Total synthesis of broussonetine F: The orthoamide overman rearrangement of an allylic diol

Article abstract of DOI:10.1021/ol102856j

A first total synthesis of broussonetine F from diethyl l-tartrate was achieved. The cornerstone of our synthesis was an orthoamide Overman rearrangement, which provided an allylic amino alcohol with complete diastereoselectivity.

Full text of DOI:10.1021/ol102856j

ORGANIC
LETTERS
2011
Vol. 13, No. 4
616–619
Total Synthesis of Broussonetine F: The
Orthoamide Overman Rearrangement of
an Allylic Diol
Naoto Hama, Toshihiro Aoki, Shohei Miwa, Miki Yamazaki, Takaaki Sato, and
Noritaka Chida*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University,
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
chida@applc.keio.ac.jp
Received November 25, 2010
ABSTRACT
A first total synthesis of broussonetine F from diethyl L-tartrate was achieved. The cornerstone of our synthesis was an orthoamide Overman
rearrangement, which provided an allylic amino alcohol with complete diastereoselectivity.
Our laboratory has been exploring new strategies to
obtain biologically active natural products by using sigma-
tropic rearrangements of naturally occurring chiral poly-
ols, such as carbohydrates and tartaric acid, with chirality
transfer.1 For example, we developed a sequential Overman
rearrangement of allylic 1,2-bistrichloroimidate 2, which
was prepared from tartaric acid via allylic alcohol 1 to give
bistrichloroacetamide 3 (Scheme 1).2,3 The reaction pro-
ceeded with complete chirality transfer of two hydroxy
groups and installed the diamino moiety in a single opera-
tion. This strategy was successfully applied to two enan-
tioselective total syntheses of biologically active complex
molecules, A-315675 and agelastatin A.3c,d
To expand the concept of chirality transfer from enan-
tiopure polyols, we envisioned an orthoamide Overman
rearrangement (Scheme 1, 4f5f6).4,5 If cyclic orthoamide
4 could be selectively formed from allylic 1,2-diol 1, this
compound would undergo the single rearrangement via
R-hydroxy imidate 5. Although the sequential Overman
rearrangement can install two identical functional groups
(2f3), the orthoamide Overman rearrangement could
(1) For selected reviews on chirality transfer through sigmatropic
rearrangements, see: (a) Enders, D.; Knopp, M.; Schiffers, R. Tetra-
hedron: Asymmetry 1996, 7, 1847–1882. (b) Nubbemeyer, U. Synthesis
2003, 961–1008. (c) Poulin, J.; Grise- Bard, C. M.; Barriault, L. Chem. Soc.
Rev. 2009, 38, 3092–3101. (d) Ilardi, E. A.; Stivala, C. E.; Zakarian, A.
Chem. Soc. Rev. 2009, 38, 3133–3148.
(2) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597–599. For
reviews on Overman rearrangement, see:(b) Overman, L. E.; Carpenter, N. E.
In Organic Reactions; Overman, L. E., Ed.; Wiley: New York, NY, 2005;
Vol. 66, pp 1-107.
(3) For selected examples of sequential Overman/Overman rearran-
gements, see: (a) Banert, K.; Fendel, W.; Schlott, J. Angew. Chem., Int.
Ed. 1998, 37, 3289–3292. (b) Demay, S.; Kotschy, A.; Knochel, P. Synthesis
2001, 863–866. (c) Momose, T.; Hama, N.; Higashino, C.; Sato, H.; Chida, N.
Tetrahedron Lett. 2008, 49, 1376–1379. (d) Hama, N.; Matsuda, T.; Sato, T.;
Chida, N. Org. Lett. 2009, 11, 2687–2690. We have also reported the formal
total synthesis of (-)-morphine by the sequential Claisen rearrangement
starting from D-glucal; see:Tanimoto, H.; Saito, R.; Chida, N. Tetrahedron
Lett. 2008, 49, 358–362.
ꢀ
(4) We reported orthoamide-type Claisen rearrangements of allylic
diols, which was successfully applied to the total synthesis of (-)-kainic
acid; see: Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.; Chida, N.
Org. Lett. 2010, 12, 5756–5759.
(5) (a) Vyas, D. M.; Chiang, Y.; Doyle, T. W. J. Org. Chem. 1984, 49,
2037–2039. (b) Danishefsky, S.; Lee., J. Y. J. Am. Chem. Soc. 1989, 111,
4829–4837.
r
10.1021/ol102856j
Published on Web 12/31/2010
2010 American Chemical Society

Scheme 1. Sequential and Orthoamide Overman Rearrange-
ments
Figure 1. Representative broussonetines.
Scheme 2. Synthetic Plan for Broussonetine F
terminate the reaction after the first rearrangement. In con-
trast to the conventional Overman rearrangement, which re-
quires protection of the homoallylic alcohol in allylic 1,2-
diol 1, the orthoamide-type reaction would enable us to
perform the reaction with free 1,2-diols. The resulting allylic
alcohol would undergo a variety of transformations. In
spite of its utility, few orthoamide versions are documented.5
Vyas reported that a rearrangement of the seven-membered
cyclic orthoamide, prepared from Z-2-butene-1,4-diol, pro-
ceeded in 85% yield.5a Danishefsky disclosed in the total
synthesis of (()-pancratistatin that the orthoamide from an
allylic 1,2-diol did not undergo the Overman rearrangement
and also gave valuable mechanistic insight on this reaction.5b
To study the feasibility of the orthoamide Overman re-
arrangement intotal synthesis, we have taken note of a new
class of pyrrolidine alkaloids, broussonetines (Figure 1).6
Isolated from the branches of Broussonetia kazinoki by
Kusano and co-workers, broussonetines consist of a com-
mon pyrrolidine unit and a variable long hydrocarbon side
chain. Most broussonetines have been shown to possess
highly potent and selective glycosidase inhibitory activities.
Interestingly, their inhibitory profile depends on the struc-
ture of the long hydrocarbon side chain. Because of their
interesting structures and biological properties, a number of
synthetic chemists have undertaken studies on the synthesis
of broussonetines.7,8 Yoda reported the first enantiosele-
ctive total synthesis of broussonetine C (7) by Lewis acid
promoted deoxygenation of a C2-symmetrical imide as a
key step.7a Perlmutter completed the second total synthesis
of broussonetine C (7), using chiral-pool methodology
from D-arabinose.7b Trost determined the stereochemistry
of three carbon centers (C-10, C-60, C-100) on the side chain
in broussonetine G (11) and accomplished the total synth-
esis through a palladium-mediated dynamic kinetic asym-
metric transformation.7c,d Very recently, Marco reported a
convergent approach utilizing a cross-metathesis reaction,
which culminated in the total synthesis of broussonetines
D (8) and M.7e In this communication, we report the first
total synthesis of broussonetine F (10) from L-tartrate
employing the orthoamide Overman rearrangement.
Our synthetic plan toward broussonetine F is outlined
in Scheme 2. Considering a universal route toward the
broussonetine family with its variety of side chains, it would
be reasonable to adopt the late-stage coupling reaction
between common pyrrolidine unit13and side chain unit 12
by a B-alkyl Suzuki-Miyaura coupling reaction.9 Pyrro-
lidine 13 would be constructed by the alkylative cyclization
of open chain intermediate 14. This intermediate could be
synthesized from allylic amino alcohol 15 through two
diastereoselective reactions: (i) dihydroxylation (C3, C4)
and (ii) allylation (C10). As a defining feature of our
synthesis, weenvisioned that allylicamino alcohol15could
(6) For a review on isolation, biosynthesis, and biological activities of
broussonetines, see: Shibano, M.; Tsukamoto, D.; Kusano, G. Hetero-
cycles 2002, 57, 1539–1553. For selected reports on isolation of brousso-
netines, see:(a) Shibano, M.; Kitagawa, S.; Kusano, G. Chem. Pharm. Bull.
1997, 45, 505–508. (b) Shibano, M.; Kitagawa, S.; Nakamura, S.; Akazawa,
N.; Kusano, G. Chem. Pharm. Bull. 1997, 45, 700–705. (c) Shibano, M.;
Nakamura, S.; Akazawa, N.; Kusano, G. Chem. Pharm. Bull. 1998, 46,
1048–1050.
(7) For total syntheses of broussonetines, see: (a) Yoda, H.; Shimojo,
T.; Takabe, K. Tetrahedron Lett. 1999, 40, 1335–1336. (b) Perlmutter, P.;
Vounatsos, F. J. Carbohydr. Chem. 2003, 22, 719–732. (c) Trost, B. M.;
Horne, D. B.; Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42, 5987–5990.
(d) Trost, B. M.; Horne, D. B.; Woltering, M. J. Chem.;Eur. J. 2006, 12,
6607–6620. (e) Ribes, C.; Falomir, E.; Murga, J.; Carda, M.; Marco, J. A.
Org. Biomol. Chem. 2009, 7, 1355–1360.
(8) For a selected example of a synthetic study on broussonetines, see:
Brimble, M. A.; Park, J. H.; Taylor, C. M. Tetrahedron 2003, 59, 5861–
5868.
Org. Lett., Vol. 13, No. 4, 2011
617

Table 1. Orthoamide Overman Rearrangement of 19a
Scheme 3. Selective Formation of Cyclic Orthoamide 19
yield (%)
entry
additive
none
15
19
1
17
8
0
54
43
27
2
K2CO3
3
4b
BHT (100 mol %)
BHT (5 mol %)
19
56
a Conditions: 50 μmol of 19, t-BuPh, 180 °C in a sealed tube. b 406
μmol of 19 were used.
be stereoselectively synthesized by the orthoamide Over-
man rearrangement of Z-allylic 1,2-diol 16 derived from
L-tartrate.4
We then turned our attention to the construction of the
polyhydroxy pyrrolidine unit (Scheme 4). Prior to the cycli-
zation, we installed three secondary alcohols (C3, C4, C10).
The allylic alcohol in 15 was protected as a MOM ether to
give 20. Because the next dihydroxylation with achiral
OsO4 resulted in the undesired diasteroselectivity, 20 was
treated under Sharpless’ asymmetric conditions15 (dr = 3:1),
followed by recrystallization to furnish diol 21 in 61%
isolated yield. After benzyl protection and MPM depro-
tection, the C10 alcohol was stereoselectively established by
chelation-controlled Hosomi-Sakurai allylation.16 Namely,
Swern oxidation of primary alcohol 22 provided the alde-
hyde, which was treated with allyl trimethylsilane and
The synthesis of broussonetine F began with selective
formation of the cyclic orthoamide from allylic 1,2-diol 16,
which was prepared from diethyl L-tartrate (17) by a known
procedure (Scheme 3).4 To render our two novel sigma-
tropic rearrangements useful, flexible conditions to form
either bisimidate 18 or cyclic orthoamide 19 from the
common allylic 1,2-diol 16 are required. After an extensive
survey, we found that the amount of DBU and CCl3CN
and the order of addition were crucial. When excess CCl3-
CN (8 equiv) was added to a solution of 16, DBU (1 equiv),
and CH2Cl2, bisimidate 18 was selectively generated.3c,d,10
On the other hand, addition of a catalytic amount of DBU
(0.1 equiv) to a solution of 16, CCl3CN (1.3 equiv), and
CH2Cl2 resulted in the selective formation of cyclic orthoa-
mide 19 (dr = 1:1), along with a trace amount of bisimi-
date 18.
MgBr2 Et2O to afford 23 as a single diastereomer. The
resulting hydroxy group of 23 was protected as the benzyl
3
(10) The sequential Overman rearrangement of bistrichloroimidate
18 provided bistrichloroacetamide i in 92% yield.
With cyclic orthoamide 19in hand, the stage was now set
for the pivotal orthoamide Overman rearrangement (Table 1).
A solution of cyclic orthoamide 19 and tert-butylbenzene
was heated at 180 °C for 1 d in a sealed tube, giving allylic
amino alcohol 15 in 17% yield (entry 1).11 Because a
prolonged reaction time caused severe decomposition, we
next surveyed the effect of additives. Although K2CO3 did
not improve the yield (entry 2),12 we found that 2,6-di-tert-
butylhydroxytoluene (BHT) suppressed the rate of decom-
position to give 15 in 19% yield, together with recovery of
43% of 19 (entry 3).13,14 The amount of BHT was critical,
and 5 mol % of BHT gave the best results to afford 15 in
56% yield (77% yield brsm, entry 4). The reaction pro-
ceeded with complete chirality transfer probably through
a chairlike transition state,2 with 15 isolated as a single
diastereomer.
(11) Overman rearrangement of MOM-protected trichloroacetoimi-
date ii, which was synthesized from 16 in four steps, proceeded at lower
temperature and much faster than the orthoamide version. As Da-
nishefsky reported in ref 5b, we also observed that two diastereomers
of orthoamide 19 underwent equilibration at room temperature.
(12) Nishikawa, T.; Asai, M.; Ohyabu, N.; Isobe, M. J. Org. Chem.
1998, 63, 188–192.
ꢁ
(13) Ammenn, J.; Altmann, K.-H.; Bellus, D. Helv. Chim. Acta 1997,
(9) For selected reviews on B-alkyl Suzuki-Miyaura coupling, see:
(a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b) Chemler,
S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4544–4568. (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633–9695. (d) Sasaki, M.; Fuwa, H. Synlett 2004, 11, 1851–1874. (e)
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44,
4442–4489. (f) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–
286. (g) Doucet, H. Eur. J. Org. Chem. 2008, 2013–2030.
80, 1589–1606.
(14) We believe that BHT might suppress the decomposition path-
way via a radical species.
(15) (a) Becker, H.; Soler, M. A.; Sharpless, K. B. Tetrahedron 1995,
51, 1345–1376. (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547.
(16) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 16, 1295–1298.
618
Org. Lett., Vol. 13, No. 4, 2011

Scheme 4. Total Synthesis of Broussonetine F (10)
ether, followed by replacement of the MOM group with
the mesyl group. The reaction of 14 with NaOH in reflux-
ing EtOH resulted in cleavage of the trichloroacetyl group
and concomitant alkylative cyclization. Subsequent pro-
tection of the secondary amine as a benzyl carbamate gave
pyrrolidine 13 in 77% yield (2 steps).
In summary, we have achieved a total synthesis of bro-
ussonetine F (10), whose key step was orthoamide Over-
man rearrangement of an allylic diol. This reaction is a
useful transformation in total synthesis and complemen-
tary to our sequential Overman rearrangement. The flex-
ible synthetic route using the late-stage Suzuki-Miyaura
coupling to install a variety of side chain units is effective
for future investigations of potent and selective glycosidase
inhibitors.
To complete the total synthesis of broussonetine F, the
remaining task was the coupling to the long hydrocarbon
side chain (Scheme 4). Alkene 13 was treated with 9-BBN,
and the subsequent palladium-catalyzed B-alkyl Suzu-
ki-Miyaura couplingwithvinyliodide 1217 inthe presence
of AsPh3 and Cs2CO3 furnished 25 in 73% yield.18 Hydro-
genation of the alkene and removal of the benzyl groups
and the Cbz group in 25 were performed simultaneously.
Finally, methanolysis of the acetate accomplished the total
synthesis of broussonetine F (10). Our synthetic sample
was indistinguishable from the authentic natural sample
Acknowledgment. We especially thank Professor M.
Shibano (Osaka University of Pharmaceutical Sciences,
Japan) for providing naturalbroussonetine F and copies of
NMR spectra. Support from a Grant-in-Aid for Scientific
Research, B20350021 from the Ministry of Education,
Culture, Sports, Science and Technology, Japan is grate-
fully acknowledged.
1
on the basis of H NMR, 13CNMR, HRMS, IR, and its
optical rotation.
Supporting Information Available. Experimental pro-
cedures; copies of 1H NMR and 13C NMR spectra of new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Synthesis of vinyl iodide 12 is described in the Supporting
Information.
(18) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,
11014–11015.
Org. Lett., Vol. 13, No. 4, 2011
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