Synthesis of the Rubiyunnanin B Core Aglycon

Article abstract of DOI:10.1002/ejoc.201600741

Rubiyunnanin B possesses an intriguing anticancer profile whose activity is dependent on the glycosylation of a fused tyrosinyl residue. We have developed a rapid synthesis of the rubiyunnanin B dityrosine core using a Suzuki coupling. Furthermore, the atropisomeric and isomeric products obtained were identified and their distribution controlled. The two major products obtained from the dityrosine coupling were discovered to be locked cis/trans isomers of the internal amide with atropisomerization quantifiable on the NMR timescale.

Full text of DOI:10.1002/ejoc.201600741

A Journal of
Accepted Article
Title: Synthesis of the rubiyunnanin B core aglycone
Authors: Chad Arthur Lewis; Matthew Moschitto
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600741
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600741
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201600741
COMMUNICATION
Synthesis of the rubiyunnanin B core aglycone
Matthew J. Moschitto,[b] and Chad A. Lewis*[a]
Abstract: Rubiyunnanin B possesses an intriguing anticancer profile
whose activity is dependent on the glycosylation of a fused tyrosinyl
residue. We have developed a rapid synthesis of the rubiyunnanin B
dityrosine core using
a
Suzuki coupling.
Furthermore, the
atropisomeric and isomeric products obtained were identified and
their distribution controlled. The two major products obtained from
the dityrosine coupling were discovered to be locked cis/trans
isomers of the internal amide with atropisomerization quantifiable on
the NMR timescale.
The macrocyclic peptides isolated from the Rubiaceae
family1 are intriguing natural products with some members
possessing anticancer activity. The rubiyunnanins, a specific
class of compounds from this family (Figure 1), are hexapeptidic
macrocycles composed of two alanine amino acids (L-Ala, D-
Ala), three modified tyrosine residues, two of which form a fused
tyrosine dimer, and a third amino acid, which is alanine
(rubiyunnanin A and B) or glutamine (rubiyunnanin D). The
tyrosine dimer can either be formed from a carbon-oxygen bond
(deoxybouvardin and rubiyunnanin C), a carbon-carbon bond
(rubiyunnanin B), or a fused dihydrobenzofuran dimer (C-C and
C-O bond formations, rubiyunnanin A).2
Figure 2. (a) Previous Suzuki coupling by Takeya results in two distinct sets of
compounds. (b) Takeya’s atropisomeric population.3
In a majority of the rubiyunnanins, the tyrosine dimer (dityrosine)
forms a 12 membered macrocycle with an internal cis-amide.
Deoxybouvardin (4) exhibits IC50 concentrations between 0.001
and 0.014 μg/mL against various cancer cell lines; however, the
glycosylated variant, RA-XII, exhibits IC50 values substantially
higher between 1.8 and 10 μg/mL.2 Conversely, rubiyunnanin B
possesses a glycosylated tyrosine with measured IC50 values
between 3.6 and 31 μg/mL whereas the aglycone does not
possess antitumor activity (IC50 > 100 μg/mL).3,4
Given the interesting bioactivity of rubiyunnanin B, we
were keen to develop a synthesis of the core dityrosine to allow
for analogue production. Although no synthesis of rubiyunnanin
B has been reported, neo-RA-V has been prepared by the group
of Takeya.4 Their critical bond formation steps include a Suzuki
dityrosine coupling, amide bond formation, and N-methylation of
amides (Figure 2a). Suzuki coupling of the two tyrosine
fragments3 yielded the fused 12 member cycle, 8, which was
isolated as two isomers whose structures could not be
OMe
Me
N
O
N
R2
O
Me
O
N
HN
Me O
NH
O
Me
Me
O
O
HN
R3O
N
Me
deoxybouvardin RA-V (4): R3 = H, R2
RA-VII (5): R3 = b-glucose, R2 = Me
O
N
O
Me
N
O
differentiated
by
NMR
spectroscopy
but
were
Me
N
chromatographically separable.
HO
OR1
Me O
rubiyunnanin B (1) 1: R1= b-glucose, R2= Me
RA-V (2): R1= H, R2 = Me
rubiyunnanin C (3): R1 = H, R2 = CH2CH2CO2H
O
HO
rubiyunnanin A (6): R2 = Me
Figure 1. Rubiyunnanin family of macrocyclic peptides.
[a]
[b]
Prof. Dr. C. A. Lewis[+]
Department of Chemistry and Chemical Biology, Cornell University
259 East Ave., Ithaca, NY 14853 (USA)
E-mail: chad.lewis@cornell.edu
[+] Current address: Pfizer, Eastern Point Road, Groton, CT 06340
(USA). E-mail: Chad.Lewis@pfizer.com
Scheme 1. Retrosynthesis of rubiyunnanin B.
Dr. M. J. Moschitto
Department of Chemistry and Chemical Biology, Cornell University
259 East Ave., Ithaca, NY 14853 (USA)
[+] Current address: Northwestern University, Department of
Chemistry, 2145 Sheridan Road, Evanston, IL, 60208
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600741
COMMUNICATION
Scheme 2. Synthesis of rubiyunnanin B core aglycone. Reagents and conditions: a) CbzOSu, 1M NaOH/dioxane (1:1), 2 h; b) (CH2O)n, TsOH (0.1 equiv.),
C6H6:DMF (25:1), 100 °C, 2h; c) Et3SiH (3 equiv.), TFA:CH2Cl2 (1:1) 0 to 23 °C, 3h, 99% (three steps); d) SOCl2, MeOH, 80 °C, 2h, 70%; e) BnBr, K2CO3, DMF,
50 °C, 12h, 40%; f) Pd(dppf)Cl2∙CH2Cl2 (5 mol%), B2pin2 (1.3 equiv.), K2CO3, DMSO, 80 °C, 52%; g) LiOH (2 equiv.), THF:H2O,MeOH (3:1:1), 0 °C, 2h; h)
FmocOSu, 1M NaOH/dioxane (1:1), 2 h; i) (CH2O)n, TsOH (0.1 equiv.), C6H6:DMF (25:1), 100 °C, 2h; j) Et3SiH (3 equiv.), TFA:CH2Cl2 (1:1) 0 °C to 23 °C, 3h, 60%
(three steps); k) SOCl2, MeOH, 80 °C, 2h; l) MOMCl, iPr2NEt, 31% (two steps); m) Et2NH (20 equiv.), CH2Cl2, 74%; n) EDC-HCl (1.3 equiv), HOAt (1.5 equiv), 11
(1.3 equiv.), iPr2NEt (2.1 equiv.), 0 °C to 23 °C, 48h, 66%; o) Pd(dppf)Cl2∙CH2Cl2 (0.15eq), K2CO3 (2 equiv.), DMSO, 80 °C, 4 h, 34% yield, 46:41:14 ratio (P-cis-
9a:M-trans-9b:P-trans-9a, see Table 2; p) 4M HCl:THF (1:2), 50 °C, 2h, 54%. Abbreviations:; DMSO: dimethylsulfoxide; TFA: trifluoroacetic acid; DMF: N,N-
dimethylformamide; THF: tetrahydrofuran; dppf: diphenylphosphinoethane; MOM: monomethyoxy methyl; EDC-HCl: N-(3-Dimethylaminopropyl)-N'-
ethylcarbodiimide hydrochloride; HOAt: 1-Hydroxy-7-azabenzotriazole.
Compound P-cis-9 was isolated in 50% yield while the
second isomer was isolated in 15% yield. The minor structure
could be converted to the major isomer by heating in toluene at
80 °C. The authors suspected the minor compound to be M-cis-
7. Each compound, however, readily interconverted on the NMR
timescale with a second set of compounds, which were believed
to be atropisomers (M-cis-8 and M-trans-8, Figure 2b).5
We sought to optimize the established synthesis and
elucidate the three dimensional structure of the two compounds
obtained from the Suzuki coupling (Scheme 1). Rubiyunnanin B
will be obtained via macrocyclization and hydrogenolysis of the
benzyl carbamate and benzyl ether. Similar to previous work, we
will form the dityrosine dimer using a Suzuki coupling of aryl
iodide 12 and aryl bis(pinicolato)boronic ester 11. To avoid late
stage N-methylation, both amino acids will be methylated prior to
coupling. The A-ring Bpin-tyrosine will be installed through a
to silica gel chromatography and was sufficiently pure to be used
directly.
Initial attempts at the Suzuki coupling of 10 employing
conditions
used
in
the
synthesis
of
arylomycin
(Pd(dppf)Cl2∙CH2Cl2, K2CO3, DMSO, 80 °C) yielded 20 in
modest recovery (34%).6a Purification by silica gel
chromatography yielded two entities, whose mass spectra
matched compound 20 (see Figure S1 in Supporting
Information). 1H NMR at 23 °C indicated multiple compounds
with broadening of all peaks similar to what Takeya reported in
the synthesis of neo-RA-V.4 1H NMR at -40 °C revealed a
defined set of two signals.
The comixture was then deprotected with 4M HCl at 50 °C
for 2 hours in 54% yield. The resulting material was purified to
yield three distinct species by LC/MS, whose mass spectra
matched that of 9. Analysis of 1H NMR showed two major sets of
compounds (P-cis-9a and M-trans-9b, vide infra), each of which
exchanged with a second rotameric compound. In addition to the
two major sets, a minor contributor (P-trans-9a) was observed
and chromatographically separable. ROESY data indicated that
Miyaura coupling from 3-iodotyrosine derivative.
The B-ring
tyrosine will be protected with a methoxy methyl ether (MOM)
group derived from 3-iodotyrosine.
The synthesis of the A-ring tyrosine began with benzyl
chloroformate protection of 3-iodotyrosoine (Scheme 2). A two
step N-methylation procedure yielded known Cbz-N-Me-3I-
tyrosine-OH (14). Esterification and benzyl protection afforded
15 which was converted to Bpin compound 16 in 52% yield
using the Miyaura borylation protocol.4 Construction of the B
ring of rubiyunnanin B began from Fmoc-N-Me-3I-tyrosine-OH
(18, prepared in the same manner), which was esterified and
protected as the monomethoxy ether (31% yield). Deprotection
of 19 proceeded cleanly with diethylamine in 77% yield.
Coupling of acid 17 and amine 11 was accomplished with EDC
and HOAt to yield 10 in 66% yield. Dipeptide 10 proved unstable
P-cis-9a possessed
a nOe correlation between α-protons
(Figure 3, H2 and H17). Additional nOe correlations were
observed between an axial β-proton (H2ax) and the Cbz N-methyl
as well as between an axial β proton (H16ax) and the internal N-
methyl. This supports an internal cis-amide as expected within
the rubiyunnanin family. Furthermore, ring A is twisted above
the biaryl plane with the B ring below. α-Proton H2 has strong
nOe correlations with both internal aryl protons (H5 and H15)
whereas α-proton H17 shows a strong correlation to the ring B
aryl proton (H15) with a weak interaction to the A ring aryl proton
(H5). Strong four bond COSY correlations between β protons
H2eq, H16eq, and H16ax and aryl protons (and weak COSY
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600741
COMMUNICATION
Figure 3: 3-D representations of compound 9. nOe correlations are indicated with solid red line, weak nOe
correlations are indicated with a dashed red line. The α protons, H2 and H17, are highlighted in blue.
Table 1: Important 1H NMR data for comparison of isomers of 9.
δ (ppm)
J3ax,2
(Hz)
J16ax,17
(Hz)
Strong cosy Weak cosy
correlation[a] correlation[b]
compound
H2
H17
H3ax
H3eq
H16ax
3.06
H16eq
3.61
H5-H3eq
P-cis-9a
5.52
5.60
4.12
2.45
9.0
15.0
H13-H16eq
H13-H16ax
H5-H3ax
H5-H3eq
H13-H16eq
H13-H16ax
H5-H3ax
M-trans-9b
P-trans-9a
5.65
5.56
5.81
3.91
3.56
3.51
2.80
2.73
3.08
3.41
3.51
3.13
9.0
12.0
5.9
11.4
H5-H3ax
H15-H16ax
[a]
Four bond correlations are indicated, strong COSY correlation indicates a high intensity cross peak between
[b]
corresponding protons;
four bond correlations indicated, weak cosy correlation indicates a weak cross peak
between corresponding protons; any couplings not indicated signify that no cross peak was seen; see Supporting
Information for additional detail.
interactions with H2eq and aryl protons) confirm the orientation of
H17 retains the same stereochemistry as P-cis-9a, which is
supported by the smaller coupling constant between H16ax and
H17 (J16ax,17 = 5.9 Hz). The position of the rings is also supported
by long range four bond COSY couplings.
the rings as per the Karplus equation for benzylic four bond
coupling (see Table 1).7 We therefore believe that P-cis-9a is
oriented in a manner shown in Figure 3.
P-cis-9a exchanges with a second compound, P-cis-9a-rot
(not shown), as evidenced by exchange peaks present in
ROESY data. This compound contains similar correlations,
between each α-proton and the α-proton to the aryl ring, as well
as an identical pattern in four bond COSY couplings. This
second compound therefore cannot be an atropisomer or trans-
amide isomer. It is possible that this second compound (P-cis-
Broad 1H NMR signals in 20 could be a result of
isomerization between eight distinct compounds and their Cbz
N-methyl rotamers. 20a could consist of both atropisomers and
cis/trans isomers resulting in four different compounds P-cis-20a,
M-cis-20a, P-trans-20a, and M-trans-20a (see Figure S2 for
detailed depictions). If epimerization has occurred, it is also
possible that four more compounds may be observed: P-cis-20b,
M-cis-20b, P-trans-20b, and M-trans-20b. Exchange between
each set, due to either atropisomerism or cis/trans amide
exchange, would lead to broadening. Deprotection of the
material, however, results in only two 9a compounds: P-cis-9a
and M-trans-9b. Decreasing the steric bulk of the ortho position
of an atropisomeric compound should encourage more rotational
9a-rot) is
a rotamer at the Cbz N-methyl, although no
correlations could confirm this hypothesis.
The second isomeric compound isolated was determined
to be a H17 epimer. This compound (M-trans-9b) contains a
trans-amide. Strong nOe correlations are observed between the
internal N-methyl and protons H2, H5, H15, and H16ax. The
epimerized α-proton H17 correlates only with H15. Large coupling
constants (J16ax-17 = 12.0 Hz) also support this conformation.
These data are also supported by four bond COSY correlations,
which indicate that only one proton (H2ax) is perpendicular to the
aryl ring. It is likely that ring B in this compound resides above
the biaryl plane whereas ring A is canted below. We therefore
believe this compound, M-trans-9b is oriented as shown in
Figure 3.
1
freedom that would bolster broadening of H NMR signals; this,
however, was not observed.7 The lack of broadening could be
explained by a critical hydrogen bond between the newly
deprotected phenol and the benzyl ether, thus stabilizing the
atropisomer isolated.9 Rubiyunnanin B would be able to adopt
this same critical hydrogen bond, thus stabilizing the ring.
In order to efficiently produce the rubiyunnanin architecture,
the reduction or elimination of the unwanted stereoisomers is
essential. Increasing the loading of Pd(dppf)2∙CH2Cl2 decreased
epimerization but also reduced yield; reaction time was
unaltered. Changing catalyst and solvent to Pd(PPh3)4 in
THF:water reduced epimerization but also resulted in low yield
(Table 2, entry 3). A more electron rich phosphine, Pd(PtBu3)2,
resulted in almost a 90:10:0 ratio of epimers favoring P-cis-9a,
however, in a combined yield of only 13% (Table 2, entry 4).
Mild Suzuki conditions pioneered by the Buchwald group,
involving the use of Xphos Pd G2, resulted in >99:1 ratio of
epimers and completion of the reaction in 30 minutes at 40 °C.10
Optimization of the reaction conditions by eliminating silica gel
chromatography of 20 and directly exposing the crude reaction
mixture to 4M HCl at 50 C for 30 minutes resulted in an
1H NMR indicated a third compound was also formed.
This isomer was separable from P-cis-9a and M-trans-9b by
preparatory TLC, and its structure assigned P-trans-9a. The
isomer was present in small quantities when Pd(dppf)Cl2∙CH2Cl2
(15 mol%) was used at a ratio of 42:44:4 (P-cis-9a: M-trans-9b:
P-trans-9a) but increased to 23:34:44 when catalyst loading of
Pd(dppf)Cl2∙CH2Cl2 was increased (vide infra, see Supporting
Information). A nOe was not observed between α-protons H2
and H17 indicating a trans isomer. H5 showed correlations to an
axial β-proton (H3ax), α-proton H2 and the internal N-methyl. This
suggested that the A ring is canted above the biaryl plane. The
B ring aryl proton H15 has correlations with axial β-proton H16ax
and with the internal N-methyl. It does not show a correlation
with H17 indicating that the B ring is canted below the biaryl plane.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600741
COMMUNICATION
increase of P-cis-9a to 56% yield over two steps (Figure 4). The
room temperature and stirred under argon for 48 hours.
Upon
completion, the reaction was diluted with EtOAc (10 mL), washed with
1M HCl (2 x 10 mL) and saturated sodium bicarbonate solution (10 mL).
The solution was dried over Na2SO4 and concentrated in vacuo to yield
230 mg (0.254 mmol, 63 % yield) of 10 as an unstable white solid, yet
sufficiently pure to be used in the next step.
facile
Table 2: Suzuki coupling of 10
Dityrosine P-cis-9a: 10 (20 mg, 0.03 mmol) was dissolved in 0.2 mL
THF and 0.2 mL of 0.5M K3PO4 solution. The reaction was degassed by
sparging with argon over sonication for 15 minutes. Xphos Pd G2 was
added and the reaction heat at 40 °C for 30 minutes. The reaction was
cooled and diluted with 1.0 mL 1M HCl. The aqueous layer was
extracted with EtOAc (2 x 3.00 mL), and the organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The material
could be purified at this point by flash chromatography (3:1
hexanes/EtOAc, v/v) but was used in the next step without purification.
HRMS (DART+) calc’d for C38H41N2O8 653.2863, found 653.2858. TLC
Rf= 0.67 (1:1 hexanes/EtOAc, v/v). Crude 20 was dissolved in THF (0.2
mL) and 4M HCl (0.1 mL) was added. The reaction was heated at 50 °C
for 30 minutes and then cooled. Concentration and purification by flash
chromatography (3:1 hexanes/EtOAc, v/v) yielded 9 (8.50 mg, 0.014
mmol, 56% yield) as a single diastereomer.
entry
catalyst (eq)
solvent
DMSO
DMSO
20 Yield[a]
34%
Ratio 9[b]
46:41:13
46:22:35
Pd(dppf)Cl2-DCM
(0.15)
Pd(dppf)Cl2-DCM
(0.30)
1
2
18%
THF:H2O
(6:1)
3
4
Pd(PPh3)4(0.30)
Pd(PtBu3)2 (0.15)
15%
13%
73:24:4
90:10:0
DMSO
[a] Isolated yields of 20 after flash chromatography; [b] ratio: (P-cis-9a:M-
trans-9b:P-trans-9a) determined by LC/MS analysis of 9 and 20 and 1H
NMR analysis of 9 after deprotection using 4M HCl in THF).
.
1
P-cis-9a: []D = -21.9 (c 0.85, CDCl3) H NMR: (600 MHz, CDCl3)  7.35
– 7.40 (m, 10H), 7.06 (dd, J = 8.1, 2.6 Hz, 1H), 7.04 (dd, J = 8.2, 2.4 Hz,
1H), 6.82 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 8.2 Hz,
1H), 6.73 (d, J = 2.6 Hz, 1H), 5.60 (dd, J = 11.6, 4.4 Hz, 1H), 5.52 (dd, J
= 10.2, 1.2 Hz, 1H), 5.24 (d, J = 11.6 Hz, 1H), 5.16 (d, J = 11.5 Hz, 1H),
5.12 (d, J = 12.4 Hz, 1H), 5.04 (d, J = 12.5 Hz, 1H), 4.12 (m, 1H), 3.61
(dd, J = 16.3, 4.5 Hz, 3H), 3.60 (s, 3H), 3.06 (dd, J = 16.8, 11.6 Hz, 1H),
2.98 (s, 3H), 2.70 (s, 3H), 2.45 (dd, J = 14.8, 1.4 Hz, 1H). 13C NMR (126
MHz, CDCl3, mixture of rotamers)  172.1, 171.3, 156.2, 153.6, 152.3,
140.7, 139.9, 136.4, 136.1, 131.3, 129.5, 129.0, 128.6, 128.4, 128.3,
127.5-128.5, 127.5-128.5, 127.5-128.5, 127.7, 127.6, 126.0, 115.6, 111.0,
71.0, 71.0, 67.9, 67.9, 60.6, 56.7, 52.5, 34.7, 34.7, 32.7, 32.7, 29.8, 29.7.
IR (cm-1) 3339, 2926, 2850, 1741, 1694, 1650, 1217, 735. HRMS
(DART+) calc’d for C36H37N2O7 609.2601, found 609.2593. TLC Rf = 0.56
(1:1 hexanes/EtOAc, v/v)
Figure 4. Final optimization for the synthesis of the rubiyunnanin B aglycone.
coupling conditions streamline the preparation of the
rubiyunnanins and allow for further exploration of their syntheses.
Further work is needed to install the glycoside and
complete the macrocyclic ring. Both steps have precedent given
work done by Romesberg6a and Takeya.4 We have presented a
synthesis of the dityrosinyl core of rubiyunnanin B that takes
advantage of a palladium catalyzed Suzuki coupling to forge the
biaryl bond. This coupling resulted in multiple isomers which
were characterized by in-depth NMR spectroscopy as product
9a with internal cis and trans-amides, and epimerized product,
9b with an internal trans-amide. Optimization of the coupling
resulted in the major product (P-cis-9a) being the sole isolable
product. Two step coupling and deprotection yielded the
aglycone of the dityrosine peptide of rubiyunnanin B. The
streamlined approach to the core of the rubiyunnanins and NMR
studies allows access to these rare and understudied
compounds.
M-trans-9b: 1H NMR (600 MHz, CDC3)  7.41–7.30 (m, 10H), 7.11 (m,
1H), 7.05 (dd, J = 9.23, 1.78 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.79 (d, J
= 8.5 Hz, 1H), 6.62 (bs, 2H), 5.81 (dd, J = 10.8, 4.0 Hz, 1H), 5.65 (dd, J =
12.2, 3.6 Hz, 1H), 5.23 (d, J = 11.8 Hz, 1H), 5.20 (m, 1H), 5.17 (m, 1H),
5.16 (m, 1H), 3.76 (s, 3H), 3.57 (m, 1H), 3.51 (m, 1H), 3.08 (m, 1H), 3.01
(s, 3H), 2.96 (s, 3H), 2.82 (m, 1H); 13C NMR  171.6, 171.5, 156.0, 152.8,
152.6, 138.2, 136.8, 136.4, 135.8, 130.2, 129.0, 128.8, 128.7, 128.6,
128.5, 128.5, 128.5, 128.1, 127.6, 126.7, 126.7, 115.6, 112.0, 71.4, 71.4,
68.0, 68.0, 55.7, 55.2, 52.6, 32.5, 32.5, 30.9, 30.9, 30.3, 29.8
Experimental Section
Dipeptide 10: CbzMeN-3Bpin-tyrosine(OBn)-OMe (220.0 mg, 0.40
mmol) was dissolved in THF:MeOH:H2O (3.20 mL, 3:1:1 ratio) and
cooled to 0 °C. LiOH∙H2O (37.30 mg, 0.79 mmol, 2.0 eq.) was added
and the reaction is stirred at 0 °C for 2 hours. Upon completion, the
solution was carefully acidified to pH 2 by the addition of 1 M HCl (10 mL)
and extracted with EtOAc (2 x 10 mL). After drying over Na2SO4, the
solution was concentrated to yield CbzMeN-3Bpin-tyrosine(OBn)-OH
(180.0 mg, 0.33 mmol, 83 % yield) which was used in the next reaction
without purification.
Acknowledgements
The authors would like to acknowledge Ivan Keresztes for
assistance with NMR spectroscopy and structural determination,
David Kiemle for NMR spectroscopy and Professors Brett Fors
and Bruce Ganem for insightful discussions. This project was
supported by Cornell University.
CbzMeN-3Bpin-tyrosine(OBn)-OH (220 mg, 0.40 mmol) was
dissolved in THF (2.00 mL), and EDC-HCl (100.50 mg, 0.52 mmol, 1.3
eq.) and HOAt (82.30 mg, 0.61 mmol, 1.5 eq) were added at 0 °C. The
reaction was stirred for 5 minutes before HNMe-3I-tyrosine(OMOM)-OMe
(200.00 mg, 0.524 mmol, 1.3 eq) in 0.50 mL of THF and DIPEA (0.14 mL,
0.85 mmol, 2.1 eq.) was added. The reaction was allowed to warm to
Keywords: Macrocyclic Peptide • Synthesis • Suzuki couplings•
Atropisomerism
[1]
(a) H. Itokawa, K. Takeya, N. Mori, T. Hamanaka, T. Sonobe, K. Mihara,
Chem. Pharm. Bull. 1984, 32, 284. (b) H. Itokawa, K. Takeya, N. Mori,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600741
COMMUNICATION
T. Sonobe, N. Serisawa, T. Hamanaka, S. Mihashi, Chem. Pharm. Bull.
1984, 32, 3216.
[2]
[3]
[4]
[5]
D. L. Boger, M. A. Patane, Q. Jin, P. A. Kitos, Bioorg. Med. Chem. 1994,
2, 85-100.
J. T. Fan, J. Su, Y. M. Peng, Y. Li, J. Li, Y. B. Zhou, G. Z. Zeng, H. Yan,
N. H. Tan, Bioorg. Med. Chem. 2010, 18, 8226-8234.
Y. Hitotsuyanagi, M. Odagiri, S. Kato, J. Kusano, T. Hasuda, H. Fukaya,
K. Takeya, Eur. J. Chem. 2012, 18, 2839-2846.
The authors comment that the two compounds could not be
differentiated by NMR techniques and that 1H NMR signals showed line
broadening. Given the data presented, multiple possibilities exist given
no conclusive NMR or crystallographic data.
[6]
For examples of peptidic diaryl couplings using Suzuki coupling
conditions see: a) J. Liu, C. Luo, P. A. Smith, J. K. Chin, M. G. Page, M.
Paetzel, F. E. Romesberg, J. Am. Chem. Soc. 2011, 133, 17869-
17877; b) K. C. Nicolaou, H. Li, C. N. C. Boddy, J. M. Ramanjulu, T.-Y.
Yue, S. Natarajan, X.-J. Chu, S. Bräse, F. Rübsam, Eur. J. Chem.
1999, 5, 2584-2601; c) O. Skaff, K. A. Jolliffe, C. A. Hutton, J. Org.
Chem. 2005, 70, 7353-7363.
For examples of dityrosine cross-coupling using a Suzuki strategy, see:
(d) D. L. Boger, J. Zhou, J. Org. Chem. 1996, 61, 3938-3939; (e) A.-C.
Carbonnelle, J. Zhu, Org. Lett. 2000, 2, 3477-3480; (f) P. J. Krenitsky,
D. L. Boger, Tetrahedron Lett. 2003, 44, 4019-4022; (g) M. Bosi-
Choussy, P. Cristau, J. Zhu, Angew. Chem. Int. Ed. 2003, 42, 4238-
4241; (h) J. R. Cochrane, J. M. White, U. Wille, C. A. Hutton, Org. Lett.
2012, 14, 2402-2405.
[7]
[8]
E. W. Garbisch, J. Am. Chem. Soc. 1964, 86, 5561-5564.
For reviews on atropisomerism in biaryl compounds see: (a) P. Lloyd-
Williams, E. Giralt, Chem. Soc. Rev. 2001, 30, 145-157; (b) G.
Bringmann, A. J. Price Mortimer, P. A. Keller, M. J. Gresser, J. Garner,
M. Breuning, Angew. Chem. Int. Ed. 2005, 44, 5384-5427.
For reviews of atropselective synthesis of biaryl compounds, see: (c) G.
Bringmann, T. Gulder, T. A. M. Gulder, M. Breuning, Chem. Rev. 2011,
111, 563-639; (d) T. O. Ronson, R. J. K. Taylor, I. J. S. Fairlamb,
Tetrahedron 2015, 71, 989-1009.
[9]
(a) A. V. Vorogushin, W. D. Wulff, H. J. Hansen, J. Org. Chem. 2003,
68, 9618-9623; (b) B. Goldfuss, F. Rominger, Tetrahedron 2000, 56,
881-884; (c) T. B. Freedman, X. Cao, L. A. Nafie, M. Kalbermatter, A.
Linden, A. J. Rippert, Helv. Chim. Acta 2003, 86, 3141-3155.
[10] T. Kinzel, Y. Zhang, S. L. Buchwald, J. Am. Chem. Soc. 2010, 132,
14073-14075.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600741
COMMUNICATION
Layout 2:
COMMUNICATION
Matthew J. Moschitto and Chad A.
Lewis*
Page No. – Page No.
Synthesis and structural
determination of the rubiyunnanin B
core aglycone
Rubiyunnanin B, a macrocyclic peptide possesses an intriguing anticancer profile.
Currently, no synthesis of the dityrosinyl core exists. We have developed a rapid
synthesis of the core of rubiyunnanin B and have characterized and controlled the
distribution of the products formed from a biaryl Suzuki coupling.
This article is protected by copyright. All rights reserved