Desymmetrization of (R,R)-hexa-1,5-diene-3,4-diol via monofunctionalization and rhodium-catalyzed allylic substitution

Article abstract of DOI:10.1021/jo2001337

A sequence of selective monoprotection and Rh-catalyzed enantioconservative allylic substitution is established as a desymmetrization strategy for C ₂-symmetric hexa-1,5-diene-3,4-diol. A benzyl protecting group and ethyl carbonate as a leaving

Full text of DOI:10.1021/jo2001337

ARTICLE
pubs.acs.org/joc
Desymmetrization of (R,R)-Hexa-1,5-diene-3,4-diol via
Monofunctionalization and Rhodium-Catalyzed Allylic Substitution
Bernd Schmidt* and Lucia Staude
Institut fuer Chemie (Organische Synthesechemie), Universitaet Potsdam, Karl-Liebknecht-Strasse 24-25,
D-14476 Potsdam-Golm, Germany
S Supporting Information
b
ABSTRACT: A sequence of selective monoprotection and Rh-cata-
lyzed enantioconservative allylic substitution is established as a desym-
metrization strategy for C2-symmetric hexa-1,5-diene-3,4-diol. A benzyl
protecting group and ethyl carbonate as a leaving group emerged as the
most useful combination with respect to reproducibility, stereoselectiv-
ity, and yield. A remarkable deviation from the normally observed regiospecificity of Rh-catalyzed allylic alkylations was observed for
unprotected carbonates. In this case, a linear, rather than a branched alkylation product was obtained exclusively.
’ INTRODUCTION
pathway to more complex structures. Our interest in this
enantiopure building block was triggered by a study of directing
effects exerted by polar functional groups, in particular allylic
hydroxy groups, on the rate and selectivity of ring closing olefin
(RCM) and enyne metathesis (RCEYM) reactions. For instance,
we could demonstrate that dihydropyrans and dihydrofurans are
selectively accessible from 1 in two or three steps, respectively,
via ring size selective RCM18,20 and ring size selective RCEYM21
reactions. With a view toward the synthesis of other precursors
for hydroxy group directed, ring size selective metathesis reac-
tions, we became intrigued by the opportunity to combine a
desymmetrization of 1 with a stereoconservative allylic substitu-
tion (Scheme 1).
Literature precedence for the use of 1 or its stereoisomers in
allylic substitution reactions is scarce. An interesting example was
published by Trost et al., who used a Pd-catalyzed allylic
asymmetric alkylation of the cyclic carbonates derived from a
mixture of 1, ent-1, and meso-1 to obtain enantiopure amino
alcohols.34,35 If 1 is desymmetrized by monoprotection, the
remaining hydroxy group in 2 needs to be converted into a
leaving group (LG). The steric demand of the protecting group
(PG) and the leaving group in substrate 3 will most likely
influence the formation of an assumed Rh-σ-π-enyl intermediate,
and we therefore investigated different protecting and leaving
groups (Scheme 2). A further complication might arise from the
formation of Rh-chelate complexes by coordination of the
remaining C-C double bond or the protected hydroxy group,
which are both in close proximity to the Rh atom. In particular,
coordination of the alkene is a possibility that must be taken into
account, considering a recent report on the use of dienediol 1 as a
chiral ligand for Rh-catalyzed conjugate addition reactions.36
Formation of such a chelate will most likely disturb the regio- and
stereochemical integrity of the Rh-σ-π-enyl intermediate and
Transition metal-catalyzed allylic alkylation reactions were for
many years considered to be a domain of organopalladium
chemistry.1-4 Complexes of other metals, such as nickel,2
molybdenum,3 copper,5 iridium,6-8 iron,9-11 or rhodium,12 have
attracted considerably less attention as precatalysts for this
reaction, which is probably a consequence of the early observa-
tion that the reactivity of palladium exceeds that of rhodium,
platinum, or ruthenium.13 Against this background some draw-
backs of Pd-catalyzed intermolecular allylic substitution reactions
were accepted for quite some time. For instance, these reactions
normally suffer from low selectivities, unless they proceed via
symmetrical or electronically biased π-allyl complexes. This is
attributed to the highly fluxional behavior of Pd-π-allyl com-
plexes, which undergo rapid π-σ-π-rearrangement.1 In contrast,
Rhodium catalysts were as early as 1984 found to promote allylic
substitution reactions with high regiospecificity.14 Thus, second-
ary allylic carbonates yield predominantly branched substitution
products, and primary allylic carbonates yield predominantly
linear substitution products. Significant improvements of reac-
tivity and selectivity were achieved over the past decade by Evans
et al., who introduced phosphite-modified Wilkinson’s catalyst
for the regiospecific allylic alkylation.15,16 Particularly important
was the observation that the absolute configuration of an
enantiopure secondary allylic carbonate is retained with this
catalytic system,17 which suggests the presence of a σ,π-coordi-
nated enyl intermediate that undergoes a rather slow σ-π-σ-
rearrangement.12
Over the past few years, we18-23 and others24-31 reported a
number of examples for the successful application of the C2-
symmetric building block 132 or ent-133 in stereoselective synth-
esis. Normally, a desymmetrization of 1 is required, which is in
most cases achieved by selective monofunctionalization, e.g.
protection, of one hydroxy group. Following the desymmetriza-
tion step, a selective secondary functionalization of the remaining
hydroxy group or of one C-C double bond in 2 opens up a
Received: January 19, 2011
Published: March 07, 2011
r
2011 American Chemical Society
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ARTICLE
Scheme 1. Application of Diene 1 in Ring Size Selective
RCM Reactions
Table 1. Synthesis of Carbonates 3 and Results for Rh-
Catalyzed Allylic Substitutiona
entry PG
2
reagent (R) 3 (yield)
4
dr
yield
n.d.c
1
2
3
4
5
6
TBS 2a
TBS 2a
TBS 2a
5a (Me)
5b (Et)
3a (79%) 4a 3:1
3b (88%) 4a 5:1 to 10:1 56-83%
b
6a (t-Bu) 3c (45%) 4a
3d (86%) 4b >8:1
3e (58%) 4b >10:1
2b 6a (t-Bu) 3f (54%) 4b 1:1
-
Bn
Bn
Bn
2b 5a (Me)
2b 5b (Et)
47-71%
58-63%
79%
a See Scheme 3 for reagents and conditions. b Unreacted starting
material was recovered in 88% yield. c Not determined. Complete
conversion as judged from 1H NMR spectrum of the crude mixture.
Scheme 3. Rh-Catalyzed Allylic Alkylationa
Scheme 2. Mechanistic Considerations for the Envisaged
Stereoconservative Allylic Substitution of Monoprotected
Dienes 2
a See Table 1 for results.
ethyl chloroformate (5b), or by deprotonation with NaH and
trapping with Boc2O (6a). In this way, six precursors 3a-f for
the envisaged Rh-catalyzed allylic substitution were synthesized,
which differ significantly in the steric demand of the side chain
and at the reacting position. For the subsequent substitution
reaction, Na-malonate was chosen as a nucleophile. The catalytic
system tested for this transformation was trimethyl phosphite in
combination with Wilkinson’s catalyst (Scheme 3).
We conclude from the results summarized in Table 1 that a
sterically demanding protecting group such as TBS is less suitable
for this reaction. In combination with leaving groups with low
or intermediate steric demand results for the Rh-catalyzed
substitution reaction were difficult to reproduce: for substrates
3a and 3b yields varied from 56% to 83%, and diastereomeric
ratios in the range of 3:1 to 10:1 were observed (entries 1 and 2).
Reproducibly, no reaction was observed for 3c, which is sterically
highly congested due to a combination of a TBS-protecting
group and tert-butyl carbonate as a leaving group (entry 3).
Significantly better results were obtained with a benzyl protecting
group. In this series, both methyl and ethyl carbonates 3d,e
react in synthetically useful yields and selectivities. Results
for 3e appear to be slightly better, as the substitution product
4b is generally formed in diastereomeric ratios better than
10:1 (entry 5). In contrast to the tert-butyl carbonate 3c with a
TBS-protecting group, the analogous benzyl protected
derivative 3f reacts with malonate in a substitution reaction;
however, no diastereoselectivity was observed for this derivative
(entry 6).
should therefore be detrimental to the overall regio- and stereo-
specificity of the allylic substitution. Even if the assumed Rh-σ-π-
enyl intermediate undergoes a σ-π-σ-rearrangement only slowly
in absolute terms, the overall result might still be unsatisfactory if
the final nucleophilic attack is hampered by steric constraints, e.g.
resulting from the protecting group.
The numerous imponderables described above and outlined
in Scheme 2 prompted us to investigate stereoconservative Rh-
catalyzed allylic alkylations of dienes 3 for a variety of protecting
and leaving group combinations.
’ RESULTS AND DISCUSSION
Two protecting groups with different steric demand were
tested in this study. Monoprotected derivatives 2a (PG = TBS)
and 2b (PG = Bn) were synthesized from 1 as described
previously.20 The remaining hydroxy group was converted into
a carbonate, either by lithiation and reaction with methyl (5a) or
Currently, we do not fully understand why certain combina-
tions of protecting group and leaving group (Table 1, entries 2
and 4) result, under apparently identical conditions, in a
rather high spreading of conversion and isolated yield in the
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Scheme 4. Rh-Catalyzed Allylic Substitution with Unpro-
tected Carbonates 3g,h
Scheme 5. Mechanistic rationale for the γ-Selective Allylic
Alkylation of 3g,h
Rh-catalyzed allylic alkylation. It is, however, quite striking that
high conversion seems to correlate with a lower diastereoselec-
tivity. For these reasons, a combination of a benzyl protecting
group and ethyl carbonate as a leaving group (substrate 3e,
entry 5) appears to be the best choice for synthetic purposes,
because isolated yields of ca. 60% and diastereomeric ratios
exceeding 10:1 are reliably obtained under these reaction
conditions.
Scheme 6. Diastereoselective Propargylation of a Na-Eno-
late Derived from 9
Polar functional groups, in particular protic groups, often exert
a significant effect on the reactivity and selectivity of transition
metal-catalyzed reactions.37 Therefore, we also included the
unprotected carbonates 3g19 and 3h in this study. These were
selectively synthesized from diol 1 and anhydrides 6a,b, respec-
tively, using Clarke’s method.38 We first tested tert-butyl carbo-
nate 3g, which was subjected to the previously established
conditions of the Rh-catalyzed allylic substitution. After
the standard reaction time of 15 h, only the ketone 8 could
be isolated in 54% yield. We assume that 8 results from a
γ-substitution and subsequent isomerization of the terminal
allylic alcohol to an ethyl ketone. Therefore, the reaction time
was reduced to 8 h, leading to a 1:1 mixture of γ-substitution
product 7 and ketone 8, which could be separated and isolated in
24% and 20% yield, respectively. If the reaction time was further
reduced to 2 h, no isomerization product 8 was detected and allyl
alcohol 7 was selectively obtained in 55% yield. Starting from
ethyl carbonate 3h, the same product was isolated, albeit in lower
yield (Scheme 4).
A mechanistic rationale for this unusual regioselectivity is
outlined in Scheme 5. Under the reaction conditions, the
hydroxy group is rapidly deprotonated to the Na-alkoxide A by
excess NaH. Oxidative addition gives the σ-π-enyl complex B,
which might undergo a σ-π-σ-rearrangement to C, facilitated by
coordination of the alkoxide to the Rh atom. Assuming that the
chloro ligand remains bound to the Rh during the entire catalytic
cycle, formation of a six-membered chelate complex D, in which a
Naþ ion interacts with the alkoxide and the Rh-chloro ligand
simultaneously, would be an alternative scenario. Both organo-
metallic intermediates C and D should preferrably undergo
nucleophilic attack at the terminus, leading to an alkoxide E
which, after hydrolytic workup, gives the observed product 7. If
the alkoxide is exposed to the Rh-catalyst for longer periods of
time, it isomerizes slowly to the enolate F, which upon hydrolysis
yields ketone 8 (Scheme 5). Remarkably, the Rh-catalyzed allylic
substitution of 3g,h proceeds to completion within 2 h, whereas
benzyl- and TBS-protected carbonates 3a-f require a reaction
time of 15 h. Thus, the presence of an alkoxide does not only lead
to an inverted regioselectivity, but also accelerates the reaction
significantly.
To establish the relative configuration assigned to the sub-
stitution products 4 and to test further opportunities for their
stereoselective functionalization, 4b was converted to the ester 9
via saponification, decarboxylation, and esterification in 76%
overall yield. In the following step, the possibility of a stereo-
selective R-alkylation was tested. It has previously been demon-
strated that acyclic ester enolates with benzyloxy substituents in
the proximity can be alkylated with high diastereoselectivity,
presumably via formation of a chelate.39 Upon treatment of 9
with NaHMDS and subsequent reaction of the resulting enolate
with propargyl bromide, the R-propargylated ester 10 was
obtained as a 10:1 mixture of two diastereomers. Gratifyingly,
separation of the diastereomers was possible by column
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Thus, nuclear Overhauser effects were observed between HR and
Hγ, and between the vinyl group at Cβ and HR and Hγ. In
addition, we were able to determine the vicinal coupling con-
3
3
stants J(HR-Hβ) = 11.1 Hz and J(Hβ-Hγ) = 9.7 Hz, and
found that their values match those reported for the structurally
related natural products nephrosteranic and rocellaric acid very
well.44,45
The diastereoselectivity observed for the propargylation of the
enolate derived from ester 9 may be rationalized assuming the
formation of a seven-membered chelate G, which is preferantially
alkylated from the less hindered Si-face (Scheme 7).
While the formation of such a chelate is not impossible, we
believe that this scenario is less likely, because Naþ has, com-
pared to Liþ, a lower tendency to form sufficiently stable and
rigid chelate complexes. Therefore, we propose an alternative
explanation that is based on the minimization of allylic strain in
the transition state.46 If such a model is working in this case,
transition state H should be favored over I, which would also
result in a preferred attack of the enolate Si-face (Scheme 7).
Figure 1. Assignment of relative configuration of lactone 11 by NMR
methods and comparison with reference data.45
Scheme 7. Mechanistic Rationale for the Diastereoselective
R-Alkylation of Ester 9
’ CONCLUSION
Monoprotection in combination with enantioconservative Rh-
catalyzed allylic substitution was established as a desymmetrization
method for the enantiopure C2-symmetric bisallylic alcohol 1. This
approach allows for further diastereoselective functionalization,
e.g. enolate alkylation, which might become a useful route to
olefin and enyne metathesis precursors. Another remarkable
result of this study is the unusual γ-selectivity observed for the
Rh-catalyzed allylic alkylation of a derivative with an unprotected
hydroxy group adjacent to the leaving group.
’ EXPERIMENTAL SECTION
(3R,4R)-4-(tert-Butyldimethylsilyloxy)hexa-1,5-dien-3-yl-
methyl Carbonate (3a). A solution of 2a (2.00 g, 8.8 mmol) in dry
and degassed THF (88 mL) was cooled to 0 °C. Butyllithium (1.6 M
solution in hexanes, 9.7 mmol, 6.0 mL) was added and the reaction
mixture was stirred for 10 min. Methyl chloroformate (5a, 10.6 mmol,
0.8 mL) was added and stirring was continued for 20 min. The reaction
was then quenched by addition of a saturated aqueous solution of
NH4Cl. The aqueous phase was extracted with diethyl ether (3 ꢀ
20 mL) and the combined organic phases were dried with MgSO4.
Filtration, evaporation, and column chromatography on silica (hexanes/
MTBE) gives 3a (2.01 g, 80%). 1H NMR (300 MHz, CDCl3) δ 5.86-
5.73 (m, 2H), 5.36-5.16 (m, 4H), 5.02 (dddd, J = 6.6, 6.2, 1.2, 1.2 Hz,
1H), 4.20 (dddd, J = 6.6, 5.8, 1.3, 1.3v, 1H), 3.78 (s, 3H), 0.89 (s, 9H),
0.08 (s, 3H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 155.4, 136.5,
132.4, 118.7, 117.1, 81.0, 74.5, 54.6, 25.7, 18.1, -4.6, -5.1; IR (neat) ν
3409 (bm), 2955 (s), 2932 (s), 2861 (m), 1749 (m), 1466 (m), 992 (m);
LRMS (ESI) m/z 211 (8%), 285 (5%), 313 (70%), 341 (100%), 359
(50%); HRMS (ESI) calcd for C14H26O4NaSi 309.1498, found
309.1475; [R]27D 13.0 (c 0.79, CH2Cl2).
(3R,4R)-4-(tert-Butyldimethylsilyloxy)hexa-1,5-dien-3-ylethyl
Carbonate (3b). The title compound was obtained from 2a (200 mg,
0.9 mmol) and ethyl chloroformate (5b, 1.1 mmol, 103 μL) following
the procedure given above for 3a. Yield of 3b: 231 mg (88%). 1H NMR
(300 MHz, CDCl3) δ 5.87-5.73 (m, 2H), 5.36-5.16 (m, 4H), 5.02
(dddd, J = 6.5, 6.5, 1.3, 1.3 Hz, 1H), 4.26-4.14 (m, 3H), 1.30 (t, J =
7.1 Hz, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 155.3, 136.4, 132.4, 118.6, 117.1, 80.7, 74.5, 63.9,
25.7, 18.2, 14.3, -4.6, -5.0; IR (neat) ν 2958 (w), 2930 (w), 2858 (w),
1750 (s), 1256 (s); LRMS (EI) m/z 147 (100%), 301 (M þ H, 10%);
chromatography and enabled the isolation of (2S)-10 in 69% and
(2R)-10 in 7% yield. Assignment of the relative configuration was
achieved after debenzylation and cyclization to the more rigid
lactone 11. As a hydrogenative debenzylation catalyzed by Pd/C
is obviously not an option, other methods were tested.40 Lewis
acids such as TiCl4 or Ti(OiPr)4 resulted in the complete
41
recovery of unreacted starting material (2S)-10, while BBr3 led to
extensive decomposition. Partial deprotection with formation of
the desired lactone 11 was achieved by using DDQ under
photoirradiation; however, conversion did not exceed 63%.42
Quantitative and selective debenzylation with concomitant lac-
tonization was eventually achieved with a large excess of DDQ in
aqueous dichloromethane at ambient temperature.43 Under
these conditions, lactone 11 could be isolated in quantitative
yield as a single isomer (Scheme 6).
Evidence for the assigned relative configuration of 11 came
from one- and two-dimensional NMR experiments (Figure 1).
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HRMS (ESI) calcd for C15H28O4SiNa (M þ Na) 323.1655, found
323.1676; [R]24D 29.7 (c 1.24, CH2Cl2).
1455 (w), 1272 (s), 1252 (s), 1161 (m), 1122 (m), 1087 (m), 1071 (m),
929 (m), 697 (m); LRMS (EI) m/z 305 (M þ H, 15%), 271 (35%), 169
(40%), 117 (100%), 91 (55%); HRMS (ESI) calcd for C18H25O4 (Mþ
þ H) 305.1753, found 305.1741; [R]24D -41.0 (c 1.09, CH2Cl2). Anal.
Calcd for C18H24O4 (304.38): C, 71.0; H, 8.0. Found: C, 71.1; H, 7.9.
tert-Butyl-(3R,4R)-4-hydroxyhexa-1,5-dien-3-yl Carbonate
(3g). The title compound was obtained from 1 (5.00 g, 43.2 mmol)
and Boc2O (6a, 87.6 mmol, 19.7 g) following the previously published
procedure.19 Yield of 3g: 8.00 g (85%). All analytical data match those
previously reported in the literature.
tert-Butyl-(3R,4R)-4-(tert-butyldimethylsilyloxy)hexa-1,5-
dien-3-yl Carbonate (3c). A solution of 2a (6.90 g, 30.2 mmol) in
dry and degassed THF (150 mL) was cooled to 0 °C and NaH (60%
dispersion in mineral oil, 1.81 g, 45.3 mmol) and Boc2O (6a, 13.18 g,
60.4 mmol) were added. The reaction mixture was stirred at ambient
temperature for 12 h and then quenched by addition of water. The
aqueous phase was extracted with MTBE and the combined organic
phases were washed with brine and then dried with MgSO4. Filtration,
evaporation, and column chromatography on silica gives 3c (4.50 g,
45%). 1H NMR (300 MHz, CDCl3) δ 5.83 (ddd, J = 17.0, 10.5, 5.7 Hz,
1H), 5.77 (ddd, J = 17.0, 10.6, 6.3 Hz, 1H), 5.30 (ddd, J = 17.3, 1.4, 1.4
Hz, 1H), 5.28 (ddd, J = 17.1, 1.4, 1.4 Hz, 1H), 5.23 (ddd, J = 10.7, 1.3,
1.3 Hz, 1H), 5.18 (ddd, J = 10.4, 1.6, 1.6 Hz, 1H), 4.96 (ddm, J = 6.6, 6.5
Hz, 1H), 4.21 (ddm, J = 5.8, 5.8 Hz, 1H), 1.48 (s, 9H), 0.89 (s, 9H), 0.09
(s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 152.9, 136.6,
132.8, 118.3, 116.9, 81.9, 80.0, 74.4, 27.9, 25.8, 18.2, -4.6, -4.9; IR
(neat) ν 2957 (w), 2930 (w), 2887 (w), 2858 (w), 1742 (s), 1647 (w),
1473 (w), 1463 (w), 1369 (w), 1273 (s), 1252 (s), 1144 (s), 836 (s);
LRMS (ESI) m/z 351 (M þ Na, 80%), 329 (M þ H, 10%), 295 (20%),
251 (20%), 211 (100%); HRMS (EI) calcd for C17H32O4Si (M)
328.2070, found 328.2087; [R]24D 37.9 (c 1.67, CH2Cl2). Anal. Calcd
for C17H32O4Si (328.52): C, 62.2; H, 9.8. Found: C, 62.0; H, 10.1.
(3R,4R)-4-(Benzyloxy)hexa-1,5-dien-3-ylmethyl Carbonate
(3d). The title compound was obtained from 2b (200 mg, 1.0 mmol) and
methyl chloroformate (5a, 1.2 mmol, 93 μL) following the procedure
Ethyl-(3R,4R)-4-hydroxyhexa-1,5-dien-3-yl Carbonate (3h).
To a solution of 1 (500 mg, 4.4 mmol) in dichloromethane (44 mL) was
added CeCl3 (163 mg, 0.4 mmol, 10 mol %) and diethyl dicarbonate (6b,
1.3 mL, 8.8 mmol). The reaction mixture was stirred at ambient
temperature for 12 h, diluted with ethyl acetate, and then washed with a
saturated aqueous solution of Na2CO3, followed by water and brine. The
organic phase was dried with MgSO4, filtered, and evaporated. The
residue was purified by column chromatography to give 3h (704 mg,
86%). 1H NMR (300 MHz, CDCl3) δ 5.87 (ddd, J = 16.1, 9.2, 5.5 Hz,
1H), 5.81 (ddd, J = 17.2, 10.4, 6.7 Hz, 1H), 5.45-5.29 (m, 3H), 5.26 (dm,
J = 10.5 Hz, 1H), 5.03 (ddm, J = 6.5, 6.4 Hz, 1H), 4.22 (m, 1H), 4.20 (q, J
= 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
154.5, 135.5, 132.3, 119.7, 117.6, 80.8, 73.7, 64.2, 14.2; IR (neat) ν 3469
(bw), 3087 (w), 2986 (w), 1744 (m), 1372 (m), 1250 (s), 991 (m), 928
(m); LRMS (EI) m/z 169 (15%), 130 (5%), 95 (8%), 71 (20%), 57
(100%); HRMS (ESI) calcd for C9H14O4 (Mþ) 186.0887, found
186.0905; [R]24 -25.0 (c 1.08, CH2Cl2). Anal. Calcd for C9H14O4
D
1
given above for 3a. Yield of 3b: 220 mg (86%). H NMR (300 MHz,
(186.21): C, 58.1; H, 7.6. Found: C, 57.8; H, 7.6.
Diethyl 2-((30S,40R)-40-(tert-Butyldimethylsilyloxy)hexa-
10,50-dien-30-yl)malonate (4a). The following procedure is repre-
sentative for the synthesis of 4a: To a suspension of Wilkinson’s catalyst
(79 mg, 0.1 mmol, 5 mol %) in dry and degassed THF (37 mL) was
added P(OMe)3 (80 μL, 0.7 mmol) and the mixture was stirred for
15 min at ambient temperature. In a separate flask, diethyl malonate
(0.6 mL, 4.3 mmol) was dissolved in dry and degassed THF (6.0 mL)
and NaH (60% dispersion in mineral oil, 204 mg, 5.1 mmol) was added
to this solution. This solution was also stirred for 15 min at ambient
temperature. The solution of the phosphite-modified Rh-catalyst was
then transferred to the solution of the malonate via canula, and
subsequently a solution of carbonate 3b (500 mg, 1.7 mmol) in dry
and degassed THF (6.0 mL) was slowly added to the malonate/catalyst
mixture. The reaction mixture was warmed to 30 °C and stirred at this
temperature for 15 h. The reaction was quenched by careful addition of
water, the organic layer was separated, and the aqueous layer was
extracted with MTBE. The combined organic layers were washed with
brine, dried with MgSO4, filtered, and evaporated. The residue was
purified by column chromatography on silica to give 4a (352 mg, 56%)
CDCl3) δ 7.35-7.30 (m, 5H), 5.92-5.68 (m, 2H), 5.41-5.25 (m, 4H),
5.21 (dddd, J = 6.7, 6.7, 1.3, 1.3 Hz, 1H), 4.66 (d, J = 12.1 Hz, 1H), 4.44 (d,
J = 12.1 Hz, 1H), 3.92 (ddm, J = 7.5, 6.4 Hz, 1H), 3.78 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 155.2, 138.1, 133.9, 132.4, 128.3, 127.6, 127.5, 120.0,
119.0, 81.0, 79.5, 70.6, 54.7; IR (neat) ν 3030 (w), 2956 (w), 2864 (w),
1747 (s), 1441 (m), 1256 (s), 1070 (m), 1028 (w), 965 (m), 931 (m);
LRMS (ESI) m/z 285 (M þ Na, 100%), 263 (M þ H, 20%), 227 (40%),
117 (50%); HRMS (ESI) calcd for C15H19O4 (M þ H) 263.1283, found
263.1262; [R]25 8.7 (c 1.19, CH2Cl2). Anal. Calcd for C15H18O4
D
(262.30): C, 68.7; H, 6.9. Found: C, 68.6; H, 6.9.
(3R,4R)-4-(Benzyloxy)hexa-1,5-dien-3-ylethyl Carbonate
(3e). The title compound was obtained from 2b (2.91 g, 14.3 mmol)
and ethyl chloroformate (5b, 17.2 mmol, 1.6 mL) following the
1
procedure given above for 3a. Yield of 3e: 2.30 g (58%). H NMR
(300 MHz, CDCl3) δ 7.37-7.25 (m, 5H), 5.88 (ddd, J = 17.2, 10.6, 6.5
Hz, 1H), 5.77 (ddd, J = 18.3, 10.9, 7.5 Hz, 1H), 5.42-5.32 (m, 3H), 5.29
(ddd, J = 10.6, 1.3, 1.3 Hz, 1H), 5.22 (dddd, J = 6.5, 6.5, 1.2, 1.2 Hz, 1H),
4.67 (d, J = 12.1 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.21 (q, J = 7.1 Hz,
2H), 3.93 (dd, J = 7.4, 6.5 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 179.6, 138.2, 133.9, 132.5, 128.3, 127.6, 127.5,
120.0, 118.8, 81.0, 79.3, 70.6, 64.0, 14.2; IR (neat) ν 2983 (w), 2868 (w),
1744 (s), 1371 (m), 1250 (s), 1089 (m), 1071 (m), 991 (m); LRMS
(EI) m/z 277 (M þ H, 2%), 91 (100%); HRMS (EI) calcd for
1
as a 10:1 mixture of diastereomers. H NMR (300 MHz, CDCl3) δ
5.93-5.26 (m, 2H), 5.18-4.99 (m, 4H), 4.25-4.06 (m, 5H), 3.73 (d, J
= 7.1 Hz, 1H), 2.87 (m, 1H), 1.25 (t, J = 7.0 Hz, 6H), 0.88 (s, 9H), 0.03
(s, 3H), 0.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.9, 168.2, 139.1,
134.7, 118.8, 116.4, 74.6, 61.3, 61.0, 52.5, 50.8, 25.8, 18.1, 14.1, 14.0, -
4.1, -5.0; IR (neat) ν 2930 (w), 2857 (w), 1732 (m), 1464 (w), 1369
(w), 1252 (m), 1078 (m), 836 (m); LRMS (EI) m/z 393 (M þ Na,
15%), 371 (M þ H, 5%), 239 (30%), 165 (100%); HRMS (ESI) calcd
for C19H34O5NaSi (M þ Na) 393.2073, found 393.2036; [R]23D -0.1
(c 0.80, CH2Cl2).
Diethyl 2-((30S,40R)-40-(Benzyloxy)hexa-10,50-dien-30-yl)-
malonate (4b). The title compound was obtained from 3e (3.00 g,
10.9 mmol), Wilkinson’s catalyst (502 mg, 0.5 mmol, 5 mol %), P(OMe)3
(0.5 mL, 4.3 mmol), and diethyl malonate (4.1 mL, 27.1 mmol) following
the procedure given above for 4a. The diastereomeric ratio of 4b was 20:1.
Yield of 4b: 2.18 g (58%). 1H NMR (300 MHz, CDCl3) δ 7.36-7.27 (m,
5H), 5.84 (ddd, J = 16.7, 10.6, 9.8 Hz, 1H), 5.67 (ddd, J = 17.2, 10.3, 8.0
C16H20O4 (Mþ) 276.1362, found 276.1342; [R]28 þ5.8 (c 0.87,
D
CH2Cl2). Anal. Calcd for C16H20O4 (276.33): C, 69.5; H, 7.3. Found:
C, 69.2; H, 7.5.
(3R,4R)-4-(Benzyloxy)hexa-1,5-dien-3-yl-tert-butyl Carbo-
nate (3f). The title compound was obtained from 2b (2.00 g, 9.8
mmol) and Boc2O (6a, 19.6 mmol, 4.5 mL) following the procedure
1
given above for 3c. Yield of 3e: 1.60 g (54%). H NMR (300 MHz,
CDCl3) δ 7.37-7.25 (m, 5H), 5.85 (ddd, J = 17.2, 10.6, 6.4 Hz, 1H),
5.77 (dddd, J = 16.3, 11.3, 8.8, 7.4 Hz), 5.41-5.23 (m, 4H), 5.19 (dddd, J
= 6.5, 6.5, 1.0, 1.0 Hz, 1H), 4.67 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz,
1H), 3.92 (ddm, J = 7.3, 6.6 Hz, 1H), 1.49 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 152.9, 138.2, 134.0, 132.7, 128.2, 127.5, 127.4, 119.7, 118.4,
82.0, 81.2, 78.4, 70.6, 27.7; IR (neat) ν 2980 (w), 1741 (s), 1646 (w),
2224
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ARTICLE
Hz, 1H), 5.30 (ddd, J = 10.3, 1.7, 0.5 Hz, 1H), 5.22 (ddd, J = 17.2, 1.7, 0.7
Hz, 1H), 5.15 - 5.05 (m, 2H), 4.56 (d, J = 11.5 Hz, 1H), 4.28 (d, J = 11.5
Hz, 1H), 4.15-4.00 (m, 4H), 3.88 (dd, J = 8.4, 8.3 Hz, 1H), 3.83 (d, J =
6.7 Hz, 1H), 3.03 (ddd, J = 9.1, 9.1, 6.7 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H),
1.20 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.8, 168.2,
138.2, 136.5, 134.5, 128.2, 127.8, 127.4, 119.2, 119.2, 81.0, 70.5, 61.2, 61.0,
53.1, 49.1, 14.0, 14.0; IR (neat) ν 2982 (w), 1730 (s), 1443 (w), 1370 (w),
1262 (s), 1093 (m), 926 (m), 732 (s); LRMS (ESI) m/z 369 (M þ Na,
5%), 347 (M þ H, 10%), 279 (45%), 165 (100%); HRMS (ESI) calcd for
C20H27O5 (M þ H) 347.1858, found 347.1839; [R]24D -11.4 (c 0.90,
CH2Cl2).
silica to give 9 (1.33 g, 76% over three steps, based on 4b). 1H NMR
(300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.81-5.62 (m, 2H), 5.31
(dm, J = 10.4 Hz, 1H), 5.23 (dm, J = 17.2 Hz, 1H), 5.08 (dm, J = 17.2 Hz,
1H), 5.06 (dm, J = 10.6 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H), 4.32 (d, J =
11.9 Hz, 1H), 3.68 (dd, J = 7.5, 7.2 Hz, 1H), 3.60 (s, 3H), 2.82 (m, 1H),
2.65 (dd, J = 15.3, 5.4 Hz, 1H), 2.33 (dd, J = 15.3, 8.6 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 173.0, 138.4, 137.4, 136.5, 128.3, 127.7, 127.4,
118.7, 116.6, 82.5, 70.3, 51.4, 45.0, 35.6; IR (neat) ν 2950 (w), 1736 (s),
1641 (w), 1454 (w), 1251 (m), 1170 (m), 1066 (s), 920 (s), 697 (s);
LRMS (ESI) m/z 283 (Mþ þ Na, 100%), 261 (Mþ þ H, 10%), 153
(5%); HRMS (EI) calcd for C16H20O3 (Mþ) 260.1412, found
(R,E)-Diethyl 2-(40-Hydroxyhexa-20,50-dienyl)malonate (7).
The title compound was obtained from 3g (500 mg, 2.3 mmol),
Wilkinson’s catalyst (108 mg, 0.12 mmol, 5 mol %), P(OMe)3 (55
μL, 0.47 mmol), and diethyl malonate (886 μL, 5.8 mmol) following the
procedure given above for 4a. The reaction was quenched after 2 h. Yield
of 7 from 3g: 328 mg (55%). Alternatively, compound 7 was obtained
from 3h (500 mg, 2.7 mmol), Wilkinson’s catalyst (124 mg, 0.14 mmol,
5 mol %), P(OMe)3 (63 μL, 0.50 mmol), and diethyl malonate
(1.00 mL, 6.7 mmol) following the procedure given above for 4a. The
reaction was quenched after 2 h. Yield of 7 from 3h: 248 mg (36%). 1H
NMR (300 MHz, CDCl3) δ 5.84 (ddd, J = 17.2, 10.4, 5.8 Hz, 1H), 5.67
(ddd, J = 15.4, 6.3, 6.3 Hz, 1H); 5.58 (dd, J = 15.4, 5.4 Hz, 1H), 5.22 (dm,
J = 17.2 Hz, 1H), 5.11 (dm, J = 10.4 Hz, 1H), 4.56 (m, 1H), 4.18 (q, J =
7.1 Hz, 4H), 3.39 (t, J = 7.5 Hz, 1H), 2.62 (dd, J = 7.5, 5.7 Hz, 2H), 1.78
(bs, 1H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 168.8,
139.3, 134.2, 127.3, 115.0, 73.3, 61.4, 51.7, 31.3, 14.0; IR (neat) ν 3466
(bw), 2982 (m), 1727 (s), 1369 (m), 1223 (m), 1152 (s), 1030 (m);
LRMS (ESI) m/z 279 (Mþ þ Na, 22%), 165 (100%); HRMS (ESI)
calcd for C13H21O5 (Mþ þ H) 257.1389, found 257.1370; [R]28D -3.6
(c 0.96, CH2Cl2). Anal. Calcd for C13H20O5 (256.13): C, 60.9; H, 7.9.
Found: C, 60.9; H, 7.7.
260.1400; [R]23 -25.4 (c 0.86, CH2Cl2). Anal. Calcd for C16H20O3
D
(260.33): C, 73.8; H, 7.7. Found: C, 73.6; H, 8.0.
Propargylation of 9. A solution of ester 9 (1.10 g, 4.2 mmol) in
dry and degassed THF (42 mL) was cooled to -78 °C. NaHMDS (1.5
M solution in THF, 3.4 mL, 5.1 mmol) was added and the mixture was
stirred at this temperature for 30 min. Propargyl bromide (80 wt %
solution in toluene, 0.70 mL, 6.3 mmol) was added; the reaction mixture
was then allowed to warm to ambient temperature and stirring was
continued for 12 h. Water and MTBE were added to the reaction
mixture, the organic layer was separated, and the aqueous layer was
extracted with MTBE. The combined organic phases were washed with
brine, dried with MgSO4, filtered, and evaporated. The residue was
purified by column chromatography to give two diastereomers in a ratio
of 10:1. The major diastereomer (2S)-10 (870 mg, 69%) is more polar
and was eluted in the second fraction, the minor diastereomer (2R)-10
(86 mg, 7%) is less polar and was eluted first. Analytical data of
(2S,3S,4R)-methyl-4-(benzyloxy)-2-(prop-2-inyl)-3-vinylhex-5-eno-
ate ((2S)-10): 1H NMR (300 MHz, CDCl3) δ 7.38-7.26 (m, 5H), 5.66
(ddd, J = 17.9, 10.3, 8.1 Hz, 1H), 5.47 (ddd, J = 16.9, 10.1, 6.9 Hz, 1H),
5.29 (dm, J = 10.3 Hz, 1H), 5.21 (dm, J = 17.1 Hz, 1H), 5.15 (dm, J =
10.3 Hz, 1H), 5.09 (dm, J = 17.1 Hz, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.32
(d, J = 11.7 Hz, 1H), 3.70 (dd, J = 7.7, 7.7 Hz, 1H), 3.55 (s, 3H), 2.85 (m,
1H), 2.75 (m, 1H), 2.43-2.35 (m, 2H), 1.96 (dd, J = 2.5, 2.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 174.0, 138.1, 136.2, 134.4, 128.3, 127.9,
127.5, 119.6, 119.1, 81.8, 81.0, 70.2, 69.9, 51.6, 50.8, 46.0, 18.9; IR (neat)
ν 3296 (bm), 2950 (w), 1734 (s), 1641 (w), 1454 (w), 1170 (m), 1066
(m), 923 (s), 732 (s); LRMS (ESI) m/z 321 (Mþ þ Na, 100%); HRMS
(E)-Diethyl 2-(40-Oxohex-20-enyl)malonate (8). The title
compound was obtained from 3g (500 mg, 2.3 mmol), Wilkinson’s
catalyst (108 mg, 0.12 mmol, 5 mol %), P(OMe)3 (55 μL, 0.47 mmol),
and diethyl malonate (886 μL, 5.8 mmol) following the procedure given
above for 4a (reaction time: 15 h). Yield of 8: 320 mg (54%). 1H NMR
(300 MHz, CDCl3) δ 6.72 (dt, J = 15.8, 7.0 Hz, 1H), 6.12 (dm, J = 15.9
Hz, 1H), 4.17 (q, J = 6.8 Hz, 4H), 3.46 (t, J = 7.4 Hz, 1H), 2.75 (ddd, J =
7.1, 7.1, 1.0 Hz, 2H), 2.51 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.1 Hz, 6H),
1.04 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 200.4, 168.3,
141.3, 131.9, 61.6, 50.7, 33.4, 31.2, 14.0, 7.9; IR (neat) ν 2981 (m), 2940
(w), 1729 (s), 1675 (m), 1633 (m), 1369 (m), 1153 (s), 1030 (s);
LRMS (ESI) m/z 279 (100%, M þ Na), 257 (35%, M þ H), 239 (10%);
HRMS (EI) calcd for C13H20O5 (Mþ) 256.1311, found 256.1322.
(3R,4R)-Methyl 4-(Benzyloxy)-3-vinylhex-5-enoate (9). To
a solution of 4b (2.34 g, 6.7 mmol) in ethanol (14 mL) was added a
solution of NaOH (944 mg, 23.6 mmol) in H2O (3 mL). The reaction
was heated to reflux and stirred at this temperatur for 3 h. All volatiles
were removed in vacuo, and the residue was dissolved in ethyl acetate
and diluted hydrochloric acid. The organic layer was separated, and the
aqueous layer was extracted with ethyl acetate. The combined organic
layers were washed with diluted hydrochloric acid, saturated aqueous
NaHCO3 solution, and brine. It was then dried with MgSO4, filtered,
and evaporated. The residue was heated in substance to 140 °C and
stirred at this temperature for 2 h. After cooling to ambient temperature,
the residue was dissolved in methanol (30 mL) and a catalytic amount of
concd H2SO4 (70 mg, 10 mol %) was added. The mixture was heated to
reflux for 12 h, cooled to ambient temperature, and then evaporated. The
residue was partitioned in water and ethyl acetate, the organic layer was
separated, and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with a saturated aqueous
solution of NaHCO3 and brine, dried with MgSO4, filtered, and
evaporated. The residue was purified by column chromatography on
(EI) calcd for C19H22O3 (Mþ) 298.1569, found 298.1583; [R]30
-
D
20.0 (c 0.81, CH2Cl2). Anal. Calcd for C19H22O3 (260.33): C, 76.5; H,
7.4. Found: C, 76.1; H, 7.4. Analytical data of (2R,3S,4R)-methyl-
4-(benzyloxy)-2-(prop-2-inyl)-3-vinylhex-5-enoate ((2R)-10): 1H
NMR (300 MHz, CDCl3) δ 7.38-7.25 (m, 5H), 5.67 (ddd, J = 17.4,
10.3, 8.0 Hz, 1H), 5.60 (ddd, J = 17.0, 10.2, 10.2 Hz, 1H), 5.29 (dm, J =
10.3 Hz, 1H), 5.22 (dm, J = 17.3 Hz, 1H), 5.15 (dm, J = 10.3 Hz, 1H),
5.12 (dm, J = 17.0 Hz, 1H), 4.59 (d, J = 11.3 Hz, 1H), 4.32 (d, J = 11.3
Hz, 1H), 3.82 (dd, J = 8.4, 8.4 Hz, 1H), 3.60 (s, 3H), 3.23 (ddd, J = 8.1,
7.4, 4.2 Hz, 1H), 2.64 (ddd, J = 9.4, 8.4, 4.2 Hz, 1H), 2.56 (ddd, J = 16.8,
7.4, 2.6 Hz, 1H), 2.33 (ddd, J = 16.8, 8.1, 2.6 Hz, 1H), 1.99 (dd, J = 2.6,
2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 173.3, 138.3, 137.1, 134.2,
128.3, 128.0, 127.5, 119.3, 118.7, 81.7, 81.0, 70.5, 69.9, 51.4, 50.8, 43.8,
19.7; [R]31D -41.5 (c 0.57, CH2Cl2).
(3S,4S,5R)-3-(Prop-20-inyl)-4,5-divinyldihydrofuran-2(3H)-
one (11). To a solution of (2S)-10 (396 mg, 1.3 mmol) in dichlor-
omethane (25 mL) was added water (0.5 mL) and DDQ (3.01 g, 13.27
mmol). The reaction mixture was stirred at ambient temperature for 12 h.
It was then diluted with water, the organic layer was separated, and the
aqueouslayer wasextracted withdichloromethane. The combinedorganic
phases were washed with brine, dried with MgSO4, filtered, and evapo-
rated. The residue was purifiedbycolumnchromatography to give lactone
11 (233 mg, 100%). 1H NMR (600 MHz, CDCl3) δ 5.83 (ddd, J = 17.2,
10.5, 6.7 Hz, 1H), 5.69 (ddd, J = 17.3, 10.0, 8.3 Hz, 1H), 5.39 (ddd, J =
17.2, 1.1, 1.1 Hz, 1H), 5.31 (ddd, J = 10.5, 1.0, 1.0 Hz, 1H), 5.25 (ddd, J =
17.3, 1.1, 1.1 Hz, 1H), 5.24 (dm, J = 10.0 Hz, 1H), 4.51 (dddd, J = 9.7, 6.7,
2225
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ARTICLE
1.0, 1.0 Hz, 1H), 2.89 (m, 1H), 2.73 (ddd, J = 17.1, 4.8, 2.6 Hz, 1H), 2.64
(ddd, J = 11.1, 4.8, 4.8 Hz, 1H), 2.50 (ddd, J = 17.1, 4.8, 2.7 Hz, 1H), 2.03
(dd, J = 2.7, 2.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 175.2, 133.4,
133.3, 120.1, 119.2, 82.6, 79.4, 71.3, 51.0, 44.9, 17.1; IR (neat) ν 3296
(bm), 3085 (w), 2987 (w), 2915 (w), 1770 (s), 1645 (w), 1426 (m), 1182
(s), 986 (s), 929 (s); LRMS (ESI) m/z 199 (Mþ þ Na, 100%); HRMS
(EI) calcd for C11H12O2 (Mþ) 176.0837, found 176.0822; [R]29D -59.9
(c 1.01, CH2Cl2).
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’ AUTHOR INFORMATION
Corresponding Author
*E-mail: bernd.schmidt@uni-potsdam.de.
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This work was generously supported by the Deutsche For-
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