Asymmetric formal synthesis of schulzeines A and C

Article abstract of DOI:10.1039/c2ob25772f

The asymmetric formal synthesis of schulzeines A and C is described. Key features of the synthesis include the efficient and stereoselective construction of the benzoquinolizidine skeleton via the aza-Claisen rearrangement-induced ring expansion of the 1-

Full text of DOI:10.1039/c2ob25772f

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COMMUNICATION
Asymmetric formal synthesis of schulzeines A and C†
Jaebong Jang,a Jong-Wha Jung,b Jaeseung Ahn,a Jaehoon Sim,a Dong-Jo Chang,a Dae-Duk Kima and
Young-Ger Suh*a
Received 23rd April 2012, Accepted 30th May 2012
DOI: 10.1039/c2ob25772f
A (1) and C (2) via a chiral transfer strategy that has not been
previously reported. Herein, we describe the efficient and highly
stereoselective formal synthesis of schulzeines A and C that
employs a tandem chiral transfer strategy.
Pictet–Spengler-type cyclocondensation has been successfully
utilized by several groups in the synthesis of the 3-aminobenzo
[α]quinolizidine core (3) of schulzeines A and C through 1,4-
asymmetric induction.4a–d Pictet–Spengler-type cyclocondensa-
tion preferentially produced the cis-isomer (C11b α-H) over the
trans-isomer (C11b β-H). However, the diastereocontrol of the
two stereocenters remains a challenging task because the 1,4-
asymmetric induction to form the new remote stereocenter had
low or moderate stereoselectivity. As shown in Fig. 1, we
The asymmetric formal synthesis of schulzeines A and C is
described. Key features of the synthesis include the efficient
and stereoselective construction of the benzoquinolizidine
skeleton via the aza-Claisen rearrangement-induced ring
expansion of the 1-vinyl-N-glycyl-isoquinoline, which was
prepared by the highly enantioselective asymmetric allylation
of the 8-benzyloxy-substituted dihydroisoquinoline and
by the acid-catalyzed transannulation of the resulting
10-membered lactam.
α-Glucosidase plays an important role in various biological pro-
cesses such as protein folding in the endoplasmic reticulum, cell
surface glycoprotein stabilization, cell–cell and cell–virus
recognition processes and oligosaccharide metabolism.1 Thus,
α-glucosidase has been considered as a promising molecular
target for the treatment of cancer, diabetes and viral infections.2
Furthermore, some iminosugars, including the 1-deoxynojirimy-
cin derivatives, have proven to be effective α-glucosidase
inhibitors for the treatment of hepatitis B infection and non-
insulin-dependent type 2 diabetes.2c Recently, marine invert-
ebrates were reported to produce novel classes of α-glucosidase
inhibitors that are structurally distinct from the classic glycoside
derivatives.3 In particular, schulzeines, isolated from the extracts
of the marine sponge Penares schulzei, exhibited quite potent
α-glucosidase inhibitory activities (IC50 48–170 nM).3a
Schulzeines share O-sulfated fatty acid structures with
penasulfates3b and penarolides3c but contain a unique 3-amino-
benzo[α]quinolizidine core, which is not based on a sugar
scaffold. Thus, the production of schulzeines has attracted
special attention from synthetic and medicinal chemists due to
the novel structures and intriguing biological activities
of these compounds. Several successful strategies have been
introduced for the synthesis of schulzeines A–C.4 We have also
achieved a highly efficient asymmetric synthesis of schulzeines
aCollege of Pharmacy, Seoul National University, 1 Gwanak-ro,
Gwanak-gu, Seoul 151-742, Korea. E-mail: ygsuh@snu.ac.kr;
Fax: +82-2-888-0649; Tel: +82-2-880-7875
bCollege of Pharmacy, Kyungpook National University, Daegu 702-701,
Korea
†Electronic supplementary information (ESI) available: Experimental
details, spectral data of all the new compounds and HPLC data of com-
pounds 11 and 16. See DOI: 10.1039/c2ob25772f
Fig. 1 Retrosynthetic analysis.
5202 | Org. Biomol. Chem., 2012, 10, 5202–5204
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Table 1 ACR of cyclic glycinamides 6 and 13–15
envisioned that the trans-3-aminobenzo[α]quinolizidine skeleton
of schulzeines A (1) and C (2) could be easily constructed by an
aza-Claisen rearrangement (ACR)-induced ring expansion of the
1-vinyl-N-glycyl-isoquinoline 6 and a subsequent stereospecific
transannulation of the resulting 10-membered lactam 5. The
initial C11b-chiral center of ACR precursor 6 would be intro-
duced by the asymmetric alkylation of the 3,4-dihydroisoquino-
line 7, which could be readily prepared from the commercially
available amine 8.
The first obstacle to overcome in our synthetic approach
involved the asymmetric allylation of dihydroisoquinoline 7.
Asymmetric alkylations of 8-alkoxy-substituted dihydroisoqui-
nolines such as 7 have been limited due to low enantioselectivi-
ty.4h,5 Only a few successful examples have been reported to
date, and most of the reactions gave moderate or good enantio-
selectivities up to 82% ee.4h,5a However, we were able to
achieve the highly enantioselective allylation of the 8-benzy-
loxy-substituted dihydroisoquinoline 7, with a high enantioselec-
tivity of 90% ee, by utilizing the Nakamura protocol6 as shown
in Scheme 1. We assumed the absolute stereochemistry of 9 as
R-configuration based on the previous report6 and confirmed it
based on the optical rotation of 3. To the best of our knowledge,
we present the first application of the enantioselective allylation
of an 8-alkoxy-substituted dihydroisoquinoline with high facial
selectivity.
Entry
X
Solvent
Base (equiv.)
Temp.
Yielda (%)
1
2
3
4
5
6
7
8
9
10
N3
N3
PhMe
PhMe
PhMe
PhMe
PhMe
PhH
PhH
PhH
PhH
PhH
LHMDS (3)
iPrMgCl (3)
LHMDS (3)
LHMDS (4)
iPrMgCl (4)
LHMDS (4)
iPrMgCl (4)
iPrMgCl (4)
iPrMgCl (4)
iPrMgCl (4)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
50 °C
NRb
NR
NR
10
22
18
NHBoc
NH2
NH2
NH2
NH2
NH2
NH2
NHFmoc
64
65
25 °Cc
Reflux
50
40d
a Isolated yield by flash column chromatography. b No reaction. c Room
temperature. d See text.
afford the homoallylic amine 9 with an excellent enantioselectiv-
ity of 90% ee. The secondary amine 9 was coupled with 2-azi-
doacetic acid 10, which was prepared from glycine,8 to provide
amide 11. Subsequent oxidative cleavage of the terminal olefin
followed by reduction of the resulting aldehyde with NaBH4 in
methanol afforded alcohol 12. Alcohol 12 was converted into
olefin 13 using the Grieco procedure.9 Reduction of azide 13
using the Staudinger reaction10 gave the free amine 6. The reac-
tion of amine 6 with (Boc)2O or FmocCl produced the N-pro-
tected glycinamines 14 and 15.
The syntheses of the ACR precursors 6 and 13–15 are shown
in Scheme 1. Dihydroisoquinoline 7 was prepared by the treat-
ment of the commercially available amine 8 with hexamethylene
tetramine in TFA and acetic acid.4h,7 The dihydroisoquinoline 7
was then subjected to Nakamura’s asymmetric allylation6 to
With three types of ACR precursors (6, 13–15) in hand, we
carried out the pivotal ACR-induced ring expansion as summar-
ized in Table 1. As the Tsunoda group proposed, the reaction
seemed to proceed through a dianionic transition state, which
rendered the desired rearrangement feasible even at room temp-
erature.11 The free amine 6 proved to be the most appropriate for
the ring expansion reaction, whereas the N-Boc-protected glyci-
namide 14 did not undergo ACR (entry 3). Despite our extensive
efforts, the ACR of azide 13 was not successful (entries 1 and
2). The ACR of the N-Fmoc-protected glycinamide 15 provided
the free amine product 16, possibly due to the in situ generation
of the ACR precursor 6 (entry 10). The use of isopropyl mag-
nesium chloride as a base provided higher yields than did
LHMDS, and the use of toluene as a solvent significantly
reduced the chemical yields compared with the use of benzene
(entries 4–7). The ACR of the free amine 6 was successful even
at room temperature although the yield slightly decreased
(entries 7–9). The plausible transition state (6′) of the ACR-
induced ring expansion is shown in Scheme 2.
Finally, the acid-promoted highly stereoselective transannula-
tion of 16 afforded the desired benzoquinolizidine 3, which can
be efficiently transformed into schulzeines A and C according to
previous reports.4a,d–f The structure of 3 was confirmed by com-
1
parison of its spectral data including H NMR, 13C NMR, IR,
and HRMS with the data for an authentic sample. The stereo-
chemistry of 3 was also confirmed by comparison of the optical
Scheme 1 Preparation of ACR precursors 6 and 13–15.
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Korea grant funded by the Korean government (MEST)
(NRF-C1ABA001-2011-0018561).
Notes and references
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Scheme 2 Formal synthesis of schulzeines A and C.
rotation of 3 ([α]2D4 +170.8, c 0.50, CHCl3) with the reported one
(lit. [α]2D4 +182.4, c 2.10, CHCl3).4a
Conclusions
In conclusion, we have achieved a highly stereoselective formal
synthesis of schulzeines A and C in 10 steps with a 24% overall
yield starting from the commercially available amine 8. The key
features of our synthesis are the highly enantioselective
Nakamura’s asymmetric allylation of the 8-benzyloxy-substi-
tuted dihydroisoquinoline, the ring expansion of 1-vinyl-N-
glycyl-isoquinoline through amide enolate-induced ACR and
stereospecific transannulation for the efficient construction of the
benzoisoquinolizidine scaffold.
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Acknowledgements
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean government (MEST)
(No. 2011-0030635) and a National Research Foundation of
11 T. Tsunoda, S. Tatsuki, Y. Shiraishi, M. Akasaka and S. Itô, Tetrahedron
Lett., 1993, 34, 3297.
5204 | Org. Biomol. Chem., 2012, 10, 5202–5204
This journal is © The Royal Society of Chemistry 2012