Stereocontrolled total synthesis of (-)-FR901483

Article abstract of DOI:10.3987/COM-12-S(N)38

The total synthesis of a potent immunosuppressant (-)-FR901483 is accomplished. The skeleton itself is constructed by the Ugi 4CC reaction, subsequent intramolecular Dieckmann condensation, and a diastereoselective intramolecular aldol reaction. However, the remarkable feature is the stereoselective incorporation of the p-methoxybenzyl and methylamino groups within the tricyclic core skeleton.

Full text of DOI:10.3987/COM-12-S(N)38

HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1071 - 1092. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 18th June, 2012, Accepted, 7th August, 2012, Published online, 28th August, 2012
DOI: 10.3987/COM-12-S(N)38
STEREOCONTROLLED TOTAL SYNTHESIS OF (–)-FR901483
Shigeru Ieda,c Akitaka Masuda,b Mami Kariyama,b Toshiyuki Wakimoto,a,b
Tomohiro Asakawa,b Tohru Fukuyama,*a and Toshiyuki Kan*b
aGraduate School of Pharmaceutical Science, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, 113-0033, Japan, E-mail: fukuyama@mol.f.u-tokyo.ac.jp
bSchool of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada,
Suruga-ku, Shizuoka-shi, 422-8526, Japan E-mail: kant@u-shizuoka-ken.ac.jp
cAstellas Pharma Inc., 160-2, Akahama, Takahagi, Ibaraki 318-0001, Japan
Abstract – The total synthesis of a potent immunosuppressant (–)-FR901483 is
accomplished. The skeleton itself is constructed by the Ugi 4CC reaction,
subsequent intramolecular Dieckmann condensation, and a diastereoselective
intramolecular aldol reaction. However, the remarkable feature is the
stereoselective incorporation of the p-methoxybenzyl and methylamino groups
within the tricyclic core skeleton.
INTRODUCTION
(–)-FR901483 (1) is a novel immunosuppressant isolated from the fermentation broth of Cladobotryum sp.
No. 11231.1 Unlike Cyclosporin A and tacrolimus,1 which are powerful, but have strong side effects, 1
has a different mode of action and is expected to replace or reduce their dosages. Moreover, 1 is an
attractive total synthesis target due to its promising biological activity and unique tricyclic structure.
Although several total syntheses and synthetic studies of 1 have been reported to date, few are
stereoselective.2-4 Previously, we reported the stereocontrolled synthesis of optically active key
intermediate 3.3l Herein we describe a detailed stereocontrolled total synthesis of optically active 1. This
synthesis may realize diverse analogues.
RESULTS AND DISCUSSION
Scheme 1 illustrates our retrosynthetic analysis of 1. Because the crucial step in our racemic synthesis is
an intramolecular aldol reaction of keto-aldehyde 5a to provide tricycle intermediate 4a, we initially
attempted an enantioselective intramolecular aldol reaction of 5a by means of a chiral organocatalyst.
Dedicated to Prof. Ei-ichi Negishi on celebration of his 77th birthday.

OPO(OH)2
OH
OP
HO
HO
O
O
P
OMe
OP
Ar
N
N
N
HO
Ar
O
MeHN
MeHN
1'
2
(ꢀ) - FR901483 (1)
(Ar = p-MeOC6H4)
OTBS
O
O
O
OH
R
CHO
R
N
N
N
Ar
O
O
O
4a (R = H)
4b (R = p-MeOC6H4CH2)
5a (R = H)
5b (R = p-MeOC6H4CH2)
3
Scheme 1. Retrosynthetic analysis of (–)-FR901483
Organocatalytic mediated aldol reactions have received much attention.5 Thus, we anticipated that 5a
would provide optically active 4a and incorporate three stereocenters. Although we tested several
catalysts for the enantioselective desymmetrization6 of 5a, the results were unsatisfactory. Table 1 shows
typical reaction conditions.
Table 1. Desymmetrization of5a by an intramolecular chiral aldol reaction
O
O
OH
CHO
chiral catalyst
DMF, rt
N
N
O
O
5a
4a: optically active
yield (%)
ee (%)
Catalyst
L-proline
Entry
24
0
1
2
trace
18
L-phenylalanine
L-phenylalanine/D-CSA
65a
5
3
4
20
trace
18
/
6:
O2N
SO3H
N
N
H

Next we examined a diastereoselective aldol reaction of 5b to construct tricycle intermediate 4b, which
could easily be converted into intermediate 2 relying on our racemic synthesis. We envisioned the facile
construction of optically pure azaspiro intermediate 5b to be the crucial step. Although !-trisubstituted
amines have been synthesized via numerous procedures, we opted to construct 7 using the Ugi 4CC
reaction7 because the Ugi reaction can assemble complex molecules from simple components (Scheme
2).
O
O
O
O
MeO
OMe
OH
Ar
CHO
Ar
R1O
C
H2N
11
N
O
N
N
N
O
9
R2
Ar
O
Ar
OH
8
O
O
O
5b
7
4b
(Ar = p-MeOC6H4)
10
Scheme 2. Retrosynthetic analysis of 4b
Due to the limited examples of the Ugi 4CC reaction with a ketone system, we initially explored suitable
reaction conditions using commercially available cyclohexanedione monoethylene acetal 9, acetic acid 10,
p-methoxyphenyl isocyanide 12, and amine moieties 138 in MeOH. As indicated in Table 2, the R3
substituent in fragment 13 was essential, and the ethereal substituents in 12 were unsatisfactory, but an sp2
carbon in R3 accelerated the reaction rate. Consequently, we selected the vinyl group as an aldehyde
equivalent.
Table 2. Screening of Ugi 4CC reaction conditions
R4
O
R4
MeO
N C
O
O
O
N
OH
O
O
13
H2N
R3
12
10
H
N
R3
MeOH
O
MeO
O
9
14
R3
R4
time (hour)
144
yield (%)
60
Entry
1
temp.
rt
CH2OTBS
CH2OTBS
H
H
50 �
2
3
4
96
144
48
25
56
rt
CH2OBn
CO2Me
H
H
rt
69
5
6
rt
rt
73
18
CO2t-Bu
96
H
144
CH(OMe)2
MeO
7
rt
48
81
HC CH2
MeO

Optically active amine 11 was prepared in seven steps from commercially available N-Boc-tyrosine
methyl ester 15,9 while oxirane 19 was prepared in accordance with Kaneka’s patent.10 A classical
reduction of oxirane via thiirane afforded desired compound 20, and recrystallization improved its
enantiomeric excess up to 100% ee.
Cl
CO2Na
O
OMe
O
HO
Cl
Cl
Et3N, t-BuMgCl
THF, 0 °C to rt
71%
NaBH4
BocHN
BocHN
BocHN
MeOH, rt
Ar
Ar
Ar
17
18
MeI, K2CO3
DMF, rt
15: Ar = p-HOC6H4
16: Ar = p-MeOC6H4
99%
O
1) KSCN
THF-H2O
60 °C
NaOH
6N-HCl
MeOH, rt
98%.
H2N
BocHN
BocHN
2) Ph3P
toluene
80 °C
THF-H2O, rt
Ar
Ar
Ar
97%
(2 steps)
11
19
20
100% ee
47%
(2 steps)
Scheme 3. Preparation of amine 11
A mixture of cyclohexanedione monoethlyene acetal 9, acetic acid 10, optically active amine 11,
p-methoxyphenyl isocyanide 12, in MeOH was allowed to stand at room temperature to afford 21. This
reaction efficiently assembled all the carbon atoms necessary to construct tricyclic key intermediate 3 in a
single step. Although hydrolysis of the C-terminal amide bond in the Ugi adduct can be troublesome,11
methanolysis of the p-methoxyphenyl amide in 21 proceeded smoothly with a concomitant acetal
exchange to provide 22.
AcOH
10
MeO
OMe
O
O
N
O
O
CSA
HC(OMe)3
Ar
N
12
C
+
H
MeOH, rt
85%
MeOH, rt
77%
MeO
N
H2N
N
O
Ar
Ar
O
O
Ar
O
Ar
11
Me
9
Me
21
O
22
(Ar = p-MeOC6H4)
Scheme 4. Ugi 4CC reaction and subsequent transformation
Presumably, this reaction proceeded via oxazolonium intermediate 24 through neighboring group
participation. As shown in Scheme 5, the acetamide moiety should play a key role in this transformation;

this speculation is supported by the fact that the amide of Passerini compound 25, which has an acetate
instead of an acetamide moiety, is unaffected under the same methanolysis conditions. Additionally,
trimethyl orthoformate should play a key role in dehydration and trapping of p-anisidine.
R5O
OR5
R5O
OR5
O
O
N
H+, MeOH
H+
H
N
H
N
O
N+
Ar
N:
Ar
O
Ar
O
Ar
O
Ar
O
Me
21
O
MeOH
23
(R5 = -CH2CH2- or Me)
24
(Ar = p-MeOC6H4)
MeO
OMe
O
O
O
O
H
N
MeO
O
N
Ar
Ar
Me
O
O
22
25
Scheme 5. Neighboring group participation in the methanolysis of 21
Recently, we developed a novel, odorless isonitrile, which is advantageous for cleavage of the amide
bond in the Ugi adduct (Scheme 6). Additionally, the Ugi 4CC reaction with isonitrile 26 yielded 22 after
treatment under acidic conditions. These results are reasonable because the mechanism appears to be
similar to the methanolysis of 21. ꢀ
PhOCO2
N
C
MeO
OMe
O
O
N
O
O
26
CSA
HC(OMe)3
AcOH
PhOCO2
9
H
MeO
+
N
N
O
MeOH, rt
93%
H2N
MeOH, rt
85%
O
Ar
O
Ar
Ar
O
Me
Me
27
O
9
11
(Ar = p-MeOC6H4)
22
Scheme 6. Ugi 4CC reaction using odorless isonitrile 26
The subsequent intramolecular Dieckmann condensation effectively constructed the spiro-lactam ring.
Thus, treatment with LHMDS caused 22 to cyclize, yielding 28. The ensuing deoxygenation of the
carbonyl group in 28 was performed via a three-step sequence to give desired lactam 31: the reduction of
the ketone with NaBH4, dehydration with phosphoryl chloride, and a chemoselective one-electron

reduction of the resultant unsaturated lactam. In addition, simultaneous hydrolysis of the dimethyl acetal
occurred in the last step of the acidic work-up.
MeO
OMe
MeO
OMe
MeO
OMe
NaBH4
LHMDS
MeO
O
HO
N
O
N
O
N
O
MeOH, rt
THF
!78 °C to rt
O
Ar
Ar
Ar
Me
95%
(Ar = p-MeOC6H4)
29
22
28
O
MeO
OMe
POCl3
pyridine, 60 °C
Mg, MeOH;
H+, rt
N
N
Ar
Ar
66%
O
(3 steps)
O
30
31
Scheme 7. Construction of the azaspiro[4.5]lactam system
During the dehydration reaction with phosphoryl chloride, concomitant formation of methyl enol ethers
occurred. After the mixture was reduced with magnesium metal in methanol without purification,
hydrolysis of both the enol ether and dimethyl ketal in an acidic work up gave ketone 31. At this stage,
the oxidative cleavage of the terminal olefin in 31 was performed by ozonolysis to afford 5b.
With desired optically active keto-aldehyde 5b in hand, we then focused on the diasteroselective
intramolecular aldol reaction. Although Snider has reported a similar intramolecular cyclization of 5b,
their reaction conditions could not be applied to our study because the cyclization reaction proceeded with
a significant amount of racemization under basic conditions and the reproducibility was insufficient.
Therefore, we selected acidic conditions at room temperature. Treatment of keto-aldehyde 5b with acetic
acid and a catalytic amont of pyrrolidine12 afforded 4b via the desired cyclization where the two chiral
centers were generated in one step. Although the stereochemistry of the hydroxy group in 4b was the
opposite of the natural product,13 it was necessary to control the endo-reduction of the ketone in 4b.
O
O
O
AcOH
cat. pyrrolidine
AcOEt, rt
OH
Ar
O3, MeOH;
Me2S, !78 °C
CHO
Ar
N
N
N
Ar
93%
60%
O
O
O
5b
4b
31
Scheme 8. Construction of tricyclic ketone 4b

It is plausible that thermodynamic control is responsible for the stereochemistry of diequatorial aldol
product 4b. The ratio of the byproducts, which can analyze the selectivity of the intramolecular aldol
reaction (Scheme 9), indicates that chelation with hydrogen bonding via a proton and steric hinderance of
p-methoxybenzyl group contributed to the selectivity.
Scheme 9. Selectivity of the intramolecular aldol reaction in 5b

Similar to the route established for 4b, stereoselective reduction of 4b was carried out by
14,15
NaBH(OAc)3,
through coordination with the hydroxyl group to give 36. Selective protection of the
exo-oriented hydroxy group of 36 as a TBS ether and a subsequent Swern oxidation of the remaining
alcohol provided key intermediate 3, whose enantiomeric excess (96% ee) was determined by chiral
HPLC.
O
OTBS
N
OH
8
6
OH
Ar
OH
Ar
OH
Ar
NaBH(OAc)3
AcOH, MeCN, 0 °C
62%
TBSOTf, Et3N,
CH2Cl2, !20 °C
64%
N
N
O
O
O
37
36
4b
OTBS
DMSO
(COCl)2; Et3N
O
CH2Cl2, !78 °C
N
O
Ar
93%
3
96% ee
Scheme 10. Synthesis of key intermediate 3
A one-electron reduction converted ketone 3 into the exo-oriented alcohol because the reduction with
lithium aluminum hydride exclusively gave the undesired endo-alcohol. Because the hydride should
attack from the convex face of 3, a one-electron reduction with samarium (II) was investigated. Thus,
treatment with samarium (II) diiodide (SmI2)16 in the presence of HMPA at –78 °C smoothly reduced
ketone 3 to provide desired 38. In this SmI2 mediated reduction of 3, the addition of HMPA was essential
for high selectivity17. Subsequent protection of 38 with the TBS ether gave 39. As shown in Scheme 11,
an amine group was stereoselectively incorporated using a one-electron reduction as a key step. Upon
treatment of 40 with sodium nitrite under acidic conditions in a biphasic medium, sequential nitrosylation
and decarboxylation proceeded smoothly to provide oxime 41. The addition of a phase transfer catalyst
improved the reproducibility in the reaction. The crucial reduction of 41 was accomplished by treatment
with zinc in acetic acid to provide desired amine 42 as a single isomer. As shown in Figure 1, the
approach of the proton from the convex face of more stable intermediate 43 could explain the selectivity.

OTBS
N
OTBS
N
OTBS
N
TBSOTf
2, 6-lutidine
LDA, THF;
CO2
O
OH
Ar
OTBS
Ar
SmI2
MeOH, HMPA
THF, !78 °C
CH2Cl2, rt
!78 °C
Ar
54% (2 steps)
O
O
O
38
39
3
OTBS
N
OTBS
N
OTBS
N
NaNO2, HCl
OTBS
OTBS
OTBS
Zn, NH4Cl
AcOH, rt
TBAB
Et2O/H2O
0 °C to rt
Ar
Ar
Ar
66% (2 steps)
O
O
O
N
H2N
HO2C
OH
40
41
42
single isomer
Scheme 11. Conversion of amine 42
H+
L
OTBS
OTBS
OTBS
L
Zn
O+
HN
O
O
N
N
HN
>>
O+
OTBS
Zn
L
L
H+
OMe
OMe
43
44
Figure 1. Selectivity of the reduction of 41 with zinc metal
Mono-N-methylation of primary amine 42 was achieved in a stepwise manner. After the conversion of 42
into formamide 45, treatment with lithium aluminum hydride allowed the simultaneous reduction of both
the lactam and formamide, while concomitant deprotection of one of the TBS groups provided
corresponding methylamine derivative 46, which was subsequently protected with a Cbz group to afford
47.

OTBS
N
OTBS
N
OTBS
N
OH
Ar
OTBS
Ar
OTBS
Ar
HCO2H, Ac2O
CH2Cl2, 0 °C
LiAlH4
THF, 50 °C
O
O
Me NH
H2N
OHC NH
42
45
46
(Ar = p-MeOC6H4)
OTBS
N
OH
(BnO)2PN(i-Pr)2
tetrazole, CH2Cl2;
OH
Ar
OH
Ar
CbzCl, Na2CO3
CH2Cl2/H2O, rt
61% (4 steps)
HF
TBHP
MeCN
0 °C
N
35% (2 steps)
Me
N
Me
N
47
Cbz 48
Cbz
O
O
OBn
OBn
P
N
OPO(OH)2
OH
OH
OMe
H2, Pd/C
MeOH
77%
N
Ar
Me
N
Me NH
49
Cbz
(!)-FR901483 (1)
["]D23 = -10.3
lit. ["]D25 = -11
Scheme 12.
Total synthesis of (–)-FR901483 (1)
After the deprotection of the TBS ether, the phosphate ester was selectively incorporated via the
phosphoramidite method18 to give 49.19 Finally, simultaneous cleavage of Cbz and the benzyl ester groups
under hydrogenolysis conditions yielded (–)-FR901483 (1). The spectral data (relative optical rotation, 1H
NMR, 13C NMR, IR, and HRMS) of 1 fully agreed with those of the natural product (Scheme 12).
In conclusion, a highly stereoselective total synthesis ofꢀ(–)-FR901483 (1) was achieved via the Ugi 4CC
reaction, subsequent intramolecular Dieckmann condensation, and a diastereoselective intramolecular
aldol reaction. Our synthesis stereoselectively constructed the exo-oriented alcohol by a SmI2 mediated
reduction. Finally, a one-electron reduction determined the amine stereochemistry at C(10). The
versatility and flexibility of this total synthesis should contribute to future syntheses of FR901483
analogues.

EXPERIMENTAL
General. Nuclear magnetic resonance [13C NMR (68 MHz)] spectra were determined on a JEOL EX-270
instrument, [1H NMR (400 MHz) and 13C NMR (100 MHz)] spectra were determined on a JEOL-LA400
instrument, and [1H NMR (500 MHz) and C NMR (125 MHz)] spectra were determined on a JEOL
13
1
ECA 500 instrument and JEOL !"500 instrument. Chemical shifts for H NMR are reported in parts
per million (ppm) downfield from tetramethylsilane (#) in deuterochloroform (CDCl3) or
deuteromethanol (CD3OD) as an internal standard or relative to the signal at 7.26 (3.31) ppm for
deuterochloroform (deuteromethanol), while coupling constants are in hertz (Hz). The following
abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
and br = broad. Chemical shifts for 13C NMR are reported in ppm relative to the centerline of the triplet at
77.0 ppm for deuterochloroform or the centerline of a septet at 118.2 (49.0) ppm for deuteroacetonitrile
(CD3CN) [deuteromethanol (CD3OD)]. Melting points (mp) were determined on a Yanaco Micro Melting
Point Apparatus. Infrared spectra (IR), which are reported in wavenumbers (cm–1), were recorded on a
JASCO FT/IR-410 Fourier Transform Infrared Spectrometer. Mass spectra (MS) were obtained on a
JEOL JMS-GCmate MS-DIP20 with polyethylene glycol as the matrix or a JEOL MStation 700 using the
Fast Atom Bombardment (FAB) method and 3-nitrobenzylalcohol as the matrix. Analytical thin layer
chromatography (TLC) was performed on 0.25-mm thick Merck precoated analytical plates of silica gel
60 F254. Preparative TLC separations were conducted on 0.50-mm thick Merck precoated of silica gel 60
F254. Compounds were eluted from the adsorbent with 10% methanol (MeOH) in chloroform (CHCl3).
Flash column chromatography separations were performed on KANTO CHEMICAL Silica Gel 60
(40-100 mesh). All non-aqueous reactions were carried out in oven-dried glass apparatuses under a slight
positive pressure of argon. Prior to use, all solvents were dried over molecular sieves 3A or 4A. All other
reagents were commercially available, and unless otherwise specified, were used without further
purification.
tert-Butyl [(2S)-1-(4-methoxyphenyl)but-3-en-2-yl]carbamate (20).
Potassium thiocyanate (22.0 g, 226 mmol) was added to a stirred suspension of 19 (22.1 g, 75.3 mmol) in
EtOH (400 mL) and H2O (300 mL) at room temperature. The mixture was heated to 60 °C and stirred for
24 h before cooling to room temperature. Then H2O (400 mL) was added. The mixture was extracted with
AcOEt twice. The combined organic layer was washed with brine, dried over anhydrous MgSO4, and then
passed through a pad of silica gel. The solvent was removed under reduced pressure. The residual mixture
was used in the next step without further purification.
To a stirred solution of the crude product in toluene (50 mL), PPh3 (7.29 g, 27.8 mmol) was added at
room temperature. The mixture was heated to 80 °C and stirred for 12 h before cooling to room
temperature. The mixture was diluted with toluene (50 mL), and then H2O (50 mL) was added. The

resulting precipitate was filtered with a sintered glass filter. After the organic layer was separated, the
aqueous layer was extracted with AcOEt twice. The combined organic layer was washed with brine and
dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residual mixture
was purified by silica gel chromatography (toluene-AcOEt:n-hexane=1:20) to give 20 (10.9 g, 39.2
mmol) as a colorless crystal. The resulting crystal was recrystallized from toluene–n-heptane to afford
26.4
purified 20 (9.81 g, 35.2 mmol, 47%, 100% ee20) as a colorless crystal. [!]D 34.5 (c 1.01, CHCl3); IR
(firm) 3363, 2981, 1685, 1612, 1511, 1441, 1244, 1167 cm-1; 1H-NMR (CDCl3, 400MHz) # 1.41 (9H, s),
2.77 (2H, br. d, J = 6.4 Hz), 3.78 (3H, s), 4.37 (1H, br. s), 4.52 (1H, br. s), 5.06-5.11 (2H, m), 5.78 (1H,
13
ddd, J = 5.3, 10.3, 15.9 Hz), 6.83 (2H, d, J = 8.5 Hz), 7.09 (2H, d, J = 8.5 Hz); C-NMR (CDCl3,
100MHz) # 28.3, 40.4, 53.5, 55.1, 79.2, 113.6, 129.3, 130.4, 138.1, 144.6, 155.2, 158.1; HRMS (ESI)
calculated for C16H23NNaO3 300.1576 [(M+Na)+], found 300.1563.
(2S)-1-(4-Methoxyphenyl)but-3-en-2-amine (11).
6N-HCl (13 mL) was added to a solution of 20 (1.30 g, 4.69 mmol) in MeOH (26 mL) at room
temperature and stirred for 24 h. Then the reaction mixture was washed with toluene. The addition of
12% aqueous sodium hydroxide created basic conditions. The mixture was extracted with Et2O three
times. The combined organic layer was washed with brine and dried over anhydrous MgSO4. After
filtration, the solvent was removed under reduced pressure. Resulting colorless oil 11 (819 mg, 4.60
mmol, 98%) was used in the next step without further purification.
1H-NMR (CDCl3, 400MHz) # 1.84 (2H, br, s), 2.57 (1H, dd, J = 7.8, 13.2 Hz), 2.78 (1H, dd, J = 6.2, 13.2
Hz), 3.56 (1H, dd, J = 6.2, 13.2 Hz), 3.79 (3H, s), 5.05 (1H, d, J = 10.4 Hz), 5.14 (1H, d, J = 17.0 Hz),
5.88 (1H, ddd, J = 6.2, 10.4, 17.0 Hz), 6.84 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz).
8-{Acetyl[(2R)-1-(4-methoxyphenyl)but-3-en-2-yl]amino}-N-(4-methoxyphenyl)-1,4-dioxaspiro[4.5]-
decane-8-carboxamide (21).
Acetic acid 10 (0.48 mL, 8.32 mmol) was added to a solution of ketone 9 (1.08 g, 6.92 mmol), amine 11
(1.47 g, 8.29 mmol), and isonitrile 12 (1.39 g, 10.4 mmol) in MeOH (30 mL) at room temperature. The
solution stood at room temperature for 3.5 days. The mixture was concentrated under reduced pressure,
and then the residual mixture was purified by silica gel chromatography (AcOEt:n-hexane=1:2 to 1:1) to
give 21 (2.70 g, 53.6 mmol, 77% from ketone 9) as a thick, pale brown amorphous solid. [a]D20.5 –17.1 (c
0.46, CHCl3); 1H-NMR (CDCl3, 500 MHz) # 1.64 - 1.67 (3H, m), 1.86 (1H, quint, J = 7.4 Hz), 2.06 - 2.16
(4H, m), 2.20 (3H, s), 2.54 (1H, br. s), 3.06 (1H, dd, J = 7.4, 13.1 Hz), 3.32 (1H, br. s), 3.67 (3H, s), 3.77
(3H, s), 3.92 (4H, s), 4.48 (1H, br. s), 5.24 (2H, dd, J = 11.4, 15.1 Hz), 6.15 - 6.29 (1H, m), 6.80 (2H, d, J
13
= 8.9 Hz), 6.82 (2H, d, J = 8.9 Hz), 7.14 (4H, d, J = 8.9 Hz); C-NMR (CDCl3, 100MHz) # 14.0, 20.9,
25.6, 31.4, 31.8, 39.5, 54.9, 55.3, 60.2, 64.0, 64.1, 66.3, 107.5, 113.7, 114.1, 116.8, 122.9, 130.1, 138.1,
156.4, 158.3, 171.0, 174.2; IR (firm) 3379, 2935, 2247, 1649, 1513, 1248, 1107, 1035 cm-1; HRMS (ESI)

calcd for C29H36N2NaO6 531.2478 [(M+Na)+], found 531.2473.
Methyl 1-{acetyl[(2R)-1-(4-methoxyphenyl)but-3-en-2-yl]amino}-4,4-dimethoxycyclohexane
carboxylate (22).
Racemic camphor sulfonic acid (1.20 g, 5.31 mmol) was added to a stirred solution of 21 (2.70 g, 5.31
mmol) in MeOH (20 mL) and trimethyl orthoformate (20 mL) at room temperature. After a stirring for 16
h, the solvent was removed under reduced pressure. Aqueous NaHCO3 was added to the residual mixture,
and then the mixture was extracted with AcOEt twice. The combined organic layer was washed with
brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The resulting
mixture was purified by silica gel chromatography (AcOEt:n-hexane=1:2) to give 22 (1.90 g, 4.53 mmol,
85%) as a colorless crystal. mp 107 °C; [!]D25.6 3.28 (c 1.04, CHCl3); 1H-NMR (CDCl3, 400MHz) # 1.31
(1H, m)ꢀꢀ1.66 (1H, m), 2.00-2.20 (4H, m), 2.15 (3H, s), 3.00-3.30 (2H, m), 3.10 (3H, br. s), 3.71 (3H, s),
3.80 (3H, s), 4.41 (1H, br. s), 5.28 (1H, m), 6.02 (1H, m), 6.88 (2H, d, J = 8.36 Hz), 7.15 (2H, d, J = 8.36
13
Hz); C NMR (CDCl3, 100MHz) # 25.0, 28.4, 28.6, 28.8, 28.8, 40.3, 47.2, 47.6, 51.6, 51.9, 57.5, 65.0,
98.6, 114.0, 113.9, 115.9, 129.9, 130.0, 130.4, 137.5, 158.2, 172.2, 173.7; IR (firm) 2950, 2832, 1739,
1641, 1514, 1249, 1107 cm-1; HRMS (ESI): calcd for C23H33NNaO6 442.2206 [(M+Na)+], found
442.2206.
8,8-Dimethoxy-1-[(2S)-1-(4-methoxyphenyl)but-3-en-2-yl]-1-azaspiro[4.5]decane-2,4-dione (28).
1.6 M Lithium hexamethyldisilazide in THF (2.81 mL, 4.50 mmol) was added to a solution of 22 (629 mg,
1.50 mmol) in THF (7 mL) at –78 °C under argon atmosphere, and was stirred for 2 h before being
allowed to warm to room temperature. Then aqueous NH4Cl was added. The mixture was extracted with
AcOEt three times. From the combined organic layer, the solvent was removed under reduced pressure.
The residual mixture was purified by silica gel chromatography (AcOEt:n-hexane=1:2) to give 28 (552
26.4
1
mg, 1.43 mmol, 95%) as a yellow oil. [!]D 6.67 (c 1.33, CHCl3); H-NMR (CDCl3, 400MHz) # 0.62
(1H, br. d, J = 14.0 Hz), 1.23 (1H, m), 1.52 (1H, br. d, J = 13.3 Hz), 1.74-1.89 (3H, m), 3.03 (2H, s), 3.13
(3H, s), 3.16 (3H, s), 3.55-3.78 (2H, m), 3.78 (3H, s), 5.09-5.30 (2H, m), 6.34 (1H, ddd, J = 6.9, 10.3,
17.2 Hz), 6.82 (2H, d, J = 8.48 Hz), 7.11 (2H, d, J = 8.48 Hz); 13C-NMR (CDCl3, 100MHz) # 26.6, 27.4,
27.5, 27.9, 37.2, 40.4, 47.2, 47.6, 54.9, 58.9, 69.1, 98.1, 114.0, 113.5, 116.0, 130.3, 130.3, 136.5, 158.1,
167.8, 208.3; IR (firm) 2949, 2832, 1477, 1758, 1691, 1513, 1307, 1248 cm-1; HRMS (ESI) calcd for
C22H29NNaO5 410.1943 [(M+Na)+], found 410.1941.
1-[(2S)-1-(4-Methoxyphenyl)but-3-en-2-yl]-1-azaspiro[4.5]decane-2,8-dione (31).
Sodium borohydride (2.00 g, 52.9 mmol) was added to a stirred solution of 28 (4.10 g, 10.6 mmol) in
MeOH (100 mL) at room temperature. After stirring for 24 h, aqueous NH4Cl was added, and the
resulting mixture was extracted with AcOEt twice. The combined organic layer was washed with brine
and dried over anhydrous MgSO4. The solution was removed under reduced pressure. The resulting crude

product was used in the next step without further purification.
To a stirred solution of the crude product from the previous step, phosphoryl chloride (3.30 g, 21.6 mmol)
in pyridine was added at room temperature. The mixture was heated at 60 °C, and stirred for 2 h. The
mixture was allowed to cool to room temperature, aqueous NaHCO3 was added, and then the mixture was
extracted with AcOEt twice. The combined organic layer was washed with brine and dried over
anhydrous MgSO4. The solvent was removed under reduced pressure. The resulting crude product was
used in the next step without further purification.
Mg metal (4.20 g, 173 mmol) was added to a stirred solution of the crude product in MeOH (100 mL) at
room temperature. Until hydrogen gas was generated, the suspension was heated with a heat gun. After
stirring for 5 h and confirming the metal tips disappeared, 3 N HCl was added at 0 °C. After stirring at
room temperature for 2 h, the mixture was extracted with AcOEt twice. The combined organic layer was
washed with brine and dried over anhydrous MgSO4. The solvent was removed under reduced pressure.
The resulting mixture was purified by silica gel chromatography (AcOEt:n-hexane=1:1 to 2:1) to give 31
(2.27 g, 6.91 mmol, 66%) as a colorless oil. [!]D25.6 4.26 (c 0.99, CHCl3); 1H-NMR (CDCl3, 400 MHz) #
0.76 (1H, dq, J = 3.2, 13.5 Hz), 1.47 (1H, dt, J = 4.8, 13.8 Hz), 1.72-1.78 (2H, m), 1.93-1.98 (2H, m),
2.19-2.12 (2H, m), 2.24-2.44 (4H, m), 2.81 (2H, s), 2.90 (1H, m), 3.55-3.63 (1H, m), 3.78 (3H, s),
5.03-5.11 (1H, m), 6.34 (1H, ddd, J = 7.2, 10.3, 17.4 Hz), 6.81 (2H, d, J = 11.6 Hz), 7.07 (2H, d, J = 11.6
Hz); 13C-NMR (CDCl3, 100 MHz) # 28.3, 29.5, 33.3, 34.2, 37.1, 37.5, 51.1, 55.1, 58.9, 63.0, 113.5, 115.7,
130.4, 130.8, 137.0, 158.1, 174.3, 208.9; IR (firm) 2936, 1716, 1679, 1666, 1513, 1410, 1246 cm-1;
HRMS (ESI) calcd for C20H25NNaO3 350.1732 [(M+Na)+], found 350.1745.
(2S)-2-(2,8-Dioxo-1-azaspiro[4.5]dec-1-yl)-3-(4-methoxyphenyl)propanal (5b).
Ozone gas was passed through a stirred solution of 31 (2.26 g, 6.90 mmol) in MeOH (40 mL) at –78 °C.
After starting material 31 was no longer detected by TLC, argon gas was passed through the solution for a
few minutes before Me2S (858 mg, 13.8 mmol) was added. The mixture was allowed to warm to room
temperature, and then the solvent was removed under reduced pressure. Brine was added to the residual
mixture, which was extracted with AcOEt twice. The solvent was removed under reduced pressure. The
resulting crude product 5b (2.11 g, 6.41 mmol, 93%) was used in the next step without further
purification. [!]D24.8 –48.9 (c 1.16, CHCl3); 1H-NMR (CDCl3, 400 MHz) # 0.71 (1H, m), 1.27 (1H, dt, J =
5.0, 18.8 Hz), 1.81 (2H, dt, J = 5.4, 13.3 Hz), 2.13 (1H, m), 2.26 (1H, dd, J = 6.0, 14.7 Hz), 2.35-2.60 (5H,
m), 3.30-3.50 (3H, m), 4.97 (3H, s), 6.83 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 8.7 Hz), 9.65 (1H, s);
13C-NMR (CDCl3, 100 MHz) # 28.7, 32.4, 33.7, 34.4, 34.5, 37.4, 37.5, 55.3, 62.1, 62.8, 114.0, 128.2,
129.0, 129.5, 130.6, 158.5, 175.1, 198.7, 208.3; IR (firm) 3382, 2934, 1477, 1666, 1511, 1248 cm-1;
HRMS (ESI) calcd for C19H23NNaO4 352.1525 [(M+Na)+], found 352.1528.
(5S,6R,7R,10aR)-6-Hydroxy-5-(4-methoxybenzyl)tetrahydro-1H-7,10a-methanopyrrolo[1,2-a]azocine-

3,8(2H,5H)-dione (4b).
Pyrrolidine (149 mg, 2.09 mmol) and acetic acid (503 mg, 8.38 mmol) were added to a stirred solution of
5b (2.30 g, 6.98 mmol) in AcOEt at 0 °C. The mixture was warmed to 20 °C, and stirred for 24 h. The
solvent was removed under reduced pressure, and the residual mixture was purified by silica gel
chromatography (AcOEt:n-hexane=2:1) to give 4b (1.38 g, 4.20 mmol, 60%) as a colorless crystal. mp
23.7
1
156.3 °C; [!]D –93.2 (c 1.18, CHCl3); H NMR (CDCl3, 400 MHz) # 1.52 (1H, br. d, J = 13.5 Hz),
1.72-1.87 (6H, m), 2.05 (1H, dd, J = 3.6, 13.2 Hz), 2.18 (1H, m), 2.48-2.55 (4H, m), 2.81 (1H, s), 3.56
(1H, dd, J = 4.4, 14.0 Hz), 3.78 (3H, s), 3.71-3.80 (1H, m), 3.95 (1H, dd, J = 6.2, 8.5 Hz), 6.82 (2H, d, J =
8.5 Hz), 7.18 (2H, d, J = 8.5 Hz); 13C NMR (CDCl3, 100 MHz) # 31.2, 32.2, 33.4, 35.2, 35.8, 38.1, 51.1,
55.1, 59.5, 59.6, 70.4, 113.7, 129.4, 131.0, 158.1, 175.5, 211.1; IR (firm) 3382, 2934, 1666, 1511, 1248
cm-1; HRMS (ESI) calcd for C19H24NNaO4 352.1525 [(M+Na)+], found 352.1538.
(5S,6R,7S,10aR)-6,8-Dihydroxy-5-(4-methoxybenzyl)octahydro-3H-7,10a-methanopyrrolo[1,2-a]-
azocin-3-one (36).
Sodium triacetoxyborohydride (45.9 mg, 217 µmol) was added to a stirred solution of 4b (23.8 mg, 72.3
µmol) in MeCN (2 mL) and acetic acid (1 mL) at 0 °C. After stirring for 1 h, brine was added. The
mixture was extracted with AcOEt twice. The combined organic layer was washed with brine and dried
over anhydrous MgSO4. The solvent was removed under reduced pressure. The residual mixture was
purified by silica gel thin layer chromatography (AcOEt:MeOH=10:1) to give 36 (14.9 mg, 45.0 µmol,
22.7
1
62%) as a colorless crystal. mp 197.9 °C; [!]D 75.3 (c 0.75, MeOH); H-NMR (CDCl3, 400 MHz) #
1.02 (1H, br. d, J = 13.0 Hz), 1.57 (1H, m), 1.73-1.80 (8H, m), 2.16 (1H, dd, J = 4.1, 13.0 Hz), 2.24 (1H,
br. s), 2.36 (1H, dd, J = 9.4, 17.4 Hz), 2.51 (1H, m), 3.10 (1H, m), 3.78 (3H, s), 3.75-3.90 (1H, m),
3.86-4.00 (2H, m), 4.26 (1H, br. s), 6.84 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.5 Hz); 13C-NMR (CDCl3,
100 MHz) # 28.6, 31.2, 31.3, 31.6, 33.4, 36.6, 41.2, 44.6, 55.2, 59.9, 60.4, 60.7, 64.1, 72.0, 114.1, 129.5,
130.9, 158.3, 175.4; IR (firm) 3372, 2932, 1658, 1511, 1406, 1250 cm-1; HRMS (ESI) calcd for
C19H26NNaO4 354.1681 [(M+Na)+], found 354.1670.
(5S,6R,7R,10aR)-8-{[tert-Butyl(dimethyl)silyl]oxy}-6-hydroxy-5-(4-methoxybenzyl)octahydro-3H-
7,10a-methanopyrrolo[1,2-a]azocin-3-one (37).
Triethylamine (103 mg, 1.02 µmol) and TBS triflate (134 mg, 508 µmol) were added to a solution of 36
(112 mg, 339 µmol) in CH2Cl2 at –20 °C, which was stirred for 24 h. Aqueous NH4Cl was added. The
mixture was allowed to warm to room temperature, and was extracted with AcOEt twice. The combined
organic layer was washed with brine and dried over anhydrous MgSO4. The solvent was removed under
reduced pressure. The residual mixture was purified by silica gel thin layer chromatography
20.4
(AcOEt:n-hexane=1:2) to give 37 (96.7 mg, 216 µmol, 64%) as a colorless oil. [!]D 32.7 (c 1.02,
CHCl3); IR (firm) 2930, 1660, 1551, 1251, 1031 cm-1; 1H-NMR (CDCl3, 400 MHz) # -0.03 (3H, s), -0.02

(3H, s), 0.84 (9H, s), 1.10 (1H, d, J = 12.8 Hz), 1.51-1.70 (7H, m), 1.76 (1H, dd, J = 8.2, 11.9 Hz), 2.13
(1H, br. s), 2.18 (1H, dd, J = 4.1, 12.8 Hz), 2.33 (1H, dd, J = 9.6, 17.4 Hz), 2.49 (1H, m), 2.80 (1H, m),
3.75 (3H, s), 3.70-3.85 (1H, m), 4.13 (1H, d, J = 3.2 Hz), 4.16 (1H, br. s), 6.83 (2H, d, J = 7.6 Hz), 7.18
13
(2H, d, J = 7.6 Hz); C-NMR (CDCl3, 100 MHz): # -5.1, -4.9, 18.0, 25.7, 29.1, 31.2, 31.6, 31.7, 33.5,
37.6, 41.7, 55.1, 60.3, 60.8, 64.6, 72.8, 114.2, 129.7, 130.8, 158.4, 175.4; IR (firm) 2930, 1660, 1551,
1251, 1031 cm-1; HRMS (ESI) calcd for C25H39NNaO4Si 468.2546 [(M+Na)+], found 468.2532.
(5S,7S,10aR)-8-{[tert-Butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)tetrahydro-1H-7,10a-methano-
pyrrolo[1,2-a]azocine-3,6(2H,5H)-dione (3).
Oxalyl chloride (281 mg, 2.21 mmol) was added to a solution of DMSO (230 mg, 2.94 mmol) at –78 °C,
which was stirred for 20 min. Then a solution of 37 (98.5 mg, 221 µmol) and triethylamine (816 mg, 8.07
mmol) was added. The mixture was warmed to 0 °C and stirred for an additional 10 min before aqueous
NH4Cl was added. The mixture was allowed to warm to room temperature, and was extracted with AcOEt
twice. The combined organic layer was washed with brine and dried over anhydrous MgSO4. The solvent
was removed under reduced pressure. The residual mixture was purified by silica gel thin layer
chromatography (CH2Cl2:MeOH=10:1) to give 3 (91.6 mg, 206 µmol, 93%, 96.4% ee) as a colorless oil.
[!]D23.6 32.6 (c 0.91, CHCl3); 1H-NMR (CDCl3, 400 MHz) # 0.00 (3H, s), 0.00 (3H, s), 0.12 (1H, br. d, J =
8.5 Hz), 0.81 (9H, s), 1.27 (1H, m), 1.51 (2H, m), 1.69-1.86 (5H, m), 2.18 (1H, m), 2.24 (1H, br. s), 2.40
(1H, dd, J = 9.2, 17.4 Hz), 2.60 (1H, ddd, J = 8.2, 12.4, 17.0 Hz), 3.08 (1H, dd, J = 2.8, 13.7 Hz), 3.75
(3H, s), 3.80-3.75 (1H, m), 3.96 (1H, m), 4.52 (1H, br. s), 6.76 (2H, d, J = 8.5 Hz), 6.86 (2H, d, J = 8.5
13
Hz); C-NMR (CDCl3, 100 MHz) # -5.1, -5.1, 17.9, 25.6, 26.9, 28.9, 30.9, 31.5, 34.1, 34.1, 35.2, 51.7,
55.2, 59.4, 64.2, 68.0, 113.8, 128.7, 131.0, 158.7, 174.5, 210.1; IR (firm) 2934, 1687, 1512, 1396, 1251,
1028 cm-1; HRMS (ESI) calcd for C25H37NNaO4Si 466.2390 [(M+Na)+], found 466.2401.
(5S,6S,7R,10aR)-8-{[tert-Butyl(dimethyl)silyl]oxy}-6-hydroxy-5-(4-methoxybenzyl)octahydro-3H-
7,10a-methanopyrrolo[1,2-a]azocin-3-one (38).
Diiodomethane (0.57 mL, 7.1 mmol) was added to a suspension of Sm0 (1.28 g, 8.52 mmol) in THF(71
mL) at –78 °C. After stirring at room temperature for 16 h, a degassed mixture of MeOH (0.58 mL, 14.2
mmol), HMPA (6.2 mL, 35.5 mmol), and THF (30 mL) was added. Then key intermediate 3 (630 mg,
1.42 mmol) in degassed THF (9 mL) was added dropwise at –78 °C, and the reaction was stirred
overnight. Saturated aqueous sodium bicarbonate was added at room temperature, and the mixture was
extracted with AcOEt (three times). The combined organic layer was washed with brine, and then dried
over MgSO4. The solvent was removed under reduced pressure. The resulting residue was purified by
silica gel chromatography (AcOEt:n-hexane=4:1-1:1) to afford crude alcohol 38 (553 mg) containing
inseparable HMPA, which was used in the next reaction without further purification.
(5S,6S,7S,10aR)-6,8-bis{[tert-Butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)octahydro-3H-7,10a-

methanopyrrolo[1,2-a]azocin-3-one (39).
2,6-Lutidine (0.4 mL, 3.7 mmol) followed by TBSOTf (0.6 mL, 2.5 mmol) were added to a stirred
solution of the crude product of 38 (554 mg, 1.2 mmol) in CH2Cl2 (10 mL) at room temperature. After
stirring at room temperature for 5 h, saturated aqueous ammonium chloride was added and the mixture
was extracted with CH2Cl2 (three times). The combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure. The resulting residue was purified by silica gel chromatography
(AcOEt:n-hexane=5:95) to afford pure product 39 (360 mg, 0.664 mmol, 54% for 2 steps) as a pale
22.0
1
yellow oil. [!]D 18.3 (c 1.03, CHCl3); H-NMR (CDCl3, 500 MHz) # 0.00 (3H, s), 0.01 (3H, s), 0.02
(1H, s), 0.02 (1H, s), 0.87 (9H, s), 0.92 (9H, s), 1.59-1.83 (7H, m), 1.86-1.94 (1H, m), 2.28-2.42 (2H, m),
3.11 (1H, dd, J = 7.9, 14.7 Hz), 3.62-3.65 (1H, m), 3.75-3.78 (1H, m), 3.79 (3H, s), 3.85 (1H, dd, J = 5.1,
13
14.2 Hz), 4.04-4.09 (1H, m), 6.82 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz); C-NMR (CDCl3, 68
MHz): # –4.9, –4.8, –4.7, –4.1, 18.0, 18.3, 25.7, 26.0, 27.3, 29.5, 31.1, 32.1, 33.7, 34.0, 45.4, 55.2, 58.6,
60.6, 67.5, 69.4, 113.6, 130.2, 132.6, 157.7, 176.1; IR (firm) 2953, 2930, 2857, 1693, 1513, 1250, 1077,
1053 cm-1; HRMS (FAB) calcd for C31H53NO4Si2 559.3513 (M+), found 559.3528.
(5S,6S,7S,10aS)-6,8-bis{[tert-Butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)-3-oxooctahydro-1H-
7,10a-methanopyrrolo[1,2-a]azocine-2-carboxylic acid (40).
n-BuLi (2.0 M in hexane)(4.8 mL, 12.9 mmol) was added to a solution of diisopropylamine (2.3 mL, 16.1
mmol) in THF (15 mL) at –78 °C. The resulting solution was stirred at 0 °C for 20 min before cooling to
–78 °C. Then a solution of 39 (600 mg, 1.07 mmol) in THF (5 mL) was added dropwise. After stirring
for 1 h at –78 °C, crushed dry-ice blocks were added until dry-ice solids were observed. After stirring at
–78 °C for 20 min, saturated aqueous ammonium chloride was added, and the mixture was extracted with
AcOEt (six times). The combined organic layer was dried over Na2SO4. The solvent was removed under
reduced pressure. The resulting residue was washed with hexane and filtered over a pad of Celite. The
filtrate was concentrated under reduced pressure to give the crude product of 40 (672 mg), which was
used in the next reaction without further purification.
(2Z,5S,6S,7S,10aS)-6,8-Bis{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxyimino)-5-(4-methoxybenzyl)-
octahydro-3H-7,10a-methanopyrrolo[1,2-a]azocin-3-one (41).
NaNO2 (1.2 g, 17.0 mmol) was added to a stirred solution of the crude product of 40 (100 mg) and
tetra-n-butylammonium bromide in 5:1 Et2O:H2O (2.4 mL) at 0 °C, and then conc. HCl (0.25 mL, 3.00
mmol) was added cautiously in four portions over 9 h. Saturated aqueous ammonium chloride was added.
The mixture was stirred for an additional 1 h before extracting with AcOEt (four times). The combined
organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The resulting
residue was purified by silica gel chromatography (AcOEt:n-hexane=7:1 to 4:1) to afford pure oxime 41
(64 mg, 115 µmol, 66% for 2 steps) as a pale orange solid. [!]D24.0 16.8 (c 1.00, CHCl3); 1H-NMR (CDCl3,

400 MHz) # 0.01-0.04 (12H, m), 0.86 (9H, s), 0.92 (9H, s), 1.60-2.08 (7H, m), 2.56 (2H, q, J = 18.0 Hz),
3.12 (1H, dd, J = 9.2, 15.6 Hz), 3.65 (1H, s), 3.78 (3H, s), 4.11-4.18 (2H, m), 6.82 (2H, d, J = 8.2 Hz),
7.20 (2H, d, J = 8.2 Hz), 9.42 (1H, br. s) 13C-NMR (CDCl3, 100 MHz): # –5.0, –4.9, –4.8, –4.1, 18.0, 18.3,
25.7, 26.0, 28.8, 30.2, 32.7, 33.5, 37.1, 45.2, 55.2, 57.9, 60.1, 66.7, 68.9, 113.7, 130.0, 131.9, 152.8, 157.8,
163.9; IR (firm) 3269, 2953, 2930, 2857, 1708, 1660, 1513, 1251 cm–1 ; HRMS (FAB) calcd for
C31H52N2O5Si2 588.3415 (M+), found 588.3410.
(2S,5S,6S,7S,10aS)-2-Amino-6,8-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)octahydro-
3H-7,10a-methanopyrrolo[1,2-a]azocin-3-one (42).
Activated zinc dust (1.30 g, 19.4 mmol) and NH4Cl (520 mg, 9.7 mmol) were added to a stirred solution
of oxime 41 (285 mg, 0.510 mmol) in AcOH (12 mL) at room temperature. After stirring at 50 °C
overnight, the mixture was filtered over a pad of Celite, and the filtrate was concentrated under reduced
pressure. To the resulting residue, saturated aqueous sodium bicarbonate was added, and the mixture was
extracted with CH2Cl2 (three times). The combined organic layer was dried over Na2SO4. The solvent was
removed under reduced pressure to give the crude product of 42 (297 mg), which was used in the next
reaction without further purification. 1H-NMR (CDCl3, 400 MHz) # –0.02-0.06 (12H, m), 0.85 (9H, s),
0.93 (9H, s), 1.61-2.07 (10H, m), 2.21 (1H, m), 3.13 (1H, dd, J = 7.3, 14.6 Hz), 3.46 (1H, dd, J = 8.7,
10.5 Hz), 3.51 (1H, s), 3.70 (1H, br), 3.79 (3H, s), 3.87 (1H, t, J = 6.9 Hz), 3.98 (2H, dd, J = 6.4, 14.7 Hz),
6.83 (2H, d, J = 8.2 Hz), 7.19 (2H, d, J = 8.2 Hz); 13C-NMR (CDCl3, 100 MHz) # –5.0, –4.9, –4.8, –4.0,
18.0, 18.1, 25.7, 25.8, 26.4, 30.2, 32.6, 33.5, 42.7, 45.4, 52.6, 55.2, 57.2, 59.3, 67.2, 69.5, 113.7, 129.7,
132.4, 157.8, 176.7.
N-[(2S,5S,6S,7S,10aS)-6,8-Bis{[tert-butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)-3-oxooctahydro-
1H-7,10a-methanopyrrolo[1,2-a]azocin-2-yl]formamide (45).
A mixture (3.8 mL) of HCOOH (6.0 mL, 157 mmol) and Ac2O (3.8 mL, 40 mmol) were added to a
stirred solution of amine 42 (297 mg) in CH2Cl2 (15 mL) at 0 °C dropwise, and the solution was stirred
for 10 min at 0 °C. Then the reaction mixture was warmed to room temperature, and a small amount of
toluene was added. The solvent was removed under reduced pressure to give the crude product of 45 (323
mg). This unstable product was used immediately in the next reaction without further purification.
(2S,5S,6S,7R,10aS)-8-{[tert-Butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)-2-(methylamino)octa-
hydro-1H-7,10a-methanopyrrolo[1,2-a]azocin-6-ol (46).
Lithium aluminum hydride (405 mg, 11 mmol) was added to a stirred solution of the crude product of 45
(323 mg) in THF (15 mL) at 0 °C. After stirring at 50 °C for 16 h, water (0.4 mL), 15% aqueous sodium
hydroxide (0.4 mL), water (1.2 mL), and a sufficient amount of Et2O were added successively at room
temperature. After stirring for 30 min, the mixture was filtered over a pad of Celite. The filtrate was
concentrated under reduced pressure to give crude methylamine 46 (259 mg). This polar product was

used in the next reaction without further purification.
Benzyl [(2S,5S,6S,7R,10aS)-8-{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-5-(4-methoxybenzyl)octa-
hydro-1H-7,10a-methanopyrrolo[1,2-a]azocin-2-yl]methylcarbamate (47).
Na2CO3 (488 mg, 4.6 mmol) followed by CbzCl (0.32 mL, 2.3 mmol) were added to a stirred solution of
crude methylamine 46 (259 mg) in 3:1 CH2Cl2:H2O (16 mL) at room temperature. After stirring for 3 h,
saturated aqueous ammonium chloride was added, and the mixture was extracted with CH2Cl2. The
combined organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The
resulting residue was purified by silica gel chromatography (AcOEt:n-hexane=1:9 to 1:1) to afford pure
24.0
alcohol 47 (174 mg, 0.293 mmol, 61% for 4 steps) as a pale yellow oil. [!]D 7.65 (c 1.00, CHCl3);
1H-NMR (CDCl3, 500 MHz): # -0.02 (3H, s), -0.01 (3H, s), 0.86 (9H, s), 1.47 (1H, dd, J = 6.2, 13.6 Hz),
1.52 – 2.12 (9H, m), 2.71 – 2.89 (6H, m), 3.19 – 3.29 (1H, m), 3.35 – 3.57 (2H, m), 3.72 (1H, br. s), 3.79
(3H, s), 4.83 (1H, br. s), 5.12 (2H, s), 6.84 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.28 - 7.39 (5H,
13
m,); C-NMR (CDCl3, 68 MHz): # -4.8, -4.7, 18.1, 25.9, 29.1, 29.8, 31.1, 35.9, 42.9, 45.9, 50.1, 52.1,
55.3, 59.0, 59.3, 67.2, 67.4, 67.7, 113.9, 128.0, 128.0, 128.6, 130.3, 131.0, 137.0, 156.5, 158.0; IR (firm)
3448, 2952, 2931, 1698, 1512, 1329, 1249, 1161, 1041 cm–1; HRMS (FAB) calcd for C34H51N2O5Si
595.3562 [(M+H)+], found 595.3531.
Benzyl [(2S,5S,6S,7S,10aS)-6,8-dihydroxy-5-(4-methoxybenzyl)octahydro-1H-7,10a-methano-
pyrrolo[1,2-a]azocin-2-yl]methylcarbamate (48).
Aqueous HF (48%, 1.6 mL) was added to a stirred solution of alcohol 47 (174 mg, 0.293 mmol) in MeCN
(9 mL) at 0 °C. After stirring at 0 °C for 5 h, the reaction mixture was diluted with CH2Cl2 and saturated
aqueous sodium bicarbonate was added. The mixture was extracted with CHCl3 (six times), and the
combined organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give
the crude product of 48 (150 mg), which was used in the next reaction without further purification.
Benzyl[(2S,5S,6S,7R,10aS)-8-{[bis(benzyloxy)phosphoryl]oxy}-6-hydroxy-5-(4-methoxybenzyl)octa-
hydro-1H-7,10a-methanopyrrolo[1,2-a]azocin-2-yl]methylcarbamate (49).
1-H-tetrazole (21 mg, 0.30 mmol) was added to a stirred solution of diol 48 (50 mg) in CH2Cl2 (4 mL) at
0 °C, and the mixture was stirred for 20 min. Then dibenzyl(N,N-diisopropyl)phosphoramidite (90%)(ca.
58 µL, 0.20 mmol) was added slowly until the starting material was no longer detected by TLC analysis.
Then the reaction mixture was cooled to –78 °C, and TBHP (5.5 M in decane) (40 µL) was added. Prior
to the addition of saturated aqueous Na2SO3, the mixture was stirred for 1 h at –78 °C. Then the mixture
was extracted with CH2Cl2, and the combined organic layer was dried over Na2SO4. The solvent was
removed under reduced pressure. The resulting residue was purified by silica gel chromatography
(AcOEt:n-hexane=2:3 to 5:1) and silica gel thin layer chromatography (AcOEt:n-hexane=3:1) to afford
23.0
pure dibenzyl phosphate 49 (25 mg, 34 µmol, 35% for 2 steps) as a colorless oil. [!]D 6.69 (c 1.70,

CHCl3); IR (firm) 3408, 2935, 1695, 1512, 1454, 1248, 1009 cm–1; 1H-NMR (CD3OD, 500 MHz) # 1.22 –
1.52 (2H, m), 1.61 - 2.11 (6H, m), 2.26 (1H, br. s), 2.70 (3H, s), 2.75 – 2.98 (3H, m), 3.26 (1H, br. s),
3.38 (1H, br. s), 3.54 – 3.72 (1H, m), 3.74 (3H, s), 4.31 (1H, br. s), 4.72 (1H, br. s), 4.96 – 5.04 (4H, m),
5.08 (2H, s), 6.84 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.27 - 7.40 (m, 15H); 13C-NMR (CD3OD,
68 MHz) # 23.0, 29.3, 29.6, 31.3, 36.3, 44.1, 44.8, 51.7, 53.4, 55.7, 59.5, 68.0, 68.3, 70.8 (d, J = 6.0 Hz),
77.1, 114.7, 128.8, 129.1, 129.2, 129.6, 129.8, 131.2, 132.4, 137.2 (d, J = 6.0 Hz), 137.2 (d, J = 6.0 Hz),
138.2, 158.0, 159.6; HRMS (FAB) calcd for C42H50N2O8P 741.3299 [(M+H)+] found 741.3298.
(–)-FR901483 (1).
Aqueous 1 N HCl (18 µL) was added to a solution of dibenzyl phosphate 49 (34 mg, 46 µmol) in MeOH
(3 mL), and the solvent was removed under reduced pressure giving 1·HCl. Pd/C (5%, wet) (30 mg) and
MeOH (4 mL) were added. The mixture was stirred at room temperature under 1 atm of hydrogen gas for
6 h and filtered. The residue was washed with MeOH. The combined filtrate was concentrated under
23.0
reduced pressure to give FR901483 (1) (15 mg, 35.2 mmol, 77%) as a white solid. [!]D -10.3 (c 0.68,
CHCl3); 1H-NMR (CD3OD, 500 MHz) # 1.84 - 1.92 (1H, m), 2.01 - 2.28 (6H, m), 2.43 (1H, br. s), 2.51 -
2.59 (1H, m), 2.68 (3H, s), 2.97 - 3.06 (1H, m), 3.21 - 3.28 (1H, m), 3.57 (1H, br. s), 3.73 - 3.84 (2H, m),
3.78 (3H, s), 4.09 - 4.24 (2H, m), 4.42 (1H, dd, J = 9.7, 13.2 Hz), 6.88 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J
13
= 8.0 Hz); C-NMR (CD3OD, 68 MHz) # 22.5, 28.1, 28.5, 32.3, 34.1, 42.0, 43.0, 51.8, 55.0, 55.7, 61.5,
64.3, 67.8, 70.6 (d, J = 6.0 Hz), 115.2, 128.9, 131.7, 160.3; IR (firm) 3336, 2933, 1612, 1514, 1458, 1248,
1180, 1009 cm–1; HRMS (FAB) calculated for C20H32N2O6P 427.1992 [(M+H)+] found 427.1996.
ACKNOWLEDGEMENTS
The authors thank Mr. Koji Nagao (Astellas Pharma Inc.) for the sample of natural product 1. This work
was financially supported by CREST, JST, and a Grant-in-Aid from the Ministry of Education, Science,
Sports, Culture and Technology of Japan.
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and 3b were equatorially oriented and syn to the carbonyl groups.
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19. For a similar regioselective phosphitylation, see ref 4a.
20. Eluted with 1% EtOH-n-hexane at flow rate of 1.0 mL/min on Daicel Chemical Ind., Ltd.
CHIRALCEL OJ column (0.46 cm ! 25 cm). Retention time: (–)- = 9.7 min, (+)- = 10.5 min.