Stereodivergent approach to both c2,8a-syn and c2,8a-anti relative stereochemical manifolds in the lepadin family via a ticl4-promoted aza-[3+3] annulation

Article abstract of DOI:10.1055/s-0029-1216920

Details in developing a stereodivergent approach to the lepadin family and establishing an entry to both C2,8a-syn and C2,8a-anti relative stereochemical manifolds through a common intermediate are described here. This works paves the foundation for const

Full text of DOI:10.1055/s-0029-1216920

PAPER
2905
Stereodivergent Approach to Both C2,8a-syn and C2,8a-anti Relative
Stereochemical Manifolds in the Lepadin Family via a TiCl4-Promoted
Aza-[3+3] Annulation
T
iCl -PromotedA
a
za-[3+3]
A
nnulation g Li, Lauren J. Carlson, Irina K. Sagamanova, Brian W. Slafer, Richard P. Hsung,* Claudio Gilardi,
4
Heather M. Sklenicka, Nadiya Sydorenko
Division of Pharmaceutical Sciences and Department of Chemistry, Wisconsin Center for Natural Products Research, School of Pharmacy,
Rennebohm Hall, University of Wisconsin, Madison, WI 53705, USA
Fax +1(608)2625345; E-mail: rhsung@wisc.edu
Received 23 May 2009
Consequently, the unique feature of being a small stereo-
Abstract: Details in developing a stereodivergent approach to the
chemically diversified library has attracted many synthet-
lepadin family and establishing an entry to both C2,8a-syn and
ic efforts.9–15 These stereochemical relationships could be
categorized into three subsets as shown in Scheme 2.
C2,8a-anti relative stereochemical manifolds through a common in-
termediate are described here. This works paves the foundation for
constructing all members of the lepadin family, which consists of While the most challenging aspect would be the 1,3-ste-
three subsets based on an array of interesting relative configura-
tions. These efforts underline the prominence of aza-[3+3] annula-
tion as a unified strategy in alkaloid synthesis.
reochemical relationship at C2 and C8a, which can be syn
as in A–E, and H, and anti as in F and G, we envisioned
that all three subsets could be accessed from the aza-
Key words: titanium(IV) chloride, aza-[3+3] annulation, vinylo-
[3+3]-annulation product 1 in a stereodivergent manner.
gous amides, iminium ions, alkaloid synthesis, lepadin alkaloids,
We report here our efforts in developing a stereodivergent
approach to the lepadin family with the focus on the
stereodivergent approach, episulfide contraction
C2,8a-syn and C2,8a-anti relative stereochemical mani-
folds.
We1–3 have been embarking on the chemistry of an aza-
The unique advantage of developing a stereodivergent ap-
[3+3]-annulation strategy4 involving vinylogous amides
proach to the lepadin family featuring the aza-[3+3] annu-
and vinyliminium ions5 for the past decade (Scheme 1).
lation product 1 can be seen in Scheme 3. That is, the
This unique aza-annulation has come to represent a uni-
annulation product 1 could be assembled rapidly from
commercially available chiral amino alcohol 2 and cyclo-
hexane-1,3-dione in just three steps. Under standard con-
ditions, the annulation product 1 was attained in 73%
yield with a diastereomeric ratio of 96:4. While the imin-
ium ion chemistry has served us well, operationally it has
not always been trivial.
fied strategy amenable for de novo syntheses of many al-
kaloids.6,7 To ascertain this annulation as a unified
strategy to alkaloids, and to establish this imminent con-
cept, the lepadin family attracted out attention.
The lepadin family (Scheme 2), isolated from various
sources such as tunicate Clavelina lepadinformis,8a flat-
worm Prostheceraeus villatus,8b tropical marine tunicate
During this exercise, we found that the annulation could
also be carried out using 1.0 equivalents of titanium(IV)
chloride as a promoter at room temperature to give 1 and
2-epi-1 in 80% yield as a 51:49 isomeric mixture. This
Didemnum sp,8c and Australian great barrier reef ascidian,
Aplidium tabascum.8d is comprised of eight cis-decahyd-
roquinoline members and possesses a range of biological
activities such as cytotoxicity, antiplasmodial, anti-trypa-
isomeric mixture, however, could be thermally equilibrat-
nosomal properties, and antimalarial properties.8 While
ed all to 1 through a sequence of pericyclic aza-ring
all contain a cis-1-azadecalin, stereochemically, members
opening and ring closure.2a While most other Lewis
of the lepadin family display a highly diversified array of
acids [i.e., BF3·OEt2. SnCl4. AlCl3. TMSOTf. Cu(OTf)2.
relative configurations at C2, C3, C4a, C5, and C8a.
iminium ions
aza-[3+3]
O
O
6π-electron
O
X
NR2
aza-ring-closure
Knoevenagel
R2
R2
N
H
N
R1
N
R1
R2
R1
R
R
R
vinylogous amides
Scheme 1 An aza-[3+3]-annulation strategy
SYNTHESIS 2009, No. 17, pp 2905–2914
x
x.
x
x
.
2
0
0
9
Advanced online publication: 30.07.2009
DOI: 10.1055/s-0029-1216920; Art ID: C01709SS
© Georg Thieme Verlag Stuttgart · New York

2906
G. Li et al.
PAPER
O
7'
all are
HO
cis-1-aza-decalin
5'
OH
OH
H
H
H
H
H
H
O
OH
O
OH
3
2
5
4a
8a
O
O
N
N
H
N
N
H
H
H
H
H
(–)-lepadin A
(–)-lepadin B
(–)-lepadin C
(+)-lepadin D [Ma13
]
OH
OH
OH
OH
5"
5"
5'
5'
5'
5'
4"
O
O
O
O
H
H
H
H
H
H
O
O
O
O
N
H
N
N
N
H
H
H
H
H
(–)-lepadin E [Ma13
]
(+)-lepadin F
(+)-lepadin G
(+)-lepadin H [Ma13
]
stereo aza-[3+3]
R2
H
R2
R2
O
H
H
OR1
OR1
OR1
via a
common
intermediate
3
2
3
5
5
4a
4a
8a
S
2
N
H
N
N
N
H
H
H
H
H
Ph
R
S
Ph
lepadins A–C
C2,3-cis
F and ent-G
C2,3-cis
C4a,5-cis
C2,8a-anti
D, E, and H
C2,3-trans
C4a,5-cis
OTBS
C4a,5-trans
C2,8a-syn
1: via aza-[3+3]
annulation
C2,8a-syn
Scheme 2 A stereodivergent approach to the lepadin family
MgBr2·OEt2. ZnCl2] were not successful, the titanium(IV) lieve that this set of stereochemical manifolds could be at-
chloride protocol (0.5 equiv used) proved to be general in tained through manipulations of the N-substituent.
synthesizing other aza-annulation products 4–7, thereby Specifically, when 12-NH was used, the C2-Pr group dic-
rendering the aza-[3+3] annulation operatively simpler.
tated the facial bias, and the hydrogenation led to the
C2,8a-syn [see 13-syn] stereochemical outcome. On the
other hand, 12-N-acyl afforded 13-anti because the
N-acyl substituent preferred to be axial and anti to C2-Pr
to alleviate allylic-type strain, thereby shielding the top
p-face of the olefin.2a
The annulation product 1 sets the stage for constructing
the key 1-azadecalenone 11. As shown in Scheme 4, the
sequence involved essentially a hydration equivalent at
the C3–4 olefin via dihydroxylation16,17 followed by re-
ductive removal of the C4-OH group in the resulting diol
8 using either triethylsilane18 or alternatively hydrogen as With this initial success, we proceeded to construct a se-
the reductant. This synthetic sequence solidifies an access ries of N-acylated substrates that can be suitable for set-
to the C2,3-trans relative stereochemistry. Protection of ting the C2,8a-anti stereochemical manifold. These N-
the C3-OH group in 9 followed by removal of the chiral acylated substrates could be prepared starting either from
auxiliary in alcohol 10 via hydrogenolysis gave 1-aza- 9 or 11 as shown in Scheme 7. Reductive removal of the
decalenone 11.
chiral auxiliary in 9 via hydrogenolysis gave alcohol 17.
While silylation of 17 would lead to silyl ether 18 that
matches Ma’s mid-stage intermediate in their efforts to-
ward the lepadin family,13 a double acylation would lead
to N-acylated acetate 19, which could also be obtained
from N-acylating 11. Acylation of silyl ether 18 using tri-
fluoroacetic anhydride afforded trifluoroacetamide 20,
and finally, acylation using acetic anhydride followed by
desilylation gave N-acylated alcohol 21.
The significance of 1-azadecalenone 11 is revealed in
Scheme 5. While the original stereodivergent plan19
would include: (1) inversion of C3-OH to install the C2,3-
cis stereochemistry in lepadin A–C, F, and G, and (2) ho-
mologation of C5-ketone, the most challenging endeavor
would be to identify an appropriate reduction of the C4a–
8a olefin in 11 that would give either C2,8a-syn or C2,8a-
anti relative stereochemistry. However, from our earlier
work related to pumiliotoxins,2a we have reasons to be-
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

PAPER
TiCl4-Promoted Aza-[3+3] Annulation
2907
O
piperidine (1.0 equiv)
Ac2O (1.0 equiv)
NH2
S
1) TBSCl, imidazole, MeCN
O
Ph
R
Ph
O
EtOAc–toluene (2:3)
2)
in PhH with
Dean–Stark
HO
NH
S
H
Ph
R
O
Ph
2
91% yield overall
3
OTBS
X
O
O
O
NR2
EtOAc–toluene (2:3)
150 °C, 36 h
150 °C
2
NH
N
N
61% yield
73% yield
Ph
R
Ph
R
Ph
R
S
dr = 91:9 to 96:4
dr = 96:4
S
S
Ph
Ph
Ph
OTBS
OTBS
OTBS
aza-[3+3] via
iminium ion
1 and 2-epi-1
1
dr = 51:49
TiCl4 (1.0 equiv)
4 Å MS, CH2Cl2
80%
yield
r.t., 24 h
O
O
O
O
O
TiCl4
(0.5 equiv)
R2
N
N
NH
N
R
R1
Bn
Bn
R*
Bn
4: R = Me: 82%
5: R = n-Pr: 70%
aza-[3+3]
6: 37% yield
7: 84% yield
via Lewis acid
Scheme 3 A de novo titanium(IV) chloride promoted aza-[3+3] annulation
11. Intriguingly, the C5-ketone in 11 was also reduced un-
der these conditions, and this was true even when not us-
ing Adam’s catalyst and when the hydrogen pressure is
<68.95 bar. Nevertheless, N-protection followed by
Dess–Martin periodinane oxidation led to 1-azadecalone
16 that should be suitable for lepadins D, E, and H, and for
A–C after inverting the C3 stereogenic center.
O
O
OH
4
OH
OsO4 (1.0 equiv)
3
4
pyridine, CH2Cl2, r.t., 24 h
N
N
then
mannitol, 10% KOH, r.t., 48 h
Ph
Ph
Ph
Ph
OTBS
OTBS
8: 60–75%
1
O
However, we encountered an immense number of prob-
lems in hydrogenations of the C4a–8a olefin in N-acylated
substrates 19–21 (Scheme 8). After employing a variety
of conditions, we were unable to isolate any of the desired
respective products 22–24. Instead, the major products
that we were able to identify appeared to have the C5-
ketone partially or completely reduced with the C4a–8a
olefin being mostly untouched (see 25–27). We were sur-
prised by this outcome because the only difference be-
tween compounds 19–21 and 12-N-acyl (see Scheme 5) is
the additional oxygen substituent at C3. Given that N-acy-
lated alcohol 21 with an unprotected C3-OH also failed,
we believed that the cause is likely not the nature of the
C3-OH protecting groups but its own stereochemical ori-
entation. We proceeded to invert the C3-OH group, but
only to find that that neither 9 nor 21 would undergo the
Mitsunobu inversion employing standard conditions.
OAc
3
Et3SiH (excess)
OR: H2
5
TFA (10–12 equiv) Pd(OH)2/C
2
N
CH2Cl2, –20 °C
48–72 h
MeOH, TFA
r.t., 20 h
64%
H
11: 95%
70–80%
4.14 bar H2
Pd(OH)2/C, TFA (1.1 equiv), MeOH
O
O
4
OH
OAc
3
3
Ac2O, Et3N, DMAP, CH2Cl2
2
N
N
0 °C to r.t., 48 h
Ph
Ph
Ph
Ph
OTBS
OTBS
10: 91%
9: C2,3-trans
Scheme 4 Hydration of C3–4 olefin and the auxiliary removal
Based on the above analysis, we were able to quickly es-
tablish the C2,8a-syn pathway via the concise sequence
shown in Scheme 6. The C2,8a-syn relative stereochemis-
try was confirmed via NOE experiments (see the box in
Scheme 6) using alcohol 14, which was attained from the
hydrogenation of the C4a–8a olefin in 1-azadecalenone
We then examined an alternative route for inverting the
C3 stereocenter. As shown in Scheme 9, ketone 28 could
be directly prepared from diol 8 under acidic conditions.
However, with the chiral auxiliary intact, sodium borohy-
dride reduction of ketone 28 gave alcohol 9 as an epimeric
mixture at C3 that still favored b-C3-OH. Fortuitously,
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

2908
G. Li et al.
PAPER
homologation: [C4a,5-cis or trans]
C3-inversion
[for A-C, F,
and ent-G]
R2
H
3
R2
R2
H
H
H
OR1
OR1
OR1
3
2
5
O
5
4a
4a
8a
3
4a
8a
OAc
5
2
N
N
N
H
H
H
H
H
2
N
H
lepadins A–C
C2,3-cis
D, E, and H
C2,3-trans
C4a,5-cis
F and ent-G
C2,3-cis
C4a,5-cis
C2,8a-anti
11
C4a,5-trans
C2,8a-syn
C4a,8a-cis reduction
[C2,8a-syn or anti]
C2,8a-syn
H-H
C2,8a-syn path
O
R
O
O
H
O
O
H
8a
2
N
H
H
2
H
8a
H
N
N
H
ROC
N
2
2
H
H
H
H-H
12-N-acyl
C2,8a-anti path
13-syn
12-NH
13-anti
Scheme 5 Original designs for the stereodivergent approach
O
HO
H
OAc
PtO2, 68.95 bar, H2, AcOH–TFA (1:1)
OAc
4a
8a
5
4a
8a
2
2
N
N
14: NOE
H
H
H
H
11
14: dr at C5 = 1:1
H
O
N
Ac
Me
(Boc)2O
H
H
K2CO3
HO
anhyd MeCN
useful For
lepadins
O
HO
H
Dess–Martin
H
OAc
OAc
3
2
periodinane [O]
D, E, and H;
also for
4a
8a
8a
58%
2
N
N
A–C with
H
Boc
H Boc
inverted C3
16: C2,8a-syn
15: 35% overall
Scheme 6 A stereoselective pathway to C2,8a-syn stereochemistry
O
Ma's Intermediate
O
O
OH
Pd(OH)2/C
TBSOTf
OH
OTBS
H2 (0.7–1 bar)
2,6-lutidine
N
TFA (1.1 equiv)
in MeOH
MeCN, r.t.
N
N
H
Ph
H
Ph
9
OTBS
17: 90% yield
18: 95%
TFAA, Et3N
Ac2O, Et3N
DMAP
Ac2O, and
50%
DMAP
1 M HCl
CH2Cl2
CH2Cl2
and TBAF
O
O
O
O
OH
OTBS
OAc
OAc
Ac2O
50%
N
N
N
H
N
Ac
TFA
Ac
11
19
21: 40% overall
20: 95%
Scheme 7 Precursors for setting C2,8a-anti stereochemistry
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

PAPER
TiCl4-Promoted Aza-[3+3] Annulation
2909
O
O
H
H
4a
8a
OAc
OAc
OAc
3
5
5
8a
2
N
N
N
Ac
Ac
Ac
22: C2,8a-anti
19
25
O
O
R
H
variable
yields
4a
8a
OTBS
3
OTBS
OTBS
5
5
8a
2
N
N
N
H
TFA
TFA
TFA
23: C2,8a-anti
20
26a,b: R = OH or H
O
O
H
4a
8a
OH
OH
OH
3
5
5
8a
N
N
N
2
H
Ac
Ac
Ac
24: C2,8a-anti
21
27
Scheme 8 Failed attempts in installing C2,8a-anti stereochemistry. Reagents and conditions: Examples attempted, H2 (1 bar, 4.14 bar, or
68.95 bar), r.t., catalyst: Pd/C, Pd(OH)2/C, or PtO2, solvent: EtOH, MeOH or AcOH–TFA, additive: Na2CO3.
sodium borohydride reduction of ketone 29, attained from These difficulties led us to the realization that we needed
Dess–Martin periodinane oxidation of N-acylated alcohol to revise our original plan. As shown in Scheme 10, we
21, afforded alcohol 30 in a good overall yield with com- contemplated the possibility of first pursing the homolo-
plete inversion at C3, thereby establishing a useful entry gation of the C5 carbonyl at an early stage using interme-
for inverting the C3 stereochemistry.
diates such as 33, and subsequently, deploy the
homologated intermediate 34 as the key stereodivergent
point. In this case, while the hydrogenation of 34-NH
(X = H) could again lead to the C2,8a-syn manifold, with
the chiral auxiliary still intact as in 34-N-Aux, we may
achieve the C2,8a-anti manifold because the conforma-
tion analysis reveals that one of the two phenyl rings on
the auxiliary is actually shielding the top p-face of the
C4a–8a olefin. This new design allows us to take advan-
tage of the chiral auxiliary for a threefold purpose instead
of just one. It is now useful not just for controlling the ste-
reochemical outcome of the key aza-[3+3] annulation at
This inversion provides a clear entry to the C2,3-cis rela-
tive configuration. Therefore, given our ability to access
the C2,8a-syn stereochemical manifold (see Scheme 6),
alcohol 30 represents a suitable starting point for synthe-
sizing lepadins A–C via possible intermediates such as 31
(Scheme 9). On the other hand, we remain unsuccessful in
hydrogenating the C4a–8a olefin in 30 to achieve the de-
sired C2,8a-anti manifold (see 32) after employing a
range of conditions including 5–15 mol% Crabtree’s
catalyst20 in an attempt to carry out a Stork–Crabtree di-
rected hydrogenation,21 having been inspired by a related
example reported by Padwa.22
O
OH
O
O
β:α = 82:12
OH
3
O
3
OH
3
cat. TsOH
NaBH4
MeOH
PhH, 80 °C
N
N
N
20 min
–40 °C
Ph
O
Ph
O
Ph
O
Ph
Ph
Ph
OTBS
OTBS
OTBS
8: 60–75%
28: 90%
9: 60%
NaBH4
MeOH
3
OH
3
O
3
OH
DMP [O]
CH2Cl2, r.t.
–40 °C
N
N
N
Ac
Ac
Ac
21
29: 76%
30: 76%
O
O
O
H
H
4a
3
2
OTBS
3
2
OH
OH
useful
for
8a
[H]
lepadins
A–C
2
8a
N
N
N
H
Ac
H
Ac
H
31: C2,8a-syn
30
32: C2,8a-anti
Scheme 9 A useful protocol for inverting the C3 stereochemistry
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

2910
G. Li et al.
PAPER
R2
R2
R2
X = H or Aux
H
H
H
H
R
OR1
OR1
3
OR1
3
2
5
5
4a
4a
OP
8a
5
2
N
N
N
H
H
H
H
H
8a
2
N
X
lepadins A–C
C2,3-cis
F and ent-G
C2,3-cis
C4a,5-cis
C2,8a-anti
D, E, and H
C2,3-trans
C4a,5-cis
34
C4a,5-trans
C2,8a-syn
C4a,8a-cis reduction
[C2,8a-syn or anti]
C2,8a-syn
C2,8a-anti path
homologation first
P = protecting group
C2,8a-syn path
SiMe2t-Bu
O
OP
H
O
R
OP
2
5
N
OP
R
Me
N
X
H
H
N
2
34-N-Aux
H
X = H or Aux
33
versus
Me
34-NH
Scheme 10 New designs for the stereodivergent approach
C2, but also, that of the reduction at C4a and C8a and the control at C4a, C8a, and C5 as predicted, thereby setting
side chain stereochemistry at C5.
the C2,8a-syn relative manifold that was concisely as-
signed by NOE (Figure 1).
The execution of this new plan is detailed in Scheme 11.
Vinylogous amide 18 was homologated23 employing Most critically, while 36 can be useful for constructing le-
Eschenmoser’s episulfide contraction method,24,25 while padins A–E and H, methyl dienoic ester 37 was also pre-
standard Wittig olefination was not successful.26 It is pared through homologation of vinylogous amide 10
noteworthy that homologations of vinylogous amides via (Scheme 11). The ensuing hydrogenation gave methyl es-
Eschenmoser’s episulfide contraction is much less com- ter 38 in 91% yield using Adam’s catalyst with complete
mon than using amides or lactams. The ensuing hydroge- stereochemical control at C4a and C8a (at C5 7:1 ratio fa-
nation of ethyl dienoic ester 35 afforded ethyl ester 36. voring 38). This successful sequence finally afforded the
Although only in modest yield, excellent stereochemical much anticipated C2,8a-anti manifold, thereby complet-
O
O
O
1'
EtO
EtO
OTBS
H
5
d
5
a–c
4a
OTBS
OTBS
5
4a
44%
40%
8a
N
H
8a
2
overall
N
N
H
H
H
18
35
36: C2,8a-syn
[H] and TBSOTf
O
O
for A–E/H
alcohol 9:
aza-[3+3]
3 steps
the common
intermediate
R2
F/ent-G
NH
R1
Aux
O
O
Ac2O
OAc
O
1'
MeO
MeO
H
5
5
4a
8a
OAc
OAc
a–c
e
5
4a
8a
N
91%
64%
2
N
N
Ph
H
overall
Ph
Ph
Ph
Ph
Ph
OTBS
OTBS
38: C2,8a-anti
OTBS
37
10
Scheme 11 Execution of the new stereodivergent plan. Reagents and conditions: (a) Lawesson reagent, THF, r.t., 1 h; (b) BrCH2CO2R (R =
Me or Et), K2CO3, THF or acetone; (c) Ph3P (2.0 equiv), Et3N or DIPEA, MeCN, reflux, 3 h; (d) Pt/C, AcOH, H2 (1.38 bar), r.t., 2 h; (e) PtO2,
H2 (1.02 bar), MeOH, 30 min.
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

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TiCl4-Promoted Aza-[3+3] Annulation
2911
(2S,3R)-3-Acetoxy-2-methyl-2,3,4,6,7,8-hexahydroquinolin-
5(1H)-one (11)
EtO
H
EtO
H
O
O
H
H
H
H
To a soln of 10 (446.0 mg, 0.836 mmol) in MeOH (8 mL) was added
TFA (71.0 mL, 0.919 mmol) and Pd(OH)2/C (117.0 mg). The mix-
ture was pressurized with H2 (4.14 bar) for 24 h. When the reaction
was completed (TLC analysis), the reaction was filtered through
Celite and concentrated in vacuo. Purification by column chroma-
tography (50% to 90% EtOAc–hexane) provided pure 11 (183.0
mg, 97%); Rf = 0.25 (10% MeOH–EtOAc).
H
H
H
H
H
H
H
H
OTBS
OTBS
H
H
H
H
H
N
N
H
H
H
Me
Me
IR (neat): 3254 (br w), 2936 (m), 1734 (s), 1676 (s), 1524 cm–1 (s).
EtO
H
O
H
1H NMR (400 MHz, CDCl3): d = 1.21 (d, J = 6.8 Hz, 3 H), 1.94–
1.20 (m, 2 H), 2.05 (s, 3 H), 2.42–2.51 (m, 5 H), 2.63 (dd, J = 4.4,
16.4 Hz, 1 H), 3.52 (quint, J = 6.4 Hz, 1 H), 4.88 (dd, J = 5.6, 10.0
Hz, 1 H), 6.33 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 19.2, 21.3, 21.4, 22.8, 28.9, 34.7,
50.3, 69.5, 101.5, 161.5, 170.4, 192.7.
H
H
H
H
OTBS
H
H
H
N
H
Me
MS (APCI): m/z (%) = 224.2 (100).
Figure 1 NOE experiments of ethyl ester 36
(2S,3R,4aR,8aR)-3-Acetoxy-1-(tert-butoxycarbonyl)-2-methyl-
octahydroquinolin-5(1H)-one (16)
To soln of 11 (50.0 mg, 0.224 mmol) in MeOH (4 mL) was added
PtO2 (50 mg). The mixture was placed in a high-pressure hydroge-
ing the design of a stereodivergent approach for installing
both C2,8a-syn and C2,8a-anti manifolds through a com-
mon intermediate 9, and the threefold stereochemical con- nation apparatus (steel bomb) at 68.95 bar for 24 h. When the reac-
tion was completed (TLC analysis), the mixture was filtered
through Celite and concentrated in vacuo to give the alcohol inter-
mediate 14 (21.0 mg, 41%).
trol at C2, C4a, C8a, and C5 through the chiral auxiliary.
We recently employed the methyl ester intermediate 38
and completed a total synthesis of (+)-lepadin F.27
To a soln of 14 (21.0 mg, 0.092 mmol) in anhyd MeCN (4 mL) was
added sequentially (Boc)2O (36.0 mg, 0.166 mmol) and K2CO3
(1.40 mg, 0.0090 mmol) and the mixture was heated to gentle reflux
under N2 for 24 h. After this time H2O was added to quench the re-
We have described here details of our efforts in develop-
ing a stereodivergent approach to the lepadin family and
achieving the concept of accessing both C2,8a-syn and
C2,8a-anti relative stereochemical manifolds through a action, the organic layer was separated, and the aqueous layer was
extracted with an equal volume of CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated in vacuo to give 15
(25.9 mg, 85%) as a colorless oil.
common intermediate. This work provides a solid founda-
tion for us to construct all members of the lepadin family,
which consists of three major subsets based on an array of
interesting relative configurations. Our efforts further un-
To a soln of 15 prepared above (7.0 mg, 0.021 mmol) in CH2Cl2 (4
mL) was added Dess–Martin reagent (0.025 mmol) at r.t. The re-
derline the synthetic prominence of aza-[3+3] annulation
sultant mixture was stirred for 1.5 h and then the mixture was parti-
as a unified strategy in de novo syntheses of alkaloids.
tioned with H2O and separated; the resulting aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo to give a colorless oil which
was purified by flash column chromatography (silica gel) to yield
pure 16 (4.00 mg, 58%); Rf = 0.67 (100% EtOAc).
IR (neat): 3456 (br w), 2972 (m), 1735 (m), 1686 (s), 1457 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.27 (d, J = 7.2 Hz, 3 H), 1.47 (s,
9 H), 1.53–1.58 (m, 1 H), 1.79 (dt, J = 3.6, 14.0 Hz, 1 H), 1.78–1.85
(m, 1 H), 1.91–2.02 (m, 2 H), 2.01 (dd, J = 2.4, 14.0 Hz, 1 H), 2.08
(s, 3 H), 2.28 (dd, J = 6.0, 13.2 Hz, 1 H), 2.33–2.38 (m, 1 H), 2.94
(dt, J = 4.8, 13.6 Hz, 1 H), 4.24 (q, J = 6.8 Hz, 1 H), 4.30–4.44 (br
m, 1 H), 4.90 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 19.7, 21.5, 22.0, 23.6, 26.9, 28.6,
38.2, 45.7, 69.6, 80.4, 158.0, 170.4, 212.0.
MS (ESI): m/z (%) = 348.2 (100, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H27NO5Na: 348.1782;
All reactions were performed in flame-dried glassware under a
nitrogen or argon atmosphere. Solvents were distilled prior to use.
Reagents were used as purchased (Aldrich, Fluka), except where
noted. Chromatographic separations were performed using Bodman
60 Å silica gel. 1H and 13C NMR spectra were obtained on Varian
VI-400 and VI-500 spectrometers using CDCl3 as solvent. Melting
points were determined using a Laboratory Devices MEL-TEMP
and are uncorrected/calibrated. Infrared spectra were collected on a
Bruker Equinox 55/S FT–IR Spectrophotometer, and relative inten-
sities are expressed qualitatively as s (strong), m (medium), and w
(weak). TLC analysis was performed using Aldrich 254 nm poly-
ester-backed plates (60 Å, 250 mm) and visualized using UV and a
suitable chemical stain. Low-resolution mass spectra were obtained
using an Agilent-1100-HPLC/MSD and can be either APCI or ESI,
or were performed at University of Wisconsin Mass Spectrometry
Laboratories. High-resolution mass spectral analyses were per-
formed at University of Wisconsin Mass Spectrometry Laborato-
ries. All spectral data obtained for new compounds are reported.
X-ray analyses were performed at the X-ray facility in University of
Minnesota.
found: 348.1785.
(2S,3R)-3-(tert-Butyldimethylsiloxy)-2-methyl-2,3,4,6,7,8-
hexahydroquinolin-5(1H)-one (18)
To a soln of 17 (393.0 mg, 2.17 mmol) in anhyd MeCN (60 mL) was
added 2,6-lutidine (0.76 mL, 6.50 mmol). The soln was cooled to
0 °C and TBSOTf (1.50 mL, 6.50 mmol) was added dropwise via
syringe. The soln was stirred at r.t. for 12 h, then diluted with
CH2Cl2 and quenched with H2O. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2. The combined or-
Literature references to known compounds: 1, 8: see ref. 16; 3, 12,
13: see ref. 2a; 5, 7: see ref. 3f; 9, 10, 17, 20, 26a, 26b, 37, 38: see
ref. 27.
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

2912
G. Li et al.
PAPER
ganic layers were washed with equal volumes of sat. aq NaHCO3
and sat. aq NaCl, dried (Na2SO4), and concentrated in vacuo. Puri-
fication of the crude residue via flash column chromatography (sil-
ica gel, gradient 50% to 100% EtOAc–hexanes) gave pure 18
(640.0 mg, 100%); mp 205–206 °C; Rf = 0.46 (10% MeOH–
EtOAc).
IR (neat): 3286 (br m), 2937 (m), 173s (m), 1651 (s), 1604 (s), 1525
cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 1.07 (d, J = 7.0 Hz, 3 H), 1.80–
1.92 (m, 1 H), 2.01–2.09 (m, 1 H), 2.29 (s, 3 H), 2.32–2.47 (m, 5 H),
3.20–3.30 (m, 1 H), 4.00 (br s, 1 H), 4.12 (ddd, J = 4.4, 6.8, 10.4 Hz,
1 H).
IR (thin film): 3268 (br s), 2933 (s), 2857 (s), 1571 (w), 1516 (m),
1459 cm–1 (s).
MS (APCI): m/z (%) = = 224.1 (100, [M + H]+).
1H NMR (500 MHz, CDCl3): d = 0.06 (s, 3 H), 0.09 (s, 3 H), 0.88
(s, 9 H), 1.21 (d, J = 6.0 Hz, 3 H), 1.87–1.96 (m, 2 H), 2.11 (dd,
J = 9.0, 16 Hz, 1 H), 2.26–2.32 (m, 4 H), 2.73 (dd, J = 5.0, 15.5 Hz,
1 H), 3.13 (quint, J = 6.5, 7.0 Hz, 1 H), 3.48 (ddd, J = 5.5, 9.5, 13.5
Hz, 1 H), 4.45 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = –4.6, –3.8, 18.2, 19.1, 21.9, 26.0,
29.1, 36.4, 53.6, 70.8, 103.8, 158.1, 194.8.
MS (ESI): m/z (%) = = 318.2 (92, [M + Na]+), 296.2 (100, [M]+),
284.2 (11).
HRMS (ESI): m/z [M + Na]+ calcd for C16H29NO2SiNa: 318.1865;
found: 318.1855.
(2S,3S)-1-Acetyl-3-hydroxy-2-methyl-2,3,4,6,7,8-hexahydro-
quinolin-5(1H)-one (30)
To a soln of alcohol 21 (19.0 mg, 0.085 mmol) and NaHCO3 (28.6
mg, 0.48 mmol) in CH2Cl2 (1.5 mL) was added self-made Dess–
Martin periodinane (36.0 mg, 0.085 mmol). The soln was stirred at
r.t. for ~35 min. When the reaction was completed (TLC analysis;
10% MeOH–EtOAc or LCMS), it was quenched with a few drops
of i-PrOH. The mixture was filtered through Celite and concentrat-
ed under reduced pressure. Purification of the crude residue via
flash column chromatography (silica gel, gradient 0% to 10%
MeOH–EtOAc) afforded ketone 29 (14.2 mg, 76%) as a colorless
oil, which was immediately used for the following step.
To a soln of ketone 29 prepared above (11.4 mg, 0.052 mmol) in an-
hyd MeOH (1.2 mL) under N2 at –41 °C was added NaBH4 (2.00
mg, 0.052 mmol). The soln was stirred at same temperature for 1 h
(TLC monitoring). The mixture was quenched with aq 0.5 M HCl
soln (0.5 mL) and diluted with CH2Cl2. The organic layer was sep-
arated and the aqueous layer was extracted with CH2Cl2 (3 × 20
mL). The combined organic layers were washed with sat. aq NaCl,
dried (Na2SO4), and concentrated in vacuo. Purification of the crude
residue via flash column chromatography (silica gel, gradient 0% to
5% MeOH–EtOAc) gave pure 30 (8.80 mg, 76%) as a colorless oil;
Rf = 0.45 (10% MeOH–EtOAc).
(2S,3R)-1-Acetyl-3-(tert-butyldimethylsiloxy)-2-methyl-
2,3,4,6,7,8-hexahydroquinolin-5(1H)-one
To a soln of 18 (106.0 mg, 0.359 mmol) in anhyd CH2Cl2 (3 mL)
was added 2,6-lutidine (1.38 mL, 1.18 mmol) and DMAP (8.80 mg,
0.72 mmol). Ac2O (5 mL, 46.7 mmol) was then added dropwise via
syringe. The resulting soln was stirred at 40 °C for 40 h and then di-
luted with CH2Cl2 (10 mL) and quenched with sat. aq NaHCO3. The
organic layer was separated and the aqueous layer was extracted
with an equal volume of CH2Cl2. The combined organic layers were
washed with an equal volume of sat. aq NaHCO3, dried (Na2SO4),
and concentrated in vacuo.
IR (neat): 3371 (br m), 2934 (m), 1644 (s), 1602 (s), 1375 cm–1 (s).
The above crude product was dissolved in THF (7 mL) and aq 1.0
M HCl soln (1.17 mL) was added. The acidification was allowed to
run for 6 h before it was diluted with CH2Cl2 (10 mL) and quenched
with sat. aq NaHCO3. This process was monitored via TLC analy-
sis, and more HCl was added if not complete. The organic layer was
separated and the aqueous layer was extracted with an equal volume
CH2Cl2. The combined organic layers were washed with an equal
volume of sat. aq NaHCO3, dried (Na2SO4), and concentrated in
vacuo. Purification by column chromatography gave the corre-
sponding N-acylated silyl ether intermediate (82.7 mg, 68%) and
also some N-acylated alcohol 21 (7.80 mg, 4%) that was already
desilylated; Rf = 0.80 (10%, EtOAc–hexane).
1H NMR (500 MHz, CDCl3): d = 0.01 (s, 0.75 H), 0.02 (s, 0.75 H),
0.04 (s, 2.25 H), 0.05 (s, 2.25 H), 0.82 (s, 9 H), 1.04 (d, J = 6.5 Hz,
3 H), 1.58–1.70 (m, 0.33 H), 1.83–1.92 (m, 0.67 H), 2.03–2.09 (m,
1 H), 2.23 (s, 3 H), 2.25–2.31 (m, 1.5 H), 2.34–2.39 (m, 1.5 H),
2.22–2.48 (m, 2 H), 3.20–3.29 (m, 1 H), 3.93–3.96 (m, 1 H), 4.05
(ddd, J = 3.0, 6.5, 13.5 Hz, 0.8 H), 4.14 (ddd, J = 3.0, 6.5, 13.5 Hz,
0.8 H); Non-integer counts of protons are due to rotameric issue.
1H NMR (400 MHz, CDCl3): d = 1.12 (d, J = 6.8 Hz, 3 H), 1.81–
1.92 (m, 1 H), 1.96–2.09 (m, 2 H), 2.29 (s, 3 H), 2.35–2.47 (m, 3 H),
2.80 (ddd, J = 2.4, 6.4, 17.6 Hz, 1 H), 3.23 (m, 1 H), 3.98 (br m, 1
H), 4.18 (qd, J = 4.4, 6.8 Hz, 1 H).
MS (APCI): m/z (%) = 224.2 (100, [M + H]+).
Ethyl [(2S,3R,E)-3-(tert-Butyldimethylsiloxy)-2-methyl-
2,3,4,6,7,8-hexahydroquinolin-5(1H)-ylidene]acetate (35)
Lawesson’s reagent (39.0 mg, 0.097 mmol) was added to a soln of
18 (57.0 mg, 0.19 mmol) in THF (5 mL), and the resulting mixture
was stirred at r.t. for 1 h. The solvent was removed in vacuo and
then column chromatography (silica gel) gave the desired thio-viny-
logous amide intermediate (52.0 mg, 87%) as a yellow oil.
To a soln of thio-vinylogous amide (32.9 mg, 0.11 mmol) in acetone
(5 mL) was added successively K2CO3 (29.2 mg, 0.21 mmol) and
ethyl a-bromoacetate (0.013 mL, 0.12 mmol). The resulting mixture
was stirred at r.t. for 1 h, and after which, solids were filtered. After
solvent removal in vacuo, column chromatography (silica gel) gave
the thiirane intermediate (42.2 mg, 100%) as a yellow oil.
MS (APCI): m/z (%) = 338.2 (100, [M + H]+).
A mixture of this thiirane (42.2 mg, 0.11 mmol), Ph3P (36.0 mg,
0.14 mmol), and DIPEA (7.00 mL, 0.041 mmol) in MeCN (5 mL)
was heated in a sealed tube at 90 °C for 24 h. The excess solvent was
evaporated in vacuo and the crude residue was subjected to flash
column chromatography (silica gel, gradient 0% to 2% MeOH–
EtOAc) to give 35 (19.7 mg, 51%) as a light yellow oil; Rf = 0.60
(10% MeOH–EtOAc).
(2S,3R)-1-Acetyl-3-hydroxy-2-methyl-2,3,4,6,7,8-hexahydro-
quinolin-5(1H)-one (21)
To a soln of the above silyl ether (39.4 mg, 0.12 mmol) in anhyd
THF (3 mL) at 0 °C was added dropwise 1.0 M TBAF in THF (0.12
mL). The resulting mixture was stirred for 5 h and then poured into
H2O and extracted with EtOAc (3 × 15 mL). The combined organic
layers were washed with sat. aq NaCl (45 mL), dried (Na2SO4), and
concentrated in vacuo. Purification of the crude residue by flash
column chromatography (silica gel, gradient 10% to 30% EtOAc–
hexanes) gave 21 (12.8 mg, 49%) as a colorless oil and also some
recovered silyl ether (3.60 mg, 9%); Rf = 0.25 (10% MeOH–
EtOAc).
[a]D23 –179.6 (c 0.40, CHCl3).
IR (neat): 3363 (br w), 2929 (m), 2857 (m), 1736 (m), 1560 (m),
1503 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 0.09 (s, 3 H), 0.12 (s, 3 H), 0.92
(s, 9 H), 1.20 (d, J = 6.0 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.59–
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

PAPER
TiCl4-Promoted Aza-[3+3] Annulation
2913
1.72 (m, 1 H), 1.75–1.87 (m, 1 H), 2.04–2.20 (m, 3 H), 2.44 (dd,
J = 5.6, 15.2 Hz, 1 H), 2.71 (m, 1 H), 3.08 (qd, J = 6.4, 7.2 Hz, 1 H),
3.34 (dt, J = 5.6, 17.6 Hz, 1 H), 3.55 (dt, J = 5.6, 8.8 Hz, 1 H), 3.70
(br s, 1 H), 4.13 (q, J = 7.2 Hz, 2 H), 5.23 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = –4.6, –3.8, 14.7, 18.1, 18.8, 21.8,
25.9, 27.0, 29.1, 32.8, 52.9, 58.8, 71.6, 100.2, 101.1, 148.2, 158.0,
168.5.
IR (neat): 3063 (w), 3028 (m), 2855 (m), 1732 (s), 834 cm–1 (s).
1H NMR (500 MHz, CDCl3): d = –0.42 (s, 3 H), –0.12–0.00 (m, 1
H), –0.07 (s, 3 H), 0.56 (s, 9 H), 0.82–0.94 (m, 1 H), 0.89 (d, J = 6.5
Hz, 3 H), 1.00 (qt, J = 3.5, 12.5 Hz, 1 H), 1.18–1.32 (m, 3 H), 1.38
(dtt, J = 2.5, 12.5 Hz, 1 H), 1.53 (dtt, J = 5.0, 12.0 Hz, 1 H), 1.71 (m,
1 H), 1.93 (s, 3 H), 2.03–2.12 (m, 2 H), 2.15 (dd, J = 5.0, 12.5 Hz,
1 H), 2.87 (dq, J = 6.5, 9.5 Hz, 1 H), 2.94 (dt, J = 3.5, 12.0 Hz, 1 H),
3.51 (ddd, J = 5.5, 10.0, 10.5 Hz, 1 H), 3.70 (s, 3 H), 4.28 (d, J = 9.5
Hz, 1 H), 5.11 (d, J = 9.0 Hz, 1 H), 7.18–7.32 (m, 10 H).
1H NMR (500 MHz, C6D6): d = –0.25 (s, 3 H), –0.02 (s, 3 H), 0.08–
0.14 (m, 1 H), 0.67 (qd, J = 4.0, 13.0 Hz, 1 H), 0.76 (s, 9 H), 0.89–
0.97 (m, 1 H), 0.99 (d, J = 6.0 Hz, 1 H), 1.16–1.24 (m, 3 H), 1.27
(dq, J = 3.0, 13.0 Hz, 1 H), 1.63 (s, 3 H), 1.69 (dt, J = 5.0, 12.5 Hz,
1 H), 1.85–1.94 (m, 1 H), 1.90 (dd, J = 8.0, 15.0 Hz, 1 H), 1.98 (dd,
J = 7.0, 15.0 Hz, 1 H), 2.14–2.23 (m, 1 H), 2.92–3.02 (m, 2 H), 3.43
(s, 3 H), 3.80 (ddd, J = 5.5, 9.0, 10.5 Hz, 1 H), 4.43 (d, J = 9.0 Hz,
1 H), 5.25 (d, J = 9.0 Hz, 1 H), 7.10–7.18 (m, 2 H), 7.22 (t, J = 7.5
Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.36 (d, J = 7.0 Hz, 2 H), 7.45 (d,
J = 7.5 Hz, 2 H).
MS (APCI): m/z (%) = 366.2 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H36NO3Si: 366.2459;
found: 366.2459.
Ethyl [(2S,3R,4aS,8aR)-3-(tert-Butyldimethylsiloxy)-2-methyl-
decahydroquinolin-5-yl]acetate (36)
To a soln of 35 (4.60 mg, 0.013 mmol) in anhyd AcOH (2 mL) was
added 10% Pt/C (12.3 mg). The mixture was placed in a Lab-Crest
pressure reaction vessel at 1.38 bar H2 pressure for 2 h. When the
reaction was complete (LCMS analysis), the mixture was filtered
through Celite and concentrated in vacuo. Purification of the crude
residue by flash column chromatography (silica gel, gradient 0% to
2% MeOH–EtOAc) afforded 36 (1.80 mg, 40%) as a light yellow
oil; Rf = 0.40 (5% MeOH–EtOAc).
13C NMR (125 MHz, CDCl3): d = –5.0, –4.0, 16.4, 17.9, 19.7, 21.4,
24.9, 25.1, 25.7, 26.5, 37.8, 38.4, 38.5, 51.1, 51.6, 56.1, 65.8, 75.1,
76.8, 126.6, 127.6, 127.7, 128.0, 128.1, 128.9, 141.8, 144.6, 170.3,
173.7.
MS (APCI): m/z (%) = 594.4 (95, [M + H]+), 534.3 (100).
HRMS (MALDI): m/z [M + H]+ calcd for C35H52NO5Si: 594.3609;
IR (neat): 3395 (br w), 2929 (s), 2858 (m), 1733 (s), 1462 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 0.06 (s, 3 H), 0.07 (s, 3 H), 0.89
(s, 9 H), 0.96–1.05 (m, 1 H), 1.12 (d, J = 6.5 Hz, 3 H), 1.26 (t,
J = 7.0 Hz, 3 H), 1.33–1.48 (m, 3 H), 1.48–1.67 (m, 3 H), 1.77 (br
d, J = 12.5 Hz, 1 H), 1.97–2.05 (m, 2 H), 2.17–2.28 (m, 1 H), 2.50–
2.58 (m, 2 H), 2.97 (br m, 1 H), 3.28–3.33 (m, 1 H), 4.10–4.18 (m,
2 H).
found: 594.3586.
Acknowledgment
13C NMR (125 MHz, CDCl3): d = –4.5, –4.0, 14.4, 18.2, 20.8, 26.0,
31.8, 32.4, 33.0, 36.9, 39.4, 42.1, 55.5, 60.0, 60.3, 71.0, 77.4, 173.5.
Authors thank NIH [NS38049] for funding.
MS (APCI): m/z (%) = 370.2 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H40NO3Si: 370.2772;
References
found: 370.2767.
(1) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org.
Biomol. Chem. 2005, 3, 1349. (b) Hsung, R. P.;
Methyl {(2S,3R,E)-3-Acetoxy-1-[(1S,2R)-2-(tert-Butyldimethyl-
siloxy)-1,2-diphenylethyl]-2-methyl-2,3,4,6,7,8-hexahydroquin-
olin-5(1H)-ylidene}acetate (37)
Rf = 0.30 (20% EtOAc–hexanes).
[a]D23 +499.4 (c 0.16, CHCl3).
Kurdyumov, A. V.; Sydorenko, N. Eur. J. Org. Chem. 2005,
23. (c) Coverdale, H. A.; Hsung, R. P. ChemTracts 2003, 16,
238.
(2) For leading references, see: (a) Sklenicka, H. M.; Hsung,
R. P.; McLaughlin, M. J.; Wei, L.-L.; Gerasyuto, A. I.;
Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435.
(b) Wei, L.-L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung,
R. P. Angew. Chem. Int. Ed. 2001, 40, 1516.
IR (neat): 2933 (m), 2887 (m), 2859 (m), 1739 (m), 1699 (m), 1544
(s), 1433 (m), 839 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = –0.42 (s, 3 H), 0.06 (s, 3 H), 0.18
(d, J = 6.8 Hz, 3 H), 0.65 (s, 9 H), 1.00–1.11 (m, 1 H), 1.38–1.50
(m, 2 H), 1.86–1.98 (m, 1 H), 2.16–2.30 (m, 4 H), 2.37 (dd, J = 6.0,
18.0 Hz, 1 H), 2.47–2.58 (m, 1 H), 3.02 (dt, J = 4.8, 15.6 Hz, 1 H),
3.61 (s, 3 H), 3.79 (br q, J = 6.4 Hz, 1 H), 4.96–5.00 (m, 1 H), 5.00
(d, J = 8.8 Hz, 1 H), 5.07 (d, J = 8.8 Hz, 1 H), 5.14 (s, 1 H), 7.23–
7.36 (m, 8 H), 7.56–7.60 (dd, J = 2.0, 9.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = –4.9, –3.6, 16.9, 18.0, 21.8, 21.9,
25.7, 25.8, 26.4, 27.7, 50.4, 51.4, 68.2, 70.7, 74.0, 99.7, 100.0,
127.6, 127.7, 128.0, 128.1, 128.2, 131.0, 137.8, 143.9, 148.9, 158.7,
168.8, 170.5
(3) For our general work on developing the aza-[3+3]-annula-
tion method, see: (a) Ghosh, S. K.; Buchanan, G. S.; Long,
Q. A.; Wei, Y.; Al-Rashid, Z. F.; Sklenicka, H. M.; Hsung,
R. P. Tetrahedron 2008, 63, 883. (b) Sydorenko, N.; Hsung,
R. P.; Vera, E. L. Org. Lett. 2006, 8, 2611. (c) Gerasyuto,
A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. W. J. Org.
Chem. 2005, 70, 4248. (d) Sydorenko, N.; Hsung, R. P.;
Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004, 69,
6732. (e) Sklenicka, H. M.; Hsung, R. P.; Wei, L.-L.;
McLaughlin, M. J.; Gerasyuto, A. I.; Degen, S. J.; Mulder,
J. A. Org. Lett. 2000, 2, 1161. (f) Hsung, R. P.; Wei, L.-L.;
Sklenicka, H. M.; Douglas, C. J.; McLaughlin, M. J.;
Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 1, 509.
(4) For recent studies in this area, see: (a) Guo, H.; Qihai,
X. u. Q.; Kwon, O. J. Am. Chem. Soc. 2009, 131, 6318.
(b) Alladoum, J.; Toum, V.; Hebbe, S.; Kadouri-Puchot, C.;
Dechoux, L. Tetrahedron Lett. 2009, 50, 617. (c) Hayashi,
Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew. Chem. Int.
Ed. 2008, 47, 4012. (d) Zhang, R.; Zhang, D.; Guo, Y.;
Zhou, G.; Jiang, Z.; Dong, D. J. Org. Chem. 2008, 73, 9504.
(e) Mancey, N. C.; Butlin, R. J.; Harrity, J. P. A. Synlett
MS (APCI): m/z (%) = 590.4 (100, M + H]+), 558.3 (10).
HRMS (MALDI): m/z [M + H]+ calcd for C35H48NO5Si: 590.3296;
found: 590.3305.
Methyl {(2S,3R,4aR,8aS)-3-Acetoxy-1-[(1S,2R)-2-(tert-Bu-
tyldimethylsiloxy)-1,2-diphenylethyl]-2-methyldecahydroquin-
olin-5-yl}acetate (38)
Rf = 0.35 (20% EtOAc–hexanes).
[a]D23 +27.5 (c 0.16, CHCl3).
Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York

2914
G. Li et al.
PAPER
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(17) This particular dihydroxylation was very difficult and
required a stoichiometric amount of OsO4, and Scheme 4
reveals our best conditions. Other conditions examined
were: (i) 5–60 mol% OsO4 with NMO, or with K2Fe(CN)6,
or with t-BuOOH; bases were K2CO3, MeSO2NH2, or
DABCO; (ii) cat. to 1.1 equiv of K2OsO4·2 H2O with
K2Fe(CN)6; bases were K2CO3, or TMEDA, or pyridine; (iii)
MCPBA or MMPP or AcOOH; (iv) NBS, DMSO; (v)
DMDO or Ozone; (vi) KMnO4 in H2O–EtOH or with
TEBACl in CH2Cl2; (vii) 9-BBN or BH3·SMe2 and then
H2O2, MeOH; (viii) RuCl3, NaIO4; (ix) Hg(OAc)2, NaBH4,
NaOH; (x) O2, hn, rose Bengal. However, none of these
conditions led to any synthetically useful outcome.
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Abstracts of Papers, 227th National Meeting of the
American Chemical Society, Anaheim, CA, Mar 28 to Apr 1,
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(23) Vinylogous amide 18 is again the same as Ma’s mid-stage
intermediate. However, in their beautiful studies en route to
lepadins A–E and H, hydrogenation of the C4a–8a olefin
took place prior to homologation of the C5 carbonyl group
via Wittig-type olefinations (see ref. 13).
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(26) Wittig olefination employing Ph3P=CHCHO in toluene did
not lead to any desired homologation product.
(27) Li, G.; Hsung, R. P.; Slafer, B. W.; Sagamanova, I. K. Org.
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Synthesis 2009, No. 17, 2905–2914 © Thieme Stuttgart · New York