A facile asymmetric approach to the multicyclic core structure of mangicol A

Article abstract of DOI:10.1002/chem.201404142

Chiral propargylic ether-based triene-ynes are synthesized with high enantiomeric purity by employing an asymmetric enyne addition to aldehydes catalyzed by 1,1′-bi-2-naphthol in combination with ZnEt₂, Ti(OiPr)₄ and dicy-clohexylami

Full text of DOI:10.1002/chem.201404142

DOI: 10.1002/chem.201404142
Full Paper
&
Asymmetric Synthesis
A Facile Asymmetric Approach to the Multicyclic Core Structure of
Mangicol A
Jun Ying and Lin Pu*[a]
Abstract: Chiral propargylic ether-based triene–ynes are syn-
thesized with high enantiomeric purity by employing an
asymmetric enyne addition to aldehydes catalyzed by 1,1’-
bi-2-naphthol in combination with ZnEt2, Ti(OiPr)4 and dicy-
clohexylamine at room temperature. These substrates are
found to undergo a one-pot domino Pauson–Khand and
Diels–Alder cycloaddition catalyzed by [RhCl(CO)2]2 under CO
to generate a series of multicyclic products with high che-
moselectivity and stereoselectivity. These products contain
the multicyclic core structure of mangicol A which could fa-
cilitate the synthesis and study of this class of natural prod-
ucts.
Introduction
products, high chemoselectivity is required for the PK cycload-
dition in the first step. After the PK/DA reactions, new chiral
centers are generated. Thus, high stereoselectivity is also nec-
essary in order to obtain the desired product. Recently, we
have reported an initial test of this approach by conducting
a domino PK/DA cycloaddition of an analog of the chiral prop-
argylic ether starting material without the five-membered ring.
This has led to the formation of a tetracyclic product.[5] In this
paper, we report our further expansion of this strategy to pre-
pare the pentacyclic products from the domino PK/DA cyclo-
addition. High chemoselectivity and stereoselectivity have
been achieved for this efficient multicyclic construction.
Mangicol A represents a new type of sesterterpenoids contain-
ing a tetracyclic skeleton and a quaternary chiral carbon core
(Figure 1). It was isolated in 2000 by Fenical and his co-workers
from the marine fungus Fusarium heterosporum.[1] Mangicol A
and other members of this family of natural products have ex-
hibited cytotoxic and anti-inflammatory activities. Several at-
tempts have been reported for the synthesis of this class of
compounds but no total synthesis
has been achieved to date.[2–4]
Uemura synthesized the polycyclic
core structure of mangicols in 29
steps in 2004 by employing an in-
tramolecular transannular Diels–
Alder reaction of a macrocycle.[4]
We propose a one-pot reaction
to construct the tetracyclic core
structure of mangicol A. As shown
Scheme 1. A proposed approach to the multicyclic core structure of mangi-
col A.
in Scheme 1, a catalytic Pauson–
Khand (PK) cycloaddition of
Figure 1. Mangicol A.
a
chiral propargylic ether-based
triene–yne followed by an intramolecular Diels–Alder (DA) re-
action will be conducted to generate a pentacyclic product. Results and Discussion
Cleavage of the CÀO bond of the hydrofuran ring of the penta-
Preparation of the Chiral Propargylic Ethers by the Catalytic
Asymmetric Alkyne Addition to Aldehydes
cyclic product followed by functional group modification could
eventually lead to mangicol A and its analogs. Since the chiral
propargylic ether starting material containing three alkene
functions could give more than one possible PK cyclization
In order to prepare the chiral propargylic ether-based triene–
ynes as the starting materials for the domino PK/DA cycloaddi-
tion, we have utilized a catalytic asymmetric method devel-
oped in our laboratory for the synthesis of chiral propargylic al-
cohols. Recently, we reported that the asymmetric reaction of
terminal alkynes with aldehydes can be conducted at room
temperature to generate chiral propargylic alcohols with high
enantioselectivity by using a catalytic amount of 1,1’-bi-2-
naphthol (BINOL) in combination with Ti(OiPr)4, ZnEt2 and dicy-
clohexylamine (Cy2NH).[6–8] Scheme 2 summarizes the results
[a] J. Ying, Prof. Dr. L. Pu
Department of Chemistry, University of Virginia
Charlottesville, Virginia 22904-4319 (USA)
E-mail: lp6n@virginia.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404142: Additional data for synthesis
and characterization of the compounds, HPLC plots and NMR spectra are
provided.
Chem. Eur. J. 2014, 20, 1 – 8
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
for the use of this catalytic method to prepare a series of chiral
propargylic alcohols (R)-1a–e for the proposed cycloaddition.
All these reactions were conducted in diethyl ether at room
temperature under nitrogen in a three-step-one-pot process.
In the first step, an enyne was treated with ZnEt2 and Cy2NH,
which presumably generated a nucleophilic alkynyl zinc re-
agent. In this step, it is proposed that coordination of Cy2NH
with Et2Zn could increase the basicity of the Et group on Zn to
facilitate the deprotonation of the enyne. (S)-BINOL (40 mol%)
was also added in the first step, which should be deprotonated
by ZnEt2. In the second step, Ti(OiPr)4 was added. In this step,
the combination of the deprotonated (S)-BINOL with Ti(OiPr)4
could generate a chiral Lewis acid complex to catalyze the re-
action. In the third step, an aldehyde was added and the asym-
metric alkyne addition proceeded. After aqueous workup,
a chiral propargylic alcohol product was obtained. In the
second step, after the addition of Ti(OiPr)4, additional time
(3 h) was required in order to generate the BINOL-TiIV complex
to control the stereochemistry of the next step. When the ad-
dition of Ti(OiPr)4 was immediately followed with the addition
of the aldehyde, enantioselectivity was much lower. As shown
in Scheme 2, these catalytic asymmetric enyne additions to the
aliphatic aldehydes were accomplished with 57–89% yield and
90–92% ee. The configurations of the chiral propargylic alco-
hols were determined on the basis of our previous studies.[6]
Scheme 3. Preparation of the chiral propargylic ether-based triene–ynes.
Catalytic Domino PK/DA Cycloaddition
When the solution of (R)-2a in 1,2-dichloroethane (DCE) was
heated in the presence of 10 mol% [RhCl(CO)2]2 under 1 atm
CO, a domino PK/DA cycloaddition occurred to generate the
pentacyclic product 3a with 60% yield and 94% ee
(Scheme 4).[9–11] Thus a highly chemoselective and stereoselec-
tive transformation has taken place. The enantiomeric purity of
the original propargylic alcohol generated by the catalytic
asymmetric enyne addition to aldehydes has been preserved
in this domino cycloaddition process. In this conversion, the
original propargylic chiral center has directed the formation of
four additional chiral centers. The structure of 3a was estab-
lished by high-resolution mass spectroscopic analysis and vari-
ous 1H and 13C NMR spectroscopic analysis including COSY,
NOESY, HSQC and DEPT-135 (see Supporting Information).
Scheme 4. Catalytic conversion of (R)-2a to generate 3a.
Scheme 2. Catalytic asymmetric alkyne addition to aldehydes to form chiral
propargylic alcohols.
Similar to the conversion of (R)-2a to 3a, when the triene–
yne (R)-2b was treated with [RhCl(CO)2]2 and CO, compound
3b was obtained with 54% yield and 91% ee (Scheme 5). The
geminal dimethyl groups in (R)-2b did not have much effect
on the cycloaddition. The stereochemistry of 3b was assigned
by comparing its NMR spectra with those of 3a.
The chiral propargylic alcohols (R)-1a–e are converted to the
corresponding allylic ethers as shown in Scheme 3. Treatment
of the chiral propargylic alcohols with NaH at 08C followed by
reactions with allyl bromide at 508C gave the desired propar-
gylic ethers in 69–92% yields.
The propargylic ether (R)-2c contains a cis double bond in
the alkyl chain. When this compound was subjected to the
same catalytic conditions, the pentacyclic product 3c was ob-
tained as a single diastereomer with 47% yield and 91% ee
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Scheme 5. Catalytic conversions of (R)-2b.
(Scheme 6). The ethyl group on the cis double bond of (R)-2c
is located on the a face of the six-membered ring of 3c. The
structure of 3c was determined by high-resolution mass spec-
troscopic analysis and various 1H and 13C NMR spectroscopic
analysis including COSY, NOESY, HSQC and DEPT-135 (see Sup-
porting Information).
Scheme 8. Catalytic conversions of (R)-2e and its racemic analogues 2 f–h.
Scheme 6. Catalytic conversion of (R)-2c.
3 f, 3g and 3h were obtained in 57, 44 and 64% yield, respec-
tively (Scheme 8). No intramolecular DA reaction took place.
When the isolated 3g was treated with [Rh(CO)2Cl]2 (10 mol%)
under N2 in refluxing toluene, there was still no DA reaction.
Apparently, the intramolecular DA reaction is very sensitive to
the sterics of the dienophiles in these compounds. This is in
sharp contrast to the cyclopentene-containing substrates (R)-
2a–d.
Compound (R)-2d contains a longer chain alkyl substituent
on the cis double bond than (R)-2c. When (R)-2d was treated
with [RhCl(CO)2]2 under CO, two diastereomers (9:1) were
formed in 45% yield (Scheme 7). The major product 3d con-
tains a pentyl group on the a face of the six-membered ring.
The factors contributed to the reduced enantiomeric purities
of 3d and 3d’ relative to the propargylic alcohol starting mate-
rial are not clear at this stage. The more extended reaction
time might be partially responsible.
On the basis of the previous studies on the Rh-catalyzed PK
and DA reactions,[10–12] the intermediates such as 4a and 5a
from the reaction of (R)-2a are proposed to account for the
stereoselectivity of this catalytic process (Figure 2). (R)-2a can
coordinate with the metal center of the catalyst to generate
the chair-like intermediate 4a. The oxidative coupling of the
coordinated triple bond and double bond of 4a followed by
CO insertion and reductive elimination would give the PK cycli-
zation intermediate 5a. Thus, the chair-like coordination of Rh
in 4a should lead to the trans arrangement for Ha and Hb in
5a. The coordination of the diene unit and alkene unit to the
Rh center in 5a could promote an exo DA cycloaddition to
generate the pentacyclic product 3a with the observed trans
arrangement of Hg and Hd. Previously, we have demonstrated
that in the absence of the RhI complex, there was no intramo-
lecular DA reaction for the isolated PK cycloaddition product.[5]
For compounds 1c,d that contains an ethyl or pentyl group on
the dienophile double bond, the intermediates 5c,d could
form. The RhI-mediate exo DA cycloaddition of 5c,d would
give the obtained products 3c,d with the R group of the
major diastereomer trans to Hg.
Scheme 7. Catalytic conversion of (R)-2d.
Unlike compounds (R)-2a–d, the chiral propargylic ether (R)-
2e contains a cyclohexene unit rather than a cyclopentene
unit. This compound undergoes the same domino PK/DA reac-
tion smoothly to give 3e with 71% yield and 90% ee
(Scheme 8). We also prepared the cyclohexene-containing race-
mic propargylic ethers 2 f, 2g and 2h. When these compounds
were subjected to the conditions of the RhI catalysis in the
conversion of (R)-2e to 3e, only the PK cycloaddition products
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
anhydrous Na2SO4 and concentrated by rotary evaporation. The re-
sultant oil was purified by flash column chromatography on silica
gel eluted with hexanes/ethyl acetate to give the product with 57–
89% yield and 90–92% ee.
Characterizations of the optical active propargylic alcohols
generated from the enyne additions to aldehydes
Figure 2. Proposed intermediates for the RhI-catalyzed domino reaction.
(R)-1-(Cyclopent-1-en-1-yl)hept-6-en-1-yn-3-ol [(R)-1a]: Yellow oil,
31.1 mg, 71% yield. 92% ee determined by HPLC analysis: Chiral-
pak OD column, 98:2 hexanes/iPrOH, flow rate=1.0 mLminÀ1, l=
Conclusion
254 nm, retention time: tmajor =11.0 min, tminor =13.1 min; [a]D24
=
1
À19.0 (c=0.455, CHCl3): H NMR (300 MHz, CDCl3): d = 6.03 (t, 1H,
J=2.1 Hz), 5.84 (m, 1H), 5.06 (dd, 1H, J=17.1, 1.8 Hz), 4.98 (d, 1H,
J=10.2 Hz), 4.52 (t, 1H, J=6.3 Hz), 2.42 (m, 4H), 2.23 (m, 2H), 2.03
(s, 1H), 2.03–1.80 (m, 4H); 13C NMR (75 MHz, CDCl3): d = 138.5,
138.0, 124.1, 115.4, 91.2, 82.7, 62.7, 37.1, 36.6, 33.4, 29.7, 23.5;
HRMS [EI(TOF)] for C12H16O [M+]: m/z: calcd for: 176.1201; found:
176.1199.
Using the chiral propargylic alcohols prepared from the asym-
metric enyne addition to aliphatic aldehydes catalyzed by the
BINOL/Ti(OiPr)4/Et2Zn/Cy2NH catalyst system, we have prepared
a series of chiral propargylic ether-based triene–ynes with high
enantiomeric purity. We have found that these compounds
can undergo an efficient one-pot RhI-catalyzed domino PK/DA
cycloaddition to generate multicyclic products with high che-
moselectivity and stereoselectivity. These products contain the
core structure of mangicol A which could facilitate the synthe-
sis and study of this class of natural products.
(R)-1-(Cyclopent-1-en-1-yl)-4,4-dimethylhept-6-en-1-yn-3-ol [(R)-
1b]: Colorless oil, 36 mg, 71% yield. 90% ee determined by HPLC
analysis: Chiralpak AD-H column, 98:2 hexanes/iPrOH, flow rate=
1.0 mLminÀ1, l=225 nm, retention time: tmajor =8.4 min, tminor
=
9.4 min; [a]2D7 = À20.3 (c=1.300, CHCl3); H NMR (300 MHz, CDCl3):
d = 6.02 (t, 1H, J=1.8 Hz), 5.84 (m, 1H), 5.08 (dd, 1H, J=5.4,
0.6 Hz), 5.04 (s, 1H), 4.19 (d, 1H, J=6 Hz), 2.42 (m, 4H), 2.14 (m,
2H), 1.90 (m, 3H), 0.97 (s, 3H), 0.96 (m, 3H). 13C NMR (75 MHz,
CDCl3): d = 138.2, 135.2, 124.2, 117.9, 90.0, 83.7, 70.9, 43.0, 39.1,
36.6, 33.4, 23.5, 22.9, 22.8; HRMS [EI(TOF)] for C14H20O [M+]: m/z:
calcd for: 204.1514; found: 204.1513.
1
Experimental Section
General Data
All commercial chemicals were used without further purification
unless otherwise noted. All catalysts were purchased and stored
under dry nitrogen atmosphere. Tetrahydrofuran was distilled over
sodium and benzophenone under nitrogen. Diethyl ether and
methylene chloride were dried by passing through activated alumi-
na columns under nitrogen. All the NMR spectra were obtained in
CDCl3 unless indicated otherwise.
(R,Z)-1-(Cyclopent-1-en-1-yl)non-6-en-1-yn-3-ol [(R)-1c]: Colorless
oil, 35.5 mg, 70% yield. 90% ee determined by HPLC analysis: Chir-
alpak OD column, 97:3 hexanes/iPrOH, flow rate=1.0 mLminÀ1
,
l=220 nm, retention time: tmajor =10.8 min, tminor =12.5 min; [a]D27
=
À28.7 (c=1.275, CHCl3); 1H NMR (300 MHz, CDCl3): d = 6.02 (m,
1H), 5.37 (m, 2H), 4.51 (m, 1H), 2.41 (m, 4H), 2.20 (m, 2H), 2.04 (m,
3H), 1.88 (m, 2H), 1.76 (m, 2H), 0.95 (t, 3H, J=7.5 Hz); 13C NMR
(75 MHz, CDCl3): d = 138.4, 133.0, 128.0, 124.2, 91.3, 82.6, 62.8,
37.9, 36.6, 33.4, 23.5, 23.2, 20.8, 14.6; HRMS [EI(TOF)] for C14H20O
[M+]: m/z: calcd for: 204.1514; found: 204.1512.
General procedure for the preparation of racemic propargyl-
ic alcohols from enyne addition to aldehydes
Under nitrogen, an enyne (1.5 equiv) was dissolved in THF (5 mL)
and cooled to À788C. nBuLi (2.5m in hexane, 1.2 equiv) was added
and the mixture was stirred for 30 min. Then an aldehyde
(0.5 mmol, 1 equiv) was added and the mixture was stirred for 3 h.
Afterwards, the reaction mixture was warmed up to room tempera-
ture and quenched with the addition of saturated aqueous ammo-
nium chloride solution. After extraction with CH2Cl2 for three
times, the combined organic layer was washed with brine, dried
with Na2SO4, concentrated by rotary evaporation and purified by
column chromatography on silica gel eluted with hexanes/ethyl
acetate to give the product.
(R,Z)-1-(Cyclopent-1-en-1-yl)dodec-6-en-1-yn-3-ol [(R)-1d]: Color-
less oil, 35.2 mg, 57% yield; 92% ee determined by HPLC analysis:
Chiralpak OD column, 97:3 hexanes/iPrOH, flow rate=
1.0 mLminÀ1, l=225 nm, retention time: tmajor =10.7 min, tminor
=
1
12.8 min; [a]2D7 =À25.4 (c=1.760, CHCl3); H NMR (300 MHz, CDCl3):
d = 6.03 (s, 1H), 5.39 (m, 2H), 4.51 (m, 1H), 2.42 (m, 4H), 2.21 (m,
2H), 2.06 (m, 2H), 1.89 (m, 3H), 1.78 (m, 2H), 1.29 (m, 6H), 0.88 (t,
3H, J=5.7 Hz); 13C NMR (75 MHz, CDCl3): d = 138.4, 131.5, 128.5,
124.1, 91.3, 82.6, 62.9, 38.0, 36.6, 33.4, 31.8, 29.6, 27.4, 23.5, 23.3,
22.8, 14.3; HRMS [EI(TOF)] for C17H26O [M+]: m/z: calcd for:
246.1984; found: 246.1980.
(R)-1-(Cyclohex-1-en-1-yl)hept-6-en-1-yn-3-ol [(R)-1e]: Colorless
oil, 42.4 mg, 89% yield; 90% ee determined by HPLC analysis: Chir-
General procedure for the (S)-BINOL-catalyzed enantioselec-
tive enyne addition to aldehydes
alpak OD column, 95:5 hexanes/iPrOH, flow rate=1.0 mLminÀ1
,
Under nitrogen, (S)-BINOL (40%) was weighted into a tared flask
and dissolved in Et2O (3 mL). An enyne (4 equiv), Cy2NH (5%) and
Et2Zn (4 equiv) were added and the mixture was stirred at room
temperature for 16 h. Then, Ti(OiPr)4 (100%) was added and the
stirring continued for 3 h. An aldehyde (0.25 mmol, 1 equiv) was
added and the mixture was stirred for another 4 h. The reaction
was quenched with saturated aqueous ammonium chloride and
extracted three times with CH2Cl2. The organic layer was dried with
l=225 nm, retention time: tmajor =8.5 min, tminor =9.8 min; [a]D24
=
À14.6 (c=2.120, CHCl3); 1H NMR (300 MHz, CDCl3): d = 6.09 (m,
1H), 5.83 (m, 1H), 5.08 (dd, 1H, J=18.9, 1.8 Hz), 4.98 (dd, 1H, J=
10.2, 1.8 Hz), 4.49 (t, 1H, J=6.6 Hz), 2.22 (m, 2H), 2.08 (m, 4H), 2.00
(s, 1H), 1.80 (m, 2H), 1.59 (m, 4H); 13C NMR (75 MHz, CDCl3): d =
138.0, 135.5, 120.3, 115.4, 87.4, 87.2, 62.6, 37.2, 29.7, 29.4, 25.8,
22.5, 21.7; HRMS [EI(TOF)] for C13H18O [M+]: m/z: calcd for:
190.1358; found: 190.1360.
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
General procedure for preparation of the chiral propargylic
alcohol-based triene–ynes
Characterization of the Racemic Triene–ynes
1-(3-(Allyloxy)-4,4-dimethylhept-6-en-1-yn-1-yl)cyclohex-1-ene
(2 f): Prepared from S4 (173.2 mg, 0.79 mmol), colorless oil,
187 mg, 91% yield; 1H NMR (300 MHz, CDCl3): d = 6.10 (m, 1H),
5.87 (m, 2H), 5.30 (m, 1H), 5.17 (m, 1H), 5.03 (m, 2H), 4.29 (ddt,
1H, J=12.9, 4.8, 1.5 Hz), 3.90 (m, 1H), 3.85 (s, 1H), 2.13 (m, 6H),
1.60 (m, 4H), 0.98 (s, 3H), 0.96 (s, 3H); 13C NMR (75 MHz, CDCl3): d
= 135.3, 135.1, 134.7, 120.7, 117.5, 116.9, 88.8, 84.4, 77.1, 70.2, 43.4,
38.7, 29.9, 29.6, 25.8, 23.5, 23.2, 22.5, 21.7; HRMS [ESI(TOF)] for
C18H27O [M+H+]: m/z: calcd for: 259.2062; found: 259.2066.
To a solution of NaH 60% w/w (3 equiv) in THF was added a chiral
propargylic alcohol (1 equiv) in THF at 08C under nitrogen and
stirred for 30 min. Then allyl bromide (8 equiv) was added and the
mixture was warmed to 508C overnight. The reaction was
quenched with saturated aqueous ammonium chloride solution at
room temperature and extracted with CH2Cl2 three times. The or-
ganic layer was washed with brine, dried with Na2SO4, concentrat-
ed by rotary evaporation and purified by flash column chromatog-
raphy on silica gel eluted with hexanes/ethyl acetate to give the
product in 69–92% yield.
(Z)-1-(3-(Allyloxy)non-6-en-1-yn-1-yl)cyclohex-1-ene (2g): Pre-
pared from S5 (167.8 mg, 0.77 mmol), colorless oil, 181.5 mg, 91%
yield; 1H NMR (300 MHz, CDCl3): d = 6.09 (m, 1H), 5.91 (m, 1H),
5.35 (m, 2H), 5.29 (m, 1H), 5.17 (m, 1H), 4.27 (ddt, 1H, J=12.6, 5.1,
1.5 Hz), 4.18 (t, 1H, J=6.6 Hz), 3.96 (ddt, 1H, J=12.6, 6.3, 1.5 Hz),
2.21 (q, 2H, J=7.2 Hz), 2.08 (m, 6H), 1.78 (m, 2H), 1,61 (m, 4H),
0.95 (t, 3H, J=7.5 Hz); 13C NMR (75 MHz, CDCl3): d = 135.1, 134.9,
132.8, 128.1, 120.5, 117.3, 87.9, 85.6, 69.8, 69.0, 36.1, 29.5, 25.8,
23.3, 22.5, 21.7, 20.7, 14.6; HRMS [ESI(TOF)] for C18H27O [M+H+]:
m/z: calcd for: 259.2062; found: 259.2061.
Characterization of the Optical Active Triene–ynes
(R)-1-(3-(Allyloxy)hept-6-en-1-yn-1-yl)cyclopent-1-ene
[(R)-2a]:
Prepared from (R)-1a (21.3 mg, 0.12 mmol), colorless oil, 24 mg,
1
92% yield; H NMR (300 MHz, CDCl3): d = 6.03 (t, 1H, J=1.8 Hz),
5.86 (m, 2H), 5.30 (dd, 1H, J=17.4, 1.5 Hz), 5.18 (d, 1H, J=9.3 Hz),
5.04 (dd, 1H, J=17.1, 1.5 Hz), 4.96 (d, 1H, J=11.1 Hz), 4.25 (m, 2H),
3.95 (dd, 1H, J=12.6, 6.3 Hz), 2.42 (m, 4H), 2.23 (m, 2H), 1.86 (m,
4H). 13C NMR (75 MHz, CDCl3): d = 138.2, 138.0, 134.8, 124.3, 117.4,
115.2, 89.3, 83.5, 69.8, 68.9, 36.7, 35.2, 33.4, 29.8, 23.5; HRMS
[EI(TOF)] for C15H19O [MÀH+]: m/z: calcd for: 215.14360; found:
215.14395.
(R)-1-(3-(Allyloxy)dodec-6-en-1-yn-1-yl)cyclohex-1-ene (2h): Pre-
pared from S6 (205 mg, 0.79 mmol), light yellow oil, 157.8 mg,
67% yield; 1H NMR (300 MHz, CDCl3): d = 6.10 (m, 1H), 5.92 (m,
1H), 5.38 (m, 2H), 5.30 (m, 1H), 5.17 (m, 1H), 4.27 (ddt, 1H, J=
12.6, 5.1, 1.5 Hz), 4.18 (t, 1H, J=6.6 Hz), 3.96 (ddt, 1H, J=12.3, 6,
1.2 Hz), 2.21 (q, 2H, J=6.9 Hz), 2.10 (m, 6H), 1.78 (m, 2H), 1,59 (m,
4H), 1.29 (m, 6H), 0.88 (t, 3H, J=6 Hz); 13C NMR (75 MHz, CDCl3): d
= 135.2, 134.9, 131.2, 128.7, 120.5, 117.3, 88.0, 85.6, 69.7, 69.0, 36.1,
31.8, 29.7, 29.5, 27.4, 25.8, 23.4, 22.8, 22.5, 21.7, 20.7, 14.3; HRMS
[ESI(TOF)] for C21H33O [M+H+]: m/z: calcd for: 301.2531; found:
301.2532.
(R)-1-(3-(Allyloxy)-4,4-dimethylhept-6-en-1-yn-1-yl)cyclopent-1-
ene [(R)-2b]: Prepared from (R)-1b (27 mg, 0.13 mmol), colorless
oil, 21.5 mg, 69% yield; 1H NMR (300 MHz, CDCl3): d = 6.03 (m,
1H), 5.86 (m, 2H), 5.30 (m, 1H), 5.17 (m, 1H), 5.04 (m, 2H), 4.30
(ddt, 1H, J=12.9, 4.8, 1.8 Hz), 3.93 (m, 1H), 3.87 (s, 1H), 2.45 (m,
4H), 2.16 (m, 2H), 1.90 (m, 2H), 0.99 (s, 3H), 0,97 (s, 3H); 13C NMR
(75 MHz, CDCl3): d = 137.8, 135.3, 135.0, 124.5, 117.6, 117.0, 88.3,
84.3, 77.2, 70.3, 43.4, 38.7, 36.7, 33.4, 29.9, 23.5, 23.2; GCMS (EI) for
C17H24O [M+]: m/z: calcd for: 244.37; found: 244.
General Procedure for the Domino PK/DA Cycloaddition
Under nitrogen, a triene–yne (1 equiv) and [Rh(CO)2Cl]2 (0.1 equiv)
were weighed into a tared two-necked round bottom flask and dis-
solved in DCE (3 mL). The flask was fitted with a reflux condenser
fitted with a septum and the side arm of the flask was also fitted
with a septum. The solution was bubbled with CO gas for 2 min
through the side arm fitted with septum and a vent needle in the
septum of the reflux condenser. Then, the solution was placed
under CO atmosphere by using a balloon. After the reaction mix-
ture was heated at 708C to reflux temperature for 21–37 h, it was
cooled to room temperature and the CO was released cautiously
in the hood. The reaction mixture was concentrated and the crude
product was purified by column chromatography on silica gel
eluted with hexanes/ethyl acetate to give the product in 45–71%
yield and 71–94% ee.
(R,Z)-1-(3-(Allyloxy)non-6-en-1-yn-1-yl)cyclopent-1-ene [(R)-2c]:
Prepared from (R)-1c (26 mg, 0.13 mmol), colorless oil, 24.4 mg,
80% yield; 1H NMR (300 MHz, CDCl3): d = 6.03 (m, 1H), 5.92 (m,
1H), 5.36 (m, 3H), 5.16 (m, 1H), 4.23 (m, 2H), 3.97 (ddt, 1H, J=
12.6, 6.3, 1.2 Hz), 2.42 (m, 4H), 2.20 (m, 2H), 2.06 (m, 2H), 1.89 (m,
2H), 1.79 (m, 2H), 0.95 (t, 3H, J=7.5 Hz); 13C NMR (75 MHz, CDCl3):
d = 138.1, 134.8, 132.8, 128.1, 124.3, 117.4, 89.5, 83.4, 69.8, 69.0,
36.6, 36.0, 33.4, 23.5, 23.3, 20.7, 14.6; HRMS [EI(TOF)] for C17H24O
[M+]: m/z: calcd for: 244.1827; found: 244.1818.
(R,Z)-1-(3-(Allyloxy)dodec-6-en-1-yn-1-yl)cyclopent-1-ene
[(R)-
2d]: Prepared from (R)-1d (35.2 mg, 0.14 mmol), colorless oil,
27.8 mg, 69% yield; 1H NMR (300 MHz, CDCl3): d = 6.03 (m, 1H),
5.92 (m, 1H), 5.36 (m, 3H), 5.18 (m, 1H), 4.23 (m, 2H), 3.97 (ddt,
1H, J=12.6, 6.3, 1.2 Hz), 2.43 (m, 4H), 2.21 (m, 2H), 2.03 (m, 2H),
1.90 (m, 2H), 1.79 (m, 2H), 1.29 (m, 8H), 0.88 (t, 3H, J=6 Hz);
13C NMR (75 MHz, CDCl3): d = 138.1, 134.8, 131.2, 128.6, 124.3,
117.3, 89.5, 83.4, 69.8, 69.1, 36.7, 36.0, 33.4, 31.8, 29.6, 27.4, 23.5,
23.4, 22.8, 14.3; HRMS [ESI(TOF)] for C20H30ONa [M+Na+]: m/z:
calcd for: 309.2194; found: 309.2191.
Characterizations of the Domino PK/DA Cycloaddition Prod-
ucts 3a–e
3a: Prepared from (R)-2a (24 mg, 0.11 mmol), colorless oil,
16.3 mg, 60% yield; 94% ee determined by HPLC analysis: Chiral-
(R)-1-(3-(Allyloxy)hept-6-en-1-yn-1-yl)cyclohex-1-ene
[(R)-2e]:
Prepared from (R)-1e (42.4 mg, 0.22 mmol), colorless oil, 45.1 mg,
88% yield; 1H NMR (300 MHz, CDCl3): d = 6.09 (m, 1H), 5.93 (m,
1H), 5.79 (m, 1H), 5.30 (m, 1H), 5.17 (m, 1H), 5.04 (m, 1H), 4.97 (m,
1H), 4.22 (m, 2H), 3.97 (ddt, 1H, J=12.6, 6.3, 1.2 Hz), 2.22 (m, 2H),
2.09 (m, 4H), 1.84 (m, 2H), 1.60 (m, 4H); 13C NMR (75 MHz, CDCl3):
d = 138.1, 135.1, 134.9, 120.4, 117.4, 115.2, 88.0, 85.4, 69.7, 68.9,
35.2, 29.8, 29.5, 25.8, 22.5, 21.7; HRMS [EI(TOF)] for C16H21O
[MÀH+]: m/z: cacld for: 229.1592; found: 229.1592.
pak AD-H column, 98:2 hexanes/iPrOH, flow rate=1.0 mLminÀ1
,
l=254 nm, retention time: tmajor =22.8 min, tminor =14.6 min; [a]D23
=
1
À103.6 (c=0.815, CHCl3); H NMR (600 MHz, CDCl3): d = 4.15 (m,
1H), 4.09 (dd, 1H, J=9, 4.2 Hz), 3.84 (d, 1H, J=9 Hz), 2.82 (dd, 1H,
J=19.2, 8.4 Hz), 2.64 (m, 1H), 2.52 (m, 2H), 2.28 (m, 3H), 2,09 (m,
2H), 1.91 (dd, 1H, J=13.2, 4.8 Hz), 1.82 (m, 1H), 1.75 (m, 1H), 1.71–
1.54 (m, 3H), 1.07 (m, 2H); 13C NMR (150 MHz, CDCl3): d = 205.0,
160.6, 132.4, 91.2, 73.0, 62.9, 47.5, 43.1, 42.4, 39.8, 35.7, 32.8, 32.6,
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
32.0, 31.6, 24.9; HRMS [ESI(TOF)] for C16H21O2 [M+H+]: m/z: calcd
for: 245.1542; found: 245.1544.
3g: Prepared from 2g (90.8 mg, 0.35 mmol), colorless oil, 44 mg,
44% yield; 1H NMR (300 MHz, CDCl3): d = 6.17 (m, 1H), 5.37 (m,
2H), 4.74 (m, 1H), 4.31 (m, 1H), 3.19 (m, 2H), 2.65 (dd, 1H, J=17.7,
6 Hz), 2.28–2.00 (m, 9H), 1.82–1.57 (m, 6H), 0.95 (t, 3H, J=7.5 Hz);
13C NMR (75 MHz, CDCl3): d = 208.3, 176.7, 137.1, 133.2, 130.4,
129.2, 127.9, 76.1, 71.7, 42.4, 40.0, 35.9, 29.9, 27.8, 25.7, 23.4, 22.8,
22.0, 20.8, 14.5; HRMS [ESI(TOF)] for C19H27O2 [M+H+]: m/z: calcd
for: 287.2011; found: 287.2007.
3b: Prepared from (R)-2b (21.5 mg, 0.09 mmol), light yellow oil,
13 mg, 54% yield; 91% ee determined by HPLC analysis: Chiralpak
AD-H column, 95:5 hexanes/iPrOH, flow rate=1.0 mLminÀ1, l=
254 nm, retention time:
tmajor =7.1 min, t =
minor =6.4 min; [a]D26
À79.7 (c=0.650, CHCl3); 1H NMR (600 MHz, CDCl3): d = 4.05 (m,
1H), 3.87 (d, 1H, J=9 Hz), 3.76 (s, 1H), 2.83 (dd, 1H, J=19.2,
8.4 Hz), 2.61 (m, 1H), 2.46 (m, 3H), 2.26 (m, 1H), 2.11 (m, 1H), 1.91
(m, 2H), 1.84 (m, 1H), 1.63 (m, 1H), 1,58 (m, 1H), 1.51 (m, 1H), 1.25
(m, 1H), 1.06 (s, 3H), 0.93 (s, 3H); 13C NMR (150 MHz, CDCl3): d =
204.8, 158.7, 134.2, 96.2, 72.6, 64.0, 47.6, 45.9, 43.0, 40.9, 40.2, 38.3,
32.9, 32.7, 31.7, 29.1, 24.8, 24.5; HRMS [ESI(TOF)] for C18H25O2
[M+H+]: m/z: calcd for: 273.1855; found: 273.1850.
3h: Prepared from 2h (78.9 mg, 0.30 mmol), colorless oil, 55 mg,
64% yield; 1H NMR (300 MHz, CDCl3): d = 6.18 (m, 1H), 5.39 (m,
2H), 4.74 (m, 1H), 4.31 (m, 1H), 3.19 (m, 2H), 2.65 (dd, 1H, J=17.7,
6 Hz), 2.27–2.09 (m, 6H), 2.01 (m, 2H), 1.80–1.59 (m, 6H), 1.34–1.24
(m, 7H), 0.87 (t, 3H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3): d =
208.3, 176.7, 137.1, 131.6, 130.4, 129.2, 128.4, 76.1, 71.7, 42.4, 40.0,
35.9, 31.7, 29.9, 29.6, 27.8, 27.4, 25.7, 23.5, 22.8, 22.0, 14.3; HRMS
[ESI(TOF)] for C22H33O2 [M+H+]: m/z: calcd for: 329.2481; found:
329.2480.
3c: Prepared from (R)-2c (24.4 mg, 0.10 mmol), light yellow oil,
12.7 mg, 47% yield; 91% ee determined by HPLC analysis: Chiral-
pak AD-H column, 98:2 hexanes/MeOH, flow rate=1.0 mLminÀ1
,
l=254 nm, retention time: major =9.9 min, tminor =12.9 min; [a]D24
=
1
À84.2 (c=0.635, CHCl3); H NMR (600 MHz, CDCl3): d = 4.21 (t, 1H,
J=5.4 Hz), 4.04 (dd, 1H, J=4.5, 3.6 Hz), 3.86 (d, 1H, J=9 Hz), 2.86
(dd, 1H, J=20.4, 9 Hz), 2.52 (m, 3H), 2.30 (m, 2H), 2.11 (m, 2H),
1.88 (m, 1H), 1.82 (m, 2H), 1.61 (m, 3H), 1.48 (m, 1H), 1,28 (m, 1H),
1.01 (m, 2H), 0.94 (t, 3H, J=7.2 Hz); 13C NMR (150 MHz, CDCl3): d =
205.4, 159.3, 133.9, 91.4, 72.3, 64.2, 47.3, 46.3, 44.9, 44.7, 43.5, 32.4,
32.3, 31.4, 25.3, 24.9, 24.5, 12.5; HRMS [ESI(TOF)] for C18H25O2
[M+H+]: m/z: calcd for: 273.1855; found: 273.1855.
Acknowledgements
Partial supports of this work from the US National Science
Foundation (CHE-1047104) are gratefully acknowledged.
Keywords: asymmetric synthesis
· Diels–Alder reaction ·
mangicols · Pauson–Khand cyclization · propargylic alcohols
3d: Prepared from (R)-2d (27.8 mg, 0.10 mmol), colorless oil,
13.6 mg, 45% yield, dr=9:1. 72% ee determined by HPLC analysis:
Chiralpak AD-H column, 99:1 hexanes/MeOH, flow rate=
[1] M. K. Renner, P. R. Jensen, W. Fenical, J. Org. Chem. 2000, 65, 4843–
4852.
[2] J. L. Wood, B. G. Pujanauski, R. Sarpong, Org. Lett. 2009, 11, 3128–3131.
[3] a) S. Pichlmair, M. de L. Ruiz, K. Basu, L. A. Paquette, Tetrahedron 2006,
62, 5178–5194; b) S. Pichlmair, M. de L. Ruiz, K. Basu, I. Vilotijevic, L. A.
Paquette, Tetrahedron 2006, 62, 5791–5802.
[4] K. Araki, K. Saito, H. Arimoto, D. Uemura, Angew. Chem. Int. Ed. 2004, 43,
81–84; Angew. Chem. 2004, 116, 83–86.
[5] W. Chen, J.-H. Tay, J. Ying, M. Sabat, X.-Q. Yu, L. Pu, Chem. Commun.
2013, 49, 170–172.
[6] a) Y.-H. Du, M. Turlington, X. Zhou, L. Pu, Tetrahedron Lett. 2010, 51,
5024–5027; b) M. Turlington, Y.-H. Du, S. G. Ostrum, V. Santosh, K. Wren,
T. Lin, M. Sabat, L. Pu, J. Am. Chem. Soc. 2011, 133, 11780–11794; c) W.
Chen, J.-H. Tay, J. Ying, X.-Q. Yu, L. Pu, J. Org. Chem. 2013, 78, 2256–
2265; d) M. Turlington, L. Pu, Synlett 2012, 23, 649–684.
[7] a) D. E. Frantz, R. Fꢁssler, C. S. Tomooka, E. M. Carreira, Acc. Chem. Res.
2000, 33, 373–381; b) L. Pu, Tetrahedron 2003, 59, 9873–9886.
[8] a) P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem. 2004, 4095–
4105; b) G. Lu, Y.-M. Li, X.-S. Li, A. S. C. Chan, Coord. Chem. Rev. 2005,
249, 1736–1744; c) B. M. Trost, A. H. Weiss, Adv. Synth. Catal. 2009, 351,
963–983.
[9] Selected reviews on PK cycloadditions: a) A. J. Fletcher, S. D. R. Christie,
J. Chem. Soc. Perkin Trans. 1 2000, 1657–1668; b) K. M. Brummond, J. L.
Kent, Tetrahedron 2000, 56, 3263–3283; c) J. Blanco-Urgoiti, L. AÇorbe,
L. Pꢂrez-Serrano, G. Domꢃnguez, J. Pꢂrez-Castells, Chem. Soc. Rev. 2004,
33, 32–42; d) S. E. Gibson, A. Stevenazzi, Angew. Chem. Int. Ed. 2003, 42,
1800–1810; Angew. Chem. 2003, 115, 1844–1854; e) H.-W. Lee, F.-Y.
Kwong, Eur. J. Org. Chem. 2010, 789–811.
1.0 mLminÀ1, l=254 nm, retention time: tmajor =13.9 min, tminor
=
1
9.0 min; [a]2D4 =À105.3 (c=0.530, CHCl3); H NMR (600 MHz, CDCl3):
d = 4.20 (t, 1H, J=10.2 Hz), 4.03 (m, 1H), 3.84 (d, 1H, J=18 Hz),
2.86 (dd, 1H, J=40.8, 17.4 Hz), 2.47 (m, 3H), 2.26 (m, 2H), 2.11 (m,
2H), 1.83 (m, 3H), 1.53 (m, 5H), 1.28 (m, 6H), 1.05 (m, 2H), 0.89 (t,
3H, J=13.2 Hz); 13C NMR (150 MHz, CDCl3): d = 204.7, 158.6, 133.2,
90.7, 71.6, 63.5, 46.6, 44.5, 44.2, 43.7, 42.8, 32.0, 31.8, 31.7, 30.9,
30.6, 26.7, 24.5, 24.3, 22.5, 14.0; HRMS [ESI(TOF)] for C21H31O2
[M+H+]: m/z: calcd for: 315.2297; found: 315.2323.
3e: Prepared from (R)-2e (45.1 mg, 0.20 mmol), light yellow solid,
36 mg, 71% yield. 90% ee determined by HPLC analysis: Chiralpak
AD-H column, 95:5 hexanes/iPrOH, flow rate=1.0 mLminÀ1, l=
254 nm, retention time: tmajor =13.7 min, tminor =11.1 min; [a]D25
=
1
À81.4 (c=1.800, CHCl3); M.p. 74–758C; H NMR (600 MHz, CDCl3): d
= 4.21 (d, 1H, J=4.8 Hz), 3.97 (dd, 1H, J=9, 4.2 Hz), 3.82 (m, 1H),
3.76 (d, 1H, J=9 Hz), 2.66 (dd, 1H, J=19.2, 10.2 Hz), 2.46 (m, 1H),
2.18 (m, 3H), 2.01 (m, 2H), 1.85 (m, 2H), 1.74 (m, 3H), 1.61 (m, 1H),
1.50 (m, 2H), 1.28 (m, 3H); 13C NMR (150 MHz, CDCl3): d = 206.7,
154.0, 132.6, 90.0, 74.3, 62.6, 45.7, 44.7, 40.4, 37.6, 35.2, 34.4, 32.8,
32.7, 28.8, 27.5, 25.8; HRMS [ESI(TOF)] for C17H23O2 [M+H+]: m/z:
calcd for: 259.1698; found: 259.1699.
Characterization of the PK Cycloaddition Products 3f–h
[10] Rh-catalyzed PK cycloadditions: a) N. Jeong, S. Lee, B. K. Sung, Organo-
metallics 1998, 17, 3642–3644; b) N. Jeong, B. K. Sung, Y. K. Choi, J. Am.
Chem. Soc. 2000, 122, 6771–6772; c) P. A. Evans, J. E. Robinson, J. Am.
Chem. Soc. 2001, 123, 4609–4610; d) T. Kobayashi, Y. Koga, K. Narasaka,
J. Organomet. Chem. 2001, 624, 73–87; e) B. M. Fan, J. H. Xie, S. Li, Y. Q.
Tu, Q. L. Zhou, Adv. Syn. Cat. 2005, 347, 759–762; f) T. Shibata, N. Toshi-
da, K. Takagi, Org. Lett. 2002, 4, 1619–1621; g) T. Shibata, N. Toshida, K.
Takagi, J. Org. Chem. 2002, 67, 7446–7450.
3 f: Prepared from 2 f (187 mg, 0.73 mmol), light yellow solid,
117.4 mg, 57% yield; M.p. 67–688C; H NMR (300 MHz, CDCl3): d =
1
5.79 (m, 1H), 5.69 (s, 1H), 5.06 (s, 1H), 5.01 (d, 1H, J=8.4 Hz), 4.54
(s, 1H), 4.30 (t, 1H, J=6.9 Hz), 3.14 (m, 2H), 2.61 (dd, 1H, J=18,
6 Hz), 2.40 (d, 1H, J=16.8 Hz), 2.05 (m, 5H), 1.61 (m, 4H), 1.23 (s,
1H), 0.89 (s, 3H), 0.87 (s, 3H); 13C NMR (75 MHz, CDCl3): d = 208.3,
176.8, 140.5, 134.7, 130.1, 128.6, 118.0, 82.8, 71.7, 43.6, 43.5, 39.5,
29.9, 27.4, 25.4, 23.5, 23.4, 22.6, 22.0; HRMS [ESI(TOF)] for C19H27O2
[M+H+]: m/z: calcd for: 287.2011; found: 287.2006.
[11] Rh-catalyzed intramolecular [4+2] cycloaddition of alkenes with conju-
gated dienes: a) R. S. Jolly, G. Luedtke, D. Sheehan, T. Livinghouse, J.
Am. Chem. Soc. 1990, 112, 4965–4966; b) L. McKinstry, T. Livinghouse,
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Tetrahedron 1994, 50, 6145–6154; c) P. A. Wender, T. E. Jenkins, S.
Suzuki, J. Am. Chem. Soc. 1995, 117, 1843–1844; d) S. R. Gilbertson, G. S.
Hoge, Tetrahedron Lett. 1998, 39, 2075–2078; e) S. R. Gilbertson, G. S.
Hoge, D. G. Genov, J. Org. Chem. 1998, 63, 10077; f) B. Wang, P. Cao, X.
Zhang, Tetrahedron Lett. 2000, 41, 8041–8044.
[12] M. Turlington, L. Pu, Org. Lett. 2011, 13, 4332–4335.
Received: June 26, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Asymmetric Synthesis
J. Ying, L. Pu*
&& – &&
A Facile Asymmetric Approach to the
Multicyclic Core Structure of Mangicol
A
Chiral propargylic ether-based triene–
ynes are found to undergo a one-pot
domino Pauson–Khand and Diels–Alder
cycloaddition catalyzed by [RhCl(CO)2]2
under CO to generate a series of multi-
cyclic products with high chemoselec-
tivity and stereoselectivity. These prod-
ucts contain the multicyclic core struc-
ture of mangicol A which could facilitate
the synthesis and study of this class of
natural products.
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
8
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!