Total synthesis of (+)-cylindricine C

Article abstract of DOI:10.1016/j.tetlet.2004.05.142

A stereoselective total synthesis of (+)-cylindricine C has been achieved starting with (S)-N-Boc-2-pyrrolidinone. The key elements of this synthesis involve the sequence of reactions including BF₃-mediated addition of the allyl Grignard reagen

Full text of DOI:10.1016/j.tetlet.2004.05.142

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5921–5924
Total synthesis of (+)-cylindricine C
Toshiharu Arai, Hideki Abe, Sakae Aoyagi and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 12 April 2004; revised 20 May 2004; accepted 21 May 2004
Available online 19 June 2004
Abstract—A stereoselective total synthesis of (+)-cylindricine C has been achieved starting with (S)-N-Boc-2-pyrrolidinone. The key
elements of this synthesis involve the sequence of reactions including BF3-mediated addition of the allyl Grignard reagent to the
cyclic imine, spirocyclization via enamine formation, and intramolecular Michael addition to form the tricyclic core.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Tunicates (ascidians) have been proven to be a partic-
ularly rich source of a variety of structurally fascinating
and bioactive nitrogen compounds.1 Since the first
members were reported by Blackman and co-workers in
1993, 11 cylindricines A–K2 have been identified from
the Tasmanian ascidians, Clavelina cylindrica, as new
marine alkaloids with an unusual azatricyclic skeleton.
Among this class of alkaloids, cylindricine C (1),2b
possessing the perhydropyrrolo[2,1-j]quinoline frame-
work, is intimately related to the marine tricyclic alka-
loid lepadiformine (2)3 isolated from Claverina
lepadiformis, differing structurally only in the cis/trans
stereorelationship of the perhydroquinoline ring sys-
tem and the functionality at C7. While the synthesis
of both enantiomers of cylindricine C (ent-1 and 1) has
been achieved,4 the absolute configuration of natural
cylindricine C remains unassigned since the optical
rotation of the natural product has not been determined
and no sample remains of the isolated cylindricine C.
Recently, we have reported the enantioselective synthe-
sis of ())-lepadiformine,5 which allowed us to establish
the absolute configuration of naturally occurring lep-
adiformine as shown in structure 2. Biogenetically, it can
be envisaged that both tunicate alkaloids 1 and 2 pre-
sumably arise from an amino acid-derived azaspirocy-
clic compound, corresponding to the A/C ring of these
alkaloids, by closure of the B ring (bond formed C7–
C7a). Consequently, we assumed that the correct abso-
lute stereochemistry for natural cylindricine C is defined
by 1, which is epimeric with the natural lepadiformine
(2) at C7a.
HO
HO
A
3 N
11a C
7a
N
B
5
7
O
Lepadiformine (2)
Cylindricine C (1)
In this paper, we describe the stereocontrolled total
synthesis of (+)-cylindricine C (1). Our synthetic strat-
egy for 1 was based on the approach outlined in Scheme
1, which involves cyclization to assemble the azatricyclic
core of 1 by an intramolecular Michael reaction6 of the
spirocyclic enone 3 which corresponds to a potential
biosynthetic precursor to 1 as described above. The
R1O
R1O
HN
1
N
R2
C6H13
CHO
O
4
3
R1O
R1O
O
N
R2
N
R2
Keywords: Cylindricine; Cyclic imine; Grignard reaction; Azaspiro-
cyclization; Intramolecular Michael addition.
CHO
X
6
5
* Corresponding author. Tel.: +81-426-76-3275; fax: +81-426-76-4475;
e-mail: kibayasi@ps.toyaku.ac.jp
Scheme 1. Retrosynthetic analysis of cylindricine C (1).
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.142

5922
T. Arai et al. / Tetrahedron Letters 45 (2004) 5921–5924
enone 3 should be formed from the spirocyclic alde-
hyde 4, which should be conveniently accessible from
the trisubstituted pyrrolidine 5 available using the (S)-
pyrrolidinone 6 as the starting material.
the imine 9 in the absence of a Lewis acid might proceed
via a chelated transition state A, where Mg is coordi-
nated by the nitrogen and oxygen atoms of the imine 9
and the internal delivery of the allyl group might occur
on the a-face leading to 10. In the case of the Grignard
allylation mediated by the presence of BF3ÆEt2O, on the
other hand, BF3 blocks chelation with Mg and the
reaction might proceed via an open-chain transition
state B. Addition of the allyl Grignard reagent from the
less hindered b-face then gives rise to the observed
product 11.
Following this approach, we initially examined the
stereoselective preparation of the trisubstituted pyrroli-
dine starting with (S)-N-Boc-2-pyrrolidinone 77 in pre-
liminary experiments (Scheme 2). Thus, upon treatment
with methylmagnesium bromide, 7 underwent a selective
attack on the endocyclic (ring) carbonyl group8 to yield
the N-Boc-amino ketone 8. N-Boc deprotection with
trifluoroacetic acid followed by basic treatment (3 M
NaOH) led to the cyclic imine 9. Reaction of 9 with
allylmagnesium bromide in THF at 0 ꢁC produced the
trisubstituted pyrrolidine as a separable mixture of 10
and 11 (58% total yield) in a ratio of 5.8:1 favoring the
a-allylated isomer 10.10 When 9 was treated with
BF3ÆEt2O (3 equiv) prior to the addition of allylmagne-
sium bromide, the imine addition reaction proceeded
smoothly at )78 ꢁC and reversal of the selectivity in
favor of b-allylated isomer 11 was observed, giving a
ratio of 19:1 for 11 and 10 (73% total yield).
Having established effective conditions for the highly
selective b-allylation of the imine 9, we next applied this
protocol to the diastereoselective synthesis of the tri-
substituted pyrrolidine 16. Thus, following the identical
sequence as described for 9, the (S)-N-Boc-pyrrolidi-
none 7 was treated with 4-(p-methoxybenzyl)oxybutyl-
magnesium bromide (12) to give the N-Boc-amino
ketone 13, which was converted to the (S)-pyrroline 15
via treatment with trifluoroacetic acid followed by
TBDPS protection of the primary alcohol (Scheme 3).
Addition of allylmagnesium bromide to the BF3 pre-
treated imine 15 in THF at )78 ꢁC produced the b-al-
lylated pyrrolidine 16 in 74% yield as a single isomer
The stereochemical models which provide explanation
of the observed diastereoselectivity are shown in Figure
1. The addition reaction of allylmagnesium bromide to
1
(based on H NMR). After N-protection of 16 with the
Boc group, deprotection of the TBDPS ether (Bu4NF)
followed by tosylation of the resulting primary alcohol
gave the tosylate 17, which underwent the sequential
oxidative cleavage of the olefin moiety using OsO4–
HNBoc
CF3CO2H
MeMgBr
BnO
BnO
Me
O
N
THF, 0 ˚C
85%
CH2Cl2
0 ˚C → rt
93%
Boc
O
8
7
PBMO
7
HNBoc
a
b
+
BnO
Me
PMBO
BnO
BnO
MgBr
O
N
12
13
H
10
+
MgBr
BnO
OR
d
THF, 0 ˚C
58%
BnO
Me
N
N
BnO
9
OTBDPS
H
N
Me
N
H
14 R = H
15 R = TBDPS
16
c
11
(10 : 11 = 5.8 : 1)
e—g
i
BnO
N
MgBr
BnO
N
10
(1 : 19)
+
11
X
X
Boc
BF3•Et2O (3 equiv)
THF, –78 ˚C
73%
CHO
Boc
18 X = OTs
20 X = I
17 X = OTs
19 X = I
h
Scheme 2.
BnO
N
j
BnO
Boc
N
OTs
MgBr
(from 18)
Me
N
Boc
Br
Mg
CHO
H
22
F3B–
Bn
+
N
F3B–
N
+
O
Me
21
O
Bn
Scheme 3. Reaction conditions: (a) THF, 0 ꢁC, 85%; (b) TFA, CH2Cl2,
0 ꢁC fi rt, then 3 M NaOH, 0 ꢁC, 87%; (c) TBDPSCl, DMAP, Et3N,
CH2Cl2, 79%; (d) allylmagnesium bromide (3 equiv), BF3Et2O
(3 equiv), THF, )78 ꢁC, 74%; (e) Boc2O, aqueous Na2CO3, benzene, rt,
90%; (f) Bu4NF, THF, rt, 96%; (g) TsCl, pyridine, rt, 93%; (h) NaI,
acetone, reflux, 97%; (i) OsO4, NaIO4, THF/H2O, rt, 85% for 18 and
88% for 20; (j) pyrrolidine, MS 4 A, toluene, reflux, then 50% AcOH,
rt, 60%.
H
A
B
10
11
Figure 1. Stereochemical models to explain diastereoselective forma-
tion of the 2,2,5-trisubstituted pyrrolidines 10 and 11.

T. Arai et al. / Tetrahedron Letters 45 (2004) 5921–5924
5923
25
NaIO4 to afford the aldehyde 18. The iodide 19 derived
lindricine C (1), which has an optical rotation of ½aꢀ
D
25
D
from the tosylate 17 (NaI, acetone) was also converted
to the aldehyde 20 by the oxidative cleavage of the
olefin.
+61.8 (c 0.78, CH2Cl2) (lit.4b ½aꢀ +61 (c 0.4, CH2Cl2);
25
D
for ())-cylindricine C4a ½aꢀ )64 (c 0.2, CH2Cl2)).
The synthetic material displayed spectroscopic data (1H
and 13C NMR) identical to those reported2b for the
natural product.
With the tosylate 18 having the desired configurations at
the C2 and C5 positions of the pyrrolidine in hand, we
next tried cyclization to construct the azaspirodecane
ring system 22 by means of intramolecular enolate
alkylation. However, all attempts to cyclize under basic
conditions failed resulting in no reaction at low tem-
perature, or, under more forcing conditions, to pro-
duction of a complex mixture. With the iodide 20 similar
results were obtained under the same reaction condi-
tions. These failures of 18 and 20 to undergo cyclization
were possibly due to the low stability of the enolates
formed from 18 and 20, and their propensity to undergo
retro-Michael reaction9 under these reaction conditions.
In summary, a highly stereoselective method for the
enantioselective synthesis of cylindricine C has thus been
devised. This total synthesis consists of the key elements
involving the sequence of reactions including BF3-
mediated addition of the allyl Grignard reagent to the
cyclic imine, spirocyclization via enamine formation,
and intramolecular Michael addition to form the tri-
cyclic core.
References and notes
To circumvent these problems, we then examined the
cyclization exploiting an enamine for the synthesis of 22.
Thus, upon treatment of the tosylate 18 with pyrrolidine
in refluxing toluene, the in situ generated enamine 21
underwent spontaneous cyclization under the neutral
conditions, and subsequent treatment with 50% acetic
acid provided the (6S)-azaspirocyclic aldehyde 22 as a
1. For recent reviews on marine natural products, see: (a)
Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7–55; (b)
Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1–49; (c)
Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48; (d) Blunt,
J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2004, 21, 1–49.
2. (a) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B.
W.; White, A. H. Tetrahedron 1993, 49, 8645–8656; (b) Li,
C.; Blackman, A. J. Aust. J. Chem. 1994, 47, 1355–1361;
(c) Li, C.; Blackman, A. J. Aust. J. Chem. 1995, 48, 955–
965.
3. Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.;
Vercauteren, J.; Weber, J. F.; Boukef, K. Tetrahedron
Lett. 1994, 35, 2691–2694.
4. Synthesis of ())-cylindricine C: (a) Molander, G. A.;
Ro¨nn, M. J. Org. Chem. 1999, 64, 5183–5187; Synthesis of
(+)-cylindricine C, D, and E: (b) Trost, B. M.; Rudd, M.
T. Org. Lett. 2003, 5, 4599–4602.
1
single isomer (based on H NMR)11 in 60% yield from
18. Octynyl Grignard addition to the aldehyde 22 and
MnO2 oxidation of the resulting carbinol (2:1 epimeric
mixture) afforded the ynone 23 (80% from 22), which
was converted to the (Z)-enone 24 by Lindlar hydro-
genation in toluene (Scheme 4). Removal of the Boc
protecting group (TFA, 0 ꢁC) and subsequent treatment
of the resulting amine with a saturated NaHCO3 solu-
tion at room temperature resulted in intramolecular
Michael addition. This reaction proceeded presumably
via an (E)-enone with complete equilibration to a ther-
modynamically favorable C7a epimer 25 of the tricyclic
amine in 81% yield as a single diastereomer (within the
5. Abe, H.; Aoyagi, S.; Kibayashi, C. Angew. Chem., Int. Ed.
2002, 41, 3017–3020.
6. Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.;
McLoughlin, J. I. Org. React. 1995, 47, 315–552.
7. (a) Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.;
Minami, J.; Terashima, S. Tetrahedron Lett. 1993, 34,
5743–5746; (b) Katoh, T.; Nagata, Y.; Kobayashi, Y.;
Arai, K.; Minami, J.; Terashima, S. Tetrahedron 1994,
50, 6221–6238.
1
detection limits of H NMR).
Finally, the benzyl group of 25 was removed by hy-
drogenolysis using Pd(OH)2 in MeOH to give (+)-cy-
8. For the organometallic ring-opening reaction of N-alk-
oxycarbonyl lactams, see: Giovannini, A.; Savoia, D.;
Umani-Ronchi, A. J. Org. Chem. 1989, 54, 228–234.
9. On basic treatment of 18 and 20, ring opening is
considered to take place via the following sequence
involving retro-Michael addition generating the a,b-unsat-
urated aldehyde ii
BnO
BnO
N
N
a, b
Boc
c
Boc
22
O
O
C6H13
24
C6H13
23
RO
X
X
BnO
BnO
d
N
N
Boc
N
C6H13
H
O–
CHO
Boc
i
18 X = OTs
20 X = I
O
25 R = Bn
(+)-Cylindricine C (1) R = H
e
NHBoc
Scheme 4. Reaction conditions: (a) 1-octynylmagnesium bromide,
THF, 0 ꢁC, 88%; (b) MnO2, CH2Cl2, rt, 91%; (c) H2, Lindlar catalyst,
toluene, rt, 99%; (d) TFA, CH2Cl2, rt, then saturated NaHCO3, rt,
81%; (e) H2, Pd(OH)2–C, MeOH, rt, 83%.
BnO
X
CHO
ii

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T. Arai et al. / Tetrahedron Letters 45 (2004) 5921–5924
10. The stereostructures of the allylated products 10 and 11
were assigned based on NOESY spectra which showed
correlations between the C2-methyl protons and H5
for 10, and the C5-allyl methylene protons and H5 for
11.
11. The 1H NMR spectrum of 22 showed a large vicinal
coupling constant (J ¼ 12:1 Hz) between H6 and H7ax at
3.80 ppm, indicating their trans diaxial relationship and,
hence, the C6 formyl group existing in an equatorial
position (b configuration) on the cyclohexane ring.