Preparation of chiral α-substituted alaninates through an efficient diastereoselective synthesis of trisubstituted allylic alcohols

Article abstract of DOI:10.1002/asia.201200859

Tri without fail: The highly diastereoselective addition of vinylaluminum reagents, generated in situ from the zirconium-catalyzed carboalumination of various alkynes and Me₃Al, to the easily accessible (2S,5R,6R)-5,6-dimethyl-[1,4]dioxane-2-carbaldehyde (1 b) afforded the corresponding trisubstituted allylic alcohols, and a subsequent Overman reaction yielded allylic amines that contain chiral quaternary carbon stereocenters. Copyright

Full text of DOI:10.1002/asia.201200859

COMMUNICATION
DOI: 10.1002/asia.201200859
Preparation of Chiral a-Substituted Alaninates through an Efficient
Diastereoselective Synthesis of Trisubstituted Allylic Alcohols
Balraj Gopula, Way-Zen Lee, and Hsyueh-Liang Wu*[a]
Chiral glyceraldehydes are not only extensively used as
substrates in studying the stereochemistry of nucleophilic
addition reactions, but are also useful three-carbon building
blocks for the preparation of optically active organic mole-
cules.[1] Isopropylidene glyceraldehydes are frequently used
for such a purpose because of their ease of preparation from
readily available chiral pool starting materials of both enan-
tiomers, such as d-mannitol,[2] l-mannitol,[3] l-ascorbic acid,
and d-isoascorbic acid.[4] However, owing to the undesirable
racemization, polymerization, and a high tendency to form
hydrates,[5] a number of analogues that bear various ketal
protecting groups have been developed.[6] Ley et al. recently
introduced stable butane-2,3-diacetal-protected glyceralde-
hydes 1[7] to alleviate these long-standing problems and
demonstrated their utility in the synthesis of complex natu-
ral products (Figure 1).[7d] The stereoelectronic effects direct
kynes and Me3Al, with chiral 2,3-O-isopropylidene- and cy-
clohexylidene glyceraldehydes, the allylic alcohols were gen-
erally obtained in good yields but in moderate diastereose-
lectivities (up to 77% d.r.).[8] To employ the resulting chiral
trisubstituted E-allylic alcohols as critical intermediates in
the synthesis of some complex natural products, the stereo-
selectivity must be improved.[9] In this study, aldehydes
1 were examined in an attempt to improve the diastereose-
lectivity of the described reactions of interest.
In the initial trial, the diastereoselective addition reaction
of glyceraldehyde 1a, prepared from d-mannitol,[7a] was car-
ried out with the vinylalane reagent that was synthesized ac-
cording to Wipfꢀs protocol.[10] The rapid Zr-catalyzed car-
boalumination of 1-octyne (2a) with Me3Al in the presence
of water furnished the active (E)-2-methyl-1-octenyl alumi-
num reagent, to which 1a was added, and the corresponding
trisubstituted E-allylic alcohols (3aa and 4aa) were obtained
in an overall yield of 39% with poor diastereoselectivity
(Table 1, entry 1). The products, derived from aldehyde 1b,
were obtained in 43% yield with an improved diastereose-
lectivity (3ba/4ba=80:20; Table 1, entry 4).[11] While the ad-
dition of a slight excess of Me3Al enhanced the diastereose-
lectivity, as found by the research group of Spino,[12] the dia-
stereomeric ratio of isomers was further improved (3aa/
4aa=86:14) by adding MeLi (1.5 equiv) after the prepara-
tion of the vinylalane reagent (Table 1, entry 2). Presumably,
the corresponding Al–ate complex was formed upon the ad-
dition of MeLi, thereby enhancing the nucleophilicity of the
corresponding vinylalanate.[13] The yield was subsequently
Figure 1. Chiral butane-2,3-diacetal glyceraldehydes 1.
the two methoxy groups in the axial position, thereby giving
rise to a more rigid six-membered cyclic structure. Thus,
a high stereoselectivity is observed, partly because of chela-
tion of the magnesium ion with the axial methoxy groups, in
the nucleophilic addition of a variety of Grignard reagents
to
(2S,5R,6R)-5,6-dimethyl-[1,4]dioxane-2-carbaldehyde
Table 1. Addition of vinylalane to chiral glyceraldehydes 1.[a]
(1b), thus affording the corresponding secondary alcohols in
high yields and excellent diastereoselectivities.[7a] However,
the use of aldehydes 1 as substrates with other nucleophiles
has, since the work of Ley et al., received less attention. In
our recent studies on diastereoselective addition reactions of
trisubstituted vinylalane reagents, that were obtained from
a Zr-catalyzed carboalumination reaction of terminal al-
Entry
Aldehyde
Additive
Yield [%][b]
d.r. (3/4)[c]
1
2
1a
1a
1a
1b
1b
none
39
39
89
43
95
55 (3aa):45 (4aa)
86 (3aa):14 (4aa)
89 (3aa):11 (4aa)
80 (3ba):20 (4ba)
>99 (3ba):1 (4ba)
MeLi[d]
MeLi[d]
none
3[e]
4
[a] B. Gopula, Prof. Dr. W.-Z. Lee, Prof. Dr. H.-L. Wu
Department of Chemistry
5[e]
MeLi[d]
National Taiwan Normal University
No. 88, Section. 4, Tingzhou Rd. Taipei, 11677, ROC (Taiwan)
Fax : (+886)2-29324249
[a] Reaction conditions: Aldehyde (1.0 equiv), Me3Al (3.3 equiv),
Cp2ZrCl2 (0.22 equiv), H2O (1.67 equiv) [b] Yield of isolated product.
[c] Determined by 1H NMR spectroscopy. [d] MeLi (1.5 equiv) was
added prior to the addition of aldehyde. [e] 3.0 equiv of (E)-2-methy-1-
octenyl aluminum reagent was added.
E-mail: hlw@ntnu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200859.
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Hsyueh-Liang Wu et al.
improved to 89% by using three equivalents of the vinylala-
nate reagent (Table 1, entry 3). Under the aforementioned
optimal conditions, the addition of vinylalanate to aldehyde
1b gave the corresponding allylic alcohol 3ba in high yield
(95%) with excellent stereoselectivity (>99:1) (Table 1,
entry 5). The stereochemistry of the secondary alcohol 3ba
had the R configuration, as determined by Mosherꢀs method
(Figure 2).[14,15]
vided the corresponding allylic alcohol 3bf in both excellent
yield (96%) and diastereoselectivity (3bf/4bf= >99:1;
Table 2, entry 6). Additionally, trisubstituted E-allylic alco-
hols (3bg and 3bh) obtained by the addition of vinyl nucleo-
philes that were substituted with three and five membered
rings, were isolated in high yields and diastereoselectivities
(Table 2, entries 7 and 8). Notably, the cyclopropyl ring re-
mained unaltered after a Zr-catalyzed carboalumination re-
action, yielding the desired product 3bg (Table 2, entry 7).
In contrast, the Zr-catalyzed carboalumination of an alkyne
that had a cyclohexene substituent proceeded sluggishly, and
formed the corresponding adduct, but in only moderate
yield (42%) and diastereoselectivity (3bi/4bi=80:20;
Table 2, entry 9). Presumably, in the presence of an olefin,
the Zr-catalyzed carboalumination reaction with the alkyne
functional group proceeds but it competes with the alkene
during the catalytic cycle, thereby complicating the overall
process.[16]
Figure 2. Determination of the absolute configuration of allylic alcohol
3ba by employing Mosherꢀs method.
By considering the above observations, the addition of
various vinylalanates to aldehyde 1b was examined under
the reaction conditions that are specified in entry 5 of
Table 1. As pointed out in Table 2, by adding vinylalanates
This developed methodology was further exploited in the
synthesis of methyl a-substituted alaninates (Table 3).[17] The
Table 3. Syntheses of a-substituted alaninates.
Table 2. Diastereoselective addition of various vinylalanes to aldehyde
1b.[a]
Entry Alkyne
Yield [%][b] d.r. (3b/4b)[c]
(2a) 95 >99 (3ba):1 (4ba)
(2b) 77
(2c) 95
(2d) 70
(2e) 72
(2 f) 96
(2g) 80
1
2
3
ACHTUNGTRENNUNG
A
>99 (3bb):1 (4bb)
>99 (3bc):1 (4bc)
AHCTUNGTRENNUNG
Entry
R
Allylic Amine 5b
Alaninate 6b
Yield [%][a]
d.r. [b]
Yield [%][a]
ee [%][c]
4
5
6
N
>99 (3bd):1 (4bd)
>99 (3be):1 (4be)
>99 (3bf):1 (4bf)
1
2
3
4
Hexyl
iPentyl
tBu
52 (5ba)
46 (5bd)
65 (5be)
72 (5bf)
N.O.[d]
>99:1
>99:1
>99:1
>99:1
N.D.[e]
N.D.[e]
67 (6ba)
63 (6bd)
74 (6be)
89 (6bf)
N.D.[e]
>99
>99
>99.5
>99.5
N.D.[e]
N.D.[e]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
7
8
A
>99 (3bg):1 (4bg)
>99 (3bh):1 (4bh)
Ph
5
cyclopropyl
cyclopentyl
6[d,e]
N.O.[d]
N.D.[e]
AHCTUNGTRENNUNG
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy.
[c] Determined by chiral HPLC analysis. [d] Not observed. [e] Not deter-
mined.
9
N
80 (3bi):20 (4bi)
[a] Reaction conditions: Aldehyde 1b (1.0 equiv), Me3Al (3.3 equiv),
Cp2ZrCl2 (0.22 equiv), alkyne (3.0 equiv), H2O (1.67 equiv), MeLi
(1.5 equiv). [b] Yield of isolated product. [c] Determined by 1H NMR
spectroscopy.
preparation of these non-proteogenic amino esters has at-
tracted considerable interest because of their biological ac-
tivity in inhibiting certain types of enzymes[18] and their abil-
ity to modify the conformations of biologically active pep-
tides.[19] As illustrated in Table 3, the trisubstituted chiral al-
lylic alcohol 3ba was converted into the allylic amine 5ba
by following Overmanꢀs method.[20] Thus, compound 3ba
that were derived from alkynes bearing alkyl substituents
furnished the 1,2-adducts in high yields (77–95%) and excel-
lent diastereoselectivity (>99:1), regardless of the carbon
chain length of the alkyl substituents (Table 2, entries 1–3).
Similar results were also obtained when branched substitut-
ed alkynes, such as 5-methyl-1-hexyne (2d) and 3,3-dimeth-
yl-1-butyne (2e) (Table 2, entries 4 and 5) were used. A nu-
cleophilic vinylaluminum reagent that was prepared from
phenylacetylene (2 f) was an effective nucleophile, and pro-
was treated with 1,8-diazabicycloACTHUNTGRNEUNG[5.4.0]undec-7-ene (DBU)
and CCl3CN, and then a thermal Overman rearrangement
took place in two steps to provide the allylic amine 5ba as
a single diastereoisomer in 52% yield (Table 3, entry 1). The
RuIII-catalyzed oxidative cleavage of compound 5ba fur-
nished the corresponding butane-2,3-diacetalglyceric acid
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Hsyueh-Liang Wu et al.
and highly enantioenriched a-methyl a-hexyl amino acid;
both of these compounds were treated with iodomethane
under basic conditions to yield the corresponding methyl
amino ester 6ba in 67% yield and >99% ee[21] as well as
the methyl ester 7 (>90% yield). Following the establish-
ment of a reliable sequence for transforming allylic alcohol
3ba into a chiral quaternary alaninate 6ba, the preparation
of a-substituted alaninates bearing diverse substituents from
allylic alcohols that were obtained from a diastereoselective
addition reaction has been demonstrated (Table 3, entries 2–
4). Despite the fact that [3,3]-sigmatropic rearrangements of
chloroimidates that are derived from allylic alcohols 3bg
and 3bh do not give the desired allylic amine derivative-
s,[20a,d,22] the four-step transformation described here further
increased the utility of this sequence to afford methyl amino
esters (6bd–6bf) with high yields (63–89%) and excellent
enantioselectivity (>99% ee).[23] Furthermore, the stability
of the allylic amine 5bf with a quaternary center was dem-
onstrated in a two-step transformation to the corresponding
tert-butyloxycarbonyl (Boc)-protected allyl amine 8. The
two steps were 1) the base-mediated removal of the trichlor-
oacetyl protecting group[24] and then 2) Boc protection.[25]
Subsequent catalytic oxidative cleavage and esterification
efficiently provided the N-Boc-a-methyl-a-phenylglycine
methyl ester (9) with a high optical purity (99% ee;
Scheme 1).[26,27]
thesis of optically active compounds that have quaternary
chiral centers. Studies toward the preparation of substituted
cyclic alaninates are currently being intensively investigated.
Experimental Section
At room temperature, Cp2ZrCl2 (17 mg, 0.058 mmol, 0.22 equiv) and dry
CH2Cl2 (5 mL) were added to a dry 10 mL round bottom flask under an
argon atmosphere, and it was cooled to ꢀ258C. Me3Al (0.81 mL, 1.0m in
heptanes, 0.81 mmol, 3.33 equiv) was slowly added to this mixture, and
after being stirred for an additional 30 min, water (7.3 mL, 0.40 mmol,
1.67 equiv) was slowly added at ꢀ258C. After an additional 30 min, a so-
lution of 1-octyne (2a) (0.11 mL, 0.73 mmol, 3 equiv) in dry CH2Cl2
(3 mL) was added dropwise over 10 min and after 30 min, MeLi
(0.17 mL, 2.2m in toluene, 0.37 mmol, 1.5 equiv) was added. A solution
of S-aldehyde 1b (50 mg, 0.244 mmol, 1 equiv) in CH2Cl2 (3 mL) was in-
troduced at ꢀ258C over 30 min. After the whole mixture was stirred at
the same temperature for 3.5 h, the temperature was slowly raised to
room temperature, and was then cooled to 08C 1 h later. The reaction
was quenched by adding a sat. aq. K2CO3 solution, and 10 min later,
a 2N HCl solution was added to neutralize the solution to pH 7. The
aqueous layer was separated and extracted with CH2Cl2 (3ꢂ5mL). The
combined organic layer was dried over anhydrous NaSO4 and concentrat-
ed under reduced pressure to give the crude product. The crude com-
pound was purified by flash column chromatography (EA/hexanes 1:9)
to afford the pure compound 3ba in 95% yield.
Acknowledgements
Financial support provided by the National Science Council, Republic of
China (NSC 99-2119M-003-009-MY2) (NSC 100-2113M-003-009-MY2)
and the National Taiwan Normal University is gratefully acknowledged.
Keywords: allylic compounds · amines · butane-1,2-diacetal-
protected l-glyceraldehyde
·
diastereoselectivity
·
a-
substituted alaninates
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Chem. Asian J. 2013, 8, 80 – 83
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presence of two trans-olefinic protons; see the Supporting Informa-
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Received: September 14, 2012
Published online: November 6, 2012
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