11 using an asymmetric
aldol condensation to regulate the C21-stereochemistry as
a key transformation. A practical synthesis of the key
intermediate 11 is also described herein. These develop-
ments are depicted in Scheme 1.
Ciguatoxins (CTXs) produced by a marine dinoflagellate
(Gambierdiscus toxicus) living on macroalgae, are trans-
ferred to and accumulated in a number of fish through the
food chain, causing ciguatera seafood poisoning primarily
in tropical and subtropical areas.1 The complex structures
of more than 20 CTX congeners such as CTX3C (1),2
51-hydroxyCTX3C (2),3 CTX4B (3),4 and CTX (4)4 were
elucidated on the basis of NMR and MS analyses.
Biological studies have revealed that CTXs exert their
toxicity through the activation of voltage-sensitive sodium
channels (VSSCs).5 To elucidate the interaction with
VSSCs in more detail at the molecular level5d as well as
to develop reliable immunochemical methods for detecting
CTXs,6 a practical supply of CTXs and their structural
analogs has been required. However, the extremely low
content of CTXs in fish has limited their supply from natural
sources. Therefore, a number of synthetic efforts have been
undertaken,7 culminating in the first total synthesis of
CTX3C (1) in our laboratory.8 Our convergent strategy to
synthesize 1 relied on the coupling of the left (ABCDE)
wing and the right (HIJKLM) wing with the concomitant
construction of the central FG ring system.8,9 This strategy
is expected to be applicable to all CTXs due to the common
FG ring structure. Our recent research greatly improved the
Keywords: Asymmetric alkylation; Asymmetric aldol condensation; Ring-
closing metathesis; Ciguatoxin; CTX3C.
2. Results and discussion
* Corresponding author. Tel.: C81-22-217-6563; fax: C81-22-217-6566;
e-mail: hirama@ykbsc.chem.tohoku.ac.jp
2.1. Practical synthesis of the ABCD ring moiety
The AB ring unit 9 was synthesized from commercially
† Present address: Department of Chemistry, Graduate School of Science,
Osaka University, Osaka 560-0043, Japan.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.010

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S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
Scheme 1. Structures of ciguatoxins (CTXs) and synthetic strategy for the total synthesis of CTXs. BnZbenzyl; MPZp-methoxyphenyl; MPMZp-
methoxybenzyl; NAPZ2-naphthylmethyl.
available tri-O-benzyl-D-glucal (13) using a slight modifi-
cation of a previously reported procedure (Scheme 2),12,15
as follows. Treatment of 13 with NBS in aqueous THF gave
a diastereomeric mixture of bromohydrins 14, which was
converted to 15 using the Spilling method.16 To obtain 15
with high stereoselectivity, it was critical to maintain strict
temperature control at K78 8C during the treatment of 14
with KN(TMS)2. Alcohol 15 was then reacted with allyl
bromide to give diene 16, which was subjected to ring-
closing metathesis (RCM)17 to yield the AB ring 17.
Removal of the benzyl group of 17 under Birch conditions
or with the use of lithium 4,40-di-tert-butylbiphenyl resulted
in the partial cleavage of the allylic ether linkage in the A
ring.8a,12 After considerable investigation, Lewis acid-
18
mediated debenzylation using TiCl4 was found to be
optimal and selectively yielded triol 18, which was easily
converted to acetal 19 (91%, 2 steps). The secondary
alcohol of 19 was protected as a benzyl ether, and the
p-methoxybenzylidene acetal of 20 was selectively cleaved
to give primary alcohol 21. Finally, iodination of 21
afforded the AB ring moiety 9.
The C14–C17 unit19 was then assembled onto 9 (Scheme 3).
After considerable experimentation,20 we found that the
protected (1R,2S)-1-amino-2-indanol derivative 2421 was
suitable for diastereoselective alkylation. Amide 24 was
readily prepared from alcohol 2212b and bromide 23. The
key coupling reaction between iodide 9 and 24 (3.3 equiv.)
was successfully performed using BuLi (3.3 equiv.) in the
presence of DMPU (4.5 equiv.). The reaction reproducibly
afforded the desired isomer 25 almost exclusively, even at
the reaction scale of 17 g (33 mmol) of 9, possibly through
the transition state as shown in Figure 1, which shows attack
of electrophile 9 from the less hindered C11-si face of the
kinetically and thermodynamically favored Z-enolate of
24.21a,22 Selective removal of p-methoxybenzylidene acetal
of 25 with PPTS and subsequent TBPS protection with
TBPSOTf23 in the presence of 2,6-lutidine afforded 27 in
74% overall yield from 9. Oxidative MPM deprotection was
then carefully performed at K5 8C to avoid Bn deprotec-
tion, yielding secondary alcohol 28. Subsequent lactoniza-
tion was not trivial. After extensive experimentation, it was
found that addition of a catalytic amount of p-anisaldehyde
Scheme 2. Reagents and conditions: (a) NBS, THF–H2O (10:1), 0 8C, 1 h;
(b) KN(SiMe3)2, 18-crown-6, toluene, K78 8C, 6 h, then allylmagnesium
bromide, toluene–Et2O, K68 8C to rt, 24 h, 45% (2 steps); (c) allyl
bromide, NaH, THF–DMF (4:1), 0 8C to rt, 13 h, 99%; (d) (PCy3)2-
Cl2Ru]CHPh (2 mol%), CH2Cl2, 4.5 h, 84%; (e) TiCl4 (1.9 equiv.),
MeNO2, K5 8C, 30 min; (f) pMeOC6H4CH(OMe)2, TsOH$H2O, DMF,
0 8C to rt, 18 h, 91% (2 steps); (g) BnBr, NaH, THF–DMF (4:1), 0 8C to rt,
18 h; (h) DIBAL, CH2Cl2, K78 to K33 8C, 12 h, 97% (2 steps); (i) PPh3,
I2, imidazole, toluene, 6 h, 96%. NBSZN-bromosuccinimide; CyZcyclo-
hexyl; DIBALZdiisobutylaluminum hydride; TsZp-toluenesulfonyl.

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8377
Scheme 3. Reagents and conditions: (a) NaH, THF–DMF (4:1), 13 h, 79%; (b) 9, BuLi, DMPU, THF, K78 8C to rt, 19 h; (c) PPTS, PrOH, 16 h, 81% (2 steps);
(d) TBPSOTf, 2,6-lutidine, CH2Cl2, 0 8C, 2 h, 91%; (e) DDQ, CH2Cl2-H2O (20:1), K5 8C, 2.5 h (three cycles), 86%; (f) CSA (3 equiv.), p-anisaldehyde
(0.4 equiv.), toluene, 90 8C, 3 h; (g) tetravinyltin, MeLi, THF, K100 to K90 8C, 45 min, 77% (2 steps); (h) Et3SiH, TMSOTf, CH3CN, K40 to K20 8C,
40 min; (i) TBAF, THF, 44 h, 82% (2 steps); (j) Ac2O, pyridine, DMAP, CH2Cl2, 3 h, 89%. DMPUZN,N0-dimethylpropyleneurea; PPTSZpyridinium
p-toluenesulfonate; TBPSZt-butyldiphenylsilyl; DDQZ2,3-dichloro-5,6-dicyano-1,4-benzoquinone; CSAZ(1S)-(C)-10-camphorsulfonic acid; TMSZ
trimethylsilyl; TfZtrifluoromethanesulfonyl; TBAFZtetrabutylammonium fluoride; AcZacetyl; DMAPZ4-(dimethylamino)pyridine.
to the reaction mixture of 28 and CSA (3 equiv.) in toluene
at 90 8C reproducibly produced lactone 29 in good yield.
This can be explained as follows: acid-catalyzed cleavage of
the acetonide group on the chiral auxiliary can be expected
to compete with the direct lactonization of tertiary amide 28.
The resultant secondary amide is likely to be less
susceptible to lactonization. However, once it is converted
in the presence of p-anisaldehyde to the corresponding
p-methoxybenzylidene acetal, this tertiary amide would
become reactive enough to form 29. A vinyl group was then
added to 29 at a temperature less than K90 8C to yield
hemiacetal 30 as a mixture of diastereomers. Direct
reduction of 30 was achieved with triethylsilane in the
presence of TMSOTf in acetonitrile to afford a mixture of
bis-TBPS ether 31, diol 32, and mono-TBPS ethers. The
remaining TBPS groups were wholly removed by TBAF to
yield 32 from 28 with an overall yield of 63%.
TBPS groups (entries 1 and 2). Although the reaction with
the less hindered acetate 33 did proceed, more than 1 equiv.
of catalyst and a long reaction time were required (entries 3
and 4). On the contrary, diol 32 smoothly underwent RCM
(entries 5–7), and a catalytic amount of 37 was sufficient to
yield 11 in 99% yield (entry 7). Thus, a reliable and
stereoselective protocol for preparing the ABCD ring
moiety 11 on a several-gram scale was developed.
2.2. Attempts to construct the tetrahydrooxocin E ring
using a chlorosulfide synthon
The tetrahydrooxocin E ring of 1 and 2 was constructed by
adoption of the recently developed O,S-acetal forming
reaction9b,c,25 using the chlorosulfide synthon 4114
(Scheme 4). Since the 2-naphthylmethyl (NAP) group
proved to be optimal for the global deprotection step in the
last stage of the total synthesis of 1,8b the benzyl group of 11
was replaced by the NAP group. Debenzylation was
successfully performed under Lewis acidic conditions.26
After sequential manipulation of the protective groups,
primary alcohol 38 was converted to nitrile 39. Reduction of
the nitrile (39) with DIBAL and subsequent Wittig
olefination followed by removal of the TBS group yielded
alcohol 40. This alcohol was successfully coupled with
a-chlorosulfide 41 in the presence of AgOTf and 2,6-di-tert-
butyl-4-methylpyridine to yield O,S-acetal 42 as a major
diastereomer (6:1) in 84% yield.27 RCM of the correspond-
ing C20-alcohol 43 proceeded smoothly to afford 44 in 88%
yield. After TBS protection, sulfide 45 was carefully
oxidized to sulfone 46 by use of mCPBA at K15 8C. The
stereochemistry of 46 was established by NOE experiments.
Subsequent RCM of the diene was highly dependent on the
protective group and catalyst used, as shown in Table 1. The
reaction of bis-TBPS ether 31 using catalyst 3617 or 3724
was very sluggish, presumably due to steric hindrance of the
Figure 1. Proposed transition state of the alkylation of 24 with 9. The
energy-minimized structure of the Z-enolate of 24 was obtained using
Macro Model ver. 6.0 with the MM2* force field.
To insert the allyl group at C21, which is necessary for the
construction of the nine-membered F ring via RCM in the

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S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
Table 1. RCM of the D ring
Entry
Substrate
Catalyst
mol% of Catalyst
Temperature
Time (h)
Yield (%)
1
2
3
4
5
6
7
31
31
33
33
32
32
32
36
37
36
37
36
37
37
Excess
50
120
8
20
20
2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
42
21
39
3
5
0.5
2.5
!10
No reaction
83
No reaction
Complex mixture
48
99
total synthesis of 1 and 2,8,9a,b Lewis acid-mediated
coupling of anomeric sulfone 46 with allyltrimethylsilane
was attempted in the presence of AlCl3 (Scheme 5).14,28
However, ring-contraction products 51 and 52 were
obtained in 50 and 20% yield, respectively, instead of the
desired alkene 47.29 This can be explained as shown in
Scheme 5. The rearrangement would be initiated via
oxonium cation 48. The resultant allylic cation 49 might
form the less strained oxepin ring 50, to which allylation
could occur to produce 51 and 52. To prevent this ring
contraction, we planned insertion of the C22 carbon unit
before the formation of the eight-membered ring. Acyclic
sulfone 53, which was prepared by the selective oxidation of
42 (mCPBA, CH2Cl2, K20 8C, 1 h, 31% yield), was treated
with TMSCN and EtAlCl2 (Scheme 6). In this case, the
intramolecular cyclization product 5630 was mainly
obtained instead of the desired 54. Therefore, we abandoned
the Lewis acid-mediated coupling strategy using anomeric
sulfones, and investigated an alternative route, as described
below.
2.3. Stereocontrolled synthesis of the ABCDE ring
moiety featuring an asymmetric aldol reaction and RCM
An alternative synthesis plan for the ABCDE ring moiety is
outlined in Scheme 7. The key transformation is a chiral
auxiliary-based asymmetric aldol reaction31,32 of O-alkyl-
ated glycolic amide 57. Since Crimmins and co-workers
have recently succeeded in carrying out a 1,2-anti-selective
aldol reaction by use of titanium enolates of N-glycolylox-
azolidinethiones,33,34 model experiments were first per-
formed using chiral amides 59–61 (Table 2).
Under the Crimmins conditions,33a however, 20,21-syn
aldol products (63, 64) predominated (entry 1),35 which
implied that the 20,21-syn/anti selectivity is highly
dependent on the structure of the O-alkyl group. Further
investigation revealed that this selectivity was greatly
Scheme 4. Reagents and conditions: (a) AlCl3 (3 equiv.), CH2Cl2–CH3NO2
(3:1), 0 8C, 20 min, 97%; (b) Me2C(OMe)2, PPTS, CH2Cl2–DMF (1:1),
13 h, 84%; (c) NAPBr, NaH, TBAI, THF–DMF (3:1), 40 8C, 30 min, 88%;
(d) TsOH$H2O, MeOH–THF (2:1), 27 h; (e) TBSOTf, 2,6-lutidine,
CH2Cl2, 1 h, 98% (2 steps); (f) CSA, MeOH–THF (1:1), K15 8C, 14 h,
85%; (g) TsCl, pyridine, MS4A, 24 h, 96%; (h) NaCN, DMSO, 50 8C, 20 h,
94%; (i) DIBAL, CH2Cl2, K70 8C, 3 h; (j) Ph3PCH3Br, NaN(SiMe3)2,
0 8C, 1 h, 82% (2 steps); (k) TBAF, THF, 18 h, 91%; (l) 41 (3 equiv.),
AgOTf (3.5 equiv.), 2,6-di-tert-butyl-4-methylpyridine (4.2 equiv.),
MS4A, CH2Cl2, K40 to K20 8C, 1 h, 84% (21R/21SZ6:1); (m) TBAF,
THF, 1 h, 98%; (n) 37 (0.05 equiv.), CH2Cl2, 1 h, 88%; (o) TBSCl,
imidazole, DMF, 24 h, 95%; (p) mCPBA, CH2Cl2, K15 8C, 4 h (three
cycles), 98%. TBSZtert-butyldimethylsilyl; TBAIZtetrabutylammonium
Scheme 5. Reagents and conditions: (a) allyltrimethylsilane, AlCl3,
CH2Cl2, K60 8C, 30 min, 51 (50%, 2:1 stereoisomers), 52 (20%, 2:1
stereoisomers).
˚
iodide; MS4AZmolecular sieve 4 A; mCPBAZm-chloroperbenzoic acid.

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8379
Figure 2. Proposed transition states involved in the formation of 20,21-syn
products 64 and 63.
obtained in 15 and 61% yield, respectively. Importantly,
the use of Et3N was essential and no reaction proceeded
with iPr2NEt. The minor isomer 72 was directly converted
to the ABCDE ring moiety 512 by removal of the chiral
auxiliary and constructing the tetrahydrooxocin E ring. On
the other hand, the aldol reaction using oxazolidinone 71
gave rise to 20,21-syn-15,21-syn isomer 74 selectively in
72% yield along with a small amount of the corresponding
20,21-syn-15,21-anti product (12%). Chiral auxiliaries of
the major products 73 and 74 were removed and the
resulting diol 75 was subjected to RCM, yielding the C20-
epimer 76 of 5. Exposure of the mono-TBS ether 77 to
standard Mitsunobu conditions36,37 afforded benzoate 78
with complete inversion of the C20-stereochemistry.
Finally, removal of the protective groups of 78 except
NAP afforded 5 from 78 with an overall yield of 85%.
Scheme 6. Reagents and conditions: (a) TMSCN, EtAlCl2, CH2Cl2, K50 to
K30 8C, 1 h, 56 (35%, 2:1 stereoisomers).
affected by the amines used. A remarkable preference of
20,21-syn isomer 64 with the undesired C21-configuration
(21R) was observed when iPr2NEt or Et3N was used (entries
3 and 4). Since the stereochemistry at C20 can be readily
inverted through the Mitsunobu reaction,36,37 we decided to
change the chiral auxiliary from (R)-4-benzyl-2-oxazolidi-
nethione to its enantiomer to reverse the C21-stereochem-
istry. As expected, the titanium enolate of 60 produced by
TiCl4 and iPr2NEt afforded a 5:95 mixture of 20,21-anti 62
and 20,21-syn isomer 63, both of which possessed the
desired C21-configuration (21S) (entry 5). The use of Et3N
accelerated the reaction and increased the proportion of
20,21-anti isomer 62 (entry 6). A similar result was obtained
with (S)-4-benzyl-2-oxazolidinone 61, although the unde-
sired 15,21-anti isomer 64 was also produced (entry 7). The
observed 20,21-syn selectivity can be explained by the
Evans-type six-membered chair-like transition state as
shown in Figure 2.32–34
3. Conclusion
The left wing (5) of CTX3C (1) and 51-hydroxyCTX3C (2)
was synthesized in a stereocontrolled manner from
commercially available tri-O-benzyl-D-glucal (13). The
key features of the present synthesis involve the highly
practical and stereoselective preparation of the valuable
ABCD ring intermediate 11, as well as asymmetric
construction of the tetrahydrooxocin E ring system. This
synthesis avoids the repeated separation of undesired
isomers and subsequent epimerization processes. The high
reliability of the synthesis established here will enable a
practical supply of the left wing not only for the total
syntheses of CTXs but also for biomedical applications.
Further investigations along this line are currently underway
in our laboratory.
Based on these model experiments, either the (S)-4-benzyl-
2-oxazolidinethione or the (S)-4-benzyl-2-oxazolidinone
auxiliary was introduced into the ABCD ring moiety 40
(Scheme 8). Since the direct O-alkylation of 40 with N-
bromoacetyl-(S)-4-benzyl-2-oxazolidinone38 in the pre-
sence of NaH was unsuccessful, the auxiliary was installed
onto 40 in a stepwise manner. First, alkylation of 40 with t-
butyl bromoacetate gave ester 65, which was hydrolyzed by
10 M HCl. The resulting carboxylic acid 66 was converted
to amide 70 or 71 via pivaloyl anhydride 67, in preparation
for the key asymmetric aldol reaction. When oxazolidi-
nethione 70 was used, the desired 20,21-anti-15,21-syn
isomer 72 and 20,21-syn-15,21-syn isomer 7339 were
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded on a Varian
Mercury 200 (200 MHz) or a Varian INOVA-500
(500 MHz) spectrometer. IR spectra were recorded on a
Perkin–Elmer Spectrum BX FT-IR spectrometer. Matrix
assisted laser desorption ionization time-of-flight mass
spectra (MALDI-TOF MS) were recorded on an Applied
Biosystems Voyager DE STR SI-3 instrument using a-
cyano-4-hydroxy cinnamic acid as a matrix. Electron spray
ionization time-of flight mass spectra (ESI-TOF MS) were
recorded on an Applied Biosystems Mariner instrument.
Optical rotations were recorded on a JASCO DIP-370
Scheme 7. Synthesis plan of the ABCDE ring moiety featuring an
asymmetric aldol reaction and RCM.

8380
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
Table 2. Asymmetric aldol condensations in a model systema
Entry
Substrate
Amine
Temperature (8C)
Time (h)
Yield (%)b
Ratio
(62:63:64)c,d
Recovery of s.m.
(%)b
1e
2
3
4
5
6
7
59
59
59
59
60
60
61
(K)-Sparteine
TMEDA
iPt2NEt
Et3N
iPt2NEt
Et3N
Et3N
K78
K78 to K40
K78 to K50
K70
K78 to K50
K78
K78
1
5
4
0.5
4
1
0.5
55
34
58
69
67
71
72
13:63:24
25:50:25
2:5:93
6:13:81
5:95:0
!10
44
20
9
23
6
25:75:0
3:72:25
2
a
Performed with 4–6 equiv. of TiCl4, 10 equiv. of amine, and 10 equiv. of acrolein except entry 1.
Isolated yield.
b
c
d
e
Determined by HPLC.
Corresponding anti,anti isomer was not detected in each case.
Since Crimmins’ original method using 1.2 equiv. of (K)-sparteine and 1.2C4 equiv. of TiCl433a gave aldol products in low yield, excess (K)-sparteine
(3 equiv.) and N-methyl-2-pyrrolidinone (3 equiv.)33 were used along with 1.5C4 equiv. of TiCl4.
Scheme 8. Reagents and conditions: (a) BrCH2CO2tBu, NaH, THF–DMF (4:1), 0 8C to rt, 10 h, 92%; (b) 10M HCl–THF (1:2), 30 8C, 23 h, 81%; (c) PivCl,
Et3N, CH2Cl2, K78 8C to rt, 40 min; (d) 68 or 69, nBuLi, THF, K78 to 0 8C, 0.5–1 h, 51% for 70, 96% for 71 (2 steps); (e) TiCl4 (10 equiv.), Et3N (20 equiv.),
acrolein (20 equiv.), CH2Cl2, K78 8C, 20 min, 72 (15% from 70), 73 (58% from 70), 74 (72% from 71); (f) NaBH4, THF–H2O (4:1), 10 min, 85%; (g) 37,
(0.1 equiv.), CH2Cl2, 30 min, 82%; (h) NaBH4, THF–H2O (4:1), 10–20 min, 79% from 73, 99% from 74; (i) 37, (0.1 equiv.), CH2Cl2, 1 h, 92%; (j) TBSCl,
imidazole, CH2Cl2, 0.5 h, 83%; (k) PPh3, DEAD, BzOH, toluene, 20 min, 100%; (l) TBAF, THF, 3 h, 92%; (m) K2CO3, MeOH–THF (2:1), 1.5 h, 92%. PivZ
pivaloyl; BzZbenzoyl; DEADZdiethyl azodicarboxylate.

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8381
digital polarimeter. Melting points were measured on a
Yanaco MP-S3 micro melting point apparatus. Open
column chromatography was performed using 100–210 mm
Silica Gel 60 N (Kanto Chemical Co., Inc.), and for flash
column chromatography 40–50 mm Silica Gel 60N (Kanto
Chemical Co., Inc.) was used. All reactions sensitive to air
or moisture were carried out under argon or nitrogen
atmosphere in dry, freshly distilled solvents under anhy-
drous conditions. Dry solvents purchased from Kanto
Chem. Co. were also used.
spectroscopic data are identical to those reported in the
literature.12
4.2.4. Alcohol 19. To a solution of AB ring 17 (10.1 g,
20.7 mmol) in CH3NO2 (103 ml) was slowly added a
solution of TiCl4 (5.47 ml, 39.4 mmol) in CH3NO2 (103 ml)
at K5 8C. The mixture was stirred for 30 min at K5 8C and
quenched by the slow addition of MeOH. The resulting dark
purple suspension was concentrated, and the residue was
diluted with MeOH and filtered through a pad of Celite. The
filter cake was washed with MeOH sufficiently and the
combined filtrate was concentrated. The residue was
purified by flash column chromatography (silica gel,
EtOAc/MeOHZ10) to give triol 18 (5.59 g).
4.2. Synthesis of the ABCD ring fragment
4.2.1. Alcohol 15. To a solution of benzyl ether 13 (30.0 g,
72.0 mmol) in THF (160 ml) and H2O (16 ml) was added
NBS (14.1 g, 79.2 mmol) at 0 8C. The mixture was stirred
for 1 h at 0 8C and quenched with water. Aqueous phase was
extracted with Et2O, and the combined organic phase was
washed with saturated Na2S2O3 solution, brine and dried
over anhydrous MgSO4. Concentration of the solution gave
bromide 14 (45.3 g) as a diastereomeric mixture.
To a solution of triol 18 (5.59 g) in DMF (120 ml) were
added anisaldehyde dimethyl acetal (9.58 ml, 51.7 mmol)
and TsOH$H2O (418 mg, 2.20 mmol) at 0 8C. The mixture
was stirred for 18 h at ambient temperature and quenched
with saturated NaHCO3 solution. Aqueous phase was
extracted with EtOAc and the organic phase was concen-
trated at 70 8C (to remove DMF). Et2O was added to the
residue, and the resulting precipitate was collected by
filtration to yield acetal 19 (6.27 g, 18.8 mmol, 91% in 2
steps) as colorless powder. All spectroscopic data are
identical to those reported in the literature.12
To a 2 l three-necked round-bottom flask equipped with
mechanical stirrer and dropping funnel was added a solution
of 14 (45.3 g) and 18-crown-6 (32.0 g, 121 mmol) in
toluene (180 ml). The solution was cooled to K78 8C, and
KN(TMS)2 (1.2 M solution in toluene, 120 ml, 144 mmol)
was slowly added over 1 h. The resulting mixture was
stirred for 6 h at K78 8C and then warmed to K68 8C.
Allylmagnesium bromide (0.8 M solution in ether, 180 ml,
144 mmol) was added over 1 h, and the resulting mixture
was gradually warmed to room temperature over 24 h with
stirring. The mixture was quenched with saturated NH4Cl
solution and neutralized with conc. HCl. Aqueous phase
was extracted with hexane–EtOAc, and the organic phase
was concentrated. The residue was purified by flash column
chromatography (silica gel, hexane/EtOAcZ10–5) to give
alcohol 15 (15.5 g, 32.6 mmol, 45%) as yellow oil. All
spectroscopic data are identical to those reported in the
literature.12
4.2.5. Alcohol 21. To a solution of alcohol 19 (13.0 g,
38.9 mmol) in THF (160 ml) and DMF (40 ml) was added
NaH (60% dispersion in mineral oil, 1.70 g, 42.8 mmol) at
0 8C. The mixture was stirred for 30 min at 0 8C. BnBr
(5.09 ml, 42.8 mmol) was added and the resulting mixture
was stirred for 18 h at room temperature. The mixture
was quenched with H2O at 0 8C and the aqueous phase was
extracted with EtOAc. The combined organic phase was
washed with brine and dried over anhydrous MgSO4.
Concentration of the solution gave benzyl ether 20.
A 1 l three-necked round-bottom flask equipped with
mechanical stirrer and dropping funnel was charged with
DIBAL (0.93 M in hexane, 335 ml, 311 mmol). The
solution was cooled to K78 8C and a solution of 20 in
CH2Cl2 (78 ml) was slowly added over 1.5 h. The mixture
was gradually warmed to K33 8C over 12 h with stirring
and re-cooled to K78 8C. EtOAc (100 ml) and Rochelle salt
solution (60 ml) were added at K78 8C and the resulting
mixture was vigorously stirred for 6 h at room temperature.
The mixture was filtered through a pad of Celite and the
filter cake was washed with EtOAc. The filtrate was
concentrated and the residue was purified by flash column
chromatography (silica gel, hexane/EtOAcZ2) to give
alcohol 21 (16.1 g, 37.7 mmol, 97% in 2 steps). All
spectroscopic data are identical to those reported in the
literature.12
4.2.2. Diene 16. To a solution of alcohol 15 (12.6 g,
26.6 mmol) in THF (64 ml) and DMF (16 ml) was added
NaH (60% dispersion in mineral oil, 2.55 g, 63.8 mmol) at
0 8C. The mixture was stirred for 30 min at 0 8C followed by
the addition of allyl bromide (3.45 ml, 39.9 mmol). The
resulting mixture was further stirred for 13 h at room
temperature. The mixture was quenched with saturated
NH4Cl solution and the aqueous phase was extracted with
hexane–EtOAc. The organic phase was washed with brine
and dried over anhydrous MgSO4. After concentration, the
residue was purified by flash column chromatography (silica
gel, hexane/EtOAcZ8) to give diene 16 (13.6 g,
26.5 mmol, 99%) as yellow oil. All spectroscopic data are
identical to those reported in the literature.12
4.2.6. Iodide 9. To a solution of alcohol 21 (12.1 g,
28.3 mmol) in toluene (142 ml) were added PPh3 (14.9 g,
56.7 mmol), imidazole (5.79 g, 75.1 mmol) and iodide
(10.8 g, 42.6 mmol) in this order. The mixture was stirred
for 6 h and quenched with saturated Na2S2O3 solution.
Organic phase was separated and the aqueous phase was
extracted with EtOAc. The combined organic phase was
washed with brine and dried over anhydrous MgSO4. After
4.2.3. AB ring 17. To a solution of diene 16 (13.6 g,
26.5 mmol) in CH2Cl2 (530 ml) was added Grubbs catalyst
36 (536 mg, 0.650 mmol). The mixture was stirred for 4.5 h
at ambient temperature and quenched with Et3N (900 ml,
6.50 mmol). After concentration, the residue was purified by
flash column chromatography (silica gel, hexane/EtOAcZ
7.5) to give AB ring 17 (10.9 g, 22.4 mmol, 84%). All

8382
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/EtOAcZ50–7.9–3.0) to
give iodide 9 (14.6 g, 27.2 mmol, 96%). All spectroscopic
data are identical to those reported in the literature.12
Na]C calcd for C27H31NNaO6 488.2049, found 488.2003;
[a]2D9.0 K1218 (c 1.00, CHCl3).
4.2.9. Diol 26. To a solution of amide 24 (51.2 g, 110 mmol)
in THF (170 ml) was slowly added nBuLi (1.56 M solution
in hexane, 70.5 ml, 110 mmol) over 30 min at K78 8C. The
mixture was stirred for 20 min at K78 8C, and a solution of
iodide 9 (17.9 g, 33.3 mmol) and DMPU (18.1 ml,
150 mmol) in THF (50 ml) was slowly added over 20 min
at K78 8C. The resulting mixture was gradually warmed to
room temperature over 3 h and the stirring was continued
for an additional 15 h at room temperature. The reaction
mixture was quenched with saturated NH4Cl solution and
the aqueous phase was extracted with EtOAc. The
combined organic phase was concentrated and the residue
was roughly purified by open column chromatography
(silica gel, hexane/EtOAcZ6–3–2) to give amide 25
(47.4 g).
4.2.7. Amide 23. To a solution of (1R,2S)-1-amino-2-
indanol (20.0 g, 134 mmol) in THF (500 ml) were added
Et3N (20.6 ml, 148 mmol) and bromoacetyl bromide
(12.9 ml, 148 mmol) at 0 8C. The mixture was stirred for
2 h at room temperature and cooled to 0 8C. CSA (12.5 g,
53.8 mmol) and 2-methoxypropene (25.7 ml, 268 mmol)
were added and the resulting mixture was stirred for 2 h at
room temperature. The reaction mixture was cooled to 0 8C,
diluted with hexane (250 ml) and quenched with saturated
NaHCO3 solution (250 ml). Aqueous phase was extracted
with EtOAc and the combined organic phase was washed
with brine and dried over anhydrous MgSO4. After
concentration, the residue was recrystallized from AcOEt
to give amide 23 (14.2 g, 45.9 mmol, 34%). The filtrate was
concentrated and the residue was purified by flash column
chromatography to give 23 (17.6 g, 56.7 mmol, 42%). 23:
colorless plate; mp 134–136 8C (hexane–EtOAc); 1H NMR
(500 MHz, CDCl3) d 1.37 (s, 3H, auxiliary), 1.62 (s, 3H,
auxiliary), 3.15 (d, 1H, JZ1.0 Hz, auxiliary), 3.16 (d, 1H,
JZ4.0 Hz, auxiliary), 4.03 (d, 1H, JZ10.0 Hz, H11), 4.23
(d, 1H, JZ10.0 Hz, H11), 4.95 (dt, 1H, JZ4.0, 1.0 Hz,
auxiliary), 5.39 (d, 1H, JZ4.0 Hz, auxiliary), 7.24–7.34 (m,
4H, auxiliary); 13C NMR (50 MHz, CDCl3) d 22.95, 26.32,
29.23, 36.16, 66.16, 78.89, 96.84, 123.68, 125.97, 127.21,
128.65, 139.83, 140.74, 163.04; FT-IR (KBr) n 3038, 2984,
2933, 1654, 1458, 1373, 1312, 1221, 1168, 1116, 1049,
1024, 983, 952, 907, 823 cmK1; ESI-TOF MS [MCH]C
calcd for C14H17BrNO2 310.0443, found 310.0424; [a]D28.0
K1658 (c 1.00, CHCl3).
To a solution of 25 (47.4 g) in nPrOH (362 ml) was added
PPTS (3.64 g, 14.5 mmol). The mixture was stirred for 16 h
at room temperature and quenched with Et3N (35 ml). After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/EtOAcZ8–3–1) to give
diol 26 (21.0 g, 27.8 mmol, 76% in 2 steps) and recovery of
25 (8.47 g). The recovered 25 (8.47 g) was subjected to the
same reaction and purification conditions to yield 26
(1.08 g, 1.43 mmol, 5% in 2 steps). 26: colorless amor-
phous; 1H NMR (500 MHz, CDCl3) d 1.37 (s, 3H,
auxiliary), 1.59 (s, 3H, auxiliary), 1.72 (brs, 2H, OH),
2.08–2.18 (m, 2H, H4, H10), 2.25 (ddd, 1H, JZ15.5, 8.5,
4.5 Hz, H10), 2.44 (ddd, 1H, JZ16.0, 8.5, 4.0 Hz, H4), 2.99
(dd, 1H, JZ17.0, 4.0 Hz, auxiliary), 3.09 (d, 1H, JZ
17.0 Hz, auxiliary), 3.24 (dt, 1H, JZ9.5, 4.0 Hz, H5), 3.36
(t, 1H, JZ9.5 Hz, H6), 3.50 (dt, 1H, JZ9.5, 4.5 Hz, H9),
3.54–3.61 (m, 2H, H7, H8), 3.74 (d, 1H, JZ9.0 Hz, H17),
3.78–3.87 (m, 2H, H16, H17), 3.80 (s, 3H, OMe), 3.98 (dq,
1H, JZ16.0, 3.0 Hz, H1), 4.12 (brs, 1H, H15), 4.25 (dd, 1H,
JZ16.0, 6.0 Hz, H1), 4.61 (t, 1H, JZ4.0 Hz, auxiliary),
4.68 (d, 1H, JZ10.0 Hz, CH2Ph), 4.81 (d, 1H, JZ11.0 Hz,
CH2Ph), 4.86 (d, 1H, JZ10.0 Hz, CH2Ph), 4.94 (d, 1H, JZ
11.0 Hz, CH2Ph), 5.00 (dd, 1H, JZ8.5, 2.0 Hz, H11), 5.16
(d, 1H, JZ10.5 Hz, CH2]CH–), 5.27 (d, 1H, JZ4.0 Hz,
auxiliary), 5.32 (d, 1H, JZ17.0 Hz, CH2]CH–), 5.66 (ddt,
1H, JZ11.5, 8.5, 3.0 Hz, H3), 5.83 (ddt, 1H, JZ11.5, 6.0,
3.0 Hz, H2), 5.96 (ddd, 1H, JZ17.0, 10.5, 6.0 Hz, H14),
6.85 (d, 2H, JZ8.5 Hz, MPM), 7.21 (d, 2H, JZ8.5 Hz,
MPM), 7.24–7.39 (m, 8H, auxiliary, Bn), 7.51 (d, 1H, JZ
7.5 Hz, auxiliary); 13C NMR (50 MHz, CDCl3) d 23.67,
26.54, 33.92, 34.63, 36.17, 55.21, 63.04, 64.22, 67.78,
72.09, 74.74, 75.58, 75.90, 76.07, 76.67, 79.15, 79.84,
83.74, 85.52, 87.52, 97.15, 113.81, 116.57, 124.13, 125.89,
126.58, 127.39, 127.55, 127.85, 128.29, 128.64, 129.47,
130.40, 131.37, 136.34, 138.71, 139.69, 140.62, 159.25,
171.01; FT-IR (KBr) n 3379, 2933, 1638, 1513, 1431, 1363,
1247, 1192, 927, 822 cmK1; ESI-TOF MS [MCH]C calcd
for C44H54NO10 756.3748, found 756.3651; [a]2D8.0 K1098
(c 1.00, CHCl3).
4.2.8. Amide 24. To a solution of alcohol 2212 (26.6 g,
113 mmol) and bromide 23 (42.0 g, 135 mmol) in THF
(320 ml) and DMF (80 ml) was added NaH (60% dispersion
in mineral oil, 5.4 g, 135 mmol) at 0 8C. The mixture was
stirred for 5 h at room temperature and quenched with water
at 0 8C. Aqueous phase was extracted with hexane, and the
combined organic phase was washed with brine and dried
over anhydrous MgSO4. After concentration, the residue
was purified by flash column chromatography to give amide
1
24 (51.6 g, 110 mmol, 98%). 24: colorless amorphous; H
NMR (500 MHz, CDCl3) d 1.34 (s, 3H, auxiliary), 1.64 (s,
3H, auxiliary), 3.13 (s, 2H, auxiliary), 3.54 (dt, 1H, JZ10.0,
5.0 Hz, H16), 3.76 (t, 1H, JZ10.0 Hz, H17), 3.80 (s, 3H,
OMe), 4.18 (dd, 1H, JZ10.0, 6.0 Hz, H15), 4.45 (d, 1H, JZ
14.0 Hz, H11), 4.57 (d, 1H, JZ14.0 Hz, H11), 4.60 (dd, 1H,
JZ10.0, 5.0 Hz, H17), 4.87 (dt, 1H, JZ4.5, 2.5 Hz,
auxiliary), 5.31 (d, 1H, JZ4.5 Hz, auxiliary), 5.33 (d, 1H,
JZ11.0 Hz, CH2]CH–), 5.51 (d, 1H, JZ17.0 Hz,
CH2]CH–), 5.51 (s, 1H, CHMP), 6.09 (ddd, 1H, JZ
17.0, 11.0, 6.0 Hz, H14), 6.88 (d, 2H, JZ8.0 Hz, MP), 7.23–
7.33 (m, 4H, auxiliary), 7.43 (d, 2H, JZ8.0 Hz, MP); 13C
NMR (50 MHz, CDCl3) d 24.10, 26.44, 36.25, 55.19, 64.65,
69.14, 70.65, 74.37, 79.30, 81.12, 96.98, 100.69, 113.51,
118.48, 124.19, 125.94, 127.20, 127.42, 128.61, 130.02,
135.01, 140.32, 140.76, 159.96, 165.14; FT-IR (film) n
2935, 1661, 1615, 1518, 1426, 1376, 1249, 1172, 1142,
1103, 1032, 933, 904, 830 cmK1; MALDI-TOF MS [MC
4.2.10. TBPS ether 27. To a solution of diol 26 (30.5 g,
40.4 mmol) and 2,6-lutidine (37.6 ml, 323 mmol) in CH2Cl2
(202 ml) was added TBPSOTf (46.0 g, 118 mmol) at 0 8C.
The mixture was stirred for 2 h at 0 8C and quenched with

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8383
saturated NaHCO3 solution. Aqueous phase was extracted
with hexane–EtOAc, and the combined organic phase was
washed with 1M HCl and dried over anhydrous MgSO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/EtOAcZ10–
5–4) to give bis-TBPS ether 27 (45.2 g, 36.7 mmol, 91%).
H5), 3.26–3.30 (m, 4H, H6, H7, H8, H9), 3.71 (dd, 1H, JZ
10.5, 7.0 Hz, H17), 3.76 (dd, 1H, JZ10.5, 6.0 Hz, H17),
3.89–3.97 (m, 1H, H1), 3.93 (dd, 1H, JZ7.0, 6.0 Hz, H16),
4.24 (dq, 1H, JZ15.5, 6.0 Hz, H1), 4.71 (d, 1H, JZ11.0 Hz,
CH2Ph), 4.72 (t, 1H, JZ4.0 Hz, auxiliary), 4.75 (d, 1H, JZ
7.0 Hz, H15), 4.85 (d, 1H, JZ17.5 Hz, CH2]CH–), 4.90
(d, 1H, JZ10.5 Hz, CH2]CH–), 4.92 (d, 1H, JZ11.0 Hz,
CH2Ph), 5.03 (dd, 1H, JZ7.0 Hz, H11), 5.63 (d, 1H, JZ
4.0 Hz, auxiliary), 5.61–5.68 (m, 1H, H3), 5.80–5.89 (m,
1H, H2), 5.84 (ddd, 1H, JZ17.5, 10.0, 7.0 Hz, H14), 7.04 (t,
1H, JZ7.5 Hz, Ph), 7.20–7.39 (m, 19H, Ph), 7.53–7.58 (m,
5H, Ph), 7.62–7.66 (m, 4H, Ph); 13C NMR (125 MHz,
CDCl3) d 19.14, 19.43, 24.34, 26.72, 26.94, 27.11, 34.57,
35.99, 36.46, 63.44, 65.06, 67.87, 73.94, 75.22, 75.80,
75.95, 76.09, 76.34, 76.59, 79.38, 81.54, 84.84, 87.48,
97.10, 116.59, 125.31, 125.43, 126.81, 127.27, 127.37,
127.61, 127.74, 128.19, 128.42, 129.44, 129.53, 131.51,
133.24, 133.31, 133.94, 134.06, 135.56, 136.18, 136.93,
139.11, 140.16, 140.93, 168.61; FT-IR (KBr) n 3427, 3069,
3045, 2930, 2890, 2856, 1660, 1650, 1471, 1461, 1427,
1330, 1241, 1111, 1090, 934, 822 cmK1; MALDI-TOF MS
[MCNa]C calcd for C68H81NNaO9Si2 1134.5342, found
1134.5345; [a]2D9.0 K28.98 (c 1.00, CHCl3).
1
27: colorless amorphous; H NMR (500 MHz, CDCl3) d
0.94 (s, 9H, t-Bu), 1.00 (s, 9H, t-Bu), 1.24 (s, 3H, auxiliary),
1.58 (s, 3H, auxiliary), 1.98 (ddd, 1H, JZ13.0, 9.5, 5.0 Hz,
H10), 2.08 (ddq, 1H, JZ16.0, 9.0, 3.0 Hz, H4), 2.16 (ddd,
1H, JZ16.0, 8.0, 4.0 Hz, H4), 2.35 (ddd, 1H, JZ13.0, 9.0,
2.5 Hz, H10), 2.97 (dd, 1H, JZ17.0, 4.0 Hz, auxiliary), 3.09
(dt, 1H, JZ9.0, 4.0 Hz, H8), 3.09 (d, 1H, JZ17.0 Hz,
auxiliary), 3.16 (t, 1H, JZ9.0 Hz, H8), 3.28 (t, 1H, JZ
9.0 Hz, H6), 3.31 (ddd, 1H, JZ9.5, 9.0, 2.5 Hz, H9), 3.52 (t,
1H, JZ9.0 Hz, H7), 3.70–3.76 (m, 2H, H17, H17), 3.74 (s,
3H, OMe), 3.94 (dq, 1H, JZ15.0, 3.0 Hz, H1), 3.97 (td, 1H,
JZ7.0, 2.0 Hz, H16), 4.24 (dq, 1H, JZ15.0, 6.0 Hz, H1),
4.45 (d, 1H, JZ10.5 Hz, CH2Ph), 4.64–4.69 (m, 1H, H15),
4.65 (d, 1H, JZ10.5 Hz, CH2Ph), 4.66 (dd, 1H, JZ4.5,
4.0 Hz, auxiliary), 4.74 (d, 1H, JZ11.0 Hz, CH2Ph), 4.83
(d, 1H, JZ17.5 Hz, CH2]CH–), 4.88 (d, 1H, JZ11.0 Hz,
CH2Ph), 4.90 (d, 1H, JZ10.0 Hz, CH2]CH–), 4.99 (dd,
1H, JZ9.0, 5.0 Hz, H11), 5.59 (ddd, 1H, JZ12.0, 8.0,
3.0 Hz, H3), 5.63 (d, 1H, JZ4.5 Hz, auxiliary), 5.84 (ddt,
1H, JZ12.0, 6.0, 3.0 Hz, H2), 5.90 (ddd, 1H, JZ17.5, 10.0,
7.0 Hz, H14), 6.75 (d, 2H, JZ8.5 Hz, MPM), 7.10 (d, 2H,
JZ8.5 Hz, MPM), 7.16–7.38 (m, 21H, Ph), 7.52–7.58 (m,
4H, Ph), 7.60–7.65 (m, 4H, Ph); 13C NMR (50 MHz,
CDCl3) d 19.08, 19.42, 24.50, 26.71, 26.90, 27.08, 34.55,
35.58, 36.45, 55.20, 63.55, 65.06, 67.86, 74.64, 75.63,
75.80, 75.85, 76.05, 76.38, 76.62, 79.41, 81.40, 85.31,
87.96, 97.09, 113.67, 116.51, 125.42, 126.63, 127.26,
127.33, 127.46, 127.62, 127.83, 128.28, 129.40, 129.53,
129.59, 130.43, 131.60, 133.18, 133.25, 133.94, 134.03,
135.53, 136.17, 137.06, 139.12, 140.18, 141.01, 159.07,
168.48; FT-IR (film) n 2930, 2856, 1654, 1513, 1459, 1427,
1361, 1247, 1111, 923, 823 cmK1; MALDI-TOF MS [MC
Na]C calcd for C76H89NaNO10Si2 1254.5917, found
1254.5856; [a]2D9.0 K26.08 (c 1.00, CHCl3).
4.2.12. Hemiacetal 30. A solution of alcohol 28 (2.00 g,
1.80 mmol) and p-anisaldehyde (43.8 ml, 0.360 mmol) in
toluene (18 ml) was warmed to 90 8C. CSA (836 mg,
3.60 mmol) was added and the mixture was stirred for 1 h at
90 8C. p-Anisaldehyde (43.8 ml, 0.360 mmol) and CSA
(418 mg, 1.80 mmol) were further added to the mixture, and
the stirring was continued for an additional 1 h at 90 8C. The
reaction mixture was cooled to 0 8C, and diluted with
hexane (35 ml) and quenched with saturated NaHCO3
solution. Aqueous phase was extracted with EtOAc, and the
combined organic phase was dried over anhydrous MgSO4.
After concentration, the residue was roughly purified by
open column chromatography (FLORISILwZ10 g, hexane/
EtOAcZ5) to give lactone 29 (1.58 g). Analytical sample
was obtained by further purification using silica gel column
1
chromatography. 29: colorless syrup; H NMR (500 MHz,
CDCl3) d 0.94 (s, 9H, t-Bu), 1.01 (s, 9H, t-Bu), 1.86 (ddd,
1H, JZ14.0, 9.5, 5.0 Hz, H10), 2.26–2.36 (m, 1H, H4), 2.46
(dt, 1H, JZ14.0, 7.0 Hz, H10), 2.63 (ddd, 1H, JZ17.0, 8.0,
4.0 Hz, H4), 3.25 (td, 1H, JZ9.0, 4.0 Hz, H5), 3.28 (t, 1H,
JZ9.0 Hz, H6), 3.34 (td, 1H, JZ9.5, 7.0 Hz, H9), 3.52 (dd,
1H, JZ9.5, 9.0 Hz, H7), 3.68 (dd, 1H, JZ12.0, 9.0 Hz,
H17), 3.89 (dt, 1H, JZ9.0, 4.5 Hz, H16), 3.89 (dd, 1H, JZ
12.0, 4.5 Hz, H17), 3.98 (dd, 1H, JZ16.0, 3.0 Hz, H1), 4.21
(dd, 1H, JZ7.0, 4.5 Hz, H15), 4.24 (dd, 1H, JZ16.0,
10.0 Hz, H1), 4.26 (t, 1H, JZ9.5 Hz, H8), 4.46 (dd, 1H, JZ
7.0, 5.0 Hz, H11), 4.79 (d, 1H, JZ11.5 Hz, CH2Ph), 4.80 (d,
1H, JZ18.0 Hz, CH2]CH–), 4.88 (d, 1H, JZ11.5 Hz,
CH2Ph), 4.89 (d, 1H, JZ10.5 Hz, CH2]CH–), 5.72 (ddd,
1H, JZ18.0, 10.5, 7.0 Hz, H14), 5.72–5.77 (m, 1H, H3),
5.85 (ddt, 1H, JZ12.0, 6.0, 3.0 Hz, H2), 7.22–7.45 (m, 17H,
Ph), 7.53 (d, 2H, JZ7.5 Hz, Ph), 7.56 (d, 2H, JZ7.5 Hz,
Ph), 7.61 (d, 4H, JZ8.0 Hz, Ph); 13C NMR (50 MHz,
CDCl3) d 19.29, 26.84, 26.97, 33.30, 34.36, 64.96, 68.38,
71.07, 74.31, 75.19, 75.84, 76.84, 79.44, 81.90, 83.56,
86.65, 117.95, 126.31, 127.22, 127.37, 127.43, 127.74,
128.16, 129.40, 129.49, 129.65, 129.72, 131.30, 133.07,
133.24, 133.55, 133.75, 135.53, 136.03, 136.08, 136.91,
138.79, 169.01; FT-IR (film) n 3071, 2931, 2890, 2858,
4.2.11. Alcohol 28. To a solution of MPM ether 27 (46.2 g,
37.5 mmol) in CH2Cl2 (357 ml) and water (17.8 ml) was
added 2.41 g (10.7 mmol) each of DDQ in four portions at
intervals of 30 min at K5 8C. The mixture was totally
stirred for 2.5 h at K5 8C, and quenched with saturated
Na2S2O3 solution and then saturated NaHCO3 solution. The
resulting suspension was filtered though a pad of Celite and
the filtrate was extracted with hexane–EtOAc. The com-
bined organic phase was dried over anhydrous MgSO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/EtOAcZ10–
8–6–2.9, twice) to give alcohol 28 (29.0 g, 26.1 mmol, 70%)
and recovery of 27 (13.2 g, 10.7 mmol, 29%). The
recovered 27 (13.2 g) was subjected to the same reaction
and purification conditions another twice to give 28 (6.85 g,
6.16 mmol, 16%). 28: colorless amorphous; 1H NMR
(500 MHz, CDCl3) d 0.96 (s, 9H, t-Bu), 1.03 (s, 9H, t-
Bu), 1.24 (s, 3H, auxiliary), 1.59 (s, 3H, auxiliary), 2.03 (dt,
1H, JZ12.5, 7.0 Hz, H10), 2.14 (ddq, 1H, JZ15.0, 9.0,
3.0 Hz, H4), 2.24–2.32 (m, 2H, H4, H10), 2.41 (d, 1H, JZ
1.5 Hz, OH), 3.03 (dd, 1H, JZ17.0, 3.0 Hz, auxiliary), 3.10
(d, 1H, JZ17.0 Hz, auxiliary), 3.12 (td, 1H, JZ9.0, 4.0 Hz,

8384
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
1757, 1471, 1427, 1361, 1113, 935, 823 cmK1; MALDI-
TOF MS [MCNa]C calcd for C56H66NaO8Si2 945.4188,
found 945.4189; [a]2D9.0 K47.88 (c 1.00, CHCl3).
50–20–15–7–5–2–0.5) to give bis-TBPS ether 31 (789 mg,
0.844 mmol, 27%), C15-mono-TBPS ether (378 mg,
0.542 mmol, 17%), C17-mono-TBPS ether (277 mg,
0.397 mmol, 13%), and diol 32 (370 mg, 0.810 mmol,
24%).
To a solution of tetravinyltin (249 ml, 1.37 mmol) in THF
(13 ml) was added MeLi (0.92 M solution in Et2O, 5.58 ml,
5.13 mmol) at K78 8C. The mixture was stirred for 30 min
at K78 8C and then cooled to K100 8C. A solution of
lactone 29 (1.58 g) in THF (16 ml) was slowly added over
30 min and the resulting mixture was stirred for 15 min
at K100 8C to K90 8C. The reaction mixture was quenched
with saturated NH4Cl solution and the aqueous phase was
extracted with hexane–EtOAc. The combined organic phase
was washed with brine and dried over anhydrous MgSO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/EtOAcZ5) to
give hemiacetal 30 (1.31 g, 1.38 mmol, 77% in 2 steps). 30:
colorless amorphous; 1H NMR (500 MHz, CDCl3) d 0.95 (s,
9H), 1.02 (s, 9H), 1.56 (ketoalcohol, q, 1H, JZ12.0 Hz),
1.81 (ketoalcohol, ddt, 1H, JZ16.0, 9.0, 4.5 Hz), 2.05–2.19
(m), 2.28–2.42 (m), 2.38 (ketoalcohol, ddd, 1H, JZ16.0,
8.0, 4.0 Hz), 2.51 (hemiacetal, brs, 1H), 2.64 (hemiacetal,
ddd, 1H, JZ16.0, 8.0, 3.0 Hz), 2.96 (hemiacetal, ddd, 1H,
JZ12.0, 10.0, 4.0 Hz), 3.02 (ketoalcohol, td, 1H, JZ9.5,
4.0 Hz), 3.18–3.29 (m), 3.32 (hemiacetal, t, 1H, JZ9.0 Hz),
3.37 (hemiacetal, s, 1H), 3.45 (hemiacetal, t, 1H, JZ
9.0 Hz), 3.49–3.80 (m), 3.91 (ketoalcohol, dq, 1H, JZ15.0,
3.0 Hz), 3.98 (hemiacetal, t, 1H, JZ9.5 Hz), 4.00 (hemi-
acetal, dq, 1H, JZ15.5, 3.0 Hz), 4.22 (ketoalcohol, dd, 1H,
JZ15.0, 6.0 Hz), 4.28 (hemiacetal, dd, 1H, JZ15.5,
6.0 Hz), 4.40 (hemiacetal, d, 1H, JZ8.0 Hz), 4.46 (ketoal-
cohol, d, 1H, JZ7.0 Hz), 4.47 (hemiacetal, m, 1H), 4.53
(ketoalcohol, dd, 1H, JZ8.0, 4.0 Hz), 4.58–4.99 (m), 5.20
(hemiacetal, dd, 1H, JZ10.5, 1.5 Hz), 5.46 (hemiacetal, dd,
1H, JZ17.0, 1.5 Hz), 5.56 (ketoalcohol, dd, 1H, JZ11.0,
2.0 Hz), 5.69 (ddt, 1H, JZ12.0, 8.0, 3.0 Hz), 5.76 (ddd, 1H,
JZ18.0, 10.5, 7.0 Hz), 5.81–5.89 (m), 5.84 (ketoalcohol,
ddt, 1H, JZ12.0, 6.0, 3.0 Hz), 6.08 (hemiacetal, dd, 1H, JZ
17.0, 10.5 Hz), 6.28 (ketoalcohol, dd, 1H, JZ17.5, 2.0 Hz),
6.81 (ketoalcohol, dd, 1H, JZ17.5, 11.0 Hz), 7.22–7.44 (m,
17H), 7.50–7.66 (m, 8H); 13C NMR (50 MHz, CDCl3) d
19.05, 19.30, 26.77, 27.08, 31.11, 34.02, 34.69, 34.86,
63.46, 63.92, 67.70, 68.40, 72.96, 73.00, 73.37, 74.32,
74.55, 75.04, 75.71, 75.83, 76.49, 76.71, 77.19, 81.24,
81.44, 81.66, 83.03, 84.94, 87.30, 87.86, 94.71, 115.97,
117.12, 126.60, 127.27, 127.45, 127.55, 127.64, 127.77,
127.86, 128.06, 128.33, 128.49, 129.47, 129.57, 129.63,
131.28, 131.39, 132.42, 133.15, 133.21, 133.67, 133.84,
135.51, 136.03, 136.29, 139.04, 139.10, 139.40, 200.32; FT-
IR (film) n 3470, 3071, 2931, 2857, 2360, 1702, 1611, 1589,
1471, 1427, 1361, 1112, 998, 935, 823 cmK1; MALDI-TOF
MS [MCNa]C calcd for C58H70NaO7Si2 973.4501, found
973.4455; [a]D28.0 K13.18 (c 1.50, CHCl3).
To a mixture of bis-TBPS ether 31 (789 mg, 0.844 mmol,
27%), C15-mono-TBPS ether (378 mg, 0.542 mmol, 17%),
and C17-mono-TBPS ether (277 mg, 0.397 mmol, 13%) in
THF (18 ml) was added TBAF (1.0 M solution in THF,
4.46 ml, 4.46 mmol). The mixture was stirred for 44 h at
room temperature and concentrated. The residue was
purified by flash column chromatography (silica gel,
hexane/EtOAcZ3–0.5, then hexane/EtOAc/MeOHZ
5:10:1) to give diol 32 (818 mg, 1.78 mmol, 58% in 2
steps). 32: colorless powder; mp 159–160 8C (hexane–
1
CH2Cl2); H NMR (500 MHz, CDCl3) d 1.52 (q, 1H, JZ
11.5 Hz, H10), 1.90 (brs, 1H, OH), 2.33 (ddq, 1H, JZ16.0,
9.0, 3.0 Hz, H4), 2.39 (brs, 1H, OH), 2.56 (dt, 1H, JZ11.5,
4.5 Hz, H10), 2.63 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4), 3.14
(ddd, 1H, JZ11.5, 9.0, 4.5 Hz, H9), 3.20 (t, 1H, JZ9.0 Hz,
H8), 3.29 (td, 1H, JZ9.0, 4.0 Hz, H5), 3.31–3.38 (m, 1H,
H11), 3.34 (t, 1H, JZ9.0 Hz, H6), 3.46–3.50 (m, 1H, H16),
3.49 (t, 1H, JZ9.0 Hz, H7), 3.65 (brd, 1H, JZ12.0 Hz,
H17), 3.68–3.73 (m, 1H, H17), 3.73 (dd, 1H, JZ9.5, 5.5 Hz,
H12), 4.02 (dq, 1H, JZ15.0, 3.0 Hz, H1), 4.29 (dd, 1H, JZ
15.0, 6.0 Hz, H1), 4.33 (brs, 1H, H15), 4.81 (d, 1H, JZ
11.0 Hz, CH2Ph), 4.88 (d, 1H, JZ11.0 Hz, CH2Ph), 5.24
(dt, 1H, JZ11.0, 1.5 Hz, CH2]CH–), 5.35 (dq, 1H, JZ
10.0, 1.5 Hz, CH2]CH–), 5.37 (dt, 1H, JZ17.0, 1.5 Hz,
CH2]CH–), 5.46 (dt, 1H, JZ17.0, 1.5 Hz, CH2]CH–),
5.76 (ddt, 1H, JZ11.0, 8.0, 3.0 Hz, H3), 5.84 (ddd, 1H, JZ
17.0, 11.0, 5.5 Hz, H14), 5.86 (ddt, 1H, JZ11.0, 6.0,
3.0 Hz, H2), 6.00 (ddd, 1H, JZ17.0, 10.0, 5.5 Hz, H13),
7.23–7.28 (m, 1H, Ph), 7.32 (t, 2H, JZ8.0 Hz, Ph), 7.40 (d,
2H, JZ8.0 Hz, Ph); 13C NMR (50 MHz, CDCl3) d 34.58,
36.21, 61.55, 68.34, 72.84, 75.03, 76.04, 76.34, 76.79,
80.75, 81.01, 81.80, 87.18, 116.68, 118.25, 126.52, 127.33,
127.80, 128.10, 131.82, 135.78, 135.91, 138.99; FT-IR
(film) n 3446, 3028, 2930, 2874, 1455, 1361, 1263, 1096,
926, 738 cmK1; ESI-TOF MS [MCNH4]C calcd for
C26H38NO7 476.2648, found 476.2623; [a]2D8.0 C23.18 (c
1.30, CHCl3).
4.2.14. ABCD ring 11. A solution of diol 32 (500 mg,
1.09 mmol) and Grubbs catalyst 37 (18.5 mg, 0.0218 mmol)
in CH2Cl2 (55 ml) was stirred for 2.5 h at room temperature.
Et3N (400 ml) was added and the mixture was concentrated.
The residue was washed with hexane by decantation and the
remaining precipitate was recrystallized from hexane–
EtOAc to give ABCD ring 11 (463 mg, 1.08 mmol, 99%).
1
11: colorless solid; mp 190 8C (hexane–AcOEt); H NMR
(500 MHz, CDCl3) d 1.55 (q, 1H, JZ11.0 Hz, H10), 2.15 (t,
1H, JZ6.5 Hz, OH), 2.19 (d, 1H, JZ6.0 Hz, OH), 2.30–
2.36 (m, 1H, H4, H10), 2.64 (ddd, 1H, JZ16.5, 7.5, 4.0 Hz,
H4), 3.08–3.16 (m, 2H, H8, H9), 3.28 (td, 1H, JZ9.5,
4.0 Hz, H5), 3.32–3.37 (m, 1H, H11), 3.34 (t, 1H, JZ
8.5 Hz, H6), 3.44 (ddd, 1H, JZ9.5, 6.0, 4.0 Hz, H16), 3.48
(t, 1H, JZ8.5 Hz, H7), 3.73 (dt, 1H, JZ12.0, 6.0 Hz, H17),
3.84–3.88 (m, 2H, H12, H17), 4.01 (brdt, 1H, JZ15.5,
3.0 Hz, H1), 4.29 (dd, 1H, JZ15.5, 6.0 Hz, H1), 4.29–4.38
(m, 1H, H15), 4.83 (d, 1H, JZ11.5 Hz, CH2Ph), 4.87 (d,
1H, JZ11.5 Hz, CH2Ph), 5.66–5.74 (m, 2H, H13, H14),
4.2.13. Diol 32. To a solution of hemiacetal 30 (3.02 g,
3.17 mmol) and Et3SiH (5.06 ml, 31.7 mmol) in CH3CN
(14 ml) was added TMSOTf (500 ml, 2.76 mmol) at K40 8C.
The mixture was gradually warmed to K20 8C over 40 min
with stirring and quenched with saturated NaHCO3 solution.
Aqueous phase was extracted with EtOAc, and the
combined organic phase was dried over anhydrous
MgSO4. After concentration, the residue was purified by
flash column chromatography (silica gel, hexane/EtOAcZ

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8385
5.74–5.80 (m, 1H, H3), 5.84–5.89 (m, 1H, H2), 7.24–7.29
(m, 1H, Ph), 7.33 (t, 2H, JZ8.0 Hz, Ph), 7.41 (d, 2H, JZ
8.0 Hz, Ph); 13C NMR (50 MHz, CDCl3) d 34.75, 36.89,
64.35, 68.53, 71.76, 73.23, 75.33, 77.00, 78.51, 80.45,
81.12, 82.20, 84.01, 87.54, 126.85, 127.59, 127.90, 128.36,
131.30, 131.53, 134.37, 139.29; FT-IR (film) n 3331, 3208,
3032, 2935, 2873, 2824, 1488, 1453, 1363, 1326, 1289,
1261, 1105, 1066, 1040, 978, 957 cmK1; ESI-TOF MS
[MCNH4]C calcd for C24H34NO7 448.2335, found
448.2314; [a]D19.2 K7.38 (c 0.670, CHCl3).
hexane/EtOAcZ30–1.5) to give a corresponding NAP–
ether (3.31 g, 6.36 mmol, 88%). All spectroscopic data are
identical to those reported in the literature.14
To a solution of the NAP–ether (1.14 g, 2.18 mmol) in
MeOH (32 ml) and THF (16 ml) was added TsOH$H2O
(57.0 mg, 0.218 mmol). The mixture was stirred for 27 h at
room temperature and quenched with Et3N (1 ml). Concen-
tration of the solution gave a corresponding diol (1.11 g). 1H
NMR (500 MHz, CDCl3) d 1.56 (q, 1H, JZ11.5 Hz, H10),
2.31–2.37 (m, 2H, H4, H10), 2.64 (1H, ddd, JZ16.0, 8.0,
4.0 Hz, H4), 3.10–3.16 (m, 2H, H8, H9), 3.29 (ddd, 1H, JZ
10.5, 10.5, 4.0 Hz, H5), 3.35 (ddd, 1H, JZ11.5, 9.5, 5.0 Hz,
H11), 3.38 (dd, 1H, JZ9.0, 9.0 Hz, H6), 3.45 (ddd, 1H, JZ
9.0, 6.0, 4.0 Hz, H16), 3.53 (t, 1H, JZ9.0 Hz, H7), 3.74 (dt,
1H, JZ11.5, 5.5 Hz, H17), 3.86 (dd, 1H, JZ7.0, 4.0 Hz,
H17), 3.89 (brd, 1H, JZ9.5 Hz, H12), 4.04 (ddd, 1H, JZ
15.5, 5.5, 2.5 Hz, H1), 4.31 (dd, 1H, JZ15.5, 5.5 Hz, H1),
4.37 (brdd, 1H, JZ9.0, 5.5 Hz, H15), 5.00 (d, 1H, JZ
12.0 Hz, NAP), 5.04 (d, 1H, JZ12.0 Hz, NAP), 5.72 (s, 2H,
H13, H14), 5.78 (ddt, 1H, JZ11.5, 8.5, 3.0 Hz, H3), 5.88
(ddt, 1H, JZ11.5, 6.0, 3.5 Hz, H2), 7.44–7.47 (m, 2H, NAP)
7.55 (dd, 1H, JZ9.0, 2.0 Hz, NAP) 7.81–7.84 (m, 4H,
NAP); 13C NMR (125 MHz, CDCl3) d 30.79, 34.74, 36.87,
44.93, 49.95, 64.34, 68.53, 71.75, 73.21, 75.35, 78.47,
80.44, 81.09, 82.10, 83.98, 87.62, 125.81, 126.05, 126.22,
126.48, 126.91, 127.82, 128.02, 131.55, 134.36, 146.88;
MALDI-TOF MS [MCNa]C calcd for C28H32NaO7
503.2046, found 503.2215.
4.3. Attempts to construct the tetrahydrooxocin E ring
using a chlorosulfide synthon
4.3.1. Alcohol 38. To a solution of diol 11 (500 mg,
1.16 mmol) in CH2Cl2 (17 ml) was added a solution of
AlCl3 (465 mg, 3.48 mmol) in CH3NO2 (5 ml) at 0 8C. The
mixture was stirred for 20 min at 0 8C and quenched by the
slow addition of MeOH (8 ml). After concentration, the
residue was purified by flash column chromatography (silica
gel, hexane/EtOAcZ5–3.5–0.5, then EtOAc/MeOHZ20–
10) to give a corresponding triol (384 mg, 1.13 mmol, 97%).
To a solution of the triol (384 mg, 1.13 mmol) in DMF
(6 ml) and CH2Cl2 (6 ml) were added 2,2-dimethoxypro-
pane (1.38 ml, 11.3 mmol) and PPTS (85.0 mg,
0.338 mmol). The mixture was stirred for 13 h at room
temperature and quenched with saturated NaHCO3 solution.
Aqueous phase was extracted with Et2O, and the combined
organic phase was washed with brine and dried over
anhydrous MgSO4. After concentration, the residue was
recrystallized from hexane–EtOAc to give a corresponding
acetonide (360 mg, 0.946 mmol, 84%). colorless powder;
mp 245–245 8C (hexane–AcOEt); 1H NMR (500 MHz,
CDCl3) d 1.39 (s, 3H, Me), 1.47 (s, 3H, Me), 1.52 (q, 1H,
JZ11.5 Hz, H10), 2.29 (dt, 1H, JZ11.8, 4.4 Hz, H10),
2.34–2.40 (m, 1H, H4), 2.61 (brddd, 1H, JZ16.0, 8.5,
2.8 Hz, H4), 3.04 (t, 1H, JZ9.3 Hz, H8), 3.13 (ddd, 1H, JZ
11.8, 9.3, 4.5 Hz, H9), 3.21–3.28 (m, 2H, H5, H6), 3.30–
3.38 (m, 2H, H11, H16), 3.60 (d, 1H, JZ11.0 Hz, H17),
3.62–3.66 (m, 1H, H7), 3.82 (dd, 1H, JZ11.5, 5.5 Hz, H17),
3.92 (brdq, 1H, JZ9.3, 2.2 Hz, H12), 4.02 (brdq, 1H, JZ
15.0, 3.0 Hz, H1), 4.33 (dd, 1H, JZ15.5, 6.0 Hz, H1), 4.35
(brdd, 1H, JZ9.0, 2.0 Hz, H15), 5.64 (brdt, 1H, JZ12.7,
2.4 Hz, H13), 5.74 (brdt, 1H, JZ12.5, 2.1 Hz, H14), 5.80–
5.86 (m, 1H, H3), 5.90–5.95 (m, 1H, H2); 13C NMR
(50 MHz, CDCl3) d 18.68, 28.75, 34.25, 36.47, 62.51,
68.16, 72.75, 72.96, 74.01, 75.21, 75.94, 76.79, 80.14,
80.59, 87.61, 98.33, 127.54, 131.29, 131.60, 132.46; FT-IR
(film) n 3446, 3028, 2930, 2874, 1455, 1361, 1263, 1096,
926, 738 cmK1; [a]D19.3 K9.38 (c 1.03, CHCl3).
To a solution of the diol (1.11 g) and 2,6-lutidine (763 ml,
6.55 mmol) in CH2Cl2 (44 ml) was added TBSOTf (1.5 ml,
6.55 mmol) at 0 8C. The mixture was stirred for 1 h at 0 8C
and quenched with saturated NaHCO3 solution. Aqueous
phase was extracted with EtOAc and the combined organic
phase was washed with 1M HCl, brine and dried over
anhydrous Na2SO4. After concentration, the residue was
purified by flash column chromatography (silica gel,
hexane–hexane/AcOEtZ10) to give a corresponding bis-
1
TBS ether (1.52 g, 2.15 mmol, 98% in 2 steps). H NMR
(500 MHz, CDCl3) d 0.04–0.10 (m, 12H, TBS), 0.88–0.92
(m, 18H, TBS) 1.56 (q, 1H, JZ11.0 Hz, H10), 2.32–2.37
(m, 2H, H4, H10), 2.65 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4),
3.11–3.18 (m, 2H, H8, H9), 3.27–3.34 (m, 2H, H5, H11),
3.36–3.40 (m, 2H, H6, H16), 3.53 (t, 1H, JZ8.5 Hz, H7),
3.64 (dd, 1H, JZ11.0, 6.0 Hz, H17), 3.82 (dd, 1H, JZ10.5,
1.5 Hz, H17), 3.87 (d, 1H, JZ8.5 Hz, H12), 4.04 (brdd, 1H,
JZ15.5, 3.0 Hz, H1), 4.26 (d, 1H, JZ9.0 Hz, H15), 4.31
(dd, 1H, JZ15.5, 5.5 Hz, H1), 4.99 (d, 1H, JZ12.0 Hz,
NAP), 5.04 (d, 1H, JZ11.5 Hz, NAP), 5.65 (s, 2H, H13,
H14), 5.78 (ddt, 1H, JZ11.0, 7.5, 3.0 Hz, H3), 5.88 (ddd,
1H, JZ12.5, 6.5, 3.5 Hz, H2), 7.43–7.48 (m, 2H, NAP),
7.55 (dd, 1H, JZ8.5, 1.5 Hz, NAP), 7.81–7.84 (m, 4H,
NAP); 13C NMR (125 MHz, CDCl3) d K4.96, K4.87,
K4.33, K3.43, 18.11, 18.66, 25.79, 25.85, 25.93, 26.14,
34.78, 36.95, 64.21, 68.51, 71.27, 73.42, 75.29, 78.27,
80.75. 81.12, 82.15, 85.74, 87.57, 104.90, 125.76, 126.00,
126.24, 126.44, 126.91, 127.80, 128.00, 128.04, 130.42,
131.58, 136.26, 136.84; FT-IR (film) n 2953, 2930, 2857,
To a solution of the acetonide (2.75 g, 7.24 mmol) in THF
(120 ml) and DMF (40 ml) were added NAPBr (4.80 g,
21.7 mmol) and NaH (60% dispersion in mineral oil, 1.45 g,
36.2 mmol) at room temperature. After stirring for 5 min,
TBAI (2.67 g, 7.24 mmol) was added and the resulting
mixture was stirred for 30 min at 40 8C. The reaction
mixture was quenched with saturated NH4Cl solution and
the aqueous phase was extracted with EtOAc. The
combined organic phase was washed with brine and dried
over anhydrous MgSO4. After concentration, the residue
was purified by flash column chromatography (silica gel,
1469, 1362, 1254, 1091, 1007, 940, 869, 836 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C40H60NaO7Si2
731.3775, found 731.3781.

8386
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
To a solution of the bis-TBS ether (1.52 g, 2.15 mmol) in
MeOH (22 ml) and THF (22 ml) was added CSA (50.0 mg,
0.215 mmol) at K15 8C. The mixture was stirred for 14 h at
K15 8C, and quenched with Et3N (218 ml) and then
saturated NaHCO3 solution. After concentration, the residue
was purified by flash column chromatography (silica gel,
hexane/AcOEtZ3–1) to give alcohol 38 (1.09 g,
1.83 mmol, 85%), recovery of bis-TBS ether (130 mg,
0.183 mmol, 9%) and a corresponding diol (38.2 mg,
0.0795 mmol, 4%). 38: colorless solid; mp: 160–161 8C
(hexane/EtOAc); 1H NMR (500 MHz, CDCl3) d 0.08 (s, 3H,
SiMe3), 0.10 (s, 3H, SiMe3), 0.90 (s, 9H, tBu), 1.55 (dd, 1H,
JZ11.5 Hz, H10), 2.14–2.16 (m, 1H, H17), 2.32–2.37 (m,
2H, H4, H10), 2.65 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4),
3.10–3.16 (m, 2H, H8, H9), 3.29 (td, 1H, JZ9.0, 4.0 Hz,
H5), 3.34 (ddd, 1H, JZ13.5, 5.0, 2.5 Hz, H11), 3.38 (t, 1H,
JZ9.0 Hz, H6), 3.46–3.55 (m, 2H, H7, H16), 3.77–3.82 (m,
1H, H17), 3.90 (d, 1H, JZ8.5 Hz, H12), 4.04 (brdd, 1H, JZ
12.5, 2.5 Hz, H1), 4.22 (brd, 1H, JZ8.5 Hz, H15), 4.32 (dd,
1H, JZ15.0, 5.5 Hz, H1), 4.99 (d, 1H, JZ12.5 Hz, NAP),
5.04 (d, 1H, JZ12.0 Hz, NAP), 5.68 (s, 2H, H13, H14), 5.78
(ddt, 1H, JZ11.0, 8.5, 2.5 Hz, H3), 5.88 (ddd, 1H, JZ12.0,
6.0, 3.0 Hz, H2), 7.43–7.48 (m, 2H, NAP), 7.55 (dd, 1H, JZ
8.5, 1.5 Hz, NAP), 7.81–7.84 (m, 4H, NAP); 13C NMR
(125 MHz, CDCl3) d K4.90, K4.32, 18.06, 25.87, 34.73,
36.82, 63.79, 68.51, 72.45, 73.14, 75.30, 78.07, 80.44.
81.01, 82.03, 84.42, 87.58, 125.78, 126.01, 126.23, 126.46,
126.92, 127.80, 128.01, 128.02, 130.77, 131.54, 133.11,
133.41, 136.13, 136.77; FT-IR (film) n 2931, 2859, 2070,
1254, 1087, 864, 838 cm–1; MALDI-TOF MS [MCNa]C
calcd for C34H46NaO7Si 617.2910, found 617.2963;
[a]2D2.0C25.78(c 0.780, CHCl3).
78.18, 80.33, 81.10, 82.07, 82.18, 87.58, 125.76, 126.00,
126.19, 126.40, 126.88, 127.78, 127.97, 128.00, 128.13,
129.86, 129.97, 131.31, 131.50, 133.10, 133.29, 133.41,
135.25, 136.81, 144.77; FT-IR (film) n 3026, 2928, 1919,
1733, 1654, 1599, 1509, 1495, 1462, 1368, 1258, 1258,
1098, 838 cmK1; MALDI-TOF MS [MCNa]C calcd for
C41H52NaO9SSi 771.2999, found 771.2968; [a]1D8.0 C13.28
(c 0.874, CHCl3).
To a solution of the tosylate (582 mg, 0.778 mmol) in
DMSO (11 ml) was added NaCN (78.9 mg, 1.61 mmol).
The mixture was stirred for 20 h at 50 8C and diluted with
AcOEt. The organic phase was washed with water and
brine, and dried over anhydrous MgSO4. After concen-
tration, the residue was purified by flash column chroma-
tography (silica gel, hexane–hexane/AcOEtZ10) to give
nitrile 39 (443 mg, 0.733 mmol, 94%). 39: colorless solid;
mp 121–122 8C (hexane/EtOAc); 1H NMR (500 MHz,
CDCl3) d 0.11 (s, 3H, SiMe3), 0.12 (s, 3H, SiMe3), 0.91
(s, 9H, tBu), 1.58 (q, 1H, JZ11.0 Hz, H10), 2.32–2.43 (m,
2H, H4, H10), 2.49 (dd, 1H, JZ16.5, 8.0 Hz, H17), 2.64
(ddd, 1H, JZ16.5, 8.5, 4.5 Hz, H4), 2.75 (dd, 1H, JZ16.5,
3.5 Hz, H17), 3.09–3.16 (m, 2H, H8, H9), 3.28 (td, 1H, JZ
9.5, 4.0 Hz, H5), 3.34 (ddd, 1H, JZ13.5, 4.0, 2.5 Hz, H11),
3.39 (t, 1H, JZ9.5 Hz, H6), 3.53 (t, 1H, JZ8.5 Hz, H7),
3.63 (td, 1H, JZ7.5, 3.0 Hz, H16), 3.91 (brdd, 1H, JZ9.0,
2.5 Hz, H17), 4.04 (brdd, 1H, JZ15.5, 2.5 Hz, H1), 4.17
(brdd, 1H, JZ9.0, 2.0 Hz, H15), 4.32 (dd, 1H, JZ15.5,
5.5 Hz, H1), 5.00 (d, 1H, JZ11.5 Hz, NAP), 5.03 (d, 1H,
JZ12.5 Hz, NAP), 5.66 (dt, 1H, JZ13.5, 2.5 Hz, H13),
5.72 (dt, 1H, JZ12.5, 2.5 Hz, H14), 5.78 (ddt, 1H, JZ11.0,
8.0, 2.0 Hz, H3), 5.87 (ddd, 1H, JZ12.0, 6.0, 3.0 Hz, H2),
7.44–7.48 (m, 2H, NAP), 7.55 (dd, 1H, JZ9.0, 1.5 Hz,
NAP), 7.82–7.84 (m, 4H, NAP); 13C NMR (125 MHz,
CDCl3) d K4.83, K4.16, 17.99, 22.80, 25.84, 34.71, 36.55,
68.50, 73.07, 73.56, 75.25, 78.49, 80.06, 80.27, 81.04,
82.04, 87.59, 117.84, 125.77, 126.00, 126.19, 126.42,
126.96, 127.78, 127.98, 128.00, 131.47, 131.97, 133.09,
133.39, 134.83, 136.78; FT-IR (film) n 3023, 2954, 2858,
2359, 2252, 1509, 1467, 1365, 1302, 1258, 1094, 1009, 910,
861 cm–1; MALDI-TOF MS [MCNa]C calcd for C35H45-
NaNO6Si 626.2914, found 626.2835; [a]2D6.8 C24.48 (c
1.01, CHCl3).
4.3.2. Nitrile 39. To a suspension of alcohol 38 (1.05 g,
1.76 mmol) and MS4A (powder, activated) in pyridine
(22 ml) was added TsCl (1.34 g, 7.03 mmol). The mixture
was stirred for 24 h at room temperature, and diluted with
EtOAc and quenched with saturated NaHCO3 solution.
Aqueous phase was extracted with EtOAc and the combined
organic phase was washed with brine and dried over
anhydrous MgSO4. After concentration, the residue was
purified by flash column chromatography (silica gel,
hexane/AcOEtZ10–5) to give a corresponding tosylate
1
(1.26 g, 1.68 mmol, 96%). H NMR (500 MHz, CDCl3) d
0.06 (s, 3H, SiMe3), 0.09 (s, 3H, SiMe3), 0.88 (s, 9H, tBu),
1.39 (dd, 1H, JZ11.5 Hz, H10), 2.18 (dt, 1H, JZ11.5,
4.5 Hz, H10), 2.33–2.39 (m, 1H, H4), 2.44 (s, 3H, Ts), 2.66
(ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4), 3.04–3.12 (m, 2H, H8,
H9), 3.20 (ddd, 1H, JZ13.5, 5.0, 1.5 Hz, H11), 3.28 (td, 1H,
JZ9.5, 4.0 Hz, H5), 3.38 (t, 1H, JZ9.0 Hz, H6), 3.53 (t,
1H, JZ8.0 Hz, H7), 3.58 (ddd, 1H, JZ8.5, 6.5, 2.0 Hz,
H16), 3.83 (brdd, 1H, JZ9.0, 2.0 Hz, H12), 4.02 (dd, 1H,
JZ10.5, 7.0 Hz, H17), 4.05 (brdd, 1H, JZ15.5, 2.5 Hz,
H1), 4.19 (brdd, 1H, JZ9.5, 2.0 Hz, H15), 4.24 (dd, 1H, JZ
10.5, 2.5 Hz, H17), 4.32 (dd, 1H, JZ15.5, 6.0 Hz, H1), 5.00
(d, 1H, JZ12.0 Hz, NAP), 5.04 (d, 1H, JZ12.5 Hz, NAP),
5.62 (dt, 1H, JZ13.5, 2.0 Hz, H13), 5.67 (dt, 1H, JZ13.0,
2.0 Hz, H14), 5.79 (ddt, 1H, JZ11.0, 8.0, 2.5 Hz, H3), 5.88
(ddd, 1H, JZ12.5, 6.5, 3.5 Hz, H2), 7.33 (d, 2H, JZ8.0 Hz,
Ts), 7.46 (dt, 2H, JZ5.5, 2.0 Hz, NAP), 7.56 (dd, 1H, JZ
8.5, 1.5 Hz, NAP), 7.79–7.84 (m, 6H, NAP, Ts); 13C NMR
(125 MHz, CDCl3) d K4.95, K4.28, 17.95, 21.73, 25.81,
25.90, 34.75, 36.56, 68.51, 70.85, 71.36, 73.11, 75.25,
4.3.3. Alcohol 40. To a solution of nitrile 39 (854 mg,
1.41 mmol) in CH2Cl2 (60 ml) was added DIBAL (0.93 M
solution in hexane, 3.00 ml, 2.83 mmol) at K70 8C. The
mixture was stirred for 3 h at K70 8C and quenched with
saturated Rochelle salt solution. The resulting mixture was
stirred for 2 h at room temperature and the aqueous phase
was extracted with EtOAc. The combined organic phase
was washed with brine and dried over anhydrous MgSO4.
Concentration of the solution gave a corresponding
aldehyde, which was subjected to the next reaction without
purification.
To a suspension of methyltriphenylphosphonium bromide
(3.03 g, 8.49 mmol) in THF (100 ml) was added
NaN(SiMe3)2 (2.0 M solution in THF, 3.50 ml,
7.07 mmol) at 0 8C. The mixture was stirred for 30 min at
0 8C followed by the addition of the crude aldehyde in THF
(40 ml). The resulting mixture was stirred for 1 h at 0 8C and
quenched with saturated NH4Cl solution. Aqueous phase

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8387
was extracted with AcOEt and the combined organic phase
was washed with brine and dried over anhydrous MgSO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/AcOEtZ10)
to give a corresponding alkene (246 mg, 0.407 mmol, 29%
in 2 steps) and recovery of aldehyde (457 mg, 0.753 mmol,
53%). The recovered aldehyde (457 mg, 0.753 mmol) was
subjected to the same reaction and purification conditions to
give the alkene (481 mg, 0.795 mmol, 56% in 2 steps).
To a solution of the TBS ether 42 (129 mg, 0.165 mmol) in
THF (3 ml) was added TBAF (1.0 M in THF solution,
329 ml, 0.329 mmol). The mixture was stirred for 1 h at
room temperature and concentrated. The residue was
purified by flash column chromatography (silica gel,
hexane/AcOEtZ10–5–3) to give alcohol 43 (92.3 mg,
0.138 mmol, 84%) and a C21-epimer of 43 (15.4 mg,
0.0230 mmol, 14%). 43: colorless solid; 1H NMR
(500 MHz, CDCl3) d 1.50 (q, 1H, JZ11.5 Hz, H10), 2.09
(dt, 1H, JZ15.0, 7.5 Hz, H17), 2.23–2.37 (m, 2H, H4, H10),
2.47–2.53 (m, 1H, H17), 2.57 (d, 1H, JZ4.5 Hz, OH), 2.63
(ddd, 1H, JZ14.0, 7.5, 3.5 Hz, H4), 3.07–3.15 (m, 2H, H8,
H9), 3.25–3.31 (m, 2H, H5, H11), 3.38 (t, 1H, JZ9.0 Hz,
H6), 3.49 (td, 1H, JZ9.0, 3.0 Hz, H16), 3.53 (t, 1H, JZ
8.5 Hz, H7), 3.83 (brdd, 1H, JZ8.5, 2.0 Hz, H12), 4.04
(brdd, 1H, JZ15.5, 2.5 Hz, H1), 4.08 (brdd, 1H, JZ8.5,
2.0 Hz, H15), 4.27–4.33 (m, 2H, H1, H20), 4.80 (d, 1H, JZ
5.5 Hz, H21), 4.99–5.06 (m, 4H, CH2]CH-, NAP), 5.34
(brd, 1H, JZ10.0 Hz, CH2]CH–), 5.47 (dt, 1H, JZ15.5,
1.5 Hz, CH2]CH–), 5.73 (dt, 1H, JZ13.0, 2.5 Hz, H14),
5.76–5.83 (m, 2H, H3, H18), 5.87 (ddd, 1H, JZ12.0, 6.0,
3.0 Hz, H2), 5.98 (dt, 1H, JZ13.0, 2.5 Hz, H13), 6.04 (ddd,
1H, JZ17.0, 10.5, 5.5 Hz, H19), 7.31–7.34 (m, 3H, Ph),
7.45–7.48 (m, 2H, NAP), 7.50–7.52 (m, 2H, Ph), 7.56(dd,
1H, JZ8.5, 1.5 Hz, NAP), 7.82–7.86 (m, 4H, NAP); 13C
NMR (125 MHz, CDCl3) d 34.73, 36.65, 37.12, 68.49,
73.27, 74.17, 75.31, 78.61, 80.40, 81.05, 81.13, 82.15,
83.43, 87.60, 96.67, 117.23, 118.19, 125.77, 126.01, 126.18,
126.41, 126.86, 127.79, 127.99, 128.00, 128.30, 129.39,
131.46, 131.48, 132.79, 132.91, 133.09, 133.20, 133.41,
133.58, 134.83, 135.87, 136.79; FT-IR (film) n 3466, 2877,
To a solution of the alkene (1.02 g, 1.68 mmol) in THF
(60 ml) was added TBAF (1.0 M solution in THF, 3.80 ml,
3.80 mmol). The mixture was stirred for 18 h at room
temperature and quenched with water. Aqueous phase was
extracted with EtOAc and the combined organic phase was
washed with brine and dried over anhydrous MgSO4. After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/AcOEtZ30–10–3) to
give alcohol 40 (749 mg, 1.53 mmol, 91%). 40: colorless
solid; mp 178–179 8C (hexane/EtOAc); 1H NMR
(500 MHz, CDCl3) d 1.54 (dd, 1H, JZ11.0 Hz, H10),
1.79 (brs, 1H, OH), 2.26 (dt, 1H, JZ15.0, 7.5 Hz, H17),
2.31–2.37 (m, 2H, H4, H10), 2.53–2.58 (m, 1H, H17), 2.63
(ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4), 3.09–3.17 (m, 2H, H8,
H9), 3.26–3.31 (m, 2H, H5, H11), 3.35–3.40 (m, 2H, H6,
H16), 3.53 (t, 1H, JZ8.0 Hz, H7), 3.87 (d, 1H, JZ9.0 Hz,
H12), 4.04 (brdd, 1H, JZ15.5, 2.5 Hz, H1), 4.15 (brd, 1H,
JZ10.0 Hz, H15), 4.31 (dd, 1H, JZ16.0, 6.0 Hz, H1), 4.99
(d, 1H, JZ12.0 Hz, NAP), 5.04 (d, 1H, JZ12.0 Hz, NAP),
5.08 (d, 1H, JZ10.5 Hz, CH2]CH–), 5.12 (d, 1H, JZ
17.0 Hz, CH2]CH–), 5.70 (dd, 2H, JZ16.5, 13.0 Hz, H13,
H14), 5.77 (ddt, 1H, JZ11.5, 8.5, 2.5 Hz, H3), 5.85–5.97
(m, 2H, H2, H18), 7.43–7.47 (m, 2H, NAP), 7.55 (d, 1H,
JZ8.5 Hz, NAP), 7.81–7.85 (m, 4H, NAP); 13C NMR
(125 MHz, CDCl3) d 34.76, 36.79, 37.71, 68.53, 73.36,
73.81, 75.34, 78.78, 80.54, 81.13, 82.21, 84.50, 87.60,
117.22, 125.78, 126.02, 126.21, 126.43, 126.91, 127.80,
128.00, 128.02, 131.35, 131.51, 133.11, 133.42, 134.29,
135.03, 136.80; FT-IR (KBr) n 3327, 3021, 2881, 2351,
1737, 1439, 1368, 1260, 1098, 922, 855, 817 cmK1
;
MALDI-TOF MS [MCNa]C calcd. for C40H44NaO7S
691.2705, found 691.2722.
4.3.5. TBS ether 45. A solution of alcohol 43 (106 mg,
0.158 mmol) and Grubbs catalyst 37 (4.0 mg, 4.7 mmol) in
CH2Cl2 (16 ml) was stirred for 6 h at room temperature.
Et3N (100 ml) was added and the mixture was concentrated.
The residue was purified by flash column chromatography
(silica gel, hexane/AcOEtZ5–3–1–AcOEt only) to give
alcohol 44 (91.2 mg, 0.142 mmol, 90%).
1842, 1638, 1505, 1438, 1353, 1099, 1008, 916, 854 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C30H34NaO6Si
513.2253, found 513.2307; [a]2D8.0 K5.938 (c 1.01, CHCl3).
To a solution of the alcohol 44 (91.2 mg, 0.142 mmol) in
DMF (7 ml) were added imidazole (194 mg, 2.85 mmol)
and TBSCl (215 mg, 1.42 mmol). The mixture was stirred
for 25 h at room temperature and diluted with AcOEt and
quenched with saturated NH4Cl solution. Aqueous phase
was extracted with AcOEt and the combined organic phase
was washed with brine and dried over anhydrous Na2SO4.
After concentration, the residue was purified by flash
column chromatography (silica gel, hexane/AcOEtZ20–
5) to give TBS ether 45 (103 mg, 0.136 mmol, 95%). 45:
4.3.4. Alcohol 43. To a solution of (2S)-1-phenylthio-2-tert-
butyldimethylsilyloxy-3-butene14 (187 mg, 0.636 mmol) in
CCl4 (6 ml) was added NCS (98.0 mg, 0.734 mmol). The
mixture was stirred for 2 h at room temperature and filtered.
The filter cake was washed with CCl4 and the filtrate was
concentrated to give the a-chlorosulfide 41. To a suspension
of alcohol 40 (95.7 mg, 0.195 mmol) and MS4A (50 mg,
powdered, activated) in CH2Cl2 (5 ml) were added AgOTf
(151 mg, 0.683 mmol) and 2,6-di-tert-butyl-4-methylpyri-
dine (168 mg, 0.819 mmol) at K40 8C. After stirring for
15 min at K40 8C, a solution of 41 in CH2Cl2 (5 ml) was
added and the resulting mixture was gradually warmed to
0 8C over 1 h with stirring. The mixture was eluted through
a short plug of silica gel (silica gelZ2.5 g, hexane/AcOEtZ
0.5) to give yellow oil, which was further purified by flash
column chromatography (silica gel, hexane/AcOEtZ10–5–
2–1) to give TBS ether 42 (129 mg, 0.165 mmol, 84%) as a
6:1 diastereomeric mixture, and recovery of 40 (7.1 mg,
0.0145 mmol, 7%).
1
colorless solid; H NMR (500 MHz, CDCl3) d 0.13 (s, 3H,
SiMe3), 0.16 (s, 3H, SiMe3), 0.94 (s, 9H, tBu), 1.47 (q, 1H,
JZ12.5 Hz, H10), 2.22–2.25 (m, 2H, H10, H17), 2.29–2.34
(m, 1H, H4), 2.62 (ddd, 1H, JZ16.0, 7.5, 4.0 Hz, H4), 2.76
(ddd, 1H, JZ13.0, 9.0, 4.0 Hz, H17), 3.02–3.08 (m, 2H, H8,
H9), 3.10–3.15 (m, 1H, H11), 3.25 (td, 1H, JZ9.0, 4.0 Hz,
H5), 3.33 (t, 1H, JZ8.0 Hz, H6), 3.46 (t, 1H, JZ8.0 Hz,
H7), 3.54 (dt, 1H, JZ8.5, 3.5 Hz, H16), 3.68 (brdd, 1H, JZ
9.0, 2.0 Hz, H12), 3.90 (brdd, 1H, JZ9.0, 2.0 Hz, H15),
4.01 (brdd, 1H, JZ16.0, 3.0 Hz, H1), 4.29 (dd, 1H, JZ15.5,

8388
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
6.5 Hz, H1), 4.46 (dd, 1H, JZ8.5, 3.0 Hz, H20), 4.65 (dt,
1H, JZ13.0, 3.0 Hz, H13), 4.93 (d, 1H, JZ8.5 Hz, H21),
4.94 (d, 1H, JZ12.5 Hz, NAP), 4.99 (d, 1H, JZ12.5 Hz,
NAP), 5.29 (dt, 1H, JZ12.5, 2.0 Hz, H14), 5.73 (d, 2H, JZ
3.0 Hz, H18, H19), 5.73–5.78 (m, 1H, H3), 5.83–5.88 (m,
1H, H2), 7.29–7.54 (m, 8H, Ph, NAP), 7.79–7.83 (m, 4H,
NAP); 13C NMR (125 MHz, CDCl3) d K4.73, K4.24,
18.41, 25.78, 25.99, 32.61, 34.74, 36.90, 68.50, 72.94,
73.24, 75.22, 77.93, 80.51, 80.99, 82.13, 82.25, 84.22,
87.48, 97.05, 125.77, 126.00, 126.16, 126.38, 126.80,
126.88, 127.80, 127.86, 127.93, 127.99, 129.05, 129.13,
130.29, 130.64, 131.49, 133.08, 133.41, 133.70, 133.93,
134.13, 136.82, 137.21; FT-IR (film) n 3009, 2931, 2858,
1735, 1648, 1602, 1584, 1509, 1472, 1440, 1391, 1363,
1302, 1256, 1216, 1087, 837 cmK1; MALDI-TOF MS [MC
Na]C calcd for C44H54NaO7SSi 777.3257, found 777.3306;
[a]2D2.0 K27.58 (c 0.412, CHCl3).
addition of sulfone 46 (47.2 mg, 0.0600 mmol) in CH2Cl2
(3 ml), and the resulting mixture was stirred for 30 min
at K60 8C. The reaction mixture was quenched with
saturated NaHCO3 solution and the aqueous phase was
extracted with AcOEt. The combined organic phase was
washed with brine and dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/AcOEtZ7–3–1) to give
NAP ether 51 (20.8 mg, 30.3 mmol, 50%, 2:1 stereoisomers)
and a corresponding C7-alcohol 52 (6.7 mg, 12.3 mmol,
20%, 2:1 stereoisomers).
To a solution of TBS ether 51 (29.2 mg, 0.0430 mmol, 2:1
stereoisomers) in THF (2 ml) was added TBAF (1.0 M
solution in THF, 85 ml, 0.085 mmol). The mixture was
stirred for 24 h at room temperature and concentrated. The
residue was purified by flash column chromatography (silica
gel, hexane/AcOEtZ5–3–1) to give a corresponding C21-
alcohol (24.7 mg, 0.043 mmol, 100%) as a 2:1 stereo-
isomers. The stereoisomers were separated by HPLC for
spectral analyses. Major stereoisomer: 1H NMR (500 MHz,
CDCl3) d 1.51–1.58 (m, 1H, H10), 2.26–2.31 (m, 3H, H4,
H17, H22), 2.34–2.39 (m, 2H, H10, H22), 2.64 (ddd, 1H,
JZ16.0, 8.0, 4.0 Hz, H4), 2.77 (brdd, 1H, JZ15.5, 6.5 Hz,
H17), 3.09–3.15 (m, 2H, H8, H9), 3.28 (td, 2H, JZ9.5,
4.0 Hz, H5, H11), 3.38 (t, 1H, JZ9.0 Hz, H6), 3.51–3.56
(m, 2H, H7, H16), 3.67 (brs, 1H, H21), 3.89 (ddd, 1H, JZ
9.0, 4.5, 2.5 Hz, H12), 4.04 (brdd, 1H, JZ15.0, 2.5 Hz, H1),
4.08 (td, 1H, JZ4.0, 2.0 Hz, H20), 4.25 (brdd, 1H, JZ8.0,
2.5 Hz, H15), 4.31 (dd, 1H, JZ15.5, 6.0 Hz, H1), 4.99 (d,
1H, JZ12.5 Hz, NAP), 5.04 (d, 1H, JZ12.0 Hz, NAP),
5.11–5.16 (m, 2H, H24, H24), 5.66 (dd, 1H, JZ12.5,
4.0 Hz, H19), 5.68 (dt, 1H, JZ12.0, 2.5 Hz, H14), 5.79 (ddt,
1H, JZ10.5, 8.5, 2.5 Hz, H3), 5.79–5.92 (m, 4H, H2, H13,
H18, H23), 7.44–7.47 (m, 2H, NAP), 7.55 (dd, 1H, JZ8.5,
1.5 Hz, NAP), 7.81–7.85 (m, 4H, NAP); 13C NMR
(125 MHz, CDCl3) d 33.24, 34.76, 37.02, 37.42, 68.52,
72.82, 73.33, 75.32, 78.06, 80.61, 81.05, 82.16, 82.33,
82.71, 82.74, 87.62, 117.82, 125.79, 126.03, 126.24, 126.47,
126.94, 127.82, 128.01, 128.04, 128.33, 128.38, 129.19,
130.85, 130.98, 131.54, 133.12, 133.44, 134.13, 134.55,
136.82; FT-IR (film) n 3468, 3027, 2931, 2875, 1640, 1509,
4.3.6. Sulfone 46. To a solution of sulfide 45 (103 mg,
0.136 mmol) in CH2Cl2 (30 ml) was added m-CPBA
(180 mg, 0.679 mmol) at K15 8C. The mixture was stirred
for 4 h at K15 8C and quenched with Et3N and then
saturated NaHCO3 solution. Aqueous phase was extracted
with AcOEt, and the combined organic phase was washed
with brine and dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/AcOEtZ10–5–3–1) to
give sulfone 46 (79.1 mg, 0.101 mmol, 74%) and a
corresponding sulfoxide (29.8 mg). The sulfoxide
(29.8 mg) was subjected to the same reaction and purifi-
cation conditions another twice to give 46 (25.9 mg,
0.033 mmol, 24%). 46: colorless solid; 1H NMR
(500 MHz, CDCl3) d 0.16 (s, 3H, SiMe3), 0.22 (s, 3H,
SiMe3), 0.96 (s, 9H, tBu), 1.43 (q, 1H, JZ12.0 Hz, H10),
2.20–2.33 (m, 3H, H4, H10, H17), 2.61 (ddd, 1H, JZ16.0,
8.0, 4.0 Hz, H4), 2.67 (ddd, 1H, JZ12.5, 8.5, 3.5 Hz, H17),
3.00–3.03 (m, 2H, H8, H9), 3.07 (ddd, 1H, JZ11.0, 9.0,
5.0 Hz, H11), 3.24 (td, 1H, JZ9.5, 4.0 Hz, H5), 3.32 (t, 1H,
JZ9.0 Hz, H6), 3.44 (t, 1H, JZ8.5 Hz, H7), 3.48 (dt, 1H,
JZ9.0, 2.5 Hz, H16), 3.62 (brdd, 1H, JZ8.5, 2.0 Hz, H12),
3.83 (brdd, 1H, JZ8.5, 2.5 Hz, H15), 3.87 (brd, 1H, JZ
12.5 Hz, H14), 4.00 (brdd, 1H, JZ15.0, 3.0 Hz, H1), 4.28
(dd, 1H, JZ16.0, 6.0 Hz, H1), 4.31 (d, 1H, JZ8.5 Hz,
H21), 4.92 (d, 1H, JZ12.0 Hz, NAP), 4.93 (d, 1H, JZ
8.5 Hz, H20), 4.96 (d, 1H, JZ12.0 Hz, NAP), 5.18 (dt, 1H,
JZ12.5, 2.5 Hz, H13), 5.71–5.77 (m, 3H, H3, H18, H19),
5.85 (ddd, 1H, JZ7.5, 6.0, 3.0 Hz, H2), 7.42–8.08 (m, 12H,
Ph, NAP); 13C NMR (125 MHz, CDCl3) d K4.77, K4.36,
14.27, 18.33, 22.80, 25.96, 31.74, 32.59, 34.72, 36.79,
68.51, 69.92, 73.12, 75.22, 77.90, 80.31, 80.96, 82.14,
83.62, 84.10, 87.47, 97.59, 125.82, 126.03, 126.12, 126.34,
126.86, 127.82, 127.94, 127.96, 129.09, 129.60, 129.96,
131.24, 131.48, 131.55, 133.07, 133.40, 133.65, 133.81,
136.79, 138.79; FT-IR (film) n 3026, 2931, 2858, 1726,
1438, 1367, 1270, 1087, 1011, 915, 855, 817 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C35H40NaO7
595.2672, found 595.2608; [a]2D3.0 K34.38 (c 0.150,
CHCl3). Minor stereoisomer: H NMR (500 MHz, CDCl3)
1
d 1.51–1.56 (m, 1H, H10), 2.00 (d, 1H, JZ6.0 Hz, OH),
2.26–2.31 (m, 3H, H10, H17, H22), 2.33–2.39 (m, 2H, H4,
H22), 2.64 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4), 2.76–2.81
(m, 1H, H17), 3.08–3.14 (m, 2H, H8, H9), 3.28 (td, 2H, JZ
10.0, 4.0 Hz, H5, H11), 3.38 (t, 1H, JZ9.0 Hz, H6), 3.52 (t,
1H, JZ8.5 Hz, H7), 3.56 (dt, 1H, JZ8.5, 5.0 Hz, H16), 3.78
(dtd, 1H, JZ9.0, 8.5, 4.5 Hz, H21), 3.89 (ddd, 1H, JZ9.0,
4.0, 2.0 Hz, H12), 4.04 (brdd, 1H, JZ15.5, 3.0 Hz, H1),
4.18 (brs, 1H, H20), 4.24 (ddd, 1H, JZ8.5, 5.0, 3.0 Hz,
H15), 4.31 (dd, 1H, JZ16.0, 6.0 Hz, H1), 4.99 (d, 1H, JZ
12.5 Hz, NAP), 5.04 (d, 1H, JZ12.0 Hz, NAP), 5.12–5.17
(m, 2H, H24, H24), 5.67 (dt, 1H, JZ12.5, 2.5 Hz, H14),
5.70 (brdd, 1H, JZ11.5, 3.0 Hz, H19), 5.77 (ddt, 1H, JZ
11.5, 8.5, 3.0 Hz, H3), 5.83 (dt, 1H, JZ13.0, 3.0 Hz, H13),
5.85–5.89 (m, 2H, H2, H23), 5.88–5.93 (m, 1H, H18), 7.44–
7.47 (m, 2H, NAP), 7.55 (dd, 1H, JZ9.0, 1.5 Hz, NAP),
7.81–7.85 (m, 4H, NAP); 13C NMR (125 MHz, CDCl3) d
1446, 1328, 1257, 1153, 1089, 1006, 857, 839 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C44H54NaO9SSi
809.3155, found 809.2830; [a]2D0.0 K54.28 (c 1.12, CHCl3).
4.3.7. Attempted allylation of 46 with allyltrimethylsi-
lane in the presence of AlCl3. Allyltrimethylsilane
(95.3 ml, 0.600 mmol) was added to a suspention of AlCl3
(40.0 mg, 0.300 mmol) in CH2Cl2 (3 ml) at K70 8C. The
mixture was stirred for 30 min at K70 8C, followed by the

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8389
33.24, 34.78, 37.02, 37.12, 68.53, 73.17, 73.35, 75.32,
77.11, 78.02, 80.67, 81.06, 82.18, 83.13, 83.32, 87.62,
118.07, 125.78, 126.02, 126.24, 126.46, 126.94, 127.82,
128.00, 128.04, 128.16, 130.12, 130.73, 131.53, 133.14,
133.46, 134.41, 134.84, 136.85; FT-IR (film) n 3481, 3025,
2875, 1734, 1643, 1508, 1454, 1367, 1261, 1087, 1011, 914,
855, 817 cm–1; MALDI-TOF MS [MCNa]C calcd for
C35H40NaO7 595.2672, found 595.2677.
4.4. General procedure of asymmetric aldol reaction in a
model system
To a solution of amine (10 equiv.) in CH2Cl2 was added
TiCl4 (1.0 M solution in CH2Cl2, 4–6 equiv.) at K78 8C.
The mixture was stirred for 30 min at K78 8C followed by
the addition of amide 59, 60, or 61 (1 equiv.) and the stirring
was continued for an additional 30 min at K78 8C. Freshly
distilled acrolein (10 equiv.) was added and the resulting
mixture was stirred for indicated times at indicated
temperature as shown in Table 2. The reaction mixture
was quenched with saturated NH4Cl solution and the
aqueous phase was extracted with AcOEt. The combined
organic phase was washed with brine and dried over
anhydrous Na2SO4. After concentration, the residue was
purified by flash column chromatography to give a mixture
of aldol products 62, 63, 64, and recovery of amide 59, 60,
or 61. The aldol products were separated by HPLC for
spectral analysis.
4.3.8. Attempted cyanization of 53 with TMSCN in the
presence of EtAlCl2. To a solution of sulfide 42 (129 mg,
0.165 mmol) in CH2Cl2 (8 ml) was added m-CPBA
(131 mg, 0.495 mmol) at K20 8C. After stirring for 1 h at
K20 8C to K10 8C, the reaction mixture was quenched with
saturated NaHSO3 solution and then saturated NaHCO3
solution. Aqueous phase was extracted with AcOEt, and the
combined organic phase was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue
was purified by flash column chromatography (silica gel,
hexane–hexane/AcOEtZ10–5–2) to give sulfone 53
(41.7 mg, 0.0512 mmol, 31%).
4.4.1. 20,21-anti-15,21-syn Aldol product of 59. Colorless
oil; 1H NMR (500 MHz, CDCl3); d 1.43 (ddd, 1H, JZ23.0,
12.0, 5.5 Hz, H3) 1.58–1.64 (m, 2H, H2, H2) 1.99 (brdd,
1H, JZ12.0, 3.0 Hz, H3), 2.29 (dt, 1H, JZ15.0, 7.5 Hz,
H6), 2.66–2.71 (m, 1H, H6), 2.72 (dd, 1H, JZ13.5, 10.0 Hz,
H13), 2.85 (d, 1H, JZ9.0 Hz, OH), 3.21 (ddd, 1H, JZ10.0,
8.5, 4.0 Hz, H4), 3.28–3.33 (m, 3H, H1, H5, H13), 3.87 (dt,
1H, JZ11.0, 2.0 Hz, H1), 4.35–4.41 (m, 2H, H15, H15),
4.48 (dt, 1H, JZ9.5, 6.0 Hz, H11), 5.01 (ddd, 1H, JZ14.0,
7.0, 3.5 Hz, H14), 5.09 (d, 1H, JZ9.5 Hz, H8), 5.14 (dd,
1H, JZ17.0, 1.5 Hz, H8), 5.32 (dt, 1H, JZ10.5, 1.0 Hz,
H9), 5.42 (dt, 1H, JZ17.5, 1.5 Hz, H9), 5.90 (dddd, 1H, JZ
17.5, 10.0, 8.0, 7.0 Hz, H7), 6.10 (ddd, 1H, JZ17.5, 10.5,
6.0 Hz, H10), 6.30 (d, 1H, JZ6.5 Hz, H12), 7.23–7.35 (m,
5H, Bn); 13C NMR (125 MHz, CDCl3) d 25.45, 30.26,
36.70, 37.74, 60.63, 67.67, 71.28, 74.52, 78.11, 79.23,
79.86, 117.07, 117.81, 127.69, 129.23, 129.53, 135.09,
135.15, 136.29, 173.32, 186.21; FT-IR (film) n 3481, 3073,
3028, 2930, 2855, 1711, 1642, 1497, 1454, 1369, 1326,
1285, 1197, 1161, 1098 1028, 963 cmK1; MALDI-TOF MS
[MCNa]C calcd for C23H29NaNO5S 454.1664, found
454.1661; [a]D21.0 K1128 (c 0.500, CHCl3).
Trimethylsilyl cyanide (29.9 ml, 0.238 mmol) was added to
a suspension of EtAlCl2 (132 ml, 0.119 mmol) in CH2Cl2
(1 ml) at K50 8C. The mixture was stirred for 10 min at
K50 8C followed by the addition of the sulfone 53
(9.7 mg, 0.0119 mmol) in CH2Cl2 (1 ml). The resulting
mixture was stirred for 2 h at K50 8C to K30 8C. The
reaction mixture was quenched with saturated NaHCO3
solution and then saturated Rochelle salt solution. Aqueous
phase was extracted with AcOEt and the combined organic
phase was washed with brine and dried over anhydrous
Na2SO4. After concentration, the residue was purified by
flash column chromatography (silica gel, hexane/AcOEtZ
7–3–1) to give chloride 56 (3.6 mg, 5.08 mmol, 35%) as a
2:1 stereoisomers. 56 (2:1 stereoisomers): 1H NMR
(500 MHz, CDCl3) d 0.04 (s, 3H, TBS major), 0.05 (s,
3H, TBS minor), 0.08 (s, 3H, TBS minor), 0.08 (s, 3H, TBS
major), 0.90 (s, 9H, TBS major), 0.90 (s, 9H, TBS minor),
1.48–1.53 (m, 1H, H10), 1.82–1.89 (m, 1H, H19 minor),
1.91 (ddd, 1H, JZ14.0, 9.5, 5.5 Hz, H19 major), 2.23–2.40
(m, 4H, H4, H10, H17, H19), 2.44 (dd, 1H, JZ13.5, 4.0 Hz,
H17), 2.64 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4), 3.08–3.14
(m, 2H, H8, H9), 3.21–3.31 (m, 2H, H5, H11), 3.38 (t, 1H,
JZ9.0 Hz, H6), 3.44 (td, 1H, JZ9.5, 4.5 Hz, H16), 3.52 (t,
1H, JZ8.5 Hz, H7), 3.60 (ddd, 1H, JZ10.0, 5.5, 5.0 Hz,
H20), 3.85 (brdd, 1H, JZ9.0, 2.0 Hz, H12), 3.95 (brdd, 1H,
JZ9.0, 2.0 Hz, H15), 4.02–4.08 (m, 2H, H1, H21), 4.11–
4.20 (m, 1H, H18 major), 4.30 (dd, 1H, JZ16.0, 6.0 Hz,
H1), 4.41 (brdd, 1H, JZ10.0, 7.5 Hz, H18 minor), 4.98 (d,
1H, JZ12.0 Hz, NAP minor), 4.99 (d, 1H, JZ12.0 Hz,
NAP major), 5.03 (d, 1H, JZ12.0 Hz, NAP minor), 5.04 (d,
1H, JZ12.0 Hz, NAP major), 5.17–5.20 (m, 1H, H23), 5.27
(dt, 1H, JZ17.0, 2.0 Hz, H23 minor), 5.29 (dt, 1H, JZ17.0,
2.0 Hz, H23 major), 5.64 (ddd, 1H, JZ12.0, 2.5 Hz, H14
minor), 5.67 (dt, 1H, JZ12.5, 2.5 Hz, H14 major), 5.74–
5.90 (m, 4H, H2, H3, H13, H22), 7.43–7.47 (m, 2H, NAP),
7.54 (dd, 1H, JZ9.0, 2.0 Hz, NAP), 7.81–7.85 (m, 4H,
NAP); FT-IR (film) n 3024, 2955, 2929, 2857, 1645, 1603,
1509, 1471, 1462, 1455, 1361, 1338, 1257, 1091, 1032,
1007 cmK1; MALDI-TOF MS [MCNa]C calcd for
C40H53NaClO7Si 731.3147, found 731.3147.
4.4.2. 20,21-syn-15,21-syn Aldol product of 59. Colorless
1
oil; H NMR (500 MHz, CDCl3) d 1.39 (tdd, 1H, JZ13.0,
10.5, 5.0 Hz, H3), 1.66 (ddt, 1H, JZ26.0, 13.5, 4.5 Hz, H2),
1.71–1.74 (m, 1H, H2), 2.27 (dt, 1H, JZ15.0, 7.5 Hz, H6),
2.40 (brdd, 1H, JZ12.0, 3.0 Hz, H3), 2.45 (d, 1H, JZ
7.0 Hz, OH), 2.82 (dd, 1H, JZ13.0, 10.5 Hz, H13), 2.82–
2.87 (m, 1H, H6), 3.21 (td, 1H, JZ8.5, 4.0 Hz, H4), 3.25
(ddd, 1H, JZ8.5, 3.0 Hz, H5), 3.35 (td, 1H, JZ11.5,
2.5 Hz, H1), 3.37 (dd, 1H, JZ13.0, 3.5 Hz, H13), 3.92 (ddt,
1H, JZ11.0, 4.5, 1.5 Hz, H1), 4.26 (dd, 1H, JZ9.0, 7.5 Hz,
H15), 4.35 (dd, 1H, JZ9.5, 2.0 Hz, H15), 4.44 (ddt, 1H, JZ
12.5, 5.5, 1.0 Hz, H11), 4.83 (dddd, 1H, JZ10.0, 7.5, 4.0,
2.0 Hz, H14), 5.07 (ddt, 1H, JZ10.5, 2.0, 1.0 Hz, H8), 5.16
(ddd, 1H, JZ17.0, 4.0, 2.0 Hz, H8), 5.22 (dt, 1H, JZ10.5,
1.5 Hz, H9), 5.36 (dt, 1H, JZ17.5, 1.5 Hz, H9), 5.93 (ddt,
1H, JZ17.5, 10.5, 7.5 Hz, H7), 6.01 (ddd, 1H, JZ17.0,
11.0, 5.5 Hz, H10), 6.64 (d, 1H, JZ5.5 Hz, H12), 7.22–7.36
(m, 5H, Bn); MALDI-TOF MS [MCNa]C calcd for
C23H29NaNO5S 454.1664, found 454.1767.

8390
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
4.4.3. 20,21-syn-15,21-anti Aldol product of 59. Colorless
oil; H NMR (500 MHz, CDCl3) d 1.34 (tdd, 1H, JZ12.5,
67.67, 71.09, 74.13, 78.50, 79.59, 79.93, 116.99, 117.56,
127.70, 129.22, 129.55, 135.09, 135.15, 136.35, 172.38,
185.54; FT-IR (film) n 3468, 3074, 3028, 2931, 2855, 1714,
1
10.5, 4.5 Hz, H3), 1.64 (ddt, 1H, JZ26.0, 12.5, 4.5 Hz, H2),
1.72 (brd, 1H, JZ12.5 Hz, H2), 2.31 (dt, 2H, JZ16.0,
8.0 Hz, H3, H6), 2.46 (d, 1H, JZ8.5 Hz, OH), 2.84 (dd, 1H,
JZ13.0, 10.0 Hz, H13), 2.88 (dddt, 1H, JZ14.5, 6.5, 2.5,
1.5 Hz, H6), 3.21 (td, 1H, JZ8.5, 4.5 Hz, H4), 3.26 (td, 1H,
JZ8.5, 3.0 Hz, H5), 3.34 (td, 1H, JZ11.5, 2.5 Hz, H1),
3.36 (dd, 1H, JZ13.0, 3.5 Hz, H13), 3.91 (brdd, 1H, JZ
11.5, 5.0 Hz, H1), 4.30 (dd, 1H, JZ9.5, 7.5 Hz, H15), 4.37
(dd, 1H, JZ9.0, 2.0 Hz, H15) 4.50 (brs, 1H, H11), 4.87
(dddd, 1H, JZ10.0, 7.5, 3.5, 2.0 Hz, H14), 5.08 (dd, 1H,
JZ10.5, 1.5 Hz, H8), 5.17 (dd, 1H, JZ17.0, 1.5 Hz, H8),
5.24 (d, 1H, JZ10.5 Hz, H9), 5.36 (d, 1H, JZ17.0 Hz, H9),
5.90–5.99 (m, 2H, H7, H10), 6.43 (d, 1H, JZ3.5 Hz, H12),
7.23–7.36 (m, 5H, Bn); 13C NMR (125 MHz, CDCl3) d
25.22, 29.08, 36.71, 37.70, 61.02, 67.68, 71.13, 73.83,
76.03, 76.31, 80.15, 116.64, 117.24, 127.65, 129.16, 129.49,
135.07, 135.65, 136.51, 171.54, 185.60; FT-IR (film) n
3431, 3073, 3028, 2938, 2854, 1714, 1641, 1604, 1497,
1454, 1364, 1327, 1285, 1196, 1098, 960 cmK1; MALDI-
TOF MS [MCNa]C calcd for C23H29NaNO5S 454.1664,
found 454.1735; [a]2D2.0 C21.18 (c 2.04, CHCl3).
1642, 1497, 1454, 1366, 1327, 1286, 1196, 1098, 958 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C23H29NaO5S
454.1664, found 454.1793; [a]2D3.0 C51.88 (c 1.10, CHCl3).
4.4.6. 20,21-anti-15,21-syn Aldol product of 61. 1H NMR
(500 MHz, CDCl3) d 1.36 (brddd, 1H, JZ23.0, 13.0,
5.0 Hz, H3), 1.57–1.72 (m, 2H, H2, H2), 2.11 (brdt, 1H,
JZ12.5, 3.0 Hz, H3), 2.30 (dt, 1H, JZ14.5, 7.0 Hz, H6),
2.56 (d, 1H, JZ7.5 Hz, OH), 2.65–2.70 (m, 1H, H6), 2.80
(dd, 1H, JZ13.0, 10.0 Hz, H13), 3.25 (ddd, 1H, JZ10.0,
8.5, 4.0 Hz, H4), 3.32–3.40 (m, 3H, H1, H5, H15), 3.89–
3.92 (m, 1H, H1), 4.23–4.27 (m, 2H, H13), 4.37–4.40 (m,
1H, H11), 4.66–4.71 (m, 1H, H14), 5.11 (brd, 1H, JZ
10.5 Hz, H8), 5.15 (dt, 1H, JZ17.0, 1.5 Hz, H8), 5.28 (dt,
1H, JZ11.0, 1.5 Hz, H9), 5.30 (d, 1H, JZ3.5 Hz, H12),
5.39 (dt, 1H, JZ17.0, 1.5 Hz, H9), 5.88–5.94 (m, 1H, H7),
5.98 (ddd, 1H, JZ17.0, 11.0, 6.0 Hz, H10), 7.24–7.38 (m,
5H, Bn); MALDI-TOF MS [MCNa]C calcd for
C23H29NNaO6 438.1893, found 438.1861.
1
4.4.7. 20,21-syn-15,21-syn Aldol product of 61. H NMR
4.4.4. 20,21-anti-15,21-syn Aldol product of 60. Colorless
oil; H NMR (500 MHz, CDCl3) d 1.41–1.51 (m, 1H, H3),
(500 MHz, CDCl3) d 1.51 (brddd, 1H, JZ23.0, 12.0,
5.0 Hz, H3), 1.60–1.71 (m, 2H, H2, H2), 2.11 (brdt, 1H,
JZ12.5, 3.0 Hz, H3), 2.30 (dt, 1H, JZ14.5, 7.0 Hz, H6),
2.56 (d, 1H, JZ7.5 Hz, OH), 2.65–2.70 (m, 1H, H6), 2.80
(dd, 1H, JZ13.0, 10.0 Hz, H13), 3.25 (ddd, 1H, JZ10.0,
8.5, 4.0 Hz, H4), 3.32–3.40 (m, 3H, H1, H5, H15), 3.89–
3.92 (m, 1H, H1), 4.23–4.27 (m, 2H, H13), 4.37–4.40 (m,
1H, H11), 4.66–4.71 (m, 1H, H14), 5.11 (brd, 1H, JZ
10.5 Hz, H8), 5.15 (dt, 1H, JZ17.0, 1.5 Hz, H8), 5.28 (dt,
1H, JZ11.0, 1.5 Hz, H9), 5.30 (d, 1H, JZ3.5 Hz, H12),
5.39 (dt, 1H, JZ17.0, 1.5 Hz, H9), 5.88–5.94 (m, 1H, H7),
5.98 (ddd, 1H, JZ17.0, 11.0, 6.0 Hz, H10), 7.24–7.38 (m,
5H, Bn); 13C NMR (125 MHz, CDCl3) d 25.46, 30.20,
36.81, 37.90, 55.71, 67.07, 67.65, 74.06, 79.06, 79.56,
79.88, 117.02, 117.49, 127.64, 129.16, 129.52, 135.05,
135.09, 136.49, 153.68, 171.21; FT-IR (film) n 3480, 3074,
3029, 2933, 2855, 1770, 1713, 1642, 1604, 1496, 1481,
1454, 1392, 1350, 1211, 1097, 999, 920 cmK1; MALDI-
TOF MS [MCNa]C calcd for C23H29NNaO6 438.1893,
found 438.1846; [a]2D2.6 C59.08 (c 1.85, CHCl3).
1
1.64–1.69 (m, 2H, H2, H2), 2.16 (brd, 1H, JZ12.5 Hz, H3),
2.32 (dt, 1H, JZ14.5, 7.5 Hz, H6), 2.39 (d, 1H, JZ7.0 Hz,
OH), 2.68 (ddt, 1H, JZ14.5, 6.5, 1.0 Hz, H6), 2.77 (dd, 1H,
JZ13.0, 10.5 Hz, H15), 3.30–3.39 (m, 4H, H1, H4, H5,
H15), 3.89 (brdt, 1H, JZ11.5, 2.0 Hz, H1), 4.27 (dd, 1H,
JZ9.5, 7.5 Hz, H13), 4.36 (dd, 1H, JZ9.5, 2.0 Hz, H13),
4.44 (dd, 1H, JZ13.0, 6.0 Hz, H11), 4.85 (dddd, 1H, JZ
11.0, 7.5, 3.5, 2.0 Hz, H14), 5.10 (dd, 1H, JZ10.0, 1.0 Hz,
H8), 5.14 (dd, 1H, JZ17.5, 1.5 Hz, H8), 5.27 (d, 1H, JZ
10.5 Hz, H9), 5.39 (brd, 1H, JZ17.0 Hz, H9), 5.92 (dddd,
1H, JZ17.0, 10.0, 7.0, 6.0 Hz, H7), 6.02 (ddd, 1H, JZ17.5,
11.0, 5.5 Hz, H10), 6.52 (d, 1H, JZ5.5 Hz, H12), 7.23–7.36
(m, 5H, Bn); 13C NMR (125 MHz, CDCl3) d 25.50, 30.47,
36.83, 37.76, 60.95, 67.73, 71.13, 74.09, 77.85, 79.16,
79.79, 116.99, 117.54, 127.71, 129.24, 129.56, 135.12,
135.22, 135.96, 173.19, 186.22; FT-IR (film) n 3400, 3073,
3028, 2933, 2855, 1705, 1641, 1497, 1454, 1364, 1327,
1285, 1196, 1098, 961 cmK1; MALDI-TOF MS [MCNa]C
calcd for C23H29NaNO5S 454.1664, found 454.1757; [a]D22.2
C37.78 (c 0.395, CHCl3).
4.4.8. 20,21-syn-15,21-anti Aldol product of 61. 1H NMR
(500 MHz, CDCl3) d 1.33 (brddd, 1H, JZ23.5, 12.5,
4.5 Hz, H3), 1.56–1.72 (m, 2H, H2, H2), 2.24 (brdt, 1H,
JZ13.0, 3.5 Hz, H3), 2.30 (dt, 1H, JZ15.0, 7.0 Hz, H6),
2.52 (d, 1H, JZ8.0 Hz, OH), 2.81 (dd, 1H, JZ13.5, 9.5 Hz,
H13), 2.90–2.95 (m, 1H, H6), 3.12 (ddd, 1H, JZ10.5, 8.5,
4.0 Hz, H4), 3.25–3.30 (m, 2H, H5, H13), 3.35 (td, 1H, JZ
12.0, 2.0 Hz, H1), 3.92 (brdd, 1H, JZ11.0, 4.5 Hz, H1),
4.26 (dd, 1H, JZ9.5, 3.5 Hz, H15), 4.32 (dd, 1H, JZ9.0,
8.5 Hz, H15), 4.48–4.51 (m, 1H, H11), 4.78–4.83 (m, 1H,
H14), 5.10 (brdd, 1H, JZ10.0, 1.0 Hz, H8), 5.18 (brd, 1H,
JZ17.0, 1.5 Hz, H8), 5.28 (brd, 1H, JZ11.5 Hz, H9), 5.35
(d, 1H, JZ3.0 Hz, H12), 5.41 (brd, 1H, JZ17.5 Hz, H9),
5.92–6.00 (m, 1H, H7), 5.99 (ddd, 1H, JZ17.5, 11.0,
6.0 Hz, H10), 7.25–7.38 (m, 5H, Bn); FT-IR (film) n 3525,
3073, 2938, 2855, 1775, 1715, 1640, 1497, 1454, 1393,
4.4.5. 20,21-syn-15,21-syn Aldol product of 60. Colorless
oil; 1H NMR (500 MHz, CDCl3) d 1.49 (ddd, 1H, JZ23.0,
12.0, 5.5 Hz, H3), 1.60–1.70 (m, 2H, H2, H2), 2.16 (brdd,
1H, JZ12.5, 3.0 Hz, H3), 2.29 (dt, 1H, JZ14.5, 7.0 Hz,
H6), 2.50 (brd, 1H, JZ8.0 Hz, OH), 2.66 (dddt, 1H, JZ
14.5, 6.5, 3.5, 1.5 Hz, H6), 2.81 (dd, 1H, JZ13.5, 10.0 Hz,
H15), 3.26–3.31 (m, 1H, H4), 3.33–3.37 (m, 3H, H1, H5,
H15), 3.89 (ddt, 1H, JZ11.5, 4.0, 2.0 Hz, H1), 4.30 (dd, 1H,
JZ8.5, 7.5 Hz, H13), 4.37 (dd, 1H, JZ9.0, 1.0 Hz, H13),
4.50 (brs, 1H, H11), 4.86 (dddd, 1H, JZ10.5, 7.0, 3.0,
2.0 Hz, H14), 5.10 (d, 1H, JZ10.5 Hz, H8), 5.14 (dd, 1H,
JZ17.5, 1.5 Hz, H8), 5.27 (d, 1H, JZ11.0 Hz, H9), 5.39 (d,
1H, JZ17.5 Hz, H9), 5.91 (ddt, 1H, JZ17.0, 10.0, 7.0 Hz,
H7), 6.00 (ddd, 1H, JZ17.0, 10.0, 5.5 Hz, H10), 6.37 (d,
1H, JZ3.5 Hz, H12), 7.23–7.36 (m, 5H, Bn); 13C NMR
(125 MHz, CDCl3) d 25.48, 30.25, 36.86, 37.62, 61.00,
1352, 1275, 1215, 1099, 1052, 995 cmK1 13C NMR
;
(125 MHz, CDCl3) d 25.25, 28.97, 36.76, 37.79, 55.09,

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8391
66.99, 67.75, 73.68, 76.31, 76.46, 80.26, 116.58, 117.27,
127.61, 129.14, 129.64, 134.88, 135.83, 136.81, 153.76,
170.32; MALDI-TOF MS [MCNa]C calcd for
C23H29NNaO6 438.1893, found 438.1879; [a]2D2.6 C1158
(c 0.445, CHCl3).
(dd, 1H, JZ16.0, 6.0 Hz, H1), 4.99 (d, 1H, JZ12.0 Hz,
NAP), 5.04 (d, 1H, JZ12.0 Hz, NAP), 5.07 (brd, 1H, JZ
11.5 Hz, CH2ZCH–), 5.09 (brd, 1H, JZ17.5 Hz, CH2Z
CH–), 5.74–5.80 (m, 2H, H3, H13), 5.82–5.92 (m, 3H, H2,
H14, H18), 7.44–7.47 (m, 2H, NAP), 7.54 (dd, 1H, JZ9.0,
1.5 Hz, NAP), 7.81–7.84 (m, 4H, NAP); FT-IR (KBr) n
3026, 2961, 2885, 1742, 1602, 1436, 1355, 1261, 1094,
1024, 806 cm–1; MALDI-TOF MS [MCNa]C calcd for
C32H36NaO8 571.2308, found 571.2390; [a]2D1.0 K1.18 (c
0.400, CHCl3).
4.5. Stereocontrolled synthesis of the ABCDE ring
moiety
4.5.1. Ester 65. To a solution of alcohol 40 (93.4 mg,
0.190 mmol) in THF (5 ml) and DMF (1.3 ml) was added
NaH (60% dispersion in mineral oil, 15.2 mg, 0.381 mmol)
at 0 8C. After stirring for 5 min, t-butyl bromoacetate
(54.1 ml, 0.571 mmol) was added and the resulting mixture
was stirred for 10 h at room temperature. The reaction
mixture was quenched with saturated NH4Cl solution and
the aqueous phase was extracted with AcOEt. The
combined organic phase was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue
was purified by flash column chromatography (silica gel,
hexane–hexane/AcOEtZ10–5–1) to give ester 65 (106 mg,
0.175 mmol, 92%). 65: colorless solid; 1H NMR (500 MHz,
CDCl3) d 1.49 (s, 9H, tBu), 1.49–1.60 (m, 1H, H10), 2.24
(dt, 1H, JZ15.0, 8.0 Hz, H17), 2.32–2.37 (m, 2H, H4, H10),
2.61–2.67 (m, 2H, H4, H17), 3.09–3.16 (m, 2H, H8, H9),
3.26–3.32 (m, 2H, H5, H11), 3.37 (t, 1H, JZ8.5 Hz, H6),
3.48 (td, 1H, JZ9.5, 3.0 Hz, H16), 3.53 (t, 1H, JZ8.5 Hz,
H7), 3.87 (d, 2H, JZ8.5 Hz, H12, H15), 4.00 (d, 1H, JZ
16.0 Hz, H21), 4.03 (brd, 1H, JZ16.5 Hz, H1), 4.06 (d, 1H,
JZ16.5 Hz, H21), 4.31 (dd, 1H, JZ15.5, 6.0 Hz, H1), 4.99
(d, 1H, JZ12.0 Hz, NAP), 5.04 (d, 2H, JZ11.5 Hz, CH2Z
CH-, NAP), 5.09 (dd, 1H, JZ17.5, 2.0 Hz, CH2ZCH–),
5.75–5.91 (m, 5H, H2, H3, H13, H14, H18), 7.43–7.48 (m,
2H, NAP), 7.55 (dd, 1H, JZ8.5, 1.5 Hz, NAP), 7.81–7.85
(m, 4H, NAP); 13C NMR (125 MHz, CDCl3) d 28.26, 34.76,
36.73, 37.27, 67.95, 68.52, 73.34, 75.32, 78.59, 80.56,
81.11, 81.91, 81.97, 82.24, 83.60, 87.62, 116.96, 125.76,
126.01, 126.21, 126.42, 126.91, 127.80, 127.98, 128.02,
131.50, 131.71, 132.37, 133.11, 133.44, 135.23, 136.85,
169.21; FT-IR (film) n 2977, 2876, 1750, 1452, 1368, 1301,
1228, 1131, 1098, 1008, 956, 915, 851, 817 cmK1; MALDI-
TOF MS [MCNa]C calcd for C36H44NaO8 627.2934,
found 627.2738; [a]2D4.5 C24.08 (c 0.460, CHCl3).
4.5.3. Amide 70. A solution of carboxylic acid 66 (48.4 mg,
88.2 mmol) and Et3N (86.1 ml, 0.618 mmol) in CH2Cl2
(3 ml) was cooled to K78 8C. PivCl (109 ml, 0.882 mmol)
was added and the mixture was stirred for 1 h at 0 8C to
produce a mixed anhydride 67. In another flask, to a solution
of (S)-4-benzyl oxazolidinethione 68 (141 mg, 0.730 mmol)
in THF (3 ml) was added n-BuLi (1.56 M solution in
hexane, 340 ml, 0.529 mmol) at K78 8C. The solution was
stirred for 15 min at K78 8C and transferred into the cooled
solution of the mixed anhydride 67 via cannula at K78 8C.
After stirring for 15 min at K78 8C, the mixture was
warmed to 0 8C and the stirring was continued for an
additional 1 h. The reaction mixture was quenched with
saturated NH4Cl solution and the aqueous phase was
extracted with AcOEt. The combined organic phase was
washed with brine and dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane–hexane/AcOEtZ5–4–
3) and then HPLC to give amide 70 (32.4 mg, 44.8 mmol,
1
51%). 70: colorless solid; H NMR (500 MHz, CDCl3) d
1.51–1.57 (m, 1H, H10), 2.27–2.36 (m, 3H, H4, H10, H17),
2.64 (ddd, 1H, JZ16.5, 8.0, 4.0 Hz, H4), 2.65–2.71 (m, 1H,
H17), 2.81 (dd, 1H, JZ13.0, 9.5 Hz, auxiliary), 3.10–3.17
(m, 2H, H8, H9), 3.26–3.35 (m, 3H, H5, H11, auxiliary),
3.38 (t, 1H, JZ8.0 Hz, H6), 3.54 (t, 1H, JZ8.0 Hz, H7),
3.57 (td, 1H, JZ8.0, 3.0 Hz, H16), 3.89 (brdd, 1H, JZ9.0,
2.0 Hz, H12), 3.96 (brdd, 1H, JZ9.0, 2.0 Hz, H15), 4.04
(brdd, 1H, JZ16.0, 2.5 Hz, H1), 4.31 (dd, 1H, JZ16.0,
6.0 Hz, H1), 4.37–4.42 (m, 2H, auxiliary), 4.95 (tt, 1H, JZ
10.0, 4.0 Hz, auxiliary), 4.99 (d, 1H, JZ12.0 Hz, NAP),
5.04 (d, 1H, JZ12.0 Hz, NAP), 5.04 (d, 1H, JZ17.5 Hz,
H21), 5.05–5.08 (m, 1H, CH2ZCH–), 5.11 (brdd, 1H, JZ
17.5, 2.0 Hz, CH2ZCH–), 5.21 (d, 1H, JZ18.0 Hz, H21),
5.75–5.80 (m, 1H, H3), 5.82 (dt, 1H, JZ13.0, 2.0 Hz, H4),
5.85–5.89 (m, 1H, H2), 5.89 (dt, 1H, JZ12.5, 2.5 Hz, H13),
5.89–5.95 (m, 1H, H18), 7.22–7.36 (m, 5H, auxiliary),
7.43–7.47 (m, 2H, NAP), 7.55 (dd, 1H, JZ8.5, 1.5 Hz,
NAP), 7.81–7.84 (m, 4H, NAP); 13C NMR (125 MHz,
CDCl3) d 34.77, 36.76, 37.29, 37.68, 60.05, 68.53, 71.40,
71.60, 73.33, 75.34, 78.56, 80.57, 81.14, 81.88, 82.24,
83.50, 87.63, 117.12, 125.77, 126.02, 126.21, 126.42,
126.90, 127.70, 127.80, 128.00, 128.02, 129.25, 129.55,
131.49, 132.75, 133.12, 133.44, 135.08, 135.15, 136.84,
170.57, 184.84; FT-IR (film) n 3027, 2878, 1714, 1367,
4.5.2. Carboxylic acid 66. To a solution of ester 65
(66.1 mg, 0.109 mmol) in THF (3.3 ml) was added HCl
(10 M, 1.64 ml, 16.4 mmol) at 0 8C. The mixture was
warmed to 30 8C and stirred for 23 h. The reaction mixture
was diluted with water and AcOEt. Aqueous phase was
extracted with AcOEt and the combined organic phase was
dried over anhydrous Na2SO4. After concentration, the
residue was purified by flash column chromatography (silica
gel, hexane/AcOEtZ5–1) to give carboxylic acid 66
(48.4 mg, 88.2 mmol, 81%). 66: colorless powder; 1H
NMR (500 MHz, CDCl3) d 1.54 (q, 1H, JZ11.5 Hz,
H10), 2.26 (dt, 1H, JZ15.0, 7.5 Hz, H17), 2.31–2.38 (m,
2H, H4, H10), 2.55–2.60 (m, 1H, H17), 2.63 (ddd, 1H, JZ
16.5, 7.5, 4.0 Hz, H4), 3.09–3.16 (m, 2H, H8, H9), 3.26–
3.33 (m, 2H, H5, H11), 3.39 (t, 1H, JZ9.0 Hz, H6), 3.52 (td,
1H, JZ9.0, 3.5 Hz, H16), 3.54 (t, 1H, JZ8.5 Hz, H7), 3.87
(brdd, 1H, JZ8.5, 2.0 Hz, H12), 3.95 (brdd, 1H, JZ8.5,
2.0 Hz, H15), 4.04 (brdd, 1H, JZ15.5, 2.5 Hz, H1), 4.15 (d,
1H, JZ16.5 Hz, H21), 4.24 (d, 1H, JZ16.5 Hz, H21), 4.31
1330, 1207, 1167, 1096, 1011, 963, 911, 857, 818 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C42H45NNaO8S
746.2764, found 746.2737; [a]2D2.0 C66.38 (c 0.530,
CHCl3).
4.5.4. Amide 71. A solution of carboxylic acid 66 (70.2 mg,
0.128 mmol) and Et3N (154 ml, 1.11 mmol) in CH2Cl2
(5 ml) was cooled to K78 8C. PivCl (195 ml, 1.58 mmol)

8392
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
was added and the mixture was stirred for 1 h at 0 8C to
produce a mixed anhydride 66. In another flask, to a solution
(S)-4-benzyl oxazolidinone 69 (168 mg, 0.948 mmol) in
THF (5 ml) was added n-BuLi (1.56 M solution in hexane,
506 ml, 0.79 mmol) at K78 8C. The solution was stirred for
15 min at K78 8C and transferred into the cooled solution of
the mixed anhydride 67 via cannula at K78 8C. After
stirring for 15 min at K78 8C, the mixture was warmed to
0 8C and the stirring was continued for an additional 30 min.
The reaction mixture was quenched with saturated NH4Cl
solution and the aqueous phase was extracted with AcOEt.
The combined organic phase was washed with brine and
dried over anhydrous Na2SO4. After concentration, the
residue was purified by flash column chromatography (silica
gel, hexane/AcOEtZ10–5–1) to give amide 71 (87.4 mg,
0.123 mmol, 96%). 71: colorless solid; mp 160 8C (hexane–
(16.5 mg, 21.1 mmol, 58%) and 20,21-anti-15,21-syn iso-
mer 72 (4.2 mg, 5.39 mmol, 15%). 72: colorless solid; H
1
NMR (500 MHz, CDCl3) d 1.53 (dd, 1H, JZ11.0 Hz, H10),
2.24–2.31 (m, 1H, H17), 2.31–2.36 (m, 2H, H4, H10), 2.43
(d, 1H, JZ6.5 Hz, OH), 2.60–2.66 (m, 2H, H4, H17), 2.81
(dd, 1H, JZ13.0, 10.0 Hz, auxiliary), 3.09–3.16 (m, 2H,
H8, H9), 3.27 (td, 1H, JZ10.0, 4.0 Hz, H5), 3.32–3.35 (m,
1H, H11), 3.36 (t, 1H, JZ9.0 Hz, H6), 3.35–3.40 (m, 1H,
auxiliary), 3.51 (t, 1H, JZ8.5 Hz, H7), 3.56 (td, 1H, JZ8.0,
3.0 Hz, H16), 3.88 (brdd, 1H, JZ9.5, 2.5 Hz, H12), 4.02
(brdd, 1H, JZ15.5, 2.5 Hz, H1), 4.11–4.14 (m, 1H, H15),
4.26 (brt, 1H, JZ8.0 Hz, auxiliary), 4.30 (dd, 1H, JZ15.5,
6.0 Hz, H1), 4.36 (dd, 1H, JZ9.5, 2.0 Hz, auxiliary), 4.50
(brdd, 1H, JZ12.0, 6.0 Hz, H20), 4.85 (dddd, 1H, JZ10.0,
7.0, 3.5, 2.0 Hz, auxiliary), 4.95 (d, 1H, JZ12.5 Hz, NAP),
5.00 (d, 1H, JZ12.0 Hz, NAP), 5.08 (dd, 1H, JZ10.5,
2.0 Hz, CH2ZCH–), 5.12 (brdd, 1H, JZ17.0, 2.0 Hz,
CH2ZCH–), 5.27 (dt, 1H, JZ11.0, 1.5 Hz, CH2ZCH–),
5.41 (dt, 1H, JZ17.0, 1.5 Hz, CH2ZCH–), 5.76–5.79 (m,
2H, H3, H14), 5.84–5.93 (m, 3H, H2, H13, H18), 6.03 (ddd,
1H, JZ17.0, 10.0, 5.0 Hz, H19), 6.70 (d, 1H, JZ5.0 Hz,
H21), 7.23–7.36 (m, 5H, auxiliary), 7.40–7.44 (m, 2H,
NAP), 7.52 (dd, 1H, JZ8.5, 2.0 Hz, NAP), 7.77–7.81 (m,
4H, NAP); 13C NMR (125 MHz, CDCl3) d 34.78, 36.72,
37.28, 37.85, 61.00, 68.54, 71.15, 73.32, 75.29, 78.47,
79.30, 80.52, 81.21, 82.20, 82.39, 83.57, 87.58, 117.25,
117.70, 125.74, 126.00, 126.19, 126.39, 126.88, 127.75,
127.79, 127.97, 128.02, 129.27, 129.60, 131.51, 131.83,
132.67, 133.10, 134.99, 135.07, 135.64, 136.85, 172.47; FT-
IR (film) n 3452, 2876, 1707, 1366, 1327, 1197, 1160, 1097,
962, 856, 818 cmK1; MALDI-TOF MS [MCNa]C calcd
for C45H49NaNO9S 802.3026, found 802.3214. 73: color-
less solid; 1H NMR (500 MHz, CDCl3) d 1.53 (dd, 1H, JZ
11.0 Hz, H10), 2.22 (brdt, 1H, JZ15.0, 8.0 Hz, H17), 2.31–
2.36 (m, 2H, H4, H10), 2.45 (d, 1H, JZ8.5 Hz, OH), 2.58–
2.64 (m, 1H, H17), 2.63 (ddd, 1H, JZ16.5, 8.0, 4.0 Hz, H4),
2.84 (dd, 1H, JZ13.0, 10.0 Hz, auxiliary), 3.09–3.16 (m,
2H, H8, H9), 3.28 (td, 1H, JZ10.0, 4.0 Hz, H5), 3.33–3.40
(m, 3H, H6, H11, auxiliary), 3.52 (t, 1H, JZ8.5 Hz, H7),
3.56 (td, 1H, JZ9.0, 2.5 Hz, H16), 3.87 (ddt, 1H, JZ9.0,
2.5, 2.0 Hz, H12), 4.01–4.05 (m, 2H, H1, H15), 4.30 (dd,
1H, JZ15.5, 6.0 Hz, H1), 4.31 (dd, 1H, JZ9.5, 8.0 Hz,
auxiliary), 4.37 (dd, 1H, JZ9.0, 2.0 Hz, auxiliary), 4.54–
4.58 (m, 1H, H20), 4.89 (dddd, 1H, JZ9.5, 7.5, 3.5, 2.0 Hz,
auxiliary), 4.95 (d, 1H, JZ12.5 Hz, NAP), 5.00 (d, 1H, JZ
12.0 Hz, NAP), 5.08 (dd, 1H, JZ10.5, 2.0 Hz, CH2ZCH–),
5.11 (brdd, 1H, JZ17.5, 1.5 Hz, CH2ZCH–), 5.29 (dt, 1H,
JZ10.0, 1.5 Hz, CH2ZCH–), 5.41 (dt, 1H, JZ17.5, 1.5 Hz,
CH2ZCH–), 5.74–5.81 (m, 2H, H3, H14), 5.84–5.92 (m,
2H, H2, H18), 5.98–6.01 (m, 1H, H13), 6.02 (ddd, 1H, JZ
18.0, 11.0, 6.0 Hz, H19), 6.52 (d, 1H, JZ3.0 Hz, H21),
7.23–7.36 (m, 5H, auxiliary), 7.40–7.45 (m, 2H, NAP), 7.52
(dd, 1H, JZ9.0, 1.5 Hz, NAP), 7.80 (brt, 4H, JZ8.5 Hz,
NAP); 13C NMR (125 MHz, CDCl3) d 34.78, 36.71, 37.25,
37.70, 61.06, 68.53, 71.14, 73.31, 75.28, 78.40, 80.27,
80.49, 81.23, 82.18, 82.68, 83.75, 87.57, 117.28, 117.59,
125.74, 126.00, 126.19, 126.38, 126.87, 127.75, 127.79,
127.97, 128.02, 129.26, 129.60, 131.51, 131.90, 132.46,
133.09, 133.42, 134.92, 135.07, 136.39, 136.84, 171.86; FT-
IR (film) n 3462, 3027, 2876, 1710, 1452, 1366, 1328, 1197,
1160, 1097, 1013, 961, 912, 857, 819 cm–1; MALDI-TOF
MS [MCNa]C calcd for C45H49NaNO9S 802.3026, found
802.3301.
1
EtOAc); H NMR (500 MHz, CDCl3) d 1.54 (dd, 1H, JZ
11.5 Hz, H10), 2.26–2.37 (m, 3H, H4, H10, H17), 2.64 (ddd,
1H, JZ16.5, 8.0, 4.0 Hz, H4), 2.66–2.67 (m, 1H, H17), 2.82
(dd, 1H, JZ13.5, 10.0 Hz, auxiliary), 3.10–3.17 (m, 2H,
H8, H9), 3.28 (td, 1H, JZ9.0, 4.0 Hz, H5), 3.29–3.33 (m,
1H, H11), 3.35 (dd, 1H, JZ13.0, 3.5 Hz, auxiliary), 3.38 (t,
1H, JZ9.0 Hz, H6), 3.53 (t, 1H, JZ8.5 Hz, H7), 3.56 (td,
1H, JZ8.5, 2.5 Hz, H16), 3.89 (brdd, 1H, JZ9.5, 2.0 Hz,
H12), 3.96 (brdd, 1H, JZ9.0, 2.0 Hz, H15), 4.04 (brdd, 1H,
JZ15.5, 3.0 Hz, H1), 4.24 (dd, 1H, JZ8.5, 3.0 Hz,
auxiliary), 4.28–4.29 (m, 1H, auxiliary), 4.32 (dd, 1H, JZ
9.5, 6.0 Hz, H1), 4.67–4.72 (m, 1H, auxiliary), 4.71 (d, 1H,
JZ17.5 Hz, H21), 4.81 (d, 1H, JZ18.0 Hz, H21), 4.99 (d,
1H, JZ12.0 Hz, NAP), 5.04 (d, 1H, JZ11.5 Hz, NAP),
5.05–5.07 (m, 1H, CH2ZCH–), 5.11 (brdd, 1H, JZ18.0,
2.0 Hz, CH2ZCH–), 5.75–5.95 (m, 5H, H2, H3, H13, H14,
H18), 7.21–7.36 (m, 5H, auxiliary), 7.43–7.85 (m, 8H,
NAP); 13C NMR (125 MHz, CDCl3) d 14.26, 22.79, 29.18,
30.07, 31.72, 34.77, 36.74, 37.28, 37.92, 45.03, 55.03,
62.22, 67.48, 68.52, 69.59, 73.34, 75.33, 76.94, 78.57,
80.56, 81.12, 81.96, 82.25, 83.49, 87.62, 117.06, 125.76,
126.01, 126.21, 126.43, 126.90, 127.65, 127.80, 127.99,
128.03, 129.19, 129.54, 131.47, 131.50, 132.67, 133.12,
133.44, 135.03, 135.17, 136.85, 153.54, 169.72; FT-IR
(film) n 3020, 2881, 1786, 1714, 1642, 1390, 1351, 1297,
1260, 1213, 1139, 1099, 1010, 976, 922, 858, 821, 755, 705
cm–1; ESI-TOF MS [MCNH4]C calcd for C42H49N2O9
725.3438, found 725.3390; [a]22.0 C44.58 (c 1.03,
D
CHCl3).
4.5.5. Aldol reaction of 70. To a solution of Et3N (102 ml,
0.732 mmol) in CH2Cl2 (2 ml) was added TiCl4 (1.0 M
solution in CH2Cl2, 366 ml, 0.366 mmol) at K78 8C. A
solution of amide 70 (26.5 mg, 36.6 mmol) in CH2Cl2 (6 ml)
was then added, and the resulting mixture was stirred for
30 min at K78 8C. To the resulting violet solution, freshly
distilled acrolein (49.0 ml, 0.732 mmol) was added, and the
stirring was continued for 20 min at K78 8C. The reaction
mixture was quenched with saturated NH4Cl solution and
the aqueous phase was extracted with AcOEt. The
combined organic phase was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue
was purified by flash column chromatography (silica gel,
hexane/AcOEtZ3–1) to give a mixture of aldol products 72
and 73 (21.7 mg, 27.8 mmol, 76%) and recovery of 70
(4.0 mg, 5.5 mmol, 15%). The aldol products were further
separated by HPLC to give 20,21-syn-15,21-syn isomer 73

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8393
4.5.6. Synthesis of the ABCDE ring moiety (5) from 72.
To a solution of amide 72 (4.2 mg, 5.4 mmol) in THF (1 ml)
was added a solution of NaBH4 (1.0 mg, 27 mmol) in water
(0.25 ml). The mixture was stirred for 10 min at room
temperature and quenched with saturated NH4Cl solution.
Aqueous phase was extracted with AcOEt and the combined
organic phase was washed with brine and dried over
anhydrous Na2SO4. After concentration, the residue was
purified by flash column chromatography (silica gel,
hexane/AcOEtZ2–1–0.5) to give a corresponding diol
(2.7 mg, 4.6 mmol, 85%).
OH), 2.59–2.63 (m, 1H, H17), 2.63 (ddd, 1H, JZ16.0, 8.0,
4.0 Hz, H4), 2.83 (dd, 1H, JZ13.5, 9.5 Hz, auxiliary), 3.09–
3.16 (m, 2H, H8, H9), 3.28 (td, 1H, JZ9.5, 4.0 Hz, H5),
3.32–3.39 (m, 3H, H6, H11, auxiliary), 3.51 (t, 1H, JZ
8.5 Hz, H7), 3.54–3.58 (m, 1H, H16), 3.87 (dq, 1H, JZ8.5,
2.5 Hz, H12), 3.98 (dq, 1H, JZ9.0, 2.5 Hz, H15), 4.02
(brdd, 1H, JZ15.5, 3.0 Hz, H1), 4.23–4.25 (m, 2H,
auxiliary), 4.30 (dd, 1H, JZ15.0, 6.5 Hz, H1), 4.40–4.44
(m, 1H, H20), 4.68 (ddt, 1H, JZ10.0, 7.0, 3.5 Hz,
auxiliary), 4.95 (d, 1H, JZ12.0 Hz, NAP), 5.00 (d, 1H,
JZ11.5 Hz, NAP), 5.07 (dd, 1H, JZ10.5, 2.0 Hz, CH2Z
CH–), 5.11 (dd, 1H, JZ17.0, 2.0 Hz, CH2ZCH–), 5.28 (dt,
1H, JZ11.0, 1.5 Hz, CH2ZCH–), 5.39 (dt, 1H, JZ16.0,
1.5 Hz, CH2ZCH–), 5.41 (d, 1H, JZ3.5 Hz, H21), 5.74–
5.79 (m, 2H, H3, H14), 5.83–5.91 (m, 2H, H2. H18), 5.94–
6.01 (m, 2H, H13, H19), 7.22–7.36 (m, 5H, auxiliary), 7.41–
7.43 (m, 2H, NAP), 7.52 (dd, 1H, JZ8.5, 1.5 Hz, NAP),
7.77–7.81 (m, 4H, NAP); 13C NMR (125 MHz, CDCl3) d
34.73, 36.68, 37.23, 37.88, 55.73, 67.10, 68.49, 73.26,
73.88, 75.24, 76.91, 78.33, 80.44, 80.85, 81.16, 82.15,
82.81, 83.60, 87.53, 117.26, 117.55, 125.71, 125.96, 126.16,
126.35, 126.83, 127.67, 127.75, 127.93, 127.98, 129.17,
129.55, 131.46, 131.89, 132.52, 133.06, 133.38, 134.86,
134.97, 136.44, 136.80, 153.60, 170.74; FT-IR (film) n
3437, 3059, 3027, 2930, 2876, 1779, 1711, 1642, 1603,
A solution of the diol (2.7 mg, 4.6 mmol) in CH2Cl2 (1 ml)
was added the Grubbs catalyst 37 (0.4 mg, 0.457 mmol). The
mixture was stirred for 30 min at room temperature and
concentrated. The residue was purified by flash column
chromatography (silica gel, hexane/AcOEtZ1–0.5–0.33) to
give the ABCDE ring moiety 5 (2.1 mg, 3.7 mmol, 82%). 5:
colorless solid; mp 126–126.5 8C (hexane–AcOEt); 1H
NMR (500 MHz, CDCl3) d 1.52 (q, 1H, JZ11.5 Hz,
H10), 2.18–2.24 (brs, 2H, OH), 2.25–2.38 (m, 3H, H4,
H10, H17), 2.63 (ddd, 1H, JZ16.5, 8.0, 4.0 Hz, H4), 2.67
(ddd, 1H, JZ13.0, 9.5, 3.5 Hz, H17), 3.09–3.12 (m, 2H, H8,
H9), 3.24 (ddd, 1H, JZ12.0, 9.5, 4.5 Hz, H11), 3.28 (td, 1H,
JZ9.5, 4.0 Hz, H5), 3.37 (t, 1H, JZ8.5 Hz, H6), 3.41 (m,
1H, H21), 3.52 (t, 1H, JZ8.5 Hz, H7), 3.61 (td, 1H, JZ9.0,
3.0 Hz, H16), 3.77–3.83 (m, 3H, H12, H22, H22), 4.04
(brdd, 1H, JZ15.5, 2.5 Hz, H1), 4.14 (brdd, 1H, JZ8.5,
2.5 Hz, H15), 4.31 (dd, 1H, JZ15.5, 6.0 Hz, H1), 4.46 (brd,
1H, JZ6.5 Hz, H20), 4.98 (d, 1H, JZ12.5 Hz, NAP), 5.02
(d, 1H, JZ12.5 Hz, NAP), 5.64 (dt, 1H, JZ13.0, 2.5 Hz,
H14), 5.71–5.81 (m, 4H, H2, H3, H13, H18), 5.86 (ddd, 1H,
JZ11.5, 6.0, 3.5 Hz, H19), 7.43–7.48 (m, 2H, NAP), 7.56
(dd, 1H, JZ8.5, 1.5 Hz, NAP), 7.79–7.85 (m, 4H, NAP);
13C NMR (125 MHz, CDCl3) d 32.50, 34.59, 36.83, 64.48,
68.36, 70.20, 73.17, 75.15, 78.03, 80.47, 80.81, 81.09,
82.01, 84.70, 84.99, 87.46, 125.63, 125.87, 126.06, 126.30,
126.76, 126.84, 127.64, 127.84, 127.86, 130.89, 131.36,
132.96, 133.27, 134.89, 136.22, 136.62; FT-IR (film) n
3399, 2875, 2360, 1367, 1260, 1093 cm–1; MALDI-TOF
MS [MCNa]C calcd for C33H38NaO8 585.2465, found
585.2457; [a]D21.0 K61.18 (c 0.82, CHCl3).
1497, 1479, 1454, 1392, 1350, 1261, 1212, 1099, 1009 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C45H49NaNO10
786.3254, found 786.3293; [a]2D0.5 C32.78 (c 0.800,
CHCl3). 20,21-syn-15,21-anti isomer: colorless amorphous;
1H NMR (500 MHz, CDCl3) d 1.51 (q, 1H, JZ11.5 Hz,
H10), 2.28 (brdt, 1H, JZ15.0, 8.0 Hz, H17), 2.30–2.37 (m,
2H, H4, H10), 2.47 (d, 1H, JZ8.5 Hz, OH), 2.63 (ddd, 1H,
JZ16.0, 7.5, 4.0 Hz, H4), 2.79 (dd, 1H, JZ14.0, 9.0 Hz,
auxiliary), 2.83–2.88 (m, 1H, H17), 3.08–3.14 (m, 2H, H8,
H9), 3.25–3.34 (m, 3H, H5, H11, auxiliary), 3.37 (t, 1H, JZ
8.5 Hz, H6), 3.49–3.54 (m, 1H, H7, H16), 3.83–3.88 (m, 2H,
H12, H15), 4.04 (brdd, 1H, JZ15.5, 3.0 Hz, H1), 4.24 (dd,
1H, JZ8.5, 3.0 Hz, auxiliary), 4.30 (t, 1H, JZ8.5 Hz,
auxiliary), 4.31 (dd, 1H, JZ15.5, 6.0 Hz, H1), 4.50–4.55
(m, 1H, H20), 4.74–4.79 (m, 1H, auxiliary), 4.98 (d, 1H, JZ
12.0 Hz, NAP), 5.02 (d, 1H, JZ12.0 Hz, NAP), 5.06 (dd,
1H, JZ10.5, 1.0 Hz, CH2ZCH–), 5.13 (dd, 1H, JZ17.5,
2.0 Hz, CH2ZCH–), 5.30 (dt, 1H, JZ10.5, 1.5 Hz, CH2Z
CH–), 5.36 (d, 1H, JZ3.5 Hz, H21), 5.42 (dt, 1H, JZ17.5,
1.5 Hz, CH2]CH–), 5.74 (dt, 1H, JZ13.0, 2.5 Hz, H13),
5.75–5.80 (m, 1H, H3), 5.82 (dt, 1H, JZ13.0, 2.5 Hz, H14),
5.85–5.94 (m, 2H, H2, H18), 6.01 (ddd, 1H, JZ17.0, 11.0,
6.0 Hz, H19), 7.23–7.36 (m, 5H, auxiliary), 7.43–7.47 (m,
2H, NAP), 7.54 (d, 1H, JZ8.0 Hz, NAP), 7.81–7.83 (m, 4H,
NAP); 13C NMR (125 MHz, CDCl3) d 34.77, 36.72, 37.31,
37.78, 55.16, 67.02, 68.53, 73.30, 73.69, 75.36, 77.73,
78.26, 80.20, 80.44, 81.12, 82.17, 83.47, 87.63, 116.63,
117.66, 125.79, 126.04, 126.25, 126.48, 126.89, 127.64,
127.82, 128.04, 129.16, 129.65, 130.67, 131.52, 133.14,
133.47, 134.87, 135.73, 136.63, 136.78, 153.68, 169.81; FT-
IR (film) n 3503, 3027, 2927, 2874, 1778, 1714, 1639, 1603,
4.5.7. Aldol reaction of 71. To a solution of Et3N (50.4 ml,
0.362 mmol) in CH2Cl2 (2 ml) was added TiCl4 (1.0 M
solution in CH2Cl2, 181 ml, 0.181 mmol) at K78 8C. A
solution of amide 71 (12.8 mg, 18.1 mmol) in CH2Cl2 (5 ml)
was then added, and the resulting mixture was stirred for
30 min at K78 8C. To the resulting violet solution, freshly
distilled acrolein (24.2 ml, 0.362 mmol) was added and the
stirring was continued for 20 min at K78 8C. The reaction
mixture was quenched with saturated NH4Cl solution and
the aqueous phase was extracted with AcOEt. The
combined organic phase was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue
was purified by flash column chromatography (silica gel,
hexane/AcOEtZ3–1) and then HPLC to give 20,21-syn-
15,21-syn isomer 74 (9.9 mg, 13.0 mmol, 72%), a corre-
sponding 20,21-syn-15,21-anti isomer (1.6 mg, 2.1 mmol,
12%), and recovery of 71 (1.3 mg, 1.9 mmol, 10%). 74:
1454, 1392, 1351, 1216, 1099, 1006, 923, 856 cmK1
;
MALDI-TOF MS [MCNa]C calcd for C45H49NaNO10
786.3254, found 786.3272; [a]2D7.0 C62.68 (c 0.332,
CHCl3).
1
colorless amorphous; H NMR (500 MHz, CDCl3) d 1.53
(q, 1H, JZ11.5 Hz, H10), 2.21 (brdt, 1H, JZ15.5, 8.5 Hz,
H17), 2.31–2.36 (m, 2H, H4, H10), 2.48 (d, 1H, JZ7.5 Hz,
4.5.8. Diol 76. To a solution of amide 73 (18.0 mg,
23.1 mmol) in THF (2 ml) was added a solution of NaBH4

8394
S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
(4.4 mg, 120 mmol) in water (0.5 ml). The mixture was
stirred for 20 min at room temperature and quenched with
saturated NH4Cl solution. Aqueous phase was extracted
with AcOEt and the combined organic phase was washed
with brine and dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column
chromatography (silica gel, hexane/AcOEtZ3–1–0.33) to
give diol 75 (10.8 mg, 18.3 mmol, 79%).
JZ7.5 Hz, NAP), 7.80–7.85 (m, 4H, NAP); 13C NMR
(125 MHz, CDCl3) d K5.36, K5.29, 18.37, 25.98, 33.38,
34.75, 37.03, 64.87, 68.48, 69.29, 73.35, 75.27, 76.90,
78.30, 80.62, 81.01, 82.22, 82.86, 85.08, 87.59, 125.72,
125.97, 126.19, 126.40, 126.88, 127.77, 127.94, 128.00,
130.66, 131.48, 132.43, 133.10, 133.43, 135.36, 136.86;
FT-IR (film) n 3467, 3020, 2952, 2929, 2882, 2858, 1602,
1509, 1470, 1462, 1363, 1300, 1257, 1216, 1091, 1008 cm–1;
MALDI-TOF MS [MCNa]C calcd for C39H52NaO8Si
699.3329, found 699.3374; [a]2D4.5 K46.88 (c 1.02, CHCl3).
A solution of the diol 75 (10.8 mg, 18.3 mmol) and Grubbs
catalyst 37 (0.8 mg, 0.9 mmol) in CH2Cl2 (4 ml) was stirred
for 1 h at room temperature. Et3N was added and the
mixture concentrated. The residue was purified by flash
column chromatography (silica gel, hexane/AcOEtZ1–
0.5–0.33) to give diol 76 (9.5 mg, 17 mmol, 92%). 76:
colorless solid; mp 175–177 8C (CH2Cl2–AcOEt); 1H NMR
(500 MHz, CDCl3) d 1.52 (dd, 1H, JZ11.5 Hz, H10), 2.13
(brs, 1H, 22-OH), 2.26 (brs, 1H, 20-OH), 2.27–2.37 (m, 3H,
H4, H10, H17), 2.64 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4),
3.09–3.18 (m, 3H, H8, H9, H17), 3.28 (td, 2H, JZ10.0,
4.0 Hz, H5, H11), 3.37 (t, 1H, JZ9.0 Hz, H6), 3.52 (brt, 1H,
JZ8.5 Hz, H7), 3.62–3.66 (m, 2H, H16, H21), 3.76–3.84
(m, 3H, H12, H22, H22), 4.03 (brdd, 1H, JZ15.5, 2.5 Hz,
H1), 4.11 (brdd, 1H, JZ8.5, 2.5 Hz, H15), 4.31 (dd, 1H, JZ
15.5, 6.0 Hz, H1), 4.40 (brd, 1H, JZ6.5 Hz, H20), 4.99 (d,
1H, JZ12.5 Hz, NAP), 5.03 (d, 1H, JZ12.5 Hz, NAP),
5.67 (dt, 1H, JZ13.0, 2.5 Hz, H14), 5.75–5.81 (m, 1H, H3),
5.80 (dt, 1H, JZ12.5, 2.5 Hz, H13), 5.85–5.97 (m, 3H, H2,
H18, H19), 7.43–7.48 (m, 2H, NAP), 7.54 (dd, 1H, JZ8.5,
1.5 Hz, NAP), 7.80–7.84 (m, 4H, NAP); 13C NMR
(125 MHz, CDCl3) d 33.47, 34.77, 37.05, 64.50, 68.52,
69.96, 73.35, 75.34, 78.39, 80.56, 81.03, 82.20, 82.71,
83.15, 84.92, 87.65, 125.79, 126.03, 126.22, 126.46, 126.92,
127.81, 128.00, 128.02, 128.05, 131.12, 131.52, 132.00,
132.03, 134.75, 134.76; FT-IR (film) n 3415, 3025, 2879,
1450, 1366, 1264, 1092, 909, 857, 818, 733 cmK1; MALDI-
TOF MS [MCNa]C calcd for C33H38NaO8 585.2464,
found 585.2494; [a]2D4.1 K43.48 (c 1.14, CHCl3).
4.5.10. Benzoate 78. To a solution of alcohol 77 (7.9 mg,
12 mmol) in toluene (2 ml) were added PPh3 (15.3 mg,
58.4 mmol), BzOH (8.6 mg, 70 mmol) and DEAD (9.2 ml,
58 mmol). The mixture was stirred for 20 min at room
temperature and quenched with water. Aqueous phase was
extracted with AcOEt and the combined organic phase was
washed with brine and dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column
chromatography (silica gelZ1 g, hexane–hexane/AcOEtZ
10–5) to give benzoate 78 (9.2 mg, 12 mmol, 100%). 78:
colorless amorphous; 1H NMR (500 MHz, CDCl3) d 0.02 (s,
3H, TBS), 0.04 (s, 3H, TBS), 0.88 (s, 9H, TBS), 1.53 (dd,
1H, JZ11.0 Hz, H10), 2.28–2.37 (m, 3H, H4, H10, H17),
2.65 (ddd, 1H, JZ16.5, 8.0, 4.0 Hz, H4), 2.88 (ddd, 1H, JZ
13.5, 10.0, 3.5 Hz, H17), 3.09–3.15 (m, 2H, H8, H9), 3.27
(td, 1H, JZ9.5, 5.0 Hz, H11), 3.29 (td, 1H, JZ9.0, 4.5 Hz,
H5), 3.38 (t, 1H, JZ9.0 Hz, H6), 3.53 (t, 1H, JZ8.5 Hz,
H7), 3.68–3.73 (m, 3H, H16, H21, H22), 3.82–3.86 (m, 2H,
H12, H22), 4.04 (brdd, 1H, JZ15.0, 3.0 Hz, H1), 4.18
(brdd, 1H, JZ9.0, 2.5 Hz, H15), 4.31 (dd, 1H, JZ16.0,
6.0 Hz, H1), 4.99 (d, 1H, JZ12.5 Hz, NAP), 5.05 (d, 1H,
JZ11.5 Hz, NAP), 5.58 (ddd, 1H, JZ8.5, 5.5, 1.5 Hz,
H20), 5.64 (dt, 1H, JZ12.5, 2.5 Hz, H14), 5.68 (dd, 1H, JZ
11.0, 5.5 Hz, H19), 5.78 (ddt, 1H, JZ11.0, 8.0, 3.0 Hz, H3),
5.83–5.89 (m, 2H, H2, H18), 5.94 (dt, 1H, JZ12.5, 3.0 Hz,
H13), 7.43–7.64 (m, 4H, Bz, NAP), 7.81–7.86 (m, 4H,
NAP), 8.02 (brd, 2H, JZ7.5 Hz, Bz), 8.12 (dd, 2H, JZ8.0,
1.0 Hz, Bz); 13C NMR (125 MHz, CDCl3) d K5.15, K5.10,
18.46, 26.06, 32.86, 34.78, 37.01, 64.34, 68.52, 71.76,
73.38, 75.31, 78.21, 80.80, 81.04, 81.69, 82.25, 84.73,
85.19, 87.62, 125.77, 126.01, 126.24, 126.46, 126.96,
127.81, 127.94, 127.98, 128.04, 128.59, 128.64, 129.76,
130.35, 130.61, 131.50, 132.85, 133.13, 133.30, 133.91,
135.21, 136.87, 165.38; FT-IR (film) n 3030, 2931, 2883,
1724, 1693, 1603, 1453, 1415, 1319, 1268, 1091, 1023, 977,
908, 837, 775, 712 cmK1; MALDI-TOF MS [MCNa]C
calcd for C46H56NaO9Si 803.3591, found 803.3536; [a]D26.2
K35.48 (c 0.968, CHCl3).
4.5.9. TBS ether 77. To a solution of diol 76 (14.8 mg,
26.3 mmol) in CH2Cl2 (4 ml) were added imidazole
(17.9 mg, 263 mmol) and TBSCl (19.8 mg, 132 mmol).
The mixture was stirred for 30 min at room temperature
and quenched with saturated NH4Cl solution. Aqueous
phase was extracted with AcOEt and the combined organic
phase was washed with brine and dried over anhydrous
Na2SO4. After concentration, the residue was purified by
flash column chromatography (silica gel, hexane/AcOEtZ
10–3–2) to give TBS ether 77 (14.8 mg, 21.9 mmol, 83%).
1
77: colorless solid; mp 134–135 8C (hexane–AcOEt); H
NMR (500 MHz, CDCl3) d 0.10 (s, 6H, TBS), 0.92 (s, 9H,
TBS), 1.52 (dd, 1H, JZ11.5 Hz, H10), 2.28–2.34 (m, 3H,
H4, H10, H17), 2.64 (ddd, 1H, JZ16.0, 8.0, 4.0 Hz, H4),
2.70 (d, 1H, JZ4.5 Hz, 20-OH), 3.10–3.13 (m, 3H, H8, H9,
H17), 3.24–3.30 (m, 2H, H5, H11), 3.37 (t, 1H, JZ9.5 Hz,
H6), 3.52 (brt, 1H, JZ9.0 Hz, H7), 3.58–3.61 (m, 2H, H16,
H21), 3.79 (d, 2H, JZ5.5 Hz, H22, H22), 3.80–3.84 (m, 1H,
H12), 4.03 (brdd, 1H, JZ15.5, 3.0 Hz, H1), 4.08 (brdd, 1H,
JZ8.5, 2.0 Hz, H15), 4.30 (dd, 1H, JZ16.0, 6.0 Hz, H1),
4.40 (brd, 1H, JZ4.5 Hz, H20), 4.98 (d, 1H, JZ12.0 Hz,
NAP), 5.04 (d, 1H, JZ12.0 Hz, NAP), 5.64 (brd, 1H, JZ
12.5 Hz, H14), 5.75–5.84 (m, 2H, H3, H13), 5.84–5.91 (m,
3H, H2, H18, H19), 7.43–7.46 (m, 2H, NAP), 7.54 (brd, 1H,
4.5.11. Synthesis of the ABCDE ring moiety 5 from 78.
To a solution TBS ether 78 (16.9 mg, 21.6 mmol) in THF
(2 ml) was added TBAF (1.0 M solution in THF, 65 ml,
65 mmol). After stirring for 1 h at room temperature, TBAF
(65 ml, 65 mmol) was further added to the mixture and the
stirring was continued for an additional 2 h. The reaction
mixture was quenched with saturated NH4Cl solution and
the aqueous phase was extracted with AcOEt. The
combined organic phase was washed with brine and dried
over anhydrous Na2SO4. After concentration, the residue
was purified by flash column chromatography (silica gel,
hexane–hexane/AcOEtZ5–2) to give a corresponding
alcohol (13.3 mg, 19.9 mmol, 92%). colorless solid; mp

S. Kobayashi et al. / Tetrahedron 60 (2004) 8375–8396
8395
143–144 8C (hexane–AcOEt); 1H NMR (500 MHz, CDCl3)
d 1.52 (q, 1H, JZ11.5 Hz, H10), 2.25–2.37 (m, 3H, H4,
H10, H17), 2.64 (ddd, 1H, JZ16.5, 8.0, 4.0 Hz, H4), 2.70
(ddd, 1H, JZ13.0, 9.5, 3.5 Hz, H17), 3.08–3.12 (m, 2H, H8,
H9), 3.23 (ddd, 1H, JZ12.0, 9.5, 4.5 Hz, H11), 3.27 (td, 1H,
JZ9.5, 4.0 Hz, H5), 3.37 (t, 1H, JZ8.5 Hz, H6), 3.51 (brt,
1H, JZ9.0 Hz, H7), 3.61–3.66 (m, 2H, H16, H21), 3.81
(ddd, 1H, JZ9.0, 5.0, 2.5 Hz, H12), 4.03 (brdd, 1H, JZ
15.5, 3.0 Hz, H1), 4.15 (brdd, 1H, JZ9.0, 2.5 Hz, H15),
4.30 (dd, 1H, JZ16.0, 6.0 Hz, H1), 4.39 (brdd, 1H, JZ9.0,
4.5 Hz, H20), 4.59 (dd, 1H, JZ11.5, 3.0 Hz, H22), 4.67 (dd,
1H, JZ11.5, 6.0 Hz, H22), 4.97 (d, 1H, JZ12.0 Hz, NAP),
5.03 (d, 1H, JZ12.5 Hz, NAP), 5.59 (dt, 1H, JZ12.5,
2.5 Hz, H14), 5.73–5.83 (m, 4H, H3, H13, H18, H19), 5.86
(ddt, 1H, JZ12.0, 6.5, 3.0 Hz, H2), 7.43–7.49 (m, 4H, Bz,
NAP), 7.54 (dd, 1H, JZ8.0, 1.5 Hz, NAP), 7.58–7.61 (m,
1H, Bz), 7.80–7.84 (m, 4H, NAP), 8.09–8.11 (m, 2H, Bz);
13C NMR (125 MHz, CDCl3) d 32.67, 34.78, 36.99, 66.30,
68.52, 69.26, 73.32, 75.28, 78.10, 80.69, 81.01, 81.56,
82.18, 83.95, 84.70, 87.59, 125.77, 126.01, 126.22, 126.44,
126.92, 127.34, 127.80, 127.98, 128.02, 128.61, 129.94,
130.05, 130.30, 130.97, 131.51, 133.12, 133.38, 133.44,
135.17, 135.92, 136.83, 167.35; FT-IR (film) n 3468, 3023,
2932, 2876, 1718, 1602, 1584, 1509, 1452, 1369, 1350,
1316, 1276, 1175, 1078, 1027 cmK1; MALDI-TOF MS
[MCNa]C calcd for C40H42NaO9 689.2727, found
689.2797; [a]D26.4 K90.68 (c 1.00, CHCl3).
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To a solution of the alcohol (9.0 mg, 14 mmol) in MeOH
(2 ml) and THF (1 ml) was added K2CO3 (9.3 mg,
68 mmol). The mixture was stirred for 1 h and quenched
with saturated NH4Cl solution. Aqueous phase was
extracted with AcOEt and the combined organic phase
was dried over anhydrous Na2SO4. After concentration, the
residue was purified by flash column chromatography (silica
gel, hexane/AcOEtZ1–0.5–0.33) to give the ABCDE ring
moiety 5 (7.0 mg, 12 mmol, 92%).
10. (a) Oishi, T.; Uehara, H.; Nagumo, Y.; Shoji, M.; Le Brazidec,
J.-Y.; Kosaka, M.; Hirama, M. Chem. Commun. 2001,
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Acknowledgements
This work was supported by the CREST and SORST
programs from the Japan Science and Technology Corpor-
ation (JST) and by a Grant-in-Aid for Scientific Research
(S) from the Japan Society for the Promotion of Science
(JSPS). Fellowships to S. K. and S. S. from JSPS are also
acknowledged.
11. (a) Tatami, A.; Inoue, M.; Uehara, H.; Hirama, M. Tetra-
hedron Lett. 2003, 44, 5229–5233. (b) Inoue, M.; Yamashita,
S.; Tatami, A.; Miyazaki, K.; Hirama, M. J. Org. Chem. 2004,
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M. Heterocycles 2001, 54, 93–99. (b) Maruyama, M.; Inoue,
M.; Oishi, T.; Oguri, H.; Ogasawara, Y.; Shindo, Y.; Hirama,
M. Tetrahedron 2002, 58, 1835–1851.
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