Total synthesis of (-)-Haouamine B pentaacetate and structural revision of haouamine B

Article abstract of DOI:10.1002/anie.201407686

The enantiocontrolled total synthesis of (-)-haouamine B pentaacetate was accomplished via an optically active indane-fused β-lactam, which was prepared by a newly developed Friedel-Crafts reaction. Subsequent cleavage of the β-lactam and an intramolecular McMurry coupling reaction provided the core indane-fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zuba.

Full text of DOI:10.1002/anie.201407686

Angewandte
Chemie
DOI: 10.1002/anie.201407686
Natural Product Synthesis
Total Synthesis of (ꢀ)-Haouamine B Pentaacetate and Structural
Revision of Haouamine B**
Yuichi Momoi, Kei-ichiro Okuyama, Hiroki Toya, Kenji Sugimoto, Kentaro Okano, and
Hidetoshi Tokuyama*
Dedicated to Professor Amos B. Smith, III on the occasion of his 70th birthday
Abstract: The enantiocontrolled total synthesis of (ꢀ)-haou-
amine B pentaacetate was accomplished via an optically active
indane-fused b-lactam, which was prepared by a newly
developed Friedel–Crafts reaction. Subsequent cleavage of
the b-lactam and an intramolecular McMurry coupling
reaction provided the core indane-fused tetrahydropyridine,
which led to the elucidation of the structure, as proposed by
Trauner and Zubꢀa.
Figure 1. Revision of the structure of haouamine B. 1: initially pro-
posed structure, 2: newly proposed structure by Trauner and Zubꢀa.
H
aouamines were isolated from a tunicate, Aplidium
haouarianum, at the southern coast of Spain by Zubꢀa and
co-workers in 2003.[1] They exhibit highly specific and strong
cytotoxicity against the HT-29 human colon carcinoma cell
line (haouamine A; IC50 = 200 nm). Structurally, haouamines
have unique features, such as the cis-fused indeno-tetrahy-
dropyridine and 3-aza-[7]-paracyclophane containing a bent
aromatic ring. The intriguing structure of haouamine A was
elucidated by X-ray crystallographic analysis[1] and through
total synthesis by Baran and Burns.[2a] The structure of
haouamine B (1) was also determined by Zubꢀa in 2003 using
2D NMR data. Very recently, however, Trauner and Zubꢀa
structure, but this has not been achieved despite considerable
synthetic endeavors to construct the indeno-tetrahydropyr-
idine core and cyclophane moiety in the haouamine family of
compounds.[4,5] Herein we describe the first enantiocontrolled
synthesis of natural haouamine B (2), based on the develop-
ment of a mild Friedel–Crafts alkylation of the azetidium ion
for the construction of the sterically hindered dihydroxyin-
deno-tetrahydropyridine and confirm the newly proposed
structure by Trauner and Zubꢀa.
The retrosynthetic analysis of structure 2 is depicted in
Scheme 1. Considering the utilization of Baranꢁs protocol,[2c]
we set indane-fused dihydropyridone 3 as a key intermediate
for 2. On the basis of our preliminary synthetic studies on the
initially proposed structure 1,[5b] the dihydropyridone would
be formed through an intramolecular McMurry coupling[6] of
4, which should be derived through the ring-opening of b-
lactam 5. The cis-fused b-lactam 5 should be accessible from
mesylate 8 by an intramolecular Friedel–Crafts alkylation of
the cationic species 7. The cyclization should proceed at the
hindered C2b position to form the 1,2,3,4-tetrasubstituted
aromatic ring. Therefore, mesylate 8 should have a removable
substituent R, such as a halogen atom or a pseudohalogen
moiety, at the less-hindered C6 position. Mesylate 8 would be
derived from b-aminoester 9, which we planned to prepare by
Ellmanꢁs diastereoselective Mannich reaction using optically
active sulfinimine 10 and glycolate 11.[7]
We started the synthesis by preparing sulfinimine 17 from
the known allylbenzene derivative 13, which was readily
available from 3,4-dimethoxyphenol (12) (Scheme 2).[8] Dihy-
droxylation of alkene 13 afforded diol 14 in 96% yield over
four steps. After the oxidative cleavage of diol 14, dehydrative
condensation of the resultant aldehyde 15 and optically active
sulfinamide 16[7] provided the corresponding sulfinimine 17.
Using 17, we then examined the diastereoselective Mannich
reaction. Thus, treatment of 17 with a lithium enolate,
prepared from O-Boc glycolate 11,[9] provided b-aminoester
18 as a single isomer in 86% yield. Interestingly, unlike in the
1
reported an inconsistency between the H NMR spectra of
the natural compound and that of their synthetically obtained
haouamine B.[3] After careful inspection of the 1H NMR
spectra of the synthetic 1 and natural haouamine B, they
concluded that the initially proposed structure of haouami-
ne B, 1, should be revised to 2 (Figure 1).
The total synthesis of this newly proposed structure of
haouamine B (2) should end the argument regarding the
[*] Y. Momoi, Dr. K.-i. Okuyama, Dr. H. Toya, Dr. K. Sugimoto,
Dr. K. Okano, Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: tokuyama@mail.pharm.tohoku.ac.jp
[**] This work was financially supported by the Cabinet Office, Govern-
ment of Japan, through its “Funding Program for Next Generation
World-Leading Researchers” (LS008), the JSPS KAKENHI, a Grant-
in-Aid for Scientific Research (B) (20390003) and Scientific
Research (A) (26253001), the Nagase Science and Technology
Foundation for H.T., a Grant-in-Aid for Young Scientists (B)
(19790004) for K.S., and JSPS predoctoral fellowship for Y.M. We
thank Prof. D. Trauner for his valuable suggestions on the formation
of the aza-paracyclophane, and Professors H. Ishibashi and T.
Taniguchi (Kanazawa Univ.) for their valuable discussions on the
reduction of the unsaturated lactam.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407686.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Scheme 1. Retrosynthetic analysis of haouamine B (2).
related report by Qin and co-workers, who used an arylsulfi-
nimine,[9] the absolute configuration of the C2 and C3
positions was 2R and 3S, which was determined by compar-
ison of specific rotations after transformation of 18 to
a known compound.[10] Having successfully constructed the
consecutive stereogenic centers, we then focused on the
intramolecular Friedel–Crafts alkylation of the tertiary alco-
hol 22.[5b] After manipulation of protecting groups, the
resultant compound 19 was subjected to the Merck proto-
col[11] to provide b-lactam 20. N-Benzylation and subsequent
removal of the TES group gave the secondary alcohol 21,
which was converted to substrate 22 for the key Friedel–
Crafts alkylation through Swern oxidation and diastereose-
lective 1,2 addition of an aryl Grignard reagent to the
azetidin-2,3-dione.[12] Conversion of the tertiary alcohol to its
mesylate,[13] which was treated with TfOH,[5b] unexpectedly
afforded chromane 24 in 44% yield. The reaction proceeded
through a nucleophilic attack of the oxygen atom of the
benzyl ether to form the six-membered oxonium intermediate
23 followed by the removal of the benzyl cation.[14]
Scheme 2. Preparation of the optically active b-aminoester 18.
Reagents and conditions: a) OsO4 (1 mol%), NMO, THF/tBuOH/
H2O, RT, 96% (over 4 steps); b) NaIO4, MeOH/H2O, RT; c) 16, cat.
PPTS, MgSO4, CH2Cl2, RT, 53% (over 2 steps); d) 11, LHMDS, THF,
ꢀ788C, 86% (sole isomer); e) HCl, MeOH/1,4-dioxane, 08C!RT;
f) TESCl, Et3N, CH2Cl2, 08C!RT, 97% (over 2 steps); g) tBuMgCl,
THF, 08C; h) KHMDS, THF, ꢀ788C, then BnBr, TBAI, ꢀ78!08C;
i) TBAF, THF, 08C, 61% (over 3 steps); j) (COCl)2, DMSO, CH2Cl2,
ꢀ78!ꢀ458C, then Et3N, ꢀ45!08C; k) 3-methoxyphenyl magnesium
bromide, THF, 08C, 76% (over 2 steps); l) MsCl, Et3N, CH2Cl2, 08C;
m) TfOH, CH3CN, ꢀ408C!RT, 44% (over 2 steps). NMO=N-methyl-
morpholine oxide, PPTS=pyridinium p-toluenesulfonate,
LHMDS=lithium hexamethyldisilazide, TES=triethylsilyl,
KHMDS=potassium hexamethyldisilazide, TBAI=tetra-n-butylammo-
nium iodide, TBAF=tetra-n-butylammonium fluoride, DMSO=dime-
thylsulfoxide.
mane 24 in 36% yield (Scheme 3, entry 1). In this case, the
TIPS ether was primarily deprotected, and subsequent
cyclization to the carbocation from the generated phenolic
hydroxy group provided chromane 24. Next, we examined
a variety of Lewis acids for preventing the undesired
To circumvent the undesired cyclization, we switched the
benzyl group to the more bulky TIPS group with the intention
of reducing the nucleophilicity of the oxygen atom and
investigated a variety of Brønsted/Lewis acids (Scheme 3).
After hydrogenolysis of the benzyl ether, introduction of the
TIPS group followed by mesylation of the tertiary alcohol
afforded substrate 26 for the Friedel–Crafts alkylation.
Treatment of 26 with TfOH in acetonitrile provided chro-
[15]
protodesilylation and found that Sc(OTf)3 was a superior
acid to selectively afford indeno-b-lactam 27, albeit in low
yield (Scheme 3, entry 2). Speculating that the low yield was
attributed to the in situ generation of TfOH, we performed
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
the reaction in the presence of 2,6-di-tert-butylpyridine
(DTBPy). As expected, the desired compound 27 was
obtained in 80% yield with the labile TIPS group intact
(Scheme 3, entry 3).
The silyloxy blocking group was essential for the Friedel–
Crafts alkylation (Scheme 4). We first tested substrate 28[16]
with a bromo group in accordance with Rawalꢁs synthesis of
Scheme 3. Successful intramolecular Friedel–Crafts alkylation.
Reagents and conditions: a) H2 (1 atm), Pd/C (20 mol%), EtOAc/
EtOH, RT; b) TIPSCl, Et3N, DMF, 08C; c) MsCl, Et3N, CH2Cl2, 08C,
88% (over 3 steps). TIPS=tri-iso-propylsilyl, DTBPy=2,6-di-tert-butyl-
pyridine.
Scheme 4. Preliminary trials in the Friedel–Crafts alkylation. Reagents
and conditions: a) TfOH, CH3CN, ꢀ408C!RT or TfOH, CH2Cl2,
ꢀ408C!RT. n.d.=not detected.
Scheme 5. Total synthesis of (ꢀ)-haouamine B pentaacetate (42).
Reagents and conditions: a) TBAF, THF, 08C, quant.; b) Tf2O, Et3N,
CH2Cl2, 08C; c) Pd(OAc)2, DPPF, HCO2H, DMF, 808C, 89% (over
2 steps); d) Na, tBuOH, anisole, liq. NH3/THF, ꢀ788C; e) Boc2O,
DMAP, CH2Cl2, 08C, 92% (over 2 steps); f) LiAlH4, THF, 08C; g) HCl,
CH2Cl2/1,4-dioxane, 08C!RT; h) TBSCl, imidazole, CH2Cl2/DMF, RT,
73% (over 3 steps); i) BnBr, K2CO3, CH3CN, 08C!RT; j) TBAF, THF,
608C, 81% (over 2 steps); k) 37, DMT-MM, THF, RT, 57%; l) (COCl)2,
DMSO, CH2Cl2, ꢀ78!ꢀ458C, then Et3N, ꢀ45!08C; m) TiCl4, Zn/Cu,
DME, 08C!reflux, 47% (over 2 steps); n) BBr3, TBAI, CH2Cl2, 08C;
o) Ac2O, pyridine, 08C!RT, 53% (over 2 steps). TBAF=tetra-n-buty-
lammonium fluoride, Tf=trifluoromethanesulfonyl, DPPF=1,1’-bis(di-
phenylphosphino)ferrocene, DMAP=N,N-dimethyl-4-aminopyridine,
TBS=tert-butyldimethylsilyl, DMF=N,N-dimethylformamide, DMT-
MM=4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholium chloride,
DMSO=dimethylsulfoxide, DME=1,2-dimethoxyethane, TBAI=tetra-
n-butylammonium iodide, Ac2O=acetic anhydride.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
haouamine A,[4e] providing not only the desired compound 29,
but also the unexpected indeno-b-lactam 30 in 37% yield (in
dichloromethane) and the debrominated compound 31 in
34% yield (in acetonitrile).[17]
[2] a) P. S. Baran, N. Z. Burns, J. Am. Chem. Soc. 2006, 128, 3908 –
3909; b) N. Z. Burns, P. S. Baran, Angew. Chem. Int. Ed. 2008, 47,
205 – 208; Angew. Chem. 2008, 120, 211 – 215; c) N. Z. Burns,
I. N. Krylova, R. N. Hannoush, P. S. Baran, J. Am. Chem. Soc.
2009, 131, 9172 – 9173; d) N. Z. Burns, M. Jessing, P. S. Baran,
Tetrahedron 2009, 65, 6600 – 6610; e) R. A. Shenvi, D. P. OꢁMal-
ley, P. S. Baran, Acc. Chem. Res. 2009, 42, 530 – 541.
We then focused on the construction of the indenotetra-
hydropyridine core (Scheme 5). Initially, the OTIPS group
was reductively removed via the corresponding triflate to give
key intermediate 5. The b-lactam was reductively cleaved
after switching the benzyl group to the Boc group to enhance
the electrophilicity of the carbonyl group. Thus, the benzyl
group was removed by Birch reduction in the presence of
excess anisole to prevent over-reduction of the aromatic
ring.[18] Reduction of N-Boc-b-lactam 34 with LiAlH4 pro-
ceeded to give the primary alcohol. Subsequent removal of
the Boc group and protection of the hydroxy group provided
primary amine 35, which was converted to ketoamide 38
through condensation of 36 and a-keto acid 37 using DMT-
MM.[19] The sterically hindered alcohol was smoothly con-
verted by Swern oxidation to aldehyde 4, which was treated
with TiCl4 and Zn/Cu in refluxing DME to give the cis-fused
indeno-dihydropyridone 3 in 47% yield over two steps.[6] The
stage was set for the synthesis of 2, the newly proposed
structure of haouamine B by Trauner and Zubꢀa. According
to Ishibashiꢁs conditions,[4c] we transformed lactam 3 to
tetrahydropyridine 39 in a three-step sequence. Following
Baranꢁs protocol,[2c] we conducted Suzuki–Miyaura cross-
coupling of borylated compound 39 and iodocyclohexenone
40,[2c,20] followed by oxidation of the resulting cyclohexenone
to provide aza-paracyclophane 41.[21] Finally, cleavage of all
methyl ethers in 41 by a combination of BBr3 and TBAI[22]
followed by acetylation of the resulting phenolic hydroxy
groups provided (ꢀ)-haouamine B pentaacetate (42)
[3] M. Matveenko, G. Liang, E. M. W. Lauterwasser, E. Zubꢀa, D.
Trauner, J. Am. Chem. Soc. 2012, 134, 9291 – 9295.
[4] a) J. H. Jeong, S. M. Weinreb, Org. Lett. 2006, 8, 2309 – 2312;
b) A. Fꢃrstner, J. Ackerstaff, Chem. Commun. 2008, 2870 – 2872;
c) T. Taniguchi, H. Zaimoku, H. Ishibashi, J. Org. Chem. 2009,
74, 2624 – 2626; d) E. Fenster, C. Fehl, J. Aubꢄ, Org. Lett. 2011,
13, 2614 – 2617; e) N. D. Smith, J. Hayashida, V. H. Rawal, Org.
Lett. 2005, 7, 4309 – 4312; f) P. Wipf, M. Furegati, Org. Lett. 2006,
8, 1901 – 1904.
[5] a) M. A. Grundl, D. Trauner, Org. Lett. 2006, 8, 23 – 25; b) K.
Okuyama, Y. Momoi, K. Sugimoto, K. Okano, H. Tokuyama,
Synlett 2011, 73 – 76; c) T. Tanaka, H. Inui, H. Kida, T. Kodama,
T. Okamoto, A. Takeshima, Y. Tachi, Y. Morimoto, Chem.
Commun. 2011, 47, 2949 – 2951; d) A. M. Belostotskii, J. Org.
Chem. 2008, 73, 5723 – 5731.
[6] a) A. Fꢃrstner, D. N. Jumbam, N. Shi, Z. Naturforsch. 1995, 50B,
326 – 332; b) A. Fꢃrstner, D. N. Jumbam, Tetrahedron 1992, 48,
5991 – 6010; c) J. E. McMurry, Chem. Rev. 1989, 89, 1513 – 1524;
´
d) A. Fꢃrstner, B. Bogdanovic, Angew. Chem. Int. Ed. Engl.
1996, 35, 2442 – 2469; Angew. Chem. 1996, 108, 2582 – 2609.
[7] T. P. Tang, J. A. Ellman, J. Org. Chem. 2002, 67, 7819 – 7832.
[8] G. Bꢃchi, P.-S. Chu, J. Am. Chem. Soc. 1981, 103, 2718 – 2721.
[9] Y. Wang, Q.-F. He, H.-W. Wang, X. Zhou, Z.-Y. Huang, Y. Qin, J.
Org. Chem. 2006, 71, 1588 – 1591.
[10] The diastereoselectivity of the Mannich adduct 18 was deter-
mined by the comparison of its optical rotation with that of the
aminoalcohol derivative (see the Supporting Information). R.
Badorrey, C. Cativiela, M. D. Dꢀaz-de-Villegas, J. A. Gꢂlvez,
Tetrahedron 2002, 58, 341 – 354. In our previous report
(Ref. [5b]), we tentatively assigned the absolute configuration
of a similar compound as its enantiomer according to Ref. [9].
[11] a) T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen, F. A.
Bouffard, J. Am. Chem. Soc. 1980, 102, 6161 – 6163; b) J. K.
Lynch, M. W. Holladay, K. B. Ryther, H. Bai, C.-N. Hsiao, H. E.
Morton, D. A. Dickman, W. Arnold, S. A. King, Tetrahedron:
Asymmetry 1998, 9, 2791 – 2794; c) J. A. DeMattei, M. R.
Leanna, W. Li, P. J. Nichols, M. W. Rasmussen, H. E. Morton,
J. Org. Chem. 2001, 66, 3330 – 3337.
1
(1.2 mg).[23] Its H and 13C NMR spectra and analytical data
were identical to those of pentaacetylated haouamine B from
isolated natural haouamine B (2) [derived from natural
20
haouamine B by Zubꢀa: ½aꢁD ¼ꢀ27.1 (c = 0.14, CHCl3),[1]
30
synthetic: ½aꢁD ¼ꢀ28 (c = 0.17, CHCl3)].
In summary, we have put an end to the arguments
concerning the structure of natural haouamine B by the
enantiocontrolled total synthesis of the newly proposed
structure of (ꢀ)-haouamine B pentaacetate (42) from com-
mercially available 3,4-dimethoxyphenol (12) in 40 steps in
0.055% overall yield with an average 83% chemical yield for
each step. Our synthesis features Ellmanꢁs diastereoselective
Mannich reaction to generate b-aminoester and the Sc(OTf)3-
mediated intramolecular Friedel–Crafts alkylation to con-
struct the unusual indane-fused b-lactam 27, which was
converted to (ꢀ)-haouamine B pentaacetate (42) through an
intramolecular McMurry coupling.
[12] The stereochemistry was tentatively assigned based on the
general reactivity of 4-substituted azetidine 2,3-dione. For an
example, see: J. Kant, W. S. Schwartz, C. Fairchild, Q. Gao, S.
Huang, B. H. Long, J. F. Kadow, D. R. Langley, V. Farina, D.
Vyas, Tetrahedron Lett. 1996, 37, 6495 – 6498.
[13] The activation of the alcohol as a mesylate was necessary for the
smooth conversion of the starting material.
[14] For a similar example of the formation of a chromane by
removal of a methoxymethyl group, see: a) J. Xue, X. Zhang, X.
Chen, Y. Zhang, Y. Li, Synth. Commun. 2003, 33, 3527 – 3536.
Other phenol methoxymethyl ethers in the starting material
remained intact in the above example, which indicated the
intermediate formation of the oxonium ion.
[15] a) H. Kotsuki, T. Oshisi, M. Inoue, Synlett 1998, 255 – 256; b) H.
Kotsuki, T. Ohishi, M. Inoue, T. Kojima, Synthesis 1999, 603 –
606.
[16] In our early experiments, we examined the reaction with
substrate 28, which has opposite configurations to those of
natural haouamine B.
[17] These compounds would be generated via ipso-substituted
intermediate 32 and subsequent intramolecular transfer or
trapping of the bromine atom with a nucleophile to give the
Received: July 28, 2014
Published online: && &&, &&&&
Keywords: alkaloids · aromatic substitution · cross-coupling ·
.
cyclization · total synthesis
[1] L. Garrido, E. Zubꢀa, M. J. Ortega, J. Salvꢂ, J. Org. Chem. 2003,
68, 293 – 299.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
compounds 30 or 31.
the undesired reduction of the 3-methoxyphenyl group, and thus
is essential for the high-yielding process.
[19] M. Kunishima, C. Kawachi, K. Hioki, K. Terao, S. Tani,
Tetrahedron 2001, 57, 1551 – 1558.
[20] a) J. Jiricek, S. Blechert, J. Am. Chem. Soc. 2004, 126, 3534 –
3538; b) S. Shimizu, K. Omori, T. Arai, H. Sasai, M. Shibasaki, J.
Org. Chem. 1998, 63, 7547 – 7551.
[21] J. Matsuo, D. Iida, K. Tatani, T. Mukaiyama, Bull. Chem. Soc.
Jpn. 2002, 75, 223 – 234.
[22] P. R. Brooks, M. C. Wirtz, M. G. Vetelino, D. M. Rescek, G. F.
Woodworth, B. P. Morgan, J. W. Coe, J. Org. Chem. 1999, 64,
9719 – 9721.
Compounds 30 and 31 were also obtained by utilizing Sc(OTf)3
and 2,6-di-tert-butylpyridine in dichloromethane in 34% and
26% yields, respectively (for details, see the Supporting
Information). The structure of compound 30 was determined
by the synthesis of 30 using another approach and comparison of
1H NMR spectra. The structure of 31 was determined by X-ray
diffraction analysis. CCDC 981399 (31) contains the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[23] We attempted the deacetylation of (ꢀ)-haouamine pentaacetate
(42) to obtain haouamine B (2) according to Traunerꢁs protocol
in their synthesis of isohaouamine B.[3] Monitoring of the
reaction by ESI-MS analysis of aliqots taken from the reaction
mixture indicated a progress of smooth deacetylation to mainly
provide haouamine B. Disappointingly, however, we failed to
isolate haouamine B (2) using potassium carbonate in methanol.
Treatment of (ꢀ)-haouamine pentaacetate (42) with 10%
NH4OH in methanol provided a product whose m/z (ESI mass
spectrometry) was corresponding to that of haouamine B (2).
For details, see the Supporting Information.
[18] In the absence of anisole, the desired product was obtained in
a low yield because of the concomitant over-reduction of the 3-
methoxyphenyl group. The excess amount of anisole suppressed
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Natural Product Synthesis
Revision: Key steps in the total synthesis
of (ꢀ)-haouamine B pentaacetate (see
structure) are the enantiocontrolled con-
struction of indane-fused tetrahydropyri-
dine based on Ellman’s diastereoselective
Mannich reaction and the newly devel-
oped mild Friedel–Crafts alkylation. The
synthesis led to the revision of the
structure, as proposed by Trauner and
Zubꢀa.
Y. Momoi, K.-i. Okuyama, H. Toya,
K. Sugimoto, K. Okano,
H. Tokuyama*
&&&& — &&&&
Total Synthesis of (ꢀ)-Haouamine B
Pentaacetate and Structural Revision of
Haouamine B
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!