Scalable Enantioselective Synthesis of Fmoc-β2-Serine and Fmoc-β2-Threonine by an Organocatalytic Mannich Reaction

Article abstract of DOI:10.1002/ejoc.201500636

The diastereoselective Mannich reaction of functionalized aldehydes, using a phenethylamine-derived iminium precursor, by activation with prolines and prolinol derivatives have been studied. Optimized reaction conditions have been developed, allowing for scale-up and preparation of γ-amino alcohol derivatives on multi-gram scale from β-hydroxypropanal and -butanal, with diastereoselectivites of typically >73:27 and yields of >60. After chromatographic diastereoisomer separation, hydrogenolytic debenzylation, enantiomerically pure Fmoc-β²-Ser(tBu)-OH and Fmoc-β²-Thr(tBu)-OH were thus prepared on multi-gram scale in 6 steps and with overall yields of 24 and 10, respectively, starting from commercially available starting compounds.

Full text of DOI:10.1002/ejoc.201500636

FULL PAPER
DOI: 10.1002/ejoc.201500636
Scalable Enantioselective Synthesis of Fmoc-β2-Serine and Fmoc-β2-Threonine
by an Organocatalytic Mannich Reaction
Daniel Meyer,[a] Roger Marti,*[a] and Dieter Seebach[b]
Keywords: Synthetic methods / Asymmetric catalysis / Organocatalysis / Aminomethylation / Mannich reaction / Amino
acids
The diastereoselective Mannich reaction of functionalized
aldehydes, using a phenethylamine-derived iminium precur-
sor, by activation with prolines and prolinol derivatives have
been studied. Optimized reaction conditions have been de-
veloped, allowing for scale-up and preparation of γ-amino
alcohol derivatives on multi-gram scale from β-hydroxy-
propanal and -butanal, with diastereoselectivites of typically
Ͼ73:27 and yields of Ͼ60%. After chromatographic dia-
stereoisomer separation, hydrogenolytic debenzylation, en-
antiomerically pure Fmoc-β2-Ser(tBu)-OH and Fmoc-β2-
Thr(tBu)-OH were thus prepared on multi-gram scale in 6
steps and with overall yields of 24% and 10%, respectively,
starting from commercially available starting compounds.
phile in the Mannich process.[8] First, Gellman et al. and
Córdova et al. examined l-proline and chiral pyrrolidine
derivatives as catalysts for nucleophilic activation of alde-
hyde reactants using dibenzyl-N,O-acetal as iminium ion
sources.[7a,7d] This process was further modified by the use
of N,O-acetal 1 to yield diastereomeric products, which can
be readily separated via column chromatography or
crystallization of the HCl salts.[7b] So far, this process has
been mostly applied to non-functionalized aldehydes and to
a milligram scale.
Introduction
Since the discovery in 1996[1] that peptides containing
homologated proteinogenic amino acids form more stable
secondary structures than the natural counterpart, the
chemistry of β-peptides was investigated intensively.[2] In
addition to this variety of structures, β-peptides (and mixed
β/α-peptides) are generally proteolytically and metabolically
stable in vitro and in vivo, and they can mimic biological
activities of natural peptides, which makes them interesting
for biomedical research.[3] The synthesis of β2-amino acids
is still a big challenge and only a few of them are commer-
cially available. In contrast to β3-amino acids, the β2-iso-
mers cannot be obtained simply by enantiospecific homolo-
gation of the α-amino acids, but have to be prepared by
multistep enantioselective reactions.[4] β2-Amino acids with
functionalized side chains, such as β2-serine and β2-threon-
ine require up to 9[5] respectively 13[6] steps from commer-
cially available starting materials.
Figure 1. Synthesis of β2-amino acids.
One possible way to synthesize β2-amino acid is the
enantioselective aminomethylation of aldehydes via organo-
catalytic Mannich reactions (Figure 1).[7] As formaldehyde
does not form stable imines, the iminium source has to be
generated in situ from N,O-acetals to provide the electro-
Herein, we report the process optimization of an organo-
catalytic overall enantioselective α-amino-methylation and
preparation of β2-amino acids from β-heterosubstituted
aldehydes on multi-gram scale. Fmoc-β2-Serine and Fmoc-
β2-threonine were thus synthesized in 6 steps starting from
commercially available starting materials.
[a] HES-SO Haute école spécialisée de Suisse occidentale,
Haute école d’ingénierie et d’architecture Fribourg,
Institute ChemTech,
Bd. de Pérolles 80, 1700 Fribourg, Switzerland
E-mail: roger.marti@hefr.ch
http://chemtech.heia-fr.ch
Results and Discussion
Optimization of Condition for the Organocatalytic Step,
Using 3-Methylbutanal
[b] Laboratorium für Organische Chemie, Departement für
Chemie und Angewandte Biowissenschaften, ETH-Zürich,
Hönggerberg HCI,
Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland
E-mail: seebach@org.chem.ethz.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500636.
N,O-Acetals 1 and 2 were prepared by reaction of benz-
yl-phenethylamine with paraformaldehyde in anhydrous
MeOH or iPrOH in yields of 79% and 59%, respectively.[9]
Eur. J. Org. Chem. 2015, 4883–4891
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D. Meyer, R. Marti, D. Seebach
FULL PAPER
Since both enantiomers of the chiral amine are commer- Table 2. The additives LiBr and AcOH were only used with
cially available, both enantiomers of 1 and 2 are thus access- the diarylprolinol derivatives C5–C16 as catalysts.[7a,7b,7d] In
ible.
In initial experiments, we screened different reaction con- ral the selectivity and were therefore not used.
ditions – reaction temperature, equivalents and type of ad- Generally, reactions catalyzed with diarylprolinol ethers
proline-catalyzed reactions these additives lowered in gene-
ditives – using isovaleraldehyde and iminium sources 1 and showed higher conversion rates compared with these cata-
2 in the diastereoselective Mannich reaction by activation lyzed by proline. With l-proline C2, the dr was 82:18 while
with diphenylprolinol TMS-ether C9 (Table 1). The two im- with d-proline C3 the product was formed with a diastereo-
inium sources (S)-1 and (R)-1 gave the same diastereomeric selectivity of 74:26 (Table 2, entries 2 and 3). This difference
ratio (dr = 92:8) of the product, indicating that the chirality of stereoselectivity is a case of so-called matched/mis-
center of the iminium ion has no influence on enantioface matched relationship between the source of chirality of the
selectivity of the prolinol-derived enamine in the Mannich imminium ion and that of the proline-derived enamine in
reaction (Table 1, entries 1 and 2). Under similar conditions the transition state.
Gellman et al. had obtained a dr of 95:5.[7b] Decreasing the
Interestingly, such an effect was not observed in the di-
reaction temperature from –25 °C to –35 °C had no influ- arylprolinol ether activation. Replacement in the diphen-
ence on the selectivity (Table 1, entries 4 and 5), whereas at ylprolinol of the methyl ether (C5 and C8, Table 2, entries
higher reaction temperature the diastereoselectivity de- 5 and 8) by a TMS ether (C6 and C9) has no influence
creased from 92:8 to 86:14 (Table 1, entry 6). The addition on the diastereoselectivity (Table 2, entries 6 and 9). The
of acetic acid increases the reaction rate but has no influ- substitution with a TBDMS ether slightly enhance the dia-
ence on the selectivity (Table 1, entries 1, 8 and 9). Replace- stereoselectivity from 92:8 to 94:6 (Table 2, entries 7 and
ment of acetic acid by the more acidic monochloroacetic 10). With 3,5-disubstituted diarylprolinol catalysts C11–
acid (MCA, pKa 2.87) and dichloroacetic acid (DCA, pKa C16 the diastereoslectivities and conversion rate decreased
= 1.25)[10] lowered the selectivity of the reaction to 77:23 (Table 2, entries 11–16).
and 68:32, respectively (Table 1, entries 10 and 11). Ad-
Based on this optimization work the best conditions for
dition of higher quantities of LiBr (1 equiv. instead of further scale-up of the organocatalytic Mannich approach
0.4 equiv.) had no influence on the reaction selectivity but is the reaction of 1 equiv. iminium source (S)-1 or (R)-1
made the reaction mixture more viscous and less practical with 2 equiv. of the corresponding aldehyde by activation
to handle (Table 1, entry 7).
with 0.2 equiv. organocatalyst at –25 °C in DMF. Using
Next, we used N,O-acetal (S)-1 and isovaleraldehyde for pyrrolidines C5–C16 as catalysts 0.4 equiv. LiBr and
a catalysts screening of proline and diarylprolinol deriva- 0.2 equiv. AcOH should be added to enhance the selectivity
tives (C1–C16) at –25 °C. The results are summarized in and the reaction rate. Taking into account the price for the
Table 1. Diastereoselective Mannich reaction using isovaleraldehyde and the Hayashi catalyst C9. C9, LiBr (1 mmol) and the acid were
stirred in DMF (5 mL) at room temperature for 5 min. Next, isovaleraldehyde (5 mmol) and the N,O-acetal (2.5 mmol) were added at
1
–25 °C. Conversion and dr were determined by H-NMR of the reaction mixture after 2 h.
Entry
N,O-Acetal
Acid
C9 [equiv.]
Conversion [%]
dr (S,S):(R,S)
1
2
3
4
(S)-1
(R)-1
(S)-2
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
(S)-1
0.2 equiv. AcOH
0.2 equiv. AcOH
0.2 equiv. AcOH
0.1 equiv. AcOH
0.1 equiv. AcOH
0.1 equiv. AcOH
0.2 equiv. AcOH
–
0.2
0.2
0.2
0.1
0.1
0.1
0.2
0.2
0.2
0.1
0.1
Ͼ95
Ͼ95
Ͼ95
50
40
70
Ͼ95
80
Ͼ95
90
92:8
92:8[a]
92:8
92:8
92:8
86:14
91:9
92:8
92:8
77:23
68:32
5[b]
6[c]
7[d]
8
9
10
11
0.5 equiv. AcOH
0.1 equiv. MCA
0.1 equiv. DCA
20
[a] dr (S,R):(R,R). [b] –35 °C reaction temperature. [c] –15 °C reaction temperature. [d] 2.5 mmol (1 equiv.) LiBr was added.
4884 Eur. J. Org. Chem. 2015, 4883–4891
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Scalable Enantioselective Synthesis of Fmoc-β2-Amino Acids
Table 2. Screening of various catalysts C1–C16 at –25 °C. The cata- catalysts, the proline catalysts C2 and C3 are preferred to
lysts (0.2 mmol), LiBr (0.4 mmol) and AcOH (0.2 mmol) were
stirred in DMF (4 mL) at room temperature for 5 min. Next, iso-
the diarylpyrolinol ethers C5–C16.
valeraldehyde (2 mmol) and N,O-acetal (S)-1 (1 mmol) were added
1
at –25 °C. Conversion and dr were determined by H-NMR of the
reaction the mixture after 2 h.
Mechanistic Considerations
As expected, catalysis by l-proline[11] and by (S)-diaryl-
prolinol ethers[12] provide enantiomeric products, see the
trajectories in Scheme 1 and an extensive discussion in a
review article.[13] For the prolinol ether catalyzed Mannich
reaction Córdova et al. have also considerated an SN2-type
substitution of the OR group in the formaldehyde N,O-
acetal by the enamine nucleophile, i.e. a mechanism without
formation of an iminium ion.[7d] We have observed exactly
the same selectivity with the N,O-acetals carrying an MeO
and an iPrO group, see (S)-1 and (S)-2 (Table 1, entries 1
and 3). We would have expected that the two different leav-
ing groups in an SN2-type reaction would give detectably
different results. Therefore we do not include this alterna-
tive mechanism in Scheme 1.
Entry
Cat.
Conversion [%][b]
dr (S,S):(R,S)
1
C1
C2
60
20
20
53:47
82:18
26:74
69:31
8:92
8:92
6:94
92:8
92:8
94:6
85:15
89:11
73:27
85:15
90:10
91:9
2[a]
3[a]
4[b]
5
Application of the Mannich Reaction with β-Hydroxy
Aldehyde Derivatives
C3
C4
Ͼ 95 (r.t.)
C5
90
80
70
90
80
70
20
20
2
For the preparation of β2-serine and β2-threonine we
chose 3-tert-butoxy-propanal and 3-tert-butoxybutanal as
aldehyde components. Both contain a potential leaving
group in the β-position of the carbonyl group. Compounds
of this type are known to undergo β-elimination under ba-
sic and acidic conditions. For the purpose of our synthesis
the tBuO group would have to “survive” the organocata-
lysis step and the condition of subsequent transformations
(NaBH4 reduction, TEMPO/NaOCl or Na2Cr2O7 oxid-
ation, see below). Furthermore, the 3-tert-butoxybutanal 9
is a chiral derivative, the stereogenic center of which could
influence the stereochemical course of the reaction. Finally,
6
7
8
9
10
11
12
13
14
15
16
C6
C7
C8
C9
C10
C11
C12
C13
C14
C15
C16
20
20
20
[a] No LiBr and AcOH added. [b] Reaction control after 24 h at
room temp.
Scheme 1. Transition states of the proline and prolinol-catalyzed Mannich reaction.
Eur. J. Org. Chem. 2015, 4883–4891
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4885

D. Meyer, R. Marti, D. Seebach
FULL PAPER
the scale-up from 2 mmol of the N,O-acetal 1 by a factor
up to 100 is accompanied by a change of addition-time
periods.
Preparation of Fmoc-(S)-β2-Ser(tBu)-OH and Fmoc-(R)-β2-
Ser(tBu)-OH
For the preparation of β2-serine, we first prepared the 3-
tert-butoxypropanal 4 in two steps starting from commer-
cially available acrolein ethylene acetal by addition of tert-
butanol followed by aqueous acidic cleavage of the acetal
group in an overall yield of 42%.[14] Aldehyde 4 was then
used for the Mannich reaction with the above described op-
timized condition, using proline C2 and C3 as well as the
prolinol ethers C9 and C10 as catalysts (Table 3). The Hay-
ashi-type catalysts C9 and C10 gave a slightly lower selectiv-
ity as compared to the reaction of isovaleraldehyde (cf.
Table 3, entries 4 and 5 with Table 2, entries 9 and 10). On
the other hand, the activation with d-proline gave a slightly
better dr of 84:16, compared to l-proline with a dr of 80:20
with the N,O-acetal (S)-1 (Table 3, entries 1 and 2).
Scheme 2. Enantioselective synthesis of Fmoc-(S)-β2-Ser(tBu)-OH
(S)-8 and Fmoc-(R)-β2-Ser(tBu)-OH (R)-8. The minor dia-
stereomer of the Mannich reaction (R,S)-6 (10% yield) was con-
verted in the same manner to give (S)-7 and (R)-8 in yields of 95%
and 88%, respectively.
Catalytic hydrogenolytic removal of the benzyl and the
phenethyl group, followed by Fmoc-protection of the re-
sulting primary amino group gave the Fmoc-amino
alcohols (R)-7 and (S)-7 in yields of 97% and 95%, respec-
tively. By optimization the process, we reduced the quantity
of Pd/C 10% from 100 wt.-% to 10 wt.-% and the ammo-
nium formate as hydrogen source from 10 equiv. to 5 equiv.
making the process less expensive.[7a,7b,7d] Subsequent oxid-
ation provided Fmoc-(S)-β2-Ser(tBu)-OH (S)-8 and Fmoc-
(R)-β2-Ser(tBu)-OH (R)-8 in yields of 90% and 88%,
respectively. For the scale-up run [49 g of (R)-7], we re-
placed the originally employed Jones oxidation[7a,7b] and
Table 3. Diastereoselective Mannich reaction of aldehyde 4. The
catalysts (0.5 mmol), LiBr (1 mmol) and AcOH (0.5 mmol) were
stirred in DMF (5 mL) at room temperature for 5 min. Next, alde-
hyde 4 (5 mmol) and the N,O-acetals (2.5 mmol) were added at
–25 °C. Conversion and dr were determined by 1H-NMR of the
reaction mixture after 2 h.
RuCl3/NaIO4[7d] in CCl4 by the “greener” TEMPO/NaOCl/
Entry
N,O-
Acetal
Cat.
Conv.
[%]
dr
Favored
diastereomer
[15]
NaClO2
system. The optical rotation [α]2D0 of (S)-8 was
+7.3 (c 2.0, CHCl3) – identically with the value reported
1
2
3
4
5
(S)-1
(S)-1
(R)-1
(S)-1
(S)-1
C2
C3
20
20
20
Ͼ95
Ͼ95
80:20
84:16
80:20
89:11
84:16
(R,S)
(S,S)
(S,R)
(R,S)
(R,S)
in the literature[5b] {[α]D20 = +7.32 (c 0.68, CHCl3)}. The
C3
enantiopurity was also determined by HPLC on
a
C9
C10
CHIRALPAK IA-3 column indicated the high enantio-
meric purity of (S)-8 and (R)-8 of 99.8:0.2 and 99.6:0.4,
respectively.
As outlined in Scheme 2, we synthesized alcohol 6 in a
multi-gram scale [51 g of N,O-acetal (R)-1] by the diastereo-
selective Mannich reaction followed by reduction with
NaBH4. To obtain the (S)-β2-Ser(tBu)-OH precursor (R,R)-
6 as major diastereoisomer, d-proline C3 was used as cata-
Preparation of Fmoc-(S,R)-β2-Thr(tBu)-OH
The required aldehyde 9 was prepared from ethyl (R)-3-
lyst. Compared to the small scale experiments, the scale-up hydroxybutyrate[16] in two steps: by etherification with tert-
by a factor of 100 improved the diastereomeric ratio of the butyl 2,2,2-trichloroacetimidate (66% yield),[17] followed by
crude product slightly to 87:13. The two diastereoisomers DIBAL reduction of the ester group (57% yield).[18] The
could be easily separated by column chromatography to diastereselective Mannich reaction of aldehyde 9 was in ge-
give the diastereomerically pure (dr Ͼ99.5:0.5) alcohol neral less selective than with the aldehyde 4 and activation
(R,R)-6 in 66% yield together with 10% of alcohol (S,R)-6 with d-proline C3 gave product 10 of higher dr than with
(dr 99.5:0.5). For the scale-up procedure, a slurry of d-pro- prolinol silyl ethers C9 and C10, see Table 4.
line in DMF had to be stirred overnight before carrying out
The corresponding in situ sequence of Mannich reaction
the reaction. Otherwise the yield dropped dramatically [9 + (R)-1/cat. C3], followed by reduction with NaBH4
(Ͻ 20%). This may be caused by the slow dissolution of the yielded the amino alcohol derivative (R,R)-11 with a dr of
catalysts or by forming finer partials (i.e. larger surface) by 73:27 (Scheme 3). Separation by column chromatography
grinding with the magnetic stirring bar.
afforded (R,R)-11 in a yield of 45% with a dr of 99:1.
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Eur. J. Org. Chem. 2015, 4883–4891

Scalable Enantioselective Synthesis of Fmoc-β2-Amino Acids
Table 4. Diastereoslective Mannich reaction of aldehyde 9. The cat- a subsequent hydrogenolytic removal of the benzylic groups
alysts (0.5 mmol), LiBr (1 mmol) and AcOH (0.5 mmol) were
was not successful, due to of the well-known sulfur poison-
stirred in DMF (5 mL) at room temperature for 5 min. Next, alde-
ing of the Pd/C.[20]
hyde 9 (5 mmol) and the N,O-acetals (2.5 mmol) were added at
–25 °C. Conversion and dr were determined by 1H-NMR of the
reaction mixture after 2 h.
Table 5. Diastereoselective Mannich reaction of aldehyde 14. The
catalysts (0.5 mmol), LiBr (1 mmol) and AcOH (0.5 mmol) were
stirred in DMF (5 mL) at room temperature for 5 min. Next, alde-
hyde 14 (5 mmol) and the N,O-acetals (2.5 mmol) were added at
1
–25 °C. Conversion and dr were determined by H-NMR of reac-
tion mixture after 2 h.
Entry
N,O-
Acetal
Cat.
Conv.
[%]
dr
Favored
diastereomer
1
2
3
4
(S)-1
(R)-1
(S)-1
(S)-1
C3
C3
20
20
40
20
76:24
73:27
71:29
59:41
(S,S)
(S,R)
(R,S)
(R,S)
C9
Entry
N,O-
Acetal
Cat.
Conv.
[%]
dr
Favored
diastereomer
C10
1
2
3
4
(S)-1
(R)-1
(S)-1
(S)-1
C3
C3
70
70
50
40
88:12
83:17
85:15
80:20
(R,S)
(R,R)
(S,S)
(S,S)
Hydrogenolytic deprotection followed by Fmoc-protection
and Jones oxidation gave Fmoc-(S,R)-β2-Thr(tBu)-OH (S)-
13 in a yield of 57%.
C9
C10
Scheme 4. Synthesis of (R)-N-benzyl-N-α-methylbenzyl-(R)-β2-
cysteine(tBu) alcohol (R,R)-16.
Conclusions
In summary, we optimized and tested several proline and
Scheme 3. Enantioselective synthesis of Fmoc-(S)-β2-Thr(tBu)-OH prolinol catalysts for direct catalytic asymmetric α-amino-
(S)-13.
methylation of isovaleraldehyde using chiral N,O-acetals
derived from benzylphenethylamine. The simple reactions
are highly chemo- and diastereoelective with a dr up to
94:6. We applied the diastereoselective Mannich reaction to
β-hetero-substituted aldehydes to get the precursor γ-amino
Attempted Preparation of β2-Cysteine Derivative
We also tried to prepare a β2-cysteine derivative from 3- alcohol derivatives of Fmoc-β2-Ser(tBu)-OH, Fmoc-β2-
tert-butylthiopropanal (14) and the Mannich reagent 1. The Thr(tBu)-OH and Fmoc-β2-Cys(tBu)-OH with a diastereo-
aldehyde 14 was obtained in 86% yield from acrolein and selectivity of Ͼ73:27 in the crude product and of Ն99:1
tert-butyl-mercaptan.[19] This aldehyde and its derivatives after chromatographic separation of the diastereoisomers.
will be even more prone to undergo β-elimination than the The Fmoc-β2-amino acids can be synthesized by
oxygen analogs 4 and 9.
hydrogenolytic removal of the benzylic groups followed by
The diastereoselective Mannich reaction with aldehyde Fmoc-protection and oxidation with TEMPO/NaOCl/
14 gave actually the desired product 15 even with higher dr NaClO2. Our scalable catalytic diastereoselective method
of 83:17 compared to aldehydes 4 and 9 (Table 5) and, after provides a facile and practical access to – so far hard to
NaBH4 reduction and separation by column chromatog- synthesize – enantiopure Fmoc-β2-Ser(tBu)-OH and Fmoc-
raphy, in approximately the same yield as with aldehyde 4: β2-Thr(tBu)-OH in 6 steps starting from commercially
60% with dr Ͼ99.5:0.5 (Scheme 4). As was to be expected available starting materials on multi-gram scale.
Eur. J. Org. Chem. 2015, 4883–4891
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Meyer, R. Marti, D. Seebach
FULL PAPER
Diastereoselective Mannich Reaction with Isovaleraldehyde. General
Procedure for Proline Catalysts C2, C3, C4: d-Proline C3 (23 mg,
0.2 mmol) was stirred in DMF (4 mL) at room temperature for
5 min. Next, isovaleraldehyde (172 mg, 2.0 mmol) and N,O-acetal
(S)-1 (255 mg, 1.0 mmol) were added at –25 °C. The conversion of
20% and the dr of 28:72 (S,S):(R,S) were determined by H NMR
[(S,S)-3 8.94 ppm, (R,S)-3 9.39 ppm, isovaleraldehyde 9.75 ppm] of
the reaction mixture after 2 h.
Experimental Section
General Remarks: d-Proline was purchased from Bachem AG. All
other starting materials were provided from Sigma–Aldrich. All re-
actions involving oxygen- or moisture-sensitive compound were
carried out under a dry argon atmosphere. Reaction temperatures
refer to external bath temperatures. Column chromatography was
performed with Macherey–Nagel Silica gel 60 M (pore size 60 Å,
230–400 mesh particle size) packed in glass columns. Reactions
were monitored by thin-layer chromatography (TLC) using alumi-
num Merck 60 UV254 silica gel plates (0.2 mm thickness). Visual-
ization was performed by ultraviolet light or by KMnO4 stain, fol-
lowed by gentle heating. NMR spectra were recorded at 300 MHz
(for 1H NMR) or 75 MHz (for 13C NMR) in CDCl3. Chemical
shifts are reported as δ (ppm) downfield from tetramethylsilane (δ
= 0.00 ppm) using residual solvent signal as an internal standard:
δ singlet 7.26 (1H), triplet 77.0 (13C). Enantiomer purity was deter-
mined by HPLC on a CHIRALPAK IA-3 column (250 mm,
4.6 mm, 3 μm) using hexane/iPrOH/TFA, 80:20:0.1 as a mobile
phase (flow rate 1 mL/min, λ = 264 nm). IR spectra were obtained
on neat samples (ATR spectroscopy). High-resolution mass spectra
were recorded on an ESI-TOF MS spectrometer. Optical rotations
were obtained at a wavelength of 589 nm using a 1.0 dm cell.
1
Diastereoselective Mannich Reaction with Isovaleraldehyde. General
Procedure for Diarylprolinol Catalysts C5-C16: The Hayashi cata-
lyst C9 (65 mg, 0.2 mmol), LiBr (35 mg, 0.4 mmol) and AcOH
(12 mg, 0.2 mmol) were stirred in DMF (4 mL) at room tempera-
ture for 5 min. Next, isovaleraldehyde (172 mg, 2.0 mmol) and
N,O-acetal (S)-1 (255 mg, 1.0 mmol) were added at –25 °C. The
conversion of 80% and the dr of 92:8 (S,S):(R,S) were determined
by 1H NMR [(S,S)-3 8.94 ppm, (R,S)-3 9.39 ppm, isovaleraldehyde
9.75 ppm] of the reaction mixture after 2 h.
3-tert-Butoxypropanal (4): To a mixture of p-toluenesufonic acid
monohydrate (7.61 g, 0.040 mol) in tert-butanol (741 g, 10.0 mol)
was added acrolein ethylene acetal (100.1 g, 2.00 mol) and stirred
at room temperature for 24 h. The reaction mixture was quenched
with a solution of saturated NaHCO3 (1000 mL) and extracted
with TBME (1000/500/500 mL). The organic layers were washed
with brine, dried with MgSO4, and concentrated. The residue was
diluted with a solution of AcOH (10% in H2O, 1300 mL) and
heated to 85 °C for 2 h. After cooling to room temperature the
mixture was extracted with diethyl ether (1000/500/500 mL). The
organic layers were washed with a solution of K2CO3 (10% in H2O,
3ϫ 500 mL), dried with MgSO4, and concentrated. The residue
was once more diluted with a solution of AcOH (10% in H2O,
1300 mL) and heated to 85 °C for 2 h. After workup as described
above the crude product was purified by vacuum distillation (65 °C,
40 mbar) to provide 4 as a colorless liquid; yield 110.2 g (42%); 1H
NMR (300 MHz, CDCl3): δ = 1.20 (s, 9 H), 2.60 (td, J = 6.1,
1.9 Hz, 2 H), 3.71 (t, J = 6.1 Hz, 2 H), 9.78 (t, J = 1.9 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 27.4, 44.4, 55.7, 73.2, 202.1
(R)-N-Benzyl-N-(methoxymethyl)-1-phenylethan-1-amine
[(R)-1]:
Paraformaldehyde (16.0 g, 532 mmol) was added to a mixture of
(R)-N-benzyl-1-phenylethan-1-amine (102.1 g, 483 mmol) and po-
tassium carbonate (1.34 g, 9.67 mmol) in MeOH (196 mL,
4.83 mol) at 10 °C. The reaction mixture was stirred for 30 min at
10 °C and 2 h at room temperature. The reaction mixture was di-
luted with DCM (400 mL), dried with Na2SO4, and concentrated.
The crude product was purified by vacuum distillation (120 °C,
2.5ϫ10–3 mbar) to provide (R)-1 as a colorless oil; yield 97.3 g
(79%); 1H NMR (300 MHz, CDCl3): δ = 1.46 (d, J = 7.8 Hz, 3 H),
3.14 (s, 3 H), 3.72 (d, J = 13.6 Hz, 1 H), 3.77 (d, J = 13.6 Hz, 1
H), 3.93 (d, J = 9.4 Hz, 1 H), 4.07 (q, J = 6.8 Hz, 1 H), 4.19 (d, J
= 9.4 Hz, 1 H), 7.16–7.35 (m, 8 H), 7.39–7.45 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.8, 52.6, 55.0, 59.2, 82.5, 126.76,
ppm. IR (neat): ν = 2974, 1725, 1465, 1391, 1363, 1195, 1088, 976,
˜
126.83, 127.5, 128.1, 128.2, 128.8, 139.8, 145.0 ppm. IR (neat): ν =
˜
864 cm–1. HRMS (ESI-TOF) m/z calcd. for C7H14O2Na+ 153.0886
3027, 2973, 1602, 1493, 1452, 1165, 1062, 1028, 912, 761, 739,
[M + Na]+, found 153.0887.
696 cm–1. [α]2D0 = +4.9 (c 5.0, MeOH).
(R,R)-6 and (S)-3-{Benzyl[(R)-1-phenylethyl]amino}-2-(tert-butoxy-
methyl)propan-1-ol [(S,R)-6]: A suspension of d-proline C3 (4.61 g,
40 mmol) in DMF (400 mL) was stirred at room temperature over-
night. Aldehyde 4 (52.1 g, 400 mmol) was added to the reaction
mixture at –25 °C followed by the addition of N,O-acetal (R)-1
(51.1 g, 200 mmol). The reaction mixture was stirred at –25 °C for
18 h. NaBH4 (22.7 g, 600 mmol) was added at Ͻ –20 °C followed
by dropwise addition of MeOH (130 mL). The reaction mixture
was stirred at –25 °C for 30 min and at 0 °C for 2 h. The reaction
mixture was slowly poured into a solution of saturated NH4Cl
(700 mL) at Ͻ5 °C. The mixture was allowed to stir at 0 °C for
30 min and at room temperature for 1 h. The mixture was extracted
with TBME (600/200 mL) and the organic layers were washed with
H2O (300 mL) and brine (300 mL). The organic layers were dried
with MgSO4, and concentrated. The diastereoisomers (dr of 83:17
in the crude product) were separated by column chromatography
(EtOAc/heptane, 2:8) to provide (R,R)-6 and (S,R)-6 as colorless
oils.
(S)-N-Benzyl-N-(methoxymethyl)-1-phenylethan-1-amine
N,O-Acetal (S)-1 was prepared according (R)-1 using (S)-N-benzyl-
[(S)-1]:
1-phenylethan-1-amine as starting material. Colorless oil; yield
1
78%; H NMR (300 MHz, CDCl3): δ = 1.46 (d, J = 7.8 Hz, 3 H),
3.16 (s, 3 H), 3.72 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1
H), 3.94 (d, J = 9.4 Hz, 1 H), 4.07 (q, J = 6.8 Hz, 1 H), 4.19 (d, J
= 9.4 Hz, 1 H), 7.17–7.37 (m, 8 H), 7.40–7.46 (m, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.8, 52.6, 54.9, 59.2, 82.4, 126.75,
126.82, 127.5, 128.1, 128.2, 128.8, 139.7, 145.0 ppm. IR (neat): ν =
˜
3027, 2973, 1602, 1493, 1452, 1165, 1063, 1028, 911, 761, 739,
696 cm–1. [α]2D0 = –5.0 (c 5.0, MeOH).
(S)-N-Benzyl-N-(isopropoxymethyl)-1-phenylethan-1-amine [(S)-2]:
N,O-Acetal (S)-2 was prepared according (S)-1 using iPrOH as
starting material. Amorphous solid; yield 59%; 1H NMR
(300 MHz, CDCl3): δ = 1.06 (t, J = 6.2 Hz, 6 H), 1.45 (d, J =
6.8 Hz, 3 H), 3.44 (hept, J = 6.2 Hz, 1 H), 3.68 (d, J = 13.5 Hz, 1
H), 3.75 (d, J = 13.5 Hz, 1 H), 3.96 (d, J = 9.4 Hz, 1 H), 4.07 (q,
J = 6.8 Hz, 1 H), 4.25 (d, J = 9.4 Hz, 1 H), 7.17–7.37 (m, 8 H),
7.39–7.49 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.8, (R,R)-6: Yield 47.1 g (66%); dr Ͼ99.5:0.5; Rf = 0.25 (EtOAC/hept-
1
22.3, 22.4, 52.4, 59.1, 68.1, 78.5, 126.67, 126.74, 127.5, 128.1, 128.2,
ane, 2:8); H NMR (300 MHz, CDCl3): δ = 1.14 (s, 9 H), 1.37 (d,
J = 6.9 Hz, 3 H), 1.99–2.16 (m, 1 H), 2.32 (dd, J = 12.9, 9.4 Hz, 1
H), 2.54 (dd, J = 12.9, 5.3 Hz, 1 H), 3.14 (dd, J = 8.8, 7.6 Hz, 1
H), 3.30 (dd, J = 8.8, 4.9 Hz, 1 H), 3.40 (dd, J = 10.7, 5.6 Hz, 1
128.8, 140.1, 145.4 ppm. IR (neat): ν = 3028, 2969, 1602, 1493,
˜
1453, 1367, 1162, 1023, 1003, 955, 910, 761, 738, 696 cm–1. [α]2D0
–4.8 (c 5.0, iPrOH).
=
4888
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4883–4891

Scalable Enantioselective Synthesis of Fmoc-β2-Amino Acids
H), 3.46 (d, J = 13.5 Hz, 1 H), 3.54 (dd, J = 10.7, 5.3 Hz, 1 H),
3.70 (d, J = 13.5 Hz, 1 H), 3.90 (s, 1 H), 3.98 (q, J = 6.9 Hz, 1 H),
1075, 1007, 758, 738 cm–1. HRMS (ESI-TOF) m/z calcd. for
C23H29NO4Na 406.1989 [M + Na]+, found 406.2000. [α]2D0 = +9.4
7.20–7.38 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.6, (c 2.0, CHCl3).
27.4, 38.6, 49.6, 54.8, 56.7, 63.4, 66.1, 73.0, 127.0, 127.1, 128.10,
(S)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-(tert-butoxy-
128.13, 128.4, 129.0, 139.6, 142.6 ppm. IR (neat): ν = 3431, 3027,
˜
methyl)propanoic Acid [(S)-8]: A mixture of alcohol (R)-7 (48.9 g,
127.4 mmol) and TEMPO (1.39 g, 8.92 mmol) in ACN (650 mL)
and phosphate buffer (430 mL, 0.67 mol/L, pH = 6.7) was heated
to 35 °C. Solutions of sodium chlorite [23.0 g (w = 80%) in 130 mL
of H2O, 255 mmol] and sodium hypochlorite [1.46 g (w = 13%) in
65 mL of H2O] were added simultaneously over 2 h. The mixture
2971, 1602, 1493, 1452, 1362, 1196, 1072, 1025, 748, 730, 697 cm–1.
HRMS (ESI-TOF) m/z calcd. for C23H34NO2 356.2584 [M + H]+,
found 356.2588. [α]2D0 = –13.8 (c 2.0, CHCl3).
(S,R)-6: Yield 7.09 g (10%); dr 99.5:0.5; Rf = 0.18 (EtOAc/heptane,
1
2:8); H NMR (300 MHz, CDCl3): δ = 1.12 (s, 9 H), 1.46 (d, J =
7.0 Hz, 3 H), 2.06–2.20 (m, 1 H), 2.30 (dd, J = 13.0, 5.4 Hz, 1 H), was stirred at 35 °C for 4 h. The mixture was cooled to room tem-
2.50 (dd, J = 13.0, 8.9 Hz, 1 H), 3.02 (dd, J = 8.9, 7.4 Hz, 1 H), perature, diluted with H2O (400 mL), and the pH was adjusted to
3.22 (d, J = 13.6 Hz, 1 H), 3.29 (dd, J = 8.9, 5.0 Hz, 1 H), 3.54 8.0 with a 2 m aqueous solution of NaOH. The reaction was
(dd, J = 10.5, 6.3 Hz, 1 H), 3.64 (dd, J = 10.5, 5.3 Hz, 1 H), 3.80
(d, J = 13.6 Hz, 1 H), 3.98 (q, J = 7.0 Hz, 1 H), 4.48 (s, 1 H), 7.20–
quenched by pouring into a 0.5 m aqueous solution of Na2SO3 at
Ͻ20 °C and stirred for 30 min at this temperature. The mixture
7.38 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.0, 27.3, was extracted with TBME (800/400 mL) and washed with a 0.1 m
38.4, 50.7, 54.8, 57.5, 63.5, 66.8, 73.0, 127.0, 127.1, 128.0, 128.4,
aqueous solution of Na2SO3 (200 mL). The combined organic lay-
128.5, 129.0, 139.5, 140.8 ppm. IR (neat): ν = 3431, 3028, 2971, ers were diluted with TBME (800 mL) and acidified to pH 3 with
˜
1602, 1493, 1452, 1362, 1196, 1073, 1026, 748, 730, 697 cm–1.
HRMS (ESI-TOF) m/z calcd. for C23H34NO2 356.2584 [M + H]+,
found 356.2594. [α]2D0 = +58.4 (c 2.0, CHCl3).
a 2 m aqueous solution of HCl. The layers were separated and the
aqueous layer extracted with TBME (400 mL). The organic layers
were washed with H2O (400 mL), dried with MgSO4, and concen-
trated. The residue was twice diluted with DCM (300 mL), concen-
trated, and dried under high vacuum to provide (S)-8 as an
(9H-Fluoren-9-yl)methyl
(R)-[3-(tert-Butoxy)-2-(hydroxymethyl)-
propyl]carbamate [(R)-7]: To a mixture of alcohol (R,R)-6 (46.9 g,
131.9 mmol) and Pd/C 10% (4.69 g) in MeOH (1400 mL) was
added ammonium formate (41.6 g, 659 mmol) and stirred at 50 °C
for 8 h. The mixture was cooled to room temperature, filtered
through celite with an excess of MeOH, and concentrated to yield
the deprotected amine as a slightly yellow oil. The product was
dissolved in DCM (1 L). Triethylamine (26.7 g, 264 mmol) and
Fmoc-OSu (43.6 g, 129.3 mmol) was added at 0 °C and stirred 3 h
at this temperature. The reaction mixture was extracted with solu-
tions of NaHSO4 (10% in H2O, 700 mL), saturated NaHCO3
(200 mL) and H2O (200 mL). The aqueous layers were extracted
consecutively with DCM (200 mL). The combined organic layers
were dried with MgSO4, and concentrated. The crude product was
purified by column chromatography (EtOAc/heptane, 1:1) to pro-
1
amorphous white solid; yield 45.64 g (90%); er 99.8:0.2; H NMR
(300 MHz, CDCl3): δ = 1.15 (s, 2.25 H), 1.18 (s, 6.75 H), 2.47–2.64
(m, 0.25 H), 2.82 (p, J = 5.5 Hz, 0.75 H), 3.26–3.78 (m, 4 H), 4.15–
4.27 (m, 1 H), 4.28–4.41 (m, 1.5 H), 4.42–4.54 (m, 0.5 H), 5.54 (t,
J = 5.8 Hz, 0.75 H), 6.30–6.47 (m, 0.25 H), 7.28 (t, J = 7.4 Hz, 2
H), 7.37 (t, J = 7.4 Hz, 2 H), 7.57 (d, J = 7.4 Hz, 2 H), 7.73 (d, J
= 7.4 Hz, 2 H), 10.92 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 27.3, 40.0, (40.4), 45.8, (46.4), 47.2, (60.3), 60.7, 66.8, (67.3),
(73.5), 74.1, 120.0, 125.1, 127.0, 127.7, 141.3, 143.9, 156.6, (157.6),
(176.5), 176.8 ppm. IR (neat): ν = 3342, 3250, 2971, 1705, 1517,
˜
1449, 1363, 1232, 1190, 1080, 758, 738 cm–1. HRMS (ESI-TOF)
m/z calcd. for C23H27NO5Na 420.1781 [M + Na]+, found 420.1782.
[α]2D0 = +7.3 (c 2.0, CHCl3).
vide (R)-7 as a colorless oil; yield 49.2 g (97%); Rf = 0.35 (EtOAc/
heptane, 1:1); H NMR (300 MHz, CDCl3): δ = 1.18 (s, 9 H), 1.59 methyl)propanoic Acid [(R)-8]: Amorphous white solid; yield 88%;
(br. s 0.1 H), 1.89 (hept, J = 5.4 Hz, 0.9 H), 3.13 (t, J = 5.9 Hz, 1
H), 3.33 (q, J = 6.1 Hz, 2 H), 3.44 (d, J = 5.4 Hz, 2 H), 3.62 (t, J
(R)-3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-2-(tert-butoxy-
1
er 99.6:0.4; 1H NMR (300 MHz, CDCl3): δ = 1.15 (s, 2.25 H), 1.18
(s, 6.75 H), 2.47–2.64 (m, 0.25 H), 2.82 (p, J = 5.7 Hz, 0.75 H),
= 5.4 Hz, 2 H), 4.20 (t, J = 6.8 Hz, 1 H), 4.35–4.45 (m, 1.8 H), 3.26–3.78 (m, 4 H), 4.15–4.27 (m, 1 H), 4.28–4.41 (m, 1.5 H), 4.42–
4.46–4.57 (m, 0.2 H), 5.04 (br. s 0.1 H), 5.32 (t, J = 5.8 Hz, 0.9 H), 4.54 (m, 0.5 H), 5.54 (t, J = 5.9 Hz, 0.75 H), 6.30–6.47 (m, 0.25
7.29 (td, J = 7.4, 1.1 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 2 H), 7.58 (d, J H), 7.28 (t, J = 7.4 Hz, 2 H), 7.37 (t, J = 7.4 Hz, 2 H), 7.57 (d, J
= 7.4 Hz, 2 H), 7.75 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR (75 MHz, = 7.4 Hz, 2 H), 7.74 (d, J = 7.4 Hz, 2 H), 10.92 (s, 1 H) ppm. 13C
CDCl3): δ = 27.4, 40.2, 41.3, 47.3, 62.5, 62.9, 66.6, 73.3, 120.0,
NMR (75 MHz, CDCl3): δ = 27.3, 40.0, (40.4), 45.8, (46.3), 47.2,
125.0, 127.0, 127.7, 141.3, 143.9, 157.3 ppm. IR (neat): ν = 335,
(60.3), 60.7, 66.8, (67.3), (73.5), 74.1, 120.0, 125.1, 127.0, 127.7,
˜
3284, 2971, 2932, 2873, 1697, 1517, 1449, 1363, 1246, 1193, 1075,
1007, 758, 738 cm–1. HRMS (ESI-TOF) m/z calcd. for
C23H29NO4Na 406.1989 [M + Na]+, found 406.1995. [α]2D0 = –9.3
(c 2.0, CHCl3).
141.3, 143.9, 156.6, (157.6), (176.5), 176.8 ppm. IR (neat): ν = 3340,
˜
3249, 2972, 1705, 1517, 1449, 1363, 1232, 1191, 1081, 758,
738 cm–1. HRMS (ESI-TOF) m/z calcd. for C23H27NO5Na
420.1783 [M + Na]+, found 420.1782. [α]2D0 = –7.1 (c 2.0, CHCl3).
(9H-Fluoren-9-yl)methyl
(S)-[3-(tert-Butoxy)-2-(hydroxymethyl)- (R)-3-tert-Butoxybutanal (9): To a solution of ethyl (R)-3-hydroxy-
propyl]carbamate [(S)-7]: Colorless oil; yield 95%; Rf = 0.35 butyrate (24.1 g, 188 mmol) and tert-butyl 2,2,2-trichloroacetimid-
1
(EtOAc/heptane, 1:1); H NMR (300 MHz, CDCl3): δ = 1.18 (s, 9 ate (82.2 g, 376 mmol) in pentane (400 mL) was added DCM
H), 1.59 (br. s 0.1 H), 1.89 (hept, J = 5.5 Hz, 0.9 H), 3.17 (t, J = (50 mL). Trifluoromethanesulfonic acid (0.14 g, 0.94 mmol) was
6.1 Hz, 1 H), 3.33 (q, J = 6.1 Hz, 2 H), 3.44 (d, J = 5.5 Hz, 2 H), added at –70 °C and let slowly warmed to –60 °C whereby a sus-
3.62 (t, J = 5.5 Hz, 2 H), 4.19 (t, J = 6.9 Hz, 1 H), 4.35–4.45 (m, pension was formed. The reaction mixture was stirred at –60 °C for
1.8 H), 4.46–4.57 (m, 0.2 H), 5.10 (br. s 0.1 H), 5.36 (t, J = 5.9 Hz, 1 h and after warmed to room temperature. The suspension was
0.9 H), 7.29 (td, J = 7.4, 1.1 Hz, 2 H), 7.37 (t, J = 7.4 Hz, 2 H), diluted with cyclohexane (300 mL), filtered, and concentrated. The
7.58 (d, J = 7.4 Hz, 2 H), 7.74 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR crude product was purified by vacuum distillation (56 °C, 5 mbar)
(75 MHz, CDCl3): δ = 27.4, 40.2, 41.3, 47.3, 62.5, 62.9, 66.6, 73.3,
to provide ethyl (R)-3-tert-butoxybutyrate as a colorless liquid;
yield 23.3 g (66%); H NMR (300 MHz, CDCl3): δ = 1.18 (d, J =
1
120.0, 125.0, 127.0, 127.7, 141.3, 143.9, 157.3 ppm. IR (neat): ν =
˜
3352, 3280, 2971, 2933, 2873, 1697, 1517, 1449, 1363, 1246, 1193,
6.1 Hz, 3 H) 1.19 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 2.35 (dd, J =
Eur. J. Org. Chem. 2015, 4883–4891
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4889

D. Meyer, R. Marti, D. Seebach
FULL PAPER
14.5, 7.1 Hz, 1 H), 2.50 (dd, J = 14.5, 6.2 Hz, 1 H), 3.94–4.27 (m,
Fmoc-OSu (961 mg, 2.85 mmol) was added at 0 °C and stirred 4 h
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3, 23.4, 28.4, 44.4, at this temperature. The reaction mixture was diluted with EtOAc
60.2, 64.8, 73.8, 171.8 ppm. IR (neat): ν = 2976, 2936, 1734, 1465,
and extracted with a solution of NaHSO4 (10% in H2O, 100 mL),
˜
1367, 1180, 1077, 1033, 995 cm–1. HRMS (ESI-TOF) m/z calcd. for a solution of saturated aqueous NaHCO3 (100 mL) and H2O
C10H20O3Na 211.1305 [M + Na]+, found 211.1304. [α]2D0 = –15.8 (c
2.0, CHCl3).
(100 mL). The aqueous layers were extracted consecutively with
EtOAc (50 mL). The combined organic layers were dried with
MgSO4, and concentrated. The crude product was purified by col-
umn chromatography (EtOAc/heptane, 4:6) to provide (R)-12 as a
colorless oil; yield 918 mg (77%); Rf = 0.25 (EtOAc/heptane, 4:6);
1H NMR (300 MHz, CDCl3): δ = 1.17 (s, 9 H), 1.18 (d, J = 6.3 Hz,
3 H), 1.70 (dt, J = 10.7, 5.4 Hz, 1 H), 3.15–3.26 (m, 1 H), 3.37–
3.48 (m, 1 H), 3.52–3.68 (m, 2 H), 3.77–3.88 (m, 1 H), 4.20 (t, J =
6.8 Hz, 1 H), 4.35–4.47 (m, 1.9 H), 4.48–4.53 (m, 0.1 H), 5.11 (br.
s 0.05 H), 5.31–5.46 (m, 0.95 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.39 (t,
J = 7.3 Hz, 2 H), 7.59 (d, J = 7.3 Hz, 2 H), 7.75 (d, J = 7.3 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6, 28.6, 38.7, 46.8,
47.3, 61.6, 66.6, 68.2, 74.1, 120.0, 125.0, 127.0, 127.6, 141.3, 143.9,
To a solution of ethyl (R)-3-tert-butoxybutyrate (21.7 g, 115 mmol)
in pentane/diethyl ether, 9:1 (400 mL) was added dropwise a solu-
tion of DIBAL (1.0 m in cyclohexane, 132 mL, 132 mmol) at –70 °C
and stirred at this temperature for 3 h. The reaction was quenched
by the addition of MeOH (50 mL) and stirred at –70 °C for 10 min.
The reaction mixture was warmeded to 0 °C and poured into a
solution of saturated aqueous NH4Cl (400 mL) and warmed to
room temperature. The mixture was diluted with H2O (200 mL)
and extracted with TBME (400/200/200 mL). The organic layers
were washed with brine (200 mL), dried with MgSO4, and concen-
trated. The crude product was purified by vacuum distillation
(51 °C, 15 mbar) to provide 9 as a colorless liquid; yield 9.40 g
144.0, 157.3 ppm. IR (neat): ν = 3391, 3280, 2972, 2935, 2892,
˜
1698, 1515, 1449, 1365, 1250, 1191, 1075, 1006, 758, 738 cm–1
.
1
(57%); H NMR (300 MHz, CDCl3): δ = 1.20 (s, 9 H), 1.22 (d, J
HRMS (ESI-TOF) m/z calcd. for C24H31NO4Na 420.2145 [M +
= 6.2 Hz, 3 H), 2.48 (ddd, J = 15.9, 6.2, 2.3 Hz, 1 H), 2.58 (ddd, J
= 15.9, 6.2, 2.3 Hz, 1 H), 4.15 (h, J = 6.2 Hz, 1 H), 9.79 (t, J =
2.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.8, 28.4,
Na]+, found 420.2154. [α]2D0 = –19.5 (c 2.0, CHCl3).
(2S,3R)-2-[({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)methyl]-3-
(tert-butoxy)butanoic Acid [(S)-13]: To a solution of alcohol (R)-12
(648 mg, 1.63 mmol) in acetone (15 mL) was added Jones reagent
(0.5 m Na2Cr2O7 in 2 m aqueous H2SO4, 6.5 mL, 3.25 mmol) at
0 °C. The reaction was allowed to stir at 0 °C for 1 h and at room
temperature for 3 h. The reaction was quenched by addition of
iPrOH (5 mL) and stirred at room temperature for 20 min. The
mixture was diluted with H2O (50 mL) and extracted with EtOAc
(100/50/50 mL). The organic layers were washed with H2O (3ϫ
50 mL), dried with MgSO4, and concentrated. The crude product
was purified by column chromatography (AcOH/EtOAc/heptane,
2:30:70). The residue was twice diluted with DCM (10 mL), con-
centrated, and dried under high vacuum to provide (S)-13 as an
amorphous white solid; yield 498 mg (74%); Rf = 0.35 (AcOH/
52.6, 63.3, 74.0, 202.3 ppm. IR (neat): ν = 2976, 1729, 1465, 1391,
˜
1365, 1195, 1088, 976, 864 cm–1. HRMS (ESI-TOF) m/z calcd. for
C8H16O2Na+ 167.1043 [M + Na]+, found 167.1046.
(2R,3R)-2-({Benzyl[(R)-1-phenylethyl]amino}methyl)-3-(tert-but-
oxy)butan-1-ol [(R,R)-11]: A suspension of d-proline C3 (230 mg,
2.00 mmol) in DMF (20 mL) was stirred at room temperature for
1 h. Aldehyde 9 (2.88 g, 20.0 mmol) was added to the reaction mix-
ture at –25 °C followed by the addition of N,O-acetal (R)-1 (2.55 g,
10.0 mmol). The reaction mixture was stirred at –25 °C for 18 h.
NaBH4 (1.14 g, 30.0 mmol) was added at Ͻ –20 °C followed by
dropwise addition of MeOH (6 mL). The reaction mixture was
stirred at –25 °C for 30 min and at 0 °C for 2 h. The reaction mix-
ture was slowly poured into a solution of saturated aqueous NH4Cl
(35 mL) at Ͻ5 °C. The mixture was allowed to stir at 0 °C for
30 min and at room temperature for 1 h. The mixture was extracted
with TBME (100/50/50 mL) and the organic layers were washed
with H2O (50 mL) and brine (50 mL). The organic layers were
dried with MgSO4, and concentrated. The crude product (dr 73:27)
was purified by column chromatography [EtOAc/DCM/heptane,
2:3:5] to provide (R,R)-11 as a colorless oil; yield 1.67 g (45%); dr
99:1; Rf = 0.53 [EtOAc/DCM/heptane, 2:3:5]; 1H NMR (300 MHz,
CDCl3): δ = 0.89 (d, J = 6.4 Hz, 3 H), 1.15 (s, 9 H), 1.40 (d, J =
6.9 Hz, 3 H), 2.02–2.14 (m, 1 H), 2.24 (dd, J = 13.0, 8.8 Hz, 1 H),
2.39 (dd, J = 13.0, 5.8 Hz, 1 H), 3.32 (dd, J = 10.6, 6.0 Hz, 1 H),
3.55 (s, 2 H), 3.56 (dd, J = 10.6, 7.4 Hz, 1 H), 3.63–3.76 (m, 1 H),
3.97 (q, J = 6.9 Hz, 1 H), 4.39 (s, 1 H), 7.15–7.43 (m, 10 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.7, 18.0, 28.3, 43.3, 49.6, 54.8,
57.1, 64.0, 68.7, 73.9, 127.05, 127.11, 128.1, 128.2, 128.4, 129.1,
1
EtOAc/heptane, 2:30:70); H NMR (300 MHz, CDCl3): δ = 1.08–
1.20 (m, 1.8 H), 1.16 (d, J = 6.2 Hz, 3 H), 1.27 (s, 7.2 H), 2.5 (br.
s 0.2 H), 2.74 (dt, J = 8.3, 4.1 Hz, 0.8 H), 3.27 (ddd, J = 13.8, 9.0,
4.7 Hz, 1 H), 3.46 (ddd, J = 12.0, 8.1, 3.9 Hz, 1 H), 3.82–3.93 (m,
0.2 H), 3.96–4.11 (m, 0.8 H), 4.19 (t, J = 7.0 Hz, 1 H), 4.28–4.48
(m, 1.8 H), 4.49–4.53 (m, 0.2 H), 5.47–5.66 (m, 0.8 H), 6.44 (br. s
0.2 H), 7.30 (dt, J = 7.4, 1.1 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 2 H),
7.57 (d, J = 7.4 Hz, 2 H), 7.75 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 19.8, (21.3), 28.2, (28.3), 39.3, 47.2, 51.8,
(53.0), 66.9, 67.1, (67.3), (74.5), 76.3, 120.0, 125.1, 127.0, 127.7,
141.3, (143.6), 143.8, 143.9, 156.5, (157.8), 174.9, 175.9 ppm. IR
(neat): ν = 3339, 3241, 2973, 1706, 1515, 1449, 1365, 1232, 1190,
˜
1083, 758, 738 cm– 1 . HRMS (ESI-TOF) m/z calcd. for
C24H29NO5Na 434.1938 [M + Na]+, found 434.1948. [α]2D0 = +6.4
(c 2.0, CHCl3).
139.4, 142.0 ppm. IR (neat): ν = 3472, 3028, 2971, 1602, 1493,
˜
3-(tert-Butylthio)propanal (14): To a solution 2-methyl-2-prop-
anethiol (36.1 g, 400 mmol) was added acrolein (31.4 g, 560 mmol)
and triethylamine (10.1 g, 100 mmol) at 0 °C. The mixture was al-
lowed to stir at 0 °C for 2 h and at room temperature overnight.
1451, 1365, 1195, 1120, 1072, 1028, 1005, 748, 730, 698 cm–1
.
HRMS (ESI-TOF) m/z calcd. for C24H36NO2 370.2741 [M + H]+,
found 370.2742. [α]2D0 = –1.0 (c 2.0, CHCl3).
(9H-Fluoren-9-yl)methyl [(2R,3R)-3-(tert-Butoxy)-2-(hydroxy- The reaction mixture was concentrated, and the crude product was
methyl)butyl]carbamate [(R)-12]: To a mixture of alcohol (R,R)-11 purified by vacuum distillation (59 °C, 5 mbar) to provide 14 as a
1
(1103 mg, 3.00 mmol) and Pd/C 10% (222 mg) in MeOH (40 mL)
was added ammonium formate (1.89 g, 30.0 mmol) and stirred at
50 °C for 5 h. The mixture was cooled to room temperature, filtered
through celite with an excess of MeOH, and concentrated to yield
the deprotected amine as slightly yellow oil. The product was dis-
solved in DCM (25 mL). Triethylamine (607 mg, 6.00 mmol) and
colorless liquid; yield 50.3 g (86%); H NMR (300 MHz, CDCl3):
δ = 1.34 (s, 9 H), 2.67–2.74 (m, 2 H), 2.77–2.85 (m, 2 H), 9.78 (t,
J = 1.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.7, 30.8,
42.5, 43.7, 200.7 ppm. IR (neat): ν = 2962, 2724, 1723, 1460, 1365,
˜
1163, 1054, 1025, 853 cm–1. HRMS (ESI-TOF) m/z calcd. for
C7H14OSNa+ 169.0658 [M + Na]+, found 169.0657.
4890
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 4883–4891

Scalable Enantioselective Synthesis of Fmoc-β2-Amino Acids
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(R)-3-{Benzyl[(R)-1-phenylethyl]amino}-2-[(tert-butylthio)methyl]-
propan-1-ol [(R,R)-16]: A suspension of d-proline C3 (173 mg,
1.5 mmol) in DMF (15 mL) was stirred at room temperature for
1 h. Aldehyde 14 (1.95 g, 15.0 mmol) was added to the reaction
mixture at –25 °C followed by the addition of N,O-acetal (R)-1
(1.92 g, 7.50 mmol). The reaction mixture allowed stirred at –25 °C
for 18 h. NaBH4 (0.85 g, 22.5 mmol) was added at Ͻ –20 °C fol-
lowed by dropwise addition of MeOH (6 mL). The reaction mix-
ture was stirred at –25 °C for 30 min and at 0 °C for 2 h. The reac-
tion mixture was slowly poured into a solution of saturated aque-
ous NH4Cl (25 mL) at 0 °C. The mixture was allowed to stir at
0 °C for 30 min and at room temperature for 1 h. The mixture was
extracted with TBME (80/40/40 mL) and the organic layers were
washed with H2O (40 mL) and brine (40 mL). The organic layers
were dried with MgSO4, and concentrated. The crude product (dr
83:17) was purified by column chromatography (EtOAc/heptane,
1.5:8.5) to provide (R,R)-16 as a colorless oil; yield 1.42 g (60%);
dr Ͼ99.5:0.5; Rf = 0.30 (EtOAc/heptane, 1.5:8.5); 1H NMR
(300 MHz, CDCl3): δ = 1.28 (s, 9 H), 1.37 (d, J = 6.9 Hz, 3 H),
1.94–2.13 (m, 1 H), 2.18–2.36 (m, 2 H), 2.45 (dd, J = 12.9, 10.6 Hz,
1 H), 2.70 (dd, J = 12.9, 2.9 Hz, 1 H), 3.19 (dd, J = 10.7, 7.2 Hz,
1 H), 3.41 (d, J = 13.2 Hz, 1 H), 3.64 (dd, J = 10.3, 2.0 Hz, 1 H),
3.82 (d, J = 13.2 Hz, 1 H), 3.90–4.08 (m, 2 H), 7.11–7.39 (m, 10
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 9.9, 28.6, 30.8, 38.0,
42.0, 52.8, 54.9, 56.3, 66.7, 127.1, 127.3, 128.1, 128.2, 128.5, 129.1,
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139.0, 142.5 ppm. IR (neat): ν = 3583, 3422, 3027, 2964, 1602,
˜
1493, 1451, 1362, 1196, 1070, 1028, 748, 729, 697 cm–1. HRMS
(ESI-TOF) m/z calcd. for C23H34NOS 372.2356 [M + H]+, found
372.2367. [α]2D0 = –77.9 (c 2.0, CHCl3).
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Acknowledgments
The authors thank V. Sadiku for valuable lab support for the scale-
up experiments. Special thanks go to A. K. Beck for critical reading
of the manuscript.
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Received: May 15, 2015
ˇ
Sebesta, M. A. Campo, A. K. Beck, Tetrahedron 2004, 60,
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Published Online: June 18, 2015
Eur. J. Org. Chem. 2015, 4883–4891
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4891