Highly stereoselective syntheses of all 1,2,3-Me,OH,Me triads via asymmetric hydrogenation reactions

Article abstract of DOI:10.1002/adsc.201200709

Iridium-catalyzed asymmetric hydrogenations of chiral alkenes were used to access four pivotal α,ω-functionalized chirons, that contain widely occurring stereochemical 1,2,3-Me,OH,Me motifs. A chiral analogue of Crabtree's catalyst was used in key hydrogenation steps to form these motifs with high stereochemical purities. An application of one of these chirons is illustrated here with a synthesis of (-)-invictolide. Copyright

Full text of DOI:10.1002/adsc.201200709

FULL PAPERS
DOI: 10.1002/adsc.201200709
Highly Stereoselective Syntheses of All 1,2,3-Me,OH,Me Triads
via Asymmetric Hydrogenation Reactions
Ye Zhua and Kevin Burgessa,*
a
Department of Chemistry, Texas A&M University, Box 30012, College Station, TX 77842-3012, USA
Fax : (+1)-979-845-8839; phone: (+1)-979-845-4345; e-mail: burgess@tamu.edu
Received: August 8, 2012; Published online: January 3, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200709.
Abstract: Iridium-catalyzed asymmetric hydrogena- high stereochemical purities. An application of one
tions of chiral alkenes were used to access four pivo- of these chirons is illustrated here with a synthesis of
tal a,w-functionalized chirons, that contain widely (À)-invictolide.
occurring stereochemical 1,2,3-Me,OH,Me motifs. A
chiral analogue of Crabtreeꢀs catalyst was used in Keywords: asymmetric synthesis; catalysis; hydroge-
key hydrogenation steps to form these motifs with nation; iridium; polyketides
Introduction
the “complex fragment” has reactive functional
groups and exerts significant substrate control.
Convergent alternatives to incorporate the featured
Acyclic chains with 1,2,3-Me,OH,Me substituents (A–
D) are found in many polyketide-derived materials.[1] triads can involve construction of suitable chirons,
Many strategies to access these stereochemical triads then grafting them onto complex molecular fragments
are linear as illustrated in Scheme 1, b.[2] Such ap- (Scheme 1, c). This strategy has advantages because
proaches tend to be less efficient than convergent stereocenters in the triads are set in the absence of
routes. More importantly, it can be difficult to find the complex fragment. However, to generally imple-
suitable reagents and conditions to effect linear trans- ment this approach all stereoisomers of a,w-bifunc-
formations with high yields and stereoselectivities if tional 1,2,3-Me,OH,Me triads have to be accessible. If
that were accomplished in scalable, commercialized
syntheses then this would facilitate syntheses of many
polyketide-derived natural products.
Roche ester derivatives are excellent starting mate-
rials for syntheses of a,w-functionalized species con-
taining fragments A–D. So much work has been done
in this area that it can only be outlined here. Methods
to elaborate Roche ester derivative aldehydes into
a,w-functionalized chirons containing fragments A–D
may be divided into: (i) reactions with chiral reagents
for aldol or crotylation reactions;[3] (ii) aldol or croty-
lation reactions involving achiral reagents and chiral
catalysts;[4] and (iii) routes relying mostly on substrate
controlled diastereoselective reactions (Scheme 1,
b).[5]
Relatively few methodologies, however, can be
used to obtain all stereoisomers of a,w-bifunctional
1,2,3-Me,OH,Me triads. For instance, none of the new
catalyzed aldol or crotylation reactions will do this.[4]
Methods that do give all the stereomers are restricted
to those that feature resolved allenyl-stannane,[6]
Scheme 1. Routes to complex materials containing triads A–
D.
-silane,[5h,7] -zinc[8] and crotylsilane[9] reagents, or cro-
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Ye Zhu and Kevin Burgess
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tylsilanes functionalized with chiral auxiliaries.[10]
These methods have the compelling advantage that
À
a C C bond and two chiral centers are formed in one
step. On the other hand, they have the disadvantages
with respect to scale-up. This is because these meth-
ods involve multistep syntheses of optically active cro-
tylation reagents and feature a-chiral aldehyde sub-
strates that cannot be easily purified without degrada-
tion of optical purities.
In the work described here, the first objective was
to establish methodology featuring alkene hydrogena-
tions with cat[11] that would enable access to all four
stereoisomers of a,w-bifunctional 1,2,3-Me,OH,Me
triads. The other objectives were to avoid stereochem-
ically delicate Roche aldehyde derivatives, and to
only use stoichiometric reagents that are commercial-
ly available and inexpensive enough to be used in
large-scale work.
Scheme 2. Catalytic hydrogenation reactions to obtain a,w-
bifunctional 1,2,3-Me,OH,Me triads.
Results and Discussion
Scheme 2 outlines the strategy that guided the initial
phase of this research, which, in fact, was successful. reduction of the corresponding 1,3-hydroxy ketone
It involves formation of the carbon skeleton in key in- 4,[13–14] affording the syn-alkenes 6 and 7 after some
termediate 1, then reduction reactions to introduce functional group manipulations (Scheme 3, b).
the chiral centers.
Alkenes 2/3, and 6/7 have different protecting
Scheme 2 shows four key intermediates that pre- groups on the same scaffold. In fact, the protecting
ceded the hydrogenations steps: 2, 3, 6, and 7. To groups were varied throughout this study to enhance
make these, a literature procedure[12] was adapted to the stereoselectivities in the hydrogenations reactions;
allow the silyl ether 1 to be made in gram amounts in total, 17 substrates were tested to reach this conclu-
(Scheme 3, a). This route involved protection of the sion (see the Supporting Information). Scheme 4
Roche ester, reaction with a phosphonate-stabilized shows data for hydrogenations of the key substrates
anion, and alkene formation. Ketone 1 can be ob- with matched and mismatched catalysts; all these re-
tained just as easily as the Roche aldehyde derivatives actions were catalyst controlled. The least selective
but, critically, it can be columned without loss of opti- one (Scheme 4, d) gave a 1.0:18 bias in the crude re-
cal activity.
action material, and the most (Scheme 4, c) gave only
Felkin–Anh-selective DIBAL reduction of ketone one diastereomer in our HPLC analysis (UV detec-
1 (by analogy with Boger[13]) gave the anti-alcohol 2 tion). In two cases (Scheme 4, b and d), it was con-
with high diastereoselectivity. The minor and major venient to modify the hydrogenation products to facil-
diastereomers produced were easily separated by itate removal of trace stereoisomers by chromatogra-
column chromatography. Simple deprotection of com- phy, but in the other two cases the stereoisomers
pound 2 gave the diol 3.
could be separated directly, if necessary. Chirons 8–11
The routes that afford the key allylic alcohol deriv- represent all the stereoisomers in the Me,OH,Me
atives 6 and 7 diverge from substrate 1. Specifically, series, and each has differentially functionalized ter-
enone 1 was desilylated to allow chelation-controlled mini.
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Highly Stereoselective Syntheses of All 1,2,3-Me,OH,Me Triads
Scheme 3. The two key hydrogenation substrates for this
study were formed via hydrides.
A synthesis of (À)-invictolide was performed to il-
lustrate that these chirons can be used to prepare
polyketide-derived natural products (Scheme 5).
More than a gram of chiron 9 was prepared via the
reaction indicated in Scheme 4, b. Debenzylation gave
the alcohol 12, which was then oxidized and homolo-
gated to alkene 13. Reduction and deprotection of 13
gave the diol 14; global silylation then selective desi-
Scheme 4. Preparation of chirons for a,w-functionalized
triads: a anti,anti-type; b anti,syn; c syn,syn; and d syn,anti.
All ratios quoted were from HPLC on a Chiralcel-OD
column. All reactions were run in CH2Cl2 at 258C.
lylation of this gave the primary alcohol 16.[15] Oxida- even if they do not contain a group that typically co-
tion and reactions with a stabilized ylide gave the re- ordinates to hydrogenation catalysts. Cat hydrogen-
quired alkene substrate 18. Another diastereoselec- ates alkenes with selectivities that are usually high
tive hydrogenation, but to produce a 1,3-disposed di- enough to override inherent biases of chiral sub-
methyl fragment,[16] was used to complete the con- strates, i.e., catalyst control.[19] Substrate characteris-
struction of the chiral centers, before the last step in tics can be manipulated simply by varying protecting
the synthesis: deprotection and cyclization to the lac- groups to optimize the stereoselectivities obtained.
tone target.[17]
Two syntheses provided all four key substrates for the
hydrogenation reactions, and all four of the targeted
chirons were obtained with high stereoselectivities.
Two of the chiral centers in the invictolide synthesis
above were derived from hydrogenation reactions,
Conclusions
This work illustrates how chiral analogues of Crab- and there is at least the potential to prepare all the
treeꢀs catalyst[18] can hydrogenate hindered alkenes stereoisomers of the product using this route. Never-
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Ye Zhu and Kevin Burgess
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tained from commercial source and used without further pu-
rification. All the solvents were used after appropriate distil-
lation or purification.
Flash column chromatography was performed using silica
gel 60 (230–400 mesh). Analytical thin layer chromatogra-
phy (TLC) was carried out on Merck silica gel plates with
QF-254 indicator and visualized by UV. Optical rotations
were measured on Jasco DIP-360 digital polarimeter. 1H
and 13C NMR spectra were recorded on a Varian 300
1
(300 MHz H; 75 MHz 13C) or Varian Unity-500 (500 MHz
1H; 125 MHz 13C) spectrometer at room temperature.
Chemical shifts are reported in ppm relative to the residual
1
CDCl3 (d=7.28 ppm H; d=77.26 ppm 13C). Coupling con-
stants (J) are reported in Hertz. Iridium catalysts (S)-Cat
and (R)-Cat were prepared using literature methods.[11b]
General Catalytic Hydrogenation Conditions
The alkene was dissolved in CH2Cl2 (0.5M) and the iridium
catalyst [(S)-Cat or (R)-Cat] (1 mol%) was then added. The
resulting solution was degassed by three cycles of freeze-
pump-thaw using nitrogen, then transferred to a Parr bomb.
The bomb was flushed with hydrogen for 1 min without stir-
ring. The mixture was then stirred at 700 rpm under 50 bar
of H2. After 4 h, the bomb was vented and the solvent was
evaporated. The crude product was passed through a silica
plug (EtOAc/hexanes=3/7). The diastereomeric ratio of the
crude material was then measured through chiral HPLC
[The HPLC analysis was performed on a Beckman Series
HPLC, UV detection monitored at wavelength 254 nm,
using Chiralcel@ OD (250ꢂ4.6 mm ID)].
(R)-E-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)oxy]-
2,4-dimethylhex-4-en-3-one (1)
n-BuLi (2.5M in hexanes, 12.5 mL) was added to a solution
of diethyl ethylphosphonate (5.66 g, 34.1 mmol) in THF
(70 mL) at À788C over 10 min. The resulting mixture was
stirred at À788C for 0.5 h. Then a solution of 3-(tert-butyldi-
phenylsilanyloxy)-2-(R)-methylpropionic acid methyl ester
(4.86 g, 13.6 mmol) in THF (70 mL) was added to this mix-
ture over 30 min. The solution was further stirred for 0.5 h
at À788C and then NH4Cl(s) (50 mL) was added to quench
the reaction. The mixture was warmed to 258C and diluted
with H2O (20 mL). The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (3ꢂ100 mL). The com-
bined organic layers were dried with Na2SO4, and concen-
trated under vacuum. Purification of the residue by flash
chromatography on silica gel, eluting with EtOAc/hexanes
(30:70) gave the desired phosphonate as a colorless oil;
Scheme 5. Total synthesis of (À)-invictolide via two hydro-
genation steps mediated by cat (including the one used to
make the starting material 9).
theless, invictolide is a sub-optimal illustrative target
because one of the terminal functional groups in the
key chiron was not used, instead it was simply re-
moved. More streamlined applications might involve
homologation of both termini in different directions
for syntheses of more complex materials; we have not
1
yield: 6.41 g (13.1 mmol, 96%). H NMR indicated the prod-
yet demonstrated this, but propose to do so in further uct as a mixture of two diastereoisomers. The purified phos-
phonate (7.30 g, 14.9 mmol) was dissolved in THF (80 mL)
and H2O (2 mL). The solution was cooled to 08C and
Ba(OH)2 (2.55 g, 14.9 mmol) was added in one portion. The
mixture was stirred for 0.5 h and then a solution of benzy-
loxyacetaldehyde (2.3 mL, 16.4 mmol) in THF (10 mL) was
added dropwise. The resulting mixture was further stirred
for 2 h at 258C before being quenched with NaHCO3(s)
(50 mL). The mixture was diluted with Et2O (50 mL) and
the precipitates were removed via filtration on a Buchner
funnel. The filtrate were separated and the aqueous layer
was extracted with Et2O (3ꢂ50 mL). The combined organic
applications of this work.
Experimental Section
General Experimental Methods
All reactions were carried out under an atmosphere of dry
nitrogen. Glassware was oven-dried prior to use. Unless oth-
erwise indicated, common reagents or materials were ob-
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Highly Stereoselective Syntheses of All 1,2,3-Me,OH,Me Triads
layers were dried with Na2SO4 and concentrated under
vacuum. Purification of the residue by flash chromatography
on silica gel, eluting with EtOAc/hexanes (5:95) gave enone
1 as a colorless oil; yield: 6.30 g (12.9 mmol, 87%); [a]2D1:
À19.1 (c 0.83, CHCl3). 1H NMR (300 MHz, CDCl3): d=
7.64–7.60 (m, 4H), 7.41–7.26 (m, 11H), 6.72 (t, J=4.5 Hz,
1H), 4.56 (s, 2H), 4.28–4.25 (m, 2H), 3.86–3.83 (m, 1H),
3.64–3.52 (m, 2H), 1.75 (s, 3H), 1.03 (d, J=6.0 Hz, 3H),
1.00 (s, 9H); 13C NMR (75 MHz, CDCl3): d=204.6, 138.9,
137.9, 135.8, 135.8, 133.8, 133.6, 129.9, 128.8, 128.1, 128.1,
127.9, 73.3, 67.8, 67.2, 42.0, 27.0, 19.4, 14.7, 12.2; HR-MS
(ESI): m/z=487.2684, calcd. for C31H39O3Si [M+H]+:
487.2668.
128.0, 125.1, 84.4, 72.7, 68.4, 66.5, 37.4, 14.0, 11.6; HR-MS
(ESI): m/z=273.1472, calcd.: for C15H22NaO3 [M+Na]+:
273.1467.
(R)-E-6-(Benzyloxy)-1-hydroxy-2,4-dimethylhex-4-en-
3-one (4)
The enone 1 (4.78 g, 9.8 mmol) was dissolved in THF
(100 mL) followed by addition of TBAF (1M in THF,
10.3 mL, 10.3 mmol). The resulting solution was stirred at
08C for 1 h, then the reaction was quenched by addition of
NH4Cl(s) (20 mL). The layers were separated, and the aque-
ous layer was extracted with Et2O (3ꢂ20 mL). The organic
extract was dried (Na2SO4) and concentrated under vacuum.
Purification by flash column chromatography, eluting with
EtOAc/hexanes (30:70) gave enone 4 as a colorless oil;
yield: 1.60 g (6.6 mmol, 67%); [a]2D2:2: À12.5 (c 1.27, CHCl3).
1H NMR (300 MHz, CDCl3): d=7.41–7.26 (m, 5H), 6.78–
6.72 (m, 1H), 4.58 (s, 2H), 4.30–4.22 (m, 2H), 3.92–3.64 (m,
2H), 3.47–3.35 (m, 1H), 2.21 (t, J=6.0 Hz, 1H), 1.74 (s,
3H), 1.13 (d, J=9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=140.0, 137.8, 136.9, 128.8, 128.2, 128.1, 73.4, 67.7, 65.1,
41.5, 15.3, 12.1 (missing the peak for the carbonyl carbon);
HR-MS (ESI): m/z=249.1488, calcd. for C15H21O3 [M+H]+:
249.1491.
ACHTUNGTRENNUNG(2R,3R)-E-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)-
oxy]-2,4-dimethylhex-4-en-3-ol (2)
To a solution of enone 1 (4.31 g, 8.86 mmol) in toluene
(100 mL) cooled to À788C was added the neat DIBAL
(3.16 mL, 17.7 mmol) in a period of 5 min. The reaction mix-
ture was stirred for an additional 2 h before dropwise addi-
tion of anhydrous EtOAc (5 mL) at À788C and transferred
quickly into a vigorously stirred mixture of EtOAc/saturated
potassium sodium tartrate aqueous solution (300 mL/
100 mL). Stirring was continued for 1 h and the layers were
separated. The aqueous layer was extracted with EtOAc
(3ꢂ50 mL). The combined organic extracts were dried
AHCTUNGTREG(NNNU 2R,3S)-E-6-(Benzyloxy)-2,4-dimethylhex-4-ene-1,3-
diol (5)
1
(Na2SO4) and concentrated under vacuum. H NMR of the
crude product suggested the syn:anti diastereoisomer ratio
was 1.0:14. After purification by flash chromatography on
silica gel, eluting with EtOAc/hexanes (10:90), the desired
anti-allylic alcohol 2 can be obtained with 88% isolated
yield and the syn:anti diastereoisomer ratio was further in-
creased to >99% de (check by HPLC). [a]2D0:6: À14.0 (c 0.71,
Tetramethylammonium
triacetoxyborohydride
(13.9 g,
52.8 mmol) was dissolved in CH3CN/AcOH (60 mL, 1:1)
and the mixture was stirred for 30 min at 258C. The result-
ing clear solution was cooled to À308C and a solution of 4
in MeCN (6 mL, 2ꢂ2 mL for rinse) was added dropwise.
The reaction mixture was stirred at À308C for an additional
48 h before dropwise addition of saturated potassium
sodium tartrate aqueous solution (20 mL). Stirring was con-
tinued for 1 h and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3ꢂ30 mL). The combined
organic extracts were washed with NaHCO3(s) (30 mL),
brine (30 mL) and then dried with Na2SO4. The solution was
concentrated under vacuum. Purification by flash column
chromatography, eluting with EtOAc/hexanes (50:50 to
80:20) gave diol 5 as a colorless oil; yield: 1.40 g (5.6 mmol,
1
CHCl3); H NMR (500 MHz, CDCl3): d=7.69–7.65 (m, 4H),
7.45–7.23 (m, 11H), 5.66 (t, J=7.5 Hz, 1H), 4.51 (s, 2H),
4.11 (d, J=10.0 Hz, 2H), 4.00 (d, J=10.0 Hz, 1H), 3.90 (s,
1H), 3.80–3.78 (m, 1H), 3.67–3.63 (m, 1H), 1.96–1.89 (m,
1H), 1.64 (s, 3H), 1.06 (s, 9H), 0.73 (d, J=5.0 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=140.0, 138.7, 135.8, 132.9,
128.1, 127.8, 124.8, 95.0, 83.2, 72.3, 69.2, 66.6, 37.5, 27.0, 19.3,
14.0, 11.8; HR-MS (ESI): m/z=511.2633, calcd. for
C31H40NaO3Si [M+Na]+: 511.2644.
1
81%). H NMR of the crude product indicated the syn:anti
diastereoisomer ratio was >19:1.0. [a]2D1:9: À32.2 (c 0.62,
ACHTUNGTRENNUNG(2R,3R)-E-6-(Benzyloxy)-2,4-dimethylhex-4-ene-1,3-
diol (3)
1
CHCl3). H NMR (300 MHz, CDCl3): d=7.39–7.26 (m, 5H),
5.70 (t, J=6.0 Hz, 1H), 4.53 (s, 2H), 4.18–4.08 (m, 3H),
3.72–3.64 (m, 2H), 2.07–1.83 (m, 3H), 1.63 (s, 3H), 0.91 (d,
J=9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=140.8,
138.6, 128.7, 128.1, 127.9, 121.9, 78.4, 72.6, 67.1, 66.5, 37.7,
13.9, 10.6; HR-MS (ESI): m/z=273.1463, calcd. for
C15H22NaO3 [M+Na]+ 273.1467.
The allylic alcohol 2 (0.59 g, 1.2 mmol) was dissolved in
THF (5 mL) followed by addition of TBAF (1M in THF,
1.4 mL, 1.4 mmol). The resulting solution was stirred at
258C for 1 h, then the reaction was quenched by addition of
NH4Cl(s) (5 mL). The layers were separated, and the aque-
ous layer was extracted with Et2O (3ꢂ5 mL). The organic
extract was dried (Na2SO4) and concentrated under vacuum.
Purification by flash column chromatography, eluting with
EtOAc/hexanes (50:50) gave diol 3 as a colorless oil; yield:
0.30 g (1.2 mmol, 100%); [a]2D2:1: À11.0 (c 1.09, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.37–7.26 (m, 5H), 5.62 (t,
J=6.0 Hz, 1H), 4.52 (s, 2H), 4.08–4.02 (m, 2H), 3.92 (d, J=
9.0 Hz, 1H), 3.74–3.61 (m, 2H), 2.93 (br, 1H), 2.60 (br, 1H),
1.97–1.85 (m, 1H), 1.65 (s, 3H), 0.75 (d, J=9.0 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=140.2, 138.4, 128.7, 128.1,
AHCTUNGTREG(NNUN 2R,3S)-E-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)-
oxy]-2,4-dimethylhex-4-en-3-ol (6)
To a solution of compound 5 (0.88 g, 3.5 mmol) and imida-
zole (0.26 g, 3.85 mmol) in CH2Cl2 (10 mL) was added a solu-
tion of TBDPSCl (1.02 g, 3.7 mmol) in CH2Cl2 (5 mL, 2ꢂ
1 mL for rinse) dropwise at À308C. The reaction was stirred
for 2 h, then quenched with NaHCO3(s) (10 mL). The or-
ganic layer was separated and the aqueous layer was ex-
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Ye Zhu and Kevin Burgess
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tracted with CH2Cl2 (3ꢂ10 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated under vacuum.
Purification by flash column chromatography, eluting with
EtOAc/hexanes (20:80) gave alcohol 6 as a colorless oil;
yield: 1.30 g (2.7 mmol, 76%); [a]2D2:2: À15.0 (c 0.80, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.70–7.65 (m, 4H), 7.47–
7.26 (m, 11H), 5.74 (t, J=6.0 Hz, 1H), 4.51 (s, 2H), 4.28 (m,
1H), 4.09 (d, J=6.0 Hz, 2H), 3.72–3.64 (m, 2H), 2.42 (d, J=
3.0 Hz, 1H), 1.91–1.82 (m, 1H), 1.58 (s, 3H), 1.08 (s, 9H),
0.90 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
140.2, 138.7, 135.8, 133.4, 130.0, 128.0, 127.8, 121.9, 77.4,
72.3, 67.9, 66.5, 37.9, 27.1, 19.5, 13.8, 10.5; HR-MS (ESI):
m/z=489.2848, calcd. for C31H41O3Si [M+H]+: 489.2825.
AHCTUNGTRENNUNG
methyl-1,3-dioxane (9)
Hydrogenation of 3 (310 mg, 1.2 mmol) was carried out ac-
cording to the general procedure using (R)-Cat (1 mol%,
19 mg) in CH2Cl2 (1 mL). NMR of the crude product
showed 100% conversion. Thus without purification, the
crude diol was dissolved in CH2Cl2 (10 mL). TsOH (22.8 mg,
0.12 mmol) and 2,2-Dimethoxypropane (0.74 mL, 6.0 mmol)
were then added to the solution of diol and the resulting
mixture was stirred for 1 h at 258C. The reaction was
quenched by adding NaHCO3(s) (5 mL). The organic layer
was separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic extracts were
dried (Na2SO4) and concentrated under vacuum. HPLC
analysis of the crude material showed syn:anti ratio to be
21:1.0. Purification by column chromatography EtOAc/hex-
anes (5:95) gave the anti,syn triad 9[20] as a colorless oil;
yield: 319 mg (91% from 3); HPLC analysis showed syn:anti
ACHTUNGTRENNUNG(2R,3S)-E-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)-
oxy]-2,4-dimethylhex-4-en-3-yl Acetate (7)
To a solution of compound 6 (0.86 g, 1.75 mmol) and
DMAP (22 mg, 0.18 mmol) in CH2Cl2 (10 mL) was added
Ac2O (0.33 mL, 3.5 mmol) and Et3N (0.49 mL, 3.5 mmol)
dropwise at 258C. The reaction was stirred for 1 h, and then
quenched with NaHCO3(s) (5 mL). The organic layer was
separated and the aqueous layer was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic extracts were dried
(Na2SO4) and concentrated under vacuum. Purification by
flash column chromatography, eluting with EtOAc/hexanes
(5:95) gave acetate 7 as a colorless oil; yield: 0.85 g
(1.6 mmol, 92%); [a]2D0:8: À20.6 (c 0.87, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.67–7.60 (m, 4H), 7.43–7.26 (m,
11H), 5.53 (t, J=6.0 Hz, 1H), 5.31 (d, J=3.0 Hz, 1H), 4.44
(s, 2H), 4.11–3.97 (m, 2H), 3.49 (d, J=9.0 Hz, 2H), 2.05 (s,
3H), 2.04–1.96 (m, 1H), 1.56 (s, 3H), 1.05 (s, 9H), 0.89 (d,
J=9.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=170.3,
138.5, 136.4, 135.9, 135.8, 133.9, 133.8, 127.8, 123.6, 77.8,
77.5, 72.1, 66.3, 65.6, 37.7, 27.1, 21.3, 19.5, 13.8, 11.7; HR-MS
(ESI): m/z=553.2765, calcd. for C33H42NaO4Si [M+Na]+:
553.2750.
>99% de; [a]2D1:1
:
À34.7 (c 0.92, CHCl3). 1H NMR
(300 MHz, CDCl3): d=7.40–7.28 (m, 5H), 4.56 (d, J=
12.0 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 3.70–3.65 (m, 1H),
3.56–3.36 (m, 4H), 1.97–1.60 (m, 4H), 1.34 (s, 3H), 1.33 (s,
3H), 0.88 (d, J=6.0 Hz, 3H), 0.72 (d, J=6.0 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=138.9, 128.6, 128.0, 127.8,
98.3, 76.7, 73.2, 68.4, 66.7, 33.8, 31.1, 30.1, 29.9, 19.2, 12.7,
12.5.
AHCTUNGTREG(NNUN 2R,3R,4S)-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)-
oxy]-2,4-dimethylhexan-3-ol (10)
Hydrogenation of 6 (250 mg, 0.50 mmol) was carried out ac-
cording to the general procedure using (S)-Cat. (1 mol%,
8 mg) in CH2Cl2 (1.0 mL). NMR of the crude product
showed 100% reduction to 10. HPLC analysis of the crude
material can only detect the syn,syn triad. One simple
column chromatography on silica gel, eluting with EtOAc/
hexanes (5:95) give syn,syn triad 10 as a colorless oil; yield:
230 mg (0.45 mmol, 90%); [a]2D1:1: À8.9 (c 0.89, CHCl3).
1H NMR (300 MHz, CDCl3): d=7.71–7.65 (m, 4H), 7.48–
7.29 (m, 11H), 4.53 (d, J=12.0 Hz, 1H), 4.49 (d, J=12.0 Hz,
1H), 3.73–3.47 (m, 5H), 2.72 (d, J=3.0 Hz, 1H), 1.91–1.69
(m, 3H), 1.46–1.37 (m, 1H), 1.08 (s, 9H), 1.01 (d, J=6.0 Hz,
3H), 0.96 (d, J=6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=138.6, 135.8, 133.4, 130.0, 130.0, 128.6, 128.0, 127.9, 127.8,
77.5, 73.3, 68.8, 68.6, 37.2, 33.6, 33.5, 27.1, 19.5, 15.1, 11.3;
HR-MS (ESI): m/z=491.2995, calcd. for C31H43O3Si [M+
H]+: 491.2981.
ACHTUNGTRENNUNG(2R,3S,4S)-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)-
oxy]-2,4-dimethylhexan-3-ol (8)
Hydrogenation of 2 (175 mg, 0.36 mmol) was carried out ac-
cording to the general procedure using (S)-Cat. (1 mol%,
6 mg) in CH2Cl2 (0.72 mL). NMR of the crude product
showed 100% reduction. HPLC analysis of the crude mate-
rial showed syn:anti ratio to be 1.0:48. One simple column
chromatography on silica gel, eluting with EtOAc/hexanes
(5:95) gave anti,anti triad 8 (syn:anti=1.0:48 from HPLC
analysis) as a colorless oil; yield: 155 mg (0.32 mmol, 89%);
1
[a]2D0:8: À21.7 (c 0.92, CHCl3). H NMR (300 MHz, CDCl3):
AHCTUNGTREG(NNUN 2R,3R,4R)-6-(Benzyloxy)-1-[(tert-butyldiphenylsilyl)-
oxy]-2,4-dimethylhexan-3-ol (11)
d=7.72–7.66 (m, 4H), 7.49–7.27 (m, 11H), 4.57 (d, J=
12.0 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H), 3.80–3.36 (m, 6H),
1.99–1.79 (m, 3H), 1.61–1.53 (m, 1H), 1.07 (s, 9H), 0.99 (d,
J=6.0 Hz, 3H), 0.87 (d, J=9.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=138.9, 135.8, 133.1, 130.1, 128.6, 128.0, 128.0,
127.8, 127.7, 81.1, 73.1, 69.2, 69.0, 37.5, 33.2, 30.3, 27.1, 19.4,
17.3, 14.2; HR-MS (ESI): m/z=491.3002, calcd. for
C31H43O3Si [M+H]+: 491.2981.
Hydrogenation of 7 (440 mg, 0.83 mmol) was carried out ac-
cording to the general procedure using (R)-Cat (1 mol%,
15 mg) in CH2Cl2 (1.5 mL). NMR of the crude product
showed 100% conversion. Thus without purification, the
crude acetate was dissolved in CH2Cl2 (10 mL) and cooled
to À788C. DIBAL-H (1.0M in hexanes, 2.0 mL, 2.0 mmol)
was added dropwise and the solution was stirred at À788C
for 1 h. EtOAc (2 mL) was added to the mixture followed
by addition of saturated potassium sodium tartrate aqueous
solution (5 mL). Stirring was continued for 1 h and the
layers were separated. The aqueous layer was extracted with
112
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Highly Stereoselective Syntheses of All 1,2,3-Me,OH,Me Triads
EtOAc (3ꢂ10 mL). The combined organic extracts were
dried (Na2SO4) and concentrated under vacuum. HPLC
analysis of the crude material showed syn:anti ratio to be
1.0:18. Purification by column chromatography EtOAc/hex-
anes (5:95) gave the syn,anti triad 11 as a colorless oil;
yield: 340 mg (0.69 mmol, 83% from 7): HPLC analysis
showed syn:anti >99% de; [a]2D1:4: À5.5 (c 1.08, CHCl3).
1H NMR (300 MHz, CDCl3): d=7.70–7.65 (m, 4H), 7.45–
7.28 (m, 11H), 4.55 (d, J=12.0 Hz, 1H), 4.51 (d, J=12.0 Hz,
1H), 3.73–3.51 (m, 5H), 3.00 (d, J=3.0 Hz, 1H), 1.99–1.51
(m, 4H) (integrated with a huge H2O peak), 1.08 (s, 9H),
0.93 (d, J=6.0 Hz, 3H), 0.85 (d, J=6.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=138.7, 135.9, 133.6, 130.0, 129.9, 128.6,
127.9, 127.9, 127.8, 77.5, 73.2, 68.9, 68.9, 37.0, 34.3, 33.4, 27.2,
19.5, 16.7, 9.6; HR-MS (ESI): m/z=491.2969, calcd. for
C31H43O3Si [M+H]+: 491.2981.
oil; yield: 0.49 g (74% over two steps); [a]1D9:6: À27.1 (c 0.81,
1
CHCl3). H NMR (300 MHz, CDCl3): d=5.86–5.72 (m, 1H),
5.06–4.96 (m, 2H), 3.71 (dd, J=3.0, 12.0 Hz, 1H), 3.54–3.45
(m, 2H), 2.22–1.70 (m, 4H), 1.40 (s, 3H), 1.38 (s, 3H), 0.90
(d, J=9.0 Hz, 3H), 0.71 (d, J=6.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=138.2, 116.0, 98.3, 76.2, 66.7, 38.5,
33.6, 31.1, 30.0, 19.3, 12.8, 12.5; HR-MS (ESI): m/z=
199.1670, calcd. for C12H23O2 [M+H]+: 199.1698.
AHCTUNGTREGUN(NN 2R,3S,4R)-2,4-Dimethylheptane-1,3-diol (14)
To a solution of 13 (0.49 g, 2.5 mmol) in MeOH (10 mL)
was added Pd/C (10% on carbon, 266 mg, 0.25 mmol) in one
portion. The air inside the reaction flask was vacuumed out
and then hydrogen gas was purged into the flask. The mix-
ture was stirred under 1 atm H2 pressure at room tempera-
ture for 8 h. The mixture was filtered on a plug of silica gel
(5 cm) and washed with MeOH (5 mL). To the filtrate the
TsOH (48 mg, 0.25 mmol) was added in one portion and the
solution was stirred for 4 h at 258C. The reaction mixture
was quenched with saturated aqueous NaHCO3 (5 mL), ex-
tracted with ether (3ꢂ10 mL), dried over MgSO4, and con-
centrated. Purification by column chromatography (silica
gel, EtOAc/hexanes, 50:50) gavediol 14 as a colorless liquid;
yield: 0.32 g (80%, 2 steps); [a]2D1:7: À21.9 (c 0.73, CHCl3).
1H NMR (300 MHz, CDCl3): d=3.79–3.63 (m, 2H), 3.53–
3.47 (m, 1H), 2.94–2.91 (m, 1H), 2.34 (d, J=6.0 Hz, 1H),
1.96–1.82 (m, 1H), 1.67–1.60 (m, 1H), 1.41–1.24 (m, 4H),
0.94 (t, J=6.0 Hz, 3H), 0.90 (d, J=9.0 Hz, 3H), 0.84 (d, J=
6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=80.7, 69.1,
37.7, 36.5, 35.1, 20.7, 14.5, 13.8, 12.5; HR-MS (ESI): m/z=
161.1535, calcd. for C9H21O2 [M+H]+: 161.1542.
(R)-3-[(4S,5R)-2,2,5-Trimethyl-1,3-dioxan-4-yl]butan-
1-ol (12)
To a solution of 9 (1.06 g, 3.64 mmol) in MeOH (20 mL)
was added Pd/C (10% on carbon, 194 mg, 0.18 mmol) in one
portion. The air inside the reaction flask was vacuumed out
and then hydrogen gas was purged into the flask. The mix-
ture was stirred under 1 atm H2 pressure at room tempera-
ture for 8 h. The mixture was filtered on a plug of silica gel
(5 cm), washed with MeOH, and concentrated to give free
saturated alcohol 12 as a colorless oil; yield: 0.68 g (93%);
1
[a]2D2:0: À42.8 (c 0.70, CHCl3): H NMR (300 MHz, CDCl3):
d=3.78–3.65 (m, 3H), 3.61–3.46 (m, 2H), 2.14–2.10 (m,
1H), 2.01–1.89 (m, 2H), 1.85–1.59 (m, 2H), 1.43 (s, 3H),
1.38 (s, 3H), 0.93 (d, J=6.0 Hz, 3H), 0.75 (d, J=6.0 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=98.5, 77.9, 66.5, 60.4,
37.3, 31.1, 30.8, 29.9, 19.3, 12.7, 12.4; HR-MS (ESI): m/z=
203.1654, calcd. for C11H23O3 [M+H]+: 203.1647.
AHCTUNGTREG(NNUN 5S,6R)-2,2,3,3,6,9,9,10,10-Nonamethyl-5-[(R)-pentan-
2-yl]-4,8-dioxa-3,9-disilaundecane (15)
The diol 14 (0.32 g, 2.0 mmol) was dissolved in CH2Cl2
(10 mL). TBSOTf (1.15 mL, 5.0 mmol) and iPr2NEt
(1.05 mL, 6.0 mmol) were added sequentially. The solution
was stirred at 258C for 2 h, and then the reaction was
quenched by adding NH4Cl(s) (10 mL). The mixture was di-
luted with CH2Cl2 (10 mL) and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL).
The combined organic layers were dried (Na2SO4) and con-
centrated. Purification by column chromatography (silica
gel, hexanes) gave 15 as a colorless liquid; yield: 0.75 g
ACHTUNGTRENNUNG(4S,5R)-2,2,5-Trimethyl-4-[(R)-pent-4-en-2-yl]-1,3-
dioxane (13)
The alcohol 12 (0.68 g, 2.0 mmol) was dissolved in CH2Cl2
(60 mL) at 08C. DMSO (6.0 mL, 84.5 mmol) and DIPEA
(5.9 mL, 33.8 mmol) were added. To this solution at 08C,
.
SO3 Py complex (2.69 g, 16.9 mmol) was added and the re-
sulting solution was stirred at that temperature for 1 h. The
reaction was quenched with NH4Cl(s) (20 mL). The layers
were separated and the aqueous layer was extracted with
CH2Cl2 (3ꢂ30 mL). The combined organic solution was
dried (Na2SO4) and concentrated under vacuum. The result-
ing residue was carried out to the next step without any fur-
ther purification. In a separate round-bottom flask, methyl-
triphenylphosphonium bromide (2.41 g, 6.76 mmol) suspen-
sion in THF (20 mL) was cooled to 08C and n-BuLi (2.0M
in pentane, 3.4 mL, 6.8 mmol) was added dropwise. The re-
action was stirred for 0.5 h before the crude aldehyde in
THF solution (8 mL, 2ꢂ 1 mL for rinsing) was cannulated.
After 1 h, saturated NH4Cl aqueous solution (10 mL) was
added and the mixture was stirred and allowed to warm to
258C. The layers were then separated and the aqueous layer
was extracted with Et2O (3ꢂ10 mL). The combined organic
extracts were dried (Na2SO4) and concentrated under vacuu,
at 108C. Purification by flash column chromatography, elut-
ing with Et2O/pentane (5:95) gave alkene 13 as a colorless
1
(1.94 mmol, 97%); [a]2D0:9: +12.3 (c 0.65, CHCl3). H NMR
(500 MHz, CDCl3) d 3.70 (dd, J=5.0, 10.0 Hz, 1H), 3.51–
3.50 (m, 1H), 3.42 (dd, J=5.0, 10.0 Hz, 1H), 1.83–1.78 (m,
1H), 1.63–1.53 (m, 1H), 1.34–1.13 (m, 4H), 0.91–0.89 (m,
36H), 0.86 (d, J=5.0 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=77.2, 65.9, 40.6, 37.4, 36.0, 26.4, 26.2, 26.0, 21.0, 18.6,
14.8, 14.6, 14.5, À2.7, À3.6, À3.7, À5.0, À5.1; HR-MS (ESI):
m/z=389.3257, calcd. for C21H49O2Si [M+H]+: 389.3271.
AHCTUNGTREG(NNNU 2R,3S,4R)-3-[(tert-Butyldimethylsilyl)oxy]-2,4-di-
methylheptan-1-ol (16)
The silyl ether 15 (0.70 g, 1.8 mmol) was dissolved in
CH2Cl2/MeOH (20 mL, 1/3) at 08C. TsOH (34 mg,
0.18 mmol) was added in one portion. The resulting solution
was stirred at that temperature for 1 h. Et3N (5 mL) was
then added to the reaction and all the solvents were evapo-
Adv. Synth. Catal. 2013, 355, 107 – 115
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
113

Ye Zhu and Kevin Burgess
FULL PAPERS
rated under vacuum. The residue was purified though
column chromatography, eluting with EtOAc/hexanes
(10:90) to give desired primary alcohol as a colorless liquid;
yield: 16 (0.42 g (1.55 mmol, 86%); [a]2D1:5: 13.9 (c 1.15,
{lit.[17e] [a]D: À99.2 (c 0.7, CHC13)}. 1H NMR (500 MHz,
CDCl3): d=3.92 (d, J=10.0 Hz, 1H), 2.69–2.62 (m, 1H),
2.05–1.95 (m, 1H), 1.69 (t, J=10.0 Hz, 2H), 1.38–1.27 (m,
5H), 1.23 (d, J=10.0 Hz, 3H), 0.99 (d, J=5.0 Hz, 3H), 0.92
(t, J=5.0 Hz, 3H), 0.88 (d, J=12.0 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=176.7, 85.7, 36.1, 35.4, 33.6, 32.5, 28.4,
20.4, 16.6, 14.1, 12.3; HR-MS (ESI): m/z=199.1691, calcd.
for C12H23O2 [M+H]+: 199.1698.
1
CHCl3). H NMR (500 MHz, CDCl3): d=3.68–3.58 (m, 2H),
3.52 (dd, J=5.0, 10.0 Hz, 1H), 2.63 (t, J=7.5 Hz, 1H), 1.91–
1.84 (m, 1H), 1.66–1.61 (m, 1H), 1.47–1.37 (m, 2H), 1.24–
1.13 (m, 2H), 0.98 (d, J=5.0 Hz, 3H), 0.94–0.90 (m, 15H),
0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3): d=
81.5, 66.5, 38.4, 37.8, 35.6, 26.3, 21.1, 18.5, 16.6, 15.4, 14.6,
À3.7, À3.9; HR-MS (ESI): m/z=275.2419, calcd. for
C15H35O2Si [M+H]+: 275.2406.
Acknowledgements
(4R,5S,6R,E)-Methyl 5-[(tert-butyldimethylsilyl)oxy]-
2,4,6-trimethylnon-2-enoate (18)
We thank Dr, Jian Zhao for some preliminary experiments.
Financial support for this work was provided by The Nation-
al Science Foundation (CHE-0750193) and The Robert A.
Welch Foundation (A1121).
The alcohol 16 (275 mg, 1.0 mmol) was dissolved in CH2Cl2
(30 mL) at 08C. DMSO (0.11 mL, 1.5 mmol) and DIPEA
.
(0.87 mL, 5.0 mmol) were added. To this solution SO3 Py
complex (478 mg, 3.0 mmol) was added and the resulting so-
lution was stirred at that temperature for 1 h. The reaction
was quenched with NH4Cl(s) (10 mL). The layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (3ꢂ
20 mL). The combined organic solution was dried (Na2SO4)
and concentrated under vacuum. Without any further purifi-
cation, the resulting crude aldehyde was immediately dis-
solved in toluene (10 mL) and the Wittig reagent (1.74 g,
5.0 mmol) was added in one portion at 258C. The reaction
mixture was then put on an oil bath (preheated to 808C)
and stirred for 16 h. After being cooled to 258C, the reac-
tion mixture was diluted with hexanes (80 mL) and filtrated
through Celite. The filtrate was concentrated and purifica-
tion of the residue by flash chromatography on silica gel,
eluting with EtOAc/hexanes (5:95) gave alkene 18 as a color-
less oil; yield: 300 mg (0.88 mmol, 88%); [a]2D1: 20.9 (c 0.86,
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CHCl3). H NMR (300 MHz, CDCl3): d=6.85 (d, J=9.0 Hz,
1H), 3.76 (s, 3H), 3.50–3.46 (m, 1H), 2.77–2.65 (m, 1H),
1.86 (s, 3H), 1.39–1.00 (m, 4H), 0.93 (d, J=6.0 Hz, 3H),
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(À)-Invictolide (19)
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according to the general procedure using (S)-Cat. (11 mol%,
10 mg) in CH2Cl2 (1.0 mL). NMR of the crude product
1
showed 100% reduction. H NMR analysis of the crude ma-
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cooled to 258C and quenched by addition of NaHCO3(s)
(5 mL). The solution was diluted by addition of Et2O
(20 mL) and the layers were separated. The aqueous layer
was extracted with Et2O (3ꢂ10 mL). The organic extract
was dried (Na2SO4) and concentrated under vacuum. Purifi-
cation by flash column chromatography, eluting with Et2O/
pentane (10:90) gave (À)-invictolide 19[17c] as a colorless oil;
yield: 104 mg (0.52 mmol, 90%); [a]2D1: À99.7 (c 0.77, CHCl3)
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Highly Stereoselective Syntheses of All 1,2,3-Me,OH,Me Triads
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